Vaginal estrogen tablets unlikely to increase risk of stroke recurrence

Among women who have previously had an ischaemic stroke, the use of vaginal estradiol tablets does not raise the risk of having another stroke, according to new research.

In a nested case-control cohort of Danish women with a history of a first ischaemic stroke, exposure to vaginal estradiol tablets showed no association with the risk of a second stroke. This was consistent across time-stratified exposure categories: current (0–3 months before index stroke event: adjusted hazard ratio [aHR], 0.79, 95 percent confidence interval [CI], 0.52–1.20; p=0.27), recent (3–24 months before index event: aHR, 1.09, 95 percent CI, 0.73–1.63; p=0.67), and past (>24 months before index: aHR, 1.48, 95 percent CI, 0.95–2.30; p=0.08). [Stroke 2025;doi:10.1161/STROKEAHA.125.05098]

Even when dose was factored in, the analysis still yielded null results: high-dose current use (aHR, 0.70, 95 percent CI, 0.41–1.21; p=0.20) or low-dose current use (aHR, 1.14, 95 percent CI, 0.68–1.91; p=0.62).

A total of 56,642 female stroke survivors (median age 75 years) were included in the analysis, of which 3,353 experienced a recurrence (case group). The recurrent stroke event occurred a median of 188 days after the index event.

Compared with the control group, the case group had a markedly lower prevalence of current use (1.9 percent vs 3.2 percent; p=0.001), recent use (2.1 percent vs 3.6 percent; p=0.001), and past use of vaginal estradiol tablets (1.5 percent vs 2.4 percent; p=0.010). No significant difference was seen in the prevalence of high-dose current use (≥50 mg per week; 0.8 percent vs 1.5 percent) and low-dose current use (<50 mg per week; 1.2 percent vs 1.8 percent).

Systemic vs vaginal estrogen

“Certain forms of systemic hormone replacement therapy, particularly oral estrogen formulations, are associated with an increased risk of ischaemic stroke in postmenopausal women and, consequently, contraindicated in those with a history of ischaemic stroke,” the investigators noted. [JAMA 2002;288:321-333; JAMA 2004;291:1701-1712; Menopause 2022;29:767-794]

Systemic estrogen replacement therapy raises the body’s overall estrogen levels, which can stimulate the production of clotting factors and lead to a prothrombotic state, they explained. [Thromb Res 2020;192:40-51]

On the other hand, the locally administered vaginal estrogen therapy is absorbed systemically potentially to a small degree. The resulting increase in blood estradiol levels is minimal and has been shown to be harmless in healthy postmenopausal women. [Menopause 2020;27:361-370]

“Our results provide reassurance that vaginal estradiol tablets are unlikely to affect the risk of stroke recurrence in women with prior ischaemic stroke,” the investigators said.

They acknowledged several study limitations, including the observational design and lack of data on clinical factors such as stroke severity, functional status, lifestyle, or specific stroke aetiologies.

“In addition, the prescription data used to define exposure in our study only indicate whether a patient filled a prescription for vaginal estradiol tablets. We do not have information on whether the medication was used,” they said.