A first-of-its-kind non-hormonal drug to treat hot flushes has been approved in the US. Targeting connections in the brain that change during menopause, the drug, called fezolinetant, could provide relief for those who aren’t able to take hormonal replacement therapy. Madeleine Finlay speaks to endocrinologist and menopause specialist Prof Annice Mukherjee to find out what we know about the mechanism that causes hot flushes, how this new drug works, and what it might mean for those experiencing menopause in the future.. Help support our independent journalism at theguardian.com/sciencepod

You're sat on the sofa at home, watching TV, and suddenly...

A heat starts to radiate from the centre of your chest.

You begin to sweat and the heat travels up your neck.

There's sweat coming out of your scalp, the crooks of your elbows trickling down your back.

It's a hot flush, or flash, and all you can do is wait it out.

For people going through menopause, this will probably be a very familiar sensation.

And for many, hot flushes can be hugely disruptive and unpleasant.

But last week, the Food and Drug Administration in the US approved Fezolentent, a first-of-its-kind non-hormonal drug to treat hot flushes by targeting what's happening in the brain.

The drug could also be appraised by the National Institute for Health and Care Excellence in the UK by the end of this year.

It's an intriguing advance in the treatment of menopausal symptoms.

So today we're asking, what's going on in the brain to cause hot flushes?

And how much of a difference could it make?

From The Guardian, I'm Madeline Findlay and this is Science Weekly.

Before we start, in this episode we'll be using the words woman and women to refer to people experiencing menopause while acknowledging that not all people who go through menopause will identify as women and not all people who identify as women will go through the menopause.

Professor Anis Mukherjee, you're a consultant endocrinologist, you're a professor at Coventry University, you're author of the Complete Guide to the Menopause, and you've been through the menopause yourself.

So I think just to start out defining our terms, what is the menopause and how does it differ from the perimenopause?

The menopause is 1 point in time and it's defined by when your periods stop.

But because In the period before menopause, periods can become irregular.

We don't know that a woman has gone through menopause until she's not had a bleed for 12 months.

So, it's slightly messy because it's a retrospective diagnosis.

Perimenopause is a period of time of hormone fluctuation and imbalance that leads up to the time point of menopause.

And during perimenopause, because of the hormone imbalances, hormones can surge and trough, periods can become heavier or lighter, they can be very frequent and more frequent or less frequent and erratic.

So perimenopause is a very changeable state, Whereas when menopause occurs, hormones without any replacement become permanently low.

And what are some of the most common symptoms somebody might experience when they're going through the menopause?

The most classic and well-studied symptoms associated with menopause are what we call the vasomotor symptoms, which are the hot flushes, flashes, night sweats, sweating at other times in the day, which could be quite debilitating and unexpected.

So 70 to 80% of women will recognize those symptoms, even if they're not bothersome.

But for a smaller group of women, those symptoms are extremely severe.

And in addition to those symptoms, because they can disrupt sleep, because they can occur at night, and if you have a lot of sleep disturbance anyone will know that you can then be more irritable during the day.

Cognitive symptoms, better known as brain fog and other symptoms like anxiety and palpitations are really quite common in women.

So how long can the perimenopause, menopause transition and those symptoms last?

So some women will have very short term symptoms or even no symptoms at all for a lucky minority of women.

And for most women, symptoms will last somewhere between 2 and 10 years.

Average number of years in Caucasian women is about 7 years.

It tends to be longer, particularly for the vasomotor symptoms in black women.

And for some women, symptoms never settle.

Particularly the vasomotor symptoms can be very long-term or indefinite.

The average age of menopause in Caucasian women is 51.

Indian women have an earlier menopause at about 45.

Black women have an early menopause around 48 usually.

But it's very individual, so people can, you know, not follow the trends frequently.

Many of the symptoms that you've mentioned and that people experience are very obviously related to the brain.

You've got mood changes like depression and anxiety, brain fog.

For some of the others the link is less clear.

So I'm interested in understanding what do we know about what happens to the brain during the menopause?

We're mainly talking in terms of the cause of symptoms about oestrogen because oestrogen changes tends to be linked tightly with symptoms.

Oestrogen affects pretty much every cell in the body.

