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

20:42Dr. Austin Baraki: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.

21:11Dr. Austin Baraki: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, you know, I want to pivot from the labs that may be a little bit less useful to maybe ones that are a little bit more.

21:44Dr. Austin Baraki:So, assessing their thyroid function, assessing their, you know, 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.

22:17Dr. Austin Baraki: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.

22:28Dr. Jordan Feigenbaum:Yeah, yeah, no, that's good. Let's pivot to the other Dr. Baraki and see what she has to say.

22:35Dr. Austin Baraki: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 perimenopause, and it even lags in the postmenopause timeframe. So premenopause, there is no FSH level that would diagnose perimenopause. 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 post-menopause, it can take three to six years to reach and stay at a menopausal level to be of any utility.

23:31Dr. Austin Baraki: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.

24:25And why make this distinction?

24:29Dr. Austin Baraki:And the reason is because the clinical stakes are fundamentally different. There's already a lower pretest 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 hysterectomy and a woman has had her uterus removed but she's kept her ovaries.

25:31It can be

25:32Dr. Austin Baraki: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.

26:23Dr. Austin Baraki: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.

27:13Dr. Austin Baraki: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 perimenopausal 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 menopausal hormone therapy would be labs for cardiometabolic screening.

28:14Dr. Austin Baraki: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.

28:55Dr. Austin Baraki: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.

29:45Dr. Austin Baraki: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.

30:07Dr. Jordan Feigenbaum: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. 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, her 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.

30:41Dr. Jordan Feigenbaum:This assumes that it was diagnosed correctly also. Now, when 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. Vasomotor 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.

31:23Dr. Jordan Feigenbaum:Genital urinary syndrome of menopause comes second. That's vaginal dryness, painful intercourse, recurrent UTIs, 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 post-menopausal years. It's also massively undertreated. Patients don't bring it up. Clinicians don't ask. But we will come back to it in this episode. Now, sleep is more complicated.

31:54Dr. Jordan Feigenbaum: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 loud snoring 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 flash is what needs to be treated.

32:27Dr. Jordan Feigenbaum:Next up is weight gain. Now, 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.

32:59Dr. Jordan Feigenbaum:And the 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.

33:35Dr. Jordan Feigenbaum: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 15-25%. The rest is the same osteoarthritis trajectory that drives joint pain in men of a similar age, particularly in adults who aren't training. Now, 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.

34:12Dr. Jordan Feigenbaum:The 1896 involutional melancholia diagnosis we mentioned in the intro, well, that 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. It's 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.

34:44Dr. Jordan Feigenbaum: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. Vasomotor symptoms and the genitourinary 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. Joint pain is mostly osteoarthritis and a lack of regular exercise. Cognitive complaints are mostly downstream of sleep and mood. The hormone therapy will treat what's hormonal, but the sleep apnea, the energy balance, and the joint health usually need different answers.

35:21Dr. Jordan Feigenbaum:yeah all right well let's let's uh let's 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

35:43Dr. Austin Baraki:these beliefs came from is the first step. And these sorts of kind of management decisions, they're necessarily, you know, 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, you know, 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.

36:15Dr. Austin Baraki: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, oh, maybe it isn't going to fix all of these things. So that's kind of the context that I'm coming in with is more important is establishing the rapport up front and then planning on longer term kind of management strategies. Now, with that said, most patients, when you have conversations about these types of multifactorial 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.

37:02Dr. Austin Baraki: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, you know, 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.

37:36Dr. Austin Baraki:So if it's sleep, you know, maybe we assess your risk of sleep apnea and might go down that route of things. Maybe there is some role of the vasomotor symptoms or some sleep fragmentation happening, but maybe also there's some untreated, unmanaged anxiety issues that might need to be dealt with in another way. When it comes to the joint pain, tell me about your physical activity levels. Tell me if you're in the gym, what are you doing in the gym? How hard? How often? How much? Things like that. Can we use our usual aches and pains type approach to mitigate that potentially alongside this? and then 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.

38:20Dr. Austin Baraki: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 over 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 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.

38:46Dr. Austin Baraki:And we want to be kind of comprehensive to address all of the concerns. So it's a, it's a little bit of a give and take, and I'm not there to dismiss the, the, you know, the, 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, 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 wanting to be comprehensive and thorough at the same time.

