Hormone Replacement Therapy Decoded: Why the FDA Removed the Blackbox Warning on HRT

The FDA just removed the black box warning on HRT for menopause. Who should not go on hormone replacement therapy? Active breast cancer or active cancer if someone has not worked up vaginal bleeding and stroke. Benefits of hormone replacement therapy include a reduced risk of all-cause mortality, fractures. HRT has also been associated with a 50% reduction in heart attack risk. 64% reduction in cognitive decline, 34% lower risk of Alzheimer's. We think about testosterone and we think about muscle mass, but there are testosterone receptors all over the body. There are estrogen receptors all over the body. It's not just, oh my gosh, I'm going to give you testosterone and then you're going to grow a beard and muscles. It's not going to happen. You know, we think about testosterone replacement therapy for men. Noe, Blinks and I. Women aren't even thinking about that. Similarly, just how men aren't even thinking about estrogen, which is equally important for men and women. Wow. What's up, friends? I'm Dr. Gabrielle Lyon. And before we jump into this episode, I want to put together a handful of definitions so that we are all on the same page. And the first definition that you are going to hear is called virulization. And this is the development of male characteristics by being exposed to an androgen and androgen like testosterone. They include the following, deepening in the voice, coarse hair on your body, increase in clitoris, increase in muscle mass. And that is called virulization. The second definition that you might hear is something called hematocrit. And this is a simple blood test and it refers to the oxygen carrying capacity in the blood. The higher your hematocrit, the more oxygen that you carry. The third definition that I think is important is something called an androgen. And an androgen is a steroid hormone. And this is typically related to the development and maintenance of male sex characteristics, but it's present in both men and women. And finally, something called liquid chromatography. And this is a way or a chemical technique that allows us to identify certain compounds in the body like testosterone. You've heard me say before muscle is the organ of longevity. Now I'm putting the playbook in your hands. My new book, the forever strong playbook is your roadmap to building real strength, not just in your body, but in your health, your energy, your life. This isn't theory. Inside, you'll find the exact workouts, protein for recipes, recovery strategies, and mindset tools I use with my patients and live by myself. This book is for anyone and everybody who wants to age powerfully, stay vibrant for their family and show up strong every single day. When you pre-order, you're not just getting a book, you're joining a movement. The links in the show notes and I cannot wait for you to dive in. We have some really important stuff that we have to cover. Yes. The FDA just removed the black box warning on HRT for, I know, for menopause. And why is this important? This is important because for the last since 2003 or so, women have stopped using hormone replacement therapy for risk of breast cancer, cancers, heart disease, stroke, and it's really changed the landscape of health and wellness for women. And we're now entering a new landscape. Is that because of your advocacy? No, but what I think has really happened is that up until 2003, women were prescribed hormones. These hormones include estrogen, progesterone, and testosterone. So testosterone replacement therapy has been around for, I don't know, 80 years very effectively. And then all of a sudden, the Women's Health Initiative came out and that changed the trajectory and people became afraid both of the hormones and also prescribing. But again, now we get a review of what the science says, what are the logistics, should women take testosterone? You were asking me, will women grow a beauty? That's what I want to know. Will they grow a beard? That's what my wife would want to know. Be like, am I going to grow a beard? No. And if you look at the normal laboratory values of total testosterone in women, it is dependent on age and menopausal status, also the type of testing used. Depending on the assay used, depending on the lab, you might get a higher number or a lower number. And the gold standard is liquid chromatography. Okay. Just thought I'd throw that out. So if you're getting... Is that specific, like, so should that be something when you go to your physician? Yes, it should. Your request. Okay. Yes, it should. Liquid chromatography. That's right. And you should at least find out, is it liquid chromatography mass spec? But let's talk about the ranges. Total testosterone ranges. So there's total testosterone and then there is free testosterone. I suppose before we talk about testosterone, we talk about androgens. And androgens, you know, they're also precursors for estrogens. Estrone, estradiol, and estriol, E3 in pregnancy. But the primary, most well-known androgen of them all is... Testosterone. That's right. Which can aromatize into estrodial in both men and women? Well, it just seems like men get... Do you, would you say, overly worried about that? Totally. Okay. And we test, in our clinic, we do test for estrogen levels in men. And men, estrogen is actually... You know what we should do? We should also do an episode on estrogen in men. Yes. Why not? Why don't we just balance the playing field? That's true. Yeah, yeah. Just reverse. We're going to talk about testosterone in women. And then we're going to talk estrogen in men. Okay. I actually really like this. Yeah. What level of estrogen do we find effective and valuable for men? And that is really between 30 and 50. So if you go and you look, typically, you will see a range between 30 and 50. If estrogen is too high in men in clinical practice, I have seen that they don't like the way they feel. And they might... And again, this is subjective reports of increasing in mood, like, lability. Maybe they're feeling more emotional or their mood is a bit depressed. And low estrogen seems to kill sex drive in men. So if they're on an aromatase inhibitor, say, for example, they go to their doctor and they're getting too high a dose of testosterone. Say they are taking 300 milligrams of testosterone a week. And some of that testosterone gets converted to estrogen. So the guys, a lot of the bodybuilders, they think, oh, well, more is better. More is not always better because it aromatizes to estrogen. And you don't want really high estrogen levels in men. Conversely, you don't want low estrogen levels in men because that can affect bone density. They can get low bone density, just like women with low estrogen. They also can have low sex drive. Yeah, just let's make sure everybody's