HRT — It Can Increase Seizure Frequency in Postmenopausal Women with Epilepsy

Abstract & Commentary

By Cynthia L. Harden, MD, Associate Professor, Neurology and Neurosciences, Weil Cornell Medical Center, Cornell University. Dr. Harden does research for Schwarz, GlaxoSmithKline, UCB, Ortho, and Ivax, is a consultant for Cyberonics and GlaxoSmithKline, and is on the speaker's bureau for Cyberonics, GlaxoSmithKline, UCB, Novartis, Pfizer, and Ortho.

Synopsis: This randomized, double-blind, placebo-controlled study showed that standard hormone replacement therapy using Prempro can increase seizure frequency in postmenopausal women with epilepsy in a dose-related manner.

Source: Hormone Replacement Therapy in Women with Epilepsy: A Randomized, Double-Blind, Placebo-Controlled Study. Cynthia L. Harden, et al. Epilepsia. 2006;47(9):1447-51.

This study is the first and likely shall be the only report in which Prempro is studied for its effects on brain excitability in women. The study was undertaken based on results of a survey in which postmenopausal women with epilepsy reported on the course of their seizure disorder during life changes,1 and almost incidentally, they reported that hormone replacement therapy (HRT) was associated with seizure exacerbation. This interesting result prompted further exploration of the effect of HRT on seizure frequency. It was especially provocative since estrogen has long been reported as neuroexcitatory and proconvulsant in animal models, leading to the question of whether the neuroactivity of exogenous estrogen could be adverse in women with epilepsy. Further, postmenopausal women, who have a stable reproductive hormonal milieu, are ideal subjects with which to test this hypothesis compared to women of reproductive potential who have monthly estrogen and progesterone surges.

The study herein used a single dose or a double dose of Prempro, which is 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate or CEE/MPA, and compared it to placebo for an effect on seizure worsening. Both doses of Prempro were in common use at the time this study began, making this study of imminent practical relevance. Subjects underwent a 3-month baseline observation period, followed by a 3-month treatment period. Seizure outcome was analyzed simply by comparing the proportion of women whose seizure frequency increased with those whose seizure frequency did not increase. Women enrolled in this study generally had very stable epilepsy with infrequent seizures, which reflects the general population of persons with epilepsy. Although the enrollment of the study was limited due to the growing unpopularity of HRT, which reached its culmination with the WHI2 results showing an increased risk of breast cancer, the authors were able to show an adverse effect on seizure frequency with the small numbers of subjects in the study.


These results indicate that in addition to other risks now shown with Prempro, there is a risk of seizure increase when it is used in postmenopausal women with epilepsy. Women with epilepsy will need to use HRT for relief of postmenopausal symptoms however, and sleeplessness due to "hot flashes" could also be a strong precipitant of increased seizure frequency. What can women with epilepsy use for short-term relief of menopausal symptoms?

It is possible that at least part of the risk shown in this study is due to the special components of Prempro, which is a mixture of estrogens present in pregnant mare's urine, and consists largely of estrone, with small components of the most potent estrogen, 17-beta estradiol, and other estrogenic molecules. Further, the progestin in Prempro is a powerful synthetic progestogenic molecule, medroxyprogesterone acetate. Rodent studies of the effects of hormones on brain excitability show that surges in 17-beta estradiol increase seizure activity; almost nothing is known about the effects of medroxyprogesterone acetate on neurophysiology.

Therefore, although an adverse effect on seizures was shown using Prempro in women with epilepsy, it is possible that low and stable doses of a more simplified regimen, such as 17 beta estradiol only with natural progesterone, which in and of itself has anticonvulsant properties in animal models,3 may be safer for short term use in women with epilepsy. It should be emphasized that this study evaluated only one HRT regimen, albeit the most widely used one at the time. The use of another form of HRT, especially at lower doses, may be without this risk. The best advice from the author of this study is that women with epilepsy who need HRT for symptom relief could be treated carefully and cautiously with such a regimen.


1. Harden CL, Pulver MC, Jacobs AR. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia 1999:40(10):1402-1407.

2. The Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy post-postmenopausal women: Principle results of the Women's Health Initiative randomized, controlled trial. JAMA. 2002;288:321-333.

3. Herzog AG. Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology. 1999;52(9):1917-8.