Sex-specific responses to stroke

Abstract

Stroke is a sexually dimorphic disease, with differences between males and females observed both clinically and in the laboratory. While males have a higher incidence of stroke throughout much of the lifespan, aged females have a higher burden of stroke. Sex differences in stroke result from a combination of factors, including elements intrinsic to the sex chromosomes as well as the effects of sex hormone exposure throughout the lifespan. Research investigating the sexual dimorphism of stroke is only in the beginning stages, but early findings suggest that different cell death pathways are activated in males and females after ischemic stroke. A greater understanding of the mechanisms underlying sex differences in stroke will lead to more appropriate treatment strategies for patients of both sexes.

Figure 1. Approximate risk of stroke by age and sex

Approximate risk is estimated from data compiled from available sources [,,,,,–136].

Figure 2. Model of how various factors result in sex differences in stroke phenotype

An individual’s genetic inheritance determines biologic sex. The Sry gene is normally inherited on the Y chromosome. If Sry is present, the individual differentiates into a phenotypic male (XY) and develops testes. If Sry is absent, the individual differentiates into a phenotypic female (XX) and develops ovaries. Sex steroid hormones released by the testes (i.e., testosterone) and ovaries (i.e., estrogen and progesterone) subsequently trigger both organizational effects (irreversible changes) and activational effects (reversible effects dependent on the continued presence of the hormone). The sex chromosomes themselves may also trigger nongonadal effects and differential gene expression, further affecting phenotype. Prenatal environment and epigenetics can also influence phenotype. The combination of these factors results in sex differences in phenotype. Model based on concepts developed by AP Arnold [23,24].

Figure 3. Relative changes in sex steroid hormone levels over the lifespan

Exposure to sex steroid hormone levels spikes during prenatal development and puberty. After puberty, sex steroid hormones remain elevated until late middle age.

Figure 4. Sex-specific ischemic cell death pathways

Ischemic cell death in males occurs predominantly through a caspase-independent pathway involving PARP activation and AIF translocation. The female ischemic cell death pathway is caspase dependent, with early release of cytochrome c. XIAP can block caspase activation. Mitochondrial dysfunction and energy depletion occurs in both cell death pathways. PARP: Poly(ADP-ribose) polymerase; AIF: Apoptosis-inducing factor; XIAP: X-linked inhibitor of apoptosis protein.