People with epilepsy may experience changes in their seizure patterns at times of hormonal fluctuation; for example, epilepsy in some individuals either develops or subsides during puberty. However, the connection between hormones and seizures is not well understood. This relationship is particularly challenging to understand in women, whose hormone levels change according to their menstrual cycles and during pregnancy. Seizures associated with a women’s menstrual cycle are referred to as “catamenial seizures.”

This webinar discusses how epilepsy and anti-seizure medications can affect hormones and reproductive health, how sex steroid hormones can affect anti-seizure medications and seizure control, and how the menopausal transition can affect epilepsy. Viewers will also learn about potential treatment options for catamenial epilepsy.

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About the Speaker
Page B. Pennell, MD is Professor of Neurology at Harvard Medical School, Vice-Chair of Academic Affairs in the Department of Neurology, and Director of Research for the Division of Epilepsy at Brigham and Women’s Hospital, with a secondary appointment in the Division of Women’s Health. She is a clinician investigator with a focus on sex-specific outcomes in epilepsy. Dr. Pennell’s current clinical studies focus on the effects of hormones on seizure provocation, pharmacokinetic changes of AEDs with exogenous hormones or differing reproductive phases, and maternal and fetal outcomes during pregnancy in women with epilepsy.

Q&A with Dr. Page B. Pennell

Here’s a question regrading a rare epilepsy. This person has noted clustering. The question is about PCH 19, and the person has noted clustering with menstrual period being a trigger for seizures. What’s the best treatment for stopping the period to keep the hormones from triggering the seizures in somebody like this?

Dr. Pennell: I actually had a slide about that and took it out. That is a very specific syndrome that is predominantly in females, and is very much related to this topic. There are some treatments that are currently in investigation and actually Dr. Lubbers, you might know more about the most recent, but really acts on that allopregnanolone basis. There’s a synthetic allopregnanolone called Ganaxolone. So there was a treatment trial specifically for this. Then also allopregnanolone, it’s only in infusion is a problem. But that’s being used in post-partum depression, so that hopefully will also get to the point that it can be used directly and developed as not just an infusion. But do you know the latest on the trial results?

That’s a great question. I know that it’s still under study for some specific rare diseases, including tuberous sclerosis. I don’t think the results have been reported yet, but that’s a great thing to pay attention to, as those trials are progressing, and thinking about it in the context of not just general seizure control, but seizure control in women. Great point. Here’s a question for you. Are there any known interactions between hormone changes and epilepsy devices, such as the vago-neural stimulator?

Dr. Pennell: Yes. There’s no known interactions between that. There have been not so much publications, but some investigators have looked to make sure that it has no effect on the reproductive axis hormones. Now in addition to VNS, of course we have RNS now. I guess technically, it’s a good question. If it’s in an area that’s going to cause a change in firing to the hypothalamus maybe. But I don’t know that any studies yet. That gives us another great idea to try to get funding, and just to make sure, maybe in those people who have it in an area that’s likely to cause hormonal change to look at the effect. But nothing reported to my knowledge.

How does elevated testosterone in polycystic ovary syndrome figure into the progesterone/estrogen balance? And particularly, the influence of Estradiol on seizure activity?

Dr. Pennell: Polycystic ovarian syndrome can potentially increase seizure frequency by first of all having more anovulatory cycles. Going back in the slides, I don’t know if you remember, but a C3 pattern, when you have anovulation, you don’t get the rise in progesterone, so you can have increased seizures because of that. Then as mentioned, it also causes hyper-androgynism, and testosterone levels. Back in the slide, I don’t know if I can go back, there is a metabolite, of testosterone, DH, which is an androgen, DHEAS. Which can be excitatory. Those are two ways it could contribute potentially to increased seizures. DHEA sulfate is actually from, you can see here’s the androgen and testosterone. Those don’t directly have an effect on seizures. They do have an effect on the brain, but not on seizures that we know of. But also, the androgen can maybe decrease the DHEA sulfate, which could increase seizures.

Does supplementing progesterone have an impact on the elevated testosterone?

Dr. Pennell: Not that I know of. Supplementing progesterone, yes. Not that I know of. Good question though.

Why do you prescribe progesterone lozenges for the C1 group rather than birth control?

Dr. Pennell: The lozenges that were used in the study are actually pretty high dose compared to the progesterone you would get in any of the birth control options. But more importantly, in the birth control options are synthetic progestins. They’re not quite this progesterone. The synthetic progestins do not metabolize to allopregnanolone. You really need natural progesterone and it is not easily taken as a pill, and actually gotten into the blood system through GI absorption. There’s two ways to give it, which is a lozenge, which it gets through the mucosa into the bloodstream. Or as an actually vaginal suppository. There is a micronized progesterone that can be taken as something you swallow, so that is another option.

Can medication become less effective post-menopause?

