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Let's Talk HRT: The Secrets of the Women's Healthy Ageing Study with Dr. Michelle Woolhouse and Professor Cassandra Szoeke

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Let's Talk HRT: Secrets of Women's Healthy Ageing with Dr Michelle Woolhouse & Prof Cassandra Szoeke

The reputation of hormone replacement therapy (HRT) took a big hit following the release of the Women’s Health Initiative study, causing many women to abandon HRT. As a result, many women suffer debilitating, or life changing menopausal symptoms and increased cardiovascular and dementia risks.  

In this podcast, Dr Michelle Woolhouse interviews Professor Cassandra Szoeke on her extensive work on women’s health and the process of healthy ageing. Together, they discuss the impact of the groundbreaking Women’s Health Initiative study on healthcare over the past 20 years, and focus on hormone replacement therapy (HRT). Professor Cassandra Szoeke shares her knowledge on reducing postmenopausal oestrogen levels and the need to assess and monitor the symptoms and risk profile of every individual when considering treatment options.  

Covered in this episode

[00:45] Welcoming Professor Cassandra Szoeke
[02:42] The Women’s Healthy Ageing Project
[04:25] Long term findings from the 2002 Women’s Health Study 
[09:54] When should we start HRT
[13:24] The difficulty in determining preventative treatment
[16:51] When to stop HRT
[20:11] Taking women’s symptoms seriously
[21:44] Controlling your heath in middle age
[24:25] Can HRT prevent disease?
[29:18] HRT and libido
[30:59] Hormone levels impact on the brain
[34:51] HRT and breast cancer
[38:02] Menopause isn’t just about hormones
[41:30] Cassandra’s tips for healthy ageing
[46:55] Is our fear of HRT warranted?
[48:17] Thanking Cassandra and final remarks

Resources discussed in this episode

Professor Cassandra Szoeke
Cassandra's book: Secrets of Women's Healthy Ageing: Living Better, Living Longer
The Women's Healthy Ageing Project
Women's Health Initiative Website
Research: Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol (ELITE), (Hodis, et al., 2016)
Research: Women’s Health Initiative Study of Cognitive Aging

Michelle: Hi, and welcome to FX Medicine, where we bring you the latest in evidence-based, integrative, functional, and complementary medicine. I'm Dr. Michelle Woolhouse and joining us on the line today is Professor Cassandra Szoeke. She's a general physician, geriatrician, consulting neurologist, multi-award-winning clinical researcher, and principal investigator of the Women's Healthy Ageing Project, the longest ongoing study of women's health ever done in Australia. 

Thanks for being with us today, Professor Szoeke.

Cassandra: My pleasure.

Michelle: Firstly, thank you so much for writing this book, the Secrets of Women's Healthy Ageing. What I loved about this read is how broad the concepts were, and how straightforward and inspiring they are, and how by reading it, I felt particularly a significant call to action as a woman in their middle years of life. 

So, in a healthcare system that's so fragmented, how did you become so interested in the complexities of the whole?

Cassandra: Well, look, I think I always wanted to be a generalist. So, in medicine we're getting increasingly super, super subspecialised, and I absolutely did that. I became a neurologist, I then did a subspecialisation in epilepsy, and I did sub-subspecialised in the neurocognitive side effects of epilepsy. Through that journey, I got really interested in cognitive side effects of medications. And so, that kind of led me to broaden out, and also to really look at our ageing. 

Because I really feel we haven't focused on ageing research or in health. It's mainly focused around diseases. And once you get to over 50, in Australia, 80% of people don't have one disease. They either are disease-free or they have several diseases. 

Michelle: Yeah, that’s right.

Cassandra: So, disease focus can be a bit confusing for them because they have to look up several websites to see what to do, and sometimes those websites conflict with each other.

Michelle: Absolutely. And so, you started the Women's Healthy Ageing Project, which really is what this book is all about. And it started, what, 30 years ago, and it's still going to go on.

Cassandra: I'm actually not that old. I'm not that old. I actually am really, really old, but I like to say I'm not that old.

Michelle: Yeah, but you know how to age well.

Cassandra: The study was started in the late '80s by Professor Dennerstein, Professor Henry Burger, and Professor John Hopper. And Professor Burger and Professor Dennerstein are now emeritus professors. And Professor John Hopper, still to this day, is working at the University of Melbourne. And I took over the study after the noughties.

Michelle: Fantastic.

Cassandra: So, it was started initially back in the '80s, and the first people came in in the early '90s.

Michelle: And is this the first study of its kind across the world, or is there others that have helped to inform?

Cassandra: Oh, I mean, there's so many amazing studies across the world and even locally. Our study is the longest-running study of women's health in Australia. 

Michelle: Fantastic.

Cassandra: And something that makes it really unique internationally is it's not only the longest running, but we have detailed measures. So, there are studies that have been going almost as long as ours, which do questionnaires or online surveys, and sometimes bring a sub-cohort of people in for measures. But our study has been incredibly detailed. These over 400 women have spent 4 to 6 hours at the University of Melbourne, going through all sorts of tests and blood tests and scans, bone scans, brain scans. And so, that level of detail actually becomes really important when you're trying to work out the overlaps and intersections of different diseases as we get older.

Michelle: That's brilliant. So, I wanted to focus our conversation today on the role of hormone replacement therapy for women. Not to take that away from the holistic approach, but more to kind of nut it down. Because I know that there is so much confusion about hormone replace therapy. 

