Is It Too Late to Start Hormone Replacement Therapy?

The 65+ age frontier. Is it too late to start hormone replacement therapy? So today I'm going to do a deep dive. I've been digging into this, and I'm actually working on a systematic review of the literature right now, which is nerd speak for digging in and actually writing a scientific article about where the gaps are in women's health and, and really how to make clinical decisions about hormones when we are living in an evidence vacuum. It isn't an accident. It's a legacy from the Women's Health Initiative that was— that basically left healthy women, older women particularly, in a clinical no man's land, forcing us to choose between mechanistic promises and/or historical fear. So I want you to imagine a woman in her early 70s, you know, maybe late 60s, She's vibrant, metabolically healthy, proactive, and she didn't miss the menopause conversation. She lived through its evolution. But now she's facing a set of new questions. Her sleep is fragmented. Her bone density is slipping. She carries maybe the Alzheimer's gene. Maybe she carries a little increased risk for dementia or is very concerned about dementia. And she goes to the doctor and asks Is it too late for me to do hormone replacement therapy, particularly transdermal estrogen? Right. Transdermal estrogen, just for everybody, that is a bioidentical form of estrogen. It is either in a cream, a patch, an oil, a pellet, or an injectable. And the transdermal form is very, very different than what was used in the Women's Health Initiative. But here's the thing. The usual answer that women get is it's a reflexive No, based on the 2002 data. However, so her doctors basically say you're too old for hormone replacement therapy, but it's built on a foundation of missing pieces. And so today, what I'm going to do is a clinical autopsy on what's available in the literature. And by the end of this episode, you're going to understand why that critical window may not always apply to you.. And it may not always be close, particularly if we think about bones, we think about overall health and well-being, and the fact that we are not just a set of breasts and ovaries and uterus, but we're talking about quality of life. And particularly, we're trying to understand how it may play a role in the quality of our life and our longevity in reducing our risk of fragility. So let's get into it. So here's the core misconception. And the common one. The common one is that menopausal hormone therapy, I would argue bioidentical, is universally dangerous to start after 65, regardless of the woman's health status or the delivery mechanism. Number 2, the invisible problem. So this is an evidence vacuum. We aren't just lacking data, we are operating in a research desert that was created by the chilling effects of the overstatement of the 2002 Women's Health Initiative that basically stopped the vast majority of research testing on women in this very, very vital age group. And the reframing understanding risk in your 70s isn't just about age, it's about the delivery system. How is the hormone being delivered? Transdermal versus oral. Genetic susceptibility, especially some of the research coming out about APOE4. 4, which has a genetic risk for Alzheimer's, and moving from population-based fear and population-based data to a phenotype, which is— a phenotype is your genetics and your epigenetics put together— and having a more precise answer for an individual. Population data does not equal individual data. So let's talk about this, why this matters now. Well, healthier older women is a nationally growing demographic. I happen to be one of those, and it is largely ignored in medicine. We have to remember that the only thing that gets studied, the only thing that gets treated and reimbursed, is the treatment of disease. Insurance does not reimburse prevention. Medicare does not pay for quality of life, nor does it reimburse for prevention. And so therefore, those kind of studies are largely unfunded. And so we have this entire vacuum gap. And as our lifespan increases, you know, 10 years, 15 years, 20, 30, 40 years post-menopause. The gap at the end of menopause can easily span 30 years, and the hormone landscape is different at 70 than it was at 50. But the one-size-fits-all, can't start it, never can have it if you missed that perfect window, or the idea of halting it early despite its improvement in your health, is missing the boat. So here's number 1: the myth, right? So, the myth that started after the Women's Health Initiative and the pushback, really, from women who were on hormone replacement therapy, and the women who also recognized that they didn't want to survive without hormones, was you could do it for a little bit of time, but you had to stop early, and that you had this kind of hard stop around 60. So, I'm going to challenge the guidelines of hormone replacement therapy ending just after the first few years when you get done with your hot flashes and night sweats. You know, while we look at this, you know, window of treatment, the reality is, is we have some studies. There is one small study of 56 women. While small, really provided a rare window into women that were actually treated for a longer period of time, 20 years, and particularly looking at vertebral bone density. So what does that mean? We have a small study that looked at 56 women, and we're looking at the vertebral bone and the risk for fracture. Right. Vertebrae bone, especially the lower lumbar, is one of the areas that we look at in bone density and, and risk for osteoporosis. Because when you lose that, that, that bone and you get especially compression fractures, not even big fractures, what happens is it destabilizes the hip and increases your risk of falling and having a bigger break. Well, this particular study, while being small, had women that stayed on hormones for 20 years, and