Postmenopausal Hormone Therapy and Stroke
Postmenopausal Hormone Therapy and Stroke
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: The Nurses' Health Study reports an increased risk of stroke associated with hormone therapy that may be related to the dose of estrogen
Source: Grodstein F, et al. Postmenopausal hormone therapy and stroke. Role of time since menopause and age at initiation of hormone therapy. Arch Intern Med. 2008;168:861-866.
The Nurses' Health Study reported an update of its data on the use of hormone therapy and stroke, focusing on the timing of initiation of treatment and the effect of estrogen doses.1 In the analyses adjusted for age, BMI, cholesterol levels, diabetes, hypertension, smoking, and family history of early coronary heart disease, the following relative risks were observed for ischemic stroke (there was no significant increase in hemorrhagic stroke):
| Current use of estrogen alone | RR=1.43 (CI=1.17-1.74) | |
| Current use of estrogen-progestin | RR=1.53 (CI=1.21-1.95) |
There was no significant increase in fatal stroke. For nonfatal stroke the relative risks were:
| Current use of estrogen alone | 243 cases | RR=1.41 (CI=1.19-1.68) | |
| Current use of estrogen-progestin | 123 cases | RR=1.31 (CI=1.05-1.62) |
The results did not change after adjustments for dietary factors, physical activity, regular aspirin use, and vitamin supplementation. Comparing initiation of hormone therapy near menopause with initiation 10 or more years after menopause, the authors concluded that there was no major difference. However a close look at the data reveals that the risks associated with estrogen alone were statistically significant for near and far initiation, but the risks with estrogen-progestin were not! Looking at the age of initiation, the risk of stroke for estrogen alone was significantly increased for women age 50-59, but the risk with estrogen-progestin was not statistically significant. For women 60 years of age and older, the risks with both estrogen alone and estrogen-progestin were statistically significant.
The Nurses' Health Study also reported an increasing risk of stroke with an increasing dose of estrogen:
| 0.3 mg estrogen | 25 cases | RR=0.93 (CI=0.62-1.40) | |
| 0.625 mg | 268 cases | RR=1.54 (CI=1.31-1.81) | |
| 1.25 mg | 60 cases | RR=1.62 (CI=1.23-2.14) |
Commentary
It is not easy to derive a take-home message from this Nurses' Health Study report. The authors provide a table of attributable risk for current hormone use based on their numbers, and the fact that the risk of stroke greatly increases with increasing age.
| Age less than 50 | 0.9 strokes per 10,000 women per year | |
| Age 50-54 | 1.5 |
|
| Age 55-59 | 2.2 | |
| Age 60-64 | 2.8 | |
| Age 65 and older | 7.2 |
The authors state that their findings are "virtually identical to those of the WHI trials." However, in the last report from the WHI, when women with prior cardiovascular disease or those older than 60 years were excluded, the risk of stroke in women less than 10 years since their menopause was not significantly increased.2 Therefore, there is disagreement. The authors further state that neither study found a difference in age. However, the increase with combined estrogen-progestin in the Nurses' Health Study was not statistically significant—is this because the case numbers were too small or is this real?
The authors conclude that their data suggest a small risk of stroke in younger postmenopausal women, a risk that might be further reduced with lower doses and shorter durations of treatment. The conclusions by the authors are not as clear-cut as they would seem. In my view, this risk in women who do not have risk factors for stroke (especially hypertension) may be zero. How confident can we be that the mathematical adjustment for risk factors in the Nurses' Health Study gives us a definitive answer? It makes sense that stroke risk is related to the dose of estrogen, but the Nurses' Health Study data on this issue are limited by small numbers.
So what is the take-home message? I believe the risk of stroke is minimal if not zero in young, healthy postmenopausal women. In women with risk factors for stroke, it is prudent to use low doses of estrogen and to vigorously address the risk factors, such as effective treatment of hypertension. Would the transdermal route of administration be safer? That is an important question that cannot be answered because of a lack of data, but because stroke risk is limited to ischemic events and it is possible that the transdermal route has a lower risk of thrombosis, it seems wise to promote this route of administration in older postmenopausal women and in women with risk factors for stroke.
References
- Grodstein F, et al. Postmenopausal hormone therapy and stroke. Role of time since menopause and age at initiation of hormone therapy. Arch Intern Med. 2008;168:861-866.
- Rossouw JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-1477.
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