Menopause, Part 1: What It Actually Is and the 24-Year WHI Correction

In 1889, on the 1st of June, a French neurologist named Charles Edward Browns the card stood up at a conference in Paris and announced that he had rejuvenated himself at age 72 by injecting himself with a water-based extract of ground-up guinea pig and dog testicles. He published it in the Lancet that July, a testosterone would not be isolated for another 46 years, and the extract contained no meaningful androgen because it wasn't in a lipid. The announcement, however, triggered a global market for what was called organotherapy. Within 30 years, a Russian-born French surgeon named Sergei Boneroff was grafting chimpanzee testicle onto human testicles. An American named John Brinkley was implanting goat testicle into the scrotums of pain patients, which included Sigmund Freud, at $750 a procedure. He later ran for governor in Kansas in 1930 and finished third. None of it worked, but all of it sold. Now the market these men were selling into had been built by 60 years of physician monographs that turned the end of men's seas into a disease. A Paris doctor coined the word menopause in 1812. An English doctor cataloged 100 symptoms and prescribed leeches ward in 1857. A German psychiatrist invented "involuitional melancholia" in 1896, a diagnosis that survived in the DSM for 84 years before being removed because it was indistinguishable from depression. Then in 1966, a Brooklyn gynecologist named Robert Wilson published feminine forever. Wilson argued that menopause was a deficiency disease, that without estrogen, women would deteriorate into what he called living decay, and that the answer was estrogen replacement from menopause until death. The book became a bestseller, and after Wilson's death, his son Ronald confirmed that the Wilson Research Foundation had been funded by Erst, the maker of Premerin. That was the drug that by 1975 was the single most dispensed medication in the United States. At the peak in 2001, 38% of American postmenopause women were on hormone therapy. On July 9, 2002, the Women's Health Initiative was stopped early. The headlines reported increased breast cancer, stroke, and clots on combined hormone therapy. The United States prescribing fell from 91 million dispensed prescriptions in the first half of 2002, to 57 million by the end of 2003, a 38% collapse in 18 months, a generation of physicians had stopped prescribing. Well, now it's 2026, and 24 years of follow-up have changed the picture again. The 18-year all-cause mortality data from the WHO are neutral. The 20-year follow-up of the estrogen-only arm showed a 22% reduction in breast cancer incidents, and a 40% reduction in breast cancer mortality. The breast cancer signal that drove the 2002 headlines was almost entirely in the combined arm, driven by a specific synthetic progestin that's no longer prescribed. Three different correct answers about menopause in 60 years. Today, a 49-year-old woman walks into her primary care office with hot flashes and disrupted sleep, and she shares every version of this story depending on who she's talking to, and how much that person has kept up with the research. Welcome to our Menopause series. This is Episode 1. I'm Dr. Jordan Faganbaum, and this is the Barbell Medicine Podcast. And here to discuss 200 years of doctors getting menopause wrong, why the most consequential menopause trial of the last 25 years was misread by everyone, including the people who ran it, and what the data actually says now that we have all this follow-up. It's the second most handsome doctor in North America, Dr. Austin Barocky. What's going on, man? She's putting a lot of pressure on us to fire some shots here. Let's keep it civil. Well, that's true. Well, we do have both Barockies on this menopause series. So I think to be in better than one, we can, you know, I'm not trying to oversell it, but we got both Barockies. What are we supposed to do here? Yeah, I think that my counterpart, my better half, as it were, will do a great job to supplement this with her uncleanical expertise and experience as well. Absolutely. All right, well, before we get into parimenopause, we need a brief sort of anatomy and physiology setup because the rest of this episode won't make sense without it and will aim to avoid getting overly complex, but there are some fundamentals we got to cover. So here are the basics of the menstrual cycle. The hypothalamus, it's a small structure at the base of the brain. It sends a hormone called GNRH, Ganatotropin, releasing hormone to the nearby pituitary gland. Now the pituitary gland responds by releasing two hormones of its own, FSH, which is follicle stimulating hormone and LH, luteinizing hormone. Those two hormones traveled to the ovaries and tell them to mature a follicle in the follicular phase of the cycle and at just the right time to trigger the release of an egg, which is known as ovulation. Now throughout the follicular phase, the follicle produces estradiol, the primary circulating form of estrogen in the premenopausal woman. After ovulation, the ruptured follicle forms a structure called the corpus luteum, which starts producing progesterone during what's known as the luteal phase. Now the estradiol and progesterone then feed back to the hypothalamus and pituitary in the brain and when they're high, the brain releases less FSH. If a pregnancy occurs, the corpus luteum keeps producing progesterone and the cycle pauses. If it doesn't, the corpus luteum breaks down and estradiol and progesterone fall. If when those hormones drop, the brain releases more FSH and the ovaries recruit the next group of follicles and the whole sequence runs again. That's what makes it a cycle about once a month for roughly 35-ish years. But estradiol does a whole lot more than just manage reproduction. In our book Signal, which we're releasing this year, we refer to it as the sort of estrogen shield. estradiol is anti-catebolic, so anti-breaking down at the level of the bone and the muscle tissue and it preserves the satellite cells that repair muscle. estradiol also influences the lipid profile, so your cholesterol carrying particles and helps maintain the health and function of the blood vessel linings, which is known as endothelium. It also restrains a specific set of neurons in the hypothalamus that will get into shortly, also playing a critical role in temperature regulation. So for 35 years, this system runs in the background and most women don't have to think about it. You don't have to quote "no" about your hormones, it just kind of happens automatically. But what changes at perimenopause is that the estradiol output from the ovaries starts to become more erratic, with more dramatic swings and an eventual decline throughout the metapausal transition. Sort of closed loop feedback starts to destabilize and to understand why we need to talk about follicles. So a woman is born with a fixed number of follicles in her ovaries. It's somewhere in the millions at birth and it declines across the lifetime through a process called atreja, which is the program cell death of follicles that were never activated. By puberty, the number is somewhere in the thousands and every menstrual cycle, the body recruits a group of follicles that mature and then it selects the best one, the rest kind of die off. So each cycle costs not one follicle, but dozens. And by a woman's late 40s, the reserve is in the low hundreds or even lower. Now these follicles produce estradiol. Again, that's the main type of estrogen. Also produce a hormone called inhibin B. Inhibin B feeds back to the pituitary in the brain and it suppresses FSH. As the follicle pool gets depleted and inhibin B falls, that sort of break comes off, allowing FSH to rise. This is the central mechanism of early perimenopause. And this is also why FSH is an imperfect clinical test for menopause. And from other reasons, it's sort of a lagging indicator. It's behind and it does not stabilize in the menopausal range for like three to six years after the final menstrual period. So by the time FSH is consistently elevated on a sort of blood draw, the underlying follicle depletion has been underway for months to years. And even then postmenopausal range FSH levels can still occasionally be followed by normal ovulatory cycles. That a single elevated FSH test does not rule out ongoing fertility. The major menopause in OB/GYN societies, including the American College of Obstetricians and Gynecologists, that's ACOG and the National Menopause Society, to think it's been rebranded to the Menopause Society, all emphasized that in a woman over the age of 45, the classic menopausal symptoms, you do not need to get an FSH test to diagnose menopause. It's a clinical diagnosis. And within this specific context, we're looking at age symptoms and changes in the menstrual pattern, not just an FSH test. In other contexts, such as when there's a suspicion for early menopause or premature ovarian failure, this is when this would happen in women who are under the age of 40 to 45. And during infertility evaluations, the FSH test itself has much more utility, but not really for diagnosing menopause. So the next question becomes, well, how long does perimenopause last? And the medical community uses a staging system called straw plus 10, which stands for the stages of reproductive aging workshop, pretty good acronym, but do you say so? So straw divides a woman's reproductive life into three phases, the reproductive years, the menopausal transition and postmenopause. So the system anchors on one event, just called the final menstrual period, which it calls stage zero. The reproductive years are the stages before the transition. The part that matters here is the late reproductive cycle, which is stage negative three. Yeah, that's negative three. I know it doesn't really make intuitive sense here, but that's when fertility is starting to decline and a woman may notice her cycles subtly changing even though they're still somewhat regular. The menopausal transition is perimenopausin. It has two stages. The early transition, stage negative two, begins when cycle length becomes persistently irregular. The difference of seven or more days between consecutive cycles that keeps a reoccurring. The late transition, which is stage negative one, begins with the first stretch of six year more days without a period. That late transition, so stage negative one, is the symptomatic stretch most of the time. Hormones, swing, wildly, hot flashes are most likely to start and on average at last somewhere between one to three years, although sometimes much longer. Then comes the final menstrual period, which again is stage zero, which can only be defined in retrospect like a year after not having a period. So again, you don't know that it's your final menstrual period until a year after. Sometimes we've talked about this in the context of training. You don't know when you fit your last PR until much, much later. So same sort of thing here. Everything after that, however, is postmenopause. Early postmenopause is called stage