Menopause and Ischemic Stroke: A Brief Review

Abstract

Ischemic stroke is one of the leading causes of morbidity and mortality worldwide. Females are protected against stroke before the onset of menopause. Menopause results in increased incidence of stroke when compared to men. The mechanisms of these differences remain to be elucidated. Considering that there is a postmenopausal phenomenon and females in general, are living longer sex hormone-dependent mechanisms have been postulated to be the primary factors responsible for the premenopausal protection from stroke and later to be responsible for the higher incidence and increased the severity of stroke after menopause. Animal studies suggest that administration of estrogen and progesterone is neuroprotective and decreases the incidence of stroke. However, the real-world outcomes of hormone replacement therapy have failed to decrease the stroke risk. Despite the multifactorial nature of sex differences in stroke, here, we briefly discuss the pathophysiology of sex steroid hormones, the molecular mechanisms of estrogen receptor-dependent signaling pathways in stroke, and the potential factors that determine the discrepant effects of hormone replacement therapy in stroke.

Keywords: Epidemiology; Gender; Hormones; Receptors; Stroke.

Figure 1

Neuroprotective role of 17β-estradiol. 17β-estradiol binds to intracellular estrogen receptor (ER). It activates endothelial nitric oxide synthase (eNOS) in the endothelium and neuronal nitric oxide synthase (nNOS) in the vascular smooth muscle cells (VSMC). Thus, resulting in enhanced release of nitric oxide (NO) and inhibits actin-myosin based vasoconstriction through activation of cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway that inhibits myosin light chain (MLC) phosphorylation and activates the large conductance calcium-activated potassium channel (BK). 17β-estradiol binds to the ER to increase the expression and activity of Na+/K+- ATPase and has a direct effect to activate BK channels, both of which cause membrane hyperpolarization and vascular relaxation. The vasodilation effect plays a critical role in neuroprotection.