At the beginning of my career when I was in medical school, it was the go-to panacea. It was like, that's what you should prescribe pretty much all women going through menopause, even those not suffering symptoms at that particular time.

But that all changed with the Women's Health Initiatives study that came out in 2002. Tell us about the impact of that study on the prescribing habits of GPs and medicine, and also the community attitudes.

Cassandra: Globally, across the world, they showed that...I like to say, overnight. Almost overnight, 80% of women stopped taking their hormone therapy. 

Michelle: Wow.

Cassandra: So, it was a huge, dramatic impact. And so, that's what happened around that time. And there's a reason you were saying it was a panacea. And, look, it is difficult in medicine when we get excited about something and so often when we don't understand it well, we perhaps take it up too quickly.

But what happened was, everyone had observed for a very long time, and tested in animals, and tested in primates, that when oestrogen left a woman's system around menopause, which is a mean age of 50, all of a sudden, women who were protected against heart disease, protected against bone disease, are having much less pathology than men, so are much healthier. All of a sudden, when oestrogen had left their system, they were getting the same rates of disease as men, and actually higher rates.

Michelle: Wow.

Cassandra: So, that was the reason it was felt, to maintain those hormones which were protecting women would be the right thing to do. However, the Women's Health Initiative didn't actually answer that question. It didn't answer the question of whether maintaining hormones would be beneficial. What the study did was it recruited almost 50,000 people. So, an enormous number of people, really strong study. However, the mean age of those people was 63.

So, again, menopause happens at 50. So, the mean age of these women, they were over a decade from their menopause. So, they'd already had oestrogen drop to levels that are undetectable by usual assays. And then in joining this study, they were randomised to either get a placebo tablet or to receive combined hormone therapy, which was reintroducing hormones 10 years after. They had, reduced down to negligible levels. So, it was more a test of the reintroduction of hormones at mean age 63 and that showed us several things.

First of all, that whilst it was true it was very good for bone health, and there were less fractures and less falls in the group of people who were taking the hormone therapy, there were side effects. So, there were more clots, there was more breast cancer, and it didn't help heart disease, and it didn't help dementia. So, that was the first thing it showed, that reintroducing hormones around mean age 63 did not have the same benefits. It still benefited bones, but it didn't benefit the other organ systems that we were expecting it to benefit.

But the second thing it showed was those preparations that were used back in the '90s which was...it's called CEE, and that's a conjugated equine oestrogen. So, in the study, it was conjugated equine oestrogen…

Michelle: So, that means it's from pregnant mares?

Cassandra: Mares.

Michelle: Yes.

Cassandra: Yes. And it's got a whole mix of different kinds of oestrogens. And also, it was the old kind of progesterone that was used.

Michelle: Right.

Cassandra: And interestingly, that Women's Health Initiatives just published in 2020 and 2021 their long, long, long-term outcomes which was wonderful to see. And it really showed that people who were taking just oestrogen, so without the progesterone, they actually didn't have an increased risk of...

Michelle: So, just an oestradiol, not the conjugated equine...

Cassandra: No. The CEE on its own.

Michelle: Oh, okay.

Cassandra: Because back then, they didn't have oestradiol. Some of the new treatments have been shown to be much better, but they weren't tested in this big study. So, no, no. People taking that...not great oestrogen, the conjugated equine oestrogen, taking that without progesterone because they didn't have uterus. Obviously, with the uterus, you have to take progesterone to protect you. But the people taking just oestrogen on its own did not have an increased risk of breast cancer. So, already, looking into it...and this is now, 2020. That's two decades after the study initiated.

Michelle: Yeah, that's significant.

Cassandra: It shows that it was progesterone that was being used that really gave that extra impact in terms of the breast cancer risk. And then you look today, we don't use CEE.

Michelle: No.

Cassandra: We use oestradiol. And also, we don't use those progesterones. The MPA was what was used in the Women's Health Initiative. And we use micronised.

Michelle: That's right. So, now, we're using a more natural form that the body can identify much more closely. 

So, you talk about in your book the timing of the commencement of HRT, which being critical to long-term health benefits. And this timing issue isn't a new concept. We see it in embryology, and we see it for timing of toxins, for example, in children compared to adults. 

So, why is it so critical for HRT and those in menopause and perimenopause? If we're thinking about starting an HRT, is there a timing period that we need to consider?

Cassandra: I mean, the answer is, absolutely yes. So, in the Women's Health Initiative, as I said, the mean age of women was 63. However, they did a sub-analysis years later. And they looked at those women, a really tiny proportion, I have to say. Mind you, they had 50,000 people. So, even a tiny proportion is a good sample size.

Michelle: Yeah, it’s quite significant.

Cassandra: Yeah. So, they looked at women who were under 60. So, that was up to 59 years of age. And they analysed them separately from the women who were 60 or over. And they found that the women up to 59 years of age did not have the negative side effects, and did have benefits. So, that's out there. So, segregating the group like that, that's where they said, "Oh gosh. It looks like if you do start close to your final menstrual period, you have the benefits without the risks."

Michelle: Fantastic.

Cassandra: And as I said, at the moment, they published recently their 20-year data on that. But you see, the trial wasn't designed to look at the time you took hormone therapy. So, the first thing is, we're saying under 60. But is that the optimum time? Or is 45? Or the first time you skip a period, the best time? And that's what we really don't know. We're working backwards from that massive study.
There's been some amazing papers written, and you know, as specialists, we can discuss this with your program. When you fund a study like this, it costs tens of millions of dollars.

Michelle: Wow. Amazing.