here in that right. Low estrogen, if men get their levels too low, it can suppress their sex drive, bone density, all those sort of issues. So guys taking things that suppress their estrogen kind of willy-nilly or in lieu of getting on TRT could be a bad idea. Yes. And typically, we don't recommend aromatase inhibitors, things like anastrosol. And we don't recommend them in high doses. So, for example, if someone is getting peripheral conversion, so from their fat cells, they are now converting testosterone to estrogen. But we will give them an aromatase inhibitor at a very low dose to keep that estrogen in check. But it's not... The first thing that we're going to do is we're going to try to address their dosing of testosterone first because if their testosterone is too high and they aromatize it too much to estrogen, then we have a problem. Conversely, let's just think about the normal laboratory values because you want to know. Yes. You want to know when your wife goes, hey, Catherine, to the doctor, and she gets her lab values back and she sees that her total testosterone, premenopausal, her number should be, again, this is what the ranges are, should be 0.3 to 1.6 nanomoles per liter, or, again, I don't want to totally overcomplicate, 8.7 to 46 nanograms per deciliter. And you want to make sure that you're comparing apples to apples. So, we're going to talk about both the ranges in men and women with using the same values. Most laboratories will report nanomoles per liter, and that's by liquid chromatography and in tandem this mass spec. Post menopausal, their total testosterone, this is untreated, is 0.2 to 1 nanomoles per liter, which, let's take a pause, that's not that big of a difference. Right. Now, because it was, it was, what, 0.3 to 1.6? Yep. And then post menopausal, their total testosterone is 0.1. Yeah. Okay. What this tells me is that the premenopausal, post menopausal, testosterone numbers don't change. And now this is the reference range. Do I believe that this is an ideal number? I don't. And let's talk about free testosterone. So, free testosterone is the bioavailable form. And hormones are like children. They can't go anywhere alone. And typically they're bound to things, sex hormone, binding, globulin. But the free testosterone is what it would be considered the most biologically and bioavailable. So, a premenopausal free testosterone level would be 5.2 to 26 picomoles per liter, or 1.5 to 7.5 nanograms per deciliter. Post menopausal women, free testosterone is roughly half. And that's 2.5 to 13 picomoles per liter, or 0.7 to 3.8 nanograms per deciliter. How do we make sense of this? And why should a woman consider testosterone? And number one, is it safe? I would argue that it is safe. When would we be concerned about testosterone? Really, there's two reasons why. And then we'll kind of then double back to all of hormone replacement therapy. What would be a red flag as to who should not start hormone replacement therapy? But testosterone alone is what I would consider from my professional opinion. Again, I'm not giving anyone medical advice. Please see the disclaimer. But this is for educational purposes. Thank you to Manicora for sponsoring today's episode. Winter means more time indoors, more travel, and if you have kids, a new bug cough or sneeze every other day. I like keeping my routine simple and Manicora has become something I reach for almost every morning. And why do I love it? It is rich and creamy. It tastes delicious. I either take it right from the spoon or I use these little packs. It coats my throat tastes amazing. Now, what makes Manicora special is where it comes from. They're beekeepers work in this remote forest of New Zealand where the bees collect nectar from the Manuka tea tree. Yeah, so cool. 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So for example, we think about testosterone and we think about muscle mass, but there are testosterone receptors all over the body. There are estrogen receptors all over the body. It's not just, Oh my gosh, I'm going to give you testosterone and then you're going to grow a beard and muscles. It's not going to happen. So there's no concern. That would be like a much higher dose, right? We start seeing those. The biggest concern is virulization. If we dose testosterone, which is very, it is highly androgenic, meaning testosterone is androgenic, meaning it will affect, it can affect virulization, hair growth, clitoral enlargement at higher doses versus, and we're not going to talk about this in too much detail. Other anabolic agents like nanderloin, which is an anabolic steroid, which is FDA approved for anemia of chronic disease. It's used in osteoporosis. This agent is highly anabolic versus androgenic. And I think that that becomes important. Again, we're talking about this overview of hormone replacement in females. Underneath hormone replacement, we've got estrogen, progesterone, testosterone. This is what the body would make. So this is over in one category. And then we have muscle building and anabolic agents in the other corner. And these agents are things like nanderloin and oxanderloin, oxanderloin, also known as anavar, which is not typically used any more, but was used back in the day. You and I talked about this for burn victims and maintaining lean mass and muscle. Anavar or oxanderloin is an oral agent. So again, it was tea. I don't want to say taken off the market because places still make it, but it isn't used so much in a practicing physician environment because of the increase in liver enzymes, which it does seem to increase liver enzymes versus say a nanderloin seems to have a better safety profile. And nanderloin is an anabolic agent or anabolic steroid, which people are, they hear it and then they get very upset. But again, anabolic steroids or androgens, androgen derivatives, there's a place for them in clinical use. So when we think about the normal laboratory values for men, and I think that this is best used when we think about age reference range for a healthy, non obese male age 19 to 39 years old, typically the total testosterone is, and again, these numbers are funny, 264 to 916 nanograms per deciliter. And this is yeah, that's a big, that's a big, yeah, a lot of variability. Yeah, but also what 264 and on the low end, by the way, the low end, if you are considered low testosterone, it's dependent on geography. And it's also dependent on what organization you're looking at, which is which is fascinating. So the low number of testosterone might be different in Italy, what they would consider as a cutoff is low. So it's geography dependent, which signals to me that it's not a hard and fast biological number. But there's a level of interpretation. Then so for free testosterone, the most robust recent data that you know, we have using mass spec or