39:10Dr. Jordan Feigenbaum:That is a perfect segue into our break here. Now, when we come back from the break, we're going to talk about how to treat hot flashes because that here's something I realized about myself. I eat well when the setup is there. When there's something healthy and ready to go in my fridge, I'll eat it. When there's not, I end up staring at a cast iron skillet at about 8 p.m. and just, yeah, I'm not doing that. Well, Factor solved that for me. These are fully prepared meals designed by dieticians and crafted by chefs delivered right to your door. I've been using the Muscle Pro collection because the macros tend to line up with my energy targets, but they have meals built around whatever your goals are.

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40:13Dr. Jordan Feigenbaum:New subscribers only while supplies last. See the website for more details. That's factormeals.com slash BBM50off. Lately, I've been trying to upgrade my style, basically what I wear day to day. Fewer pieces, but ones that actually feel good and look put together without overthinking it. Quince has been my go-to for that. The fabrics feel elevated, the fits are clean, and everything just works. Right now, they have all the spring staples dialed in. 100 % European linen shorts and shirts starting at just$34. Lightweight, breathable, comfortable, and they still look polished. They also have these clean 100 % Pima cotton tees with a softness that just has to be felt.

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41:14Dr. Jordan Feigenbaum:Yeah, that's the Quince thing in a nutshell. Refresh your everyday with luxury you'll actually use. Head to Quince.com slash BBM for free shipping on your order and 365-day returns. Now available in Canada, too. That's Q-U-I-N-C-E dot com slash BBM for free shipping and 365 day returns. Quince dot com slash BBM. If you spend any time following Barbell Medicine, you know that we don't recommend things just because they have a popular logo. We look at the evidence plus our experience and our experience with standard issue hospital scrubs is actually not so good. Most of the time you're wearing something that fits like a repurposed parachute and feels about as soft as 400 grit sandpaper.

41:50Dr. Jordan Feigenbaum:Needless to say, we were excited when Figs came on board to sponsor our podcast. They realized healthcare workers are basically athletes who just happen to be doing rounds instead of marathon sessions in the gym. These are lightweight, they handle endless laundry cycles without falling apart, and they're antimicrobial. That last part is key because as we all know, hospitals can be a bit of a biohazard. They also finally moved past the era of boxy, scratchy scrubs. These are actually tailored so you don't look like you're walking around in a big blue cardboard box. They also have a new collab with New Balance for footwear and compression socks for those 14 hour shifts where your legs are starting to feel like lead weights.

42:23Dr. Jordan Feigenbaum:They even have outerwear for when the hospital administration decides to turn the ICU into a walk-in freezer. If you want to upgrade your work gear, FIGS is giving you 15 % off your first order. Head over to wearfigs.com and use the code FIGSRX at checkout. That's wearfigs.com, code FIGSRX for 15 % off. Your patients might not notice the tailoring, but your mirrors definitely will.

42:45Dr. Jordan Feigenbaum:One of the questions we get asked all the time is what books do you recommend for people who are interested in coaching others or who are taking their training very seriously. And it just so happens that a friend of the show, Dr. Eric Helms, along with Andy Morgan and Andrea Valdez, just released the third edition of the Muscle and Strength Pyramid books. Now, if you're not familiar, these cover the full hierarchy of what actually matters for nutrition and training, organized by priority, so you spend your time on the things that actually move the needle, and you get all of the science behind it too.

43:14Dr. Jordan Feigenbaum:Over 200 ,000 copies of the book have sold at this point, and for good reason. I read it, and it is excellent. 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 muscleandstrengthpyramids.com slash BM10 and use code BM10 for 10 % off. That's muscleandstrengthpyramids.com slash BM10. Code BM10 gets you 10 % off at checkout. Spaces definitively changed recently. And then we'll also talk about the Women's Health Initiative and cancer risks with MHT.

43:48All that after the break.

43:59Dr. Jordan Feigenbaum: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 a 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 too shall pass.

44:33Dr. Jordan Feigenbaum: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. The SWAN 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 60-year-old to remember when her hot flashes started and stopped, they measured the symptoms in real time across the entire transition. So they looked at 1 ,449 women who experienced frequent vasomotor symptoms during follow-up, defined as symptoms on six or more days in the last two weeks.

45:14Dr. Jordan Feigenbaum: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 four and a half years. The duration also varied by race and ethnicity. African-American women had the longest median duration, about 10 years. Chinese-American and Japanese-American women had the shortest, around five and just under five years, respectively. As with the timing data we covered earlier, these differences track the same social and structural factors rather than ancestry itself.

45:51Dr. Jordan Feigenbaum: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, and 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 arcuate nucleus of the hypothalamus were larger than an age-matched premenopausal women.