Cassandra: Right? And so, that was funded back in the noughties. And many scientific papers and journals and people have discussed, no one's going to fund that again.

Michelle: What a shame.

Cassandra: Because all those products are pretty much off patent.

Michelle: Yes. No one's making any money.

Cassandra: And, of course, there was a huge reduction in hormone prescriptions. So, there's a whole ecosystem that surrounds our medications. And we have never designed another Women's Health Initiative starting therapy at the time of final menstrual period.

There are a few small studies. So, there's a study called ELITE that was recently published in the New England Journal of Medicine. They took a much smaller than the Women's Health Initiative, out of necessity. Took a group of women 45 to 55 around the time of final menstrual period, and put them on hormone replacement therapy, randomised control double blind. And what they looked at...because these women are so young, so they're not getting diseases yet. 

So, five to eight years later, they looked at their carotid arteries and how patent they were. And the women who were on hormone replacement therapy had more patent arteries than the women who were not on hormone therapy. So, again, a suggestion that it is good for vascular health to be on hormone therapy.

However, of course, a lot of people are saying, "But will that lead to stroke? Will that lead to heart disease?"

Michelle: Of course.

Cassandra: It's an early stage market and we don't have those long-term effects. This is the trouble with chronic disease. They're chronic. They take decades to occur.

Michelle: That's right.

Cassandra: And, you know, clinical trials don't go for more than five years.

Michelle: Yes. And prevention, too. Like, it's so hard to kind of define how progress will occur. Those kind of microscopic changes or early markers is almost critical to prevention, but so difficult to extrapolate long-term effects.

Cassandra: I think you are spot on there, you know. So, one reason I actually...I'm the director of the Healthy Ageing Project, and that's what I've become despite being a neurologist.

Michelle: No, I love that.

Cassandra: My focus and passion for that. I think you've hit the nail on the head there, that’s our key. You know, rates of heart disease have been declining for the last three decades. Rates of cancer deaths have been declining for the last three decades. There's one thing on the incline, one disease in Australia that's on the incline.

Michelle: Is it dementia?

Cassandra: It's dementia.

Michelle: Oh, no.

Cassandra: And I think, one of the things that's also on the incline is poor quality of life in ageing. So, I think, what you said is critical. When you're looking at multiple diseases' interactions, and trying to focus on healthy ageing, to do that, you need a preventive treatment. It has to be holistic. It can't target just one organ because we all know that all the organs are...unless, as I say, in my book, unless you’re an Egyptian mummy.

Michelle: They're all connected. Exactly.

Cassandra: We don't keep them in separate jars.

Michelle: Yeah, that's right. Exactly.

Cassandra: Exactly. And so, these diseases...

Michelle: Or medical anatomy.

Cassandra: And these diseases of ageing, they just aren't in one direction. And that's why we really need to look at all of them. And this idea of inflammation especially for chronic diseases and diseases of ageing, is something also that I think we need to look at.

Michelle: That's right. And I just wanted to hone in on that because one of the questions that I had, and you make a point in your book, that the women that had the most severe menopausal symptoms, so the most severe hot flushes and the most severe symptoms, tend to have the worst long-term outcome in terms of disease. 

What's the mechanism behind that? What is thought to be going on for those women that have got severe issues through perimenopause and menopause?

Cassandra: So, I want to start a question before that question, which is, all women who get older go through menopause. So, 50% of the population is going through this. And yet, we know so little about it. Even today, we know so little about it. So, sure, people who have quality of life crushing symptoms who can't function will go and see their doctor.

Michelle: Yes.

Cassandra: But recent studies have shown 80% of people have symptoms that impact their function.

Michelle: Right. That's a lot.

Cassandra: So, 80% of half of our population is going through this, like, cataclysmic, functionally impairing...and yet we know so little about it. And we really haven't scratched the surface of people who definitely have sleep disturbance, definitely have mood disturbance, definitely have cognitive impairment. And yet, they just keep marching on. That's not something they see to their doctors about. That's not something that gets investigated. They just keep marching on.

Michelle: Yes. It's so normalised that it's almost...  And I know that there's a lot of work in menopause in the workplace and the impact as well because women are in the work force more than ever, like, more than 50 years ago. And so, that's impacting the work force as well, which is another side issue. 

But one of these questions I wanted to take on board is, for example, during that time where the WHI, the study came out. And there was often so much confusion, as being a practitioner of whether I'd start, whether I'd stop. And I remember seeing quite a lot of very healthy women here presenting to me, say, at the age of 68 or 72, still on hormones, still very well, looking after themselves nutritionally, physically, mentally, and doing all of the screening, of the breast screening, etc. Do I need to stop her HRT at a certain age as well? Like, in terms of timing, like there's a time that we start. But is there a time that we stop?

Cassandra: So, the first thing to say is, there's never going to be one answer that suits every person out there. So, there's no one answer that at this age every woman should do something. That's never going...if you hear that, question it.

Michelle: Yes. Okay.

Cassandra: Because we're all different. We're all individuals, and we all have a different risk profile. So, the first thing to say is, it's something to do in close collaboration with your clinicians because they know your medical history. The second thing to say is that a stop date is not something that has been proven.

Michelle: Yeah.

Cassandra: At all. And there's a lot of people out there who are having things stopped, and then you wouldn't believe that they actually get the symptoms in their 70s. You can get those symptoms.

