The FDA Finally Got It Right

So the FDA had a meeting to remove the black box warning on estriol, particularly vaginal cream and estradiol. What does that really mean and what does that mean to you? So today on Menopause Mastery, I'm going to dig into not only the study, the Women's Health Initiative, and what you need to understand about that study and how we got to the black box warning on estrogen related products. But I want to go a little deeper because what happened with that FDA hearing is, is we finally got a little bit of attention put on the fact that hormone replacement therapy with estradiol and estriol is safe and that that black box warning was put on erroneously because of a flawed study. However, what was really interesting to me is within the social media stratosphere, we had the group that has been pushing, like myself, with the current research and the current knowledge we have to allow women to have greater access to hormone replacement therapy. Because here's the thing, 85% of us are symptomatic, 100% of us go through menopause. But in the United States, depending on what study you're Looking at, only 4.7 to 7% of menopausal women are actually treated appropriately with hormone replacement therapy. Now, does that mean every woman needs hormone replacement therapy? No, but what it does mean is that every woman deserves the right to explore that and not be gatekept. So here's what really happened. So we have large group of people, Mary Claire Haver, Kelly Casperson, myself, lots of other providers talking about this ad nauseam. And then we had a group of practitioners that are all licensed and certified by the Menopause Society that came out against the flagrant over specification of hormone replacement therapy as a treatment for diseases of aging. So this is, you know, Jen Guntner, Liz, Lisa Larkin, we're trying to present the idea that hormone replacement therapy in the form of estrogen has only been proven to actually support the treatment of hot flashes and night sweats. Well, I'm going to go in a little bit into that research also and look at the research around osteoporosis, dementia and heart disease and vascular disease and stroke, because there is good credible data that shows that hormone replacement therapy is actually protective and preventative for these disease states. And this is where the, where the really important rubber hits the road. You know, I got into this fray because of my own experience after 20 years working with women. And I also got into this fray as a woman who went through a terrible perimenopause despite being, you know, immersed in the functional medicine community and in medicine as a whole. I'm a scientist, so I also read the research and look at things that don't always agree with me. Because the one thing you have to make sure is that whoever you're working with isn't implying their own personal bias on your care. There's definitely researching and understanding. But if you choose not to look at data, that doesn't mean it doesn't exist. It just means you chose not to look at it. And so I want to walk through, number one, the health, Women's Health Initiative, what it got wrong and specifically talk about a thing that most people don't understand, including other physicians, medical providers, scientists. And it's the idea between relative risk and absolute risk and, and particularly around the Women's Health Initiative and how they skewed the data and particularly the presentation of the data to incite fear. I want to talk also about the value of observational studies and why they are done in medicine. The gold standard. I'm going to air quote this. The double blind placebo controlled trials are really only done on, oh, I don't know, pharmaceutical drugs. And they're expensive and often are not. The only studies that are used to present and create outlines for long term care and for care decisions. Really high quality medical services require things like randomized controlled trials and observational studies. And we're going to go into why and how and where you put those together and how you put those together to really understand the, the totality of research. Because we make medical decisions across the board, across the board, including surgical decisions, prescriptive decisions, any kind of intervention decisions, also using observational data. So when a doctor comes out and says observational studies are not valid, they are undermining all of medicine. It is used in conjunction with other studies to create a overarching guideline for medical intervention. And then I'm going to talk specifically about bioidentical topical hormones and the difference between oral and topical hormones, particularly around the most recent studies that looked at, you know, long term mortality risk, where we had large populations of women that we were studying that looked at oral presentation and oral preparations of things like Premarin and primary compared to topical estradiol patches and topical estradiol. And then we'll talk about key takeaways and action steps. So I'm someone who's obviously deeply rooted in the science and also real world experience. At the end of the day, your personal experience, your own body, your own intuition and your own experience is by far more important than my opinion or anybody else's opinion. You know, the beauty of being a PhD is I get to examine the research, but I don't actually prescribe. So I'm able to take a very unbiased stance and look at both sides because I'm not receiving anything. I don't receive anything because I don't prescribe. And most prescribers aren't either, to be honest. But I have very limited bias there because I'm just talking about where the research lies. So let's talk about what you've heard, what's Ms. Dated, what's misaligned, and what you really understand. So let me go into what went wrong with the Women's Health Initiative and how to interpret the statistics. So this is often the study, the study that was presented as proof that hormone replacement therapy is dangerous for women, increasing risk for breast cancer, heart disease and stroke. However, let's really look at the data. Now, I know I've flogged this course and I have done it a million times, but I want to make sure that we all are clear. So, number one, the Women's Health Initiative was the first time we actually had a women's study that was actually paid for. And it was the most expensive study ever committed to at that time. Um, so. So there was a lot of pressure to show something, right, to show something here. So the Women's health initiative enrolled 16,000 women with an average age of 63. Less than 10% of those women were actually in their late 40s and early 50s. So all of these women were significant outside of the menopausal window. Now, the other thing is the study population wasn't healthy. 70% were overweight or obese and nearly half smoked or had hypertension. All of those are independent, independent risk factors for heart attack and stroke on their own. Doesn't matter what age you are, if you do those things or you have that condition, you're at greater risk. And like I said, only about 10% were in that first 10 year window. Now, now, why did they do this? Right, so when we look at the Women's Health Initiative, the reason why they did this is the goal of the study. So their working hypothesis were these questions. Does hormone replacement therapy in the form of conjugated equine estrogen, which is horse mare urine with 13 different estrogens, or conjugated horse mare urine with a synthetic medroxyprogestin, increase or decrease the risk for heart attack and stroke? That was the primary goal of the study. It was not to look at breast Cancer. It was not to look at all these other things. Now, one of the first things you need to understand about studies, the study quality and the method of the study is designed uniquely around answering the hypotheses or questions. Now, one of the things that happens a lot in research is we create a study. I've created a study. I had some very clear questions that I wanted to ask. And my hypothesis was either this is true or not true, right? Or null or not null.