liquid chromatography, the reference range is 184 to 749 picomoles per liter for healthy, non obese men age, you know, 19 to 39. And that's a free testosterone number. And technically, there's data to suggest that free testosterone declines with age and increasing BMI, which makes sense because you then are aromatizing. And BMI is the wrong way to look at it. So body mass index, but body fat percentage, that can decrease testosterone. Okay, let's talk about some of the risks. Who should not go on hormone replacement therapy? First of all, this is all context dependent. You work with your provider, it is a personal decision. Here is what is typically recommended as red flags, active breast cancer, or active cancers, undiagnosed, unworked up if someone has not worked up vaginal bleeding, and stroke. Those are the things where you would give you pause. And it's not that many, active cancer, undiagnosed bleeding, why are you having some kind of vaginal bleeding, and recent stroke. Wow. I mean, that's pretty straightforward. And then when you look at why there are benefits. So now switching back, so we kind of covered this idea of testosterone and androgens. And androgens are precursor for estrogens in women's bodies. The most well known androgen that we talk about all the time is testosterone, which aromatizes to estradiol. And then there are less important androgens. And when I say less important, perhaps things that we don't always test for, although we do in our clinic, DHEA, and you pulled a paper that we're going to talk about. And androgens are directly secreted by the ovaries and adrenal glands in women. Let's talk about menopause treatment and the benefits of that. And this is really from my understanding why they remove this black box warning. When the FDA puts a black box warning on something, it really makes people pause and it limits the use of these medications. And it scares people. And for a reason, a black box warning is a it's a major problem, major risk. The reason the black box warning for hormone replacement therapy happened was from the women's health initiative. It's an outrage for many years, and it's gotten more and more pronounced, which is why they reevaluated the data and took the black box warning off. And the following has found to be important. And these are the benefits of menopause treatment. And ideally, right before you're going into menopause, so around this transition is the best time a woman could always be treated. But again, her risk of heart disease as estrogen declines, her risk of heart disease goes up, her risk of Alzheimer's disease again, Alzheimer's two thirds are in women. And of course, there are changes in lipids that happen and osteoporosis. So benefits of hormone replacement therapy include a reduced risk of all cause mortality fractures. HRT has also been associated with a 50% reduction in heart attack risk. Wow. Sign me up 64% reduction in cognitive decline 34% lower risk of Alzheimer's. This episode is brought to you by body health. Something changes in your mid 30s that no one talks about. And it's called anabolic resistance. Your muscles become less responsive to the signals from protein that trigger growth and repair. This can make hitting your body composition tough. This is why beefing up your protein intake at each meal becomes important. Often why I say hit 30 grams of protein. Now, not everyone wants to eat all of that in a meal. 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Do you think that reduction in Alzheimer's since that's the, you know, the type three diabetes is because it if I understand correctly, it reduces the risk of metabolic syndrome or the incident of metabolic syndrome. I think it's a great point. I think it's twofold. Again, this is just my professional opinion. Yeah, there are estrogen receptors in the brain estrogen. I think the longer the span of lower estrogen, the greater the risk of cognitive dysfunction. And I do think that there is a relationship between insulin resistance in the brain and estrogen. I don't know the exact mechanism. And I also think that when women indirectly are on hormone replacement therapy, they're more likely to be training and exercising. And so they're having a lower insulin resistance peripherally, which then I think can account for a lower risk of Alzheimer's again, correlation is not causation, but I do believe again, I train in geriatrics. And during the time that I was in training, so I finished my geriatric fellowship in 2015 from 2013 and 2015, right around that time, they were exploring intranasal insulin use to lower insulin resistance in the brain. It didn't pan out. It's not a treatment for Alzheimer's. But one of the things that they had not been exploring at the time, which they have now begun to look at more so frequently is estrogen use in the brain. So it's not just insulin resistance, because if you would then give insulin, you would think that there would be a reversal or a pause or some kind of treatment. So that doesn't happen. And it's probably the synergistic effect. What about hysterectomies? You're talking about all these issues. And I'm thinking about those poor women that have those early on. So imagine that puts them at greater risk for Alzheimer's and all those diseases you mentioned. And think about all the women that weren't treated. When you get, there's a hysterectomy, there's a total hysterectomy, and then there's a hysterectomy where you just take the uterus and leave the ovaries. And hopefully most women, again, it just depends on what the diagnosis is, that if they still keep the ovaries, they're still producing hormones. But if you do a total hysterectomy, and we've had many patients like this, we put them on hormone replacement, which is the Fulcibrek spectrum. Right now, the conversation really is estrogen and progesterone. Women, I think, are still really afraid of using testosterone. And I can appreciate as to why, but testosterone in women is really important. And it's important for a number of reasons. We should pull up a few of the studies. So there was one study, let's pull up that, that study on younger women. Because again, women think, okay, well, testosterone, it's just after I go through postmenopause, my postmenopausal experience. But if we look at the values of premenopausal, total testosterone, and postmenopausal, women, it's not that different. But free testosterone does seem to be the biggest change. And then looking at what is some of the data on testosterone use and women, let's look at some of the studies. And there was one in particular that I really liked looking at younger women and the use of testosterone administration. So this is a randomized controlled trial. This is the effects of moderately increased testosterone concentration on physical performance in young women, a double blind