they showed transdermal therapy maintained into the 70s was advantageous for women. So let's get into what do we need to understand, right? So let's talk about the, the physiology and the difference between the Women's Health Initiative data and the delivery mechanism that was used during that study and what is used today, because they are not the same. Now, when we look at conjugated equine estrogen, which was what was used during the Women's Health Initiative, We know that oral conjugated equine estrogen contains 13 different estrogens. It is horse mare urine. Now, I'm gonna be really honest with you. There's a couple of those metabolites that indicate they might actually be protective against estrogen-sensitive cancers. However, the vast majority of those metabolites go into your liver, pass through your liver metabolism that is driven by your genetics, your phenotype,. And depending on how you're wired, you either make some byproducts that will increase your risk for coagulation, which is a fancy word for saying clotting, that can trigger things like Factor V and fibrinogen II and other clotting factors. And many of those metabolites that we get can increase our clotting risk when we are much older. This is why birth control pills aren't used— well, shouldn't be used. There's so many things that birth control can do, particularly for transitional periods in perimenopause. That's also why they've never been prescribed for menopausal women, right? The reality is, is when you take something orally like that, you have first-pass hepatic liver metabolism, and that changes how the drug works and especially makes byproducts that may be either favorable or not favorable. In most cases, it's not favorable. So oral estrogen absolutely should not be used in women in their 70s plus. And when you look at the Women's Health Initiative, It was particularly the synthetic medroxyprogesterone, or otherwise known as progestogens. Those ingredients are what's very, very risky for clotting. And it was actually that arm that stopped the Women's Health Initiative. So what's really going on here? So transdermal delivery, transdermal delivery again is put on the body, on the skin. That's what dermal means. And it is fundamentally different. When it absorbs through the skin, it goes through the skin into the tissues, into the bloodstream. That hormone then gets utilized throughout the body at its target organs— the ovaries, the bones, the muscles, the brain, the heart, the arteries, and on and on and on. Then the small amount of estradiol from that bioidentical topical transdermal form goes to the liver to go through hepatic metabolism. Which leaves very little left over. And transdermal in observational and retrospective causal comparative studies has been shown to not carry clotting risk in older women. The 10 million retrospective women's study paid for by Medicare that came out last year, no, it was not a clinical trial. However, it did retrospectively look back at naturally occurring diagnoses like menopause and looked at other things like stroke, heart attack, breast cancer, ovarian cancer, colon cancer risk. And they retrospectively looked back at the women who were taking hormones or had taken hormones for a period of time and their delivery mechanism and the women who never did anything at all. And what they found was transdermal hormones do not increase DVT, stroke, and heart attack risk to clotting. Now, here's the thing, is I'm going to get on the soapbox because you will hear from other researchers that unless it's a double-blind placebo-controlled clinical trial, it is not real. Well, I'm going to fight that. So causal comparative studies, I actually know quite a bit about. That's actually what my study was, the methodology in which we used. And so what does that mean? So causal comparative retrospective studies look back at data about a naturally occurring experience. So, in my particular case, I was looking at IBS, but we could argue osteoporosis, yes or no, is naturally occurring, right? Some women have it, some women don't. There's lots of reasons for it, but when you're looking at retrospective data, there was no interaction that happened. It naturally occurred in some women and not others. Then, You look at it and you say, what, what hypotheses or research question do you have? So in this particular case, the research question could easily be in naturally occurring women that go through menopause. Some have osteoporosis, some do not. Does hormone replacement therapy reverse the risk of osteoporosis? Right. So let's pretend we're building a study. So I'm going to look back in diagnoses, histories, and in EMR records And I'm going to look at the group of women diagnosed with osteoporosis and the women who were not. And then I'm going to ask a very basic question. How many that did not get osteoporosis were on hormones and how many were? Right. And same thing for the other group. That is what they call a retrospective causal comparative study. Right. We use these all the time in research. And there's a reason why. When we have long duration spans that need to be done in order to understand whether somebody carries a risk with a particular intervention, right? So, for instance, if I want to test for osteoporosis and if hormone replacement therapy is protective, the longer I have a woman on treatment, the longer I know that value, right? I can't put a woman on it for 2 months and see a damn bit of difference. It's got to be for a period of time. Those studies are really expensive, and they're also difficult to get. Funded. Now, if I do a retrospective causal comparative and I look at research data that didn't have any interaction and I'm looking at answering those questions, I also am not necessarily having a placebo-controlled trial, but I'm also seeing data that is not manipulated. And I can still account for confounding variables for things that