Right.

Is basically what it shows up in a research study. So everything you do about that study then is designed to answer that very explicit question. So this study was designed to do that. There's a reason why they left out healthy women. We needed to see in a relatively short period of time, like 10 years, whether stroke and heart attack risk was reduced or increased with the use of those particular medications. Now, there was a group that ne that weren't on hormones at this time, although some of them had been on hormones previously because that was standard of care. But that was the question they were answering. They weren't answering all these other questions at all. Now, the study was designed around that. So they left out healthy women. Why? Well, if I need to show mortality from heart attack and stroke within a certain period of time, or advancing heart disease, if I put healthy women in there, I'm wasting money and time on women who have a delayed risk for that.

Right?

Now, if you're obese, a smoker, and already have high blood pressure, you already have cardiovascular disease, especially by your 60s, right? We already have risk factors, so they left out healthy women. So the first thing you have to understand is if you are a healthy woman, normal, relatively normal bmi, heart, you know, height, weight ratio, right? You're not obese, you're not significantly overweight, you don't have high blood pressure, you're not a smoker or an ex smoker, you cannot take the data from the study and apply it to your own health because it's not generalizable to a healthy group of women. Because they picked women who were unhealthy and because they wanted to see would they have disease, you know, disease increasing or mortality. So they looked at those women, and in the group that was on conjugated equine estrogen and medroxyprogestin, synthetic progestin, they had an increased risk for stroke and heart attack, which stopped the study. Now, in that group, they had a higher risk. And all the studies that we have had since then that looked at medroxyprogesterone keep showing that there is an increased risk with that synthetic form of progestin for heart attack and stroke because it causes increased clotting risk in older women. But, hey, let me tell you something. It also does that in young women, too, that progestin, the synthetic progestin, increases that risk, so they appropriately stop the study. Now, however, what they then did was called data mining. So data mining is when you start digging through data, asking other questions the study was never designed to do. Now, now, they did a lot of that. So they started digging to look for breast cancer risk, they started digging to look for other risks, dementia risk, when the study was never, ever designed to look for that. Now, the reason why this is really important is when you create a study, part of your method is to include and exclude things and also account for what they call confounding variables. Confounding variables are other variables that might influence the outcome of the data you're looking at.

Right.