Dr. Pennell: So post-menopause, often seizures get better, and the medications are still effective. It is possible to have some seizure worsening during the menopause transition. It can actually take quite a while. It can be anywhere from two years to seven years. I have worked with our gynecology specialists on suppressing that erratic hormone phase through other hormones to try to stabilize that. In rare instances, we’ve even gone to suppression of the hormone axis with things that are such as used in in vitro fertilization techniques to completely shut down the hypothalamus, pituitary, ovarian axis. But again, I only do that in concert with reproductive endocrinology specialists.

We have a listener who makes the point that there’s still too many doctors who dismiss the issue in women. And I agree. Do you have any advice? Actually now we have these transcripts, and people can take transcripts of these recordings to their doctor. But what would you advise somebody who’s faced with a situation like that?

Dr. Pennell: It’s unfortunate. I certainly got into women’s health issues and epilepsy because of a lot of the stigma that was there, that is actually often present in women’s health across all disorders, but especially epilepsy. We just didn’t have information, scientific data to be able to discuss it and that also pertains to a lot about pregnancy issues. I think the best way is still to bring information to them with some of the studies that show that a third of women with epilepsy have this pattern, and there are considerations as far as different strategies that could be added on to the primary strategy for controlling seizures that can be a benefit.

If the doctor or PA or nurse practitioner doesn’t listen then, then find a new doctor. I know it’s not that easy. There’s a lot of areas in the country there are not enough neurologists, never mind epileptologists. But certainly, I’ve had patients move to other areas of the country where they didn’t have the same resources, and that they brought the information to the doctor and it was really actually very, very effective.

Does Epidiolex, or CBD, have positive or negative effects on catamenial seizures? Or do we know?

Dr. Pennell: I don’t know. It’s also a good question. I do know that Epidiolex has a lot of interactions. The first question I would have is how does it affect these pathways? I haven’t seen anything with it yet. But obviously it’s still not as commonly used in women of reproductive age as some of the other populations. So I don’t have any information yet.

If you are thinking about getting pregnant, what is the safest way to get off of a medication? For example, Trokendi RX, or XR, beforehand.

Dr. Pennell: The question is really, really important. We know that 50% of pregnancies are unplanned, and then we have that extra in the United States, and then we have that extra problem we talked about, about interactions and causing lower efficacy of some birth control options. The best thing to do is yeah, if you can plan the pregnancy, and to speak with your neurologist hopefully about how to get onto the safest medication regimens. We have several medications which are very safe during pregnancy. It really should be the exception to stay on a medicine that’s not as safe, because you’ve already tried the other medications and they don’t work for your epilepsy.

Topiramate is one that is in the middle, where it does have some increased risk, especially for small progestational aged births, or low birth weight, and a slightly increased risk of cleft lip and cleft palette. But it’s also not one of the most dangerous ones. If the other medications were tried, and they weren’t effective, certainly it would be possible to move ahead with a pregnancy on it. But as far as how to switch over, that is so individualized according to seizure types, seizure frequency, background, what’s been tried, side effects, so many things that it’s not one size fits all, but hopefully it’s a good partnership with your neurologist to get to that point.

Have you heard of seizures destabilizing in males as it they go through puberty? Does aromatization of testosterone to estrogen play any role?

Dr. Pennell: I did mention how some seizures begin around puberty. I should’ve mentioned that there are certain epilepsy types that the seizures get better as someone moves through puberty, or even goes away. The obvious is childhood absence epilepsy, or benign rolandic epilepsy. But I don’t know, yeah, if it’s been studied beyond that. Actually at the end, we were talking about the menopause transition and how we need more studies on it. But likewise, the pubertal transition is another thing that definitely is understudied.

As a woman with epilepsy who’s hoping to become pregnant, how can I find out about research studies I might be able to qualify for when I do become pregnant?

Dr. Pennell: There’s a few ways. There’s our pregnancy registries, which have provided such incredibly helpful information to know a lot more about the risk versus benefits of many different medications, medication combinations. In North America, there’s the North American AED pregnancy registry, which can be found pretty easily through the website. I encourage everyone to enroll in. It’s only a few phone calls, it doesn’t take much time. Likewise, there’s international ones such as EURAP. Then for other studies that are very active, you can look under ClinicalTrials.gov has a listing and search by epilepsy, and that gives information about trials that are ongoing. We have a very large study going on across the country, in case anyone also participate in that. It’s called MONEAD, Maternal Outcomes and Neurodevelopmental Effects of Anti-Epileptic Drugs. It’s 20 sites across the country.

But we are fortunately in the latter stages of it, because so many people volunteered time, and for their families. We’re not enrolling new families at this time, but believe me, we are always looking for funding to continue the quest to get all the answers. Likewise, there could be something new that’s happening at that time. You could also check with your local Epilepsy Foundation Chapter. But again, if there’s any study that involves humans, we have to actually register on ClinicalTrials.gov. That’s always a good place to look. Then you might have something through CURE Epilepsy, Dr. Lubbers, as a resource?

