Clinical Science (2017) 131 533–552 DOI: 10.1042/CS20160841 Received: 2 November 2016 Revised: 16 December 2016 Accepted: 9 January 2017 Version of Record published: 17 March 2017 Review Article Sex differences in ischaemic stroke: potential cellular mechanisms Anjali Chauhan 1 , Hope Moser 2 and Louise D. McCullough 3 1 Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX 77030, U.S.A.; 2 Memorial Hermann Hospital-Texas Medical Center, Texas Medical Center, Houston, TX 77030, U.S.A.; 3 Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX 77030, U.S.A. Correspondence: Louise D. McCullough (Louise.D.McCullough@uth.tmc.edu) Stroke remains a leading cause of mortality and disability worldwide. More women than men have strokes each year, in part because women live longer. Women have poorer functional outcomes, are more likely to need nursing home care and have higher rates of recurrent stroke compared with men. Despite continued advancements in primary prevention, innov- ative acute therapies and ongoing developments in neurorehabilitation, stroke incidence and mortality continue to increase due to the aging of the U.S. population. Sex chromosomes (XX compared with XY), sex hormones (oestrogen and androgen), epigenetic regulation and environmental factors all contribute to sex differences. Ischaemic sensitivity varies over the lifespan, with females having an “ischaemia resistant” phenotype that wanes after meno- pause, which has recently been modelled in the laboratory. Pharmacological therapies for acute ischaemic stroke are limited. The only pharmacological treatment for stroke approved by the Food and Drug Administration (FDA) is tissue plasminogen activator (tPA), which must be used within hours of stroke onset and has a number of contraindications. Pre-clinical studies have identifed a number of potentially effcacious neuroprotective agents; however, nothing has been effectively translated into therapy in clinical practice. This may be due, in part, to the overwhelming use of young male rodents in pre-clinical research, as well as lack of sex-specifc design and analysis in clinical trials. The review will summarize the current clinical evidence for sex differences in ischaemic stroke, and will discuss sex dif- ferences in the cellular mechanisms of acute ischaemic injury, highlighting cell death and immune/infammatory pathways that may contribute to these clinical differences. Introduction Stroke is the second leading cause of mortality worldwide, killing almost 6 million people and affecting approximately 17 million individuals annually [1]. Although the incidence of stroke is higher for men in most age groups, stroke rates climb dramatically in women after the age of 80. Women are dispropor- tionately affected by stroke, both in terms of mortality and morbidity. In U.S., stroke has dropped to the fifth leading cause of death in men, but remains third in women [2]. Despite this higher mortality, of the estimated 6.8 million stroke survivors living in the U.S., 3.8 million (56%) are women due to the overall higher lifetime incidence of stroke [3]. Stroke is now the number one cause of long-term disability in the U.S. [4]. By 2030, it is predicted that an additional 3.4 million Americans will have an ischaemic stroke, a 20.5% increase in prevalence from 2012 [5]. The financial burden of caring for a stroke survivor will also double by 2030, due to the aging of the population. The probability of a poor outcome is higher in the elderly, leading to growing needs for long-term skilled nursing care [5]. In recent years, several national databases have been developed for the collection and storage of health-related data, rich in stroke-specific elements, yet there remains a dearth of sex-specific stroke data such as information on parity, pregnancy complications (i.e. pre-eclampsia), timing of menopause or hormone use, all of which can contribute to stroke risk in women [6]. c  2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society. 533 Downloaded from https://portlandpress.com/clinsci/article-pdf/131/7/533/445425/cs1310533.pdf by guest on 12 June 2020