I may or may not know, like other medications, other diagnoses, So here's the argument that you often hear, particularly around the Women's Health Initiative. So for those that pooh-pooh, you know, causal comparative retrospective studies and say that they're not real and that we have no evidence, are overlooking many of the recommendations that we have out today that we never actually clinically trialed. So let me give you an example. Smoking, right? People have been smoking for forever. And in the '50s, '60s, and even the early '70s, you could go into your doctor's office and light up. I remember sitting on an airplane and people lighting up in the back, right, as an adult. So here's the reality. We had already identified through observational studies and observation that smoking increased the risk for lung cancer. We didn't have to get two groups and say, okay, this group who's never smoked at all before, I want half of you to smoke and I want half of you to not smoke, and I'm going to follow you for 30 years and figure out which one of you get cancer. We never conducted that study because, A, it's unethical to do that, and B, the time and money it would take to do that is, is insurmountable. We don't have that kind of money to research it. So In medicine, it's great if we have causal comparative studies and we have observational studies where we're looking at large populations and extrapolating answers out of that and controlling for other variables. And it's awesome when we have double-blind placebo-controlled trials. But the reality is that is not the only answer. Double-blind placebo-controlled trials are fabulous, but they are not the only answer. And when we look at transdermal evidence, it is mounting heavily that transdermal estrogen is absolutely advantageous, and it is nowhere close to the, to the, the actual conjugated equine estrogen that was used in the Women's Health Initiative that has caused all of this fervor over the last 22 years. All right. So let's talk about some of the mechanistic things that we need to understand. So let's go back to the 70-year-old woman, right? We now understand that this 70-year-old woman has some concerns,. In many cases, osteoporosis and osteopenia is a concern. Definitely, if we look at dementia risk, particularly Alzheimer's. Alzheimer's is particularly predominantly female, and estrogen has the strongest correlation to the risks around Alzheimer's. Not so much for some of the other neurodegenerative diseases like ALS and MS and Parkinson's, but particularly Alzheimer's. And if you look at Alzheimer's patients, 3 out of 4 patients are female. Yes, we do outlive men, but we absolutely have the onset earlier and longer than men. All right. And so, and then if we look at some of the other data around cardiovascular disease, and I would say largely that's the area that we have the biggest gaps, we just don't know. But I'm going to start with some of the big ones because the other thing is You could do nothing, right? If you're listening to this and you happen to be in this age group and you're like, I could do nothing, right? You could do nothing. And that means you're going to probably get similar outcomes to what you do have right now. You could do something like hormone replacement therapy. And the way I always look at it in the conversations we have at Minerva and Living Well Dallas with our patients and clients is interventions medically, even with supplements and nutrition, have, have risks, right? Eating a lot of protein, eating a little protein, taking a supplement, not taking a supplement, taking a medication or not taking a medication. There's always feedback that could eventually happen in both positive outcomes and potentially negative outcomes. Right. Let's just be honest. Now, when you're sitting down to evaluate your current health compared to what you want, and what your intended outcome is, I think of it as a mathematical problem. I'm sorry, I'm a nerd, but I do think of it this way because I look at it and go, what are my biggest risk factors? Right? I know my genetics, so I'll give you some of mine. I'm an ApoA or ApoE4 carrier. I have clinical high cholesterol. Some of it is genetic. I carry significant cardiovascular risks for inflammatory response, and I am already diagnosed with some autoimmune conditions.. And those autoimmune conditions affect my ability to absorb nutrients, particularly minerals. So I have this sort of uphill battle I'm having to pay attention to for a long time, and I've been very honest about that. So when I sit down and look at my risk factors, cardiovascular disease, dementia, and bone density issues are my biggest because I'm also vertically challenged, meaning I'm short, right? And so when I look at intervention or not intervention, I'm always looking at it in the lens of What things am I trying to avoid or progressively avoid having and put those kind of in order of importance? And you, you see me, I'm not necessarily super concerned about breast cancer. You know, all women carry about a 6 in 1,000 chance today for breast cancer. By the time you get to 80, it's a 1 in 8, right? Our risk for breast cancer goes up not because of our hormone estrogen. That's complete bullshit. You don't have any estrogen if you aren't on hormone replacement therapy at 80 years old. What you do have is environmental estrogens and an inability to fix spelling errors in your DNA compared to what you were at 30. That's why we see the increase in breast cancer. It's because we can't fix DNA spelling errors when our cells replicate. So for me, I look at that and go, these other risks are very clear from my phenotype, my genetics, and my overall lifestyle and things that I've had happen to me. Over my 56 years on the planet. So I put those higher, right? So for most women, if you're in this, I'm a little bit past that perfect window for hormone replacement therapy, what