About Stroke

Estrogen, Women and Stroke

By Cheryl D. Bushnell, MD MHS, Patricia Denise Hurn, PhD and Louise D. McCullough, MD, PhD

The focus of this article is to inform women about estrogen and stroke. But first, it is important to know that stroke is a common and serious disease in women. The term "Stroke" actually refers to a group of diseases involving the blood vessels leading to, or within, the brain. Most commonly a blood vessel becomes occluded and a segment of the blood supply to the brain is cut off. This results in a localized injury within the brain.

There are nearly three-quarters of a million strokes in the United States each year, with a third of these occurring in people under the age of 65 years. So while many think of stroke as a disease of older men, this is not the case. Stroke not only afflicts younger people, but it kills more women than the number who die from breast cancer and AIDS combined. Over half of all strokes and 60% of all stroke-related deaths occur in women. In fact, stroke ranks as the second leading cause of death in women worldwide. Women of all ages should discuss their risk for stroke and heart disease with their physicians. Women with hypertension, diabetes, abnormal lipids, cigarette smoking, or a family history of stroke or heart attack are all at increased risk for stroke. African-American and Hispanic-American women are also at higher risk for stroke. The good news is that the majority of strokes that might occur in women could be prevented if women at risk are identified and treated in time.

If a stroke does occur, it is critical to get medical attention quickly. There are therapies that can reduce the injury associated with stroke or decrease the complications following a stroke. Therapies such as t-PA ('clot busters') can help reopen blocked blood vessels, but most patients fail to receive this therapy in time. Stroke is a medical emergency.

Every minute counts.

Female hormones like estrogen play a role in stroke. A hormone is a chemical signal produced in one part of the body that has actions elsewhere in the body. You can think of a hormone as a messenger. Produced in the ovaries, estrogen travels the blood stream, signaling the brain, blood vessels, uterus, breasts, bones, liver and many other organs.

Estrogen is produced throughout the first half of a woman's adult life. Production dramatically decreases at the time of menopause, in the late 40's and early 50's for most women. Decreases in estrogen have been associated with common symptoms of menopause, such as hot flashes, vaginal dryness, headaches, changes in mood and difficulty with sleeping.

Low estrogen levels have also been associated with an increased risk for heart disease, stroke, osteoporosis (thinning of the bones), cognitive changes and dementia. Estrogen actions protect teeth, the eyes and skin. New evidence also points to estrogen's supportive effects on immune response. These benefits decrease as estrogen levels decrease.

Women have been using hormone replacement therapy (HRT) after menopause for over sixty years. Estrogen alone is prescribed for women without a uterus, women who have had a hysterectomy. Women with a uterus take a progesterone-like hormone in addition to estrogen in order to protect the lining of the uterus, since unopposed estrogen can lead to uterine cancer. The addition of the progesterone essentially eliminates that risk. Most women use HRT for less than two years, primarily to control hormone deficiency symptoms at the time of menopause. Because symptoms usually persist for more than five years — and in about 25% of women, for more than ten years — hormone use can be prescribed for longer periods. However, some women opt to discontinue treatment because of possible negative side effects of chronic estrogen replacement a, such as an increased incidence of breast cancer and stroke.

New developments in hormone replacement therapy are appealing because the doses are lower, the delivery of the hormones is better controlled and the products are purer. As a result, treatment of symptoms is more effective, side effects are reduced and concern about cancer is lessened, especially among women who use HRT for about five years. These new treatments hold the possibility of more effective prevention of disease due to hormone deficiency but many are still under investigation.

Whichever HRT is used, as with all other hormone therapies, it is important that treatment be used as directed. Missing pills or forgetting to change a hormone-containing patch can lead to irregular bleeding or induce hot flashes, headaches and other "withdrawal" effects. These in turn often lead to discontinuation of treatment.

Initial epidemiological studies indicated that women who used hormone replacement therapy following menopause had lower rates of heart attack and stroke. HRT's potential benefits against stroke were also suggested by a decade of laboratory-based animal studies that repeatedly emphasized estrogen’s protective actions for the heart, blood vessels, bone and brain. In randomized clinical trials, however, it remained unclear whether to attribute the decreased disease rates to the estrogen or to the women who used the estrogen (i.e., a statistical bias). Women who use estrogen are more likely to go to their doctor, more likely to know their risk factors and have them treated and more likely to take their medications. All of these measures are associated with a lower rate of heart attack and stroke.

The best way to address the possible bias is to set up a study that randomly assigns women to hormone replacement therapy or an inactive pill (placebo). Some of these studies have now been completed. Surprising results have emerged over the past decade that have shown a possible detrimental effect of hormone replacement in both healthy women as well as women with known vascular disease.. In the Women's Estrogen for Stroke Trial (WEST) Study, postmenopausal women who had a recent stroke or a transient ischemic attack (TIA) were randomly assigned to estrogen or a placebo. They were monitored for several years for the occurrence of a recurrent stroke or death. In the WEST, women who were assigned to estrogen had the same rate of a recurrent stroke as those assigned to a placebo. Additionally, women who were randomly assigned to receive estrogen therapy had a higher risk of fatal stroke, which was a concerning finding. It is possible that estrogen loses its beneficial effects if women already have established vascular disease.

It is important to note that women in the WEST trial had known vascular disease, so hormone replacement was being investigated for prevention of future events (“secondary prevention”). Less was known about the effect of hormone replacement in healthy women until the release of the Women’s Health Initiative (WHI). In July 2002 the WHI, the largest study to date to examine the effects of hormone replacement therapy on stroke, published its findings that the combination of estrogen and a potent progestin — a drug called "Prempro" — caused an increase both in strokes and heart attacks in healthy postmenopausal women as compared with placebo. Initially it was thought that the progesterone may be responsible for the increased stroke risk, but in 2004, similar results were reported for women with a prior hysterectomy treated with estrogen without a progesterone. The use of estrogen was found to increase the risk of stroke in postmenopausal women. While there are indications for the use of hormonal therapy, available data from the WEST study indicate that women who have had a stroke should not be started on hormonal therapy to prevent a recurrent stroke, myocardial infarction, or death. The Women's Health Initiative, moreover, cautions postmenopausal women who have never had a stroke against hormone replacement therapy use if it is solely for the prevention of stroke. Many new trials are ongoing to try to figure out why hormone therapy seems to be so beneficial in observational and experimental studies, yet does not seem to protect the women who used it in the WEST and WHI. One possibility is that hormone replacement was begun to late, as most of the women in these trial were well past (over 10 years) menopause. It is quite possible that if therapy is begun early- at menopause, the beneficial effects will become apparent. Further research has never been more crucial. A women who is considering HRT should consult her physician to determine her risk.

Among women before menopause, the use of oral contraceptives has also been associated with a small increase in the risk for stroke. This small increase appears to be lower with modern, lower dose, oral contraceptives. The risk, however, remains higher among women who also have a history of migraines and who smoke. This trial of oral contraceptives, migraines and smoking should alert younger women, as well, to their potential risk for a stroke or related complication.

Women are living longer than ever before. As they do, it is vital that they also live healthier longer. Women need to be aware of their risk and the preventative measures they can take to protect themselves against the occurrence and effects of stroke. More research is also needed from the medical community. By seeking to fund medical research and to promote public awareness about stroke in women, The Goddess Fund is committed to eliminating the impact of stroke from women's lives.