Women who survive a stroke experience less favorable outcome than men

In their in-depth review article, US scientists have addressed the issue of the disproportionate burden of stroke mortality and disability in women.

Accumulated data suggest that stroke is a sexually dimorphic disease. In addition, the results indicate that the functional outcome following the stroke is influenced by gender, and that women who survive a stroke experience less favorable outcome than men.

The men have an advantage in motor and functional recovery. In addition, women are more likely to have limitations in the activities of daily living or basic components of self-care. Women also experience more depression and fatigue. Some of these differences may be related to the onset of stroke at older ages in women. However, after adjusting for age, women also have poorer outcomes, such as a greater post-stroke disabilities and mental impairments.

It has become increasingly clear that the effects of sex hormones far exceed beyond their predominant role in sexual differentiation and reproduction. The central nervous system and the peripheral nervous system are important targets for sex steroids, which affect brain development and differentiation and neuronal functions. Finally, steroids with paracrine and/or autocrine mechanisms of action (so-called neurosteroids) are synthesized locally in the central nervous system and the peripheral nervous system, by myelinating glial cells.

In vivo studies demonstrated that effects of female steroids in cerebral ischemia may be more complex than previously recognized, and far from being fully understood. Most of the experimental studies have shown that female sex steroids progesterone and 17β-estradiol exert protective effects in the experimental models of stroke, although deleterious effects have also been reported. Extensive studies on female sexual steroids in cerebral ischemia have emphasized their ability to act on multiple pathways of ischemic lesions, and the importance of numerous factors, including sex, age, brain region, duration of ischemia, and a precise dose of steroids. Neuroprotective activities of the female sex steroids include stabilization of neurotransmission, inhibition of apoptosis, reduction of cerebral edema, anti-inflammatory and antioxidant activities.

The factors determining the balance between the neuroprotective and the deleterious effects of these hormones are unknown, although the balance has usually been shifted towards neuroprotection, particularly in models of focal infarct.

A recent study explored whether a lifetime cumulative exposure to estrogens is a useful indicator of stroke risk following menopause. The results showed that women with the longest reproductive lifespan had a 5% lower ischemic stroke risk, and a 13% lower risk of intracerebral hemorrhage when compared to women with the shortest reproductive lifespan.


About the study

This review article highlighted the current knowledge, as well as a research gap in presentation, treatment response, and stroke outcomes in women.

Globally, the lifetime risk of stroke (age 25 and up) is 25.1% for women and 24.7% for men. However, regional differences exist, with the highest lifetime risks for women in Eastern Europe and East Asia (36.5% and 36.3%, respectively). In addition, women have a higher prevalence and incidence of intracranial aneurysms, and substantially higher incidence of subarachnoid hemorrhage than men, while men have higher rates of hemorrhagic stroke.

With respect to stroke risk factors, the authors reported that the change in stroke risk with age varies by gender. The incidence of stroke is higher in women than in men under 30 years of age, while rates are higher in men than in women during midlife. However, the incidence of stroke is equal or higher among women beginning in the eighth decade.

The main modifiable risk factors that seem to influence risk differently depending on gender include diabetes and hypertension. Atrial fibrillation is a modifiable risk factor for both males and females. However, the data show that women with atrial fibrillation have a higher risk of stroke and all-cause mortality compared to men. Women over 65 years with atrial fibrillation have a particularly high risk for subsequent strokes.

The authors also highlighted risk factors which are specific for women. They include factors such as reproductive life span, potentially significant for risk prediction. Factors affecting lifetime exposure to estrogen, defined as the period between menarche and menopause, are associated with stroke risk. A meta-analysis showed that a reproductive lifespan of less than 30 years was associated with a 75% increase in risk compared with 36 to 38 years. This association seems to be primarily caused by premature (less than 40 years) or early (40–44 years) menopause, although early or late menarche also appears to increase the risk of stroke.

Previous clinical trials demonstrated an increase in total and ischemic stroke among women taking the oral menopausal hormone therapy (either estrogen alone or estrogen combined with progestin). However, more recent evidence suggests that the use of low-dose transdermal estrogen formulations may effectively treat menopausal symptoms without increasing the risk of stroke.

In addition, adverse pregnancy outcomes, which include preterm delivery, gestational hypertension, preeclampsia, have been consistently associated with increased long-term risk for maternal cardiovascular diseases, including stroke. The acute cerebrovascular complications during pregnancy and postpartum, hypertensive disorders and stroke outcomes in pregnancy were also discussed.

The researchers also analyzed the controversies as to whether there are gender differences in the access, efficacy, and safety of stroke treatment. A meta-analysis of 24 studies, published between 2008 and 2018, reported on gender-specific differences in the use of intravenous thrombolysis with recombinant tissue-type plasminogen activator (IV r-tPA) in ischemic stroke. The authors noted that this missed treatment opportunity could significantly affect women’s disability status.

Regarding stroke outcome, research shows that women experience worse outcomes after strokes than men in mortality, quality of life, poststroke depression, and activity limitation. In general, these studies suggest that the baseline differences in age, the characteristics of stroke, and cerebrovascular risk factors largely explain the observed gender differences in mortality.

With respect to functional outcomes, the data have generally shown a poorer functional recovery and lower quality of life after stroke in women than in men. The men have an advantage in motor and functional recovery, including recovery of paretic arm, mobility and performance in the activities of daily living. Women experience more depression, fatigue and poorer a lower quality of life. A systematic review of the prevalence of poststroke depression in 45 publications between 1982 and 2006 showed that prevalence of post-stroke depression was 78% higher among women than in men.

Individual-level factors such as older age, poorer prestroke function, co-morbidities, and lower social support were considered to contribute to gender differences in functional outcomes and quality of life. However, the adjustment for these factors does not fully explain the differences observed in women’s and men’s outcomes.

It should be noted here that physical and sexual abuse against women with disabilities is about twice as common as for women without disabilities. Women with disabilities are twice as likely to report severe forms of violence, including being beaten, and three times more likely to report being forced into sexual activity. Many disabling neurological conditions with mobility and sensory impairments, such as spinal cord injuries, stroke, and traumatic brain injury, make strong resistance difficult.

The authors noted that while women comprise more than half of all strokes, the inclusion of women in clinical trials of stroke treatments has been lower. Awareness of gender differences in post-stroke functional outcome may improve outcomes in relevant populations.

This article was published in the scientific journal Circulation Research. Rexrode KM. et al.The Impact of Sex and Gender on Stroke. Circulation Research. 2022;130:512–528.