Why Women’s Sleep Is Different – XXplored Podcast

Voiceover:

Welcome to "XXplored: Women's Brain Health", a Dementia Researcher podcast exploring the many factors that shape women's brain health across the lifespan.

Dr Laura Stankeviciute:

Welcome back to "XXplored: Women's Brain Health. And today we're going to be talking all things sleep and how it is unique for women's brain health. Sleep is perhaps one of my favourite things to do, my favourite things to talk about, and also my favourite things to work on. And I'm extremely lucky to have been able to dedicate my career to studying sleep and how it changes across the lifespan. So, we know that sleep is universal. Everyone does need to sleep. And probably also a lot of people nowadays have their own opinion about sleep from sleep regimens to what sleep aids one should get to what is the best at bedtime routine. We know that sleep is different between men and women. Women report greater sleep need, more fragmented sleep, and also poor sleep quality.

Interestingly though, what we see when we objectively measure sleep, it's actually not the same story. And this is what we call in science the subjective versus objective sleep paradox, which we'll also talk about in this podcast. So today, we are very, very happy to be recording this podcast with Professor Christian Benedict and Dr Alana Brown, where we're going to be teasing apart all things sleep and talking about it from different angles and shining the light why sleep is a truly trans diagnostic feature, where it stretches from mood disorders, cardiovascular conditions, and where sleep is a major risk factor for Alzheimer's disease. Welcome both.

Professor Christian Benedict:

Thank you for having me.

Dr Alana Brown:

Thank you.

How our guests came to sleep research

Dr Laura Stankeviciute:

Alana, you were a doctoral fellow at the Rotman Research Institute Baycrest Academy for Research and Education, where your work examines sex differences and sex-specific trajectories of brain ageing. And you're particularly looking at sleep and cognition. Can you briefly describe how you get into this field of research and what actually keeps you awake at night or maybe motivates you to wake up every morning to do what you do?

Dr Alana Brown:

Yeah, well, I started my PhD at the University of Toronto studying the potential effects of ovarian removal, surgical ovarian removal on the brain in terms of structure, function, as well as on sleep quality. And I think I was really just surprised by the lack of women-specific research in the field of neuroscience and sort of the underrepresentation of women more broadly. So, that's what keeps me going and keeps me studying sex and gender in terms of brain health and brain ageing trajectories.

Dr Laura Stankeviciute:

Thank you so much. I feel like we both kind of went into, through the similar questions that really spurred our own research. And now, I'd like to give the space to introduce Christian Benedict. I mean he probably doesn't need an introduction, but still for some of those people who may not have come across your research or your social media activity on sleep, can you give us a brief run through what do you do?

Professor Christian Benedict:

Yes, the reason why I ended up in sleep was I think, yeah, more of a coincidence than a plan that I had from scratch because when I studied at the university, I had to of course finish my school with a little research project. And then, I joined a department at the University of Lübeck, which is in Northern Germany. And I did it really well apparently because they offered me a PhD position. And the host of this department was Jan Born and Jan Born is a quite well known sleep researcher, has conducted multiple studies into why we sleep and why this is so important for memory and for many other bodily functions. And I actually performed doctoral studies on the effects of intranasal insulin on memory functions in humans.

But I was so inspired by Jan's activity around sleep that I really try to push this and to convince him involving me in all these studies. And that is now over 20 years ago and I'm still into this. So, here I am.

Sleep architecture: what happens across the night

Dr Laura Stankeviciute:

Thank you so much. So, let's start with some basics and let's cover the ground for those listeners who are not as familiar to sleep as both of you are, so everyone who's listening can actually be on the same page. So Christian, could you actually walk us through with broad strokes on how actually sleep architecture looks like at night and why each stage of that sleep architecture is important?

Professor Christian Benedict:

So to keep a complicated story simple, right, I just start with, I start off with, you know, two major sleep stages that we often discriminate in sleep science and always in sleep medicine. On the one hand, we have the so-called non-rapid eye movement sleep stage, which can be further divided into light sleep and deep sleep or light and deep non-rapid eye movement sleep stage. And then, we have on the other hand rapid eye movement sleep. And of course, often people have like this tendency to focus on particular sleep stages because they think this is the most decisive sleep aspect that matters for health. But to be honest, if you just study sleep, you see that we circle, that we go through all these different sleep stages and sleep cycles.

That on its own shows demonstrates that sleep must fulfil important functions, but it is also a necessity that all these various sleep stages, you know, work together like a football team, right, to score the goal or to defend the goal. And yeah, we have these sleep stages, non-rapid eye movement sleep and rapid eye movement sleep. And like I said, we have sleep cycles and in the beginning of the night, we have very long non-rapid eye movement sleep stages. Whereas later in the night, we have longer episodes of rapid eye movement sleep stage. That's why we often also name the first night half as night half predominated by non-rapid eye movement sleep, especially deep sleep. There are estimations that you have about 90% of your deep non-rapid eye movement sleep within the first two, three hours after sleep onset.

Whereas later in the night, you have predominantly REM sleep. And you know, we know this from the past pandemic that many people started to report about, oh, I have so many dreams and I never had that many dreams before. And I mean one of the reasons may be that they really went into this late sleep stage which is so dense when it's in REM sleep.

