Postmenopausal women with stroke history can safely use vaginal estrogen

Using vaginal estrogen tablets was not associated with an increased risk of recurrent ischemic stroke among postmenopausal women in a registry in Denmark, according to research published today in Stroke, the peer-reviewed scientific journal of the American Stroke Association, a division of the American Heart Association.

Unlike oral estrogen or transdermal formulations such as creams and patches, the women in this registry-based study had prescriptions for estrogen tablets designed for vaginal use. These tablets dissolve locally, and the estrogen is absorbed through the vaginal mucosa to help manage common menopausal symptoms, such as vaginal dryness and discomfort during intercourse. In healthy women, this mild increase in estrogen in the bloodstream from vaginal tablets doesn't seem to cause problems. However, it was previously unknown whether the vaginal estrogen tablets posed a risk to women with a history of stroke, a group considered more vulnerable to recurrent strokes.

It is well known that taking systemic hormone replacement therapy, such as oral estrogen tablets, may increase the risk of stroke after menopause. While other studies have not detected an increased risk of stroke associated with the use of vaginal estrogen in healthy postmenopausal women, there is no data on whether vaginal estrogen tablets pose an increased risk for women who have already had a stroke."

Kimia Ghias Haddadan, M.D., study's lead author, department of cardiology, Copenhagen University Hospital – Herlev and Gentofte in Copenhagen, Denmark

This study examined prescription data for more than 34,000 postmenopausal women, aged 45 and older, who had experienced a first ischemic stroke in a national registry in Denmark. Women who used vaginal estrogen before their first stroke were excluded. During the 10-year study, researchers compared the rates of recurrent stroke in women who used vaginal estrogen tablets with the rates of women who did not use the vaginal treatment. 

The analysis found:

• The use of vaginal estrogen tablets was not associated with an increased risk of having a second stroke in postmenopausal women with a previous stroke.
• When compared to not using vaginal estrogen tablets, there was no significant association among current use, recent use or past use of the vaginal estrogen tablets with a second stroke.
• Similarly, no increased risk of a second stroke was found between high-dose current use or low-dose current use.
• Even women with higher cumulative use of vaginal estrogen tablets did not have a higher risk of a second stroke compared to non-users.

"We were cautiously hopeful about the findings, and it was reassuring to discover that the use of vaginal estrogen did not raise the risk of recurrent stroke in this high-risk population," Haddadan said. "U.S.-based studies, such as the Women's Health Initiative and the Nurses' Health Study, have shown no increased stroke risk with vaginal estrogen in healthy women. Our study extends this reassurance to women with a history of stroke.

"It is important to note that these findings suggest that vaginal estrogen is likely safe for this high-risk group of women who have already had a stroke; however, they do not imply that vaginal estrogen prevents strokes," she said.

Haddadan said the findings should be applicable to postmenopausal women in the U.S. and other countries, especially where similar vaginal estrogen products are used. The study's strengths include its large, nationwide design, which provided a comprehensive view of real-world clinical outcomes in a high-risk population. By using Danish registries, researchers could accurately track stroke diagnoses, prescriptions and relevant health and demographic information across the entire population.

"As an epidemiologist, I see this study as a valuable contribution because it focuses on a population often excluded from hormone therapy research, midlife women with a prior stroke, and examines an increasingly used route of administration: vaginal tablets. While the study did not find a statistically significant association with stroke recurrence, the findings should be interpreted with caution. Real-world data can't account for all clinical and behavioral factors, and prescription fill records don't confirm whether the medication was actually used. Still, studies like this allow us to explore important questions that are often not feasible to address in clinical trials," said Samar R. El Khoudary, Ph.D., M.P.H., FAHA, chair of the American Heart Association's 2020 Statement on Menopause Transition and Cardiovascular Disease Risk: Implications for Timing of Early Prevention. El Khoudary, who was not involved in this study, is a professor in the department of epidemiology at the University of Pittsburgh School of Public Health.

The study has several limitations. Women who used vaginal estrogen might have been healthier overall, which could affect the results. However, researchers adjusted for a range of health and demographic factors, such as medications, medical conditions, income and education, to reduce the impact of this issue. Estrogen use was determined from prescription records, which indicate the medication was dispensed but not necessarily taken as prescribed; therefore, actual use or adherence cannot be confirmed. And the study focused solely on one form of treatment, vaginal estrogen tablets, because it is the most common mode of treatment in Denmark. The findings may not apply to other estrogen formulations, such as vaginal creams, patches or rings. Cost is also not an issue, because Denmark provides free universal health care to all citizens.

Study details, background and design:

• A nationwide study using health records identified 56,642 women who had experienced a stroke between January 1, 2008, and December 31, 2017.
• A total of 34,274 women ages 45 or older (median age of 75) were included in this analysis, while 22,368 women were excluded for various reasons. Exclusions included women under the age of 45, those with a history of vaginal estrogen use, and women who had used systemic hormone therapy within one year before their first stroke.
• 3,353 women who experienced a second stroke were compared to an equal number of women who did not experience a second stroke.
• Using prescription data, researchers assessed whether the women had used vaginal estrogen tablets and categorized their use as current (within 3 months), recent (3-24 months) or past (more than 24 months before the study).
• To evaluate whether vaginal estrogen use was linked to the risk of a second stroke in postmenopausal women, researchers compared each woman who'd had a second stroke (case group) with a woman of the same age who did not (control group).
• The study did not include data on race because that information is not collected about patients in Denmark.

"We hope our findings reassure health professionals caring for postmenopausal women with a history of stroke. For these women, especially those with troubling menopause symptoms, the study shows that this type of therapy may be a safe choice. It could improve their quality of life without raising the risk of another stroke," Haddadan said.