we really are looking at is, is osteoporosis one of your biggest risks and concerns? Is your quality of life and how you feel one of your biggest concerns? So if you are absolutely symptomatic at this point still, I would say that's a big concern. And symptomatic could be anxiety, depression, lack of sleep, fractured sleep, which I'm going to talk a little bit about. And then that risk for dementia. And that's probably the area we don't know a lot of because we just have the Women's Health Initiative data. And we have some of the other imaging data from Mosconi's group that indicates the best time to start is earlier, but that doesn't mean you can't. And that's what I want to get into. So let's talk about the, the bone health benefits. I'm not gonna— there's a lot of research here. I'm going to cover some of the biggies. So, the Women's Health Initiative demonstrated that the women that were on estrogen only, conjugated equine estrogen, reduced all clinical fractures by 27% in hysterectomy women, right? So, women who had had a hysterectomy during a 7-year follow-up, right? A 20-year prospective observational data study. So, prospective means they're looking forward. Of 56 hysterectomized women that received transdermal estrogen documented sustained increased vertebral bone density T-scores. These benefits are most relevant to women without high baseline fracture risk, right? So women who are generally healthy that might have, might have lost bone, maybe osteopenia, early osteoporosis risk, that if they start hormones and stay on transdermal hormones, we have the best-case scenario. What we see in the literature based on this study, and there's many others, but I wanted to point out these two, is the fracture benefits require continuous therapy, right? So it's not, it's not one year and then let it go. And that the protective effects, once the hormone is stopped, dissipate after about 5 years of discontinuation. So most of the studies show that if you keep it in there 5 years or longer, closer to 10 years, we have sustained. But 5 years down the road, we start to see bone loss again. And estrogen is the foreman for bone building. It tells osteoblasts to build bone, build bone, and it tells osteoclasts to go home. Don't destroy the bone. So, so bone density is probably one of the best clinically studied areas for treatment for improving a major risk for women. 50% of women over 65 that fall and break a major bone will not make it through their first year. And of the women that do, 50% of them will not maintain their early mobility and freedom that they had before because of long-term damage from that injury, right? This is the leading accidental cause of living in a nursing home or assisted living. It's because we lose our independence. So bone density is one of the best areas. We have studies looking at very low-dose transdermal estrogen, particularly with patch studies using doses down to 0.014, 0.025, up to about 0.050 micrograms, and showing significant improvement in bone density and maintaining bone density. So we don't have to have very high doses to actually do that. Now, the question really then becomes, can you create enough bone with estrogen alone if there's already significant loss? We don't have that data because we largely haven't seen it. But I can tell you clinically, we've seen it in our clinic over the last 21 years because we always did hormone replacement therapy. Even women who were on a bone drug, right, whether it's a Tymlos or a bisphosphonate or a Prolia, Introducing low-dose hormone therapy can improve the overall outcome because all it does is give the body the natural hormone that instructed the bones what to do. So even if women were on treatment, they had benefit, and that benefit doesn't stop automagically at 60 or 65, right? So bone health has good clinical relevance, right? Now let's talk a little bit about sleep. So sleep is one of those major areas. And again, I talk to a lot of women because I'm online doing webinars every day or not every day. It feels like every day, which I love doing. But I talk to a lot of women who are very worried about dementia and Alzheimer's. That is my absolute biggest fear. I don't— let me lose my mind and have my physical body. I do not want that. And, you know, we, we have a lot of things that can contribute to that. One of them is the APOE4 gene. E4 gene. So, the 4 gene came about in human evolution when we needed to be able to create a significant inflammatory response to injury and infection. And this is actually during one of the ice ages when humans went— when apes went to something that looked a little more human and we went from being an herbivore to an omnivore. We got on the ground, we started hunting for food, and we were more subject to injury and infection. And so the ApoE4 gene was born. Now, that 4 gene helped us because if we got an infection, we could get a really quick inflammatory response. It also elevates cholesterol, increases lipid peroxidation and lipid accumulation potentially in the arteries as we get older. So that short-term support for inflammation that allowed us to thrive in a potentially violent and illness-producing environment also potentially put us at greater risk for inflammatory response later on. So if you are a carrier of an APOE4 gene, so you can have a 4,3, a 4,2, or 4,4. 