16-07-2025
S2 Episode 1: Caught Off Guard? Menopause in MS Deserves Better
This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.
Anne H. Cross, MD: Hello. I am Dr Anne Cross. Welcome to Medscape's InDiscussion series on multiple sclerosis. Today we'll be discussing menopause in women with multiple sclerosis (MS). I'd like to introduce my distinguished guest, Dr Riley Bove. Dr Bove is an associate professor of neurology at the University of California in San Francisco, and she's a practicing neurologist at the UCSF Multiple Sclerosis and Neuroinflammation Center.
Dr Bove's research focuses on digital health, sex and gender differences in MS, and improving access to neurologic care. And, important for today's discussion, she is a menopause expert in MS patients and the treatment of that. Welcome, Dr Bove.
Riley Bove, MD: Thanks for having me on. I'm excited to talk about this with you, Dr Cross.
Cross: Yes, me too. I'm going to dive in and ask you to tell us, how does a woman with MS know that she is in menopause, and what is menopause?
Bove: We define menopause as that final menstrual period beyond which there are no menses for at least a year. And if a woman has not had her period for a year, she looks backward, we say she's postmenopausal. That final menstrual period was the date of her spontaneous menopause. And as we know, in the years leading up to that final menstrual period, there can be changes in the menses.
They can become more frequent and then peter out. There are also marked hormonal changes. Estrogen levels can increase, decrease, or fluctuate widely before they decrease. There can be a range of symptomatology. And when we talk about menopause, often we're talking about perimenopause — those last years before the final menstrual period and those first years in the postmenopausal stage.
To answer your specific question about how a woman knows that she's going into menopause: In general, looking at the menstrual patterns, looking at symptoms, perhaps starting to have hot flashes or night sweats, starting to experience changes that may be a little bit more amorphous in terms of changes in sleep patterns, changes in mood, maybe feeling more depressed, anxious, or irritable.
Having some bladder function changes as well. And then a whole host of cognitive symptoms. Those might be some of the symptoms that a woman starts experiencing as she's moving into perimenopause. And, of course, to our listeners who are experts in MS, those are often the invisible symptoms of MS.
It can be overlapping and confusing to patients sometimes.
Cross: Do women with MS go through menopause at any different age, or does it last longer or shorter than women who don't have MS?
Bove: Yes. In terms of the timing and duration, it seems to be quite similar. The menopausal transition, the physiologic experience of it, really varies widely according to different cultures in terms of different nutritional exposures and lifespan exposures, but in Western societies, the median age of spontaneous menopause is 51, 51 and a half.
And that's the median age of spontaneous menopause in our women with MS. Some may have gone through it earlier because of some of the medications that we used to use more often — cyclophosphamide, mitoxantrone. But it seems to be within range.
Cross: Okay. One question that many of us who take care of women with MS have is what to do, what to advise them on, about hormonal therapy around menopause to treat their symptoms. I would love to hear your insights — what you do with your patients in terms of hormonal therapy.
Bove: There are three buckets of questions. The first is generally, when we're thinking about hormonal therapy, are the risks in a woman with MS different from those in the general population? And there may be a few risks that are different in the sense that someone is at higher risk for blood clots because they're not ambulatory.
But typically, for most of our patients who are perimenopausal today, the risks don't seem to be different from those in the general population. So, then, if we think about the use of hormone replacement therapy (HRT), let's define that for a second. We're talking typically about estrogen, either estradiol or the conjugated equine estrogen, Premarin. And then in women who have an intact uterus, we need to add on progesterone or a progesterone-containing IUD to protect the endometrial lining from the estrogen's extra stimulation. When we talk about HRT, we're talking about systemic, given either by pill or transdermally — distinguishing that from more topical estrogen that's given to women who have vaginal atrophy or dryness.
So when we talk about systemic hormone, typically estrogen, replacement therapy, we're thinking about it for two things. The first is for the management of the perimenopause.
