Who Needs Testosterone, and Who's Not Getting It I Signal Episode 4

0:00 [SPEAKER_01]: Alright, I want to start with the study because it basically sets up everything we're going to talk about today. [SPEAKER_01]: A group in Sydney took 45 guys all over the age of 40. [SPEAKER_01]: All of them had the stuff you blame on low testosterone. [SPEAKER_01]: They were tired, low sex drive, low mood, kind of flat, but none of them had an actual medical problem causing it.

0:17 [SPEAKER_01]: No, to stick your disease, no, but to a cherry problem, just middle-age guys who fell off and had a testosterone number on the lower end. [SPEAKER_01]: they gave each guy a testosterone gel for six weeks. [SPEAKER_01]: And a placebo gel for six weeks. [SPEAKER_01]: Same looking gel, nobody knew which was which and the researchers didn't know either.

0:33 [SPEAKER_01]: And a testosterone did exactly what it's supposed to do. [SPEAKER_01]: It pushed their levels up by more than half, right into the range of a healthy young guy. [SPEAKER_01]: and they felt exactly the same. [SPEAKER_01]: The energy, the libido, the mood, there's no better on the testosterone than on the placebo.

0:48 [SPEAKER_01]: This wasn't some sloppy little study that just missed it. [SPEAKER_01]: It was built well enough to catch even a small improvement. [SPEAKER_01]: It just wasn't there. [SPEAKER_01]: So that's where we're starting because that result runs again pretty much everything you're hearing about testosterone right now.

1:01 [SPEAKER_01]: We'll come back to these guys and we'll come back to Mark, the guy who's lab result kicked off this whole series. [SPEAKER_01]: This is the last episode and it's about treatment who actually needs testosterone who've been sold it and what the heart and prostate data actually show in addition to what it does to your fertility and how we put it all together.

1:17 [SPEAKER_01]: I'm Dr. Jordan Fuyang and this is the Barma Medicine podcast. [SPEAKER_01]: And here to close out the series with me, my co-author and the better looking half of this book, it's Dr. Austin Baroque, what's going on then? [SPEAKER_01]: Wow, that's high praise, I think that's the first that sort of compliment has come out.

1:42 [SPEAKER_01]: So I'll take, well, yeah, the second one's having to, it's not me guys, this is like if you know you know thing, if you're a long time barbell medicine listener, you know the inside joke and if you don't, I'm not telling you to go back to episode one, I think we're in. [SPEAKER_01]: I am, yeah.

1:55 [SPEAKER_00]: Yeah, it's gonna come correct. [SPEAKER_01]: Go back to the beginning. [SPEAKER_01]: So if you are a new listener, two things here, we are physicians. [SPEAKER_01]: We've been close to two decades now at this point, turning in clinical research into something you can actually use without a medical degree.

2:08 [SPEAKER_01]: At least that's our hope. [SPEAKER_01]: And this is part four of our four part series, built around our new book, Signal, which talks about testosterone and what the number really means to your health. [SPEAKER_01]: And what to do about it. [SPEAKER_01]: Episode one, took a part. [SPEAKER_01]: The broken testosterone industry and the myth that men's testosterone levels are collapsing generation over generation.

2:25 [SPEAKER_01]: Episode two was the machinery. [SPEAKER_01]: How the hormone actually works. [SPEAKER_01]: And why one lab values just a starting point and nothing more. [SPEAKER_01]: Episode three was the stuff that most commonly drives the number down. [SPEAKER_01]: Increases in body fat, poor sleep, and what happens when you're hammering your training wall not eating enough.

2:41 [SPEAKER_01]: Today we're going to talk about treatment. [SPEAKER_01]: Now every episode does stand on its own, but if you want the full story, we'd recommend starting at episode one. [SPEAKER_01]: But we're going to talk about who needs testosterone replacement therapy, what are the options and what are the risks versus benefits.

2:56 [SPEAKER_01]: But before we get to how you treat this, got to be clear about who the treatment is for. [SPEAKER_01]: Now, the current medical system gets it wrong in both directions. [SPEAKER_01]: Men who are genuinely testosterone deficient, who don't get treatment, and men who get a prescription without a full work up behind it.

3:12 [SPEAKER_01]: So inappropriate prescription. [SPEAKER_01]: By the end, you'll know if you're in one of these groups. [SPEAKER_01]: what the safety data regarding the heart and the prostate and others actually say and what testosterone does to fertility and how we put it all together and make a clinical decision.

3:25 [SPEAKER_01]: The Austin before we talk about under an over-treatment, that's sort of notion. [SPEAKER_01]: Can you review the steps of what a proper diagnosis would look like, a proper workup? [SPEAKER_00]: Sure. [SPEAKER_00]: Yeah. [SPEAKER_00]: As with most medical conditions, a proper diagnosis or a proper diagnostic journey starts with a physical and a history.

3:44 [SPEAKER_00]: And I would say the vast majority of my kind of diagnostic pathway is placed in the history for just about every condition and that includes concerns about testosterone deficiency or hypogonatism. [SPEAKER_00]: And there are some elements of the physical exam that can be useful in particular situations here.

3:59 [SPEAKER_00]: But the diagnosis itself requires the presence of symptoms and a confirmed low blood level. [SPEAKER_00]: If somebody says, hey, I feel absolutely fantastic. [SPEAKER_00]: Then there's usually not a very strong reason to proceed with a bunch more diagnostic testing and evaluation, and you don't really have a ton of evidence to [SPEAKER_00]: put a final stamp on the person or on their chart and to say that they are unequivocally clinically testosterone deficient, if they say, I feel fantastic and I have no symptoms, no signs, no complaints.

4:25 [SPEAKER_00]: I'm doing otherwise really well. [SPEAKER_00]: So the history is really aimed at elucidating what are the potential symptoms that the person could be experiencing? [SPEAKER_00]: And as we've talked about in the past, the symptoms range in terms of their specificity or how suggestive they are of something like testosterone deficiency.

4:41 [SPEAKER_00]: There are many symptoms. [SPEAKER_00]: that can be classified as non-specific, meaning that a ton of different medical conditions can cause this symptom. [SPEAKER_00]: For example, fatigue, fatigue, super-common, super-prevalent, I could list the causes of fatigue for the next several hours and talk about how we could get there.

5:00 [SPEAKER_00]: And so that alone is possibly related to a arrangement to in testosterone or signaling or something like that, but is not necessarily diagnostic on its own. [SPEAKER_00]: I would generally be looking for, you know, a set of some symptoms that together start to raise my probable the probability in my mind that this person does have this.

5:17 [SPEAKER_00]: And at the same time, when it comes to subsequent diagnostic evaluation, it may involve some lab testing of something like testosterone, but it's not exclusively going to look at that, meaning that there is no scenario where somebody presents for this sort of a concern and the only lab test that I get on them is just a testosterone level.

5:33 [SPEAKER_00]: It is almost always going to be paired with other things to evaluate for the possibility of some of those other conditions that can also kind of overlap in this way. [SPEAKER_00]: Now there may be a very clear distinct set of very suggestive or very specific symptoms. [SPEAKER_00]: Right, somebody who fails to develop, you know, in adolescence, their secondary sex characteristics.

5:52 [SPEAKER_00]: Somebody who has a previously normal libido loss of libido loss of, you know, body hair loss of some of these other sorts of things that would be more suggestive more specific than that really raises the probability. [SPEAKER_00]: Where if somebody who has more of those less specific symptoms, it's like, well, the differential diagnosis here, which is something I like to wax a very eloquent on is quite broad and needs some more digging to try to tease things apart.

6:17 [SPEAKER_00]: So that's the history component, really eliciting what is the person experiencing and how does that impact the probability that we're dealing with this issue. [SPEAKER_00]: And then when it comes to lab testing, this is something we've talked about several times before, but it involves not just something like a total testosterone level, but also a broader evaluation.

6:32 [SPEAKER_00]: And then there is some nuances to how we actually interpret those blood levels when they come back. [SPEAKER_00]: There are considerations based on, for example, what specific tests were ordered, what type of test assay is it? [SPEAKER_00]: Because that can impact things like the accuracy, the reliability, what are the normal ranges.

6:48 [SPEAKER_00]: So there's a lot of nuance to interpreting these blood levels. [SPEAKER_00]: I wish it was as simple as, you know, [SPEAKER_00]: to have the blood drawn and is the level read on the lab report or is it green? [SPEAKER_00]: A lot of patients do this on their own and they think that they're able to definitively make a diagnosis that way, not quite so simple in the vast majority of cases.

7:06 [SPEAKER_00]: So overall combination of history, symptoms, signs as well as a supportive lab evaluation that needs to be sufficiently [SPEAKER_00]: broad to determine is this just testosterone deficiency? [SPEAKER_00]: Is this multiple hormone issues? [SPEAKER_00]: Is this a non hormone issue altogether?

7:20 [SPEAKER_00]: And if it is testosterone deficiency, where is the problem? [SPEAKER_00]: Is the problem in the testies? [SPEAKER_00]: What we call primary testosterone deficiency or primary hypogonatism, which has its own set of subsequent management? [SPEAKER_00]: Or is it secondary? [SPEAKER_00]: And secondary meaning it's caused by something else?

7:34 [SPEAKER_00]: Most often things that are impacting the physiology in the pituitary or in the higher up in the brain. [SPEAKER_01]: Yeah, yeah, I think, you know, for the listeners at home, what you're trying to say is that it's not just the labs, not just the symptoms, you got to put them together. [SPEAKER_01]: And then once you've done that, you have to figure out what kind of deficiency that you're dealing with, because it does change the treatment approach.

7:55 [SPEAKER_01]: So with primary testosterone efficiency, the testies themselves generally have an issue. [SPEAKER_01]: The signal to them is there, but the testes can't produce the testosterone, just generally speaking, can be genetic, can be structural could be related to prior chemotherapy, this to my mind can tends to get caught more often, meaning there's less ambiguity around what's really going on here.

8:23 [SPEAKER_01]: compared to secondary testosterone deficiency where the testes have the potential to function normally, but they're not getting the signal, the loonizing hormone, the follicle stimulating hormone, or either low or inappropriately normal, when they should be elevated, basically screaming at the testes, hey man, do your thing.

8:41 [SPEAKER_01]: Yeah, that tends to be the most common pattern today. [SPEAKER_01]: Primarily driven by the rise in obesity specifically, this rural adiposity, [SPEAKER_01]: But also things like poor sleep, opioid use, prior antivalics, steroid use, all of these things can cause the secondary deficiency.

9:02 [SPEAKER_01]: To that end, it is often reversible. [SPEAKER_01]: which some people might take to mean, oh, cool, that we don't need testosterone then, because we can't reverse it theoretically. [SPEAKER_01]: But that's not the whole story, because it doesn't mean that men can't benefit from testosterone, even if they have the secondary deficiency.

9:18 [SPEAKER_01]: It just means that there is a potential to reverse it using other treatments, particularly, if you can identify, well, this is the, quote, root cause, and you feel like you have a good sort of sense of how to manage that, yeah. [SPEAKER_01]: But overall, that is the work up. [SPEAKER_01]: And none of it is particularly hard.

9:36 [SPEAKER_01]: The problem that we've been screaming over these last episodes and that maybe the testosterone episodes before this, most men do not get this work up, which is unfortunate. [SPEAKER_01]: And in two different ways, there's the overtreatment story, where people just don't get the full work up, but they get prescribed testosterone anyway.

9:55 [SPEAKER_01]: And then there's the under-treatment story where people are either dismissed or otherwise not fully worked up despite having real signs and symptoms of testosterone deficiency. [SPEAKER_01]: And so it's both sides of this. [SPEAKER_01]: Let's start with the overtreatment side, because to me, the numbers here are even more gaming than the under-treatment side.

10:13 [SPEAKER_01]: Now, you may remember this from episode one of this four part series that testosterone prescriptions in the United States have quadrupled or more potentially over the last 20 years for men, also women. [SPEAKER_01]: They've they've kind of significantly for women. [SPEAKER_01]: But a quarter of men starting testosterone replacement therapy had no testosterone level drawn in the year before the prescription.

