Could estrogen protect younger menopausal women from stroke?

The hypothesis that estrogen might be protective for younger women but might become neutral, or even harmful, for older women has been proposed for both cardiovascular disease and dementia [1,2]. When referring specifically to the benefits or risks of estrogen therapy (ET), this hypothesis has been called the window of opportunity, window of vulnerability, or timing hypothesis. For simplicity, we will call it the timing hypothesis. It remains unclear whether the timing hypothesis applies to stroke in general or to ischemic stroke (IS) in particular. The general consensus has been that estrogen is invariably a risk factor for IS, probably because of its short-term prothrombotic and proinflammatory effects. For example, the experimental data from the Women’s Health Initiative (WHI) clinical trials and the observational data from the Nurses’ Health Study (NHS) indicate, with remarkable consistency, that estrogen is a risk factor for IS when administered orally to women older than 50 years of age, alone or in combination with a progestin (primarily conjugated equine estrogens at a dose of 0.625 mg/day) [3–5]. The same conclusion was reached by three metaanalyses of clinical trials of ET and risk of stroke [6–8]. However, in the past 5 years, newer observational studies have challenged this simple conclusion. In a review of observational studies of the association of premature or early menopause with stroke or IS, published in English from 2006 through to 2010, we found seven studies providing evidence for a protective role of estrogen in younger women [9].