So if you've got changing levels, those cells haven't got a balance.

If you've 1 minute, you've got high levels, the next minute you've got low levels of estrogen.

It's quite difficult for your bodily functions to carry on as normal.

So if we talk about anxiety, mood changes, and brain fog, We know from very clever imaging studies looking at functional MRI, which is brain scanning and other types of brain study, that there are significant changes in activity within the brain during the menopause transition and actually at the beginning of the menopause transition, but we still don't really understand the whole story and we don't understand whether changes in the brain during the menopause transition may link with, you know, neurological or neurodegenerative diseases that are associated with ageing.

Certainly that's an area that needs more research and so there's a lot of interest in that at the moment.

But 1 thing that we have learned a lot about recently is how changes in the brain cause hot flushes.

A part of the brain produces a molecule called neurokinin B and this molecule is involved in the motor neuron pathways that end up in a hot flush.

In normal temperature control, if we get hot, if we overheat, our blood vessels dilate through those motor pathways, those neurons, and increase the blood circulation to the skin to allow heat release.

And the opposite happens when we're cold.

So neurokinin 3 is basically telling the brain to tell the body we're hot and release heat.

And that's what happens in these sort of vasomotor episodes.

So some women will say they feel very hot and go very red.

Some women will say they just feel heat coming through their body and some women will sweat profusely.

And for some women those symptoms alternate.

So it's actually very diverse but they're all consistent with the same central mechanism.

This takes us on to the new drug, Fezolentant.

Back in 2019 on this podcast, we reported on really interesting research by pioneering scientist Naomi Rantz, which looked at hot flushes in rats and what was happening in their brains and she noticed that activating the receptor for Neurokinin B in the hypothalamus in rats triggered hot flush-like changes.

And so then scientists started working on a drug which would do the opposite.

So perhaps you could give me a bit more insight into this and exactly what's happening in the brain.

We haven't really understood the vasomotor hot flush, hot sweat mechanism for menopause through my career certainly.

I've been around for 30 years and we've always said, look, we know that estrogen drops during menopause.

We know that FSH and LH, which are brain hormones that we can measure very easily, they go very high in menopause, but they don't seem to be the exact mechanism of the hot flushes.

And there was lots of research and speculation.

But then we started to understand this area in the brain and we call it the candy neurons, which is an area in the hypothalamus, which has neurons, which actually is the central control of reproduction.

So not just menopause, but the whole reproduction.

There's a hormone called cispeptin, there's a hormone called dynorphin, all these are neuro hormones.

And then there's this neurokinin B, which you mentioned.

It appears that it's the neurokinin B that binds to a receptor.

The receptor is called the neurokinin 3 receptor and the neurokinin B goes up during menopause.

It binds to this neurokinin 3 receptor and that appears to be the central mechanism to the vasomotor hot flushes.

And so some amazing researchers, actually my own colleagues in neuroendocrinology at Imperial College London in the UK, pioneered the work in humans on developing this drug, which is a neurokinin-3 receptor antagonist.

So it blocks that receptor that is activating the hot flush mechanism.

And then over the last few years, when the initial trials looked amazingly promising, many researchers across the world have reproduced the same findings.

And so we now have a drug and that is a specific treatment for vasomotor symptoms associated with menopause.

So it's fascinating and interesting, first of all, because it's targeting the exact vasomotor symptom mechanism, and we've never had anything like it.

And the second thing is it doesn't impact on oestrogen levels or FSH, which means that it may be suitable as a medication for many women who can't access HRT, hormone replacement therapy for menopause symptoms.

And there's lots of reasons why some women can't take it, don't want to take it, or it doesn't work, or causes side effects.

And so far from the trials that have been done, How effective does it look like it could be?

It looks as effective as HRT, hormone replacement therapy, which is oestrogen therapy, and it works more quickly than oestrogen works because it's targeting a very specific mechanism.

But it's only licensed for the hot flush flash mechanism, the vasomotor symptoms.

So that is specifically what it's targeting.

But in the research studies, it appears to be very well tolerated, very safe.

And because it's getting rid of those awful hot flushes, flashes, night sweats, it seems to be associated with better sleep, better mood, and overall better quality of life because those symptoms are resolved.