46:32Dr. Jordan Feigenbaum: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 KNDY neurons after the three molecules that they produce, Kispeptin, Neurokinin B, and Dynorphin. They project to 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 preoptic 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.

47:09Dr. Jordan Feigenbaum:The neurons fire, but at a controlled rate. When estradiol falls in the menopausal transition, that brake lifts. The neurons enlarge and they fire more. they release neurokinin B onto NK3 receptors in the thermoregulatory center. The result is a destabilization of the thermoneutral zone. That's the range of core 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.

47:44Dr. Jordan Feigenbaum:So if you block the NK3 receptor on the KNDY 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 Fezolinotant, an NK3 receptor antagonist, taken once daily as a pill. Skylight 1 randomized over 500 women across three groups. One group got placebo. One group got Fezolinotant 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.

48:26Dr. Jordan Feigenbaum:Both trials required at least seven moderate to severe hot flashes per day at baseline, so these were symptomatic women, the actual population the drug would be used in. What they found was that Fezalinitant at the 45 milligram dose cut moderate to severe hot flashes by about 60 to 65 percent from baseline. The The placebo-adjusted reduction was about 2.5 episodes per day at 12 weeks. For context, hormone therapy reduces hot flash frequency by about 75-90%. Fezolinotant reduces it by 60-65%, 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.

49:06Dr. Jordan Feigenbaum:The FDA updated labeling on fezolinotant 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. A 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.

49:41Dr. Jordan Feigenbaum: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?

49:54Dr. Austin Baraki:Yeah, this is an important one and one that's been coming up more and more frequently since these NK antagonists have become available. And 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. And so there are some women for whom menopausal hormone therapy might present unacceptable risks. And even in those situations, there is sometimes some room for maneuvering, particularly with informed consent and close monitoring and things like that.

50:38Dr. Austin Baraki: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 hot flashes and night sweats to include medicines like gabapentin and certain types of antidepressant medicines that are kind of used off-label in that context.

51:19Dr. Austin Baraki:And those 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 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 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.

52:13Dr. Austin Baraki: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 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.

52:45Dr. Austin Baraki:It's a combination NK1 and NK3 antagonist called Ellenzenitant. 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 upfront for the first three months. As with any 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.

53:16Dr. Jordan Feigenbaum:I really wish that most of the time 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, like if you need me, I'm here for you. Now to understand why there might be some sort of reservation about starting menopausal 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 controlled trials run in parallel.

53:58Dr. Jordan Feigenbaum: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 Premarin plus Provera. Now, Premarin is a conjugated estrogen that's extracted from the urine of pregnant mares. Provera is a specific synthetic progestin. The estrogen-only arm enrolled 10 ,000 women, just a little bit more than that, who had had a hysterectomy, and they were randomized to placebo or to premerin 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.

54:38Dr. Jordan Feigenbaum:The group was, on average, more than a decade after menopause. So this isn't a study of hormone therapy for symptomatic perimenopausal 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.

55:18Dr. Jordan Feigenbaum: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 was lower, and total mortality was neutral. The estrogen-only arm, the women who had had a hysterectomy and got Premarin without a progestin, that looked different. Breast cancer was not elevated and total mortality was, again, neutral.

55:57Dr. Jordan Feigenbaum: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.

56:35Dr. Jordan Feigenbaum:So Austin, you have this conversation with patients that are concerned or about menopausal hormone therapy because of this. This was very, very popular. Does that number, 8 in 10 ,000, actually come up? Are there concerns about cancer? And how do you talk about this with patients?

56:52Dr. Austin Baraki: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.

57:31Dr. Austin Baraki: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, 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 they, you know, if I get a sense early on in the conversation that they're kind of, you know, arithmetic math, math nerds or statisticians or something, and they really want to dig into this.

58:13Dr. Austin Baraki:Although in those situations, they've often already done the homework themselves beforehand. Yeah. Right. But, but for most folks, you know, telling them this type of number, they're like, what does that mean for me? Right. 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.

58:56Dr. Austin Baraki:If somebody is at 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 women who have like BRCA, you know, 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 it's again, going to be super individualized based on, there are standardized tools to assess breast cancer risk.

59:27Dr. Austin Baraki: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 duration of use and how long of exposure is 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's symptoms?

1:00:02Dr. Austin Baraki: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?