Why REM sleep matters for women’s brain health

Dr Laura Stankeviciute:

Thank you. I would actually like to follow on that later stage of sleep that is predominating in the second part of the night, which is REM. And I think now in the general public, a lot of people are aware of the importance of slow wave sleep, especially given that our wearable devices have taught a lot about this necessity to get that deep sleep, that cleansing restorative sleep. But now, I'd like to talk about the importance of REM sleep. It's probably an oversimplification if we call REM sleep as a state where only dreams are happening, which is also not entirely true because sleep dreaming can also happen throughout other stages of sleep. But Alana, can you actually explain what is REM sleep, what is happening during REM sleep beyond dreaming, and why it is specifically important for women's health?

Dr Alana Brown:

Yeah, so REM sleep is the sleep stage as Christian mentioned, characterised by rapid eye movements, of course, heightened brain activity, vivid dreaming, and also temporary muscle paralysis. And REM sleep is thought to be really important for also supporting memory consolidation and emotional processing. So, it has roles to play similar to non-REM sleep. There's also a lot of kind of emerging evidence that older women actually tend to show longer time taken to get to REM sleep. So, longer REM sleep latency compared to age-matched men. So, it takes them longer to enter into REM sleep. And this might be important because of that prolonged latency might be a marker of sleep fragmentation or sleep disorders like obstructive sleep apnea. And in the realm of Alzheimer's disease research, this kind of REM timing might be really important.

There's some work suggesting that prolonged time to get into REM is associated with higher build-up of these proteins that might be pathological in the context of Alzheimer's disease, like amyloid-beta and phosphorylated-Tau, suggesting this might actually reflect very early neurodegenerative processes. So, I think overall in women particularly having increased REM latency with older age might represent a perhaps sensitive marker of early brain vulnerability. Although that's kind of a new domain of research that needs a bit more attention. It's something really interesting to continue thinking about.

How much sleep do we actually need?

Dr Laura Stankeviciute:

Thank you, Alana, for running us through what is REM and definitely we are giving too little credit for it. And I love the new wave of research talking about the potential early biomarker, which is also more specific to females and this is what we are seeing across different sleep features in fact. But now, I'd like to zoom out and give a question to Christian that I'm constantly being asked that I'm sure he is also constantly being asked at dinner parties, family gatherings, podcasts, conferences. It's all about the sleep timing, right? So, what is the perfect amount of hours that I need to get in order to feel refreshed?

Professor Christian Benedict:

You know, sleep is of course multidimensional. It's not as simple as oh, as long as I spend seven to nine hours in bed and hopefully fill this in-bed time with a lot of sleep, then I'm on the right side of the spectrum, on the healthy side. Of course, sleep is or consists of different components. You have mentioned already the timing. The timing plays of course a role, because we are very much active when it is bright outside and we rest and sleep when it is dark outside, right? And we know from night shift working populations that they have huge struggle to get proper sleep during daytime. Daytime sleep is not as good as nighttime sleep because your endocrine axes are active. Your body temperature's too high.

So, all the prerequisites that you require so that the plant sleep can unfold in the best possible way are not at place during daytime. And then, we often of course speak about sleep quality. And especially when it comes to sleep quality, we speak about having very consolidated sleep that we spend certain times in different sleep stages that they follow a certain structure. But there is of course also the subjective component and you set this initially and that's something that still is under investigation. We know that many people, for instance, have rather a negative impression when it comes to their sleep. But if they undergo a sleep study, then you can see that there is some kind of mismatch, right? There are these conditions, such as paradoxical insomnia.

And you do the sleep study and you just say you know the numbers, the figures look fine but they say "No, but my sleep is a disaster," yes. And this kind of mismatch shows you it's not only what we, as of now, can objectively measure, but it is of course always a strong subjective component that contributes to it. And then, an emerging concept that is more and more, yeah, emphasising the literature of course is also sleep regularity. We have to have consistent times. Go to bed at the same time. Leave the bed at the same time. Do this day in, day out and that is like an health promoting activity in the long run. 'Cause there are even data to suggest this is more decisive than be recommended seven to nine hours of sleep for adults, yes.

But you know, I mean there are many components that you have to consider but we don't want to over complicate it. 'Cause if you go out to the public and say, "You have to consider this. You have to take care of this," then the story gets too complicated and people will not say, "Oh, thank you very much for this fantastic advice, but I'm so overwhelmed I'm just stressed about this. This is such a distrustful information." And that's why I think organisations, such as the American Academy of Sleep Medicine keep things simple and say, "Make sure that you have consistent sleep times and make sure that you sleep about seven to nine hours and it will likely help you to have a long life with a lot of health," right?

Do women need more sleep than men?

Dr Laura Stankeviciute:

Yeah, well, I suppose that there is no like one specific hour and minute recommendation for every person and even more so what we are seeing is that women actually tend to sleep longer or do they actually need to sleep longer. So, Alana can tell us a little bit more about the difference in the sleep need between men and women.

Dr Alana Brown:

Yeah, so I think there's quite a bit of suggestion that females need to sleep a bit longer given the sort of change in sleep quality that tends to be reported, for example across the menopause transition, where we see this sort of up in the number of insomnia cases for example in women compared to men. And just generally poor sleep quality reported across that transition, which isn't always aligning as you mentioned with those objective patterns of sleep. So we see women having greater total sleep time, spending more time in non-REM stage 3, the deepest sleep stage. Some of the work I've done even shows women who've had their ovaries removed have higher sort of magnitude of power in that deep delta sleep wave, which is important for memory consolidation.

