Sexual Dimorphism in Ischemic Stroke: Lessons from the Laboratory

Manwani, Bharti; McCullough, Louise D.

doi:10.2217/whe.11.22

Cited by 82 publications

(73 citation statements)

References 228 publications

(296 reference statements)

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“…Cell death pathways differ between the two sexes, caspase-independent (nitric oxide/poly[ADP-ribose] polymerase) cell death pathway predominates in males, while caspases are mediators of cell death in females. 9 A significant sex effect was seen in caspase activation. Higher αII cleaved spectin was seen in gonadectomized XXF and XYF mice as compared with XYM, XXM, and WTM mice.…”

Section: Discussionmentioning

confidence: 96%

“…The major sex hormones have both organizational and activational effects. 9 Organizational effects of hormones are permanent and long lasting, often occurring in utero. In contrast, activational effects of hormones are dependent on acute circulating hormone levels and, therefore, can be reversed by gonadectomy.…”

Section: Discussionmentioning

confidence: 99%

“…Estrogen contributes to the sexual dimorphism in incidence and prevalence of ischemic stroke, as girls and young women have lower incidence of stroke as compared with men. 9 This epidemiology reverses with advancing age, and postmenopausal women bear the brunt of this disease as incidence grows. Similarly, in animal models estradiol-mediated neuroprotection is ameliorated by ovariectomy, and has been thought to be solely an activational (reversible) effect of hormone exposure.…”

Section: Discussionmentioning

confidence: 99%

“…8 In contrast, estrogens have been consistently shown to be neuroprotective in the majority of preclinical studies. 9 Ovariectomized females have increased histologic injury compared with ovary intact females, and this is reversed with estradiol supplementation. Exogenous estradiol administration also reduces injury in males, suggesting that estrogen exercises its beneficial effects independently of the gonadal sex.…”

Section: Introductionmentioning

confidence: 99%

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Sex Differences in Ischemic Stroke Sensitivity Are Influenced by Gonadal Hormones, Not by Sex Chromosome Complement

Manwani

Bentivegna

Benashski

et al. 2014

J Cereb Blood Flow Metab

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110

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Epidemiologic studies have shown sex differences in ischemic stroke. The four core genotype (FCG) mouse model, in which the testes determining gene, Sry, has been moved from Y chromosome to an autosome, was used to dissociate the effects of sex hormones from sex chromosome in ischemic stroke outcome. Middle cerebral artery occlusion (MCAO) in gonad intact FCG mice revealed that gonadal males (XXM and XYM) had significantly higher infarct volumes as compared with gonadal females (XXF and XYF). Serum testosterone levels were equivalent in adult XXM and XYM, as was serum estrogen in XXF and XYF mice. To remove the effects of gonadal hormones, gonadectomized FCG mice were subjected to MCAO. Gonadectomy significantly increased infarct volumes in females, while no change was seen in gonadectomized males, indicating that estrogen loss increases ischemic sensitivity. Estradiol supplementation in gonadectomized FCG mice rescued this phenotype. Interestingly, FCG male mice were less sensitive to effects of hormones. This may be due to enhanced expression of the transgene Sry in brains of FCG male mice. Sex differences in ischemic stroke sensitivity appear to be shaped by organizational and activational effects of sex hormones, rather than sex chromosomal complement.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sex Differences in Ischemic Stroke Sensitivity Are Influenced by Gonadal Hormones, Not by Sex Chromosome Complement

Manwani

Bentivegna

Benashski

et al. 2014

J Cereb Blood Flow Metab

Self Cite

110

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“…These future studies might help to explain the greater incidence of orthostatic hypotension in women, if there is indeed an observable sexually dimorphic difference. Furthermore, if sex differences in the relative contributions of BP MCA or PET CO 2 to brain blood flow exist, this might establish the conditions for a greater incidence of stroke in men (30,37,73).…”

Section: Discussionmentioning

confidence: 99%

Hemodynamics and brain blood flow during posture change in younger women and postmenopausal women compared with age-matched men