And I know that the studies have gone up to 52 weeks in the clinical trials, and so far it appears that there's no tolerance to the effects.

The dose seems to work very effectively longer term.

So in understanding the relationship between the brain and the menopause transition better, it has led to a new medication, which is, as you say, really exciting and hopefully will make a big difference to women once they have access to it.

So what do you think we do need to understand better now when it comes to the brain and the menopause transition?

What's the next thing we should really be focusing on?

I think the big concern is that women during the menopause transition frequently get cognitive symptoms, commonly known as brain fog, but various different things, forgetfulness, forgetting names.

And those symptoms generally settle down during the menopause transition.

But for a subgroup of women, those symptoms don't settle down.

And that possibly could indicate that they may be more at risk of developing other neurological diseases.

And obviously the 1 that we are always concerned about is dementia because dementia across the board and in particular Alzheimer's disease is twice as common in women than men.

And it used to be thought it was simply about the fact that women live longer, but that's not a convincing mechanism.

So I think there's lots of interest in finding out if there's something different about women's brains, particularly the ageing brain and any changes in hormones that might impact on future risk of developing dementia.

There's obviously lots still to learn and a

lot of potential for more treatments to be developed.

And 1 thing that I was struck by when I was reading about this new drug that's been approved by the FDA was that many women in the trial, you know, their hot flushes didn't completely go away, but they were really keen to keep going with the drug.

And I wonder, you know, how much of a difference new research and new treatments could play in women's lives?

If it's lessening symptoms to a significant degree, it's going to help at home, it's going to help in the workplace, it's going to help with all the care roles that women have today.

The more support and help women can access to smooth that transition because the menopause transition can be very destabilizing and men don't go through it.

The more treatment we have available and the better women feel and the less impact menopause symptoms have, the better.

Professor Anis Mukherjee, thank you so much.

This episode was produced by me, Madeline Finlay, and Silas Gray.

And the executive producer is Ellie Burey.


Speaker 0: This is The Guardian. You're sat on the sofa at home, watching TV, and suddenly... A heat starts to radiate from the centre of your chest. You begin to sweat and the heat travels up your neck. You go red.

There's sweat coming out of your scalp, the crooks of your elbows trickling down your back. It's a hot flush, or flash, and all you can do is wait it out. For people going through menopause, this will probably be a very familiar sensation. And for many, hot flushes can be hugely disruptive and unpleasant. But last week, the Food and Drug Administration in the US approved Fezolentent, a first-of-its-kind non-hormonal drug to treat hot flushes by targeting what's happening in the brain.

The drug could also be appraised by the National Institute for Health and Care Excellence in the UK by the end of this year. It's an intriguing advance in the treatment of menopausal symptoms. So today we're asking, what's going on in the brain to cause hot flushes? How does this new medication work? And how much of a difference could it make?

From The Guardian, I'm Madeline Findlay and this is Science Weekly. Before we start, in this episode we'll be using the words woman and women to refer to people experiencing menopause while acknowledging that not all people who go through menopause will identify as women and not all people who identify as women will go through the menopause. Professor Anis Mukherjee, you're a consultant endocrinologist, you're a professor at Coventry University, you're author of the Complete Guide to the Menopause, and you've been through the menopause yourself. So I think just to start out defining our terms, what is the menopause and how does it differ from the perimenopause?

Speaker 1: The menopause is 1 point in time and it's defined by when your periods stop. But because In the period before menopause, periods can become irregular. We don't know that a woman has gone through menopause until she's not had a bleed for 12 months. So, it's slightly messy because it's a retrospective diagnosis. Perimenopause is a period of time of hormone fluctuation and imbalance that leads up to the time point of menopause.

And during perimenopause, because of the hormone imbalances, hormones can surge and trough, periods can become heavier or lighter, they can be very frequent and more frequent or less frequent and erratic. So perimenopause is a very changeable state, Whereas when menopause occurs, hormones without any replacement become permanently low.

Speaker 0: And what are some of the most common symptoms somebody might experience when they're going through the menopause?

