The Women's Health Initiative hormone trials identified a 44% increase in ischemic stroke risk with combination estrogen plus progestin and a 39% increase with estrogen alone. We undertook a case-control biomarker study to elucidate underlying mechanisms, and to potentially identify women who would be at lower or higher risk for stroke with postmenopausal hormone therapy (HT).
The hormone trials were randomized, double-blind, and placebo controlled.
The Women's Health Initiative trials were conducted at 40 clinical centers in the United States.
The trials enrolled 27,347 postmenopausal women, aged 50–79 y.
We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo.
Stroke was ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial.
No baseline clinical characteristics, including gene polymorphisms, identified women for whom the stroke risk from HT was higher. Paradoxically, women with higher baseline levels of some stroke-associated biomarkers had a lower risk of stroke when assigned to estrogen plus progestin compared to placebo. For example, those with higher IL-6 were not at increased stroke risk when assigned to estrogen plus progestin (odds ratio 1.28) but were when assigned to placebo (odds ratio 3.47; p for difference = 0.02). Similar findings occurred for high baseline PAP, leukocyte count, and D-dimer. However, only an interaction of D-dimer during follow-up interaction with HT and stroke was marginally significant (p = 0.03).
Biomarkers did not identify women at higher stroke risk with postmenopausal HT. Some biomarkers appeared to identify women at lower stroke risk with estrogen plus progestin, but these findings may be due to chance.
Background: The Women's Health Initiative hormone trials originally set out to evaluate whether postmenopausal hormone therapy (HT, estrogen in the case of women who had had a hysterectomy, and estrogen plus progestin for women who had not had a hysterectomy) reduced the risk of heart attacks and strokes, as compared to placebo. The trials were stopped early, and the investigators found that both estrogen alone, as well as estrogen plus progestin increased the risk of stroke amongst women participating in the trials. As part of a secondary analysis of data from these trials, the investigators aimed to explore possible associations between various biological markers (such as variants in particular genes, and levels of particular lipids, proteins, and other markers in blood), and the risk of a woman experiencing a stroke in the trials. Specifically, they wanted to evaluate whether there was any evidence for particular markers being associated with the risk of a stroke; and then whether that risk was modified by whether a woman took HT in the trials.
What the trial shows: In this study, the researchers collected early cases of ischemic stroke in the trials (combining cases among women taking estrogen with those for women taking both estrogen and progestin), and matched these to control individuals, or women participating in the trials who did not experience a stroke. Two hundred five women who experienced a stroke were compared to 878 control individuals. The markers analyzed included those for which there was already some evidence for an association with stroke. Several clinical characteristics and some biomarkers, as measured at the start of the trial, but none of the gene variants, were linked with later risk of stroke. However, none of these clinical characteristics or gene variants specifically identified women who were at greater risk of experiencing a stroke within the HT arms of the trial. High levels of two biomarkers, IL-6 and PAP, did seem to identify women who were at lower risk of experiencing a stroke within the HT arms of the trial. This finding is interesting, because high levels of these markers had previously been suggested as being associated with a higher risk of stroke. Levels of several biomarkers changed during the trial, but for only one biomarker, D-dimer, did the change (an increase in levels) seem to predict higher risk of stroke amongst women receiving HT.
Strengths and limitations: A particular strength of this study includes the nesting of a case-control study within the Women's Health Initiative trials, in which HT or placebo was randomly assigned. This design minimizes the chance that individuals taking HT differ in their stroke risk from individuals taking placebo. However, the power of this study to detect anything other than large associations is limited; together with the limitation of multiple statistical testing, the findings here must be interpreted as hypotheses for further study and not definitive conclusions.
Contribution to the evidence: This study adds data relating to possible predictive risk markers for stroke among users of HT. The hypotheses raised here remain to be tested in further studies.