4,4s and 4,3s have the absolute greatest risk. 4,2s is like 4% of the entire population, which I happen to be. 2s seem to be somewhat protected. So if you're the random 2,2, you might be protected, but a 4 carrier tends to have higher cholesterol, and also higher Alzheimer's risk over your lifetime for late onset. Right now, what's interesting is when we look at sleep, right, so gene carrier accounts for some part of it, right? Again, if you take 100% of people that carry 4s, 30% of them never get Alzheimer's. Why? It's the lifestyle pieces, right? One of the most powerful lifestyle pieces we have is the protection of high-quality sleep. So sleep quality improves cognitive function through multiple mechanisms, and one of them is, is improving sleep wave, like slow-wave sleep, improving REM state, improving the glymphatics, which is the— think of it as the sewer drainage system in the brain, and reducing amyloid plaques. Those are the things that contribute to the damage we see in Alzheimer's. So when we look at hormone replacement therapy, progesterone helps with sleep, sleep inertia, so creating sleep, particularly around its mechanism with GABA. Estrogen helps a little bit with serotonin and vasomotor. However, estrogen therapy also improves sleep without any impact to vasomotor activity, independent of that. So when we look at meta-analyses demonstrating transdermal estrogen and self-reported sleep quality. What we see is that women on transdermal estrogen have superior sleep improvements compared to studies with Premarin, right? And when they compared them head-to-head, they actually outperformed it. Transdermal estrogen has an impact on sleep independent of vasomotor symptoms also. So, so if they have sleep issues at all, transdermal estrogen decreased nocturnal movements and arousals, where the brain is being stimulated and being— you're being pulled out of those deep wave sleep, um, sleep cycles, which improve cognitive, cognitive concerns. And sleep disturbances— insomnia, waking frequently throughout the night, not getting slow wave sleep, poor deep sleep, poor REM sleep is a significant modifiable risk factor for dementia risks. And here's why. So recent meta-analysis show that insomnia and fragmented, fragmented sleep increased dementia risk by 13 to 36%. 13 to 36%. That is enormous in postmenopausal women, potentially accounting for nearly 500,000 preventable dementia cases in older adults. Per year. Now, sleep initiation insomnia poses the highest dementia risk, and some studies show it anywhere in like age-adjusted models of 51% down to about 24%. I'm sorry, 51%, but then when you adjust for age, 24% in some of the models, right? So insomnia is a major risk factor. Sleep fragmentation increases amyloid beta deposition and neurofibrillary tangles, right? The tau protein tangles. That is a key pathology in Alzheimer's. And slow-wave sleep loss is independently associated with increased dementia risk. So the therapeutic rationale to look at a woman who may be at risk for osteoporosis or have fragmented sleep, with or without hours awake— but if you are like, okay, I wake up and it's like Groundhog Day, and I'm waking up 3 or 4 or 5 times a night, or I wake up and I'm up all the or maybe you are like me and you're wearing rings and, and bands and all these other things and you're like, my sleep sucks, right? Even if you're 70, that is a massive modifiable risk factor that estrogen therapy transdermally may have major impact. Now, if you have a uterus, you have to do progesterone with it because they go together to protect the uterine lining. And progesterone affects sleep all on its own.. But some women, even with progesterone, don't get all of the sleep benefits because we need estrogen, and estrogen helps with serotonin, and it has its own mechanism. And this could be a very plausible discussion topic for you and your clinician if they're so willing to examine the research or listen, because this may carry a bigger risk than the, the modifiable vacuum that we have in studies about women taking hormone replacement therapy significantly later in life. When they are healthy. So by improving sleep quality, transdermal estradiol may provide indirect cognitive protection through restoration of sleep-dependent cognitive maintenance, and especially amyloid clearance, glymphatic clearance, and reducing tau protein tangles, fibrillary tangles. And this is a mechanistic plausible argument. Now, the problem is we don't have a ton of studies here. This is a major gap in the research. Right. However, I think it's a gap that's worth exploring. Now, let's get into the cardiovascular risk, because this is probably the greatest area where we do see some significant risk in oral estrogen. So oral estrogen and synthetic progestins absolutely have been found to increase risk in women, particularly when they're much older. Right. So significantly past menopause, and especially if it's being introduced for the first time significantly out of that 10-year window. And it's, and it's because estrogen protects the arterial wall, reduces arterial plaquing, and allows for greater remodeling of the arterial wall. When you've gone 10, 15, 20 years post-menopause, there is a chance through the process of aging that you have created atherosclerotic plaques. So hardening and plaquing of the arteries, increased cholesterol deposition that may get remodeled and broken loose. In the remodeling process of introducing estrogen. Now, how do we know whether that exists or not? We can do things like coronary angiograms, the CCTA, particularly with the Cleerly device that picks up not only hardened plaque that you can see on a calcium score, but soft, easy-to-rupture plaque, which is the bigger cause. 