plus one. It is the first several years when FSH and estradiol are still changing and symptoms are still somewhat likely. Late postmenopause, which is stage plus two, is the rest of life. When the reproductive hormones have stabilized an ordinary aging becomes the main story. The final menstrual period happens on average somewhere around 51, 50 to 51 in most westernized populations. So most women will reach it there. A small number, roughly one in 40, experience what's called premature ovarian insufficiency, where the final period happens before age 40. That's a distinct clinical situation that needs its own evaluation. And then there's another small group, roughly one in 15, that experiences early menopause, somewhere between 40 and 44. So two different things there. But the transition itself from the first persistent change in cycle pattern to the final period usually runs somewhere between four to seven years for a minority of women at shorter than two years and for a smaller minority, it's longer than seven. But that four to seven window is the most common experience that we see reported in the literature. The internet makes this sound like a 15 year ordeal starting at 35. And for most women, the longitudinal data doesn't really support that. Perhaps there's a sort of a total addressable market, sort of marketing situation going on there. If menopause lasts much longer, you have more people you can sell your supplements back to. Now two factors can alter the timing here. Smoking, for example, tends to move the final period earlier by about a year to a year and a half on average. The compounds in cigarette smoke are directly toxic to the ovarian follicles and can speed up their depletion. And socioeconomic factors matter more than most people realize. The swan study, which stands for the study of women's health across the nation, we'll talk about that a lot in this episode, tracked thousands of women every year for a decade. In the raw data, women's age at the final period appears to differ by race. African American women somewhat earlier, Chinese American women somewhat later. But when researchers adjusted for socioeconomic factors, specifically educational attainment, financial strain, and baseline health, those differences largely disappeared. What looked like a difference by race was largely a difference in chronic stress and different socioeconomic factors and how those imprint on reproductive biology. The timeline of a woman's ovaries track with her life circumstances more than her ancestry in this particular case. So often, here's a visit you probably see quite often. A 49 year old female makes an appointment because she's not sleeping well, she's tired, she's feeling irritable. Her cycle has become unpredictable and she's worried that something's wrong. She's already seen a menopause coach and she comes in with lab work and a theory about what's driving it. Walk me through that visit. Yeah, this is indeed an patient encounter that I have very often these days in the context of conversations around perimenopause, menopause, menopause, hormone therapy, and associated concerns. So the first is, as I often begin these types of encounters is gonna be listening and validating the patient's experience and trying to get a sense of what is her theory? What is the understanding that she is coming in with so that I can try to meet her at the appropriate level rather than just be dismissive up front of something or assuming that she may have maybe a stronger understanding of things that she actually does. So really just getting a sense of where is she coming from and what landed her talking to me on this particular visit. She is clearly putting in some effort as a result of those concerns, seeking out a coach, seeking out lab testing, things like that, and acknowledging that that takes effort and some some degree of validation up front. All of this is aimed at building the necessary rapport that we will need to kind of guide the remainder of the conversation here. And I'm happy to take a look at any labs that a patient wants to bring to my attention, even though as we discussed a little while ago, these labs are actually going to be far less likely than people tend to think in these types of visits. Especially in this demographic, you said she's 49, she's having some kind of prototypical perimenopausal symptoms. And as you described, one of the hallmark mechanisms of those symptoms is not just that hormones are declining, but rather that there are erratic fluctuations in these hormones that can be contributory to the person having those symptoms. And so anytime you have erratic fluctuations in hormone levels, doing a snapshot blood draw, not terribly useful. It's just giving you a single snapshot in time. You don't know if it's on its way up, if it's on its way down, if it's at its peak, if it's at its trough. And so it can be pretty challenging, especially when cycles are irregular as well. 'Cause even the idea of I'm going to take these blood tests on a particular day after your cycle, for example, in many contexts that can be useful to try to get some degree of like comparison over time, but the cycles can get very irregular. So you don't really know which way is up when you're looking at these tests. As we mentioned, FSH, not terribly useful for diagnosing perimenopause in a 49 year old. It takes years after the final menstrual period for that FSH level to stabilize at its kind of ultimate level. And again, to reiterate, as you mentioned, even after having a single elevated FSH level, a woman can have a normal, ovulatory cycle, which means if you say, hey, your menopausal, you're done ovulating, no need to worry about. For example, contraception or something like that, or there's no risk of pregnancy. It's like you might find yourself eating your words if you deliver something with that degree of confidence based on a single lab test in that situation. - Yeah, now while I was here and you described the sort of like starting and stopping, sort of just conjured up this image, it's like, I think when I first learned about menopause, what I think about like undergrad, human physiology, I was like, I assume how much less refined version of myself thought this was kind of like, you're in a car, you run out of gas and you just kind of like, post to a stop, everything's nice and smooth and predictable or whatever. But what it sounds like you're saying is that, the engine dies and then all of a sudden, it fires back up again, revs to red line and you take off and then it dies again and it's kind of unpredictable. Is that, I mean, is that a terrible thing? - Sounds like a very fitting analogy coming from a motorhead like yourself. - Okay, yeah, like every, as much as I hate car analogies with respect to the human body, I feel like I do. - It's like I was buttering. - Yeah, yeah, yeah. And so these lab tests, you know, I see folks come in with these all the time and I look over them and I do some against them, some validation, but ultimately try to convey that the erraticness of hormone levels makes these tests a little bit less useful compared with taking the history that matters. What's the person's age? Tell me about the cycles, tell me about the symptom pattern. The labs might be suggestive, but neither confirms rules in or rules out anything definitively, which will help me pivot to the more important things that matter from a history standpoint. So characterizing that menstrual pattern a little bit more specifically. So tell me about the cycles, when did they become unpredictable? Are they shorter, longer, skipping, unusually heavy? In some situations in women over the age of 45, they might actually need something like an endometrial biopsy, depending on the nature of this menstrual irregularity. So there are some guidelines around that. The other symptoms that were being described things like sleep disruption, that can be a lot of things. Is it trouble falling asleep? Why might that be? Is the person having issues with anxiety, for example? Are they falling asleep and waking up in the middle of the night from sleep fragmentation, from having vasomotor symptoms like night sweats, or are they getting to sleep and then they wake up and they feel not refreshed or restored in the morning? Maybe they have undiagnosed sleep apnea, which is more common in this demographic as well. Characterizing if they have other vasomotor symptoms like hot flashes during the day, not just night sweats at night. And then a few other sets of questions, basically to look for mimics, things that can sound a lot like perimenopause or menopause, but are in fact something else. And this is super important, especially nowadays, because of how, say, like popular and hot of a topic it is. I mean, here we are, of course, after arguably too long, finally getting around to discussing it. But it's really important and something I am treating on a day-to-day basis. But you don't want to diagnose menopause and put someone on hormones when really their problem is that they have severe iron deficiency to keep coming back to that topic, or thyroid dysfunction, or something else entirely. So, I want to pivot from the labs that may be a little bit less useful to maybe ones that are a little bit more. So assessing their thyroid function, assessing their CBC, their ferritin levels, things like that. And then other metabolic considerations just. for characterizing their risk, cardiovascular risk right now and their future cardiovascular risk. Because if we do get to a point where we're going to have discussions around hormone therapy, that can become a factor that we need to think about what is the person's cardiovascular risk and that might shape our subsequent options. So I think that's like a high level overview. I'll be interested to hear when we pivot and get the other Dr. Baraki's take how much of my approach is similarly reflected in hers. But definitely validating the experience, putting the labs that she brings in the right context, and then getting the history and labs that do really matter and trying to guide the evaluation and management in a more productive direction. - Yeah, yeah, that's good. Let's pivot to the other Dr. Baraki and see what she has to say. - So the FSH, this is a very commonly requested and ordered test by the time a patient makes it to the gynecologist. And the fact is that FSH is an unreliable marker to diagnose pyrimenopause and it even lags in the postmenopause timeframe. So premenopause, there is no FSH level that would diagnose pyrimenopause. And in this timeframe, it truly varies and fluctuates too widely to be of any value. It can be normal, it can be kind of all over the place and it doesn't guide treatment. And even postmenopause, it can take three to six years to reach and stay at a menopausal level to be of any utility. And so the good news is that it's not only valid and feasible, but recommended to treat the person and her symptoms. And so I would say that the refreshing take is that in this case, listening to women, that's the way to go. Now, what would have to be different to actually