Expert: Dual Interaction is Present Between Epilepsy and Menopause

In an interview with Pharmacy Times®, Paula E. Voinescu, PhD, MD, epilepsy physician and Brigham and Women’s Hospital Mass General Brigham, assistant professor at Harvard Medical School, and leader of the Women’s Epilepsy Program, discussed her presentation on menopause and epilepsy at the 2025 American Academy of Neurology (AAN) Annual Meeting. She highlighted the impact of sex hormone fluctuations on the frequency of seizures, as well as a correlation between seizures and early menopause. Voinescu emphasized a need for more research in this area, suggesting that studies on hormonal treatments and the potential increased risk of seizure frequency should be conducted.

Pharmacy Times: Can you introduce yourself?

Paula E. Voinescu, PhD, MD: Sure. I'm Dr. Paula Emanuela Voinescu. I'm an epilepsy physician at Brigham and Women's Hospital Mass General Brigham, assistant professor at Harvard Medical School, and I lead the Women's Epilepsy Program, which is a clinical and research program. I'm focusing my clinical and research efforts on improving the care of patients with the gestational potential throughout their lifespan.

Pharmacy Times: During the 2025 AAN Meeting, you spoke about epilepsy and menopause. In your session, what associations between these did you highlight?

Voinescu: So, it's a dual interaction between epilepsy and menopause, predominantly through the changes in the sex hormones, but also through other physiological changes that a person's body goes through at menopause. I highlighted those interactions as they pertain to the sex hormones fluctuations at perimenopause—so in that transitional window—but also with the lower sex hormone levels at menopause. And on the flip coin of what I said, I highlighted the influence that epilepsy may have on menopause, where seizures and medications can have an impact on the onset of the cessation of menstrual cycles, but also on comorbidities associated with menopause.

Pharmacy Times: What effects might epilepsy have on the timing of cessation of reproductive cycling?

Voinescu: I will say that there's very little research done, and that's surprising and upsetting, because our patients spend, with an increased life average, our patients spend more than half of their life at menopause, so I wish we knew more. And all the research I presented [at AAN] is really encompassing a few studies that looked at these questions.

So, regarding your question on how epilepsy may influence menopause, there's a couple of studies that looked at how medications may play an impact and seizures may play an impact, and there's this molecular underpinning that's triggered by the hypothalamic pituitary ovarian axis, and thinking of this connection between the central nervous system and our reproductive system, it's been hypothesized that seizures may influence the health of this neuroendocrine system and may have an influence on menopause, and indeed, there is a study showing that the number of seizures throughout the person's lifespan may lead to premature menopause. There's a study by [Cynthia L. Hardin, MD] that showed this correlation between [an] increased number of seizures and an early onset of menopause. And then there's [other] studies showing that antiseizure medications may affect the reproductive system's health, and while there is less evidence that certain medications, per se, may have an influence...one may speculate that medications that perhaps lead to [polycystic ovary syndrome] may also have an influence later in life, but those studies have not yet been conducted.

Pharmacy Times: What pharmacokinetic changes might occur during the transition to menopause?

Voinescu: That's a great question. We know a lot about the clearance of antiseizure medications. A lot of those studies have done during reproductive years. We know about the interactions with hormonal contraception, there is growing evidence about the clearance changing in pregnancy, and in pregnancy, I think the majority of epilepsy doctors these days do therapeutic drug monitoring throughout pregnancy and postpartum. But we know less about the transition to menopause and menopause per se, and I do wonder if [during] the perimenopause period, we should really do therapeutic drug monitoring, because during those times when estrogen and progesterone fluctuate, the impact on the clearance of antiseizure medications may be different.