Michelle: Yeah. And I noticed in your book, you had a few stories of women saying, like, "I would prefer to die earlier than have these symptoms within my..." I'm paraphrasing, really, but essentially, that's what they were saying. The symptoms were so severe and so debilitating that, really, risking a disease of any sort was worth considering.

Cassandra: And the second thing is, as women get into those older age groups, even in the Women's Health Initiative study, they showed in the older age groups the risk wasn't as great.

Michelle: That's interesting, too. So, there's almost like a window of risk.

Cassandra: And then the third thing is, which is against staying on hormone therapy, is that the risk from duration of use 5 years to duration of use 10 years was increased. And so, that's why when people have been on it a long time, there's a feeling from clinicians to cease the therapy because of that. But nobody's investigated over 10 years, you see.

Michelle: Right.

Cassandra: So, it's kind of an evidence-free zone.

Michelle: Right. Okay.

Cassandra: That was from the Women's...the 5-year, 10-year is from the Women's Health Initiative. And again, it was a different preparation of oestrogen. So, it's so difficult because we're trying to extrapolate conjugated equine oestrogen at high doses with NPA as a progesterone. And we're trying to extrapolate that knowledge into a different population using different hormone therapy entirely. And I should say on that note that transdermal oestrogens, be they gels or patches, so far they haven't had the side effect at all of the oral therapy.

Michelle: Really.

Cassandra: Yes, totally.

Michelle: That's fantastic.

Cassandra: So, they look like they have a completely different side effect profile. But, of course, we know less about them than on things we've been using for a very long time. And finally, I'm not an endocrinologist. Don't ask a neurologist about hormones. You know, just caveat there.

And, look. There's one other thing I want to say. And we're talking about symptoms and I know too much about women's health to let a discussion on symptoms go by without highlighting that women used to be diagnosed with hysteria for menopause symptoms.

Michelle: I know.

Cassandra: And to this day, women having heart attacks are sent home with the feeling that it's all just in their heads. So, there is an issue around symptoms in women. And I wanted to make the point that menopausal symptoms are not just an inconvenience. So, hot flushes, everyone knows about those. Hot flushes, hot flashes, whatever you call them. These are symptoms that people think are just an inconvenience. There is very hard solid evidence now to show that women who experience hot flushes are more likely to have heart disease.

Michelle: Right.

Cassandra: Heart disease is the leading cause of death in women in America, and is the second leading cause of death in women in Australia. Women now have more heart disease than men do. So, this is not trivial. This is not trivial.

Michelle: This is not trivial. No. And I mean, it's just information that isn't out there in the community. 

I wanted to talk about mood as well, because things such as anxiety and depression are really common around menopause and perimenopause. And even just what you said then about that previous diagnosis of hysteria or almost repressing our emotional response to such debilitating symptoms and not actually having them heard, or being at risk of being belittled because of them. 

Is there any research in regards to hormone replacement therapy and its role in mood? Or do you think that the mood is part and parcel of the challenges that women face at this particular time? What do you think? Is there any...

Cassandra: You're absolutely spot on there. It's a very, very difficult time for a whole sort of reasons. So, if you're experiencing... All of you are going through menopause. Eighty percent of you are experiencing symptoms that impact your function. If you're not going to be perturbed by that, then maybe there's something else wrong with you.

Michelle: That's one way of looking at it.

Cassandra: So, it's very hard in a human body. And I think this is why we've really struggled. So, the last... Before the COVID pandemic hit and completely halted all of us in our tracks, WHO had actually said, chronic diseases of ageing are our next big challenge.

Michelle: Yeah.

Cassandra: These are the diseases that's killing everyone, causing poor quality of life as we age, and yet, WHO said, 80% are preventable.

Michelle: Yeah, absolutely.

Cassandra: So, this is the last frontier of our capacity to have health. And we've done great at extending life, but we haven't taken care about the grumbling along chronic diseases that are giving us a less healthy ageing.

Michelle: Yeah. And you make the point strongly that the health of ageing starts in middle age. And I know some of my colleagues will actually say it starts in childhood or it starts even before you're born. But at least at middle age, we've got the agency to do something about it. We're in total control, really, of our health choices at that particular time of life.

Cassandra: I think that's the point. That's the point. So you're right. So, our healthy ageing program, our motto is “From Birth to Beyond.” Because often when you're running a healthy ageing program, everyone says, "Oh, I'm too young for that." But, in fact, ageing does start from birth. And yes, it does start in utero as well. 

However, in terms of your risk factor profiles, if you take away childhood obesity which is now making the risk factor profiles into teenage years, but prior to childhood obesity becoming an issue in our societies, in fact, the major risk factors that were hitting us was, you know, in our 30s to 50s.

Michelle: That's amazing.

Cassandra: And so, that's why the midlife target is so important. But with our changing lifestyles, as I said, childhood obesity, that's going to become a huge risk factor for later life disease and, you know, frankly, early ageing. Diseases you would normally associate with people in their 70s and 80s will start occurring in 50s and 60s in people who have higher risk factors.

Michelle: So, with the women, going back to, really, 30 years ago, how we used to...because we thought we had the research to suggest a better risk profile in women starting HRT using the equine oestrogen and the other form of progesterone. In women that don't suffer much or women that are… they've got mild symptoms and it's not as debilitating. Should we be considering HRT as an option for prevention in these women and all those with the risk factors such as a strong family history of heart disease or strong family history of dementia? Have we got enough research to help sway my decision one way or the other?