Which is all sort of leading up to this idea that despite the greater presence of these very seemingly positive memory promoting sleep factors, women are still reporting that their self kind of perceived sleep is not very, very good. So that all suggests that they need more sleep and that there might be other factors at place. So something I've often thought about is maybe other sociocultural factors, like maybe spending eight hours sleeping is not enough to make up for women's increased likelihood to have to be a caretaker or you know, frequent awakenings associated with childcare, caring for a parent in older age. So, kind of having that sort of biological and social perspective as well I think is really important in the context of sleep.

Professor Christian Benedict:

Can I add something to this? Yeah because you know, because I think, I mean I have even a wife and I have a daughter and I have a lot of women around me and one thing that I really notice is that women have definitely a different health awareness compared to men. I mean just think about a woman's life, how often they consult a gynaecologist or a physician because it's just expected. Because you have to do this, you have to have all these scheduled consultations. Ask men when have you been the last time meeting your GP? I think most say yeah maybe three, four decades ago or so. So if you have more awareness of health and factors that may influence health, you may also worry more about it. And I can tell you there are studies to suggest if you look into the objective sleep, often women do not sleep worse than men.

They rather sleep better even at older age. But if it comes to the expression, okay, how do I perceive my sleep, there's a huge gender gap and women of course complain far more than men. And I think it has also something to do about, you know, you can't worry about things that you're aware of, that you pay attention to. Maybe we men are just too naive. (all laughing).

Women’s sleep across the menstrual cycle

Dr Laura Stankeviciute:

Thank you so much for extrapolating what Alana said. And I do think that we still are not entirely sure why women complain of sleep difficulties more than men. But the objective and subjective paradox is definitely there and especially when it comes to higher ages, this increased slow wave sleep, which could potentially be a compensatory mechanism but still the science is yet to uncover the answers. And even though like I wanted to start with very, very basics, I think we went straight into the deepness of sleep and its complexities, which really shows that sleep doesn't really work in isolation. It's biology. It's psychosocial factors. And in females, we even have another additive factor. Apart from sleep, we have a different cycle that changes every month for females, which is the menstrual cycle.

And obviously, that leads to different sleep experiences for women across this different phases of sleep. So Alana, can you walk us through what is happening to women's sleep across four main stages of the menstrual cycle?

Dr Alana Brown:

Yeah, so there do seem to be some important sleep quality changes across the menstrual cycle. During that menstrual phase or menses, during that bleeding period when oestrogens and progesterone levels are at their lowest, sleep might be more disrupted in some women due to symptoms related to their menstrual cycle like pain, cramps, headaches, mood changes, that type of thing. Although sleep architecture itself might be relatively stable during that period. While in the follicular phase when oestrogens start to rise and progesterone remains relatively low, this is generally associated again with more stable restorative sleep, higher sleep efficiency, fewer disturbances. Then during the ovulatory phase when oestrogens peak and progesterone is also rising, sleep changes are again usually modest.

So, nothing too characteristic happening during that phase. Although some individuals might notice slight shifts in like their alertness for example during the daytime or maybe even sleep timing. But it's really during the luteal phase when progesterone and oestrogens are elevated, this is most commonly linked to poor sleep, I think, across the board with more awakenings, reduce sleep efficiency, more daytime sleepiness, some subjective sleep quality. Although this isn't consistently found across the literature, but something I would say more consistent than some of the other phases in terms of changes in sleep quality. And then, we also see some changes in that sleep micro architecture. So just like these events kind of composing that macro architecture of sleep, such as increased sleep spindles during that luteal phase as well.

So sleep spindles, these like quick bursts of brain activity that might be, that are really important for memory consolidation and stabilising memory into long-term storage. And we do see a bit of an increase in spindle activity that that might be associated with progesterone. But there's yes, lots going on during the luteal phase that I think is really interesting.

Professor Christian Benedict:

Hey, I published some, yeah last year, a review about PMDD and sleep, right? And of course, my student worked really hard to look into the existing literature. I mean one thing that you really see, what often people don't try to tease apart is, you know, like you already mentioned all these premenstrual symptoms, PMS right? A lot of things, body symptom, bodily symptoms that you can have that coincide with this kind of phase. And then, people see rather inconsistent findings when it comes to sleep because if you, for instance, think about progesterone, I just want to say naming a progesterone. Progesterone is converted in your brain to a neurosteroid called allopregnanolone, which acts on the GABA system and actually should contribute returnability to right, to calm down and also to sleep better.

And I know also, I have also some relatives that have told me this that have been menopause when they use progesterone, they sleep far better compared to when they don't use progesterone, right. So, I'm in no way, Alana, saying that what you said is not right. I'm just saying it's a very complicated story, right? And you cannot, if you go into the literature, just say it is as crystal clear as many people believe. If they go into social media and say yeah, and if you're on the luteal phase, then you see there's a disaster and so on, yes.

Dr Alana Brown:

Yeah, exactly.

Professor Christian Benedict:

A lot of compounding factors.

Dr Laura Stankeviciute:

Yes, for sure.