There are data from The North American Menopause Society, which is leading our guidance here, which say that during the peri stage, HRT is probably the best treatment for hot flashes. It's associated with downstream effects, with improved sleep function and quality of life.
People who experience a lot of joint pain during perimenopause — people have pains in their hips, their shoulders, and other joints — also report some relief there. And for management of hot flashes and other perimenopausal symptoms, HRT is considered to be very effective.
For most of my patients, if there are no general contraindications and no specific MS contraindications, by all means, get your symptoms treated. When we talk about systemic hormone therapy, we're also asking, is it protective, associated with wellness in the postmenopausal lifespan?
And that's where our ears perk up because we're thinking about neuroprotection, maintaining brain health. The bottom line is, we don't have enough data yet. We don't have enough interventional trials. I know things are underway, but we don't have data today that tell us for sure whether it's neuroprotective.
What we do know is that use of hormone therapy is associated with decreased all-cause mortality, decrease in all cancers, decreased heart disease, decreased diabetes, hyperlipidemia, etc. And we know that all of those things, heart wellness, these general categories of wellness, are also associated with brain wellness.
Certainly, through the effects on all these intermediary factors, we expect that the HRT would also do good things for the brain. But we also need to see whether it does specific things for the brain, and that's where we need a bit more data.
Cross: That's exciting, and I hope that we find that estrogens are neuroprotective and get some more guidance on that. But meanwhile, do you have a favorite regimen? Which estrogens do you tend to recommend?
Bove: Yes, there's a couple things. So the first guidance, of course, is that for every person, the risks and benefits need to be personalized, individualized. Side note: Not every woman can get systemic estrogens — people who have breast cancer, clotting risk, things like that.
And for those people, there are other treatments for hot flashes. There is fezolinetant (Veozah), which was FDA approved a few years ago. And it works well against hot flashes. And then there are also SSRIs, SNRIs, gabapentin. So people who can't take HRT can still get a lot of relief during the menopausal transition. We shouldn't abandon them.
But in terms of formulation, again, it's going to be somewhat individual. Today, typically people are preferring transdermal estradiol, transdermal estrogen, and then either oral progesterone or a progesterone-containing IUD. That seems to be the go-to.
There are wonderful online classes for clinicians to get up to speed on this because we have a whole generation of clinicians who were not trained, who were taught to avoid HRT. The Women's Health Initiative shut down the conversation.
And a lot of clinicians can absolutely go online for a couple of hours and get some good CME.
I typically see that transdermal estrogen is the preferred route.
Cross: Okay, great. Is there any benefit to using the natural remedies that my patients come in and tell me about — soybeans and black cohosh tea, and things like that?
Bove: I don't know. I have a hard time interpreting the data. As we know, the quality of data, the lack of interventional, randomized trials, makes it a lot harder to interpret risks and benefits.
I talk about, does it impact your wellness? Do you feel better on it? In which case, feeling good is going to have a lot of downstream positive effects. I don't know enough to truly weigh in on that.
Cross: Okay. And with our population of patients with MS, are there any special symptoms that go along with menopause that we should be on the lookout for that maybe don't occur in the average person without MS?
Bove: There are a couple of guidelines and first principles that I try to talk about when we're thinking about our patients. The first thing is, we cannot be surprised that menopause happens to women. It happens to every woman, right? Every woman who gets to her sixties is going to go through menopause. And we have to move from being like, oh, what's that? to, how am I going to actively manage my patient, anticipate change, and guide her through this?
A follow-up to that is that I start talking around age 45 to women and say, "Listen, you may not reach this for 10 years, 12 years, or it may have happened or may be happening soon, but to put it on your radar, you may be moving toward perimenopause, and do not be surprised when it hits you." Because often, from a quality-of-life standpoint, my patients are cruising along. We get them on these beautiful therapies, we get them on B-cell-depleting therapies that you helped pioneer. We get them on other medications and they're stable, and then they hit peri, and it's like they've fallen off a quality-of-life cliff, and they're worried that they're progressing. They're having a lot of symptomatic exacerbations, and warning them ahead of time is point number one. And then telling them, "Hey, if you get there, it's going to be very hard for you to parse out what's MS and what's menopause — what's the overlap? What's the intersection? And that's not your job. Come and tell me about what you're experiencing and we'll work through it."