85% of all heart attacks are soft plaque ruptures that would never appear on a calcium score. So, So if you're 70, 75 and carry significant cardiovascular risk and have never had those assessments, those are one of the assessments that can be done to stratify risk. Here's what we do know in the research. In a small percentage of population, very small but significant, aorta— aortic stenosis, which is narrowing of the aorta due to arterial plaquing and atherosclerosis, could show an increased risk in the first few months of hormone replacement therapy, especially initiated at higher doses. Right. So, so here's, here's how to look at it. Yes, the Women's Health Initiative showed an elevated cardiovascular risk in the women that were in that study who were smokers, obese, hypertensive, at least 3/4 of them. And they increased clotting factors because of hepatic first-pass metabolism. But when we look at women that are on transdermal low-dose estrogen, that are healthy, metabolically healthy, they don't have arterial plaquing, they're not highly hypertensive, they've got a clean calcium score. And if you want to go one step further and have a clear CT angiogram and show that you don't have that, it's likely to carry substantially less risk than what was ever extrapolated from the Women's Health Initiative. And I would argue because of the, the study gap that we have, it's probably relative to nothing at all, right? So the 20-year observational data that we have using initial standard transdermal dosing down at these much lower levels, 0.025 milligrams per day at age 60, suggests lower doses sustain benefits while minimizing this sort of systemic exposure, but may also help with bone density and improve bone density and sleep fracture while not increasing any significant major risk factors with cardiovascular disease. And transvaginal delivery of very low-dose estrogen should be done by everybody. There's no risk there. Right? So, cardiovascular disease is probably the area that we have the most substantial data and also a vacuum in which we don't always know, you know, so a good practitioner is going to walk through your own history. Like, I carry cardiovascular risk. If I was 75, having never been on hormone replacement therapy, I'm going to tell you what I would do if I wanted to go on it, because I'm worried about osteoporosis, and I'm worried about my mood and my sleep, because it's been fractured and terrible for a long time since menopause. I'm going to go get a calcium score and a deeper dive into my arterial health and possibly get a Cleerly CT angiogram. That may not be available to everybody, but I can at least identify— I can get a carotid artery screen, a CIMT, and look, is there arterial plaquing? Is there evidence of vascular disease? If there is not, if there is not, then those aortic stenosis data do not apply in the same way. And so I can tell you at Minerva, through the telemedicine company in all 50 states and even in our clinic, We use that individual data to understand each individual woman's risk because we are not all the same and we are still not all the Women's Health Initiative patients. The vast majority of them were living cardiovascular risk lifestyle and already had advancing disease by the time they were in the study. So here's the thing. The evidence vacuum is what's real, right? Because there's a vacuum of evidence. Doesn't mean the absence of evidence is a substantiation of evidence of risk, right? We have an entire gap. So here's what we do know. There are no randomized trials here specifically examining cognitive outcomes with transdermal estrogen in women 70+ initiating therapy 20 years later. The WHI memory study found non-significant, right? Non-significant. That means it wasn't even— it wasn't enough to be left to chance. So let me clarify that. When a study says we found a difference but it was not significant, right, or non-significant 49% increased rate of dementia, that means that it, it wasn't even more important than potentially chance, right? Personally, I feel like they shouldn't even state those kind of data because people read a 49% risk of dementia risk, but if it's non-significant, that meant it was no different than chance. —right?—with oral conjugated estrogen in women that were 65+. So in that WHI Women's Memory Study, they talk about dementia risk, but it wasn't even valid compared to women who did nothing at all in the study. And then when they look at what they call post-hoc analysis, they found no cognitive harm in the Women's Health Initiative data initiating estrogen-only therapy in those age ranges between 50 and 59, right? So that's where that critical 10-year window came in, right? It's mechanistically plausible that hormone therapy provides this neuroprotective benefit. And I would say all these observational data studies and some of Dr. Mosconi's studies looking at Alzheimer's risk, that there is an initial improvement and especially improvement in cognition when we start it earlier. But again, that doesn't mean that you can't start it later and have the benefit. And to me, this, this is this crazy window that that neuroprotective window may be closed for everybody. Right. And that's penalizing women when we don't have the data to say that it is penalizing women, especially with topical forms of estrogen. The absence of mechanistic activation near menopause is distinct from active toxicity, right? That's what you need to kind of understand. In women starting therapy 20+ years post-menopause, the neuroprotective window may be closed, but we wouldn't necessarily expect them to experience negative effects from starting it, particularly if they don't have obvious cardiovascular risk. And then if you look again at cognition and look at sleep situation, right? If your sleep is poor, that in itself is its own independent risk factor for dementia, between 13 and 36% if we look at the studies. So more importantly, the documented sleep improvements from estradiol completely gives us a secondary potential pathway for cognitive preservation, right? So that would increase amyloid plaque clearance, and during slow-wave sleep, reduce neuroinflammation, improve glucose metabolism, which is a big part of dementia risk in the brain, and enhance synaptic plasticity during sleep-dependent consolidation, which is what's happening in the brain while you're sleeping. It's starting to make memories and pull things together and the release of the glymphatics, which is sort of the sewer system of your brain to get all this stuff to clean out. Now, this is also really important. Remember I was talking about the ApoE4 carriers? They