randomized placebo control trial. And this was in the British Journal of Sports Med 2020. And so what this was, is this was a double blinded, meaning both parties didn't know what they were getting, randomized placebo control trial. It was 48 healthy physically active women, age 18 to 35. Wow, 18. I know. 10 weeks of treatment. And again, that's a short treatment course, 10 weeks of treatment, because we don't think about cycling testosterone, like someone would think about cycling an anabolic, 10 week of treatment with 10 milligrams of testosterone cream daily, or a placebo, everybody completed the study, which is unusual. And the primary outcome measures, what did they look at? They looked at anaerobic performance of the wind gate test. I've actually never done one of those. Oh, you're not missing anything. I've never seen the only time I've ever seen your face is like that is when we're talking about rucking 10 milligrams of testosterone cream daily. Primary outcomes were aerobic performance measured by time to exhaustion. And then the secondary outcome was anaerobic performance wind gate and muscle strength, squat jump. And it looks like they did a knee extension and a counter movement jump, which I don't know what that looks like. Yes, you jump down and you jump up and you can either reach up and like hit something up high and that's how they measure the vertical, or there's a pad that'll measure your time in the air and it'll calculate it from that. Mine would be zero. You got a vertical, you got hops. Are you kidding? Come on. And then they looked at hormone levels and body composition by DEXA was addressed. And here were the ranges. So this is 10 milligrams a day, which, you know, I remember when I started 10 years ago and we were prescribing testosterone cream, we were so concerned again, this was during this wave of the women's health initiative where we couldn't find a lot of providers that were prescribing and we would start with 0.5 milligrams of testosterone. I do anything? No. Okay. Yeah. We're so concerned with increasing. And then I remember when we got to 2.5 milligrams, we're so worried. She's like, whoa, we're really worried. Again, this is all topical, a topical delivery system. And right now I would say it depends on the provider, but maybe on average, it's five milligrams a day. Five is absolutely reasonable. It might not even be enough because it depends on skin absorption. Five milligrams a day of some kind of testosterone cream. And this was 10 milligrams of testosterone cream daily. And what they found was the serum testosterone increased from 0.9 nanomoles per liter to 4.3. So it went from 0.9 to 4.3 in the testosterone supplement group. In the running time to exhaustion, this increased. Saw a correlation of testosterone increase, but they found that it also increased their time to exhaustion by 21 seconds. That's significant. That's a lot. That's a lot. It came out to 0.5%, which doesn't sound like a lot, but can you imagine being able to push 21 more seconds? Especially if you're chasing your kid. Yeah. Yeah. Yeah. Yeah. But seriously. Right. And this is in testosterone group compared with the placebo and the wind gate average power, which increased by 15.2 Watts in the testosterone group versus 3.2 Watts. Yeah. So this is performance. 15.2 Watts. I mean, I'm assuming that that is that significant. Yeah. Yeah. I mean, if you're looking performance, if you were an athlete, that could be the difference between being on a podium and not. And then for daily life, that's also, again, being able to keep up with your kid or not keep up with your kid. Yeah. And also to be clear, maybe it's not significantly different between the two groups. So if the wind gate average power was increased by 15.2 Watts in the testosterone group compared with 3.2 Watts in the placebo group, maybe that's not significantly different because it looks like this is a low p-value. But like you said, if it's chasing a kid or some performance, it also says there was no significant change in the counter movement jump, which would make sense, right? Is that a true, that seems like that's a skill that you would. Yeah. A little bit lower body power coordination. Yeah. And then squat jump. And then surprisingly, there wasn't a change and also knee extension. There was no change. What I'm wondering, and again, I don't have the lab values here, what I'm reading from this paper, again, that there was an improvement in the aerobic capacity. That seemed to be helpful, this running time to exhaustion. But the other thing was the total lean mass for the change in baseline. Again, and I think that this is what has pushed people to not take testosterone and the total lean mass, this is not skeletal muscle, this is all mass, these are all organ systems, was 923 grams for testosterone group and 135 grams for the placebo group. And the mean change in lean mass in the lower legs was roughly 400 versus 100. So four times increase in again, that's not a huge amount, 390 grams. But I do think that this highlights that there is an effect of testosterone in increasing the aerobic capacity as well as lean mass in young physically active women. Now, if we take a pause, what this highlights is really an effect on body composition. Those are higher doses than we typically see in clinical practice. It seems to also improve lean mass. Again, I'm not saying that anyone needs to take this, but looking at some of the data, it's nice to see young, healthy people as well. Because I think a lot of when we think about a lot of the medications and hormone replacements are typically an older or unhealthy or pre diabetic type people, it's nice to know, do healthy people benefit as well as less healthy people. Thank you to BonCharge for sponsoring this episode of the show. And if you've been following me for a while, you know that I take light exposure seriously. Why? Because it impacts your sleep, your hormones, your mood, your ability to recover and focus. 