Cassandra: So, as a researcher, I'd say we don't have the research. And that question you just asked is my most favourite question. I actually think here's the one thing we did wrong with the whole hormone thing was just give half the women hormone therapy and half a placebo. We never said, "Who's got symptoms? Who hasn't? What symptoms do you have? What type of hormone therapy do you need?" So, symptoms of menopause can be dry vagina. Given the topical oestrogens have absolutely no side effects so far, why not give a topical to that person?

Michelle: Yeah.

Cassandra: And the person... So, we're really not tailoring therapies, not tailoring therapies. When you don't tailor therapies, we know you give it to people who don't need it, and then they're just dealing with risk factor profiles. And you give it to people at the wrong dose who maybe need a different dose. So, I think tailoring therapy is crucial. And I think, symptoms, now that we know that hot flushes actually predate heart disease, I really think we have to be looking at symptoms and treating symptoms. And that's the most important thing.

So, in terms of hormone therapy, the national position statements, the international position statements all say, you should only use it if the person has symptoms and that you should, of course be balancing that individual's risk. So, if someone has had breast cancer, they're not going to be given hormone therapy.

Michelle: And is that true in the case of, like, a vaginal preparation as well, or is there a way in which...

Cassandra: So, the topical preparations actually can be used. But again...and people with breast cancer can actually use oestrogens, topical, and also sometimes even oral. But it's done in close discussion with all of their training practitioners and, of course, with vigilance and monitoring.

Michelle: I mean, the evidence, though, in HRT and bone health is strong. I mean, even in the WHI study, we found that even using those older preparations and starting later, there was an impact on bone health.

Cassandra: An impact. I mean, it's so good for bones, isn't it?

Michelle: Yeah.

Cassandra: You basically have 30-year-old bones if you have hormones.

Michelle: Yeah.

Cassandra: Yeah, it is very, very good for bones. And I think, with anything as we've seen, those high doses, getting the dose right, getting the timing right, getting the therapy tailored for the person is going to reduce side effects.

Michelle: Yeah, that's fantastic.

Cassandra: And still have the benefits. And I think that's where we're at.

Michelle: So, what was the difference in dosage back in the study 30 years ago? What sort of doses were they using then, and what sort of doses are they using now?

Cassandra: Well, it's also the preparation. So, when you have an oestradiol, you can use less because all of it is actually going to receptors and acting. Whereas with the conjugated equine oestrogens, there was a whole mix of oestrogens in there that you weren't even necessarily benefiting from, but you couldn't work out which ones to get, if you know what I mean.

Michelle: Right.

Cassandra: So, the science wasn’t there.

Michelle: Well, then they would have been acting as xenoestrogens and then creating issues for the gut biome and for the liver detoxification capacity and all of those different other aspects.

Cassandra: Yes. And, look, the other thing we should say is...and I hate to medicalise menopause when it is a natural process that all women go through. So, there's always this debate because we don't want to over-medicalise anything that we can help un-medicalise.

Michelle: Absolutely.

Cassandra: Un-medicalise seems a great thing to do.

Michelle: That's right.

Cassandra: So, I think we have to remember in the 1900s, the mean age of death was 50.

Michelle: Yeah. I've got one year left.

Cassandra: So, the mean age of menopause is 50. So, there were no menopausal women before the 1900s.

Michelle: That's really interesting, yeah.

Cassandra: Yeah. So, this idea of... Yeah. So, it was very rare to have a menopausal woman before the 1900s. And then since the 1900s, we've all seen those demographics of the ageing population. So, there was a small ageing population. Whereas now, women are living a third of their lives in the post-menopause. So, it's an entirely different situation.

Michelle: Yeah, absolutely. And let alone running big companies and corporations, and doing all the other sorts of things that amazing women do. 

One of the things that I see a lot in practice is libido, having a low libido particularly around the time of perimenopause and menopause, etc. And I guess, in my clinical experience, HRT has been a bit hit and miss in terms of that. You talk about libido in the book quite a bit. Tell us about libido and HRT, and also its role in longevity.

Cassandra: So, what I would say about libido and HRT is an endocrinologist is the best person to discuss that and testosterone. When we talk about HRT, we're really talking about oestrogen and progesterone. But testosterone has a large impact on libido. But an endocrinologist is the best to discuss that. But the thing with libido is it's not just hormones.

Michelle: Yeah.

Cassandra: And, I mean, there's those little cartoons and so on about women's libido is in her brain. And, of course, everyone's libido is in their brain. But, you know, the factors surrounding all of the other symptoms is what's really important in terms of libido. And what we found in our study was the single most important thing was how you felt about your partner.

Michelle: Yeah.

Cassandra: So, it doesn't matter what your hormone levels are, what your diseases are. Maybe you've got such bad osteoarthritis, you really struggle even mobilising for activity. Doesn't matter. If you have a good relationship with your partner, you have a great sex life.

Michelle: Yeah. Menopause or not. So, that's good news.

Cassandra: So, focus on relationships.

Michelle: That'll be another podcast. 

So, how is the brain impacted by these decreasing hormone levels in perimenopause? Like, what's the mechanism that we know about the role of oestrogen, progesterone, testosterone going across the blood brain barrier? Is it about that in general, or has it got to do with blood flow? What's the mechanism behind the brain impacts in the perimenopause or menopause time period?

Cassandra: So, here's an area of cutting-edge research. So, the studies that I read from journals hot off the press have 30, 40 women who've had brain scans, who have hormone measures. That's where we're at. What we want to see is 10, 20, 30-year studies with scans and hormone information which we just don't have yet to answer those questions. 

