The Importance of Considering Sex Differences in Translational Stroke Research

Abstract

Stroke is the second leading cause of death worldwide and differences between men and women have been documented in incidence, prevalence and outcome. Here, we reviewed the literature on sex differences in stroke severity, mortality, functional outcome and response to therapies after ischemic stroke. Many of the sex differences in stroke severity and mortality are explained by differences in baseline demographics such as older age in women. However, women account for more stroke deaths, consistently suffer from worse stroke outcomes and are more often institutionalized and permanently disabled than men. These sex differences in functional outcome are equalized after treatment with tissue plasminogen activator (tPA) and women may benefit more from treatment than men. However this may depend on race, as African American women have less of a response to tPA than other groups. Regarding endovascular treatments, the few existing studies that have investigated sex differences in stroke outcome point to equal benefit in both sexes, however, many clinical trials are relatively underpowered to detect sex differences. Further, we considered sex-specific effects in animal models of stroke and present recommendations for the performance of stroke studies in female animals. The male-biased use of research animals is distinguished from the clinical situation where there is a disproportionate and growing female stroke population. Stroke in women is greatly understudied and including both sexes is especially important in both preclinical and clinical studies that evaluate potential stroke therapies.

Translational Stroke Research Opportunities and a Strategy to Develop Effective Cytoprotection

“…& Committee members recommended that aged animals be used for stroke research, comorbid conditions need to be represented (see [31,32,33]), chronic stroke models (months of survival) should be developed because rodents display adaptive plasticity, and stroke studies should incorporate atrial fibrillation, hypoperfusion, transient ischemic attack (TIA), and white matter damage. Most of these recommendations are consistent with previously stated STAIR recommendations [20].…”

To Improve Translational Research in Subarachnoid Hemorrhage

“…The proposed standards include (1) clinical relevance of animal models (detailed information on animals used (species, strain, age, weight, gender, etc. ), selection of anesthetics, inclusion and exclusion criteria), (2) sample size calculation and accurate statistical analysis, (3) treatment (randomization, allocation concealment, dose-response determinations, therapeutic time window, blood-brain barrier permeability and tissue drug levels, physiological monitoring), (4) outcome (blinded assessment, at least two outcome measures (morphology and function), covering both acute (1-3 days) and longterm (7-30 days) endpoints), and (5) reporting of animals excluded from analysis, potential conflicts of interest, and study funding [1][2][3][4][5][6][7]. In addition, several challenges exist to successfully translate the outcomes from animal research to humans in a clinical setting.…”

“…In addition, several challenges exist to successfully translate the outcomes from animal research to humans in a clinical setting. First, age and sex are two important non-modifiable risk factors for stroke [5,8]. With aging, there is a shift toward a proinflammatory phenotype in the brain as well as the periphery, and blood-brain barrier disruption [8].…”

“…With aging, there is a shift toward a proinflammatory phenotype in the brain as well as the periphery, and blood-brain barrier disruption [8]. Women are protected from stroke before menopause, but have increased stroke rates and worse outcomes at older ages [5]. On the other hand, the use of adult reproductive female animals in stroke research is complicated by the sex hormone cycle.…”

“…Genetic differences between animals and humans, and even within animal species, strains, and cell lines, may affect the immune responses and outcomes [10,12,13]. Third, stroke patients have many comorbidities or vascular risk factors including hypertension, diabetes mellitus, dyslipidemia, cardiac diseases, current smoking, obesity, poor diet, inactivity, high alcohol intake, psychosocial stress and depression, social factors such as marital and residence status (i.e., living alone), and prestroke dysfunction, causing stroke severity [5,14]. Animal models having these factors are also subjected to different stroke injuries or changes in the structure of the neurovascular unit [14].…”