10:35 [SPEAKER_01]: And 50% won't have any labs afterwards in the following year, which is is pretty interesting. [SPEAKER_01]: Now, there's the HIM study, HIM study found that nearly 40% of middle-aged men in the US primary care setting had low testosterone levels, which at that time were defined as a total testosterone level below 300 nanograms per desoliter.

10:57 [SPEAKER_01]: But because testosterone deficiency requires both a low level and matching symptoms, if you actually extrapolated that out and you said, well, look, how many of these people have symptoms? [SPEAKER_01]: Well, then the prevalence drops to 2 to 6%. [SPEAKER_01]: So why you might have this large swath of the population who's got a low level if you had to combine those symptoms, it drops precipitously.

11:18 [SPEAKER_01]: That's nearly like a sixfold spread just doing the math here. [SPEAKER_01]: So even amongst men who got tested, [SPEAKER_01]: Right, 19 and a half percent did not meet these sort of criteria for testosterone deficiency, meaning that they had labs and symptoms, but they got a prescription anyway.

11:36 [SPEAKER_01]: And again, about half of these folks, never got follow-up labs to monitor how they were doing. [SPEAKER_01]: And then there's this SHBG problem, steroid hormone binding globulin, which basically binds to testosterone in the blood and when it is bound to SAPG in the blood, it can't really do anything.

11:55 [SPEAKER_01]: We think that free testosterone is the most biologically active form of testosterone. [SPEAKER_01]: And so total testosterone counts both the sort of free fraction and the stuff that's bound to SHBG. [SPEAKER_01]: So the total can read low while the usable amount is fine and also on this can happen in reverse.

12:11 [SPEAKER_01]: But if SHBG happens to be low, then yeah, things can get murky on just a lab, which is the lab test. [SPEAKER_01]: So, for example, imagine a man who with obesity and insulin resistance and he shows up with a total testosterone of 240. [SPEAKER_01]: Now, we know that higher insulin levels metabolic syndrome tends to lower SHBG, and again, that's the protein that binds testosterone.

12:36 [SPEAKER_01]: So, when you calculate his free testosterone, the part that's actually usable, it often comes back fine. [SPEAKER_01]: So the question is, despite his normal testosterone levels, he'll be symptomatic, so what do you do? [SPEAKER_01]: You probably see this frequently, Austin. [SPEAKER_01]: Imagine a guy in his mid-40s, his BMI's, above 30s, Wester Conference is 40 inches.

12:55 [SPEAKER_01]: His total testosterone is 240. [SPEAKER_01]: He's got low SHBG. [SPEAKER_01]: When you run the free testosterone test, it's in the normal range. [SPEAKER_01]: But he's tired, his libido is down, and he's red enough to know that he's under the sort of cut-off. [SPEAKER_01]: uh... for for total testosterone he wants to know what to do now given that we have great tools from managing obesity and the resulting metabolic syndrome uh... is this something where you're thinking about that this guy would definitely benefit from testosterone would be benefit from testosterone plus weight management or just weight management alone uh... walk me through maybe the how the conversation goes and what you're thinking is in in the sort of scenario

13:32 [SPEAKER_00]: Yeah, super common situation, and as you pointed out, he has a very asymptome sum are what we would call more non-specific like feeling tired, not unusual in somebody who is in their mid 40s in general. [SPEAKER_00]: Definitely not unusual, whose BMI is above 30, whose waste measurement is above 40 inches, given the overlap with all sorts of other medical conditions, as well as things like sleep apnea.

13:52 [SPEAKER_00]: So that's like one thing that is a do not pass go. [SPEAKER_00]: I definitely want to at least assess for that, especially if his blood pressure is maybe a little higher than I would like it to be, but even if it isn't, I would probably be suspicious enough. [SPEAKER_00]: to look for something like that.

14:04 [SPEAKER_00]: On the other hand, he also has some more suggestive symptoms, like the loss of presumably a previously normal libido. [SPEAKER_00]: And so that might also impact the way I think about his symptoms. [SPEAKER_00]: Now to your point, when we have somebody who's S.H.B.G. [SPEAKER_00]: might be called abnormal or deranged or high or low, that can impact the free testosterone levels.

14:22 [SPEAKER_00]: And it would be totally fine to reasonable for somebody to say, well, you know, maybe the total testosterone alone here isn't giving me all the information I need. [SPEAKER_00]: Maybe I do want to check a free testosterone together with it, [SPEAKER_00]: symptoms do with their evidence to support this track more closely with free testosterone levels than total.

14:38 [SPEAKER_00]: The ultimate question that was what are we planning to do with that? [SPEAKER_00]: And that's where, honestly, in practice, there's two ways to go about things. [SPEAKER_00]: And I've talked about this, I think, on a few other recent podcasts that we've been on where at number one, there's the [SPEAKER_00]: ultra rigid ultra strict here what clinical practice guidelines say you you must do and then there's also their situation where it's like look I have enough experience with this I've had a lot of conversations with patients about this as long as I feel like something is safe maybe there's something else that can be negotiated with a plan for ongoing monitoring clear goals if we're getting closer to our goal we're okay if we're not.

15:08 [SPEAKER_00]: then we'll pivot and do something else, and if I feel like that plan is reasonable and safe, then I'm often comfortable doing things that might not 100% adhere to every consensus clinical practice guideline as well. [SPEAKER_00]: So there's a bit of give and take in negotiation with patients because a lot of times, they have their own priorities and goals and as long as it's safe, then I might be open to that.

15:27 [SPEAKER_00]: But in this situation, I definitely want to assess broadly for the set of things that could contribute to fatigue, so making sure he's not anemic. [SPEAKER_00]: He doesn't have a thyroid disorder. [SPEAKER_00]: He doesn't have sleep apnea. [SPEAKER_00]: I don't want iron deficient. [SPEAKER_00]: He's not using too much alcohol as something that can cause all of these things to include the testosterone being low as well, which is also very, very prevalent.

15:45 [SPEAKER_00]: Just a few examples of things off the top of my head. [SPEAKER_00]: rather than just fixating on that number alone. [SPEAKER_00]: And then it comes down to a conversation of basically how much is the patient willing to do or try in some of these other areas? [SPEAKER_00]: And oftentimes the way I have this conversation is like, look, we can make the testosterone number, whatever we want it to be.

16:04 [SPEAKER_00]: And we can make the number look pretty, we can make the number go really high. [SPEAKER_00]: That would not be wise, but we could. [SPEAKER_00]: And that might help some of the things. [SPEAKER_00]: But it might not help all of the things, and it might make some of the things that we're ignoring worse.

16:16 [SPEAKER_00]: Now, there are other strategies we have, for example, facilitating some weight loss, whether through lifestyle alone, whether with the use of a GLP, one-agonist, whether through metabolic bariatric surgery, there's all sorts of options. [SPEAKER_00]: Maybe we could reduce alcohol intake, we could address some of these other issues, get you on a CPAP, that might not only help the things you are concerned about, but also improve your health in a number of other ways that testosterone alone would probably be insufficient to accomplish.

16:40 [SPEAKER_00]: things that would markedly improve your, you know, your body composition that would improve your sleep quality there would improve your daily function that would improve your cardiovascular risk, carry your fatty liver like all these sorts of things. [SPEAKER_00]: And at the, you know, the back end of all that there's still remains the option of we can also do both it is also possible.

16:58 [SPEAKER_00]: It's just the sequencing of that. [SPEAKER_00]: Because in general, I'm going to be a little bit less in favor of doing both of these things at the same time. [SPEAKER_00]: For example, let's say he wanted to do some lifestyle things. [SPEAKER_00]: Let's say he was actually interested in trying a GLP one receptor agonist, and he was interested in the possibly using testosterone.

17:12 [SPEAKER_00]: I might negotiate a plan to sequence these things in a reasonable way, rather than saying let's do all of them at the same time. [SPEAKER_00]: So I'm quite comfortable with negotiating and modifying the plan to best fit the patient's priorities and needs as long as it is a safe strategy.

17:28 [SPEAKER_00]: But in this situation, this is not a situation where it is immediately apparent right off the bat. [SPEAKER_00]: Question number one, this patient requires testosterone therapy to maintain their health. [SPEAKER_00]: In patients who have primary testosterone deficiency, primary hypogonitis and their testes have completely failed, it's like, yeah, that person no question is going to most likely need testosterone therapy.

17:49 [SPEAKER_00]: And there's not really as much of a negotiation here that's needed. [SPEAKER_00]: This is a situation where it is plausible enough that through a variety of lifestyle measures or other medical measures, we could not only improve the testosterone, but a bunch of other things, and this could be potentially reversible.

18:02 [SPEAKER_00]: that some people are willing to try that. [SPEAKER_00]: There are a lot of people who would say, I'd rather trial that than commit to this therapy and some people would say, no, I'm only willing to go so far, but that's not something I'm willing to do. [SPEAKER_00]: And so then how can we negotiate from there to give you the best outcome we can?

18:15 [SPEAKER_01]: Yeah, well said, all right, you want to you want to take a trip down speculation lane with me? [SPEAKER_01]: Maybe maybe maybe a hot take. [SPEAKER_01]: Let's go. [SPEAKER_01]: So there are obviously new clinical trials that have been registered daily [SPEAKER_01]: Let's expect a new agent's coming out.

18:33 [SPEAKER_01]: So I do wonder if at some point we're going to get the trial that I want to see with respect to this question. [SPEAKER_01]: We'll call it the [SPEAKER_01]: if the agents are additive or synergistic potentially, or if there's no real additional gain, right? [SPEAKER_01]: Because if we assume that, you know, one of the primary drivers of testosterone deficiency, particularly secondary testosterone deficiency is, in fact, excess out of positive, then you just treat the excess out of positive, and testosterone levels are stored, and you don't have any of the potential side effects of testosterone.

19:24 [SPEAKER_01]: Yeah. [SPEAKER_01]: That said, [SPEAKER_01]: I think that there are some unique benefits to testosterone related to where body fat stored, loss of this relative post-issue in and of itself, obviously lean body mass, this and the other. [SPEAKER_01]: And so my prediction, this is the speculation line that we're traversing together.

19:43 [SPEAKER_01]: My prediction would be that the combination would be better. [SPEAKER_01]: Not only for just overall weight management, but also like body composition, you know, quality of life. [SPEAKER_01]: Yes, there's some additional side effects because now you're using two agents, but that would be my prediction.

19:55 [SPEAKER_01]: Are you on board with that prediction? [SPEAKER_01]: Maybe that's a tepid take, not a hot take. [SPEAKER_00]: No, I think that would be a reasonable kind of thought. [SPEAKER_00]: I would find that study super interesting as well. [SPEAKER_00]: I would just add a fourth arm of testosterone plus placebo.

20:07 [SPEAKER_00]: It would then it would then it would help to answer definitively the question of like comparative efficacy between one or the other and then that compared with it together because there, you know, no, a lot of people have Very strong opinions about one or the other. [SPEAKER_00]: They'll say use the GLP one because that'll lose the weight and your testosterone will normalize.

20:24 [SPEAKER_00]: It's like that for some not for all and then others to say, well, just put them on testosterone because that'll lead to them losing body fat gaining muscle that'll improve their body composition their metabolic status and that'll fix everything and it's like [SPEAKER_00]: Maybe for some.

20:36 [SPEAKER_00]: Maybe not for all. [SPEAKER_00]: And so then what about the combination and how can you compare and weigh these things? [SPEAKER_00]: Because that would really inform these conversations. [SPEAKER_00]: Because the whole conversation I described is like, here's my best take or my best attempt at this absent that data.

20:48 [SPEAKER_00]: But if I had it and I could say, look, here's what you could expect on average from maybe just using something like Trezzepatide or eventually one of the newer agents. [SPEAKER_00]: Here's what you could expect from just using testosterone. [SPEAKER_00]: Here are the pros and cons. [SPEAKER_00]: Here's what we might expect to help improve.

20:59 [SPEAKER_00]: Here's what wouldn't improve. [SPEAKER_00]: And then here's what the combination looks like and then just what's a reasonable [SPEAKER_00]: if that's the the route that we're interested in going in. [SPEAKER_00]: Having that data would be super useful for these conversations, at least to set some expectations and to help inform that strategy.

