High levels of endogenous estradiol are associated with an increased risk of stroke in postmenopausal women. Raloxifene appears to attenuate this increased stroke risk in women with high estradiol levels, said Jennifer S. Lee, MD.

Her findings come from the Multiple Outcomes of Raloxifene Evaluation (MORE), in which raloxifene's effects on bone mineral density and vertebral fracture were investigated over 4 years in postmenopausal women.

The role of endogenous estradiol levels on stroke risk after menopause is controversial, she said. "A recent meta-analysis of 28 randomized trials showed a significant 29% increased risk in ischemic stroke with hormone therapy, which typically increases serum estradiol levels well into the premenopausal range," said Dr. Lee, from California Pacific Medical Research Institute and the University of California, San Francisco.

Estradiol has complex actions in the brain and vasculature. "It may have a protective effect on the neurons, potentially have beneficial effects against atherosclerosis and lipids, with adverse effects on inflammation and thrombosis," she said.

Selective estrogen receptor modulators (SERMs), such as raloxifene, behave differently than estrogen. SERMs have both proestrogenic and antiestrogenic effects, depending on the tissue site.

A meta-analysis of nine breast cancer trials reveals an 82% increased risk of ischemic stroke in tamoxifen users compared with placebo recipients. In contrast, in the overall MORE study population, raloxifene had no significant effect on stroke risk.

In MORE, women were at least 2 years postmenopausal, age ≤ 80, and had no stroke or venous thromboembolic disease in the previous 10 years. They were randomized to placebo or 60 or 120 mg/day of raloxifene. Baseline estradiol measurements were obtained in 7,290 of the 7,705 women. Among the 2,447 taking placebo, 1,227 (50%) had undetectable levels of estradiol. Fifty percent of the remaining 1,220 had levels ≥16 pmol/L.

The women with estradiol levels of at least16 pmol/L, representing the highest quartile of estradiol levels, had 2.5 times the stroke risk compared with women with lower estradiol levels (P <0.015).

Raloxifene did not significantly affect the risk of stroke in women with lower estradiol levels. In women with estradiol levels in the highest quartile, raloxifene reduced the risk of stroke by 55%, which was of borderline significance (P = 0.11). (The conventional P value used to determine significance in tests of interaction is 0.10.)

Further study is required before measuring estradiol levels in clinical practice can be recommended, said Dr. Lee. "We need a sufficient sample size to look at this interaction and outcome," she said. "If confirmed, measuring endogenous estradiol levels is a simple blood draw and may help in assessing the risk of stroke in older women."