Introduction
Worldwide, stroke is the 3rd leading cause of death as well as the leader in long term disability etiology as of 2012.1 In addition, according to the Centers of Disease Control and Prevention, 33% of potentially preventable deaths in the US between 2008 and 2010 are attributed to stroke.2 Notably, 60% of all stroke deaths involve women.3 Current research indicates the existence of a difference between not only in how women and men present with stroke, but also how they are treated in an acute setting, and how they respond to treatment methods. Said disparities are of vital importance, given that targeted sex-specific therapies can help improve clinical outcomes and reduce the burden of disease in the population. Therefore, this review will examine the variations between men and women in risk factors, epidemiology, presentation, treatment, and outcomes for stroke.
Classification and Pathophysiology
Strokes are primarily classified as ischemic or hemorrhagic. Ischemic strokes are the most common (87% of all strokes) and occur due to obstruction of a blood vessel supplying the brain. They may be further sub-classified as thrombotic or embolic, depending on the site of occlusion.4 Physiologically, ischemic stroke occurs is preceded by endothelial damage in cerebral blood vessels that causes inflammation and fatty deposit accumulation in arterial walls. Subsequently, this leads to a decrease in blood vessel diameter and vascular flow.5 In turn, reduced oxygen and glucose supply to brain tissue creates an ischemic core (where blood flow < 10 mL/100mg/min) and an ischemic penumbra (blood flow > 10, but less than 20 mL/100mg/min).6 In the ischemic core, oxygen depletion reduces neuronal ATP production, thereby activating the ischemic cascade. The membrane ionic gradient is lost, leading to intracellular Na and Ca increases; subsequent glutamate release exacerbates calcium influx via NMDA and AMPA receptors. The resulting excitotoxicity leads to organelles and membranes degeneration and necrosis.7 In the ischemic penumbra, reduced blood flow alone is not capable of causing neuronal necrosis; rather, it is the adjacent ischemic core glutamate release that causes calcium influx via AMPA and NMDA receptors. This activates calcium-dependent enzymes such as apoptosis inducing caplain and caspases in the penumbra, leading to nitric oxide, arachidonic acid, and superoxide production that help cells die.8
In contrast, hemorrhagic strokes (13% of all strokes) are intracerebral or subarachnoid in nature, and occur due to ruptured vessels.4 Although less common than ischemic strokes, hemorrhagic strokes are more dangerous to patients due to potential hydrocephalus, increased intracranial pressure, and blood vessel spasms.8,9 With regards to incidence, men are more likely to have ischemic strokes10, while women are at greater risk for subarachnoid hemorrhage.11 These strokes are typically preceded by chronic hypertension and vascular malformations, which eventually results in a ruptured aneurysm. Blood buildup in the subarachnoid space or brain tissue can lead to infarction as well as brain tissue and vascular toxicity.12
Epidemiology
From a historical perspective, population data indicates a 42% decrease in stroke incidence from 1970 to 2000-2008 (dropping from 163 per 100,000 to 94 per 100,000).13 However, this decrease is mostly attributed to males (30.3% incidence decrease for males vs. 17.8% for men from 1950 to 2004) as noted in the Framingham study.14 Although stroke incidence is on the decline, key studies have noted that mid-life stroke incidence among women has increased. This fact is reflected in male-female incidence rate ratios decreasing from 1.49 (ages 35-44) to 1.21 (ages 75-84).15
Women also have greater lifetime risk for stroke, and are more likely to have recurrent strokes.3 A potential explanation for this trend is that the mean-age at first-ever stroke for men is 68.6 years, while for women it is 72.9 years.15 Compounded with greater life expectancy and the fact that age is a non-adjustable risk factor, more women are thus living at ages where stroke risk is higher. Finally, women also have higher mortality rates from stroke than men.16 According to the Centers for Disease Control and Prevention, men and women under the age of 45 have similar stroke morality rates.17 From this age on, women’s stroke mortality rate increases significantly, and although their rate is lower than age matched men, the difference decreased with age.18 A plausible explanation for this occurrence is the neuroprotective loss of estrogen post-menopausal women experience.19
Risk Factors
Epidemiological differences can be partly attributed to risk factors variations between men and women. Sex-nonspecific modifiable risk factors include the following: hypertension, Type 2 diabetes mellitus, hyperlipidemia, atrial fibrillation, smoking cigarettes, metabolic syndrome, and coronary artery disease.20 Innate risk factors are male sex, non-white ethnicity/race, and family history.20
Several of these risk factors generally are more common in men overall, but when considering only stroke patients, they more frequently occur in females. For example, blood pressure is higher in younger men relative to pre-menopausal women21; nevertheless, women with stroke more frequently present with atrial fibrillation and hypertension.22,23 In addition, it has been noted that Type 2 diabetes mellitus more often presents in men with stroke.24 However, the condition has a greater effect on increasing stroke risk in women.25 The same phenomenon has been observed with metabolic syndromes, where metabolic syndromes doubled ischemic stroke risk in women, but had no statistically significant effect on men.26
Sex-specific risk factors exist as well, highlighted by the use of oral contraceptives27, number of pregnancies28, and post-partum and post-menopausal periods directly increasing stroke risk for women. Indirectly, menopause is associated with body weight increases, metabolic syndrome onset, and higher blood pressure, which are all independent stroke risk factors.29 The increased risk may be associated with decreased estrogen levels, given that they significantly drop after menopause.