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This is true optimization. This isn't treating a disease state or anything like that. This is optimizing this group of women. And what I was looking at and see was, you know, they weren't on a training protocol as part of this study that I can see. And so you're talking about by just giving you this cream, I'm improving your run to exhaustion, which I imagine probably the effective testosterone, the red blood cells, maybe the iron, you know, the oxygen carry capacity, but still like all those metrics moved. And I would be curious to see if they had them both on training protocols, what it could be more pronounced even with the testosterone. Basically, this paper was a randomized control trial in young healthy women to show the short term testosterone administration led to significant increase in total lean mass. And they increase when they say significant increase in total lean mass 1.9% and leg lean mass by 2.4% with type two muscle fiber hypertrophy and increase in capitalization. What does this mean? Fiber types change as we age type one, type two, and obviously there's type two a and these combo fibers. But really, for simplicity sake, we have type one fibers, which are the long endurance type fibers, which also there is a preferential transition to type one fibers as we age. And this is the I was going to make a joke about my dad because he does listen to the podcast, but he's got some type two fibers, but we see they become more frail and thin. And then type two fibers, this is the what we think about hypertrophy. And there was a preferential improvement in these type two muscle fibers and then increased blood flow. And so that's really good for the young people. And then like you talked about that fiber type shift, I mean, that's part of the reasoning or the logic I've always heard of. Why if you look at like sprinters or, you know, power sports, once you get past the age of 30, 35, usually you don't see athletes in that, whereas like long distance running, you can have people in their 40s going into it. Yeah, because, because endurance seems to kind of stay with those athletes longer than say, you know, like a Usain Bolt versus the Kipchoge would be the best example. He just did the New York marathon. I mean, I think he finished, you know, at 40 in his 40s, top, he was a top 20, like, you know, ran like a 228 something, you know, some crazy. I remember seeing this time. She really worked on that speed. I know. I remember seeing this time and being like, yeah, that, that doesn't even get you in the top 10 or top five, but he was still able to compete at a high level versus for sprinters. I don't know if any sprinter like past the age or males, at least past the age of like 35, who are still, I actually, I hadn't thought about that. Yeah. When did he stop? When did Justin Gatlin stop sprinting? I don't know how old he was, but that's, it's a really good point. What I thought was also interesting is, you know, when we were looking at all this data that the randomized control trials showed increase in leg lean mass with a preferential increase in type two muscle fibers, which by the way, friends who are listening to this, you can improve your type two muscle fibers by getting on a great resistance training program. This could be three days a week. I put that in my book, the new book, which you have over here for average on playbook, great book, three days a week of doing resistance training. It could be full body. And we put the rep range in anywhere from six to 15, which is a wide rep range. But the whole idea is that you're going to one to two reps and reserve people will say, oh, well, you should use compound movements. And I get it. And also, if someone doesn't feel comfortable doing a deadlift or a squat or some kind of big compound movement and they want to use machines, totally fine. I'm sure you hopefully agree with that. I agree. I agree 100%. I mean, I think as we age and just, and I've seen that become more prevalent, that kind of stance, I guess on, you know, some of the Instagram stuff with, because at one point I remember it was very kind of old school, you had to squat, you had a bench, you had a deadlift, and now there's some great human performance professionals doing, hey, you can lunge. You don't have to do that. I, and thank God, because I'm terrible at squatting. The other thing here was looking at some other papers in post menopausal women, higher dose testosterone therapy for up to 24 weeks was associated with a dose dependent increase in lean mass. And this was actually up to 4.4% and muscle performance. Again, these are short term studies, I think, especially because the FDA has removed this black box warning. We're actually working on a randomized control trial now with testosterone. That's exciting. That is very exciting just to show and create a body of literature showing the safety of it. Again, I'm assuming that that's what we're going to find, but I'll keep you posted. Now, there is a few things that someone has to think about in terms of when would you be concerned about testosterone? If your hemoglobin and hematocrit go up, typically, again, whether it's up to 48%, by 50%, we are decreasing it, we are recommending a blood donation. This is a bit controversial. The science of elevated hemoglobin hematocrit, again, it's the science is a bit controversial. Some physicians will recommend a blood donation. Some will not. We typically do a blood donation. What's the alternative? To not, but then your hemoglobin hematocrit rise, but not dissimilar. Again, it depends on how the body responds, and we should talk about this. If an individual is not doing an intermuscular injection, so when you do a bolus of testosterone, you get this big bump up and you get a rethropeuesis, so you get an increase in red blood cells. If you do a lower dose sub-Q, say split it up three times a week, the same amount, you don't see the elevation in hemoglobin hematocrit. You know what I can't help but think. All your cyclists and runners listening to this podcast just went, okay, intermuscular next time the marathon's coming up. That's right. I'd never even thought about that. So would that improve performance? That's a... Well, it would. I mean, I imagine that's why all the... Remember the Tour de France cyclists were taking testosterone, that big scandal some years back. So I wonder, yeah. I didn't know. They must have wondered if they were doing it around the race. I'm not saying to do that. Nick is not saying that. So for a normal level, typically, a hematocrit is, again, 41 to 50 for men and then females are 36 to 44 percentage. Again, these are non-altitude individuals because if someone lives in altitude, those are higher. And I think that this is a bit where the controversy comes in because if we know that people live at high altitude and they have higher hematocrit, should they be not able to be put on testosterone? And so I think there's a lot of conversation that goes in and around this. And I'm hoping that we will see more about this. Now, the high hematocrit level is erythrocytosis. It's red blood cells versus a pathology condition, which is polycythemia vera, which is an increase in red blood cells and other cells. It's kind of across the board. The two are different. And that would be the one thing for testosterone replacement therapy is that people will look say, okay, well, you have an elevated hematocrit, we're going to cut back your testosterone or we're going to have you do a blood donation, split 50-50. Is that, and just to make sure I'm understanding, is that because, you know, one like risk of stroke, is that the main concern and then is that correlate with higher blood pressure naturally with that? Possibly. So those two things, yes. Thank you to our place for sponsoring today's episode. Most people focus on the ingredients they cook with, but the cookware matters just as much. Most non-stick pans still contain harmful chemicals like Teflon and other PFAS. One study found that 80% of non-stick pans contain these forever chemicals. And another study showed that a single scratch can release thousands of plastic particles into your food. That was enough for me to switch. Our place makes high performance, toxin-free cookware. 