Influence of Sex on Stroke Prognosis: A Demographic, Clinical, and Molecular Analysis

Abstract

Identifying the complexities of the effect of sex on stroke risk, etiology, and lesion progression may lead to advances in the treatment and care of ischemic stroke (IS) and non-traumatic intracerebral hemorrhage patients (ICH). We studied the sex-related discrepancies on the clinical course of patients with IS and ICH, and we also evaluated possible molecular mechanisms involved. The study's main variable was the patient's functional outcome at 3-months. Logistic regression models were used in order to study the influence of sex on different inflammatory, endothelial and atrial dysfunction markers. We recruited 5,021 patients; 4,060 IS (54.8% male, 45.2% female) and 961 ICH (57.1% male, 42.9% female). Women were on average 5.7 years older than men (6.4 years in IS, 5.1 years in ICH), and more likely to have previous poor functional status, to suffer atrial fibrillation and to be on anticoagulants. IS patients showed sex-related differences at 3-months regarding poorer outcome (55.6% women, 43.6% men, p < 0.0001), but this relationship was not found in ICH (56.8% vs. 61.9%, p = 0.127). In IS, women had higher levels of NT-proBNP and 3-months worse outcome in both cardioembolic and non-cardioembolic stroke patients. Stroke patients showed sex-related differences in pre-hospital data, clinical variables and molecular markers, but only IS patients presented independent sex-related differences in 3-months poor outcome and mortality. There was a relationship between the molecular marker of atrial dysfunction NT-proBNP and worse functional outcome in women, resulting in a possible indicator of increased dysfunction.

Sex differences in risk factors, treatment, and prognosis in acute stroke

“…Furthermore, long-term functional stroke outcome seemed to be worse in women. Our results are partly in agreement with several earlier reports [24][25][26] ; however, in the present study, female sex alone seemed to be an independent risk factor for worse functional outcome, post-stroke depression, and fatigue, contradictory to previous reports. [27][28][29] Case fatality after 27 days and after 90 days was the same in men and women, after adjustment for the aforementioned covariates.…”

“…The most intriguing finding in the present study was worse disability in women at 3-months follow-up, independent of age, previous stroke, AF, pre-stroke mRS, NIHSS at admittance, consciousness at admittance, living alone after stroke, and post-stroke depression. In agreement with our results, a higher dependency after stroke in women has previously been reported 8,13,24,25 but has in several studies been associated with higher age and more severe stroke. 6,27,32 However, in the present study, we have not identified any difference in management or treatment strategies in the acute phase that could serve to explain the worse outcome in women.…”

“…Case fatality after 27 days and after 90 days was the same in men and women, after adjustment for the aforementioned covariates. Women’s all-cause mortality has been put forward to be lower after adjustments for relevant risk factors in some reports 7 , 13 but also, conversely, to be higher 24 , 30 or similar between men and women, 8 , 31 , 32 as in the present report. Variations in mortality between sexes may be caused by a disparity in the studied populations or may reflect differences in performed statistical adjustments.…”

“… 47 In our study, more women than men were living alone before stroke, and more females had a lower level of functional activity, in accordance with previous findings. 24 , 33 How-ever, we found no independent association between living alone prior to stroke and a higher level of disability and/or post-stroke depression (not shown). These differences in outcome may be due to population characteristics or largeness of the included population.…”

Potential microglia‐based interventions for stroke

“…After cerebral ischemia, microglia in female mice exhibit a more robust anti‐inflammatory response than those in males, and male mice exhibit an increase in CD11b immunoreactivity after MCAO . Clinically, patients with ischemic stroke present sex‐related differences in 3‐month outcomes and mortality, and sex‐related differences in prehospital data, molecular markers, and clinical variables have been documented . Further research has demonstrated a marked deregulation of microglial activation in ovariectomized and/or ERα knockout mice and increased vulnerability to ischemic injury, indicating that microglial heterogeneity poststroke is sex hormone‐dependent .…”