But the little studies we have to date definitely show us. As you say, we know hormones cross, and not everything crosses. So, if you cross, you're a winner. And not only do hormones cross, but there's so many receptors within the brain for those hormones. So, they're not just crossing and doing nothing. They had activity sites in the brain.

And we also know that people's cognitive testing gets better when they have oestrogen. Even looking cyclically, there have been changes noted, in functional MRI, cognitive testing, and hormone levels. So, there's a lot, but it's early stage work. Such early stage work. And that is, of course, what led to the hypothesis that hormone therapy would be good for cognition. You may be aware that in the Women's Health Initiative, they had a sub-study. It was called the Women's Health Cognitive Initiative or something like that. Sorry, I've forgotten.

Michelle: That's okay.

Cassandra: But in their cognitive sub-study... Remember the mean age of women was 63? The mean age of the women who got into the cognitive sub-study was 70.

Michelle: Right.

Cassandra: So, here's women who were 70. How many decades is that after your last menstrual period?

Michelle: Yeah. They wouldn't remember it.

Cassandra: Yeah. And in fact, reintroduction of oestrogen in those women, they had more dementia.

Michelle: Yes, I read that.

Cassandra: Not horrifically more, but more dementia than people who didn't. But that's giving oestrogen to oestrogen-free women at 70 years of age. Right? However, there's a lot of work looking at giving oestrogen in a maintenance setting. So, not having washed it out and reintroducing it, but maintaining oestrogen and cognitive performance. And the early studies do show better blood flow, they show...and we know that blood flow to the brain, I mean, that's crucial for cognition.

Michelle: Yeah, absolutely.

Cassandra: In the old days, we used to say, there's the Alzheimer's dementia, then there's vascular dementia. And I wrote a textbook chapter on vascular cognitive disorder — God, it must be 15 years ago now — where we said, it's mixed dementia. There's no... You know, everyone with Alzheimer's dementia has...

Michelle: Yeah, it's not one or the other.

Cassandra: Yes. Yes. Everyone's got vascular change now that we're living to 80, 90. They have vascular change as well. We know now for sure that the vascular changes are also exacerbating that download of amyloids, which is characteristic of Alzheimer's dementia.

So, you know, there's no… Diseases interact, body system interact. And as you get older, the system's a lot more fragile. And so, these impacts exacerbate each other. And then in addition to that, because they're causing this perturbation of your normal functioning and less blood supply, the cells become distressed. They send out signals, "Oh, hello. Inflammatory cascade." So, there's a whole inflammatory cascade hypothesis around dementia as well.

Michelle: Yeah.

Cassandra: And it's probably not one or the other. It's not the amyloid people or the inflammatory people or the vascular people. Probably all three are operating to give us what we see.

Michelle: That's such a great way of looking at it, too. Because it gives us that holistic picture. It's not just one thing to focus on. It gives us a breadth to understand, I guess, and empower ourselves to all of the different factors that we understand to protect us against cardiovascular disease which is really...we know quite a bit about that in terms of lifestyle medicine. 

Because one of the big issues, I think, with HRT is its role in breast health. And with breast cancer now, rates are sort of 1 in 8, 1 in 10 women in Australia. It's certainly a disease that has been on the rise. Although, there has been some incredible, incredible movements in terms of treating that disease for really positive outcomes.

What's the role of HRT for breast health? And what is that mechanism? And we just spoke about, you know, perhaps using topical oestrogens or as an option for women that have got menopause and really severe symptoms. But just on the risk factor of breast health/breast cancer, what do we need to know?

Cassandra: So, look. I think this topic, you know, there's no paper out there that will give you a clear answer on that. So, what I'm saying is...

Michelle: I want a clear answer, Cassandra.

Cassandra: No, don't worry. I'll give you one. Not being either an oncologist or an endocrinologist, who are the two specialists who really know this field, why don't I give you my answer?

Michelle: Yeah.

Cassandra: What I mean to say is, people are still debating and arguing about this. So even the oncologists and endocrinologists haven't come to a really clear agreement around this. So, I'll just give you data because I'm a researcher. So, in that Women's Health Initiative, I told you there was more breast cancers in the group of people who had that high-dose conjugated oestrogen with progesterone, and not in those who just took the oestrogen. There wasn't a difference in mortality.

And then the second thing to say is that when these big studies came out looking at... And remember, it's all older preparations, but by necessity because they were looking at the 10 and 20-year risk of taking hormone therapy. So, there were big studies in The Lancet and the British Medical Journal which said, this is how many more cancers we have because of hormone therapy, which were very scary studies for people to read. And when they came out, there were a lot of people who said, "Okay. Well, let's look at this," because it turned out that the risk was mitigated by adiposity, that means your body mass index.

And when you actually break down the numbers of relative risk, being overweight is more likely to get you breast cancer than taking hormone therapy. So, then this became a big topic of discussion and then people were very upset because, it doesn’t... We shouldn't be comparing what gives you more of a risk of cancer. If anything, if you're at risk of cancer, you probably want to avoid it. I
t's such a fought area. It's really something for a panel to debate. And, of course, there's national position statements. And so, I've told you those, which is that symptoms should be treated, and that people should be monitored, and risk profiles need to be assessed on an individual basis.

Michelle: That's just such a great way to look at it because, really... I mean, clinical medicine, when we've got a patient in front of us, that's all we've got, is one patient in front of us. And then we use the research to inform our decision rather than be rigid and structured in our decision making, to actually keep the patient's life, the patient's decision making, the patient's...all of the different genetics in line with our decisions as clinicians.
But not all women want to take hormone replacement therapy for a whole variety of different reasons. It could be a cultural belief. It could be a naturalistic principle or whatever other reasons. What can practitioners help women in that time of their life to support these women? What are the other things that we can suggest that your study has shown us that help women long-term?