consider or recommend getting an FSH level? That would come down to age. And particularly if a person has stopped having periods and are having the classic symptoms under the age of 46, so if this occurs between age 40 and 45, then they would be considered having gone through early menopause and certainly under the age of 40, which would be more consistent with premature ovarian insufficiency. And why make this distinction? And the reason is because the clinical stakes are fundamentally different. There are already going to be, there's already a lower pre-test probability for a younger woman to be experiencing menopause and a few other possibilities on the table. And so getting an FSH and an estrogen level, for example, are going to be a couple of the things that are used to investigate this further. And based on those results, that can lead to some pretty different branch points for diagnosis or treatment rather. And that can also have different implications on a person's long-term health. And also their fertility options and outcomes. And the other unique situation that I would point out is the case where someone has undergone his directomy and a woman has had her uterus removed, but she's kept her ovaries. It can be tempting to want to use a test like FSH to try to answer this question because the menstrual period is no longer acting as a guide that their periods are changing or that their periods have stopped. But I would draw us back to the original points made about being in a particular age range and having classic symptoms. And those things being the stronger guide points for how we're going to diagnose and make recommendations for treatment, whether that be with MHT or other approved treatment strategies. I don't have a standardized lab panel, but rather there are some things that I do consider ordering and just tailor it to the patient. And so in particular, if a person is still having menstrual cycles and there's any reasonable or feasible possibility that they could be pregnant, then I will be checking a pregnancy test to know if the reason they're no longer having periods could be pregnancy. Another test that I will consider is a TSH checking thyroid stimulating hormone. And again, I wouldn't say that I include this in a standard panel for everyone, but really listen to the symptoms that they're having. And if there is anything else that they're experiencing, that could be explained by a thyroid disorder, then I may also get a TSH. Now the things that often are brought up in conversation or are requested that we end up having a conversation to not order would be the FSH level, the estrogen level and the cortisol level. I would say those are the most common. Now the first two could be considered if there is an age factor. So if someone stopped having periods and they're under the age of 45 and definitely under the age of 40. And to check a cortisol, there really is not a role for checking this hormone in particular for classic paramedic puzzle symptoms in a person of the usual age. Another category of labs that I'm looking into and measurements that I'm looking into for everyone that could be a candidate for a menopausal hormone therapy would be labs for cardiometabolic screening. So that includes looking at their lipid panel and checking for their diabetes screening and paying attention to their blood pressure as well. This is going to help me individualize the conversation and to really help frame the risk versus benefits conversation when it comes to different treatment strategies. And the way that I approach this visit really is to start with reassurance and validation. Specifically, I recognize that it can be discouraging and confusing to be feeling not yourself, to be suffering from a variety of symptoms and then be told that you have normal labs. It feels invalidating, it feels discouraging. And so I want to reframe the conversation and just explain that we're in the business of treating the person. And this isn't a process that is centered around treating a lab value. But the next thing I would say too is we don't necessarily need to go down the pathway of using an SSRI to target mood symptoms because if we zoom out a little bit on this, it's pretty likely that what she's experiencing as those mood swings, likely the result of irritability that is pretty expected if your sleep is disrupted night after night due to night sweats, then you're not going to feel rested and this can just be kind of a downstream effect of that. And so my main advice is to try one thing at a time. We can swap out the SSRI for some form of MHT. If she's a good candidate, we can talk about some options that include estrogen and take it in a stepwise manner. All right, so we're back here on the Barbell Medicine podcast. This is our first episode of our Menopause series. Now we're going to talk about which symptoms are most attributable to menopause. But before we walk through the specific symptoms, I think it's worth talking about why this matters practically. And it's because if a 49-year-old comes in, convinced that everything that she's feeling is related to estrogen, the weight gain, joint pain, the brain fog or mood, sleep, and she gets prescribed menopausal hormone therapy, MHT for all of it, she's going to get a real result on some of it and nothing on the rest. This assumes that it was diagnosed correctly also. Now an MHT or the menopausal hormone therapy doesn't fix her body composition or her brain fog. She might increase the dose, add testosterone as becoming more popular or decide that hormone therapy doesn't work for her. So this question kind of shapes that whole conversation. Here's how the symptoms actually sort out. Phasomotor symptoms first, which means hot flashes and night sweats. Now these are the symptoms most clearly driven by menopause itself. And the data is consistent across nearly every study. Somewhere between 60 and 80% of women report some vasomotor symptoms during the transition. And a third to one half report the frequent pattern, which means six or more days of symptoms in the previous two weeks. General urinary syndrome of menopause comes second. That's vaginal dryness, painful intercourse, recurrent uti, urinary frequency. Now these are all clearly driven by the hormonal transition. But what sets this category apart from every other menopausal symptom is that it doesn't get better on its own typically. The estrogen loss takes away what was maintaining that tissue. And without treatment, the tissue keeps thinning out across the postmenopausal years. It's also massively under treated. Patients don't bring it up. Clinician zone asks, but we will come back to it in this episode. Now sleep is more complicated. Some midlife sleep trouble is due to menopause, but most of it isn't. The single biggest driver in women over 50 is undiagnosed sleep apnea, which in women often looks like fatigue, insomnia, and morning headaches rather than the loudest and worrying we typically associate with men. Add the insomnia that comes with normal aging, plus the caregiving and workload that lands in women in their late 40s and 50s, and most of what gets called a sleep problem in midlife isn't actually estrogen driven. The piece that is hormonal is usually downstream of hot flashes. A woman wakes up because she had one and the hot flashes what needs to be treated. Next up is weight gain. Most of the weight gain during this period isn't attributable to menopause. It's 30 years of midlife arithmetic. Small, imperceptible increases in dietary intake, a slow decline in activity, and a loss of muscle in adults who aren't training. Now for people who are listening to this who do train and haven't changed anything about their workouts in a decade, the activity decline isn't what's happening in the gym. It's everything else. The spontaneous movement that doesn't count as exercise, things like fidgeting, walking around the house, standing more. Most of this is subconsciously controlled, which is why people can't really perceive it, and then changes in the dietary intake work the same way, which is why people don't recognize they're eating more even as the weight goes up. That part adds up over 30 years. Based on the swan data, the average fat gain attributable to the menopause transition itself is about 1.5 kilos over 3.5 years, with a very small loss of lean mass, about 0.2 kilos over the same period. What menopause does change is where the fat goes. During the reproductive years, estrogen directs fat storage to the hips, thighs, and buttocks. When estrogen falls, the storage shifts to the visceral compartment, the fat packed around the abdominal organs, which means that the waist can't expand without the scale moving. That redistribution is what's menopause specific. The total weight is mostly midlife behavior, but the redistribution is real. Next up is joint pain, which is mostly osteoarthritis, but there is a real, but smaller, menopause piece on top of it. The swan data puts the menopause specific share of joint pain at roughly 15 to 25%. The rest is the same osteoarthritis trajectory that drives joint pain in men of a similar age, particularly in adults who aren't training. When it comes to mood and cognition, mood does get a lot worse for some women in late menopause, but most of what gets called perimenopausal depression is just depression. With the hormone changes making it worse for some women, the 1896 "involuitional melancholia diagnosis" we mentioned in the intro, left turned out to be wrong, thankfully. Menopause doesn't cause a unique depressive illness in most women, though some women do experience hormonally driven depression. This is the same story with cognition as well. The brain fog and the word-finding problems women sometimes describe are real, but when researchers actually measure cognitive performance, the dip is small, and it usually comes back within a few years of menopause, things get better. And most of what women feel day-to-day isn't really estrogen directly acting on the brain, it's the bad sleep, the changes in mood, and the hot flashes. Fix those, and the cognitive symptoms get better. So here's the take home. Vesomotor symptoms and the genital urinary syndrome of menopause are mostly caused by menopause. Weight gain is mostly midlife behavior and imperceptible changes in diet and activity. Sleep is mostly other things, but watch out for sleep apnea. And joint pain is mostly osteoarthritis and a lack of regular exercise. Cognitive complaints are mostly downstream of sleep and mood, but the hormone therapy will treat what's hormonal, but the sleep apnea, the energy balance, and the joint health usually need different answers. Yeah, all right. Well, let's put this to the test. Austin, now look, that same patient is back, 49-year-old from the hormone panel visit. This time, she's convinced that everything that she's feeling is related to menopause. And she's expecting menopausal hormonal therapy to handle all of it. So walk me through that conversation. Yeah, getting a sense of where these beliefs came from is the first step. And these sorts of kind of