Oestrogen and stroke: the potential for harm as well as benefit

Epidemiological studies point to a beneficial influence of the female reproductive hormones on stroke risk in that women have a lower incidence of stroke prior to the menopause compared with men, but this difference weakens with age and stroke risk in women rises after the menopause. However, recent Women's Health Initiative trials in post-menopausal women report an increased stroke risk on hormone replacement therapy. An influence of gender is also apparent on stroke outcome in animal models: female rats exposed to transient MCA (middle cerebral artery) occlusion sustain less brain damage than age-matched males, with loss of protection following ovariectomy. The major hormone thought to be responsible for beneficial influences on stroke incidence and outcome is oestrogen, and a large preclinical literature now exists where exogenously administered oestrogen has been studied in male and ovariectomized female rats using a range of stroke models and outcome measures. Most of these studies administer oestrogen prior to the stroke, use a model of transient ischaemia followed by reperfusion and report a significant oestrogen-induced neuroprotection. However, in some studies where the MCA is permanently occluded, oestrogen pre-treatment in ovariectomized female rats has been shown to significantly exacerbate ischaemic damage. Therefore preclinical results demonstrate harmful as well as beneficial influences of oestrogen on the ischaemic brain, highlighting the need for further study to elucidate the mechanisms responsible for both detrimental and beneficial influences. Ultimately, this could lead to the development of new classes of oestrogenic compounds with improved risk/benefit profiles, designed to selectively activate pathways inducing only the beneficial effects of oestrogen in vivo.