Cassandra: Well, I think the other thing about this time of life is it's not all hormones. Like, we've been talking a lot about hormones, but it's not all hormones.

Michelle: Yeah. I did that on purpose.

Cassandra: This time of life... Well, a lot is going on. So, a lot is changing in terms of households and relationships and disease. So, I said before that over the age of 50, people either have no disease or two diseases. So, 50 is a number in the Bureau of Statistics that is used because once people are over 50, they're more likely to get diseases. So, in fact, obviously, I'm a neurologist, so I'm going to talk about dementia. But the risk of you having dementia doubles every five years after 50 years of age.

Michelle: Wow.

Cassandra: So, that's why when menopause is around that time as well, there's also a disease starting to enter people's lives. So, really, what's important is looking at all the other aspects. 
Now, I will say, a lot of people talked about empty nest syndrome when women are going through menopause. And there was this whole concept of empty nest, and women are getting depressed and all these things because of the empty nest. Well, the original study principal investigator, Professor Lorraine Dennerstein, threw that entire concept to the wind when she examined this cohort and found that was not the case at all.

So, with the empty next, with the leaving of children from the household, women's mood improved, their sex lives improved. Just everything was on the up.

Michelle: And when they came back, their sex life...

Cassandra: There you go. Really. And it’s interesting, when children came back, the sex life took a hit. Anyway…

Michelle: That's right.

Cassandra: The revolving door syndrome.

Michelle: That's right.

Cassandra: But the thing is, sometimes we do have these suggestions in our minds that things are going to be impacting people when they don't, you know? So, it's about really looking at people's symptoms, looking what's going on and supporting them. And, of course, we all know, talking about the leading causes of death. 

So, you know, in women, the number one cause of death is dementia. The second leading cause of death in women is heart disease in our country. And the third leading cause of death in our country is what they call cerebrovascular disease or stroke. That is the blood vessels going to your brain getting clotted.

Michelle: Yeah. And they all come from the same...

Cassandra: Part of your brain is…

Michelle: Yeah.

Cassandra: ...taking out. They're the top three causes of death. I don't think women really...because women's health tends to focus on other things. I think women don't realise what's actually causing them to have low quality of life and disability when they're older, and killing them.

Michelle: So, you also talk a lot about that you've got some five top tips around what women should be doing and starting in that middle age time. So, anytime from 40, 45, 50 onwards. What are those top tips just to leave us with that?

Cassandra: Absolutely. So, look. The number one thing to do is move. So, activity is just so important. And we're talking before about hormone therapy and heart risk and dementia risk and all of this. Oh my goodness. Just move.

Michelle: Yeah.

Cassandra: Physical activity actually reduces dementia risk. It reduces heart disease risk. It's good for your bones. So, movement is actually fantastic for you, and prevents a lot of those. Remember when I said the World Health Organization said 80% of these chronic diseases of ageing are preventable? They actually had another statement to that. Preventable with lifestyle and exercise.

Michelle: Yes. Absolutely.

Cassandra: So, you know, literally...

Michelle: Exercise is the panacea. I can say that exercise is the panacea.

Cassandra: Well, the thing is, people don't realise activity is not just about breathing hard. So, in our study, we actually thought it was going to be this cardiovascular activity that makes you breathe hard, intense activities that's going to have the best impact. Because when you look at short-term studies, 12 weeks, 2 years, people who do these studies, their blood cholesterol drops better, their blood pressure drops more. All of those kind of parameters get better which we know are associated with heart disease risk.

However, when we looked across 30 years, in normal people out there just living their lives, it was activity, 30 minutes to an hour a day every single day, those were the women who did the best. Even if that was not going to the gym. It was just going for a walk around the block with your friend for 40 minutes every day. Those people were kicking goals.

Michelle: That's inspiring.

Cassandra: So, it's activity that's the most important. Not to undermine intense activity and how it can help reduce your cholesterols and your blood sugars, but doing something each and every day for 7 years is what helps you 30 years later. Doing intense activity… 

Michelle: Yeah. So, sustainability.

Cassandra: Yeah. It's maintenance. And, you know, intense activity isn't often maintained, or really intense activity, as we know from our wonderful athletes, can actually wear down your bones.

Michelle: So, keep moving is the number one tip. What's number two?

Cassandra: Don't poison yourself. I know it sounds quite silly.

Michelle: What a great idea.

Cassandra: I know it sounds quite silly. But there truly is that...there's so many diets. And it was, "Oh, I'm going to be on this diet. I'm going to be on that diet." We did this great radar chart that they just would not let me put in the book because it was a radar chart. Who puts radar charts in books for people? But I did do my best to explain the radar chart in the book.

What we did was, you know, in my field we're all into Mediterranean diet, DASH diet. There's all these different diets that are meant to have better healthy ageing outcomes, better cognitive outcomes, better heart outcomes. And so, we did this radar chart and looked at what our women were eating, and look at the overlap between the Mediterranean diet, the DASH diet, the high-fat diet, the Western diet, the junk food diet, all these different diets. And we did a radar chart which showed what people in these diets are eating. And in fact, you wouldn't believe it. They're predominantly eating the same stuff.

Michelle: Yeah.