Speaker 1: The most classic and well-studied symptoms associated with menopause are what we call the vasomotor symptoms, which are the hot flushes, flashes, night sweats, sweating at other times in the day, which could be quite debilitating and unexpected. So 70 to 80% of women will recognize those symptoms, even if they're not bothersome. But for a smaller group of women, those symptoms are extremely severe. And in addition to those symptoms, because they can disrupt sleep, because they can occur at night, and if you have a lot of sleep disturbance anyone will know that you can then be more irritable during the day. Cognitive symptoms, better known as brain fog and other symptoms like anxiety and palpitations are really quite common in women.

Speaker 0: So how long can the perimenopause, menopause transition and those symptoms last?

Speaker 1: Again, it's very, very individual. So some women will have very short term symptoms or even no symptoms at all for a lucky minority of women. And for most women, symptoms will last somewhere between 2 and 10 years. Average number of years in Caucasian women is about 7 years. It tends to be longer, particularly for the vasomotor symptoms in black women.

And for some women, symptoms never settle. Particularly the vasomotor symptoms can be very long-term or indefinite. The average age of menopause in Caucasian women is 51. Indian women have an earlier menopause at about 45. Black women have an early menopause around 48 usually.

But it's very individual, so people can, you know, not follow the trends frequently. Not follow the trends frequently.

Speaker 0: Many of the symptoms that you've mentioned and that people experience are very obviously related to the brain. You've got mood changes like depression and anxiety, brain fog. For some of the others the link is less clear. So I'm interested in understanding what do we know about what happens to the brain during the menopause?

Speaker 1: We're mainly talking in terms of the cause of symptoms about oestrogen because oestrogen changes tends to be linked tightly with symptoms. Oestrogen affects pretty much every cell in the body. So if you've got changing levels, those cells haven't got a balance. They don't know what's going on. If you've 1 minute, you've got high levels, the next minute you've got low levels of estrogen.

It's quite difficult for your bodily functions to carry on as normal. So if we talk about anxiety, mood changes, and brain fog, We know from very clever imaging studies looking at functional MRI, which is brain scanning and other types of brain study, that there are significant changes in activity within the brain during the menopause transition and actually at the beginning of the menopause transition, but we still don't really understand the whole story and we don't understand whether changes in the brain during the menopause transition may link with, you know, neurological or neurodegenerative diseases that are associated with ageing. Certainly that's an area that needs more research and so there's a lot of interest in that at the moment.

Speaker 0: But 1 thing that we have learned a lot about recently is how changes in the brain cause hot flushes. A part of the brain produces a molecule called neurokinin B and this molecule is involved in the motor neuron pathways that end up in a hot flush. So how does this all work?

Speaker 1: In normal temperature control, if we get hot, if we overheat, our blood vessels dilate through those motor pathways, those neurons, and increase the blood circulation to the skin to allow heat release. And the opposite happens when we're cold. So neurokinin 3 is basically telling the brain to tell the body we're hot and release heat. And that's what happens in these sort of vasomotor episodes. And women experience them differently.

So some women will say they feel very hot and go very red. Some women will say they just feel heat coming through their body and some women will sweat profusely. And for some women those symptoms alternate. So it's actually very diverse but they're all consistent with the same central mechanism.

Speaker 0: This takes us on to the new drug, Fezolentant. Back in 2019 on this podcast, we reported on really interesting research by pioneering scientist Naomi Rantz, which looked at hot flushes in rats and what was happening in their brains and she noticed that activating the receptor for Neurokinin B in the hypothalamus in rats triggered hot flush-like changes. And so then scientists started working on a drug which would do the opposite. So perhaps you could give me a bit more insight into this and exactly what's happening in the brain.

Speaker 1: We haven't really understood the vasomotor hot flush, hot sweat mechanism for menopause through my career certainly. I've been around for 30 years and we've always said, look, we know that estrogen drops during menopause. We know that FSH and LH, which are brain hormones that we can measure very easily, they go very high in menopause, but they don't seem to be the exact mechanism of the hot flushes. So we just didn't know what caused them. And there was lots of research and speculation.