management decisions, they're necessarily medium to long-term, right? It's not like I can always predict this is the precise dose and formulation that you're going to need on day one, start you on it, and it's going to fix everything, like putting somebody on a five-day course of antibiotics for something where I can feel very confident. It's just going to cure the issue and then you're done. So if we're establishing upfront that this is going to be a long-term relationship, there's going to be some trial and error, some tinkering, some dose adjustments, things like that. That also gives me some time to work through some of these narratives and almost to let her experience it for herself, whether for good, for improvement, or for disappointment, and maybe realizing that like, oh, maybe it isn't going to fix all these things. So that's kind of the context that I'm coming in with is more important is establishing the report upfront and then planning on longer-term kind of management strategies. Now with that said, most patients, when you have conversations about these types of multi-factorial symptoms or symptoms that can be caused by a variety of different things, they generally do appreciate when their clinician thinks broadly and illustrates or demonstrates to them, look, it could be this, but it could be a lot of other things and I'm doing my due diligence by thinking about all these things, potentially assessing if testing is appropriate, testing for all of these things because I don't want to miss something that could be treatable in a different way. That lands just about every time. I don't know that I've ever had a patient situation where I'm like, it could be that, but it could also be this, this, this, and they're like, nah, I don't even want to think about any of those other possibilities, just give me this one thing, right? And so that, as long as that door is open, then I can have the conversation about not just it could be all these other things, but hey, even more effective is likely to be if we attack it from multiple different angles. So if it's sleep, maybe we assess your risk of sleep apnea and might go down that route of things. Maybe there is some role of the phase of motor symptoms or some sleep fragmentation happening, but maybe also there's some, you know, ang, ang, untreated, unmanaged anxiety issues that might need to be, you know, dealt with in another way. When it comes to the joint pain, tell me about your physical activity levels. Tell me what if you're in the gym, what are you doing in the gym? How hard? How often? How much? Things like that can we, you know, use our usual aches and pains type approach to mitigate that potentially alongside this? And then get it given that it's going to be a longer term, you know, treatment relationship. If it is in fact, deemed appropriate for her to initiate some level of hormone therapy, then why don't we make a plan to say we'll start something and, you know, this isn't something that tends to kick in within the first day. It can take some, you know, you might notice some changes over a few days and then it's going to notice more and more of the course of a few weeks and then some things take even a few months to really stabilize. And then once we follow up and we reassess, like what progress have we made and where have we not made progress? And then maybe we need to kind of broaden our thought process even more and attack the residual issues in other ways. Because clearly, you know, maybe there's more to it. Maybe the hormone therapy is only going to get us so far. And we want to be kind of comprehensive to address all of the concerns. So it's a little bit of a give and take and I'm not there to dismiss the, you know, the idea that she's coming in with right off the bat because that's a great way to never see that person again in follow up and they'd go find someone else to, you know, potentially lead them astray. And so as long as it's safe, I'm open to doing a lot of things, but wanted to be comprehensive and thorough at the same time. That is a perfect segue into our break. You know, when we come back from the break, we're going to talk about how to treat hot flashes because that is podcast sponsored by Figs. If you work in healthcare, you already know that the standard issued hospital scrubs are mostly an afterthought. They don't fit well. 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That's wearfigs.com. Code FigsRx for 15% off. We talk a lot about training and nutrition on this show, but sleep is probably the variable that most people are under investing in. The data on temperature and sleep quality is pretty compelling. If your sleep environment is too warm, you tend to stay in lighter sleep stages and miss out on the deeper sleep that your recovery actually needs. Chilli pad 2.0 by sleep me is a water-based mattress topper that lets you set your bed temperature anywhere from 55 to 115 degrees. It sits on top of your existing mattress and the new version has a quieter dock, a larger water tank, and a nightstand remote for each side of the bed that detects when you get in and starts your sleep schedule automatically. If you share your bed, dual zones let each of you set your own temperature. Those subscriptions, you buy it, you own it, and there's a two-year warranty and it's designed and assembled right here in the USA. 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So if you're looking for a great resource to have alongside our book signal and you want to go deeper on programming and nutrition planning, this would be a great addition to your library. Right now you can go to muscle and strengthen pyramids.com/bm10 and use code BM10 for 10% off. That's muscle and strength pyramids.com/bm10. Code BM10 gets you 10% off at checkout. Spaces definitely change recently and then we'll also talk about the Women's Health Initiative and Cancer Risks with MHT. So that after the break. [Music] All right, we're back here on the Barbell Medicine podcast. Now in the last segment, I gave you the headline from this study from Avis 2015 that frequent hot flashes run in the median of 7.4 years in duration. But we need to walk through the study behind that number because the design is what makes it trustworthy and impacts the current treatment approach. So for most of the 20th century, the clinical assumption was that hot flashes were transient. They clustered around the final menstrual period, lasted a year or two and then were gone. And that shaped how doctors counseled patients. Just hold on, this two shall pass. That assumption turned out to be wrong. Dr. Nancy Avis and colleagues at Wake Forest published their analysis in JAMA Internal Medicine in 2015 using the Swan cohort. This one, a study did something that most studies of menopausal symptoms don't. Women were enrolled before the menopausal transition and followed through it with annual symptom assessments. So instead of asking a six-year-old to remember when her hot flashes started in stop, they measured the symptoms in real time across the entire transition. So they looked at 1,449 women who experienced frequent vasomotor motor symptoms during follow-up, defined as symptoms on six or more days in the last two weeks. The question was simple. From first onset to last occurrence, how long did the symptom phase actually last? The answer was a median of 7.4 years. And for women with frequent symptoms, the median persistence after the final menstrual period was 4.5 years. The duration also varied by race and ethnicity. African American women had the longest median duration about 10 years. Japanese American and Japanese American women had the shortest around 5 and just under 5 years, respectively. As with the timing data we covered earlier, these differences track the same social and structural factors rather than ancestry itself. So a 50-year-old who hears that hot flashes last 7.4 years on average is in a completely different treatment decision than one who hears they last six months. Seven plus years of moderate to severe vasomotor symptoms affecting sleep, concentration, quality of life is a clinical problem that's probably worth treating rather than just saying hold on, it'll get better soon. So why do hot flashes even happen in the first place? In the early 1990s, two neuroscientists named Dr. Naomi Rance and W.S. Young looked at autopsy brain tissue from postmenopausal women and noticed something unique. A specific cluster of neurons in the arqueous nucleus of the hypothalamus were larger than an age-match pre-menopausal woman. The neurons were specifically enlarged in women whose ovaries had stopped producing estradiol. Now it took the field another 15 years to figure out what those neurons did. They are now called K and D Y neurons after the three molecules that they produce, kiss pepton, neurocine and B, and dynorphin. They project two two places. They go to two different areas. One is the reproductive axis. The other is the temperature regulation center of the hypothalamus, a region called the median pre-optic nucleus, which is part of the brain that decides whether you're too hot or too cold. Now, across the reproductive years, estradiol restrains these neurons. The neurons fire but add a controlled rate. When estradiol falls in the menopausal transition, that break lifts. The neurons enlarge and they fire more. They release neurocine and B onto NK-3 receptors in the thermoregulatory center. The result is a destabilization of the thermonutrile zone. That's the range of four temperatures that the brain considers acceptable. A small, normal rise in body temperature that the brain would ordinarily ignore now triggers the cascade. Peripheral vasodilation, vessels get bigger, you sweat profusely. A few minutes later, it goes away. A few minutes later, it happens again. If you block the NK-3 receptor on the K and D Y neurons themselves, just that specific receptor in the thermoregulatory circuit, you should be able to stop the cascade without any hormonal effect whatsoever. Two trials were done to test this, the Skylight Trials, both published in 2023. They tested Thesolinotant, an NK-3 receptor antagonist, taken once daily as a pill. Skylight 1 randomized over 500 women across three groups, one group got placebo, one group got Thesolinotant at 30 milligrams, and the third group got it at 45 milligrams. Skylight 2 reproduced the design in a separate group of over 500 women across seven different countries. Both trials required at least seven moderate to severe hot flashes per day at baseline, but these were symptomatic women. The actual population the drug would be used in. What they found was that Thesolinotant at the 45 milligram dose cut moderate to severe hot flashes by about 60 to 65 percent from baseline. The placebo adjusted reduction was about two and a half episodes per day at 12 weeks. For context, hormone therapy reduces hot flash frequency by about 75 to 90 percent. Thesolinotant reduces it by 60 to 65 percent, so it's smaller than hormone therapy. This can still be clinically useful though, because it works for women in whom hormone therapy is