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Well, we also talked about changes in lipid profiles. Yes. So there's an intramuscular testosterone formula that those are associated with a greater increase in hematocrit compared to the gel. I will say the gel or the patch. So there are other routes of testosterone. There's also an oral lymphatics of chisatrex is an oral testosterone, but it's not through the liver. It goes through the lymphatic system. The difference is these fluctuating serum testosterone concentrations. It's the fluctuation that seems to really affect hematocrit levels. But you can account for that by changing the delivery and the delivery schedule, which I think can be really valuable. And I will tell you one other thing. What is another perhaps subclinical risk of testosterone? And this is a pearl for any physician listening or anyone who is reading blood work, any healthcare provider is that we had a patient and we actually saved his life. He had pernicious anemia. And he was masking? It was masking his pernicious anemia. And actually it's a very good friend. He's a famous Navy SEAL. I could probably talk about him and he wouldn't care to talk about him all the time. But he, I was like, you've got sleep apnea and that's why your hematocrit's going up. So there was this testosterone. You don't want to layer on testosterone with someone with sleep apnea. It could potentially make it worse. But this is a clinical pearl. If someone has underlying anemia, pernicious anemia is a destruction of the intrinsic factor in the gut. So it's an autoimmune condition that these people cannot absorb internally. They cannot get B12. It's deadly. It can kill you. And typically you have to identify it. When you are on testosterone, because testosterone increases erythropoiesis and the generation of red blood cells and is also will mask anemia can help quote, treat anemia. It was masking his pernicious anemia. He was having these terrible symptoms of shortness of breath. So he's having, he was totally symptomatic. I mean, he had been to the ER multiple times. And so this is a pearl that if someone goes on to testosterone, it can mask underlying causes of anemia. What was it? What was the underlying for the, I'm curious, with the pernicious anemia? He had gut issues, shot in the gut or anything? He did. So he has been shot multiple times. But because of his deployments, he also had psoriasis. He had a lot of conditions. I mean, he had some kind of roundworm as well. But forever, he will always have to take a B12 shot. But the testosterone actually had masked that. And I think that what made, what triggered you to be like, Oh, I did a peripheral blood smear. And I'm extreme, if it's one thing that, you know, people say, okay, what's one word that defines you or that would represent you. And I would say relentless is in that category. Love it. It's just extremely relentless. And I care very much for him. He is in the same troop as my husband. So he's one troop, team 10, one troop, just like Shane. And there was no way I was gonna let something, there was something that I could do about it. There was no way that I wasn't going to do it. And so I was just obsessively going to be like, there's something wrong because you're going to the cardiologist, cardiologist saying you're fine, you're going to the neurologist, the neurologist is saying that you're fine. But you and I both know that it's not psychosomatic. Right. These guys, they don't complain unless something's wrong. And usually by then, something's like hanging off their body, right? Like, I'm pretty sure that that limb is supposed to be attached. Yeah, I would say extremely relentless. It's fascinating. And it's saved his life. No, that's a great case study. Wow. It absolutely saved his life. So that kind of goes about, well, how do we think about taking testosterone and what potentially could it mass. So an I am injection, which would be in the shoulder or the bed or I've got one patient that puts it in her thigh, she's bananas. I'm pretty sure that that hurts a lot. Nick, you and I were chatting, we talked all about testosterone use a little bit about the history of testosterone use, what it can do for women. However, there are various ways an individual can take and test for testosterone, both men and women. For women, we talked about the cream, we talked about intramuscular injection, we talked about a subq injection. I think eventually for women, they'll also be able to take an oral, lymphatic absorption. Men are also already there in terms of chisotracks. We talked about the best blood test and that is a liquid chromatography mass spec. And that's just a technique. We also spoke about the side effects, meaning potential for increase in virulization at supra physiologic doses, supra physiologic doses, meaning it's outside of the normal range for both men or women. And we talked about one of the things that we see in terms of side effects. So there's the virulization that will happen in much higher doses. We also talked about you wanted to bring up the change in lipid profile specifically for testosterone versus other anabolic agents. What do you got? Yes. So this is what I found fascinating. So oral testosterone therapy is associated with a significant reduction in HDL cholesterol for women, right? Non-oral testosterone therapy, so the transdermal injectable at physiological doses. So we should say that has been shown to not significantly affect HDL cholesterol in women over the short term. And even observational data on exogenous testosterone levels in older women suggests that higher physiological testosterone is associated with higher HDL and lower triglycerides. So kind of an interesting, you know, stuff to impact that it's not just testosterone, but it is all about the mechanism of delivery. And I think it's really important because there's a lot of conversation about cholesterol and HDL is the high density lipoprotein and its role is really for transporting cholesterol. You can have a high HDL people typically think of this as quote good cholesterol, but really it's not good or bad. And it's not just the amount of HDL. So if we were to look at the numbers of where we want HDL, which we'll go through, but it's