The effects of estrogen in ischemic stroke

Abstract

Stroke is a leading cause of death and the most common cause of long-term disability in the USA. Women have a lower incidence of stroke compared with men throughout most of the lifespan which has been ascribed to protective effects of gonadal steroids, most notably estrogen. Due to the lower stroke incidence observed in pre-menopausal women and robust preclinical evidence of neuroprotective and anti-inflammatory properties of estrogen, researchers have focused on the potential benefits of hormones to reduce ischemic brain injury. However, as women age, they are disproportionately affected by stroke, coincident with the loss of estrogen with menopause. The risk of stroke in elderly women exceeds that of men and it is clear that in some settings estrogen can have pro-inflammatory effects. This review will focus on estrogen and inflammation and its interaction with aging.

Fig. 1

Case of intraventricular and intracerebral hemorrhage following treatment with tPA 70-year-old man with left middle cerebral artery stroke who was administered tPA and subsequently worsened. Repeat CT scan showed intraventricular and intracerebral hemorrhage as well as midline shift. Blue arrow indicates ischemic infarct and red arrow indicates hemorrhage

Fig. 2

Influence of epigenetics and hormones on genetic expression and stroke outcome

Fig. 3

Sexual dimorphism in cell death following cerebral ischemia Caspase-dependent death predominates in females, where the influx of Ca²⁺ induces formation of the MAC which permeabilizes the mitochondrial membrane. Cytochrome c, Smac/DIABLO, and X-linked inhibitor of apoptosis protein (XIAP) are released into the cytosol. Cytochrome c and caspase-9 facilitate formation of the apoptosome which in turn activates caspase-3. Caspase-3 cleaves the inhibitor of caspase-activated DNase to give caspase-activated DNase (CAD) which subsequently cleaves DNA and results in apoptosis. Caspase-independent cell death predominates in males, in which ischemia results in an increase in reactive oxygen species (ROS) which combine with nitric oxide (NO) to form peroxynitrite (ONOO–). ONOO– damages DNA via oxygenation and nitration which activates polymerase (ADP-ribose), polymerase-1 (PARP-1), and formation of poly(ADP-ribose) (PAR) polymers. Permeabilization of the mitochondrial membrane enables apoptosis-inducing factor (AIF) to translocate from the intermembrane space of the mitochondrion to the nucleus where it causes specific DNA fragmentation patterns and chromatin condensation, ultimately resulting in apoptosis

Fig. 4

Hypothesized interaction between estradiol, TNF, and NFκB signaling At physiological levels of estradiol (E2), tumor necrosis factor (TNF) preferentially binds to TNF receptor 2 (TNFR2), denoted R2, leading to activation of nuclear factor-κ B (NFκB) which translocates to the nucleus. Balance between estrogen receptor-α (ERα) transcription of inhibitor of κ B-α (IκBα) and estrogen receptor-β (ERβ) inhibition of NFκB binding is present, resulting in balanced inflammation and net anti-apoptotic signaling. With physiological levels of E2, TNF levels are lower and there is reduced stimulation of TNF receptor 1 (TNFR1), denoted R1, and subsequent caspase signaling. In postmenopausal women, E2 levels decline and there is a lack of ERα-induced IκBα expression and ERβ-mediated inhibition of NFκB. Higher circulating TNF levels stimulate both TNFR2 and TNFR1, leading to relatively uninhibited inflammation and induction of caspase-dependent apoptosis. With high levels of E2 as seen in pregnancy and obesity, there is increased expression of IκBα which inhibits NFκB. The NFκB that translocates to the nucleus is inhibited by ERβ binding, inhibiting expression of anti-apoptotic genes by NFκB. Lack of inhibition of TNFR1 signaling results in caspase-dependent apoptosis. See reviews [120, 144]