1:00:08Dr. Jordan Feigenbaum: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, if you look back, not quite half, but just under half of like the prescriptions stopped being filled 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 there was an increased risk of stroke and a trend towards pulmonary embolism, clot in the lungs, with no benefit for cardiovascular disease.

1:00:43Dr. Jordan Feigenbaum:The trial that was stopped in 2002 is now over 20 years old, and we have 20-year follow-up 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 harm 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.

1:01:23Dr. Jordan Feigenbaum:Women who were randomized in their 50s had 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 follow-up, 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 incidence was reduced by 22 % at 20 years of follow-up.

1:02:02Dr. Jordan Feigenbaum:Breast cancer mortality was reduced by 40%. 40%. Estrogen-only in the women who had had a hysterectomy 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 Fournier 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.

1:02:46Dr. Jordan Feigenbaum: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 WHI. One more thing before we leave breast cancer. The reassuring picture from these long-term WHI numbers is strongest for estrogen only, which means it's the strongest for those who've had a hysterectomy. For a woman 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 synthetic Provera that was used in the WHI, but it would be a mistake to read any of this as saying, look, estrogen plus progesterone is risk-free.

1:03:27Dr. Jordan Feigenbaum: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.

1:03:39Dr. Austin Baraki:Yeah, I think the only other thing I would add here is definitely the type, formulation, duration, all these things, and the person's baseline risk are going to be important considerations. We had talked earlier about the, 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 confers 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.

1:04:24Dr. Austin Baraki:And those are not things that you see nearly as much common concern about. That drinking a glass or two of wine a night and lack of physical activity and 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 other types of agents that we can use here that work entirely differently. So there's an agent called basodoxaphine 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 progestogen for some reason.

1:05:07Dr. Jordan Feigenbaum:Yeah. Yeah. No, that's a good point. All right. Well, let's come back to that timing hypothesis. And specifically, we're going to talk about a Cochran review from Boardman in 2015 that pooled 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%. Coronary 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.

1:05:44Dr. Jordan Feigenbaum:Now, that cardiovascular data does seem impressive. However, there's one more layer of nuance here. You got to 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 or the subject knows what they're taking. And so when you remove those studies from the analysis, the heart disease benefit gets a lot smaller. So the major societies are aligned on the interpretation here. 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.

1:06:21Dr. Jordan Feigenbaum: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 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 vulvovaginal tissue or the genitourinary syndrome of menopause.

1:07:02Dr. Jordan Feigenbaum:The dryness, the atrophy, painful intercourse, etc. 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 estrogens, regardless of delivery route or systemic absorption.

1:07:42Dr. Jordan Feigenbaum:but for vaginal estrogen, it overstates the risk 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 Austin, 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?

1:08:09Dr. Austin Baraki: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 right so if she says i'm having very you know characteristic vasomotor symptoms very characteristic genital urinary symptoms things like that i'm way more confident that potentially offering menopausal hormone therapy may benefit her right because to the point you made earlier those are the symptoms with the highest degree of like 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 hormone therapy to potentially benefit her, but my degree of confidence in that potential benefit is substantially tempered.

1:08:55Dr. Austin Baraki:And I'm also broadening to think about like, 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, endometrial, ovarian, all those sorts of things, as well as family history, multi-generational 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.

1:09:26Dr. Austin Baraki: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, gels, creams, things like that. If her risk is sufficiently low, she may well prefer and be an appropriate candidate to use 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.

1:10:08Dr. Austin Baraki: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 prevent cardiovascular disease or something like that.

1:10:38Dr. Austin Baraki: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, you know, guide that conversation and initiate therapy in somebody like this. Yeah.

1:10:59Dr. Jordan Feigenbaum:Inconsistent with the timing hypothesis, but also when I think about how much fanfare, I mean, you and I were in high school in 2002, right? 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 Premarin at that time, I mean, not only scary, but then also like, what is the intervening in this case? It 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, you know, no, no sort of even consideration like, well, maybe the benefits actually do outweigh the risks because we just honestly didn't know.

1:11:44Dr. Jordan Feigenbaum:which kind of goes 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

1:11:55Dr. Austin Baraki: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 just pour out and it's like yeah i don't think that's happening so i saw this thing on reddit uh one thing i do is

1:12:10Dr. Jordan Feigenbaum:I tend to scrape Reddit just to see like, what's the buzz? There's a thought in the, I don't 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 Premarin and, you know, they dumped out all of their prescriptions. And the thought was they flushed it all down the toilet. Oh, okay. And so now there's all the estrogen in 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.