21:13 [SPEAKER_01]: Yeah, it would also be nice if they investigated the like different, like the different differential effects on various symptoms, right? [SPEAKER_01]: Exactly, like management, singular, singular outcome, you know, singular signal for libido might be different. [SPEAKER_01]: Yes, that's the other.

21:26 [SPEAKER_01]: Yes, we can hope. [SPEAKER_00]: that that would be a fairly complex study. [SPEAKER_00]: I don't think it would need to run for a super long period of time if I'm honest because GLP ones work relatively quickly when you get somebody out testosterone. [SPEAKER_00]: So, you know, in under a year, you could probably get a sufficiently powered trial as long as people are dosing these things reasonably to get some pretty useful information.

21:48 [SPEAKER_00]: But, you know, somebody, somebody throw us a couple, I don't know how many millions would be required to run a forearm clinical trial like that, but it certainly would be interesting to see. [SPEAKER_01]: Yeah, yeah, obviously absent the placebo arms, you could probably do like a chart review and some larger clinics that are actively prescribing both testosterone and enters appetite and or something like that or glp ones and just yeah, maybe preliminary sense of the data to refine your studies on, but yeah, whatever, look, if people want to send us millions of dollars to do this study, like I'm here for that we can.

22:20 [SPEAKER_01]: All right. [SPEAKER_01]: Well, now let's pivot to under treatment because the same medical system that does appear at least in some sectors to be prone to overtreating with testosterone also seems to under treat real testosterone deficiency. [SPEAKER_01]: So men with classical persistent symptomatic testosterone deficiency often get turned away by primary care physicians who are either uncomfortable hormonal therapy or unfamiliar with it.

22:46 [SPEAKER_01]: It's not something they generally do. [SPEAKER_01]: And they, these men may be dismissed for having testosterone levels that are technically inside the reference range, despite having some symptoms. [SPEAKER_01]: These physician may also be scared off by the risks that kind of. [SPEAKER_01]: continue to orbit testosterone therapy, whether it's related to heart disease or prostate concerns, et cetera, and so for example, in that same hymn study we talked about earlier, only one in 10 men with low testosterone were actually being treated.

23:17 [SPEAKER_01]: Now of course, just having a low level doesn't mean that you need testosterone therapy, but you would think out of the 10 men, many of them would likely have symptoms. [SPEAKER_01]: One specific example, [SPEAKER_01]: individuals who need to be on opioids for whatever reason. [SPEAKER_01]: These chronic opioid users suppress their own testosterone production at very high rates, but they're rarely evaluated for testosterone deficiency.

23:40 [SPEAKER_01]: Not to say that everybody on an opioid needs a testosterone prescription to occur as well, but if they have to be on it, you know, part of the part of the work up. [SPEAKER_01]: Then things get interesting because there's been this again, long associated scare relative to heart disease and I don't know where this was born out initially, you know, because we come from this like.

24:03 [SPEAKER_01]: Jim world, you know, it's like, look, you have all these individuals who are using. [SPEAKER_01]: antibiotics steroids at very high doses and tends to be a higher risk of heart disease sudden cardiac arrest and such in that population, it's like, oh yeah steroids, all steroids just cause heart disease testosterone included.

24:23 [SPEAKER_01]: However, around 2013, a couple of observational studies kind of showed a signal of increased heart disease with testosterone replacement therapy and then the FDA issued a sort of safety warning that suggested that testosterone might raise the risk of heart attack and stroke. [SPEAKER_01]: And this does seem to have spooked prescribers for years because at that time, [SPEAKER_01]: prescription rates for testosterone therapy fell sharply more than half between the years 2013 and 2016.

24:53 [SPEAKER_01]: And there wasn't a real trial that addressed this question, at least partially, we'll talk about this a little bit later, called the Traverse trial, that didn't come out until, you know, almost ten years later. [SPEAKER_01]: But a couple of other things happened during this time frame. [SPEAKER_01]: One, there were a number of lawsuits that came out against Andra Gel that started in 2014.

25:13 [SPEAKER_01]: This is a topical form of testosterone therapy that got combined to a single federal litigation case. [SPEAKER_01]: There were 25,000 claims or more against various producers of topical therapy for testosterone. [SPEAKER_01]: Most of them are alleging that heart attacks and strokes were tied to the drugs.

25:32 [SPEAKER_01]: Also, low T, direct to consumer advertising, that sort of built this market, fell in 2014, nearly disappearing the same year that the FDA warning and the lawsuits started to hit. [SPEAKER_01]: The advertising had been pretty substantial up into that point. [SPEAKER_01]: Advie, for example, a pharmaceutical company spent in the neighborhood of $75 million in 2012 and $65 million in 2013 promoting Andrew Gel.

25:57 [SPEAKER_01]: and the testosterone market peaked around $1.6 billion in 2014 before the decline. [SPEAKER_01]: So it looks seems like the FDA's position predated the scare as far back as 2000. [SPEAKER_01]: The FDA had told Abby that the marketing around Andrew Gel for age-related low testosterone, which I don't really.

26:15 [SPEAKER_01]: like that phrase. [SPEAKER_01]: Don't love it. [SPEAKER_01]: They said it was misleading. [SPEAKER_01]: I'm not sure which part of that they said it was misleading, but yeah, particularly because the drug at the time was only approved for testosterone deficiency from an identifiable cause.

26:28 [SPEAKER_01]: And so, I guess the question to you Austin is, do you agree that testosterone deficiency is genuinely under-treated? [SPEAKER_01]: And if so, why do you think, why do you think that's the case? [SPEAKER_00]: I do think it is under-treated and which might sound like a paradox compared to the last section because I think that both of us hold the opinion that it is both over-treated and under-treated.

26:50 [SPEAKER_00]: It is essentially like, misdirected and you know, interesting to review that history. [SPEAKER_00]: It's almost like, you know, testosterone therapy, it's almost like the men's version of the WHO I phenomenon of after that came out and like prescribing rates. [SPEAKER_00]: drop precipitously, which would both affect those who were on it and didn't need it, but also those who were not on it and did need it in problematic ways.

27:12 [SPEAKER_00]: And so, you know, if I obviously work in a general medical setting, I train junior doctors and residents, I work closely alongside colleagues. [SPEAKER_00]: And all of the time that I have been doing this and all the time that I spent for example putting together our testosterone course and our educational material and finding out in real, like nitty-gritty detail, what are the clinical guidelines recommend?

27:34 [SPEAKER_00]: And in particular, what sorts of populations are at risk and should be potentially tested in like a case finding sort of way? [SPEAKER_00]: So as an example, you mentioned the prevalence of this in patients who use chronic opioids. [SPEAKER_00]: who are also at risk of other consequences related to this, for example, like osteoporosis higher rates of that in that population, something that is both directly caused by testosterone deficiency and can be, you know, improved through effective treatment thereof.

27:58 [SPEAKER_00]: So that's just like one example, patients with all sorts of other forms of, you know, advanced chronic inflammatory diseases and things like that. [SPEAKER_00]: have a high comorbid prevalence of this sort of condition and again it's not to say that you know automatically it's just look for low number make number look better but rather that I cannot think of really almost any of my trainees or colleagues or anybody who I'm surrounded by most of the time.

28:22 [SPEAKER_00]: who would be very familiar with this, or who would be actively doing this on a regular basis. [SPEAKER_00]: Even in people who report symptoms, that could be suggestive of this issue, that is not something that tends to come to front of mind for them. [SPEAKER_00]: As I've described before, I spent some time working with HIV and AIDS populations, and that's where I've seen the all-time lowest testosterone levels that I've ever seen of literally zero in somebody who should not have had a testosterone level that low.

28:52 [SPEAKER_00]: That resonated so much for two reasons. [SPEAKER_00]: One that the level was so low, but number two is like, oh, I didn't see levels checked that often in any of the stations. [SPEAKER_00]: It was like striking to me because I was so not used to seeing it checked. [SPEAKER_00]: And there's like a lot of folks in this situation who, you know, [SPEAKER_00]: had symptoms that could be compatible with the syndrome or who might have otherwise stood to benefit from, you know, addressing it.

29:13 [SPEAKER_00]: And so, I do think it's under-treated. [SPEAKER_00]: I think that there are populations who are at risk where their clinicians, this is not something that is very high priority or that tends to come to mind. [SPEAKER_00]: And I think, you know, it's interesting that we have this series back to back with the menopausal hormone therapy.

29:28 [SPEAKER_00]: sort of series just because of how much interesting overlap there is or some degree of commonality between the two of a lot of symptoms in that context that have either been glossed over, brushed off, not directly addressed, treated with therapies that do not directly address the problem, necessarily, compared with just using the hormone therapy appropriately, dose to properly when it is safe, properly monitored, things like that, because in all [SPEAKER_00]: And so I think that that's kind of where our our argument is is that it is neither undertreated nor overtreated, but it is both.

30:03 [SPEAKER_00]: It's almost like this therapy overall is just kind of like misdirected. [SPEAKER_00]: If we could just like shift the window of like who is on this, I think that overall, you know, the health of these populations would likely improve by [SPEAKER_00]: not using it in people who shouldn't be or don't need it or who's for whom, you know, the risk is greater than the benefit, which really that comes down to just like, you know, are you using anabolic steroids?

30:25 [SPEAKER_00]: And then helping those who are actually clinically, you know, deficient and who would stand to benefit from replacement to physiologic levels, but not necessarily pushing them higher than that. [SPEAKER_01]: Yeah, and I will said, I do wonder, like, how much of this is a training gap versus fears.

30:40 [SPEAKER_01]: You know, ultimately you think about what happens in clinical practice and why it happens. [SPEAKER_01]: People end up, you know, for clinicians and up doing things they're very comfortable with, what they know, they practice how they know, otherwise, you know, what are you doing? [SPEAKER_01]: Yeah.

30:50 [SPEAKER_01]: And it is interesting thing in back to our at least my own education, I think we had obviously very similar education's given the fact we graduated your part, same school, whatever. [SPEAKER_01]: Things like hypothyroidism, hyperthyroidism, diabetes are hammered into you. [SPEAKER_01]: And so as a primary care physician, that's what you went into, you feel like I have a pretty good lay at the land here.

31:11 [SPEAKER_01]: I feel comfortable for non-complicated cases, without additional training. [SPEAKER_01]: You don't need to refer everyone to an interconnectologist when things get out of your value out of your comfort. [SPEAKER_01]: Sure, refer appropriately. [SPEAKER_01]: That is not the same case when it comes to testosterone deficiency with menopause or whatever.

31:28 [SPEAKER_01]: And so I can't tell if it's because there were too many uncertainties like when we went through our training and there still remain many uncertainties today. [SPEAKER_01]: And so, you know, if you're a instructor or you're like, [SPEAKER_01]: I really can't talk about testosterone deficiency to the same levels.

31:42 [SPEAKER_01]: We can't about hypothyroidism because there's just more unknowns and instead of half of the things you'll learn today, being out of date by the time you graduate, 75% we don't know. [SPEAKER_01]: I don't know if it's that or if it's a stigma thing or if it like, you know, since a lot of the learning happens in residency, because those individuals are even further removed from, I don't know, what do you, what's the cause here?

32:06 [SPEAKER_00]: Yeah, I think that some of these like earthquake events in medical practice like, you know, we've talked about in the women's arena the WHO I take obviously now 20 plus years to really start to get shaken up a little bit more think some of these things around testosterone especially as it relates to.

32:24 [SPEAKER_00]: You know, these concerns about cardiovascular risk, which, you know, the more we look at carefully dosed trials, we're starting to see less and less of that as a concern when it's being used properly as well as, I'm going to probably harkening back to, I don't know, maybe like the home run races and the really massively juiced up baseball players that was kind of awesome to watch when we were growing up, but that was a, you know, not a clinical scenario that we were looking at there.