We would also guide people to ClinicalTrials.gov. It’s the biggest resource, most accessible, for the most current studies. How frequent do women with epilepsy develop preeclampsia? Will preeclampsia worsen the woman’s epilepsy?

Dr. Pennell: I know it’s frustrating to get mixed messages. But there were some studies that suggested that preeclampsia was more likely to occur in women with epilepsy, and those were studies that looked at hospital records, which is coding. They’re not as pure. Because whatever is coded for insurance reasons. It’s not very specific. In the MONEAD study that I just mentioned, we actually had a primary aim of looking at obstetric complications, and there were actually no increased rates of preeclampsia, eclampsia, in women with epilepsy versus the general population.

But obviously, women with epilepsy could still develop preeclampsia. It doesn’t seem to make her underlying seizures worse. But of course, if she goes on to eclampsia, she can develop seizures because of the other vascular effects of eclampsia. It doesn’t seem to be an increased risk in women with epilepsy.

Can repeat seizures lead to loss of libido in women of childbearing age?

Dr. Pennell: We think that’s possible, as we mentioned, the medications can cause decreased libido, depression can, and the treatments for depression can. A lot of the medications that are used for depression can also cause decreased libido. It’s multifactorial. We did want to look at this really specifically in WEPOD, that study I mentioned where we had women track their sexual intercourse according to their menstrual cycle and their medications, but we had a collaborator who’s an OB-GYN, and she was so helpful to remind us of these basic things that we don’t think about as neurologists, which is that once a person is trying to get pregnant, sexual intercourse has very little to do with libido. Its primary goal is very different. She did not feel that we could use our diary data to address libido whatsoever.

There is some nice work by Martha Morell to go back and look at, that does show some interactions with types of epilepsy and also medications. But untangling all those things, such as frequency of seizures, isn’t completely clear. But I think it probably is linked to frequency of seizures to some degree.

This person mentions the start of seizures that included tonic-clonic and absence seizures starting around 12 years of age. Depakote and Onfi has been offered as the best seizure control so far, and it seems like growth has slowed drastically. This brings in another hormonal paradigm, with a delay in menarche at about 16, at almost 16. Can medications or the seizures be responsible? I think particularly around the growth issue? And what would be good treatments for people to keep in mind?

Dr. Pennell: Around the growth, I’m not sure. First of all, I should say I’m an adult epileptologist. That’s where a lot of my hesitation is. Because although I’ll see someone who’s 16 because they have a hormonal problem or a concern, hormonal concern, or they become pregnant, I don’t practice during that earlier phase. Now, that valproate in particular has actually also been shown to cause lower androgens and lower sperm count in men with epilepsy. She said it could be affecting other hormones. You’ll have to ask a pediatric epileptologist.

Is there an over-the-counter way to check progesterone and estrogen levels for somebody who might want to track what’s happening with their cycles?

Dr. Pennell: Not over the counter for progesterone. But what you can do, is very effective, is do LH test kits. Luteinizing hormone is the hormone that’s released right before ovulation, and it causes the egg to be released. Then after the egg is released, then the corpus luteum stays behind and that releases progesterone. You can use LH test kits. They’re most commonly used for fertility, when someone’s trying to get pregnant, to see if they’re ovulating. You can actually get batches of them cheaper, such as through Amazon or some other source, if you are going to be doing it on a regular basis. It’ll tell you where to being. Usually around day 10, you do a urine sample every day. Then it’ll tell you if you’re having the LH surge. It is very accurate, as to whether a person’s ovulating or not.

Although it won’t give you the progesterone level if you’re not ovulating, it means the progesterone level’s low. The other thing we do in research settings are check day 21 progesterone level, because if they’re ovulating, that’s where the progesterone should be at the level we want. Then sometimes I’ll do it before starting the progesterone lozenge treatment. Then after I start progesterone lozenges, I check it again, and I want to make sure it gets above 20 nanograms per milliliter. If you’re going to check it, check it at day 21. Or if you want to see it over several cycles, if there’s ovulation occurring, then you can use the LH test kits.

Learn More

Seizing Life® Episode #20 – What to Expect When You’re Expecting … as a Woman with Epilepsy featuring Caroline McAteer

In this episode of Seizing Life, mother Caroline McAteer speaks to her experience bringing her daughter Nora into the world. Caroline discusses how she approached the topic of pregnancy with her husband, her epileptologist, and her OB-GYN, as well as how she managed her epilepsy and medication changes throughout the process to reduce the risk of having seizures while pregnant.

The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified health care professionals who are familiar with individual medical conditions and needs. CURE Epilepsy strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified health care professionals who are familiar with the individual’s specific health situation.