1:12:46Dr. Jordan Feigenbaum:Of course, that 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 menopause content space gets right. The post-2002 prescribing collapse was an overcorrection. The pendulum swung too far in the other direction. A 52-year-old in 2026 with bothersome vasomotor symptoms is still far less likely to be offered hormone therapy than the evidence supports. It's routinely undertreated. A 2023 Mayo Clinic survey of women at large U.S.

1:13:23Dr. Jordan Feigenbaum:employers found high symptom prevalence, significant work productivity impact, and a systematic level of undertreatment. 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 that largely avoided this topic. Basically, it was just, look, this MHT can cause an increased 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.

1:13:58Dr. Jordan Feigenbaum: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.

1:14:38Dr. Jordan Feigenbaum:They attenuate over time. The zone of chaos framing applied to every woman overstates how most women will actually experienced this. The second overreach is collapsing all midlife symptoms into a single hormonal story. We walked through the attribution data in some detail earlier. Vasomotor symptoms and the genitourinary 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.

1:15:17Dr. Jordan Feigenbaum:If you tell a 49-year-old that everything she's experiencing is hormonal and resolvable with MHT, well, 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 Menopause Society, the Endocrine Society, the International Menopause Society, NICE, and the USPSTF all converge on the same point. Menopausal hormonal therapy is best used for bothersome symptoms.

1:15:55Dr. Jordan Feigenbaum: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.

1:16:08Dr. Austin Baraki: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. And the reframing piece comes in to messages that have been bullhorned, perhaps, that overstate what MHT can do, potentially describing it as a panacea. And 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.

1:17:17Dr. Austin Baraki:And so it's not a cure-all, so I need to really individualize that conversation. So that's the other part of the reframing is focusing on individualizing care. that's tailored to the patient. And 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. And in my experience, that is the best way to forge the therapeutic alliance and to do the most good for my patients. So that's the balanced view.

1:17:55Dr. Jordan Feigenbaum:a few other things worth discussing more directly we mentioned this sort of musculoskeletal syndrome of menopause earlier in the episode now 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. Now, that last point doesn't really register with me because I don't care about the ICD, but the SWAN data put the menopause attributable fraction of midlife joint pain at 15 to 25%.

1:18:35Dr. Jordan Feigenbaum:But 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. And 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. Comprehensive musculoskeletal care. Yes. 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, and that's hypoactive sexual desire disorder in postmenopausal women, a condition of chronically low libido causing significant personal distress.

1:19:24Dr. Jordan Feigenbaum:Other proposed uses for testosterone therapy in peri - and postmenopausal women are currently still being researched but have not yet been clearly established. The meta-analysis behind that statement pulled 36 randomized controlled trials and more than 8 ,400 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's no current FDA-approved female testosterone product in the United States, women receive fractional doses of male formulations or compounded preparations, which must be dosed carefully to avoid pushing testosterone several times higher than the normal female range.

1:20:10Dr. Jordan Feigenbaum:if you did that, it might, you might say, wow, this is really good. I'm growing a lot of muscle and I'm losing a bunch of fat, but there are some other side effects that tend to be irreversible.

1:20:20Dr. Austin Baraki:Unfortunately, there's a, there's a ton of, 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 the currently the most well-established. It's just that the research has historically been quite limited or of relatively poor quality. And I, as people who have listened to us for a long time probably recognize don't love relying on anecdote for you know 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 you know reasonably well-designed clinical trial in the population matching the person who's sitting in front of me.

1:21:09Dr. Austin Baraki:And I'd be 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 like, you know, more well-established than, you know, on an Instagram reel or something like that.

1:21:22Dr. Jordan Feigenbaum: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 right uh yeah so um 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.

1:22:07Dr. Jordan Feigenbaum: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

1:22:49Dr. Austin Baraki:compounded hormone products. the first thing to to point out here is that this 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?

1:23:41Dr. Austin Baraki: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 make up the compounded product.

1:24:29Dr. Austin Baraki: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.

1:25:18Dr. Austin Baraki:So we have a pretty good idea of what that safety data looks like.

1:25:25Dr. Jordan Feigenbaum: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 are we doing the test?

1:25:52Dr. Austin Baraki:Yeah, I've had a fair number of these Dutch test results sent my way. And 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, you know, various other, you know, blood-based hormone tests. And I do, and those I'm very comfortable 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. When 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.

1:26:35Dr. Austin Baraki: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.

1:27:29Dr. Austin Baraki: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.

1:27:43Dr. Jordan Feigenbaum: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?