32:46 [SPEAKER_00]: And you're right, that a lot of the clinical educators would have been trained [SPEAKER_00]: science progresses as the last generation dies off, and so it just kind of takes a lot of time for this stuff to gradually move forward over time. [SPEAKER_00]: Think you write that, you know, people have no concerns about throwing around thyroid hormone for an insulin as another form of hormone, but these other ones a lot more apprehension and concern around.

33:10 [SPEAKER_00]: And there are some unique complexities to all of them, but not something that is like insurmountable, like people can be trained, clinicians can be trained too. [SPEAKER_00]: do these assessments and to use these things properly. [SPEAKER_00]: So it is very possible. [SPEAKER_00]: But yeah, I think a long combination of historic events that get really burned into people's brains.

33:28 [SPEAKER_00]: I mean, I still these days run into in practice my trainees now who are like students who graduated medical school within the past couple years who are currently in residency. [SPEAKER_00]: still, you know, being apprehensive about doing certain things for long debunked things. [SPEAKER_00]: And I'm like, look, guys, that is definitely not a thing.

33:45 [SPEAKER_00]: Let me pull up his paper from like a decade ago that I learned about back then that show that this was not a concern that you needed to be worried about and try to erase that from your brain now so that you, you know, are practicing kind of up to date medicine moving forward. [SPEAKER_00]: So, [SPEAKER_00]: These things really get burned in and unless you go out of your way to self educate and to stay up to date with things as I very aggressively do all the time, it's easy to just practice based on how you were taught and to not keep evolving as these fields move forward.

34:10 [SPEAKER_01]: Yeah. [SPEAKER_01]: So that's the under treatment side. [SPEAKER_01]: Now I want to go back to the other end of the range, the much larger group of men whose total testosterone levels are low normal and who feel like something is off. [SPEAKER_01]: So let's go back to the study that we opened this episode with because it's worth understanding properly.

34:28 [SPEAKER_01]: The whole point was to test the guy who walks into the clinic and walks out with a testosterone prescription. [SPEAKER_01]: Not the guy with a real disease with real testosterone deficiency, the guy whose own production is in broken, his level just sits on the low end of normal, and he feels lousy.

34:42 [SPEAKER_01]: That's the patient, and that's who they recruited to the study. [SPEAKER_01]: So these guys started with a testosterone level around 310 nanograms per desoliter. [SPEAKER_01]: That's on the loose out of normal, but nowhere near what you'd see if the testicles or the pituitary had actually stopped working.

34:56 [SPEAKER_01]: The gel pushed them up to around 510, which is solidly into the healthy young man territory, right in the middle of the range. [SPEAKER_01]: Their DHT went up, their Esther dial went up, all the downstream stuff you'd expect. [SPEAKER_01]: So the hormone was absolutely getting in and absolutely doing its job.

35:11 [SPEAKER_01]: But their symptoms, they didn't really change. [SPEAKER_01]: The main thing they measured was each guy's own biggest complaint. [SPEAKER_01]: Whatever brought them in, scored over the past few weeks. [SPEAKER_01]: Their energy levels, no real difference between testosterone and the placebo.

35:23 [SPEAKER_01]: Their sexual symptoms, fame, no real difference between testosterone and the placebo. [SPEAKER_01]: Then they ran the whole stack of quality of life questionnaires on top of that. [SPEAKER_01]: physical function, mood, sex, well-being, prostate problems, the works, 22 different measures, exactly one of them favored testosterone and the authors basically said, yeah, run 22 tests and one of them is going to look good by accident.

35:45 [SPEAKER_01]: That's not really signal. [SPEAKER_01]: That's just the p-hacking. [SPEAKER_01]: It's noise wearing a lab coat. [SPEAKER_01]: And here's the part that makes this study matter. [SPEAKER_01]: This was not some underpowered little pilot study that missed a real effect, because each guy was his own control.

35:59 [SPEAKER_01]: On the hormone and off of it, the design was actually really sensitive. [SPEAKER_01]: It had over a 90% power to catch even a moderate benefit of testosterone compared to placebo. [SPEAKER_01]: It was sensitive enough to pick up the effects of age, a body weight, where the guy started testosterone was.

36:15 [SPEAKER_01]: It picked up all of that. [SPEAKER_01]: It just didn't find anything for testosterone because there wasn't anything to find. [SPEAKER_01]: Now, there's one last nuance here. [SPEAKER_01]: At the very end, they let each guy pick which gel he wanted to keep using, still totally blind to which was which.

36:28 [SPEAKER_01]: And more guys picked the testosterone, 26 out of 42. [SPEAKER_01]: So you could squint at that and say, look, they liked the testosterone, but it wasn't even statistically significant, much less clinically significant. [SPEAKER_01]: and the authors are honest that this phase was the weakest part of the study, way less powerful than the main trial.

36:45 [SPEAKER_01]: The solid finding is the big one. [SPEAKER_01]: If you take a guy with low normal testosterone levels and you raise them, his symptoms don't really do anything on testosterone that the placebo also doesn't do. [SPEAKER_01]: Now the caveats, the study was only six week long, it was only with 45 guys.

37:01 [SPEAKER_01]: All of them without actual testosterone deficiency. [SPEAKER_01]: So this does not say that testosterone doesn't work for a guy who's genuinely deficient, the guy with real, testicular or pituitary failure. [SPEAKER_01]: For that guy, testosterone replacement can absolutely be life-changing.

37:15 [SPEAKER_01]: Full stop. [SPEAKER_01]: What it does say is that when your body is already getting a good enough signal from testosterone, adding more just moves the number on the lab [SPEAKER_01]: and that low normal guy, the one who feels nothing, is exactly who's getting a lot of the prescriptions.

37:33 [SPEAKER_00]: I can't say enough about how this type of clever design is exactly the kind of thing that can be super informative. [SPEAKER_00]: And again, we're not here to debunk the idea that testosterone can help people, right? [SPEAKER_00]: It's that when it is appropriately used and does properly in people who are clinically deficient, [SPEAKER_00]: Certainly can be life-changing.

37:50 [SPEAKER_00]: I've seen it many, many times with folks. [SPEAKER_00]: But there are those who are maybe influencers in this space, maybe their entire career or practice is built around testosterone prescriptions. [SPEAKER_00]: And of course, they're going to have their own selection bias of seeing people who might be more likely to benefit.

38:06 [SPEAKER_00]: Or people who have a stronger placebo response to this thing and because in their practice everybody that they see says that they feel better or the vast majority and so that, you know, I don't doubt their experience in this but this is the type of trial that can help us to get, you know, a little bit more accurate of a perspective on this and this is the type of study also where, you know, you like how I often frame these when presented publicly it's like, here's the design that we're going to do.

38:31 [SPEAKER_00]: Based on your understanding of this condition, we're going to provide either the real testosterone therapy or placebo, the group who are getting therapy, their levels are going to go up. [SPEAKER_00]: They're going to double from 300 to 600 or something like that. [SPEAKER_00]: What would you predict is going to result in terms of their symptoms?

38:47 [SPEAKER_00]: And what would you predict is going to happen in terms of which therapy people opt to stay on? [SPEAKER_00]: And of course, those who are very in favor of testosterone cares everything. [SPEAKER_00]: Much like again, I keep drawing these parallels to the menopause influence or space, where it's like everyone needs estrogen, estrogen, fixes everything.

39:03 [SPEAKER_00]: Because there are similar types of studies in that context, too, right, where they do this kind of thing. [SPEAKER_00]: And it's like, what would you predict? [SPEAKER_00]: And of course, they would say, well, obviously, the people who's testosterone level doubled, they're going to feel way better and they're going to opt for that therapy.

39:14 [SPEAKER_00]: It's like, okay, let's see what happens. [SPEAKER_00]: And then when you see this, it should just challenge you a little bit. [SPEAKER_00]: To, again, it's not like an immediate refutation of the possibility that testosterone could be beneficial, but again, it should just like be a little chink in that armor of [SPEAKER_00]: MP doesn't fix everything.

39:29 [SPEAKER_00]: There are certainly some people who stand to benefit and those who don't. [SPEAKER_00]: And if I were, you know, a responsible clinician, I would say, man, I would really like to be able to figure out a way or help that identify those who are more likely to benefit from those who are less likely to benefit.

39:43 [SPEAKER_00]: And then also when working with patients like this, let's say I decide on, I can't really tell if you're more likely to benefit or not, why don't we give it a try because it's safe enough, obviously getting somebody up to 600 or no concerns about something like that. [SPEAKER_00]: But also it being planned as a trial of like, hey, let's do this.

39:59 [SPEAKER_00]: And if we give you six months, nine months, that's more than enough time to really get a sense of, are you feeling well and benefiting? [SPEAKER_00]: And if not, then we can also stop at that point. [SPEAKER_00]: That's also okay. [SPEAKER_00]: And that's the way I would negotiate this in practice.

40:12 [SPEAKER_01]: Yeah, it is telling people like, okay, you're saying that sometimes testosterone is helpful, particularly people are deficient, sometimes testosterone can be helpful even those who aren't deficient, you know, by lab number, I'm not sure how to parse all this. [SPEAKER_01]: Well, here's a telling statistic of individuals who start on testosterone replacement therapy.

40:31 [SPEAKER_01]: 70% will stop using it within a year. [SPEAKER_01]: 70% will stop using a year and that's not because testosterone is bad or poorly tolerated generally speaking, but just doesn't move the needle pun intended for a lot of these folks. [SPEAKER_01]: And that's the whole thing. [SPEAKER_01]: The goal of treatment here is to improve somebody's quality life, their health trajectory, you know, have them put more life in their years, you know, so to say.

40:54 [SPEAKER_01]: And if it's not working, you don't have to just stay on it because you started it. [SPEAKER_00]: Or because someone on the internet told you that it's going to be, you know, saving your life for some other reason that cannot be clinically identified. [SPEAKER_00]: Yeah, right. [SPEAKER_01]: Okay, say a guy genuinely does need testosterone therapy.

41:09 [SPEAKER_01]: What are you actually aiming for? [SPEAKER_01]: You're aiming to help the person, not to hit some specific number on the lab. [SPEAKER_01]: The current guidelines say the same thing here, get him somewhere in the middle of the normal range measured halfway between doses. [SPEAKER_01]: You call it 450 to 600 nanograms per deciliter.

41:24 [SPEAKER_01]: So a guy sitting at 550 in the middle of his cycle is being treated correctly. [SPEAKER_01]: But a guy who's sitting at 1200 isn't being really treated, he's being juiced. [SPEAKER_01]: And the will optimize you to 900 thing is mostly sales pitch based on the assumption that higher is better, which isn't necessarily true.

41:42 [SPEAKER_01]: And here's something that almost no one tells you. [SPEAKER_01]: The testosterone people actually get prescribed is often not the testosterone that's been studied. [SPEAKER_01]: There's this regimen that's falling out of favor for example. [SPEAKER_01]: You get 200 milligrams of testosterone injected every two weeks and it physically cannot hold you steady.

41:59 [SPEAKER_01]: You shoot up to like 1400 in the first few days. [SPEAKER_01]: You're super therapeutic. [SPEAKER_01]: You feel amazing and then it craters down into the basement by the end of two weeks where you're genuinely deficient, feeling worse than when you started. [SPEAKER_01]: It's a roller coaster and you're basically micro dosing a breakup with yourself every two [SPEAKER_01]: Nowadays, most men will get one or two injections per week to limit the massive swing, though many of them are on the wrong dose.

42:21 [SPEAKER_01]: Now, there was a real world study of this in over 9,000 guys on testosterone, and their average levels landed around 800. [SPEAKER_01]: Way up near the tipi top of the range, not the middle that the guidelines actually call for. [SPEAKER_01]: That means that a significant number of these guys were super therapeutic, well above normal, kind of like a mild cycle of PEDs.

42:40 [SPEAKER_01]: And the monitoring is somehow even worse than the dosing. [SPEAKER_01]: The VA looked at this and only about 3% of guys who started testosterone got the full recommended work up beforehand. [SPEAKER_01]: 3%. [SPEAKER_01]: So nobody's drawing the initial labs and the follow-up labs are pretty bad too, over half of folks who start testosterone replacement therapy will not get labs in the next year, which means the sky high levels and the side effects just cruise along.