But then we started to understand this area in the brain and we call it the candy neurons, which is an area in the hypothalamus, which has neurons, which actually is the central control of reproduction. So not just menopause, but the whole reproduction. There's a hormone called cispeptin, there's a hormone called dynorphin, all these are neuro hormones. And then there's this neurokinin B, which you mentioned. It appears that it's the neurokinin B that binds to a receptor.

The receptor is called the neurokinin 3 receptor and the neurokinin B goes up during menopause. It binds to this neurokinin 3 receptor and that appears to be the central mechanism to the vasomotor hot flushes. And so some amazing researchers, actually my own colleagues in neuroendocrinology at Imperial College London in the UK, pioneered the work in humans on developing this drug, which is a neurokinin-3 receptor antagonist. So it blocks that receptor that is activating the hot flush mechanism. And then over the last few years, when the initial trials looked amazingly promising, many researchers across the world have reproduced the same findings.

And so we now have a drug and that is a specific treatment for vasomotor symptoms associated with menopause. And it's a first-in-class medication. So it's fascinating and interesting, first of all, because it's targeting the exact vasomotor symptom mechanism, and we've never had anything like it. And the second thing is it doesn't impact on oestrogen levels or FSH, which means that it may be suitable as a medication for many women who can't access HRT, hormone replacement therapy for menopause symptoms. And there's lots of reasons why some women can't take it, don't want to take it, or it doesn't work, or causes side effects.

So it's great to have options.

Speaker 0: And so far from the trials that have been done, How effective does it look like it could be?

Speaker 1: It's incredibly effective. It looks as effective as HRT, hormone replacement therapy, which is oestrogen therapy, and it works more quickly than oestrogen works because it's targeting a very specific mechanism. But it's only licensed for the hot flush flash mechanism, the vasomotor symptoms. So that is specifically what it's targeting. But in the research studies, it appears to be very well tolerated, very safe.

And because it's getting rid of those awful hot flushes, flashes, night sweats, it seems to be associated with better sleep, better mood, and overall better quality of life because those symptoms are resolved. And I know that the studies have gone up to 52 weeks in the clinical trials, and so far it appears that there's no tolerance to the effects. The dose seems to work very effectively longer term.

Speaker 0: So in understanding the relationship between the brain and the menopause transition better, it has led to a new medication, which is, as you say, really exciting and hopefully will make a big difference to women once they have access to it. So what do you think we do need to understand better now when it comes to the brain and the menopause transition? What's the next thing we should really be focusing on?

Speaker 1: I think the big concern is that women during the menopause transition frequently get cognitive symptoms, commonly known as brain fog, but various different things, forgetfulness, forgetting names. And those symptoms generally settle down during the menopause transition. But for a subgroup of women, those symptoms don't settle down. And that possibly could indicate that they may be more at risk of developing other neurological diseases. And obviously the 1 that we are always concerned about is dementia because dementia across the board and in particular Alzheimer's disease is twice as common in women than men.

And it used to be thought it was simply about the fact that women live longer, but that's not a convincing mechanism. So I think there's lots of interest in finding out if there's something different about women's brains, particularly the ageing brain and any changes in hormones that might impact on future risk of developing dementia. There's obviously lots still to learn and a

Speaker 0: lot of potential for more treatments to be developed. And 1 thing that I was struck by when I was reading about this new drug that's been approved by the FDA was that many women in the trial, you know, their hot flushes didn't completely go away, but they were really keen to keep going with the drug. And I wonder, you know, how much of a difference new research and new treatments could play in women's lives?

Speaker 1: If it's lessening symptoms to a significant degree, it's going to help at home, it's going to help in the workplace, it's going to help with all the care roles that women have today. The more support and help women can access to smooth that transition because the menopause transition can be very destabilizing and men don't go through it. The more treatment we have available and the better women feel and the less impact menopause symptoms have, the better.

Speaker 0: Professor Anis Mukherjee, thank you so much.

Speaker 1: Thank you for having me.

Speaker 0: Thanks again to Anis Mukherjee. This episode was produced by me, Madeline Finlay, and Silas Gray. The sound design was by Tony Onuchukwu. And the executive producer is Ellie Burey. We'll be back on Tuesday.

See you then. This is The Guardian.

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Menopause: could a new brain-based treatment cure hot flushes?