how is the quality and the functioning of that HDL, which I think is really important to look at the functionality and the particle quality. Someone could do that if they do a Boston heart. And this is looking at some of the databases. This is the American, the American Association of Clinical Endocrinology, and their guidelines are the following that HDL HDL C less than 40 is an independent risk factor of aplosclerotic cardiovascular disease. And this is ASCVD. And again, this is thinking about plaque, meaning that the HDL is not able to transport the other particles. And so you get this plaque buildup. And that's in both in men and women. And less than 50 milligrams per deciliter is a marginal risk factor in women. So HDL when we think about a high density lipoprotein refers to the class of lipoprotein in the blood that's responsible for transporting cholesterol from peripheral tissues back to the liver. And this needs to be functioning, which is why it got the name of good cholesterol. However, there are certain guidelines. And basically, if someone is taking testosterone, it doesn't seem to negatively impact if they are taking it by injection or topically. Is that is that what you found? Yes, that is what I found. So oral testosterone therapy reduction, right? Oral if it goes through the liver. Yes, if it goes through the liver, but the transdermal and injectable seems not to affect it. And that's important because you want good functioning HDLs. Now, I will say something else. And we've had Dr. Mike Twyman on the podcast many times levels above 80 to 90 milligrams per deciliter is linked to increase in all-cause mortality and increase in cardiovascular disease. And that's the reverse of what people would think. That is the reverse of what, well, oh, you just you just shattered my work. I'm so sorry. Well, because because also right in practice, you look at cholesterol divided by HDL, right, for that ratio. So so that those higher numbers like 90, 95 is always going to keep it within, you know, under that five or you might be a three, two point four. So they'd be classified as low risk. But you're telling me that no, that doesn't necessarily put you at low risk. That is correct. And that's why a Boston Heart or additional testing, looking at the particle quality, looking at ApoB, looking at all these other markers, rather than these isolated ratios and independent markers, I think it's just really important. Because people typically think that 60 or higher is considered to be protective. And yes, it is 60 to 70 and potentially even higher than that. But one just has to make sure that the functionality of the HDL is good. And that becomes important. And listen, during perimenopause and menopause, we see a lot of shifts of cholesterol, LDL cholesterol, HDL cholesterol, increase in ApoB has to do with these, you know, this relationship between estrogen and these transporters. But the reality is, we have the ability to test for it. And testosterone within physiological ranges, don't seem to have a negative impact. Other anabolic agents can, depending on the agent, meaning if we're talking about anabolic steroids, and one of my goals is to really help dissolve this stigma that anabolic steroids, even the word anabolic steroids seems to have with people, because anabolic agents can be very helpful when clinically indicated. And again, not all of them affect LDL cholesterol or HDL cholesterol, there's a normal physiologic process. But I'm really glad that you brought that up. And if people are going to go on testosterone, you want an entire panel, someone gets a baseline panel of free and total testosterone, sex hormone binding globulin, estradiol, progesterone, they should also include a thyroid panel. They should also include an iron and a ferritin, really, looking at all of these things, luteinizing hormone, follicle stimulating hormone, everything. Men and also, so for the women, but also men should have comprehensive panels as well. How often, so you put somebody on testosterone, then how often are you following up with panels? You get a baseline. Make sure that everything is where it should be, see what we're looking at. And then four weeks after, we also get a baseline as to where they are so that we know if we move it up or down. Because you don't just start testosterone, men and women just always feel great. It takes time. And typically, we want to give people at least four weeks. But you still, even if they haven't gotten their full effect, you do want to start monitoring. And then of course, a CBC, some people just get a hemoglobin hematocrit, which again, we talked about hematocrit as the oxygen carrying capacity, the red blood cells, but you really want to get a full spectrum. So it's baseline four weeks after, you allow them to go for a period of time. And then we check in another three months to make sure that they are where they should be. And once someone is stable, every six months, anywhere from four to six months, you want to keep your finger on the pulse. What can a woman expect, right? Who's, you know, you determine she's low testosterone or maybe other hormones, you put her on this hormone profile. Like, you know, what and when can she expect kind of the changes you see? And I would love to hear your like most dramatic change or patient you've had over the years. The most dramatic change, and there's one patient in particular I'm thinking about, it wasn't just testosterone. So we use low dose tersepotide. And this was really about, you know, she had very low sex drive, low libido, felt like she had lost a ton of muscle. And again, testosterone is not FDA approved for muscle mass. It's not quote recommended for body recomp, which is fascinating, because we know sarcopenia is really dangerous for people, which is sarcopenia is defined as loss of muscle mass and function. We think about it as something for aging, but it's not a disease of aging. And one of the most dramatic transformations that I've seen was this woman, she had always been training, she's 60. This woman is a beast. She's incredible. And what we did is she had low libido, low recovery, a ton of joint pain, and we optimize her hormones and her testosterone dose, you know, we're not talking about 20 to 30 milligrams a week. So typically the testosterone dose is, you know, one tenth of a male dose. It was dramatic for her. And we used a low dose tersepotide. This was able to help curb her appetite. She's training a ton, just extremely hungry, very low dose, starting dose, and then optimize her testosterone, progesterone, and estrogen. I mean, her body transformation was unbelievable. This was a woman who never wanted to get on the scale ever. And you know, she's like running ultras. Wow. Her body fat percentage is 16% now. And it's not effort. It just seemed that we were able to put