43:06 [SPEAKER_01]: So, when some guy tells you that testosterone changes life or that it did nothing for him, honestly, neither one tells you much by itself. [SPEAKER_01]: Not unless you know his dose, you know why he started and you've seen his labs. [SPEAKER_01]: Otherwise, while you're hearing his story.

43:19 [SPEAKER_01]: So Austin, let's think about this. [SPEAKER_01]: You get two different patients here. [SPEAKER_01]: We want to kind of compare and contrast. [SPEAKER_01]: First, get a new patient's total testosterone's 408. [SPEAKER_01]: Pretty much in the center of the range. [SPEAKER_01]: No specific symptoms, but they're like, look, I got to be 900.

43:33 [SPEAKER_01]: Because that's the number you saw on the internet. [SPEAKER_01]: He wants you to help him get there. [SPEAKER_01]: Second, the second patient is a guy who's already on testosterone from some clinic who shows up one in a second opinion. [SPEAKER_01]: How do you run this sort of optimized me conversation without either one feeling like they're being dismissed?

43:50 [SPEAKER_00]: Yeah, challenging conversations, but certainly once that I've had with folks before, I think a lot of this relates to people having a relatively poor understanding of lab measurements here and really not noticing that these things can be super variable and so viewing the 480 as like [SPEAKER_00]: It almost becomes their identity of like this is just lower than I want it to be and therefore, you know, I must fix this without realizing that like, hey, if I just check this like tomorrow or yesterday, we might have gotten like a significantly different sort of level now some of that variation might be a bit more muted once you are on therapy because it is just kind of like a steady predictable kinetic kind of decay across the dosing interval, meaning that you check your dose and it's going to kind of gradually feel spike and then gradually decline before before the next one.

44:36 [SPEAKER_00]: But some of this depends on what their dosing interval looks like and when we're checking the lab. [SPEAKER_00]: I think that pulling back from this and just trying to get a sense of like, well, what was the original reason you were you started on this? [SPEAKER_00]: What has been the result of that treatment?

44:48 [SPEAKER_00]: Did you have suggestive signs symptoms that are now better and like back to normal? [SPEAKER_00]: Were you ever, did you ever have any sign just symptoms like was this appropriate in the first place? [SPEAKER_00]: Like what is the goal of therapy and then what are we trying to accomplish by achieving a level of nine hundred because hey I could potentially achieve a level of nine hundred by just like having you go in and get your level checked like an hour after your dose You know what I mean It might be as simple as like just check it at a different time and boom we've achieved your goal and so putting that into context can be helpful of like what was the original indication?

45:17 [SPEAKER_00]: What are the goals? [SPEAKER_00]: are we meeting those goals? [SPEAKER_00]: And what remains to be achieved by hitting this number? [SPEAKER_00]: Once you put that in perspective, then people who are, I would say, reasonable in this conversation or who have just purely like clinical goals, meaning just health and getting things to where I want them to be, they're generally on board with this sort of framing.

45:37 [SPEAKER_00]: These levels are not everything. [SPEAKER_00]: Different people have different sensitivity to the same level of hormone. [SPEAKER_00]: And if you're feeling well, doing well, performing well, recognizing that, hey, we're probably in a good enough spot. [SPEAKER_00]: And on the other hand, there are some people who are just going to be ultra rigid and say, I really have to get to this level, which getting to the bottom of that involves probably more psychology than I might be willing to get into with them.

45:58 [SPEAKER_00]: And so then the question is, like, well, how is that being measured? [SPEAKER_00]: And is it going to require you to get very superficial logic to get there? [SPEAKER_00]: In which case you're just asking me if you can go on, you know, anabolic, go on PDs and it's like, well, you can do whatever you want.

46:09 [SPEAKER_00]: I'm not necessarily going to recommend it or be the person who's prescribing you like PD level dosed. [SPEAKER_00]: You know, testosterone or something like that, but here's what you ought to know is that if you were to get up to that level, you're feeling fine now, but if you push it up to that level, you may actually experience some harm, some downsides, some of the side effects that you're hoping to avoid.

46:25 [SPEAKER_00]: There might be some mood disturbances, some acne that comes out, some, you know, other sorts of, you know, dose related toxicity, I'll call it, from being at super physiologic levels too long, because that hitting those peak levels tend to be the things that most impact some of the side effects.

46:40 [SPEAKER_00]: whether the blood counts, the skin stuff, the various other sorts of symptoms that people might experience from pushing things too high. [SPEAKER_00]: And so then it's like, well, if they want to try that, they can on their own time. [SPEAKER_00]: And if they're able, if they're sourcing it on their own already, you're getting it from someplace else, it's like, you can try, but this is what you might look out for.

46:55 [SPEAKER_00]: And if they experience the harms themselves, then they might come to their own conclusions at that point. [SPEAKER_01]: Yeah, no, good points. [SPEAKER_01]: All right. [SPEAKER_01]: So that's the story so far. [SPEAKER_01]: We come back from the break. [SPEAKER_01]: We're going to talk about a trial of testosterone, the safety data, and what to do next?

47:12 [SPEAKER_01]: All right, welcome back to the barbell medicine podcast before the break. [SPEAKER_01]: We were talking about how more testosterone and a man who isn't deficient is unlikely to make him better. [SPEAKER_01]: Now, we're going to talk about the cost side because starting testosterone is a trade off like all medications, there are no biological free lunches here.

47:28 [SPEAKER_01]: And many men only get shown half of the equation. [SPEAKER_01]: So you referenced earlier kind of running this as a trial, just because somebody starts testosterone, for example, they don't need to persist in perpetuity on it. [SPEAKER_01]: It is often viewed as a sort of like sign here forever type commitment mainly because I think enough people are aware of like the physiology.

47:49 [SPEAKER_01]: So like, well, look, if I take this exogenous testosterone from outside of the body, it's going to shut down my own production. [SPEAKER_01]: So I'm just committing to lifelong therapy. [SPEAKER_01]: But that's not necessarily true. [SPEAKER_01]: People often will bounce back. [SPEAKER_01]: And again, for a lot of people who start testosterone apparently, it doesn't seem to get them what they want.

48:08 [SPEAKER_01]: With 70% of men who start testosterone stop it within the first year. [SPEAKER_01]: As far as why, [SPEAKER_01]: At most of the studies don't really discuss the reasons, they just document that people do discontinue the therapy. [SPEAKER_01]: It doesn't seem like that it's medical complications, right?

48:25 [SPEAKER_01]: Whether it's experiencing a ton of side effects, but it just seems like [SPEAKER_01]: they're not experiencing the benefits that they thought they would. [SPEAKER_01]: Or otherwise, not experiencing the upside compared to either the financial cost, they don't like any injection, something, right?

48:42 [SPEAKER_01]: Because you would expect, and again, we're taking a trip down speculation line here, that if they were getting the benefits that they would originally been sold on or that they were expecting, that they would continue. [SPEAKER_01]: See this in GLP1 therapy, right? [SPEAKER_01]: People who started who do seem to respond well to them, [SPEAKER_01]: They are very motivated to stay on them, generally speaking, if they can't.

49:05 [SPEAKER_01]: Whereas people who take them and don't get the same results, that does happen in a small, small proportion, they're kind of ambivalent about whether or not they continue. [SPEAKER_01]: I think some of this has to do with timeline, right? [SPEAKER_01]: So if somebody gets on testosterone replacement therapy, because they were testosterone deficient, and their main symptom or motivation to investigate this was libido.

49:25 [SPEAKER_01]: or drive sexual drive. [SPEAKER_01]: Those tend to respond first, so perhaps, you know, getting that early win where they're like, oh, I do feel better in this regard. [SPEAKER_01]: Again, very motivating for people to stay on. [SPEAKER_01]: On the other hand, if it's more like this general sense of like well-being, [SPEAKER_01]: or even like body composition or like gains.

49:42 [SPEAKER_01]: And these things are generally longer term. [SPEAKER_01]: And so it may require a longer monitoring period to see if that kind of shows up. [SPEAKER_01]: And now Austin, you've obviously treated a number of folks in this domain. [SPEAKER_01]: What's been your experience here, as far as, like, how do you frame the trial?

50:00 [SPEAKER_01]: And then do tailor that based on like specific symptoms that originally led the person to be worked up in the first place? [SPEAKER_01]: Or, yeah, how do you kind of frame that whole thing? [SPEAKER_00]: Yeah, really getting a sense of what's bothering the person the most that's leading them to pursue care.

50:14 [SPEAKER_00]: And then seeing how confident MI that this is the therapy that is likely to benefit them. [SPEAKER_00]: Of course, again, if I've done my proper diagnostic evaluation, my history, my exam, things like that. [SPEAKER_00]: Then the conversation is definitely going to involve addressing all of those things to the extent possible, for example, if somebody is doesn't have a good sense of general will being and they're sleeping poorly and they're drinking too much alcohol.

50:34 [SPEAKER_00]: Yeah, I don't have a great sense that testosterone is likely to fix that, right? [SPEAKER_00]: So addressing the things that I can first, but when it comes to offering testosterone, I don't generally, even though there are some like suggested data and you'll hear different things quoted about like timelines to see a particular benefit, I don't generally use that to inform this.

50:51 [SPEAKER_00]: And part of the reasons why is [SPEAKER_00]: I think that there's like relatively low risk of just establishing an arbitrary timeline that is comfortable for the patient, that is like more patient centered than anything. [SPEAKER_00]: That's how long are they willing to try it to see a benefit rather than like, what is the average that is derived from some not perfect study data and then the other thing is just knowing that different people respond differently to things and some people take a bit longer, some people have a bit more immediate effects.

51:16 [SPEAKER_00]: And so that variation makes it so that I'm not likely to say, oh, because you have this symptom, then I would expect to benefit by this timeframe. [SPEAKER_00]: I don't generally do that very much in practice. [SPEAKER_00]: Rather, I just kind of negotiate. [SPEAKER_00]: Hey, how long would you be willing to try this for?

51:27 [SPEAKER_00]: before there's a benefit. [SPEAKER_00]: I really wouldn't expect there to be additional benefits beyond a relatively long time. [SPEAKER_00]: We'll call it nine months or something like that. [SPEAKER_00]: So somewhere within the realm of, we'll call it three to eight or nine or something like that would be somewhere.

51:43 [SPEAKER_00]: And it's like, if the person is willing to say, look, I'd be willing to keep doing this for six, seven, eight, nine months. [SPEAKER_00]: It's like, okay, we can do that. [SPEAKER_00]: The longer you're on it and the higher the doses that you're on, the more challenging it can be to come off.

51:55 [SPEAKER_00]: And there is some, you know, non-zero number of folks who can have, you know, much more long-lasting issues, especially if they use high doses for long periods of time. [SPEAKER_00]: But we see that more in the antibiotics they reduce that population than those who are just using appropriate reasonable clinically testosterone for shorter periods of time.

52:12 [SPEAKER_00]: So that's generally how I have the conversations like, what are we trying to accomplish and how long would you be willing to try this to see a benefit? [SPEAKER_00]: Because it's not going to be like, you know, you're going to go on this for five months and there's going to be no benefit for five months and then suddenly on like the day one of the six months suddenly it's going to vanish like ideally we should be seeing some incremental progress along the way.

52:30 [SPEAKER_00]: So generally over the course of a few months you start to see whether you're going to benefit or not and people can kind of come to their conclusions, which is I think what drives a lot of that 70% figure that you cited above. [SPEAKER_01]: Yeah. [SPEAKER_01]: Yeah, I agree. [SPEAKER_01]: All right.

52:41 [SPEAKER_01]: Well, so outside of like this monitoring and setting expectations regarding around a trial, there are some concerns that need to be weighed and some risks and benefits. [SPEAKER_01]: So first up is fertility. [SPEAKER_01]: Now, the moment you put exogenous testosterone into a man, the brain will pick that up and say, well, look, man, get a bunch of testosterone.

53:04 [SPEAKER_01]: I don't need to signal the testies to bruise anymore. [SPEAKER_01]: And you might think, well, cool, you got all this testosterone floating around. [SPEAKER_01]: Everything else, save for the brain signal should be working normally. [SPEAKER_01]: Unfortunately, that is not the case because the shut down happens at the level of the brain.