1:28:06Dr. Austin Baraki:First of all, like why, 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 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 super physiologic 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?

1:28:36Dr. Austin Baraki:If ultimately she's just adamant that she's going to want to continue to be on super physiologic 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, a guy sent me his labs and his hematocrit is crazy high and his testosterone level is greater than 3 ,000 on the lab panel.

1:29:10Dr. Austin Baraki:And he wants my advice on risk management and all sorts of other things. And I'm 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 doses, but not dosing you up to that level and then trying to clean up the mess afterwards. So.

1:29:34Dr. Jordan Feigenbaum:Yeah. Yeah. Look, I know why she feels awesome.

1:29:38Dr. Austin Baraki:I feel awesome forever, but yeah. Yeah.

1:29:41Dr. Jordan Feigenbaum:At least I have a signal. All right. Before we wrap through the takeaways from this episode, Austin, anything you want to leave the listeners with?

1:29:49Dr. Austin Baraki: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. But 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 Dr.

1:30:20Dr. Austin Baraki:Baranki's. And so hopefully it's helpful for folks.

1:30:23Dr. Jordan Feigenbaum:All right, three things to take away from today. 1. Menopause is a normal life stage with a physiology that has been medicalized, moralized, and monetized in waves for over 200 years. Gardin coined the word in 1812 and made it a discrete medical object. Tilt in 1857 sold leeches and bromides for it. Preplyan 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.

1:31:06Dr. Jordan Feigenbaum:Two, the Women's Health Initiative in 2002 stopped early and changed prescribing 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 arm's breast cancer signal was largely driven by Provera, the synthetic progestin that is no longer the prescribing default in most countries. Modern transdermal estradiol plus micronized progesterone has a better safety profile than what was tested in the WHI.

1:31:42Dr. Jordan Feigenbaum:Hormone therapy for symptoms in the timing window? Yes. Hormone therapy for prevention in asymptomatic women? Not so much. Three, the contemporary menopause content and influencer space is correct on the undertreatment problem, but overstated on the rest. Many midlife symptoms are not related to estrogen. Hormone 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.

1:32:21Dr. Jordan Feigenbaum:Sleep gets better when you treat sleep. Mood 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 isn't 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.

1:32:55Dr. Jordan Feigenbaum:If this episode was useful, send it to the woman in your life or to her clinician. I'm Dr. Jordan Feigenbaum, that's Dr. Austin Baraki, and this has been the Barbell Medicine Podcast. Thanks for listening. Austin and I wrote a book and it's called Signal What Testosterone Levels Are Telling You About Your Health and it is available for pre-order right now with copies shipping in June. Here's why we wrote it. The testosterone conversation right now is a mess. About a quarter of testosterone prescriptions in the United States are started without any lab work and over half of men who meet criteria for low testosterone see their levels normalized on their own without any treatment.

1:33:28Dr. Jordan Feigenbaum:And at the same time, nearly 40 % of men who are 40 and older who have low testosterone, only about 1 in 10 of them are actually getting treatment. So some men are getting medicated for problems that they don't have, while other men who would genuinely benefit from treatment or at least an evaluation, well, they're not getting it. And everyone is trying to make decisions about testosterone, whether it's lifestyle, medication, or otherwise, without a clear framework for what testosterone even does. Signal is the book that we wrote to sort all of that out. It covers the physiology of testosterone from the ground up, how levels trend across the lifespan, and what has been driving them down at the population level over the last 50 years, with a surprising increase in the last decade.

1:34:03Dr. Jordan Feigenbaum:We get into what testosterone actually does to exercise outcomes and what exercise does to testosterone, because those are two different questions that get conflated constantly. There's a full section on female hormonal physiology rather than treating it as a footnote. We cover how to interpret labs, when the testing itself is unreliable, lifestyle measures that can move the needle before medication enters the conversation, and a detailed chapter on TRT for the people where it is appropriate. This is the book we wished existed when we started out. Right now, you can pre-order the hardcover, the Kindle version, or bundle both together.

1:34:33Dr. Jordan Feigenbaum:And there's a pre-order special right now where you can add the Barbell Medicine testosterone course taught by Dr. Austin Brocky with a significant discount. The course is normally$124.99, and you can get it for$49 if you pre-order before June 17th, which also happens to be my birthday. So a little birthday present to me and help support what we do here at Barbell Medicine. Head over to barbellmedicine.com and pre-order Signal today. That's barbellmedicine.com. Look for Signal in the shop.