And the second point is, anticipatory guidance starting at age 45, and then when they start having symptoms, see them more frequently — every 3 months — to make sure that these things happen.
Maybe that's not my lane, and I know it's not my lane, but I want to make sure that she got that follow-up with the other physician. And then in terms of what women experience, the hot flashes that happen to many people, we know about Uhthoff's phenomenon. We know that our patients, when they're warm, their nerves don't conduct as well and they have quiescence of their symptoms. It's transient. That's what they're experiencing when they're having their hot flashes, and they tell us that the tingling is worse, right? I think that they're experiencing Uhthoff's phenomenon many times a day and night, and that's not good. So even though it may be "vasomotor symptoms," they should be treated to prevent the impact on their MS.
The other thing I hear a lot from my women with MS during the peri is that they're worried that now they're getting Alzheimer's because they're experiencing cognitive changes, and we know that the menopausal transition is associated with cognitive changes. People have cognitive fog, they have word-finding difficulties — the word is on the tip of the tongue.
They have what we call a senior moment, where you walk into the room and you don't know why you're there. And there's also this experience of feeling overloaded, when you have multiple stimuli and you can't direct your attention, sustain your attention, sustain a train of thought.
Those are all cognitive things that our patients tell us all the time in general with MS and perimenopausal women report as well. And that exacerbation of cognition, whether it's hormone-mediated changes in the brain or a hot flash, or the fact that they didn't sleep last night, that can be particularly distressing to our patients with MS.
Pulling apart all the triggers that we can, giving reassurance and guidance, testing, and cognitive strategies can be particularly informative for them.
Cross: Is there any role for estrogen or hormonal therapy for blocking that cognitive decline?
Bove: Certainly with Rhonda Voskuhl's leadership, and you've been heavily involved here, it'll be interesting to see whether there is a role that we have to look in the estrogen pathways, and we also have to look in other pathways.
There are other mechanisms of resilience, like the Klotho (KL) gene, which may be an avenue of promoting resilience. Women also make testosterone, of course, right?
Many of us may not have learned that in medical school: The ovaries make testosterone, and with the loss of ovaries, including with surgical menopause, we lose a lot of testosterone, and the role of testosterone in cognitive performance in women is also understudied. So there are a lot of potential avenues where we can do that.
But from a day-to-day, what do we have? What tools do we have now? Managing people's sleep, promoting their sleep, addressing depression, and quieting down the hot flashes can help cognition a lot.
Cross: You led in that direction and I'm aware that you've done a recent study, that maybe has been completed, of bazedoxifene and menopause. Would you tell us about that and what you're hoping to see in your data?
Bove: I'm experiencing a bit of a drum-roll moment. Bazedoxifene, or BZA, is a SERM, a selective estrogen receptor modulator. And as you know, tamoxifen is a SERM that's commonly used in breast cancer because it antagonizes the effects of estrogen and breast tissue. Many other SERMs either agonize or antagonize the effects of estrogen in different body tissues. So, ideally, if we're thinking about a neuroprotective agent, we want something that ramps up the beneficial effects of estrogen in the brain without ramping up the deleterious effects of estrogen in the breast and uterus.