Insomnia, PMS and PMDD

Dr Laura Stankeviciute:

I think there's a lot of conversation about doing things according to your cycle and trying to optimise your lifestyle, your behaviour, your sleep habits, your eating habits. Everything should be cycle syncing, cycle phase dependent. So, I feel like a lot of women who actually experience those sleep disturbances may be very lost because the experts that claim to be the experts are not truly aware of the mechanism behind. And we have just talked about it, but what could you recommend, given that we know that a lot of women are experiencing those issues, how can they manage their insomnia symptoms, especially those with PMDD or very severe PMS symptoms. Christian, do you have any tips on that?

Professor Christian Benedict:

I mean, one interesting part when it comes for instance to PMDD, right, premenstrual dysphoric disorder, one of it's not, it doesn't belong to the core, but it belongs to the cluster of symptoms that they often may suffer from either insomnia or hypersomnia. But if you look into the literature and check, but are there any studies where they looked into what happens if I improve sleep, for instance, through cognitive behavioural therapy for insomnia or any other measures. Of course, you can also use pharmacotherapy to improve sleep. There's not that much. Yeah, so that is not really on the agenda what can, what kind of measures are available to improve the condition. Of course, many people just say, you know, yeah but the sleep problem is secondary to the main condition, and that's it. But I mean there is a very nice analogy.

Think about depression. Many people say sleep problems, such as insomnia, are cardinal symptoms of depression. So, this is like in chicken egg scenario and you cannot really disentangle what comes first. But then, there are studies where they look into, okay, what happens if a woman with major depressive disorder undergo cognitive behavioural therapy for insomnia. You see, you improve their insomnia and that is a nice side effect, a positive one. You also improve their depression, yes. And of course when it comes to these kind of conditions such as PMDD, which is of course restricted to the luteal phase, we have to be crystal clear. It's, you know, it's intermittent, it's not like that it is throughout the cycle. It's just a specific, but of course it's interesting to think about can we do something? Are there behavioural measures?

Are there pharmacological measures to uses? And they use of course things such as SSRIs. They use also, yeah, hormonal contraceptives to avoid like fluctuations in these sex hormones and these ovarian hormones that Alana mentioned. There are various things that you can do, but it's extremely interesting to think of sleep should be part of the intervention and not just, you know, some kind of stuff that happens in the background. And we hope that there will be some kind of positive spillover effect. Maybe this is the key to improve many, many of the conditions.

Hormonal contraception, HRT and sleep in the menopause

Dr Laura Stankeviciute:

I really like how you frame it because I do feel like for the past, I don't know, decades or so, sleep has really been framed as a lifestyle factor, but it's not really a lifestyle factor. It's a physiological need. We cannot just go without sleep for days. We can choose maybe, you know, to go and socialise to knit, or read, or do certain type of activities that are considered lifestyle, but sleep should definitely be stroked out of the section of lifestyle. It is a physiological necessity. And you have already mentioned, Christian, about the hormones and the hormonal contraception. So we have been talking before about the endogenous hormones, like progesterone and oestrogen, how it has an effect on sleep quality and sleep features throughout.

But do we have any evidence pointing towards what is happening when females are taking hormonal contraception and whether their sleep is improved or whether it's changed in a different way. Christian.

Professor Christian Benedict:

I mean, you know, I can tell you that I even give lectures to layman people and menopause is often a topic that they raise, right? When we have this Q&A afterwards and then, you know, "I'm in the 50s," or "I'm in this phase of my life and I have a lot of sleep struggles." And then, they often ask, you know, "Could something like replacing hormones, hormone replacement therapy help me?" And one thing that is often raised as an issue for a woman that are in this phase of their life is, yeah, you know, if you, for instance, lack sufficient ooestradiol in your circulation in your brain, you may experience things, such as the so-called vasomotor symptoms, right? You may, you have heard about this, these hot flushes, night sweats.

And they of course very much coincide also with sleep and make sleep a very problematic condition, right, because it may keep you awake. And we know if we for instance treat people then with HRT, you can ease many of these symptoms, especially if it contains oestradiol because it acts on the hypothalamus to influence body temperature regulation. But the problem is, and now we think about a timeline, you start off with this kind of hormonal transition, this new episode of your life, and everyone is just saying to you, "This is part of your life." You know, it's your second puberty just, you know, just accept it. And then, you do this and you have all these kind of symptoms such as these vasomotor symptoms and you start to relearn sleep. You learn sleep as a mission that is doomed to fail because night after night you don't make it.

Then at some point, you are so frustrated and you go to your gynaecologist or someone else and ask for help and they say "Okay, let's try now an HRT." Then they start an HRT and out of the, you know, and immediately because we know this, you know, all these vasomotor symptoms are no longer as frequent, but you still have sleep struggles. Why this? Because you have them over a prolonged period exposed to a situation where you learned I fail with a mission sleep and this has established this kind of pattern. And that's why there it is very much needed that you undergo, for instance, through cognitive behavioural therapy for insomnia to relearn sleeping, right? Relearn. I can succeed with the mission sleep.

And that's why HRT in these people that have had a past history, have a history of failing with sleep, even if you treat them with HRT, they do not readily improve their sleep. Maybe the vasomotor symptoms improve, but the psychological concept of sleep is no longer at place. So, you see it's far more complicated, right, than just saying, "Ah, there's one easy-peasy thing like HRT and everything will be fine," Or other medications such as a elinzanetant. So that help your eyes to specifically and exclusively touch with these vasomotor symptoms. Often people say, "Yeah, but my sleep is not getting better." Yeah, because you have learned sleep and the wrong way, yes, and you have to relearn it.