contraindicated. The FDA updated labeling on Thesolinotant in 2024 with a liver toxicity warning. Liver enzyme monitoring is recommended for the first three months as a result, but the bigger picture here is the arc from mechanism to medicine. A neuroscientist looks at autopsy brain tissue in the early 1990s. It takes 15 years to figure out what those neurons do and the mechanism predicts where to intervene. The drug is subsequently designed to hit that target and two independent randomized controlled trials replicate the result, subsequently resulting in FDA approval in 2023. From first observation to approved treatment, it's about 30 years. That's pretty fast by drug development standards. So Austin, who is actually the patient that you're considering for one of these medications when you're working through this and how do you position it relative to menopausal hormonal therapy? Yeah, this is an important one and one that's been coming up more and more frequently since these NK antagonists have become available. Part of the reason why is that menopausal hormone therapy works really well for vasomotor symptoms, for hot flashes and for night sweats. But unfortunately, there are some potential risks, some potential downsides, some unique considerations to using hormone therapy. So there are some women for whom menopausal hormone therapy might present unacceptable risks. And even in those situations, there's sometimes some room for maneuvering, particularly with informed consent and close monitoring and things like that. But classically, women with a history of hormone receptor positive breast cancers, with a history of certain types of blood clots, particularly things like pulmonary embolisms that can be potentially life-threatening. Women with certain forms of active liver disease or unexplained vaginal bleeding, things like that. Those are situations where the risk that may be conferred by putting someone on estrogen might be too high. And so then the alternatives historically have been various non-hormonal agents to manage vasomotor symptoms and things like flashes and night sweats to include medicines like GABA pentin and certain types of antidepressant medicines that are kind of used off label in that context. They don't work okay, but not nearly as well. And they have their own unique considerations and downsides and cons as well. And rather than saying, well, now, you know, women have to either suffer with these symptoms, or they have to quote unquote fail these other medicines. I like to flip that framing and say these other medicines have to fail them before they can be considered for the use of something else. And so now that we have these, these are medicines that work via non-hormonal mechanisms to more directly address the mechanism of the vasomotor symptoms to your point about how these neurons work. So rather than using kind of off label medicines that work in other ways to, you know, offer smaller benefit, we're directly attacking the mechanism in a non-hormonal way for women who either should not potentially use hormone therapy or for those who maybe have a bit more caution around the use of hormone therapy. Or maybe they've tried hormone therapy before and they had side effects that they didn't like from it and they stopped and they want to try something else instead. There are, you know, all these groups of people who now they just have this option available. I would still say that more often I'm using hormone therapy to treat these types of symptoms, but I do keep this option in my back pocket for situations where somebody is too high risk and really wants the symptoms addressed or has tried hormone therapy before and didn't do well with it. The last thing I'd mention is there's a newer agent compared with the one that you mentioned. It's a combination NK1 and NK3 antagonist called Ellen's Inatent and that's a dual antagonist that has actually better efficacy and does not have that same liver risk, which is nice because then you don't even have to worry about doing the liver enzyme monitoring up front for the first three months. As with any like relatively newer medicine, of course, these are a little bit more expensive than the traditional non-hormonal options, maybe a little bit more difficult to access in various situations, but sometimes we jump through the hoops that we need to jump through to get the person on the therapy that's most likely to benefit them. I really wish that most of the time the. the trade name is far better than the generic. But in both of these cases, they're still bad. And I just feel like I'm available for consultation. Okay. - Sure. - Like you need me. I'm here for you. Now to understand why there might be some sort of reservation about starting metaposal hormone therapy, we need to go back over 20 years to when the 2002 Women's Health Initiative was done. Because this provides the foundation of everything many women and even still some clinicians believe about hormone therapy today. The Women's Health Initiative was basically two randomized control trials run in parallel. Now both of these were designed to test whether hormone therapy started in older women would prevent chronic disease. The combined arm enrolled over 16,000 women who had an intact uterus, randomized to placebo or to Pramerin plus Provera. Pramerin is a conjugated estrogen that's extracted from the urine of pregnant mayors. Provera is a specific synthetic progestin. The estrogen only arm enrolled 10,000 women, just a little bit more than that, who had a hysterectomy and they were randomized to placebo or to Pramerin alone. The mean enrollment age in both arms was 63. So only about 10% of subjects were within five years of their final menstrual period. The group was on average more than a decade after metaposal. So this isn't a study of hormone therapy for symptomatic parimenopausal women. It's a study of hormone therapy in older asymptomatic women aiming to prevent chronic disease. Now on July 9th, 2002, the combined arm was stopped early after about five years because the predefined arm thresholds were crossed. Now the headline that basically drove this panic was that there was a 26% relative increase in breast cancer. Here's how that translates to something you can actually use. In the placebo group, invasive breast cancer occurred at a rate of about 30 cases per 10,000 women per year. In the combined hormone therapy group, the rate was about 38 per 10,000. So in excess of about eight cases per 10,000 women per year, it's the same trial, the same results, just communicated differently. On top of that, stroke, pulmonary embolism, and coronary heart disease were also elevated, but we're talking about single-digit excess events per 10,000 women per year. On the other hand, hip fractures and colorectal cancer, were slower, and total mortality was neutral. The estrogen only arm, the women who had had a histrectomy and got premerined without a progestin, that looked different. Breast cancer was not elevated, and total mortality was again neutral. But at the 2002 press conference, they didn't differentiate between the two arms clearly. The way the result got applied clinically did not differentiate between them at all. A 52-year-old symptomatic woman within two years of her final menstrual period, who would have been a reasonable candidate for hormone therapy, was treated as if she were a 70-year-old being given hormones to prevent heart attacks. Prescribing fell off a cliff. 91 million dispensed hormone therapy prescriptions in the first half of 2002, fell to 57 million by the end of 2003, a 38% reduction in just 18 months. A generation of physicians stopped prescribing, and a generation of women came off hormone therapy. So, Austin, you have this conversation with patients that are concerned about menopausal hormone therapy because of this. This was very, very popular. Does that number, eight in 10,000, actually come up? Are there concerns about cancer and how do you talk about this with patients? Yeah, this is a tricky one. It's pretty complex and requires a lot of individualization based on the woman's history, as well as family history, and certain other risk factors that need to be taken into consideration. A lot of folks think about the risk here. Again, very focused on estrogen. As if the estrogen is the main kind of contributor to this risk, rather than recognizing based on the data we have, that it's actually more the progestin that's seemingly contributing to the risk than the estrogen formulation. And additionally, I would say two other things. One, being that the formulations that were used in this study are not formulations that are most commonly used today. I do not generally prescribe these formulations very commonly at all at this point. Much more often use other formulations that appear to have lower risk these days. And additionally, the conversation around relative risk and absolute risk and it requires a fair amount of numeracy, which is the mathematical equivalent of literacy, which a lot of folks don't have. And it is not terribly useful to use these sorts of numbers with a lot of patients. Sometimes they really want to dig into the numbers, especially if I get a sense early on in the conversation that they're arithmetic, math nerds, or statisticians or something, and they really want to dig into this, although in those situations they've often already done the homework themselves beforehand. - Game run. - But for most folks, telling them this type of number, they're like, "What does that mean for me?" And so then I'm much more trying to get a sense of what are their current signs, symptoms, concerns, and goals? Like if they're absolutely insanely debilitated by symptoms and they're like, "Look, I'm willing to do anything," then it might be taking a little bit more of like a, quote unquote, harm reduction standpoint of like, "How can we try to make this as safe as possible?" We can try to make sure that you're on top of your breast cancer screening, making sure that things are clear up front, making sure that we're using the lowest risk formulations, and then kind of monitoring things regularly over time. If somebody is an extremely high risk of breast cancer, though, that needs to be a prominent part of the conversation. I mean, I've had these conversations with a woman who have like the RCA gene mutations, or those types of very strong family histories, where they're like my sister, my mom, my aunt, all had breast cancer before the age. And it's like, "Okay, we need to have a much more serious conversation about this kind of thing so that we can kind of go into it eyes wide open." So I can't paint a very specific picture here, because that's again, going to be super individualized based on their arcs, standardized tools to assess breast cancer risk. There are differing monitoring and screening strategies, and again, there are different formulations of hormone therapy that may confer greater or lower risk. For example, the use of Medroxyprogesterone acetate or provera in the study, not the formulation that I'm using most often in this situation