The author: Professor Yasser Metwally
INTRODUCTION
May 9, 2008 — New analysis of data from the Nurses’ Health Study (NHS) suggests that hormone therapy (HT) is associated with an increased risk for stroke, regardless of the treatment strategy or the timing of treatment initiation.
The researchers found an increased risk of approximately 40% with estrogen alone and 30% with estrogen plus progestin, “a finding that is nearly identical to that of the Women’s Health Initiative,” they write. Stroke risk increased with increasing doses of oral conjugated estrogen.
“In younger women, with lower stroke risk, the attributable risk of stroke owing to hormone use is modest and might be minimized by lower doses and shorter treatment duration,” the researchers, with first author Francine Grodstein, ScD, from Harvard Medical School and the Harvard School of Public Health in Boston, Massachusetts, add.
Their results are published in the April 28 issue of the Archives of Internal Medicine.
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Treatment Early After Menopause
A previous analysis from the NHS showed an increased risk for stroke with current use of hormone therapy of approximately 35%, the authors write. In the NHS, a randomized trial of hormone therapy in postmenopausal women also showed a 30% to 40% increased risk with therapy either with estrogen alone or estrogen combined with progestin.
The risks in that trial appeared similar for both younger and older women, they write, but the trial included only a few women who were recently menopausal, when hormone therapy is used most often in the clinical setting, so the risk for these women is still unclear.
In the current study, they write, “we examined the most critical current questions regarding stroke risk: we explored the timing of HT initiation and further examined varying estrogen doses since we had limited power to address these questions in the previous analyses.” They also looked at the relationship with stroke type.
The NHS is a prospective, observational study including 121,700 women who were between the ages of 30 and 55 years in 1976. Subjects were observed with biennial questionnaires, including information on menopause and postmenopausal hormone use as well as cardiovascular risk factors and cardiovascular diagnoses.
They found a significant increased risk for stroke in women currently taking HT, whether it was estrogen alone or estrogen plus progestin.
Table 1. Risk for Stroke With Current Use of Estrogen or Estrogen Plus Progestin vs Never-Users*Group Relative Risk 95% CI
| Group |
Relative Risk |
95% CI |
| Current Use Estrogen Only | 1.39 | 1.18 – 1.63 |
| Current Use Estrogen Plus Progestin | 1.27 | 1.04 – 1.56 |
*These values were calculated after adjustment for major stroke risk factors.
The increased risk was seen for women initiating HT at young ages or near menopause or at older ages or more than 10 years after menopause, they note. Short-term use of less than 5 years initiated at younger ages was not associated with a clear increase in stroke risk, they note; “however, this apparently null result was based on a small number of cases.”
The incidence of stroke was relatively low in younger women, they write; the attributed risk in women aged 50 through 54 years indicated approximately an additional 2 cases of stroke per 10,000 women per year taking hormones.
There was also a strong and statistically significant relationship between the dose of oral conjugated estrogen and stroke risk, the authors add (P for trend, < .001).
Table 2. Stroke Risk by Dose of Oral Conjugated EstrogenDose of Oral Estrogen (mg) Relative Risk
| Dose of Oral Estrogen (mg) |
Relative Risk |
| 0.3 | 0.93 |
| 0.625 | 1.54 |
| 1.25 | 1.62 |
“In summary, our findings in the Nurses’ Health Study indicate that HT is associated with an increased risk of stroke, regardless of the hormone regimen or the timing of HT initiation,” the authors conclude. “However, in younger women, who are at lower absolute risk of stroke, the attributable risk of stroke owing to hormone use is modest, and our data suggest that risk might be further minimized by lower doses and shorter duration of treatment.”
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KEEPS Trial Underway
A randomized trial, the Kronos Early Estrogen Prevention Study (KEEPS), is currently underway, evaluating the effect of 5 years of HT vs placebo in 720 women aged 42 to 58 years randomized within 36 months of their final menstrual period, may provide additional data on the effect and safety of this treatment in younger women.
The work described in this article was supported by the National Institutes of Health. Dr. Grodstein has disclosed receiving an honorarium from Wyeth in 2007. Two of the study authors have received funding. A complete list of disclosures is available in the original article.