So if I'm looking at dementia, do we have family history? Do we have, you know, other, other things? Do we have other risk factors for breast cancer? Because the study needs to be designed around that, and those things need to be identified first before you even start the study. But data mining is done all the time, and it's a way for a researcher or a group of researchers to regurgitate their own data again and again and again. It's also cheaper. So we have to understand that sometimes we do that in research because we can't conduct studies all the time using randomized controlled clinical trials because they're so damn expensive. So data mining is part of that. However, when you data mine, you have to be clear about what you can't control. For. Now, one of the things that they did is when they were data mining, particularly around dementia, they switched endpoints. So the endpoint is the question you're asking. So the endpoint they were originally looking for was dementia, and then they switch when they found no data to support their hypothesis.

Right.

Their beliefs, their bias, they switched the endpoint to mild cognitive decline.

Right.

And so they kept changing it. The other thing is, is they also changed what groups they were looking at. So when you compare groups, right, so this, this was a comparison between women who took Premarin, Prem Pro, or nothing at all. Now, when you do that, you have to keep those groups distinct. But what they were doing with their data mining is they would put groups together to, to get their own outcome. So they would combine a group in one particular, you know, regurgitation of data, and then in Another group, they would combine other groups, which then therefore actually skews the data. When you're comparing between groups, you keep them distinct and separate because you can't, you can't extrapolate the data between groups when you're constantly moving people between groups. So what that means is, is they data mined to fit a particular bias to then present what they wanted to present, which was to get away, get stop the runaway train of hormone replacement therapy for women. And that was their bias. And they kept massaging the data to get to that answer. We have to understand that there's a huge amount of, of issues here. So the next thing is they ob. They really overstated risk.

Right.

And this is the thing that I think people miss the most. And it is so, so easy to misinterpret and also misinform, especially in the media. It's the difference between what we call relative and absolute risk. So let me give you an example. One of the things that they stated was that dementia risk doubled. God, that sounds scary. Holy crap. Dementia risk doubled, but the absolute risk only increased from 1% to 1.8. So the investigators claimed this is their exact statement to have identified an elephant that on closer inspection, turned out to be a mouse. Right. So this is, this is where that statement was actually from somebody that reviewed their research and pointed out that they were overstating, overstating the risk.

Right.

This is a critique from Leon on Spiroff. So again that the investigators claim to identify an elephant because that's what they said. Dementia risk doubled. Yeah, nearly doubled. Yeah, 1% dementia risk. So 1% of the population, 1.8. So when we look at relative risk and absolute risk, let's talk about what that is. So risk gets reported. And this is where the fair often unnecessarily steps in. So relative risk compares two groups, let's say those on HRT versus those who do not have hrt, and reports how much one group was more likely to have an outcome.

Right.

So, for example, what they said is HRT doubled dementia risk. What did that really mean in real numbers? So the placebo group, the women that had nothing at all over 63, followed first seven, almost eight years, 1% developed dementia. In the hormone replacement group, 1.8% developed dementia. That means they increased risk from one woman per hundred to less than one or less than two per 100. And that was a difference of just eight cases in a thousand developed dementia. That's absolute risk, the actual chances of something happen. So absolute risk is the actual chances for something Happening.

Right.

So it went from, from basically four to eight out of a thousand. So when we look at that, so, so essentially it sounds really scary when you hear dementia risk nearly doubled, but it really went from four women out of a thousand showed signs of dementia to eight out of a thousand.

Right.

And again, we weren't, that wasn't part of the study. We didn't control for all the other risk factors. Did they drink? Did they do other things that we know are significant risk factors for dementia?

Right.

We don't, we didn't control for those because that wasn't the original part of the study. Now let's talk about the breast cancer risk and how they reported that. They reported that women taking Prempro, right, the synthetic progestin and conjugated equine estrogen had a 26% increased risk of developing, developing breast cancer compared to those taking placebo. What did that really mean in their actual data? Three cases of breast cancer per 1,000 per year. In the, in the, in the arm with nothing. In the Prempro arm, that went to 4 in 1000. So that was just one additional case per 1000 women. And they have never in 22 years actually showed increased risk for mortality to breast cancer with hormone replacement therapy or mortality levels have never changed. And actually the risk that they tried to present has now basically been washed out. It never really was there. So how was it framed? Again, Prempro increased the risk by 26%, three in 1,000 to four in 1,000. So we have to put it in real world perspectives. So when somebody is presenting data that looks extreme to you, what you want to know is the absolute risk, which is your individualized risk, not relative risk. But that doesn't, that doesn't garner headlines and it doesn't make for really sensational things or career making studies. So it makes a lot of difference now. All right, so we saw all that. So let's talk about some of the things that they actually believed about their study.