So, there is a study showing that two thirds of women that are transitioning to menopause experience seizure worsening, and one may wonder, is it the hormonal fluctuations and the impact that sex steroid hormones have directly on neuronal excitability. Perhaps that's one explanation, but the other one may be that the same sex hormone fluctuations would have an impact in how the medication is cleared and when antiseizure medication levels fluctuate—especially when they drift down—women are at a higher risk of having seizures. And one particular association that we know of is glucuronidation. We know that estradiol has an impact on glucuronidation. Again, there is a lot of evidence of that from pregnancy clearance studies, and likely, the same happens at perimenopause especially in that transition window when there is variable [luteinizing hormone]. We know that estradiol can have dramatic fluctuations, and that may lead to altered clearance and lower lamotrigine levels, perhaps at times, that would trigger seizures. Lamotrigine is just an example, but oxcarbazepine is also metabolized, preglucuronidation of valproic acid, and that's just to mention 1 mechanism.

And as I said, we don't have these studies, and I wish we had more, but one can imagine also how—perhaps not at perimenopause—but at menopause, the clearance through the liver and the kidneys goes down. So, it would be the reverse, women may be at a higher risk of experiencing side effects as the clearance goes down and the medication levels may increase.

And then, one other thing to mention, because I do get, sometimes, patients that have started on different medications for their symptoms in that period, there is the added effect of medications that may be started at this time point, and especially the menopausal hormonal treatment. So, it's not only the endogenous hormones, but also the exogenous hormones that may be added and alter the picture even more.

Pharmacy Times: Does epilepsy have any effects on menopause-related comorbidities?

Voinescu: I think one big issue that has been a little more explored through research...Alison Park, MD, from Columbia looked at how antiseizure medications affect bone health, and that's something on our mind for our female patients who are known when they reach menopause to have an increased risk of osteoporosis, and perhaps our patients, through many mechanisms, may be at a higher risk for osteoporosis to begin with, and that is definitely amplified at menopause. It's known that female patients, once they reach menopause, have a dramatic increase in the risk for cardiovascular problems, and sort of to parallel that, there's this concept of epileptic heart. We think that seizure medications pose a stressor on patients' hearts and the cardiovascular health for some patients—not necessarily for all—may be affected to begin with. So again, that may be compounded at perimenopause. And again, I wish there were more studies to look into this and tell us which aspects of the cardiovascular health are particularly affected.

Urogenital, sexual health is also affected. There's changes that happens with menopause, but in our patients with epilepsy, we are concerned also about the effect that seizures—and especially antiseizure medications—may have on the sexual function of our patients. I did not, in my presentation, go in detail because there were 2 other excellent speakers, but obviously, sleep and cognitive issues are also important. And again, epilepsy and antiseizure medications. So, epilepsy, through seizures and antiseizure medications can influence these aspects.

Pharmacy Times: What do you think future research in this space should address?

Voinescu: I did bring together a consortium of clinician scientists and founded a consortium called Epilepsy in the Childbearing Years Through Menopause (ECAM) and we are planning to start longitudinal database and, hopefully in the future, we will have prospectively tracked data. But until then, I think there are studies that could be done, as I mentioned, to look at clearance changes in the transition to menopause to look at how different hormonal treatments influence, not only the clearance of our medications, but also seizures. Talking about how hormones and sex steroid hormones in particular, may influence neuronal excitability, there's definitely changes with the endogenous hormonal fluctuations that are underexplored, but also with the exogenous hormonal fluctuations.

Something that I had been mentioned earlier is we do have some information that hormonal replacement therapy may increase the risk of seizures at this time point, but the question is does any method of hormonal replacement therapy influence seizure frequency? Or are there some forms of hormonal therapy that may be safe for our patients? Remember, our patients may enter menopause earlier, so they may be those that would actually benefit the most from having hormonal therapy. And one of the conundrums in clinic is, should we start these women on hormonal therapy or not, given that they are at the high risk of seizures and they may have their seizures worsened by the hormonal therapy? But in reality, it's just a couple of retrospective studies and 1 small study that looked at temporal in particular, and there are so many other hormonal treatments these days that we really don't know [if] that's true for any hormonal treatment, and I think that's really important for the life quality of our patients.

And then we were talking about comorbidities, understanding more how seizures and antiseizure medications affect those comorbidities, that all menopausal patients may be at a higher risk. That's another area of research that's not explored enough.