Cassandra: So, 80% of what they're eating is the same. And what we did was we picked out the pings where on the radar chart only… So, only the Mediterranean and DASH people were eating fresh fruit and leafy veg.

Michelle: Yeah.

Cassandra: Ten times more than people in other diets.

Michelle: You got to eat your leafy veg.

Cassandra: The other ping... Yup. Leafy greens, and fruit and veg. The other ping was on nuts and legumes.

Michelle: Yeah.

Cassandra: So, that's beans and nuts was another ping for the good diet. And the bad diet, the ping was on processed foods, fried foods, and sugar. And, of course, the ping was on cake. There was a ping on cake, ping on confectionary, ping on... But ultimately, added sugar and processed foods, which is added sugar and salt, and fat often. Processed foods often also have fat. So, avoiding processed foods, added sugars, and eating those leafy greens, that's the secret.

Michelle: There was a couple of others to finish our top five. We had meaning and purpose.

Cassandra: Oh, this is so important for healthy ageing. And it goes to, I guess, old adage of as to what good quality of life is. And, you know, meaning and purpose, sometimes people think you have to be Gandhi. But it's not about that. It can be a really small meaning and purpose. So, people who were connected to their community, even though they didn't feel connected to their community. I give an example of... Because often people think you have to be an extrovert connected to the community, that's what I'm talking about. I'm not talking about that at all.

There's an introvert in the study who was dragged...because she had accounting skills, she was dragged out to help a club with their books. And she didn't attend the social functions because that's not her cup of tea. But she was helping this organisation and that was her purpose. You know, you can really see, every time, you have to look for it. But the people who are doing well, they do have a purpose.

Michelle: What I wanted to finish up with is that, I think, from my perspective, and I think a lot of practitioners out there, there still is a lot of fear around HRT. And women are still fearful of HRT. I just want to finish with saying, is this warranted?

Cassandra: I think we should be scared of all medications, right? That is why we... Well, no. That's why we prescribe them with such care.

Michelle: Yeah.

Cassandra: Because we know that all medications have side effects. And we also know that most of the trials, not HRT, but most of the trials of medications were done in male animals. So, it was only in 2016 that the NIH mandated that female animals need to be tested in drug trials as well as male animals.

Michelle: So, we've really only got five years.

Cassandra: So, up till 2016, every drug that went into a phase three clinical trial... I mean, there would have been women in the clinical trials because that was mandated in 1995, I think. But that medication came from only male animals. So we know that these haven't been tested often even in women. And they certainly haven't been tested in us.

Michelle: Yeah.

Cassandra: So each person is an individual with their own constellation of physiology and risk. And so, all doctors prescribe, all clinicians prescribe with that in mind, and we prescribe carefully.

Michelle: Fantastic. Thank you so much, Cassandra, for your time today. 

Cassandra: It’s been a pleasure chatting.

Michelle: Like, just the way that you position everything has just helped to clear up so many of the positive benefits that can come perhaps with the discussion of hormone replacement therapy and the risks. And I feel like, really, we're on the pathway to seeing whether we've got more options available through that time for women with perimenopause and menopause. 

And your work has just been so profound. I've absolutely loved the book. It really has helped to frame things in such a fantastic way from a clinician's point of view, but also from a personal point of view and it was a real honour to speak with you today.

Cassandra: No, it's been a pleasure. It's easy to write when I've got 400 women behind me, giving me all the secrets.

Michelle: So, Cassandra's book is the Secret of Women's Healthy Ageing and the byline is Living Better, Living Longer. Where do we get that book from, Cassandra?

Cassandra: Oh, everywhere. Melbourne University Publishing, of course. And it's on Amazon and Booktopia and Book Depository.

Michelle: Fabulous. Thanks, everyone, for listening today. And don't forget that you can find all the show notes, transcripts, and all of the resources and research from today's episode on the FX Medicine website.
I'm Dr. Michelle Woolhouse, and thanks for joining us.

About Professor Cassandra Szoeke

Professor Cassandra Szoeke is principal investigator of the Women’s Healthy Ageing Project, the longest ongoing study of women’s health in Australia, and author of the book Secrets of Women’s Healthy Ageing. She is a general physician, consultant neurologist and multi-award winning clinical researcher.

She has several hundred published articles in the medical literature, several book chapters in medical textbooks and has worked in the Commonwealth Science Industry and Research Organisation, Public Hospital system and as non-executive board director (Chair of Quality & Safety and Chair of Education, Training and Research) of the Western Health Services for the Department of Health (Vic). In addition to her medical qualifications and fellowship in the Royal College of Physicians she has a BSc with Honours in Genetics and PhD in Epidemiology, and her postdoctoral studies at Stanford University CA, focused on public health and policy. She is an associate Fellow of the Australian Institute of Digital Health and Graduate of the Australian Institute of Company Directors.

She has held many significant academic positions and teaching roles for academic institutions and specialist colleges and is recognised internationally for her contributions to healthy ageing research holding Australian clinical representative role in the world-wide Alzheimer’s Disease, then Clinical lead on the Global burden of Dementia and is currently on the executive of the International Women’s Brain Project as lead of the Asia Pacific node. She has worked in the public and private health system in clinical, leadership and governance roles as board director appointed by the state health minister including holding roles as Chair of the Q&S and Education, Training and Research board subcommittees. She has contributed to development of national health policies and currently sits on the Council of the Australian Medical Association (Vic), is appointed to Medical Panels by the Department of Health (Vic) and is the Chief medical officer for the Australian Healthy Ageing Organisation.


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