Complexities of oestrogen in stroke

Carswell, Hilary V O; Macrae, I Mhairi; Farr, Tracy D.

doi:10.1042/cs20090018

Cited by 23 publications

(17 citation statements)

References 191 publications

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“…Since many preclinical studies were performed in rodents, this section will be limited to mouse and rat models of ischemic stroke. The reader is referred to the following reviews for a discussion of animal models of stroke in other species including nonhuman primates (Casals et al, 2011; Cook and Tymianski, 2012) and estrogen action in animal models of ischemic stroke (Carswell et al, 2010). …”

Section: Estrogen Neuroprotection In Brain Injurymentioning

confidence: 99%

Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury

Engler-Chiurazzi

Brown

Povroznik

et al. 2017

Progress in Neurobiology

169

121

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There is ample empirical evidence to support the notion that the biological impacts of estrogen extend beyond the gonads to other bodily systems, including the brain and behavior. Converging preclinical findings have indicated a neuroprotective role for estrogen in a variety of experimental models of cognitive function and brain insult. However, the surprising null or even detrimental findings of several large clinical trials evaluating the ability of estrogen-containing hormone treatments to protect against age-related brain changes and insults, including cognitive aging and brain injury, led to hesitation by both clinicians and patients in the use of exogenous estrogenic treatments for nervous system outcomes. That estrogen-containing therapies are used by tens of millions of women for a variety of health-related applications across the lifespan has made identifying conditions under which benefits with estrogen treatment will be realized an important public health issue. Here we provide a summary of the biological actions of estrogen and estrogen-containing formulations in the context of aging, cognition, stroke, and traumatic brain injury. We have devoted special attention to highlighting the notion that estrogen appears to be a conditional neuroprotectant whose efficacy is modulated by several interacting factors. By developing criteria standards for desired beneficial peripheral and neuroprotective outcomes among unique patient populations, we can optimize estrogen treatments for attenuating the consequences of, and perhaps even preventing, cognitive aging and brain injury.

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Section: Estrogen Neuroprotection In Brain Injurymentioning

confidence: 99%

Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury

Engler-Chiurazzi

Brown

Povroznik

et al. 2017

Progress in Neurobiology

169

121

View full text Add to dashboard Cite

show abstract

“…Some of estrogen's neuroprotective effects have been linked to its anti-inflammatory, anti-apoptotic and vasodilatory properties and are reviewed in detail elsewhere [82, 83]. It should be noted that although the majority of experimental studies favor the beneficial effects of estrogen, there are contrasting studies [84-86], see Table 4 and detailed previous reviews [83, 87]. In summary, young female animals sustain less ischemic damage than young males when subjected to equal types of stroke, an effect that is mainly due to estrogen.…”

Section: Sex Differences In Experimental Strokementioning

confidence: 99%

The Importance of Considering Sex Differences in Translational Stroke Research

Ahnstedt

McCullough

Cipolla

2016

Transl. Stroke Res.

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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.

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“…Paradoxically, one of the suggested mechanisms for estrogens’ ability to increase damage in cerebral ischemia is the hormones’ pro -inflammatory capacity [7,37]. In several rat experiments, estrogens have been reported to potentiate leukocyte adhesion, increase P-selectin and MPO enzyme activity in cerebral ischemia [7,113], increase TNF-α, TLR-2 and IL-12 in response to LPS stress [114,115], increase IL-1β in a NMDA-toxicity model [97] and to worsen functional outcome in a model of chronic cerebral inflammation (Figure 1) [116].…”

Section: Mechanisms For Estrogens’ Neuroprotective and Neurodamaging mentioning

confidence: 99%

Mechanisms of Estrogens’ Dose-Dependent Neuroprotective and Neurodamaging Effects in Experimental Models of Cerebral Ischemia

Ström

Theodorsson

2011

IJMS

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Ever since the hypothesis was put forward that estrogens could protect against cerebral ischemia, numerous studies have investigated the mechanisms of their effects. Despite initial studies showing ameliorating effects, later trials in both humans and animals have yielded contrasting results regarding the fundamental issue of whether estrogens are neuroprotective or neurodamaging. Therefore, investigations of the possible mechanisms of estrogen actions in brain ischemia have been difficult to assess. A recently published systematic review from our laboratory indicates that the dichotomy in experimental rat studies may be caused by the use of insufficiently validated estrogen administration methods resulting in serum hormone concentrations far from those intended, and that physiological estrogen concentrations are neuroprotective while supraphysiological concentrations augment the damage from cerebral ischemia. This evidence offers a new perspective on the mechanisms of estrogens’ actions in cerebral ischemia, and also has a direct bearing on the hormone replacement therapy debate. Estrogens affect their target organs by several different pathways and receptors, and the mechanisms proposed for their effects on stroke probably prevail in different concentration ranges. In the current article, previously suggested neuroprotective and neurodamaging mechanisms are reviewed in a hormone concentration perspective in an effort to provide a mechanistic framework for the dose-dependent paradoxical effects of estrogens in stroke. It is concluded that five protective mechanisms, namely decreased apoptosis, growth factor regulation, vascular modulation, indirect antioxidant properties and decreased inflammation, and the proposed damaging mechanism of increased inflammation, are currently supported by experiments performed in optimal biological settings.

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Complexities of oestrogen in stroke

Cited by 23 publications

References 191 publications

Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury

Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury

The Importance of Considering Sex Differences in Translational Stroke Research

Mechanisms of Estrogens’ Dose-Dependent Neuroprotective and Neurodamaging Effects in Experimental Models of Cerebral Ischemia

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