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Clinical Context
The Women’s Health Initiative (WHI) and the NHS both demonstrated an increased risk for stroke in postmenopausal women using HT but it is still unclear if the risk is as high for younger women in early menopause, who are more likely to use HT for menopausal symptoms, and scarce data is available on the association between estrogen dose and stroke risk.
This is an analysis of prospective, observational data from the NHS to examine the stroke risk associated with HT use and its association with age, age at initiation, and estrogen dose.
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Study Highlights
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Included were women within the NHS cohort initiated in 1976 in nurses aged 30 to 55 years at baseline, who responded to biennial questionnaires until 2004.
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Dietary and physical activity questions were added in 1980, and menopause and hormone use data were collected including current use, duration of treatment, type of hormone taken, and dose of conjugated estrogen.
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Cohort follow-up was more than 90%.
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Fatal and nonfatal strokes were confirmed by medical record review.
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Nonfatal stroke was ascertained by questionnaire, whereas fatal stroke was ascertained by reports from relatives, the postal service, or the National Death Index.
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Of those with medical records available, 46% had never taken HT, 36% used estrogen alone, and 18% used estrogen with progestin.
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Among stroke cases, the numbers were 48%, 35%, and 17%, respectively.
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Incident stroke was confirmed by the National Survey of Stroke criteria, and stroke was classified as ischemic or hemorrhagic.
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Cerebrovascular disease from infection, traumatic injury, or malignant tumor was excluded as were women who reported stroke in addition to myocardial infarction, coronary revascularization, or cancer.
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Women were classified as postmenopausal from the time of natural menopause or hysterectomy; in those without bilateral oophorectomy, the presumed age of natural menopause was 54 years for smokers and 56 years for nonsmokers.
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A cutoff value of 4 years was used for “near menopause,” as most HT use occurs within 4 years of menopause.
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For estrogen alone, the age-adjusted relative risk (RR) for total stroke for current users was 1.33 (95% CI, 1.13 – 1.55) vs women who never used HT.
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For combined HT, the RR was 1.17 (95% CI, 0.96 – 1.42) vs women who never used HT.
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After adjustment for stroke risk factors, the respective RRs were higher at 1.39 and 1.27.
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The results did not materially change when adjusted further for diet, vitamin intake, and estrogen alone vs combined with progestin.
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RRs were similar across different stroke types.
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Overall, the increase in stroke risk was 30% to 40% for women who currently used HT, a result similar to results of the WHI.
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Timing of HT initiation did not significantly change the observed associations (RR for estrogen alone, 1.20 for near menopause and 1.31 for = 10 years after menopause).
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The increases in stroke risk were similar for women taking estrogen alone or combined with progestin.
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Stroke risk was low among younger women but increased at older ages.
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The rate of stroke was 3.8 per 10,000 person-years for those aged 50 to 54 years, doubled from aged 60 to 64 years to 7.1 per 10,000 person-years, and increased 5 times to 17.9 per 10,000 person-years for those 65 years and older.
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The attributable risks per 10,000 person-years with current hormone use were 0.9 for women younger than 50 years, 1.5 from ages 50 to 54 years, 2.2 from ages 55 to 59 years, 2.8 from ages 60 to 64 years, and 7.2 at 65 years or older.
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Thus, if 10,000 women aged 50 to 54 years used HT for 1 year, an extra 1.5 cases of stroke would be seen vs an extra 7.2 for those 65 years and older.
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There was a strong trend of increasing stroke risk with increasing estrogen dosage.
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Compared with women who had never used HT, the RR was 0.93 for those who used 0.3 mg of HT daily, 1.54 for those who used 0.625 mg of HT daily, and 1.62 for those who used 1.25 mg of HT daily.
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In the youngest group of women (aged = 55 years), combining data for estrogen and combined hormone use, short-term HT use was not associated with an increased risk for stroke, but this was based on a small number of patients.
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Pearls for Practice
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Use of HT by postmenopausal women is associated with overall increased risk for stroke of 30% to 40%.
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An increased risk for stroke associated with HT use in postmenopausal women is independent of age of initiation of HT and greater with higher doses of estrogen and older age.
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References
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Arch Intern Med. 2008;168:861-866.