Edgell

Robertson

Hughson

2012

Journal of Applied Physiology

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Edgell H, Robertson AD, Hughson RL. Hemodynamics and brain blood flow during posture change in younger women and postmenopausal women compared with age-matched men. J Appl Physiol 112: 1482-1493, 2012. First published February 23, 2012 doi:10.1152/japplphysiol.01204.2011.-Increased incidence of orthostatic hypotension and presyncopal symptoms in young women could be related to hormonal factors that might be isolated by comparing cardiovascular and cerebrovascular responses to postural change in young and older men and women. Seven young women, 11 young men, 10 older women (Ͼ1 yr postmenopausal, no hormone therapy), and 9 older men participated in a supine-to-sit-to-stand test while measuring systemic hemodynamics, end-tidal PCO2, and blood flow velocity of the middle cerebral artery (MCA). Women had a greater reduction in stroke volume index compared with age-matched men (change from supine to standing: young women: Ϫ22.9 Ϯ 1.6 ml/m 2 ; young men: Ϫ14.4 Ϯ 2.4 ml/m 2 ; older women: Ϫ17.4 Ϯ 3.3 ml/m 2 ; older men: Ϫ13.8 Ϯ 2.2 ml/m 2 ). This was accompanied by offsetting changes in heart rate, particularly in young women, resulting in no age or sex differences in cardiac output index. Mean arterial pressure (MAP) was higher in older subjects and increased with movement to upright postures. Younger men and women had higher forearm vascular resistance that increased progressively in the upright posture compared with older men and women. There was no difference between sexes or ages in total peripheral resistance index. Women had higher MCA velocity, but both sexes had reduced MCA velocity while upright, which was a function of reduced blood pressure at the MCA and a significant reduction in end-tidal PCO2. The reductions in stroke volume index suggested impaired venous return in women, but augmented responses of heart rate and forearm vascular resistance protected MAP in younger women. Overall, these results showed significant sex and age-related differences, but compensatory mechanisms preserved MAP and MCA velocity in young women. cerebrovascular; sex; age; orthostatic ORTHOSTATIC HYPOTENSION (a condition that sometimes leads to fainting) is an important and sometimes dangerous condition that particularly affects young women during daily life, as reflected by admission to emergency rooms (51). It has been speculated that female sex hormones might modulate reflex neural or vascular properties, resulting in the greater incidence of orthostatic hypotension in young women (5,14,15,52,69). An additional indication of impaired orthostatic responses in women includes the observation that women have a greater propensity towards postural orthostatic tachycardia syndrome (18, 60).Contrary to observations for young women, clinical evidence supports the concept that orthostatic hypotension occurs less frequently in women ages 40 -60 yr (many of whom could be postmenopausal) (51). Investigations of men and women from 23-77 yr of age indicated that the heart rate response to tilt was reduced with aging, but vascular responses a...

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Sex differences in the immune response to experimental stroke: Implications for translational research

Dotson

Offner

2016

J of Neuroscience Research

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Ischemic stroke is a leading cause of death and disability in the United States. It is known that males and females respond differently to stroke. Depending on age, the incidence, prevalence, mortality rate, and disability outcome of stroke differ between the sexes. Females generally have strokes at older ages than males and, therefore, have a worse stroke outcome. There are also major differences in how the sexes respond to stroke at the cellular level. Immune response is a critical factor in determining the progress of neurodegeneration after stroke and is fundamentally different for males and females. Additionally, females respond to stroke therapies differently from males, yet they are often left out of the basic research that is focused on developing those therapies. With a resounding failure to translate stroke therapies from the bench to the bedside, it is clearer than ever that inclusion of both sexes in stroke studies is essential for future clinical success. This Mini-Review examines sex differences in the immune response to experimental stroke and its implications for therapy development.

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Sexual Dimorphism in Ischemic Stroke: Lessons from the Laboratory

Cited by 82 publications

References 228 publications

Sex Differences in Ischemic Stroke Sensitivity Are Influenced by Gonadal Hormones, Not by Sex Chromosome Complement

Sex Differences in Ischemic Stroke Sensitivity Are Influenced by Gonadal Hormones, Not by Sex Chromosome Complement

Hemodynamics and brain blood flow during posture change in younger women and postmenopausal women compared with age-matched men

Sex differences in the immune response to experimental stroke: Implications for translational research

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