have the greatest risk for cognitive decline and particularly baseline Alzheimer's risk. Like, depending on it, so if you have a 3 and a 4 or a 2 and a 4, you have a 2 to 3-fold increased risk for Alzheimer's late in life. If you are a 4/4, you have between a 7 to 10 times risk for Alzheimer's later in life, right? Now, many of us may not make it to that point where it shows up, but that's where we start to see dementia and Alzheimer's in your Now, ApoE4 has been shown that transdermal estradiol has some potential to be improving on that potential risk factor. Now, it was a very small study, and we have a long way to go, and we need to look at that. And so, it might be that, you know, it's the sleep mechanism and some of these other anti-inflammatory mechanisms. And we have some studies that that sort of indicate that may be true, but we got a way to go, right? So what does that mean to you? If you have ApoE status and you've got fractured sleep, your risk for, for Alzheimer's is greater. And if your cardiovascular markers and everything look good and maybe you've done some of that, some of that scanning like a calcium score and a CIMT, and you're not seeing advancing cardiovascular disease,, but you do also have risk for osteoporosis, this is how you start to look at it. So how do you make sort of your own personal clinical decision, right? So let's say you're over 65, maybe you've got documented osteoporosis or significant osteopenia, and you have sleep disturbances, and you're metabolically healthy. So no blood pressure problems, you know, pretty healthy weight, even if you have a little extra, right? You don't have to be a BMI of 18. You're not a smoker. You don't have serious advanced cardiovascular disease. Maybe if you did smoke, maybe it was back in your, you know, teens and 20s when you were in college. And you're— you have an absence of obvious cardiovascular risk, prior thrombotic event like clot or stroke or uncontrolled hypertension or active coronary disease. Like everything's clear in your plumbing around your heart. And then You're willing also to consider treatment in the context of limited research, right? This is the gap that the Women's Health Initiative left. We basically took that as gospel and then quit funding women's research. And so we're all living in this gap. And me personally, what I'm trying to do with Minerva and with everything we're doing in our clinic is to try and narrow this gap and bring some data in so women of my age group can benefit. Right. I don't— because if we were to continue and wait for data, you're basically going to sentence the millennials and the Gen Xers to the fate of boomers. Sorry, boomers, you should be pissed because you were robbed of the right to make the decision about hormone replacement therapy at the most therapeutic window. But if we wait for other studies to be just like the Women's Health Initiative, to be perfectly controlled, placebo-controlled trials, we will sentence the millennials and everybody after that, everybody before that to the same experience. I'm not willing to go there. And so I think for you, if you're listening to this and you're trying to figure it out, what you want to understand is what's my personal risk profile? How do I, how do I analyze that in a very sort of methodical way? And, and can, do I accept that I can't have all the answers? I know every time I, I am on a live or anything else, people are like, I just want to know, can it work for me? And I, and I'm like, I have to just give you the research and what do we have and what do we not have? And we don't have that data. But I would tell you, even if we had double-blind placebo-controlled trials in every single one, every single one of these potential risk factors, that is population data. That is not data about you. You need somebody who's looking at your genetics, at your labs, at your actual body, your lifestyle, your sleep, where you are, taking you through that process, because then that becomes an end of one of your risk. Ask, not just population data, right? We are not all the same, and we are definitely not small, better-looking men either. All right, and then here's— so once you've made those decisions, right, you're looking at that. And again, these are the areas that I look at, particularly for women outside of that initial, like, optimal window. How do we monitor, right? So if therapy is initiated, I don't prescribe. I'm a PhD. I'm the nerd behind the prescribers, right? Our team always does all that analysis and then looks at women individually. So, and then we start to look at what are we monitoring for protocol adherence and also therapeutic effect, right? So we often do, like in our clinic— it's harder to do this online— but in our clinic we do baseline functional qEEG and brain scan analysis under cognitive load. So we can actually see How are women doing cognitively at any time of life, but especially if we're trying to identify this, right, sooner rather than later? Because usually by the time it starts to show up under cognitive load, we have a bigger, bigger road to hoe, right? We got a bigger thing that we got to do. So we do regular sleep quality analysis. Well, while somebody's initiating therapy, is their sleep improving? Do they feel better when they wake up? If they're wearing wearables, what's happening? Are they starting to see longer deep sleep, better REM sleep? These things aren't perfect, but they're imperfect and consistently imperfect, so they can at least give us an idea. So if your deep sleep says it's 6 minutes, it definitely ain't an hour and a half, right? They're not as good as a, as a real sleep study, but these devices are getting better and better, and they can at least help us understand your own data. We want to look at DEXAs and a TBS score on a DEXA, which is trabecular bone score, which can give you a fracture risk profile, or what we call a Reams or