And hopefully it also can do some good things for bone and for cardiovascular health. We want to get the roses without the thorns, the benefits of estrogen without the risks. The rationale for testing BZA is that SERMs come up strongly in different screens for remyelinating agents, and we tested BZA specifically. It showed good effects in preclinical animal models of demyelination, remyelination. Of course, many things have not made the translational jump to human beings, and certainly when we're trying to promote myelin repair, we want to be able to boost the effects of the oligodendrocyte precursor cells (OPCs) and wrap new myelin around axons. But we need axons that are healthy enough to do the signaling that tells the OPCs that they want myelin. In running this clinical trial — it's a clinical trial of bazedoxifene in perimenopausal women — we wanted to target this demographic. We know our patients are at risk for disability progression, axonal loss postmenopausally. We also don't know for sure whether those axons entering the perimenopausal period are robust enough after demyelination to do their part in signaling and to promote myelin repair.
So we'll see. It's an exciting approach. Many women with MS — we know that about two thirds of all people who develop MS are premenopausal women — many people could stand to benefit at some point, but we have to see.
Cross: My fingers and toes are crossed for you on this. I hope, and for our patients, that this is going to prove to be a good study. What endpoints are you using to determine whether BZA is working?
Bove: When we did our trial, we were interested in reproducing a lot of the same trial design as the clemastine trial that was done also at UCSF because there are few positive trials in myelin repair and we wanted to keep some things consistent for interpretability across the trials.
We're using a delayed-start study design. We were initially looking at chronic optic neuropathy. We screened out many patients for chronic optic neuropathy; you need to have had injury in your optic pathways — not too much, but some. A lot of patients either didn't have any or had too much.
And we've shifted to a myelin water fraction in the brain on neuroimaging as our primary outcome. That allowed us to recruit a lot more women and do the study more quickly.
Cross: When can we expect to see the results?
Bove: Hopefully, we'll get something together by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting.
Cross: Oh, that would be fantastic. Again, we're hoping that this is a positive trial. All of us are cheering for this. What's your next step after this trial?
Bove: Great question. Along the lines of, we shouldn't be surprised anymore that women go through menopause and that this is a time where they need us, stepping up as their clinicians and focusing on these comprehensive care packages, and trying to disseminate that perspective — that approach is an important step for me.
Drilling down on some of the cognitive changes that people experience, how we tease apart the different things that are going on is another next step. And, of course, if our phase 2 trial shows a positive signal, an encouraging signal, then I would want to move that forward because, if anything else, bazedoxifene is great for women's bones. And we know that postmenopausally, our patients get osteopenia and osteoporosis, if anything else, let alone the potential effects on neuroprotection. So those are some of the arenas that I'm interested in, and then trying to dial in on mechanisms. We know there's much chronological aging, biological aging, aging in different systems; how do we tease apart all of that from the specific effects of hormones on brain aging?
Cross: I have enjoyed talking with you today, Dr Bove, and you are a great doctor. If I had MS, I would want to be your patient. I'm impressed with your work and all that you've done to help women with MS in particular. Thank you very much for joining us today.
I'm looking forward to hearing you speak at the next meeting. And I'm very much looking forward — and I'm sure the whole group of MS patients and doctors who take care of them are looking forward — to the results of your study. We are keeping our fingers crossed for you and for everyone. Great work. Keep it up. Thank you so much for joining us.
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Resources
Hormonal Therapies in Multiple Sclerosis: A Review of Clinical Data
The 2022 Hormone Therapy Position Statement of The North American Menopause Society
Age-Specific Effects of Hormone Therapy Use on Overall Mortality and Ischemic Heart Disease Mortality Among Women in the California Teachers Study
Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT
Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial
Effects of Menopause in Women With Multiple Sclerosis: An Evidence-Based Review
Uhthoff's Phenomenon in Multiple Sclerosis and Neuromyelitis Optica
Molecular Basis of Klotho: From Gene to Function in Aging
Re-WRAP (Remyelination for Women at Risk of Axonal Loss and Progression): A Phase II Randomized Placebo-Controlled Delayed-Start Trial of Bazedoxifene for Myelin Repair in Multiple Sclerosis
Clemastine Fumarate as a Remyelinating Therapy for Multiple Sclerosis (ReBUILD): A Randomised, Controlled, Double-Blind, Crossover Trial