compared with oral micronized progesterone. There's still some questions, open questions in the research literature around oral micronized progesterone these days for like duration of use and how long of exposure is like safe and things like that. But that's getting a little bit further into the weeds that are much more I try to apply on an individual basis based on again, like how debilitating are the person symptoms? What is the degree of risk we're trying to manage? And how long are we aiming to do this for their specific use case? Yeah. Yeah. And I think about, man, you just think about all the millions of women who are on this and this headline comes out. And then, you know, we see that if you look back, not quite half, but just under half of like the prescriptions stop being built, because this headline was so impactful. And that was just the combined arm that we talked about. But the estrogen alone arm was also stopped early about two years later in 2004 after a mean of about seven years, because it was an increased risk of stroke and a 10 trend towards pulmonary embolism clot in the lungs with no benefit from for cardiovascular disease. The trial that was stopped in 2002 is now over 20 years old. And we have 20 year followup data on the people that were in that study. Let's look at the two major papers to see what that says. The first is from Manson. This is from 2017. It was published in JAMA. And they reported 18 year mortality data from both of the groups combined. Total mortality, cardiovascular mortality, cancer mortality were all neutral. None of them were elevated. The trial that was stopped because of an excess arm signal didn't really translate to higher mortality over the subsequent 18 years. And when the analysis was broken out by age at the start of the study, the pattern that supports the timing hypothesis started to emerge. Women who were randomized in their 50s at favorable mortality. Women who were randomized in their 60s, it was neutral. And women who were randomized in their 70s, it was neutral to mildly unfavorable. The trend across the three age groups just missed statistical significance. Then three years later, the second landmark study dropped. And this was on 20 years of followup, specifically in the estrogen only arm, specifically looking at breast cancer outcomes. Now, this particular group did not drive the 2002 headlines, but still this is important to talk about. In this group, invasive breast cancer incidents was reduced by 22% at 20 years of followup. Breast cancer mortality was reduced by 40%. Estrogen only in the women who had had a history rectomy reduced both the rate of getting breast cancer and the rate of dying from it over 20 years later. This is the opposite directional inference that most clinicians and most patients drew from the 2002 publication and the subsequent mainstream media headlines. So that was the estrogen only arm, but the combined arm kept its breast cancer signal. The progestin in that arm, which is provera, is implicated in most of the harm signal. The fornier observational cohort in 80,000 French women showed that the breast cancer signal with micronized progesterone, the form chemically identical to what a woman's ovary produces, is small to neutral. Modern prescribing in most countries has moved to this version of progesterone, which carries a substantially smaller breast cancer signal than what provera did in the WHO. One more thing before we leave breast cancer. The reassuring picture from these long term WHOI numbers is strongest for estrogen only, which means it's the strongest for those who've had a history rectomy. For women with a uterus, they're going to need a progesterone alongside the estrogen, and that reassurance gets more complicated. Observational data suggests that micronized progesterone may carry a smaller breast cancer signal than the older sin. that it provera that was used in the WHOI. But it would be a mistake to read any of this as saying, look, estrogen plus progesterone is risk-free. The consensus position is that any combined regimen carries some increased risk of breast cancer. And the long-term randomized controlled trial data on micronized progesterone is not as good as we'd want it to be compared to estrogen alone. - Yeah, I think the only thing I would add here is definitely the type formulation duration, all these things in the person's baseline risk are gonna be important considerations. We had talked earlier about the, like, I think for most patients, lack of utility of specific numerical risk type of figures with folks. With that said, sometimes looking at the same problem through the lens of other risk factors can be useful. So for example, like the risk conferred for breast cancer from obesity or the risk that habitual alcohol use conferred on the risk of breast cancer. Both of those are comparable to even greater than the risks that we're observing in these types of studies. And those are not things that you see nearly as much, you know, common concern about that, you know, drinking a glass or two of wine a night and lack of physical activity in obesity might much more substantially increase your risk of breast cancer compared with one of these things. And even with these things, many of them are using formulations that we're not using so much anymore, whether transitioning to oral micronized progesterone or there are even, you know, non, there are other types of agents that we can use here that work entirely differently. So there's an agent called vasodoxetine that kind of can mitigate the endometrial risk as well without necessarily conferring the same degree of breast cancer impact if somebody needs to avoid a progesterogen for some reason. - Yeah, yeah, that's a good point. All right, well, let's come back to that timing hypothesis. And specifically, we're gonna talk about a Cochrane review from Bordman in 2015 that pulled the hormone therapy trials and split them by one variable. Did the woman start hormone therapy within 10 years of her final menstrual period or was it more than 10 years after? In the early starters, all cause mortality was reduced by 30%. Orinary heart disease events were reduced by 48%. In the late starters, however, no significant cardiovascular benefit was detected. Stroke and clot risk were actually higher. Now that cardiovascular data does seem impressive. However, there's one more layer of nuance here. You gotta look at whether the people knew what they were taking. We call this open label trials. In open label trials, both the researcher and the patient with the subject knows what they're taking. And so when you remove those studies from the analysis, the heart disease benefits gets a lot smaller. So the major societies are aligned on the interpretation here. The hormone therapy for bothersome symptoms started within 10 years of the final menstrual period and under the age of 60 has a favorable risk benefit profile for most women. But for prevention in an asymptomatic woman, it's not really indicated. The formulation shift also matters too. The modern default in most countries is a sort of transdermal estradiol plus micronized progesterone. Transdermal delivery bypasses the liver, which mitigates the clotting and stroke risk observed in with oral estrogen pills and micronized progesterone carries a smaller breast cancer risk than the provera that was used previously. Now one more thing on vaginal estrogen because it often gets confused with systemic therapy. Vaginal estrogen is a localized low-dose treatment applied directly to the vulvo vaginal tissue or the genito urinary syndrome of menopause, the dryness, the atrophy, painful intercourse, et cetera. Systemic absorption at standard doses is next to zero. It's minimal. A Scottish registry study of over 49,000 women found no increased breast cancer risk with vaginal estrogen. It's considered appropriate even in many women with absolute contraindications to systemic menopausal hormonal therapy, including many breast cancer survivors. But up until this year, there was a black box warning on vaginal estrogen because it was on every estrogen product regardless of route or whatever. And so the FDA requires that warning on all estrogen regardless of delivery route or systemic absorption. But for vaginal estrogen, it overstates the risks substantially. So this has just recently been reversed. I don't know that people have been beating down your door now in response that the black box warning has come off, but also let's come back to our 49 year old patient. We've been discussing so far. She's heard all of this. She wants menopausal hormonal therapy and her primary care won't prescribe it because of the 2002 data so she came to you. What does that conversation look like? Similar conversation to the one we've had so far where it's really characterizing what are the nature of her symptoms, which would help me to characterize the potential benefits. So if she says I'm having very characteristic face-am-motor symptoms, very characteristic general urinary symptoms, things like that, I'm way more confident that potentially offering menopausal hormonal therapy may benefit her, right? Because to the point you made earlier, those are the symptoms with the highest degree of attribution to menopause that we can feel the most confident. On the other hand, if she did not have any of those things, but her biggest concern had to do with sleep or had to do with joint pain, I'm not saying it's impossible for a hormon therapy to potentially benefit her, but my degree of confidence in that potential benefit is substantially tempered. And I'm also broadening to think about what are the mimics, what are the other things that can contribute to this or cause it and how might I attack those in a potentially more productive sort of way. So characterizing the symptoms will help me characterize the potential benefit and then characterizing what are her potential risks. So taking her own personal history of things like cancer, breast cancer screening, things like that, and to be true of area and all those sorts of things as well as family history, multigenerational family history, and then assessing her cardiovascular risks. So that helps me to get a sense of what are the potential risks that we're faced with. And then when I weigh those things out suggesting or recommending or offering the formulation that I think is best suited to address those symptoms, minimizing the potential risks, and is delivered in a way that she is open to using. That might be transdermal, like patches, jails, creams, things like that. If her risk is sufficiently low, she may well prefer and be an appropriate candidate to use an oral estrogen for example in this situation, especially if she does not want to use a transdermal form. So I've had some women, for example, who they struggle to have the patch to stay on because they're extremely active and they live in a hot climate and sweating and it falls off all the time. Or for various other sorts of kind of more pragmatic reasons. Or there's currently actively, as we speak, a shortage on estrogen patches. So