Right.

Like I said, they manipulated the data as they looked at stuff. So what are some of the subsequent studies actually show? So cognitive health, Hundreds of studies have shown prior to the Women's Health Initiative and even after the Women's Health Initiative, that estrogen replacement therapy particular particularly started earlier in the menopause transition protected brain cells. If it was started in that 10 year window. And that's where the 10 year window sort of comes up. The brain goes through a lot of remodeling and when we start hormone replacement therapy, it doesn't shrink and it doesn't remodel as much. So we retain the younger, more youthful brain function. Now, observational studies if we look at observational studies in cardiovascular disease, observational studies and randomized controlled trials show up to a 50% reduction in coronary events when hormone replacement therapy was started near the menopause transition. Barrett, Connor, the and Bush and the Nurses Health Study all showed that. And a meta meta analysis done by Sal Piter. I'm sorry Sal, peter. Showed a 30% decrease in cardiac events among younger women, postmenopausal women in their 50s and early 60s on hormone replacement therapy. Now let's look at osteoporosis. Estrogen was approved by the FDA in 1988 for the Prevention and treatment of osteoporosis. And to date it is the most effective to reduce fractures and fracture prevention and reduce the risk of fractures. And if continued, there's long term benefits and there's even benefits after discontinuation, especially if it's been done for over 10 years. So all the other drugs that we use for osteoporosis and my team has been working with osteoporosis for decades, if we look at that, all the other ones make the density better, but they don't necessarily reduce fracture risk. Hormone replacement therapy is the only thing that has shown to do that. And again, it was approved in 1988 by the FDA for the treatment of osteoporosis. But do we do that now? No, we don't. Ladies, if you're noticing more fine lines and wrinkles, it's not just about aging. It's about the loss of estrogen. And that affects our skin structure, making it drier, thinner, less firm. But here's the great news. I've created Biased Mastery Cream to help. This luxurious bioidentical estrogen cream supports your natural hydration and elasticity. It's packed with nourishing oils like olive jojoba, aloe and coconut. So it feels amazing and helps soften those lines and bring back that healthy glow. I've been using it and let me tell you, my skin has never looked or felt better. It's smoother, more radiant, and and those little cracks and creases are way less noticeable. If you're ready to give your skin some extra love, check out by EST mastery on the Metabolic Blueprint website. And that's metabolicblueprint.com B EST mastery that's B I E S T Mastery M A S T E R Y and your face will thank you. So let's look at some of the critiques doctors Leon Spiroff, Roberta Britton and Pauline McKay. I'm sorry, Mackie, sorry. Pauline Mackey, among others, have pointed out that these issues repeatedly in journals like the New England Journal of Medicine, jama. And so when you hear that the Women's Health Initiative proved that HRT is dangerous, remember, it doesn't really reflect particularly what we do today. So we have to Understand this is 22, almost 23 years old. We don't use Premarin anymore.

Right.

Or if you're an educated doctor, you don't use Premarin anymore and definitely not Prempro.

Right.