53:19 [SPEAKER_01]: You suppress the body's own production of FSH and LH, which means that that signal doesn't get to the testes. [SPEAKER_01]: And so not only are the testes not going to produce testosterone. [SPEAKER_01]: They're also not going to produce sperm. [SPEAKER_01]: And so if fertility is a concern by a man who wants to start testosterone replacement therapy, well, you got to talk about fertility.

53:37 [SPEAKER_01]: Now, one of the craziest stats that came up in writing this book, was that there it does seem to be a knowledge gap relating to fertility, amongst like trained medical professionals. [SPEAKER_01]: Now, [SPEAKER_01]: about testosterone, they're like, oh, yeah, you get on testosterone, your ball shrink, and you're infertile for a period of time.

53:57 [SPEAKER_01]: You ask the same question to yourrologists in a survey, a quarter of them incorrectly believe that testosterone therapy would improve fertility, which is not the case. [SPEAKER_01]: In fact, when you look at like male contraceptives, most of them are an antigen-based, for example, [SPEAKER_01]: So testosterone is one of the leading eye atrogenic or medically induced causes of male infertility seen in clinical practice, recovery after stopping testosterone replacement therapy is variable.

54:29 [SPEAKER_01]: Some people will bounce back relatively quickly. [SPEAKER_01]: Other people will take a longer time. [SPEAKER_01]: Some people won't bounce back at all. [SPEAKER_01]: It depends on dosing, the duration of use, and the individual, of course. [SPEAKER_01]: So yeah, it kind of runs the gamut from 6 to 12 months, sometimes longer, and for many one kids, this has to be a discussion.

54:50 [SPEAKER_01]: So Austin, how does this conversation go? [SPEAKER_01]: You have a person, let's say, they have true testosterone [SPEAKER_01]: but they desire family, like how do you kind of weigh the benefits of testosterone replacement therapy on their life versus their life goals? [SPEAKER_01]: I mean, this has got to be complicated.

55:07 [SPEAKER_00]: It really is, and it depends on what the symptoms are and how debilitating they are. [SPEAKER_00]: But really, if one somebody says that they have a desire to maintain fragility, then the, [SPEAKER_00]: option of using testosterone therapy alone is generally not going to be recommended for that person.

55:22 [SPEAKER_00]: It doesn't mean they can't use it, but there are some other strategies that may need to be used either instead temporarily or in conjunction kind of along the way. [SPEAKER_00]: And this is getting into a little bit more advanced stuff that I'm generally not doing on a super routine basis, sometimes these folks are also working with other types of specialists, whether from the [SPEAKER_00]: infertility realm or endocrinologist or things like that, but it's something that can be done by somebody who wants to manage some of these other medicines.

55:48 [SPEAKER_00]: So again, testosterone alone not ideal should not be done on its own in this situation that would worsen the fertility concern. [SPEAKER_00]: But can be combined with the use of something like HCG, which can deliver direct stimulus to the testies to maintain fertility either on its own or to gather with testosterone therapy.

56:06 [SPEAKER_00]: And then there are sometimes also folks who will instead of using testosterone or H-C-G, they'll use something like chromophene, which is a selective modulator of some of these receptors in the body. [SPEAKER_00]: And can potentially improve testosterone levels a bit and it's impact on ultimate symptoms is a bit more.

56:23 [SPEAKER_00]: weaker and more inconsistent than testosterone therapy, but can be a way to impact that in the meantime while preserving fertility. [SPEAKER_00]: So that's an off-label use there. [SPEAKER_00]: So those are some of the strategies that you'll sometimes see used relating to fertility preservation, either in somebody who has hypogonatism relating to testosterone therapy, HCG, chromophene, and some other things that are getting even a little bit further into the weeds that we'll skip for now.

56:48 [SPEAKER_01]: Yeah, yeah, genuinely an interesting space you with think with how many men desire testosterone replacement therapy, whether due to real symptoms or other perceived symptoms, right? [SPEAKER_01]: But then there is this fertility concern, you would expect something to come up that does all the cool stuff testosterone does, you know, allegedly or otherwise true.

57:10 [SPEAKER_01]: That also doesn't compromise fertility, but yet [SPEAKER_01]: There are other safety concerns that often get brought up, some of them real, some overstated. [SPEAKER_01]: Let's start with perhaps the most concerning one, maybe not the longest lasting one, that's going to be next. [SPEAKER_01]: But the most concerning one has to do with cardiovascular disease.

57:32 [SPEAKER_01]: Right. [SPEAKER_01]: Now, for years, this space evidence wise was a mess. [SPEAKER_01]: Again, we talked about the FDA warning earlier on. [SPEAKER_01]: There were some lawsuits. [SPEAKER_01]: There was a 2010 trial on testosterone therapy. [SPEAKER_01]: They got halted early because there was an increase in cardiac events.

57:46 [SPEAKER_01]: And then people getting testosterone, a 2017 study suggested that testosterone therapy might increase non-calsified [SPEAKER_01]: of a heart attacks, for example, but overall you could sum it up and say, look, there's genuine uncertainty here. [SPEAKER_01]: Now, you move forward to the traverse trial.

58:05 [SPEAKER_01]: This is 2023 New England Journal of Medicine. [SPEAKER_01]: It found that in the medium term, right, in a study of over 5,000 men, age 45 to 80, all with testosterone deficiency plus established heart disease or high cardiovascular risk [SPEAKER_01]: or placebo, they were followed for two years on average, well, they found that there was no difference in cardiac events between the testosterone group and the placebo group, right around 7% for both.

58:35 [SPEAKER_01]: This sort of harm, this threat, that sort of haunted the field of testosterone placement therapy didn't really show up. [SPEAKER_01]: There wasn't a benefit. [SPEAKER_01]: But this is more like a safety finding, not necessarily a win. [SPEAKER_01]: Now, there's some caveats here. [SPEAKER_01]: And I think this genuinely gets under-discussed.

58:52 [SPEAKER_01]: Most people will point out, yeah, there was slightly high rate of atrial fibrillation, high rate of pulmonary embloism, not large, but enough that the statistics picked it up. [SPEAKER_01]: So here's the thing about the Traverse study that a lot of people skip. [SPEAKER_01]: It used a gel, not the injections that many guys are actually on.

59:10 [SPEAKER_01]: And the treatment group only got up to about 375 nanograms per deceler at the one year mark. [SPEAKER_01]: And this tended to decline as the follow-up period went on. [SPEAKER_01]: That's well below the middle of the range that the guidelines aim for. [SPEAKER_01]: So this is a safety result for guys who are getting gently topped up, which is hard to apply and subsequently give the all clear to some 35-year-old injecting himself up the 900 because he went to a wellness clinic because that guy wasn't even in the study.

59:35 [SPEAKER_01]: Now, from that trial, it's fair to say that at two years in that specific group, the heart safety data looks pretty good. [SPEAKER_01]: Long-term, we still don't know. [SPEAKER_01]: The trial only ran about two years on average, and while it's reassuring, it's just not long enough to rule out the stuff people are worrying about.

59:50 [SPEAKER_01]: I just don't see that being discussed very often, and so I'm still wanting for more data here. [SPEAKER_01]: Is that kind of square with your current view on this? [SPEAKER_01]: I mean, before you answer that, like my thought is that I genuinely think people with low testosterone [SPEAKER_01]: are at risk, an increased risk of cardiovascular disease, not because of the testosterone level itself per se, but because of the clustering of medical conditions that genuinely cause low testosterone, whether it's metabolic syndrome, excess antiposity, or whatever, and so I could see that holding up.

1:00:20 [SPEAKER_01]: I didn't know that replacing them necessarily reduces that risk unless all of those risk factors are otherwise corrected from the testosterone therapy. [SPEAKER_01]: That makes sense to you. [SPEAKER_00]: To some extent, I do think it kind of matters how you got there in terms of the testosterone deficiency here, right?

1:00:36 [SPEAKER_00]: That there are a lot of these very high cardiovascular risk conditions that can increase the risk visceral atoposity, insulin resistance, diabetes, et cetera. [SPEAKER_00]: But we also know that the rate of cardiovascular complications rises for example in men who are receiving prostate cancer, you know, antigen deprivation therapy.

1:00:50 [SPEAKER_00]: And it's like suddenly their testosterone is taken away. [SPEAKER_00]: And yeah, their cardiovascular risk goes up as well. [SPEAKER_00]: So I do think that having like really rigorous trials to replace it and show reduction in cardiovascular risk. [SPEAKER_00]: We would like to see some of that.

1:01:03 [SPEAKER_00]: That's not something that we have a ton of. [SPEAKER_00]: That would be really nice to have. [SPEAKER_00]: But [SPEAKER_00]: I do think it kind of matters how you got there for sure. [SPEAKER_00]: And so yeah, to your point, I mean, anytime you're interpreting a clinical trial, you need to recognize like, well, who was the population, what was done, what was achieved, and then that is the extent to which you can extrapolate the results, you know, you can, you know, try to extrapolate it beyond it, but your confidence level in applying it to other populations should not be very strong.

1:01:28 [SPEAKER_00]: In other words, you should not [SPEAKER_00]: feel very, very good about applying this to a totally different population that was studied or to people who were replaced to much, much higher levels. [SPEAKER_00]: Because then that was not something that would have been reflected, you can't say, well, this supports that.

1:01:41 [SPEAKER_00]: It's like, well, it literally doesn't. [SPEAKER_00]: So you can't say that. [SPEAKER_01]: Yeah. [SPEAKER_01]: One of the longer lasting fears, perhaps the longest lasting fear has to do with the prostate. [SPEAKER_01]: Right. [SPEAKER_01]: Now, this dates back to 1941 where the studies showed that castration actually shrink prostate tumors and then giving testosterone actually seem to make them grow.

1:02:03 [SPEAKER_01]: Now, the finding was real, but the conclusion was incomplete and the saturation [SPEAKER_01]: Austin, briefly, I know you're a big fan of saturation model and you can probably say this more eloquently than I can. [SPEAKER_01]: How would you describe the saturation model to the listener?

1:02:20 [SPEAKER_00]: I think calling me a big fan of it might be overstating it. [SPEAKER_00]: It is something that is an interesting hypothesis, and it seems to comport with some of the observations that we have in the research. [SPEAKER_00]: So for example, you know, there's the traditional idea of, well, if we withdraw testosterone from prostate cancers, then maybe they would tend to shrink.

1:02:39 [SPEAKER_00]: And so those are clearly going to be tumors that are sensitive to the stimulus of testosterone for their growth. [SPEAKER_00]: There are also hormones, sorry, there are also tumors that are not sensitive that have essentially escaped that signal and grow independently of it and those are extra high risk tumors because those are much more difficult to treat and almost like autonomously growing and doing their own thing so those are very high risk tumors.

1:03:01 [SPEAKER_00]: Now, there are various kinds of lines of evidence looking at this. [SPEAKER_00]: And one interesting one has been when testosterone is administered to folks. [SPEAKER_00]: What happens to their prostate-specific antigen levels or their PSA levels? [SPEAKER_00]: This is a marker related to the prostate and as used in various ways, relating to prostate cancer screening, diagnosis, and monitoring over time.

1:03:22 [SPEAKER_00]: And certainly when you withdraw testosterone in that situation, it tends to drop and when you replace testosterone, it tends to rise a bit. [SPEAKER_00]: But then there's this really significant clear plateau in how PPSA levels go. [SPEAKER_00]: And even when you increase testosterone levels to much higher levels, the PSA does not continuously increase to follow that trend indefinitely.

1:03:42 [SPEAKER_00]: So there does seem to be [SPEAKER_00]: This sort of plateau effect, and so there is this idea that, again, remains, I would say, as a kind of explanatory hypothesis at that time. [SPEAKER_00]: I don't think that it's, you know, super slam dunk, accepted among every clinician who's practicing in this space.

