Adult or Perinatal Brain Injury
Does Sex Matter?
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Biological sex and sex-defining steroids are strikingly under-rated as modulators of cerebral ischemic cell death. In adults, male sex has been long identified as a risk factor for clinical stroke, yet the biology behind this fact remains veiled. We know that overall stroke incidence is lower in women than in men, across widely varying ethnic and cultural backgrounds.1 Newer glimpses into this sexual dimorphism indicate that women continue to sustain lower stroke rates until beyond the menopausal years, suggesting that hormonal factors are not solely responsible. For example, stroke rates in female subjects of the Northern Manhattan Stroke Study did not exceed those of men until aged ≥85 years.2 Importantly, data from sex-stratified preclinical studies indicate that stroke sensitivity (the damage resulting when an ischemic insult occurs) is also sexually dimorphic in adults. It is less clear if ischemic injury in the developing brain develops differently in males and females. However, provocative new evidence from cells cultured directly from fetal or newborn brain suggests that mechanisms of cell death are not identical in cells that are genetically male (XY) versus female (XX). This article evaluates linkages between sex, sex steroids, and neuroprotection throughout life.
Adult Brain Injury Is Sexually Dimorphic
The presence of a male “ischemia-sensitive” phenotype has been suggested in a wide variety of animal studies. One of the most impressive early studies included >2000 animals.3 Yamori et al showed that life expectancy was longer in female spontaneously hypertensive stroke-prone rats, and the development of cerebral hemorrhage and vascular lesions was attenuated relative to male spontaneously hypertensive stroke-prone rats.3 Subsequently, female rats and mice of numerous inbred and outbred strains have been studied. These studies clearly demonstrate less tissue damage for an equivalent insult after focal or global cerebral ischemia in age-matched females versus male,4–6 accompanied by improved functional outcome. …