Synthetic medroxyprogesterone, done orally is a risk factor for clotting. And that's not really the current preparations that are used. There are bioidentical forms of hormone replacement therapy that are available at traditional, you know, pharmacies and also compounding pharmacies. So you don't have to take something synthetic. So. So if we look at Pauline McKay and Barbara Sherwin, they are out of the University of. I believe. No, it was Roberta Brinton was out of the University of Arizona. And then Pauline McKay and Barbara Sherwin looked at decades of research about cognitive ability in postmenopausal women and they showed that it reduced risk. And let me give you an example. There was a Columbia University study that followed 1124 older women and those who were on estrogen had a 60% reduced risk of developing Alzheimer's. Study. When we look at all of that, we can really identify that, hey, we, we don't have that risk. Now if we look at Dr. Moscone's work out of the Weil center at Cornell and then also at. And in the women's 10 million women study that came out earlier last year, looking at the risk of all cause mortality in women, over 10 million women, looking from 2006 to 2021 at mortality data, we saw that, that taking hormone replacement therapy to particularly in the form of topical, reduce the risk. Almost every study is somewhere between 27% to almost 60% reduced risk for dementia and Alzheimer's. So when we look at all of all of those studies, we've got lots of contra contradictions to what the Women's Health Initiative tried to present. And if we look particularly at Moscone's imaging studies, we know now that the act of going through menopause actually requires the brain to actually produce more receptors for estrogen, not less. They don't die off, they increase because the body is so desperate for estrogen. So when we look at the cognitive studies, we have plenty of studies, pretty much every study other than the Women's Health Initiative, showing hormone replacement therapy is probably the most profound and protective thing you can do to preserve the brain of a woman outside of exercise. And I would say hormone replacement therapy number one, exercise number two. Now we, this is where the critical window comes up, where it's better to start it early, before the brain has remodeled and shrunk. That's what happens when we lose our hormone. So if we can get in there early, we get the most beneficial outcome. But that doesn't mean that it doesn't help women that to introduce it later, we just may have lost some of that benefit. And if we look at some of the mood studies around depression, anxiety and sleep, we can see hormone replacement therapy even much after that window, being helpful. All right, so let's look at osteoporosis, right? So estrogen is the most effective prevention for fracture. And estrogen, progesterone and testosterone stimulate bone formation and inhibit bone reabsorption. Estrogen is the most primary support there. But the other two help a little bit. And there's been no other therapy that really has outperformed reducing fracture related osteoporosis related fractures. So there was a study done at the Fred Hitchens Cancer Research Center. There's also the Framingham study, which is the largest study looking at cardiovascular and stroke risk in a population. And that Framingham study looked at postmenopausal women on estrogen and showed that hormone replacement therapy in the form of estrogen had a 30 to 50% reduced risk for, for fracture, osteoporosis, fracture. Another Swedish study in the 1990s showed that hormone replacement therapy significantly reduced first hip fracture risk. And the duration matters, like I said before. So when you start hormone therapy and continue hormone therapy for at least 10 years, we have the best outcomes. Now, if you start it and never stop, that absolutely has the best outcomes. But you can't take it for just a few years because almost all of the benefits vanish rapidly after discontinuation. Because again, estrogen tells the construction crew to come to work and tells the demolition crew to stay at home. And then if we look at the historical perspective, Nananda Coal and historic protection perspective, if we look all the way Back to the 1940s, Fuller Albright advocated for estrogen to prevent osteoporosis related fractures all the way back to the 1940s. You got to remember, hormone replacement therapy has been standard of care all the way since the 50s until the women's health initiative. So it was given out automatically. Now let's get into the real data around around heart disease, cardiovascular disease and stroke risk. So let's look at their risk reduction, particularly when you start hormone replacement therapy early. So estrogen is protective to the blood vessels. It actually acts as an antioxidant and anti inflammatory. It helps the blood vessels restore the glycocalyx, which is this sort of hair like structure that acts kind of like a buffer for inflammation and also reduces arterial plaquing from cholesterol. So when we look at observational studies looking at populations of people like the Framingham study, which almost always is the study of observation used for almost all of our cardiovascular treatment.

Right.