Why insomnia in women is diagnosed differently

Dr Laura Stankeviciute:

Love how you framed it actually that sleep is not just biology, obviously that's a huge part. But then, it's kind of a skill, a learning thing that we develop throughout our lifespan. And obviously when the disruptions due to the hormones, due to the biology come into place, we need to adapt. We need to unlearn or relearn these new skills. And I would like to segue to another part of the episode where I really want to talk about the differences that we observe also in biology, but more so in specific sleep conditions such as insomnia, restless legs syndrome, and obstructive sleep apnea, because all of them express very significant sex differences. And I would like to start with insomnia. Obviously, it's the most common sleep related disorder globally.

And again, it strikes me that it is threefold more prevalent in females starting from puberty, which kind of points to again the hormonal milieu being involved. But what else is actually important when we are talking about insomnia in females is probably the subjective part that you've already touched a little bit upon, but can you expand a little bit on that right now, Christian?

Professor Christian Benedict:

I mean, you know, the first thing that I want to mention that is extremely important when it comes to insomnia. Insomnia because sometimes this is, you know, like circulating in social media, insomnia is not the same thing like sleep loss, right? If you go to the diagnostic criteria, I'm pretty sure Alana agrees with me, you know, is that this is like a perceived difficulty with falling asleep, staying asleep, or premature awakening and it has an impact on your daytime functioning. But the diagnostic criteria are very crystal clear about it, it's subjective. You don't need a sleep study and PSG to look into this. But you may need it to, you know, make sure maybe there's like an underlying or another underlying condition that is falsely interpreted as I suffer from insomnia, right?

I mean there are conditions, such as obstructive sleep apnea that can result in that I feel I wake up not refresh, yes, or that I have a lot of awakenings throughout the night. And that can of course lead to, if I'm not aware of this condition that I think oh you know, there's something about my sleep and maybe I'm one of many that suffer, actually 16% globally that may suffer from insomnia. It's difficult because there are a lot of factors that can play into this. Yes, you have the psychological construct that we discussed, right? That you learn on wrong terms how to fail with sleep, right, and not to succeed with sleep.

But there are of course other conditions that can also exacerbate this condition and yeah, lead to this kind of perception, there's something wrong about my sleep such as obstructive sleep apnea, such as restless legs syndrome that you already mentioned. Conditions that are also prevalent among women. And you see that's another problem. And then, I stop because we want to be concrete and focused, but if you think about obstructed sleep apnea, I mean you have this either full or partial cessation of breathing, this recurrent episodes during sleep. The issue is in men, it often expresses in a very different way compared to women. You know, men snore loudly. They have these clear witnessed, often if they have spouses, witnessed apnea. And women, they have more these kind of breathing issues in the silence unseen.

And they wake up and think, "What happens with me? I'm not really getting the best sleep. I have headaches." They've always different daytime symptoms. And they may run to the GP and ask for help and they just say, you know, "It's your stressful life. It's the menopausal transition. It's your second puberty." But maybe it's also obstructive sleep apnea, right? And they are not just, they are not, the physicians don't have this on the screen. So, there are many conditions that can contribute to it. And this is an, you know, a further example highlighting how complicated it is with sleep. And it's not as simple as going to social media and searching for one silver bullet that will solve all sleep problems. And that there are considerable differences between men and women when it comes to how sleep problems also phenotypically express. Amen.

Sleep apnea in women: the missed diagnosis

Dr Laura Stankeviciute:

I like that you brought the phenotypical expression because indeed historically OSA has been claimed to be a disorder of men only because as you explained very well, females do not present with this textbook symptoms that men do have. But what is also very interesting that in the past years, we have seen more literature coming out suggesting that actually after menopause, women's prevalence increases and kind of matches the same ratio between men and and female after this biological transition. So Alana, I would love to bring you on this point now, could you explain what is the biology telling us why females are having higher incidents and prevalence of obstructive sleep apnea episodes during night?

Dr Alana Brown:

Yeah, I think biologically, sex hormones have a big role to play here. So oestrogens and progesterone appear to support, for example, upper airway stability and ventilatory control. Progesterone, in particular, can increase respiratory drive. So during reproductive years, women have some maybe more physiological protection, whereas after menopause, when oestrogens and progesterone levels are declining, that protection might be reduced. And then, we see that kind of clear increase in obstructive sleep apnea prevalence, which is helping to explain why that sex gap might be narrowing substantially in the postmenopausal population. And I think really just sort of adding on to what's already been said, that sex differences could be related yes to the hormones. It could be related to these like social diagnostic factors.

And I think reflects a combination of that hormonal protection in midlife potentially declining as well as under recognition of those more I guess non-classic or less than textbook examples of what's been said about sleep apnea historically and the basis of those symptoms being on male models and the experiences of men.

Restless legs syndrome and brain iron

Dr Laura Stankeviciute:

Yeah, I do think a lot of older narratives should be rewritten about obstructive sleep apnea. But I do think it's something that is being now talked more and more. Whereas restless legs syndrome, it's something that is still not at the same stage in, at least in the public eye. So, I would like to bring some light to this and Christian could you actually explain what does it even mean? Because it sounds a little bit weird as a disease but it's something that is actually affecting a lot of women, and it is apparently unbearable for them to sleep and have a quality rest.