echolight, which is a sonogram that can show us the trabecular bone as well. It's a little deeper dive. We want to know that so we can track that, right? So DEXA scans on a DEXA device don't really show microchanges, but your your, uh, reams, if you have access to that, absolutely can show changes in shorter periods of time. So we at least want to do those every year, at a minimum every 2 years. Cardiovascular monitoring, looking at advanced lipids, looking at inflammatory mechanisms, looking at your, your different types of cholesterol, your heart stress markers like myeloperoxidase and troponin. Those things can help us understand what's going on with the heart. Now, cholesterol is only one part of the picture, so it's better to get a little deeper dive. And looking at clinical reassessment and considering what's happening to identify, are your symptoms getting better? And we are looking at those risk factors and seeing improvement. You know, there's alternatives, right? We have to talk about the alternatives. I'm a, I'm a PhD, and my job is not to prove my hypothesis. My job is to go out and to attempt to disprove it. So when people talk about, hey, I did the research, all you did or all they did was take their confirmation bias and go look for crap online that agreed with them. Real researchers, real scientists come up with a hypothesis and a set of questions, and then they go out to try and find the opposite, and then they try and disprove it because it's through the act of trying to disprove it. When they can't is when they prove it right and prove it's even a gray area. Here. But I have to be honest, right? Are there drugs that work for bone density, particularly if you have significant loss? Yes. It's particularly the, um, the, um, anabolic drugs will put on bone very quickly. However, you get into this sort of back and forth where you have to take that and then you have to take an anti-reabsorptive, and they have side effects, right? And some of those side effects can be significant. Um, but there are drugs, so women could easily do bone drugs all by themselves and get better bone density. For sleep, people can do cognitive behavior therapy. Um, every single drug that's used, either over-the-counter or medication for sleep, has significant cognitive risks for dementia. They are not a panacea. I don't care what you're doing, they all carry risks. And so I would say sleep is not going to be helped by medication. And cognitive behavior therapy, meditation, some of those other devices can absolutely help,. But medication here is actually going to be worse. So to look at all those things, if I'm a woman in this age group, and I'm worried about osteoporosis, I'm worried about my brain, I'm also aware of cardiovascular, which are the 3 big areas. We just need to know that low-dose transdermal estrogen with progesterone, especially if you've got a uterus, but maybe not if you don't, right? Because the research is actually stronger on hysterectomy people, women who have been through a hysterectomy, and using estrogen alone to be protective, right? And so if we look at it, bone health, 27% reduction in fracture in the WHI study alone. If we look at the transdermal studies, sleep quality gets better, particularly in older women. And we have population that are starting to use these hormones and continuing long term.. And the route of delivery, transdermal, makes a difference. Uh, one caveat, everybody should be using vaginal estrogen. It reduces your risk of UTI by 86%, which is the leading cause of sepsis, urosepsis disease in women, and death. It absolutely kills more women in assisted living, skilled nursing, and nursing homes because they get a UTI and they don't present with the symptoms that we normally expect, and they end up in sepsis. So, that infectious death is almost always urosepsis in a woman, and vaginal estrogen reduces that risk dramatically. So, even if you're my age, we still recommend vaginal estrogen because it reduces the risk of UTI and reduces the risk of yeast infections, which even if you're not going to have, you know, long-term risk later in life, we don't want those ever because what do we do to treat them? Antibiotics, antifungals, right? So vaginal estrogen always. And individuals shared decision-making with explicit informed consent. So all of the things I went through today should be exactly what you get from your clinician. So if you are a woman who's 65, 70, or maybe you went through a hysterectomy and no one gave you hormone replacement therapy and you're 20 years out, that does not mean that you can't examine hormone replacement therapy for you. We just have to understand that there is a vacuum of research and that we have a lot of observational studies. We have a lot of retrospective causal comparative studies and prospective studies that are indicating that we have some potential to use these hormones in later life women with relative safety, particularly if you don't carry a lot of those risk factors that we saw in the primary population in the Women's Health Initiative. So I hope you found this to be helpful for decision-making for you, or maybe your mom, or your best friend, or the woman that sits next to you. You know, this is why I do it. I love you guys. I show up every day. If I could sit and talk all day long and help share information, I would. And this is why I do Menopause Mastery. So I want to thank you so much for listening. So if you happen to be listening to me online, Uh, and on your favorite podcast channel, don't forget to subscribe and also leave me a 5-star review. That's how people find us. And if you happen to be on YouTube, leave a comment, subscribe so you don't miss any of the future episodes, and leave a comment because I read those. And especially if you have content you would like me to cover, I'd love to do that too. And I'll be back with you next week on Menopause Mastery.