Androgens and stroke: Good, bad or indifferent?

Abstract

Cerebral ischemia caused by loss of blood supply to the brain during cardiac arrest or stroke are major causes of death and disability. Biological sex is an important factor in predicting vulnerability of the brain to an ischemic insult, with males being at higher risk for cardio-cerebrovascular events than females of the same age. However, relative incidence of stroke between the genders appears to normalize at advanced ages. Therefore, many scientists have focused on the mechanisms of sex differences in outcome following brain ischemic injury, with a particular emphasis on the role of sex steroids. The majority of studies indicate that female sex steroids, such as estrogen and progesterone, play important roles in the relative neuroprotection following cerebral ischemia observed in females. However, less is known about male sex steroids and brain damage. This review describes the state of our knowledge of androgen-related contributions to neurological injury and recovery following cerebral ischemia that occurs following stroke. Experimental studies examining the effects of castration, androgenic agonists and antagonists and aging provide valuable insights into the role of androgens in clinical outcome following cerebrovascular events.

The Importance of Considering Sex Differences in Translational Stroke Research

“…In men, levels of testosterone decline with aging which has been associated with increased risk of stroke and low levels may worsen stroke outcome [131]. In preclinical studies androgens have a detrimental effect after stroke in young male mice but are beneficial if given to aged animals that have an age-related decline in endogenous sex steroid [131].…”

“…In men, levels of testosterone decline with aging which has been associated with increased risk of stroke and low levels may worsen stroke outcome [131]. In preclinical studies androgens have a detrimental effect after stroke in young male mice but are beneficial if given to aged animals that have an age-related decline in endogenous sex steroid [131]. Gonadectomy provides a tool for studying the effect of sex steroid hormones in stroke but do not recapitulate the overall aging phenotype as the loss of gonadal hormones is abrupt and complete, and the animals are still young, with young vasculature and brain.…”

Sex differences in mitochondrial (dys)function: Implications for neuroprotection

“…females (Wagner et al 2005). While female neuroprotection observed following injury is commonly attributed to female hormones, less attention has been paid to the influence of androgens mediating male susceptibility to brain injury (for review see (Quillinan et al 2014)). For instance, in immature neurons, activation of ionotropic γ -aminobutyric acid receptors (GABA A ) is excitatory and contributes to male vulnerability to excitotoxic injury in an androgen dependent manner (Nuñez et al 2003; Nuñez and McCarthy 2008).…”

Academic-industry Collaborations in Translational Stroke Research

“…MPTs are believed to increase the predictive value of translational stroke research and to identify those concepts exhibiting higher risks of subsequent clinical failure [28]. Challenging paradigms comprise different cerebral vessel occlusion modalities [29], simulation of comorbidity and polypharmacy [30], comparison between different ages [31] or sexes [32], as well as specialized large animal models [33]. Since these options should be combined, the resulting setup is usually too complex to be covered by a single laboratory.…”