Professor Christian Benedict:

Yeah, so you have this... By the way, very happy that your doc, right, agrees.

Dr Laura Stankeviciute:

Yeah.

Professor Christian Benedict:

On what we said.

Dr Laura Stankeviciute:

Yes.

Professor Christian Benedict:

Yes. Yep, yeah, she's on board. But anyhow, yes, yes. So you know, restless legs I mean you have these urge or drive, right, to move your limbs, your legs, your arms even be your arms, not only your legs. And this kind of urgency of unfortunately very much coincides with the night and we are supposed to sleep throughout the night, right? And if you have many awakenings because you just have the impression, I really have to move my legs. I have to move myself because that can relieve the symptoms, right? That, is of course, not very sleep promoting. And one of the underlying pathomechanisms, right, mechanisms that are contributing to this condition is that possibly people that suffer from RLS, which is more prevalent among women, have a brain iron deficiency. Why is iron so important?

I mean iron, you should not have too much iron in your brain by the way. It's not good. It has been associated with dementia such as Alzheimer's. But of course, you know, biology always thinks there's a window that is acceptable when it comes to the concentration. And iron plays very important role, a very important role for the production of a neurotransmitter in your brain called dopamine, yes. And dopamine is so important not only for reward but also for movement control. And it is also very much involved in dopamine release. So if you have this iron deficiency right in your brain, you may then have also the or that may also these kind of symptoms that you have this kind of, you feel this urgency to move your legs, right, or limbs.

And often, what they do when some patient present with these conditions is that they look into the circulating iron, your blood iron status, right, ferritin, transferrin to see okay, is this too low, so we should supplement this. We should actually supplement this more than in people that just suffer from anaemia to make really show sure that iron also goes up in the brain. But, and for some it helps to relieve the symptoms over time, but some are not responsive. And then, there are other medications that you can use. Often and for quite a while, they have used dopamine agonists, right? But the problem is if you use dopamine agonists, which you know, the aim is to increase dopamine signalling in your brain, in the beginning, it can relieve the symptoms of RLS. But as you continue with the treatment, it can result in augmentation, right?

Like the system, the brain is the dopamine system is responding to it and you get like an augmentation of your RLS symptoms. That's why nowadays also the American Academy of Sleep Medicine clearly says in their guidelines, you know, if you have this, don't use dopamine agonist rather use things such as gabapentin, which is an anti-epileptic and which has been shown to ease these symptoms. Yet of course, it's always like in trade off when you also because you have to consider also side effects. But I'm just saying, you know, it's soft course condition, a sleep movement disorder that is present, that affects many people sleep, many women sleep, but that is not at all like made a topic, right? It's just, you know, you just have to focus a little bit on sleep, or it's your second puberty, or just do a little bit stress management, yes.

It's more than this. You know, sleep is complicated. Sleep is multidimensional and movements for during sleep. Sleep movement disorders, such as RLS, can definitely make it quite difficult to, yeah, make sure that you've got a regular good night's sleep.

Do sleep supplements work? Melatonin, magnesium and valerian

Dr Laura Stankeviciute:

Thank you so much for explaining this condition and also the ways to deal and manage it clinically and pharmacologically. And obviously, we do have a lot of these conditions that need professional interventions, but we also know that there are a lot of things that are available over the counter. And I think with social media, that sometimes can really help to raise awareness. Sometimes, it can also trick people into starting and trying things that are not necessarily good for them. So we now, as we enter every pharmacy, every Boots store or even at the airports next to the books, we can see different sleep aids from melatonin gummies to magnesium to L-theanine. And women actually taking them in heaps without actually having recommendation from their doctors.

So which of these sleep aids actually have data and science that is backing them and what are the recommended doses? If we can tap into this Alana, that would be great.

Dr Alana Brown:

Yeah, I think when we look at some of the most commonly used sleep supplements, the evidence is a bit mixed or uneven perhaps. I think melatonin has some of the strongest evidence, but it's not a sedative. It's a sort of circadian signal that tells the brain it's biological night and helps align sleep timing. So, it's tends to work best for that circadian misalignment, maybe in cases of of jet lag or shift work, kind of different timing for sleep rather than in the case of chronic insomnia. Though it certainly works for some. I think for most people, lower doses like 0.5 to three milligrams, are usually sufficient. Higher doses might not improve sleep quality. It's kind of not a dose dependent response, I suppose, and may actually cause more like grogginess for example the next day. I think there's some other supplements.

like magnesium has some modest evidence mainly in older adults I would say. Also, valerian has been studied for decades, used for decades with some meta-analysis suggesting small improvements in subjective sleep quality. But again, results are a bit inconsistent overall, especially because these, as you mentioned, preparations vary quite widely. So there's, you know, like dried root powders or like more liquid extracts. There's all sorts of different types and different concentrations, which can probably add to people's confusion as well about what's best different formulations. I think that there's no, in my opinion, real supplement with this kind of like first line robust evidence for chronic insomnia treatment across the board. The strongest effects I think are pretty modest and condition specific.

And I think in combination with perhaps behavioural treatments like we mentioned earlier, cognitive behavioural therapy for insomnia, they might be most in most effective. I think, yeah, considering all of that is, it's difficult for any consumer I suppose to think about what's best for them, but there's also a lot of person specific results. So if something works for you, I think that's really important to kind of acknowledge that it's going to be on a case by case basis. Something that's a personal choice. But I, yeah, I know Christian has other- I would actually, I would like to also- Has to say.