Framingham looks at both men and women. It's following a town called Framingham for decades. So again an observational study, if we look at those and randomized controlled trials, we have a convergence. So what, what it showed is when you start hrt within about 10 years of the menopausal transition, we have reduced coronary artery disease and overall mortality. If we look at Elizabeth Barrett Connor and Trudy Bush, we saw in both of those studies looking at a 50% reduced risk in coronary event with unopposed oral estrogen. Right. So no synthetic progestin, just unopposed estrogen in women with a hysterectomy. Because if you add medroxyprogesterone, you would do that if they had a uterus. But they were looking specifically at cardiovascular disease with just estrogen. And in a study, the Nurses Health Study, Francine Grodstein showed that primary cardiovascular disease was reduced by 40% when estrogen was introduced. And when we look even at the Women's Health Initiative reports that suggested cardiovascular event only among the women on Prempro and women who started HRT at least 10 years outside of of menopause. When Leon Spiroff reanalyzed it in 2004, they found increased cardiac risk only among women who were obese, overweight, smoker, hypertensive. Again remember the majority of them were that in women who over 20 years past menopause at enrollment. So that means those women were in their 70s, right. Already having very advanced cardiovascular disease by that point. I think the thing that we need to understand as women is one out of two women will die from a cardiovascular event. We get heart disease just like men. We're just protected until menopause. That's the important part. Now if we look at meta analysis. So this was looking at large studies and pulling the data together to give us a overview of what needs to happen. Shelly Sal Peter and her team did a meta analysis of randomized controlled trial and showed a 30% reduced risk in heart attack and cardiac deaths among younger women, women in their 50s who started hormone replacement therapy. So again, we have to understand that, that you have to look at all of the different types of studies and we have to look at the true absolute risk, not relative risks. Now I want to talk about observational studies, right? So I spoke about this earlier, but I want to make sure that this gets the due diligence it should because this is where Jen Guntner and Lisa Larkin are trying to say that there's no studies out there showing that women have improved risk against cardiovascular disease, osteoporosis and breast cancer with hormone replacement therapy, despite the fact I just gave you randomized controlled trials. But let's talk about observational studies, okay? This is the idea that only placebo controlled randomized trials count as real evidence in medicine. This has been what conventional doctors have always thrown out. But you gotta remember that means a drug has to be tested, paid for by pharma and those are very expensive. So I'm not 100% anti drug, right. Obviously hormone replacement therapy is a drug, it's gender affirming care for women. But that can't be the only way in which we identify risk and or make decisions in medicine. So for over a century, major advances have come from careful observation. I'll give you the first one, Handwashing, reducing infection. Before anyone ran a trial, Dr. Semmelweis found that women who had given birth were dying at unimaginable levels because the doctors that were delivering babies had been messing with cadavers in between delivery. And what they were doing is not washing the hands and they were actually passing along infections to these women's and they were dying. When he presented his data to the conventional medicine doctors that we need to wash our hands, they destroyed his career. He died in an asylum, so they destroyed him. But no one would question today the use of hand washing to keep things from being, you know, passed along. We use, heck, we've gone so far to the other side that we use hand sanitization on everything, right? No one questions that hand washing is important to reduce infection risk, right? How about smoking linked to cancer? We don't have to make people smoke to see that. We had already observed obvious decades of research showing large cohort studies that smoking increased cancer risk. We don't have to go make people smoke and figure it out. These reflect real world populations, not just narrow groups or just the individuals willing to sign up for a study so they can also be generalized to a larger group of people. Because we're looking at the observational data of the people at large. And we can follow people for over decades and detect rare or delayed effects because you can follow people for longer periods of time. Because again, it's all about money. And sometimes there's only certain ethical ways to answer big questions. Questions like smoking. Okay, it's unethical to observe a group of people having increased risk for lung cancer and then trying to create a study to get people to smoke to see how quickly they get cancer. That's unethical. You can't get that past an institutional review board. So we have to look at this, right? You know, if we look at the careful observation of, of, of treatment, we know that things like hand washing, antibiotics, when appropriately used, have saved lives without having to do clinical trials like give somebody a terrible infectious disease and then give antibiotics to some and placebos to other and watch people die. It's unethical. So we make these observations all the time. And it also helps us look across larger population, different age groups, different socioeconomic backgrounds, different ethnicities. The truth is, women were left out of studies until 1993 intentionally. So anything that was proven, prescribed, decided before 1993 were not trialed on women. So we are the largest experiment ever done in medicine. And so when you have population observation data, you can look at larger groups of people because you're not separating it, because most studies are done on white male college students. Not helpful. Not helpful. Particularly when most diseases of aging happen in larger older populations and the risk stratification across different populations is different. And we know the biggest determinants of health and dying socioeconomic.

Right.

If you live in an impoverished area, you're likely to die anywhere from five to 10 years sooner than your wealthy counterpart. And that has nothing to do with, with anything other other than socioeconomic determinants of health. So when you look at observational data, we can extrapolate that and generalize that to a much bigger, bigger audience. And again, it's not ethical. We can't do that. And we can compare head to head insights, we can compare research to see how treatments perform against each other in real world solutions. This is critically nuanced for decision making, especially when individual patient factors matter. So I'll give you an example of this. It's a way to think about it. It's not exact, but it's close. So if you were to go and have a sleep study done Right. We can do sleep studies at home and then we can do sleep studies in a clinic where they hook you up to a big giant thing and you're in a room and somebody's observing you all night. Okay. For a woman, which study do you think is going to be more accurate?