With respect to males, heart disease, myocardial infarction, peripheral artery disease, type 2 diabetes mellitus, alcohol and tobacco are the most important risk factors.22 Finally, similar to the hormonal influences seen in women, reduced levels of total circulating testosterone has been found to be associated with increased incidence of stroke in men30 Low testosterone levels are associated with metabolic syndrome, type 2 diabetes mellitus, and aortic arterial disease.31
Sex-Steroid Hormones
The menopause related loss of estrogen’s neuroprotective effects sheds some light as to why a mid-life surge in post-menopausal women might occur. High levels of 17-β estradiol (E2) has been found to attenuate stroke effects in pre-menopausal women.32 Estrogen binds vascular smooth muscle and endothelial receptors33, triggering PIP-3 kinase and mitogen activated protein kinase pathways to increase nitric oxide and vasodilating prostanoid (PGI2) levels and decrease endothelium derived hyperpolarized factor (EDHF) levels32,34; all three changes facilitate vasodilation. Nitric oxide specifically regulates myogenic tone in cerebral vessel autoregulation to shield against blood flow fluctuations that can cause vessel damage and rupture.34 Thus, blood supply in pre-menopausal women is better than in men during and after ischemic stroke, leading to lower infarct volumes.
Progesterone receptors also exist on vascular smooth muscle and endothelial cells35,36, and their activation serve two functions. First, it decreases inflammation37, edema38, and oxidative stress39, subsequently leading to reduced cortical infarct. Second they inhibit vascular smooth muscle proliferation, which is essential for atherogenesis.40 In animal trials, micronized progestin has been shown to decrease stroke lesion volume; however, it also increased death incidence after experimental stroke.41 In addition, further controversy exists with the approach, given that in human trials by the Women’s Health Initiative (WHI), post-menopausal women taking estrogen and medroxyprogesterone acetate over several years noted an increase in stroke risk.42 However, these differences may be attributed to the use of medroxyprogesterone acetate, a synthetic variant of progesterone, in the WHI trials while animal model research uses micronized progestins. Therefore, future research conducted to ascertain the exact steroid-mediated mechanisms must consider factors such as timing of hormone exposure relative to menopause, differences in hormone preparation, and intrinsic stroke susceptibility in order to determine the viability of hormone replacement therapy.
In men, testosterone binds to androgen receptors on cerebral blood vessels.43 There has not been a consensus on testosterone’s effect, with different studies claiming an increase44,45 or decrease46,47 in vascular tone. Some research found that in contrast with estrogen, testosterone-treated rats demonstrated COX-dependent TXA2 prostanoid production that induces cerebral vasoconstriction.48 TXA2 has been associated with platelet aggregation that results in thrombogenesis.49 However, it is known that testosterone can be converted to 17-β estradiol, which can inhibit atherogenesis.50
Insulin-like growth factor (IGF), although not sex-specific in production levels, is similar to estrogen in that it confers neuroprotective effects. The IGF system mediates a variety of anabolic and somatogenic effects and is produced by a myriad of cell types.51 With respect to stroke, increased IGF levels have been connected to experimental hypoxic injury in areas of neuronal loss; specifically, microglia and astrocytes show increased post-ischemic production of IGF-1.52 Low endogenous levels of IGF-1 have been also associated with increased stroke mortality.53 In preclinical studies, exogenous IGF-1 to young males rats reduces ischemic injury54 and neuronal death55, stimulates stroke-induced neurogenesis56, neuronal myelination, and angiogenesis.55 More recently, studies on aging female rats has shown that post-stroke IGF-1 treatment is also neuroprotective, reducing infarct volume57,58, reducing cytokines and chemokines and improving the integrity of the blood brain barrier.59 Thus, the age-dependent decline of IGF-1 in middle-aged females60 in conjunction with post-menopausal estrogen level drops may further serve to explain stroke incidence and severity seen in older females.61
Differential Symptom Presentation and Associated Treatment Delays
Population based studies regarding gender differences in stroke presentation symptoms have been limited. Available studies indicate that women generally present with more diffuse symptoms than men do, often presenting with pain and less with traditional sign.62 For example, in ischemic stroke, women more often have disorientation, generalized weakness, and mental status changes.63 Women with acute ischemic and hemorrhagic stroke also display signs such as headache, facial and limb pain, change in level of consciousness, and chest pain.64 Furthermore, women have been found to present with urinary incontinence, visual deficits such as diplopia, and dysphasia.22 On the other hand, men more commonly present with nystagmus and sensory abnormalities.63 These findings are relevant because they impact the treatment methods care providers choose; in turn, this affects patient outcomes.
As with symptomatic presentation differences between men and women, there has been minimal conclusive research on the effect of symptomatic presentation differences on pre-hospital delays between men and women. Various studies have noted that women arrive later than men65-68, that women arrive sooner than men69, and that there is no significant difference.70-73 The reasons for these arrival time delays have been attributed to sex69, with studies noting that given that women seem to present with more non-traditional signs, this may in part account for greater delays for arrival to the emergency department and potential misdiagnosis.74
According to many studies though, women are significantly older than men at stroke onset15 and thus, are more likely to be living alone or in an institution during a stroke episode.75 Living alone has been associated with increased pre-hospital delays71 because the response of nearby individuals is a key element in reducing delay time.66 As of now, a consensus has not been reached regarding if there are sex-dependent delays, and if they do exist, what are the reason behind these delays. Nevertheless, it is evident that further research is necessary. In the meantime, healthcare providers must be aware of potential differences between men and women in order to choose appropriate treatment methods.