I've been having to help women find alternatives or search through different pharmacies. So basically finding the formulation that fits their goals, their preferences is most likely to give them benefit and least likely to give them risk to fit it to them. The concerns of her primary care, because of the 2002 data, I would say is not applicable here fundamentally. I mean, we have a symptomatic 49-year-old woman, not a 62-year-old asymptomatic woman who is aiming to, you know, prevent cardiovascular disease or something like that. So it's an inappropriate application of those data in this situation, particularly when you go through the steps and you're rigorous with potential benefit, potential risk, and then fitting the dose formulation, and things like that to the patient's preferences, then this is a very quite safe thing to do. So I'd be happy to guide that conversation and initiate therapy in somebody like this. Yeah, inconsistent with the timing hypothesis, but also when I think about how much fanfare, I mean, you and I were in high school in 2012. Sure. So just blissfully unaware of how much mainstream attention this got, but upon reviewing that, I can only imagine what it felt like if you were on-premarine at that time. I mean, not only scary, but then also like, what is the intervening, in this case, eight took 18 years for the review of the study results and like longer-term follow-up to come out. So you're just, you know, live in life, no sort of even consideration like, "Well, maybe the benefits actually do outweigh the risks," because we just honestly didn't know, which kind of makes me think this is even crazier when this drug started getting massively prescribed in the 40s and 50s. Sure. Yeah. Anyway. Yeah, I'm still waiting for the massive headline about how much, you know, routine habitual alcohol use is increasing breast cancer risk and for the same phenomenon to take place where, you know, wide swaths of the population suddenly. It's four out of a hundred percent. Stop it. It's like, yeah, I don't think that's happening. So I saw this thing on Reddit. One thing I do is I tend to scrape Reddit just to see like, what's the buzz? Sure. There's a thought in the, I want to say, "manosphere," that actually means something different, but there's a thought that in the early 2000s, when this headline came out and all these women were quitting premerent and, you know, they dumped out all of their prescriptions and thought was they flushed it all down the toilet. Oh, okay. And so now there's all the estrogen and the water supply, and that's what's responsible for the feminization of men. You know, that's why the testosterone levels have gone down and why men are different now. Of course, that's why they're ignored. Yeah. Well, it ignores the actual testosterone trajectory that we've actually seen in men, which has basically been flat. All right. So let's talk about the current landscape when we wrap this up. And I want to be clear about what the sort of contemporary men of pause content space gets right. The post 2002 prescribing collapse was an over correction. The pendulum has swung too far in the other direction. A 52-year-old in 2026 with bothersome basal motor symptoms is still far less likely to be offered hormone therapy than the evidence supports is routinely under-treated. A 2023 Mayo Clinic Survey of Women at large US employers found high symptom prevalence, significant work productivity impact, and a systematic level of under treatment. The training gap in menopause medicine is real. There's a generation, multiple generations at this point, of physicians who were trained in the 2000s and 2010s, they largely avoided this topic. Basically, it was just, look, this MHT can cause an increase risk of cancer, no real benefit, and so that's it. The public education work in the content space has done a lot to bring menopause back into this sort of conversational space between patient and physician, so that's probably been useful. But there has been some overreach, particularly by various influencers in three big places. The first, framing perimenopause as universally turbulent and chaotic. The hormonal variability in late perimenopause is certainly real, and day-to-day fluctuations in estradiol can be dramatic. But that variability is stage-dependent and structured, and it also varies a lot between individuals. It applies most accurately to women in late perimenopause with significant vasomotor symptoms. The population level data show that most women experience a relatively orderly transition with predictable symptoms that get less over time. They attenuate over time. The zone of chaos framing applied to every woman overstates how most women will actually experience this. The second overreach is collapsing all midlife symptoms into a single hormonal story. We walked through the attribution data in some detail earlier. Vesomotor symptoms and the genital urinary syndrome of menopause are the most clearly menopause attributable signals. Total body weight gain is mostly not attributable to the menopausal hormone changes, cognitive symptoms, mood disorders, joint pain are common, but they are also impacted by aging, sleep, physical activity, and many other factors independent of hormones. If you tell a 49-year-old that everything she's experiencing is hormonal and resolvable with MHT, that sets her up for benefits on hot flashes and often a degree of disappointment on body composition, fatigue, and joint pain, especially if you don't do anything to manage those otherwise. The third overreach is positioning menopausal hormonal therapy as a default for all women regardless of their symptom burden. The menopausal society, the endocrine society, the international menopausal society, nice, and the USPSTF all converge on the same point. Menopausal hormonal therapy is best used for bothersome symptoms. It's not currently recommended for the prevention of chronic disease like heart disease or dementia in asymptomatic women, and the clinical trial evidence does not support the framing that all women should be on hormone therapy regardless of what they're actually experiencing. My view that I would offer as the balanced view is centered on appreciation and reframing. First appreciation for increased awareness and mobilization to improve symptoms that have been historically glossed over or normalized. Symptoms of menopause do not need to be accepted by women that are silenced into acquiescence and told to tough it out. I appreciate the attention to this topic. The reframing piece comes in to messages that have been bullhorned perhaps that overstate what MHT can do, potentially describing it as a panacea. The risk of this is potentially underplaying the importance or the need to emphasize meeting and exceeding physical activity guidelines, for example, or may ignore the fact that someone should really pursue a formal sleep assessment in the right context. It's not a cure all, so I need to really individualize that conversation. That's the other part of the reframing is focusing on individualizing care. It's tailored to the patient. The only way to do this reframing is first to level with the patient. I want to understand what she cares about, where she's coming from, what matters to her, and also what she knows about this topic. In my experience, that is the best way to forge the therapeutic alliance and to do the most good for my patients. That's the balanced view. A few other things worth discussing more directly. We mentioned the musculoskeletal syndrome of menopause earlier in the episode. That phrase has been popularized on social media as a named syndrome accounting for joint pain tendon vulnerabilities and frozen shoulder in perimenopausal women. It does remain controversial. It's not currently recognized by the menopause society, the American College of Rheumatology or the American Academy of Orthopedic Surgeons, and is not a distinct diagnostic entity in the international classification of disease. The last point doesn't really register with me because I don't care about the ICD. This one data put the menopause attributable fraction of midlife joint pain at 15 to 25%. If we call it a syndrome that elevates a real symptom into a diagnostic category that is not really supported by data, it's possible that this could be true. We'll see how the data emerges over this time. I just think labeling it can be problematic, especially if the only treatment then is MHT rather than training load, actually becoming active, sleep-perensive musculoskeletal care. Absolutely. The second part here is testosterone in women. The global consensus position statement on testosterone therapy in women, published in 2019 and endorsed by many international medical societies, concludes that there is one current evidence-based use for testosterone therapy in women. That's hypoactive sexual desire disorder in postmenopausal women, a condition of chronically low libido causing significant personal distress. Other proposed uses for testosterone therapy in parry and postmenopausal women are currently still being researched but have not yet been clearly established. The meta-analysis behind that statement pooled 36 randomized controlled trials and more than 8400 participants. It found a real benefit for sexual function, but no measurable benefit for body composition or for bone or for muscle or for cognition. The statement is explicit that treatment should aim for the normal premenopausal female testosterone range because there is no current FDA-approved female testosterone product in the United States, women receive fractional doses of male formulations or compounded preparations which must be dose carefully to avoid pushing testosterone several times higher than the normal female range. If you did that, it might say, "Wow, this is really good. I'm growing a lot of muscle, but I'm losing a bunch of fat." But there are some other side effects that tend to be irreversible. Unfortunately. This is another one of these very hot topics at the moment and it's one where I remain open to the possibility that there may be benefits beyond that one indication that is currently the most well-established is just that the research has historically been quite limited or of relatively poor quality. I, as people who have listened to us for a long time, probably recognize don't love relying on anecdote for these types of things, especially when the intervention is something with so much, I don't know, like, charged cultural conversation around it and that really augments the potential like expectancy effects and placebo type effects and things like that from the use of testosterone for all sorts of other things. Show me like a reasonably well-designed clinical trial in the population matching the person who's sitting in front of me and I'm very open to using it as long as it's used safely. I think that there are ways to use this safely as long as I can feel confident that the potential benefits are more well-established than on an Instagram reel or something like that. Yeah. I think we'd both agree that the testosterone data in men