Dr Laura Stankeviciute:

Pick Christian's brain for that And specifically on the woman's angle there, because I do know that at least back in the day, most of the drugs and supplements have been really tested in men but not in women. And recently, we have seen that obviously the dosage has to be changed and revised for women for some sleep medication. So, is it also the case with supplements? What can you tell us about that, Christian?

Professor Christian Benedict:

I mean first of all, I would like to say that everything that Alana said was very good and I think what she said in the very end is extremely important because you know, we have been throughout the years so much into oh we should find something that works for everyone. But now we are back to we should find something that works for you, Laura, and that works for Alana, and that works for Christian because it has to be more personalised. And we see even that certain medications or supplements can kind of have a different effect on you. And I mean you're absolutely right if we think about metabolism, right? Also track metabolism for instance. We know that this can, the liver can very much influenced by conditions such as or treatments such as hormone contraceptives.

I mean there are many women that say, "Oh, you know, caffeine, caffeinated beverages," I'm coming back to your supplements, don't worry. They say, "They are very much affecting my sleep and I'm so sensitive to it." But we know for instance, from some early studies, I think in the '80s that caffeine, caffeine, I should say oestradiol can influence the half-life of caffeine. And that is, of course, something that you should wholly take into consideration if you use hormone contraceptives, right, or hormone replacement therapy because that can prolong your half-life of caffeine. And that can then spill over into your nocturnal window where you, that you would like to fill with sleep. But coming back to the supplements, I mean I'm sometimes, maybe I'm not so scientific, I'm a little bit more pragmatic, yes, because people ask me about this.

I mean even if I know that let's say magnesium will not make that much of a difference yet I have reviewed the paper, it looks like there may be some benefit but not extreme, yes. If someone says, you know, "I always use a little bit magnesium and it helps me," maybe it's just part of the psychological construct to prepare sleep. If this is not really like a dangerous thing or interacts with other or interferes with other kind of treatments, I just say, "I don't care, go on with it." Right? Because placebo is a very important thing, yes. And I mean we know this, the dose makes the poison and if this is, you know, I'm not so concerned and I'm not desperately searching for evidence to make the case. But of course, we have to be critically minded.

And if these are supplements or yeah, non-prescribed things that people should buy for a huge amount of money, then we have to critically evaluate this. Or if there are big claims around one thing, like oh, if you purchase a weighted blanket, it will solve all your sleep problems that exist. We all know that's not true, right? Or if you take a magnesium, there will no longer be any sleep problems. It's not true. But if some people perceive, oh that helps me or if I drink some tea or so, just go ahead and do it right. I will never change your winning routine. We have also to somehow respect their own kind of constructs and routines that help them to fall asleep. And we don't have to impose things.

But of course if they reach out to us to understand, okay, what can I do better or I have some suspicions that this may not be good for me, then we could of course offer them evidence-based, science-based guidance, yes. But we should always try to find an overlap, of course, a good overlap between what science says but also what life teaches us, right?

Creatine, sleep loss and cognition

Dr Laura Stankeviciute:

I think this is a very important point, thinking about the person, the patient in front of us, not just the evidence that we read in the literature because these are all the averages, the meta-analysis over kind of the mean. But we know that for instance, if for someone the valerian tea before going to sleep is something that they have been doing for 25 years and they sleep better, maybe that's their bedtime routine. That's the ritual that that really helps that restorative sleep to kick in. And before we close, I actually really want to talk about one last supplement because it's really boomed in the past years, which I'm sure you all know about. You've heard about it. You probably have tried it. I certainly have, especially in the preparation for my half marathons. It's creatine.

It has been known to be very effective for sports performance. It is probably one of the most studied supplements together with magnesium, as Alana said. But now, I think what is interesting in the context of sleep is that there is some evidence, I'm not sure, they're like scientific, or anecdotal, or very preliminary studies suggesting that creatine can actually revert the sleep deprivation effects on the brain and cognition. And interestingly, there is some evidence suggesting that it can also help improve cognition in Alzheimer's disease. This is a big disclaimer. I'm not definitely saying that this is the all-round supplement, but a lot of people are asking about it and I want the expert's opinion on that. So Christian, you have been laughing throughout my definitions of creatine. So, please do bust some myths if there's some to do.

Professor Christian Benedict:

I don't really know whether I dare, you know, saying anything about it because I know about all the crazy minds that really promote this and say, you know, "He has no clue." And of course, you know, I'm in no way saying that creatine is not like very useful in the sport context, right? No doubt. But I mean I'm aware of these studies, right? There are some studies in animals. There are even some studies in humans. Small studies where they have looked into whether you can mitigate some of the, let's say, cognitive effects of sleep loss such as vigilance, right? Due to the supplementation of creatine prior to the nocturnal, right? That you're awake and you cannot sleep. And they have seen indeed some benefits. But please look also when you go into these papers into the size of how they can compensate for the effects of sleep loss.