Right.

I don't know very many women who are going to sleep well in a clinical environment with somebody watching you all night with a bunch of equipment tied up to you.

Right.

Whereas a lot of the home sleep study devices, while they may not be quite as specific as the ones in clinic, you're in your own home, in your own bed, doing your own thing with a, with a couple devices that are less obtrusive, we're probably going to get better clinical data. So critical decision making requires us to look across individual patient factors, across reality, not a controlled environment. And if we look at landmark studies like the Nurses Health Study, which followed tens of thousands of nurses for years and provided kind of robust overall observational data, now it's not exact because they're asking people to recall information, you know, which. But we can look at decades of data rather than a short seven or eight year window. So even though the recall may not be perfect, perfect, we can look at large swaths of information like mortality data and illness data in that group and identify patterns. And when we look at the women's, the Nurses Health Study, what we did see in these larger group of women in this longer time span is up to a 50% reduction in cardiovascular disease in the women who started hormone replacement therapy around menopause. And we were able to follow them for a much longer time because we were following them for decades and because we could observe, you know, so if we look at a consensus of epidemiological studies, they have shown that women who were given, you know, postmenopausal estrogen, especially in these larger observational data, showed a 40 to 50% reduction in the risk of coronary disease compared to women who did not take hormones. You know, so the truth is, randomized controlled trials are not infallible. Even though they're considered the gold standard, they have major limitations. Time limit is probably one of the biggest, particularly when we're looking at long term risk. All of us care about our hot flashes and night sweats, but I guarantee you, all of us care a lot more about falling and breaking a hip, overall risk for heart disease and stroke and dementia, and then the risk for breast cancer, which actually is increasing as you go through menopause as a woman, especially when you aren't on hormone replacement therapy. Every study that was ever done before for the Women's Health Initiative showed estrogen to reduce the risk. And there's actually a lot of studies showing estrogen therapy reduces tumor cell growth in women who have cancer. So tamoxifen is also a synthetic estrogen. So we can't throw this stuff in here and then, you know, massage it and try and make it look like what we want. So the reality is, is when we look at those kind of controlled studies, they had limitations and especially that long term risk factor limitation and they can be biased by their design flaw. And Women's Health Initiative is so, so design flawed. No healthy women, women who already had advancing cardiovascular and stroke risk because of their obesity, hypertension and smoking risk, again, going to probably have it. And age of 60, 63 and less than 10% of women were even in that 50 something range. And again, they already had one of those other risk factors.

Right.

You can't take that and put that in the group of women who probably listen to my podcast who are trying to take care of themselves. You're not the same as the women in the 90s who were still pounding Marlboros.

Right.

We aren't the same. So we can't, we can't say this represents the population, particularly the population today. And sometimes results do not translate to real world practice.

Right.

So when you, when you look at this, you want to converge the evidence reviews comparing well conducted observational trials, randomized controlled trials, when we pull them together, they actually show some real world data. Benson and Hartz showed effective treatment and observational studies and randomized controlled trials were similar in most areas. So when we take the Women's Health Initiative and pull it out and we looked at the observational data that showed hormone replacement therapy was protective and we look at other randomized controlled trials, they coalesced into, into evidence pointing the same way that early initiation of hormone replacement therapy reduced heart disease risk. And the conclusions there are robust. So let's talk about the key evidence and why this is important to you. So the FDA met about the black box warning on all estrogen products. So the primary target of that was to remove it from vaginal estrogen.

Right.

Vaginal estrogen is localized. It has no systemic effect. It is safe for all women. Even if you're in the middle of breast cancer or v cancer care, it does not matter. It is safe and should probably be used because vaginal atrophy, urinary tract infections, urinary incontinence can all be treated with that. There was a precision paper created this year for the genital urinary syndrome of menopause that positions that as a pre primary support for those risks. So vaginal estrogen, it needs to be gone. Now. The other side of it is there's bioidentical forms of estrogen in the form of patch, estrad creams, estrad and or biest, which is an estriol, very weak and estradiol and or oils.

