Premature menopause or early menopause and risk of ischemic stroke

Abstract

Objective: The general consensus has been that estrogen is invariably a risk factor for ischemic stroke (IS). We reviewed new observational studies that challenge this simple conclusion.

Methods: This was a review of observational studies of the association of premature or early menopause with stroke or IS published in English from 2006 through 2010.

Results: Three cohort studies showed an increased risk of all types of stroke in women who underwent bilateral oophorectomy compared with women who conserved their ovaries before age 50 years. The increased risk of stroke was reduced by hormone therapy in one of the studies, suggesting that estrogen deprivation is involved in the association. Four additional observational studies showed an association of all types of stroke or IS with the early onset of menopause or with a shorter life span of ovarian activity. In three of the seven studies, the association was restricted to IS. Age at menopause was more important than type of menopause (natural vs induced).

Conclusions: The findings from seven recent observational studies challenge the consensus that estrogen is invariably a risk factor for IS and can be reconciled by a unifying timing hypothesis. We hypothesize that estrogen is protective for IS before age 50 years and may become a risk factor for IS after age 50 years or, possibly, after age 60 years. These findings are relevant to women who experienced premature or early menopause or to women considering prophylactic bilateral oophorectomy before the onset of natural menopause.

FIG. 1

Summary of observational studies on the association of premature or early menopause with risk of stroke. The relative risks estimated by OR or HR and 95% confidence interval were plotted using a logarithmic scale. ^aA length of 34 years of ovarian activity corresponds to the occurrence of estrogen deficiency at approximately age 46 years, assuming a median age at menarche of 12 years. HT = hormone therapy; JACC = Japan Collaborative Cohort Study; NHS = Nurses’ Health Study.

FIG. 2

Illustration of a unifying theory for the effects of estrogen on ischemic stroke across age (timing hypothesis). The relative risks estimated by OR or HR and 95% confidence interval for estrogen present versus estrogen absent were plotted using a logarithmic scale. Studies or strata were grouped into three blocks by age and study design: observational studies before age 50 years (from this review, with inversion of the definition of exposure to compare later menopause vs earlier menopause), observational studies of HT after age 50 years (using the NHS as an example), and experimental studies of HT after age 50 years (using the WHI clinical trials as an example). Most studies focused on ischemic stroke but some considered all stroke (see Table 1 for details of studies before age 50 y). E = estrogen; E + P = estrogen plus progestin therapy; HT = hormone therapy; JACC = Japan Collaborative Cohort Study; NHS = Nurses’ Health Study; WHI = Women’s Health Initiative.