And I mean there are special tests that they have, a task that they have administered. Are these memory or cognitive tasks representative for everything that you have to cope with in your daily life when you experience either short term, but also long term sleep problems? I doubt that. And I know, you know, of course I know how media and social media, you know, how they work. And I am aware of studies where they have also shown, you know, you should just be physically active, then sleep loss is no longer as relevant for your metabolic health or for cancer, whatever, yes. And I agree of course, you know, the health equation consists of many variables and they all have a certain slope, either positive or negative. And sleep is part of many equations.

And of course, I agree also when you work on other parameters that they may can partially compensate, right? But I'm very hesitant to believe that this is applicable to whatever you consider as a health outcome. I don't believe this. Still, I think it's interesting to think of are there measures also in the short term that help me to cope with this. I'm not trivialising this. It's of course interesting about, you think about people working night shifts, a cab driver, someone working in healthcare, a police officer, firefighters. Could they get any benefits from supplementing this prior to the night shift? And will this help them to restore at least some or to compensate for some of the expected sleep loss related deficits, let's say, in attention? If you would see there are some benefits, that's awesome.

I'm not saying in any way wrong, right? But don't believe that these things just, you know, turn, you know, turn the expected outcome into the opposite direction. You just use some creatine and you will, you know, sleep, you will be sleep-loss resilient. And it depends also very much on what you test, right? I mean if I would stress and the how I test, often tests are done under very relaxed conditions. Okay, and now do this. You get some compensation, they do this. But what happens if you do a test in a every or real life scenario where you are exposed to stress deadlines and so on? Maybe then creatine will not make the difference, yes.

But again, I'm not against it and I think it's kind of interesting from a, let's say, night shift work perspective to think about this, yes, whether you could somehow boost or boost cognitive functions, such as attention through the supplementation. But I'm not jumping on the train claiming this is the solution and you no longer have to worry about your sleep loss.

Dr Laura Stankeviciute:

Thank you so much. Creatine has definitely been something that I have been asked a lot in the context of sleep. So, I do believe that our listeners will be very much happy to have received this explanation. And I think when we talk about creatine, we really also need to know that, you know, if you have had a very early flight in the morning and you had to wake up at 3:00 AM probably if you have that dose that day, it's not going to help to restore the functions. Or at least we don't have evidence yet enough that a single dose of creatine, even if it's in high quantities can restore that. Potentially we need to build that capacity of our cells to obtain creatine. Is that so Christian?

Professor Christian Benedict:

Yeah, you know, and I know it's not the best example but think about this analogy. You know, it's like saying I smoke and then I say can I take vitamin C, right? Ascorbic acid to compensate for the oxidative stress. I mean there were these trials. And I think also when you think about like sleep and sleep loss, of course, it's not good for us. And we would like to find ways of, you know, yeah, ways to buffer these effects right to that we are not fully or experienced the full blown effects of sleep loss on the various health outcomes that we can imagine, yes. But in the very end, it remains sleep loss. And I think the better thing is stop smoking or paying attention to your sleep and just sleep.

What women’s brain health means to our guests

Dr Laura Stankeviciute:

Thank you so much both of you. It's been genuinely such a great time talking to you. And I've learned myself a lot of new things about sleep even though I've been in the field for some years now. So, I think our listeners will also have taken some take-home messages that they can adapt to their own life and also share with the relatives and those that are close to them. And before we wrap up, we have this tiny tradition on the episodes where we end each of them with one final sentence, one final phrase that I ask each of our guests. What does women's brain health mean to you in one sentence? So Alana, let's go ahead with you.

Dr Alana Brown:

I think women's brain health means understanding the female brain across the lifespan on its own terms, not as a variation of the male standard.

Dr Laura Stankeviciute:

Now off to Christian, what about your opinion, whether it's the male standard versus the female standard? What do you think when you're a researcher, what does women's brain health mean to you?

Professor Christian Benedict:

Extremely important, crucial and crucial research activity and unfortunately, extremely underfunded. And we have people like you, Laura, like you, Alana, that really dedicate their research life to this very important topic. And I really hope that even funding agency authorities listening to this podcast, they are increasing the awareness of the importance of this topic and provide you the funding that we need because we need more insights into what is decisive for women's brain health across the lifespan.

Dr Laura Stankeviciute:

Thank you so much. That's it for today's episode of "XXplored: Women's Brain Health." I really did feel that we've only scratched a little bit of the surface, but one thing that is definitely coming up is that sleep is incredibly complex and what we sometimes hear is just an oversimplification. And we need to consider not only the biology, but also the psychological and social aspects of it all that shapes how one goes to sleep, how one experiences sleep, how one actually, how one sleep actually looks on the objective measures, and more importantly, how the sleep disorders present differently. So, thank you so much once again to both of you, Christian and Alana. It was a pleasure. And thank you for our listeners for tuning in.

We'll see you next time on "XXplored," where we continue to uncover the many areas of women's brain health that need greater understanding, louder conversations, and actions that make change. I’m Dr Laura Stankeviciute and you have been listening to "XXplored: Women's Brain Health" a Dementia Researcher podcast. Thank you.

Dr Alana Brown:

Thank you.

Voiceover:

Thank you for listening to "XXplored: Women's Brain Health" podcast from Dementia Researcher with generous support from the National Institute for Health and Care Research, Alzheimer's Association, Alzheimer's Research UK, Alzheimer's Society, and Race Against Dementia. From hormones to cognition, from risk to prevention, we feature conversations with researchers, clinicians, and changemakers, working to challenge assumptions and close the gaps in how we understand and support the female brain.