Right.

We have it in oil compound and then you have pellet preparations as well and gels that can be used topically. Topical forms of hormones of estrogen do not, and I repeat do not carry heart attack and stroke risk even in older populations. The study that came out in the menopause journal of 10 million menopausal women. So all these women were way over 65. They look retrospectively back at three groups. Women who never did hormones, women who did hormones and stopped after a couple years to get rid of their hot flashes, and women who continued. The women who continued particularly with topical estrogen and did not take synthetic progestins had a reduced risk of all causes of dying. And some populations, even within the other hormone treatment arm, all of them showed a reduced risk of dying compared to the group who did nothing. Now if we control four topical forms of estrogen, an oral micronized bioidentical progesterone, any risk of stroke and heart attack and blood clots was completely mitigated. That is does not matter in women who are older. This is the first time a really large observational study that retrospectively looked back showed that that risk was reduced and actually at this point null. And so women who are even outside of that 10 year window can do low dose estradiol, low dose biased and oral progesterone, especially especially great for sleep and relaxation and mood and I would argue also testosterone and not show any increased cardiovascular or stroke risk based on clotting risk. So we have to look at these, look at these studies together. So when we look at evidence, evidence is not just randomized controlled trial, it's observations of decades of data, particularly when we're looking at mortality risk or long term chronic disease risk. And we have to pull these together, especially when we're looking at the progress that have made in these sort of causal comparative studies looking backwards at things that have already occurred. Right, that's where, that's where my research lies. That's where a lot of research lies because we have data that we can look back and compare populations for risk factors. And when we look at complex interventions like hormone replacement therapy to timing patient selection, long term outcomes matters. And that's where observational research is key. So when we look at all of those things, we have to understand all of the overall help for women. So let's talk about what the take home message is, right? So we don't have to, we don't have to look at all of this. The key takeaways are really important. So don't let outdated headlines and, and data that has been skewed by bias dictate your health decisions. The science has evolved and really we have to look at the more recent data that is defying basically the lies of the Women Health Initiative where researchers have gone out and been able to secure funding to do additional observational studies. We have to understand both relative risk, which sounds great on paper, 26% increased risk for dementia, or when the true risk went from 1 in 100 to 1.8 in 100.

Right.

That's the absolute risk. You should be concerned about absolute risk because that means individual risk. We also have to recognize that high quality observational studies and retrospective causal comparative studies, which are standards and medical, also apply and that the randomized controlled trial is not the only way to study people's health. And for most healthy women, particularly starting around menopause, we get the most ideal outcome and reduced risk across the board. However, starting hormone replacement therapy at any age can be beneficial, particularly if your greatest risk is osteoporosis or osteopenia and fracture risk. And we can look at those studies and understand that. And so if you're compu considering hormone replacement therapy sooner rather than later, however, that doesn't mean Even if you're 10 to 15 years outside of the window, that you can't do it. You deserve to be looked at as an individual and someone assess you because we have to remember the women that showed the greatest risk were more than 20 years outside of menopause and unhealthy. They had high blood pressure, they were obese, and in many cases smokers. So many of those women had all three, or at least two of the three. So they are not the same as the woman who is really taking good care of themselves that might be looking at hormone replacement therapy today and they're outside of that 10 year window. So it demands a more nuanced conversation. And so the truth is, is we should be removing the black box warning from all estrogen products because it's inaccurate and inappropriate. And if you've received those products, whether it's vaginal estrogen or a topical estrogen for hormone replacement therapy. Throw away the insert. Throw away the insert. It's no longer valid. And if you are listening online and you're getting confused because one group is saying it's only for hot flashes and night sweats and that's the only thing the research shows, know this. That's not true. That's not true. We have randomized controlled trials showing that it's protective for heart disease, osteoporosis and also breast cancer. And particularly osteoporosis is great because they actually used osteoporosis and fracture risk to, to approve the patch. Right. So. So we have human trials and we have observational data that has longer, longer duration that can really help you. So thank you for listening to Menopause Mastery. If you are watching this online, please don't forget to subscribe and like and share it with a friend. And if you're listening to me on the podcast, we'd love to have a review. Let me know what you thought and I'll be back with you next week.