1:03:57 [SPEAKER_00]: But I found it interesting, and, and again, seems to reflect or comport with some of the other observations in this space. [SPEAKER_00]: tissues have different levels of testosterone required to saturate their receptors. [SPEAKER_00]: And this is a phenomenon that we know in many other situations of hormone hormones, and their receptors, certain levels leading to hormone receptor saturation.

1:04:20 [SPEAKER_00]: This is also something we see pharmacologically. [SPEAKER_00]: We know that when we give people certain medicines or drugs, [SPEAKER_00]: Certain doses might saturate a given receptor and then it might kind of like spill over and start to hit other receptors. [SPEAKER_00]: We see this a lot in the realm of like psychiatric medicines where low doses have some effects medium doses have other effects high doses have yet other effects based on progressive saturation of different sets of receptors.

1:04:39 [SPEAKER_00]: And so it's an interesting idea that, you know, beyond a certain level, you might have saturated all the testosterone receptors or the antigen receptors in the prostate. [SPEAKER_00]: And so going up much higher than that would not necessarily confer much, much, much greater risk. [SPEAKER_00]: And so that would seem to challenge the concern that if we put anyone on any form of testosterone that it will necessarily increase the risk of prostate cancer.

1:05:01 [SPEAKER_00]: Now, it might be the case that [SPEAKER_00]: that they might benefit from, you know, withdrawal of that hormone to shrink the tumor, at least as far as the cancer outcomes go. [SPEAKER_00]: That does not necessarily imply at the same time that giving anybody testosterone will induce the growth of a new tumor that was not previously present.

1:05:23 [SPEAKER_00]: Those things are not necessarily two sides of the same coin. [SPEAKER_00]: those are separate arguments. [SPEAKER_00]: And the latter has not been proven or shown. [SPEAKER_00]: While the former has, the latter has not, meaning that we do not see, for example, putting somebody on a appropriately dose testosterone, you know, replacement therapy for clinical hypogonatism, that it, like, suddenly spikes the incidence of previously undiagnosed or not-present prostate cancers in these individuals, and that may be the result of this saturation model as a potential explanatory mechanism.

1:05:52 [SPEAKER_01]: Yeah. [SPEAKER_01]: Yeah. [SPEAKER_01]: The testosterone trials and the traverse trial, both found that metontestosterone had nearly identical prostate cancer rates compared to placebo. [SPEAKER_01]: So that does seem to be a reassuring signal. [SPEAKER_01]: But some new interesting data has emerged.

1:06:05 [SPEAKER_01]: Let me get your take on this. [SPEAKER_01]: So the first has to do with [SPEAKER_01]: men who have low testosterone levels. [SPEAKER_01]: They do seem to have a higher incidence of aggressive types of prostate cancer. [SPEAKER_01]: The thought here being that in that localized environment, having low testosterone levels may drive aggressive behavior.

1:06:25 [SPEAKER_01]: of these sort of unregulated cells or additional mutations, or, and, or, because two things can be true, perhaps the disease states that cause the load testosterone in the first place may sort of be additional risk factors for this aggressive, these aggressive types of prostate cancer. [SPEAKER_01]: So, for example, the 2026 retrospective study over 900 men enrolled in an active surveillance program found.

1:06:47 [SPEAKER_01]: those with low baseline testosterone levels had a 61% higher likelihood of their cancer progressing to the kind of aggressive high grade disease that requires active treatment rather than watchful waiting. [SPEAKER_01]: Low testosterone was associated with the progression to this high grade disease specifically, which I thought was interesting.

1:07:04 [SPEAKER_01]: Now whether this additional mutations, more aggressive behavior, you know, this is not really a study that was to set up to identify that, but I found that interesting, particularly with the concern around [SPEAKER_01]: Look, having low testosterone could be a risk factor too, particularly with this kind of emerging evidence.

1:07:23 [SPEAKER_01]: And further, some people might be listening to this and like, well, look, I got a history treated prostate cancer. [SPEAKER_01]: And I have some of these specific symptoms, I have testosterone deficiency, is testosterone safe for me. [SPEAKER_01]: Now, this is a medical advice. [SPEAKER_01]: This is for infotainment purposes only.

1:07:37 [SPEAKER_01]: But it does look like men who have already been treated for prostate cancer, the data is pretty reassuring here. [SPEAKER_01]: A study of 850 men following radical prostitectomy, so surgically, sort of removing the prostate found that those who received testosterone therapy afterwards had significantly lower rate of recurrence than untreated controls, which again, it kind of goes, it's not necessarily supports the saturation model in particular just saying, this is more complex and perhaps these risks that date back to 1941.

1:08:09 [SPEAKER_01]: you know, we're a little bit misguided or maybe a little too simplistic. [SPEAKER_01]: Either way, the PSA should be monitored on everyone, just to sort of watch for this. [SPEAKER_01]: What sort of gets your, you know, signals you like, I don't, I don't like this. [SPEAKER_01]: What sort of change in PSA is something your, your monitoring for?

1:08:27 [SPEAKER_00]: Yeah, I think that, you know, it's worth having one at baseline and levels, you know, like over three to four, start to get my attention and then if things maybe that were previously being monitored and maybe they're relatively stable, but if it starts to accelerate, there are various sorts of more kind of fancy ways to analyze PSA that are definitely outside the scope of this and even I don't claim to be an expert in all of them, but.

1:08:48 [SPEAKER_00]: rates of increase is another thing that will tend to get your attention. [SPEAKER_00]: So if it is rapidly or exponentially increasing or suddenly, if there's a change in that trajectory, sometimes you'll hear it described as velocity. [SPEAKER_00]: Again, not all these measurements are like super well validated for all sorts of clinical outcomes, but really it's like if something does not fit what I expect, it gets my attention at least.

1:09:09 [SPEAKER_00]: Certainly if somebody has a history of prostate cancer, then they're already working with a urologist and oncologist and things like that. [SPEAKER_00]: That's already getting outside of what I'm routinely managing. [SPEAKER_00]: But if their baseline level is unexpectedly high, or if the trajectory of it is not what I'm expecting, then suddenly I have a, you know, what we call a low threshold to get it evaluated a bit further before proceeding just to make sure that everything is safe.

1:09:29 [SPEAKER_01]: Yeah. [SPEAKER_01]: Alright, the last big sort of risk or thing to monitor has to do with the blood. [SPEAKER_01]: Now we're going to talk about Arithrasite Hoses, which is a fancy way of saying, a rise in red blood cell production, is you remember back to your biology days, the red blood cells carry around oxygen that's bound to a specialized protein called hemoglobin in your body.

1:09:51 [SPEAKER_01]: But in up to 20% of men, [SPEAKER_01]: You can get a significant rise in that almost a too high of levels if they're using injectable testosterone. [SPEAKER_01]: It seems to be worse with the injectables compared to the gels that are used. [SPEAKER_01]: And so why does this happen? [SPEAKER_01]: Well, testosterone tells the kidneys to make more earthropoetin.

1:10:11 [SPEAKER_01]: If you're not familiar with Lance Armstrong, cycling at large, the Rithrop Huitin or EPO is a specialized protein that tells your bone marrow to ramp up red blood cell production amongst other formed elements or cells in the blood. [SPEAKER_01]: So if it gets too high, the blood can become more viscous, more thick.

1:10:29 [SPEAKER_01]: And so there are various levels here that seem to suggest either the dose of testosterone is too high or the person is something else going on like untreated sleep apnea. [SPEAKER_01]: or potentially something else, even more nefarious underline the condition that's actually causing the high level of mattercrant, 54% or 54 seems to be that sort of threshold.

1:10:49 [SPEAKER_01]: This isn't like a proven line in the sand, we're like, look, if you go at this level or above, you're gonna have a blood clot bad things are gonna happen. [SPEAKER_01]: It just seems to be more of like, [SPEAKER_01]: Yeah, we need to investigate this a little bit. [SPEAKER_00]: It's really extrapolated from other conditions that lead to abnormally high blood levels and where the concerns arise in those conditions.

1:11:06 [SPEAKER_00]: So it's kind of like the best guess based on other conditions, which is admittedly a weakness of this clinical recommendation, because we actually don't have super strong direct evidence of testosterone induced or arthrocytosis to this point, having a direct causal relationship with like thrombotic complications, meaning like, [SPEAKER_00]: clotting issues and things like that, at least very, very strong or nearly as strong as we do for example, in patients with blood related disorders like polycythemia, you know, things like that abnormal excess blood production for other reasons where the same threshold is like much more clearly associated with some of these things.

1:11:38 [SPEAKER_00]: But it's kind of like, hey, that's the best analogous situation that we have to draw upon and so that leads to this recommendation in a lot of folks. [SPEAKER_01]: Yeah, yeah, so not only monitoring, right? [SPEAKER_01]: So monitoring, a hematocrit, one somebody's on therapy is part of the sort of a treatment algorithm here, but also like if it does seem to go up and best gain it further, you can manage it with smaller, more frequent doses, making sure the person's not inappropriately on something that [SPEAKER_01]: declines estrogen, crushes estrogen, like an aromatase inhibitor, for example, which can have its own set of side effects, like bone loss, joint pain, problems with body composition, libido going down, et cetera.

1:12:16 [SPEAKER_01]: So there's a lot of complexities here, which we all cover in our book signal. [SPEAKER_01]: Now Austin, as we wrap this up, are there any sort of hard stops? [SPEAKER_01]: Any sort of do not pass code and not collect $200 for a person who has the signs and symptoms of testosterone deficiency has laboratory evidence of testosterone deficiency, but otherwise you'd say, I don't think this is a good fit for you.

1:12:40 [SPEAKER_01]: Any sort of like lines in the sand that you're drawing here. [SPEAKER_00]: uh... yeah there are a few so somebody who has like newly diagnosed active prostate cancer or you know men can also get breast cancer there's a few different kind of cancers that would get my attention and another example be like one of those blood related cancers that already leads to very high blood like these are things that should be managed and under control before we're having conversations related to testosterone therapy and want to say happy having conversations that doesn't mean just with me uh... it should be with their you know oncologic uh... specialist and things like that so that's one um...

1:13:10 [SPEAKER_00]: Definitely we've alluded to this already, but the fertility concern is something that needs to come up before consideration of proceeding with this, and we talked about some of the strategies that are sometimes used. [SPEAKER_00]: And sometimes I've had a lot of folks who are just like, look, I'd rather just like try to get this done now and then I'll delay the therapy and I'll just start it on the back end rather than going through all these kind of like other convoluted methods.

1:13:29 [SPEAKER_00]: Not everybody, but that's an example. [SPEAKER_00]: I mentioned the baseline PSA as a reasonable thing to look for, they're certainly a level over four, if there's certain other unexpected findings or trajectories, that's something that deserves evaluation before proceeding. [SPEAKER_00]: Not necessarily like a hard, what we'll call counter indication if it has been evaluated and like cleared, but I'd be curious because that would be maybe unexpected depending on the person's age for it to be that high or actively rising at a rapid clip.

1:13:56 [SPEAKER_00]: And then certainly anybody who has what would consider like very dynamic, unstable health related conditions, for example, you are not seeing me, you know, initiate testosterone therapy on people who haven't admitted to the hospital for like, you know, ongoing active sort of evolving disorders, be it heart failure or sexist or something else like that.

1:14:12 [SPEAKER_00]: Those would be not the time to do something like that. [SPEAKER_00]: You want to be stable and unusual state of health, not only for like the safety of initiating this, but like, [SPEAKER_00]: So that your testing is reliable because, you know, there's the same reason why I'm not routinely pulling testosterone levels on men who are admitted to the hospital in the vast majority of situations that's very, very, very few scenarios where I'm doing that or a couple, but very few.

1:14:32 [SPEAKER_01]: Yeah. [SPEAKER_01]: Yeah. [SPEAKER_01]: So I think, you know, we spent four episodes. [SPEAKER_01]: This whole arc kind of talking about maybe inappropriate attribution of various signs, symptoms, outcomes related to testosterone, right, almost seems like a huge counterfactual, just like four episodes deep, but I think we can summarize it as follows, a person who's genuinely testosterone deficient with signs and symptoms and the lab value that supports that is highly likely to benefit from testosterone replacement there.