everything into place. And this took six months. And again, everything is within range. We're not talking about pushing super physiological numbers. She's able to recover she's sleeping. So one of the things that we see is that women that are going through perimenopause, menopause aren't sleeping. They're not recovering. You add progesterone, oral progesterone, not cream, but oral progesterone. It seems to affect as a GABA agonist in the brain, allows women to sleep. Estrogen, we know estrogen is great for bone and brain function. There are estrogen receptors on muscle. Again, I don't think it's the primary driver. But just the combination and then subcutis testosterone injection with a tiny little bit of terzapotide. And this woman, it dramatically has changed her life. That's awesome. You talk about the physical, but then also like the, what about the cognitive? What did she report? Two things. Mental freedom from thinking about food and her body weight. This is a woman who had been obsessing about how she looked and performed for 30 years. And we took that off the table and it just completely transformed her life. It was probably one of the most fulfilling moments. I mean, and again, we see this, there is, so there's the cognitive process, cognitive thought process of I've got brain fog and I'm tired. And then there are people that are super tough. And regardless if they're tired or not, they're still executing. And that was her. But from a, did her cognition improve? I would say yes, but she never complained about that. What she complained about was just constantly feeling uncomfortable in her skin and just really obsessive about how she looked and performed. And she has, I mean, this is something that consumed her for 30 years. Wow. And what's so, you know, fascinating about listening to that is that as scriptors you told me at the age of 60, I am willing to bet 99.9% of physicians would be like, you're 60, it's just part of getting older, right? It's just the expectation. She's running 100 miles. This woman, this woman outlifts me, she puts four plates. And we should all try to, she puts four plates on that sled plus, so she wraps this sled around her weight plus kettlebells, 90 pounds of kettlebells. I mean, this is extraordinary. And so we don't, you know, we think about testosterone replacement therapy for men. No, he blinks an eye. Men will come in, I have low libido, I have low muscle mass, I have brain fog, the hair is falling off my legs. Oh, you need to prefer testosterone here. Let me just put it in the water. But a woman comes in and is like, oh, I'm not feeling well, blah, blah, blah. And it's, oh, well, you know, it's in your head, maybe you need an SSRI. But we don't think, and again, I, you know, believe muscle is so important, but we don't, not even clinically indicated to say, you know what, you need testosterone. Women aren't even thinking about that. Similarly, just how men aren't even thinking about estrogen, which is equally important for men and women. And we have a lot of work to do. But the goal of this episode is what is testosterone? How is it being prescribed? What are the benefits? Where's the safety? What do we begin to think about it? And from a clinician standpoint, who is perhaps listening to this, I think in the next five years, we're going to begin to see FDA approved usage. And just because something isn't FDA approved, it can still be used quote, off label, which means you review the benefits and the side effects and what it's clinically indicated for and what it's not. There's one more aspect about testosterone that I think is important is there is a use of testosterone vaginally, estrogen, progesterone, vaginal. And why is this? Because this tissue atrophies and nobody wants that, right? Because that's just not ideal, increases risks of urinary tract infections. Before we wrap up this episode, I did want to talk about DHEA because you brought it up and I think that it's something that's important. And I'm just going to pass that over to you. So DHEA you can get is a dietary supplement, right? That's in that category, you don't require a prescription. And so I was wondering about if an individual is a little wary, maybe they're, you know, worried about needles or the stigma of testosterone. Could they consider or would you consider like higher dose DHEA to increase things like the estradiol and testosterone because it can go either way, right, in their body. And what I found was this, you know, review is 21 studies and it does seem to move the needle. So testosterone by 24 points estradiol by nearly eight, but it took higher doses of 50 milligrams or more to produce those results, especially adults over 60. So my question to you would be, do you guys use DHEA in practice or are you, you know, seeing people take it or? It's a great question. And I typically test DHEA sulfate in all my blood markers. And I will say that when women are on androgens, testosterone, etc., that we see a decrease in DHEA. So whatever the pathway is, it seems to pull it forward. And in clinical practice, we might use five to 10, maybe 20. Typically, I haven't gone up to 50. I would just move them to use testosterone or I would again, as a practicing physician, there's obviously a discussion, maybe they want to use it, maybe they want to use DHEA versus testosterone. But I would certainly be open to it. And I do think that they're where the real magic of DHEA, which DHEA may have some anti-inflammatory effects, where I think that there is benefit is if someone is on testosterone therapy, also adding in DHEA, again, because I see that the DHEA level seemed to decrease when people are on testosterone, maybe, you know, shutting something off or something of that nature. But what else did they find in the study? Anything else of relevance? Because it's interesting. So this was a review of 21 studies, and it did move the needle, it did increase estradiol, and it seemed to increase testosterone. Again, one would argue is 24 points enough. That's a lot for dietary supplement. Right. But what would be compared to testosterone? But again, it seems like all of these things are dose dependent. There is use for DHEA, they do use intervaginal DHEA, by the way. Well, Dr. Nick Bairinger, we have covered how women can utilize testosterone without getting, quote, too jacked, too hairy. No beards. No beards. And we are at a new frontier in medicine where people are really advocating both clinicians and patients are starting to advocate for themselves. And we appreciate you guys and hope you enjoy this episode. And if you want to hear more, hopefully you are involved with the behind the scenes super cast. And that is our private community where you can listen to these episodes, add free, and ask questions and find out how many push-ups does Nick really do? Not a lot.