is still lacking. We would want even more data there, but you compare that to the testosterone data in women, which is almost non-existent at this point. Right. Yeah. So watch this space. Last two things here. First is compounded bioidentical hormones. The marketing behind this argues that they're safer and more natural than FDA approved options. The word bioidentical means that the hormone molecule is structurally identical to what the ovary produces. FDA approved hormone therapy already includes bioidentical estradiol and bioidentical progesterone available at any standard pharmacy through rigorous production standards. Compounded preparations are not subject to the same quality control, the same dosing consistency or regulatory oversight as FDA approved products. There are documented cases of endometrial cancer linked to inadequate compounded progesterone doses. So the National Academies of Science report in 2020, along with every major endocrine society cautions against routine use of compounded preparations when FDA approved alternatives exist and are appropriate. So this is not an uncommon scenario that I have encountered in my clinic, particularly in the setting of an ever growing market of menopause clinics that promote direct to consumer and for profit compounded hormone products. The first thing to point out here is that these precious clinic minutes are not the time to disparage or speak ill of this for profit market. But rather to focus on the person sitting across from me to acknowledge and validate the symptoms and the experiences that she had that led to seeking this treatment out in the first place. And really shifting the focus to point out that a lot of people don't realize that there are actually FDA-approved bioidentical hormones. And so this is the time really to make the distinction. Why opt for FDA-approved options versus these compounded options? It really comes down to two main categories. The first is related to something called pharmacokinetics, and that is essentially broken down into four main components. So I'm thinking about absorption or how a medication makes it into your body. The next thing is distribution. So where does it go in your body after it's been absorbed? The next thing is metabolism or how does your body break it down? And then the final thing is elimination or how does it leave your body. Now when we're thinking about a compounded product, there is a lot of unknown there in terms of the purity, the extent of the components of that makeup, the compounded product. And all of these unknowns and variations can impact all of these different elements of how it interacts with your body and what to expect when you use it as compared to those that have FDA approval. And one of the things that leads to this FDA approval is an assessment and validation of pharmacokinetics. And then the other component is really the robust safety data and quality control. So this is linking back to what's in this medication that I'm going to put in my body or absorb in one way or another. For quality control and safety data, I know what it is. I know what's in it and it's been rigorously investigated and tested. So we have a pretty good idea of what that safety data looks like. The second here is Dutch panels and salivary hormone tests. Dutch is a branded urine test, the name stands for dried urine test for comprehensive hormones. No major endocrine society endorses either for the clinical workup of perimenopause. Reference ranges for these tests are also not established against clinical outcomes. The test anchor for the conversation in numbers that don't predict what will or won't respond to treatment. So ultimately, why we do the test? Yeah, I've had a fair number of these Dutch test results sent my way. I do my best to this is one like I have a lot of folks who send me their, you know, be it their estradiol or their progesterone or various other, you know, blood based hormone tests. And I do and those I'm very comfortable like walking through and talking about. These I have a much more difficult time kind of containing my thoughts about Dutch testing. It's generally trash and not clinically useful for guiding management decisions. And this comes up in a clinic visit first. I want to express my understanding of what leads a person to seek out a direct to consumer option when they're looking for help or they're looking for answers. But unfortunately, the Dutch test does not do that. The reality is that fluctuating hormone levels during perimenopause are inherently chaotic and variable, which is precisely why they aren't useful or helpful in helping to guide treatment and management decisions. In fact, hormone levels of any kind are really not recommended to be checked in the treatment or rather in the diagnosis or treatment in perimenopause. And the other thing that I want to do during this visit is to recognize the fact that seeds have already been planted where a patient believes that her adrenal glands are functioning improperly. And so this is my moment to provide reassurance. Reassurance that the adrenal glands do not simply wear out due to stress or at a particular age. So those are the things that I'm focusing on. All right, Austin. So let's wrap this up here. This is another patient pattern that you probably recognize. She's been on compounded bioidentical hormone pellets for 18 months from a menopause clinic. Her total testosterone is well above the normal range. Let's say two times the normal range. She feels better than she has in years, but she wants you to take over the prescribing. What do you do? First of all, like why? Well, you know, why are you coming to me for this? If you're feeling the best you have in years, you have access to this clinic, I'm not going to be somebody who's implanting pellets. That's not something that I do in my practice, but in under this kind of more hypothetical scenario, really just assessing what are their goals. And does she recognize that she is putting herself at some degree of risk by maintaining very superphysiologic testosterone levels? There is a good chance that she is not aware of what those potential risks might be. And then that might help to open the door to having a conversation of like, how can we steer this in a safer direction? If ultimately she's just adamant that she's going to want to continue to be on superphysiologic levels of pellets and things like that. This is a scenario where I'm probably less likely to continue playing along with this scenario, recommending against it and then advising that she may return to the prescribing clinician because that's a level of risk that I would prefer to not necessarily be a part of. Not unlike when I've worked with guys before who are on testosterone and just actually last week, guys sent me his labs and his hematocritz crazy high and his testosterone level is greater than 3,000 on the lab panel. And he wants my advice on like risk management and all sorts of other things. And I'm like totally happy to provide guidance and suggestions and things like that. But if you're asking me to be the prescribing physician for your testosterone, this is not a scenario where I'm as interested in playing a part in that. I'm happy to provide physiologically appropriate kind of doses, but not dosing you up to that level and then trying to clean up the mess afterwards. So. Yeah. Yeah. Look, I know why she feels awesome. I feel awesome forever, but yeah, yeah, TV. I always have a signal. All right. Before we wrap through the takeaways from this episode, Austin, anything you want to be listened with? Yeah, this was a, this was a doozy for somebody who's really interested in this topic. Definitely might require multiple listens. It's something that is a very popular topic of conversation these days, but you need to be really judicious about who you choose to follow in this space. I'm not saying that we're the best out there, but this is kind of our take on the topic. There are a lot of people who are giving not very clearly evidence-based positions on it. And so we've done our best to lay this out across the three episode series combined with our clinical experience, my own as well as the other, the other Dr. Barakis. And so hopefully it's, hopefully it's helpful for folks. All right. Three things to take away from today. One, menopause is a normal life stage with a physiology that has been medicalized, moralized, and monetized in waves for over 200 years. Gardan coined the word in 1812 and made it a discrete medical object. Till in 1857 sold leeches and bromides for it. Preppelin in 1896 invented a disease around it that survived 84 years. Till Wilson in 1966 turned it into a deficiency disease and he sold a generation of women on lifelong estrogen replacement, funded in substantial part by the pharmaceutical company that made the estrogen. The contemporary menopause content space is the most recent iteration of this pattern with different products and better cameras. Two, the women's health initiative in 2002 stopped early and changed for describing globally within months. 24 years of follow up have substantially revised the original conclusions, however. The 18 year mortality data are neutral. The 20 year breast cancer follow up of the estrogen only arm showed a 22% reduction in incidence and a 40% reduction in mortality. The combined arms breast cancer signal was largely driven by Provera, the synthetic progestin that is no longer the prescribing default in most countries. Modern trans-Nermal estradiol plus micronized progesterone has a better safety profile than what was tested in the WHO. Formal therapy for symptoms in the timing window? Yes. Formal therapy for prevention in asymptomatic women? Not so much. Three, the contemporary menopause content and influencer space is correct on the under-treatment problem, but overstated on the rest. Many midlife symptoms are not related to estrogen. And therapy is not indicated for prevention, specifically in asymptomatic women. Testosterone in women has one guideline-supported indication at this time. Compounded bioidenticals and Dutch panels are 1960s product strategy with new packaging and better distribution. We need to match the intervention to the indication and stick with the evidence. Sleep gets better when you treat sleep. Move gets better when you treat mood. Body composition gets better when you address the things that drive body composition, and bone gets stronger when you load it. The story that says all of this is hormonal and resolvable through one prescription is an accurate and is not based in evidence. Next week we walk through what actually changes in a woman's body composition and cardiometabolic health across midlife. What menopause specifically adds in addition to that and how the medical history of women's exercise got us to where we are. All of that and more on next week's episode in our menopause series. If this episode was useful, send it to the woman in your life or to her clinician. I'm Dr. Jordan Feig and Bob. That's Dr. Austin Baraki and this has been the Barbell Medicine podcast. Thanks for listening.