1:15:02 [SPEAKER_01]: a person without specific signs and symptoms, more generalized symptoms who also doesn't have a low level, frankly low, very, very low is unlikely to benefit from true testosterone replacement therapy doses, although they may feel better if they're on too high of a dose because at that point they're just running PDs at a relatively low level.

1:15:24 [SPEAKER_01]: And then people who don't have the signs and symptoms of testosterone deficiency who have normal levels, [SPEAKER_01]: are unlikely to benefit from true testosterone replacement therapy as well. [SPEAKER_01]: They might feel differently about superficial logical doses, but that's for an entire other podcast series.

1:15:38 [SPEAKER_01]: Austin, is that the way you understand it, is that the way you kind of think about it when you're evaluating a patient, whether or not they're going to see benefits or maybe just increase risks from the sort of therapy. [SPEAKER_00]: Yeah, I like the way you describe it there because really it's, you know, while you're framing it through the lens of testosterone, this whole podcast here's it really is just the broader perspective on how we do things in medicine in general, it's a game of probability when it comes to diagnosis, it's a game of probability I'm trying to assess what is the probability of this over that until I reach a sufficient level of confidence that you do have this and you don't have that that might cross a treatment threshold.

1:16:13 [SPEAKER_00]: Right. [SPEAKER_00]: And that probability varies based on the condition and it based on the stakes. [SPEAKER_00]: Right. [SPEAKER_00]: So when somebody is critically ill, I might be willing to initiate or cross a treatment threshold and start treatment on them. [SPEAKER_00]: despite a lot of uncertainty, right?

1:16:26 [SPEAKER_00]: Because I'm trying to like save the person's life in the short term. [SPEAKER_00]: For conditions that have very, very, very low stakes, then maybe you might want to be, and especially if the treatment has a potential risk or toxicities, then you want to have a very high level of confidence before you commit to a round of therapy.

1:16:42 [SPEAKER_00]: So an example of this might be, somebody who has like a super-indulant possibility of a super-indulant slow growing, slowly progressive cancer and you're talking about potentially treating them with some form of chemo that has some toxicities. [SPEAKER_00]: You'd want to be rather sure that this is going to impact their lifespan, their health span before you pull the trigger on that.

1:17:01 [SPEAKER_00]: And this is kind of in between. [SPEAKER_00]: There are a variety of symptoms that can be related to testosterone deficiency, each of which has a varying probability to be associated with the diagnosis and then layering on top of that. [SPEAKER_00]: we have a treatment that can have some benefits and some downsides and so we're trying to match like what's the probability that you have a situation that is likely to benefit from this therapy and we're trying to just match those.

1:17:26 [SPEAKER_00]: And so that's where there's a lot of gray area here. [SPEAKER_00]: There's a lot of room for trial and error, some experimentation. [SPEAKER_00]: It's not as clear cut as people would like to make it make it seem. [SPEAKER_00]: And there's also again room when I said trial and error for like, hey, there's enough of a probability and you are willing enough to try this that we can do it for a set period of time and see if it helps and if not, we can stop.

1:17:44 [SPEAKER_00]: But somebody else might reasonably say, you know, [SPEAKER_00]: You know, I'm not as confident that this is likely to be related to that, and I'm not really willing to do that. [SPEAKER_00]: Let me try some other things and see if it gets better on its own, which again, for a non-zero number of people, it also does.

1:17:57 [SPEAKER_00]: So hopefully that description of like, hey, this is medicine in general as a game of, you know, uncertainty, probabilities, risk management, benefit management, and trying to match the treatment to the patient in a way that is like acceptable to them to give them the best outcome they can.

1:18:11 [SPEAKER_00]: And why there's a lot of room for like, [SPEAKER_00]: latitude for different approaches to practice here and that's I think something that's taking me some time to arrive at this position compared with like much earlier in your career, you tend to view things as being much more rigid because maybe all you know is the clinical practice guidelines before you've like worked with enough people to see the the vagaries of day-to-day practice.

1:18:31 [SPEAKER_01]: Yeah, well said. [SPEAKER_01]: All right. [SPEAKER_01]: Here's the one idea underneath this whole series and the core message of our book, Signal. [SPEAKER_01]: Testosterone is an output. [SPEAKER_01]: It's a readout of what the rest of your body is doing. [SPEAKER_01]: And if we can fix the inputs, the output is going to look a whole lot better.

1:18:45 [SPEAKER_01]: If you think about what that means, the stuff that actually raises testosterone in most guys, losing the belly, fixing the sleep apnea, sleeping enough, none of that happens by dumping hormone in from the outside. [SPEAKER_01]: These things have to be addressed directly, versus just chasing the number for its own sake.

1:19:01 [SPEAKER_01]: So we keep coming back to the same order of operations. [SPEAKER_01]: Confirm that the low number is actually low. [SPEAKER_01]: Figure out what's driving it down, try to fix that first if possible, and then reassess. [SPEAKER_01]: Save the actual testosterone replacement for the guys who genuinely need it instead of trying to optimize to a particular level.

1:19:18 [SPEAKER_01]: The number itself is honestly the least interesting thing in the room, which brings us back to Mark. [SPEAKER_01]: Remember Mark from episode one. [SPEAKER_01]: He's 45. [SPEAKER_01]: He's a partner at an architecture firm working 12 hour days and over about a year, everything slid. [SPEAKER_01]: His focus, his energy, his marriage, and he went to a wellness clinic and they gave him one afternoon blood draw should have been done in the morning.

1:19:38 [SPEAKER_01]: And he walks out with a total testosterone level of 240 and a prescription for weekly injections. [SPEAKER_01]: By month three, as you recall, he starts feeling worse than when he started. [SPEAKER_01]: He's got morning [SPEAKER_01]: And we told you back in episode one, his problem wasn't his testosterone, and in episode three, we showed you what it actually was, severe, obstructive, sleep apnea.

1:19:58 [SPEAKER_01]: His airway was collapsing shut about 60 times an hour, once a minute, all night long. [SPEAKER_01]: Plus a bunch of Israel fats are pressing his hormones from the other side. [SPEAKER_01]: So Mark got a seat pat machine. [SPEAKER_01]: He says wearing his legs sleeping with a leaf blow or strapped his face, which fair, but within about six weeks the morning headaches were gone.

1:20:15 [SPEAKER_01]: He was actually sleeping through the night for the first time in years. [SPEAKER_01]: And once he was sleeping, everything else got easier. [SPEAKER_01]: He had the energy to train so we started doing that. [SPEAKER_01]: Three days a week nothing crazy. [SPEAKER_01]: His relationship with food also got a lot better.

1:20:27 [SPEAKER_01]: Now that he was sleeping, he had less cravings for junk food and he had the energy to cook. [SPEAKER_01]: So he started eating better, more protein, real meals made at home. [SPEAKER_01]: And over a few months, the training in the food brought his weight and waste down and subsequently he felt better.

1:20:40 [SPEAKER_01]: And then something happened that the TRT clinic never would have done. [SPEAKER_01]: He agreed to try coming off of the testosterone. [SPEAKER_01]: Now here's the thing that people get wrong about this. [SPEAKER_01]: Your own production doesn't magically switch back on the second you stop because the whole time you're on exogenous testosterone from outside of the body, it's actively suppressing your own endogenous system in your body.

1:21:04 [SPEAKER_01]: There's no guarantee. [SPEAKER_01]: Now, Mark's case, he'd spent those months clearing the stuff that was actually driving his testosterone levels down. [SPEAKER_01]: The apnea, the visceral fat, the wrecked sleep, so when we pulled the external testosterone and gave his own system a chance, it had room to work again, his levels came back up.

1:21:20 [SPEAKER_01]: That's the whole series in one guy. [SPEAKER_01]: His body was sending the signal the entire time. [SPEAKER_01]: It just took someone reading it correctly instead of immediately reaching for a prescription pad. [SPEAKER_01]: Okay, before we wrap the whole series, let me give you five things to take away from today.

1:21:33 [SPEAKER_01]: Number one, the healthcare system gets testosterone wrong in both directions at the same time. [SPEAKER_01]: About a quarter of prescriptions get written without even testing the guy's levels first. [SPEAKER_01]: And even among the guys who do get tested, roughly one and five get the script without actually meeting the criteria.

1:21:48 [SPEAKER_01]: Meanwhile, on the other side, among guys who genuinely have low testosterone, only about one antenna actually being treated. [SPEAKER_01]: So the problem isn't too much or too little, the problem is aim. [SPEAKER_01]: Number two, if you're in that low normal gray zone, more testosterone moves the number, but it doesn't really change symptoms.

1:22:06 [SPEAKER_01]: That Sydney study we walk through, they got guys up to a higher testosterone level and the symptoms didn't budge versus placebo. [SPEAKER_01]: And the guys couldn't reliably tell which gel was which. [SPEAKER_01]: Now if you're genuinely deficient, replacement can absolutely change your life.

1:22:17 [SPEAKER_01]: But for the low normal guy chasing the number, you're mostly just buffing the chart. [SPEAKER_01]: Number three, about 70% of guys who start testosterone are off of it within a year. [SPEAKER_01]: That's usually not side effects that are chasing them off is that they never felt the thing that they were promised, which lines up pretty neatly with the idea that a lot of them never had a real deficiency to begin with.

1:22:37 [SPEAKER_01]: Number four, testosterone can be considered a contraceptive. [SPEAKER_01]: The second you add it from the outside, your brain shuts down that signal that makes sperm, and your count can drop to very low levels, and coming back can be slow. [SPEAKER_01]: it never fully recovers. [SPEAKER_01]: So if kids are anywhere in your future, that conversation should happen before the first dose, not after.

1:22:59 [SPEAKER_01]: This is the one I really don't want you learning the hard way. [SPEAKER_01]: Number five, the two big scary fears have actually been walked back, but with caveats. [SPEAKER_01]: On the heart, the traverse trial found basically identical rates of cardiac events in both groups. [SPEAKER_01]: So, no sign of harm at two years, though, remember those guys only got up two levels in the mid to upper 300s.

1:23:18 [SPEAKER_01]: And they use the gel. [SPEAKER_01]: On the prostate, guys on testosterone had nearly the same prostate cancer rates as placebo, whereas low testosterone seems to be a risk factor for developing the aggressive type of prostate cancer. [SPEAKER_01]: The side effect that often shows up is real, and it's that your blood gets a little too thick, which is exactly why anybody on the stuff needs to get their blood checked.

1:23:38 [SPEAKER_01]: Bottom line here is that wall testosterone replacement therapy is relatively safe. [SPEAKER_01]: When it's correctly dosed and appropriately monitored, the words correctly and appropriately are doing a lot of heavy lifting there, because many people are not getting that level of care. [SPEAKER_01]: All right, let me tie the whole series together.

1:23:53 [SPEAKER_01]: Episode one, the testosterone crisis is mostly manufactured. [SPEAKER_01]: Men's testosterone levels have roughly stayed the same over the last few decades when you use the right test, but there is a bit of nuance here. [SPEAKER_01]: Increase rates of obesity have probably driven the average level down a little bit, though this doesn't show up in the data, but the explosion of TRT prescriptions have more than made up for it.

1:24:12 [SPEAKER_01]: Over the last 10 years, testosterone levels have actually been rising at the level of the population. [SPEAKER_01]: episode two, testosterone is the output of a complex feedback loop. [SPEAKER_01]: The number itself is often a reflection of what's going on health-wise, assuming that it's drawn correctly.

1:24:28 [SPEAKER_01]: And a real diagnosis takes actual symptoms, plus a confirmed low level, not an automated checklist, and one blood draw at 3 p.m. [SPEAKER_01]: Episode three, what actually drives the number down in most men is their body composition getting worse and a lack of high quality sleep. [SPEAKER_01]: Less commonly, men who do a ton of training can also see their levels go down, though this doesn't always cause symptoms.

1:24:49 [SPEAKER_01]: And today, who actually needs replacement, what the safety and fertility data really say, and how testosterone is both under and over prescribed. [SPEAKER_01]: We still can't draw a clean line from a single blood level and tell you which guy is gonna benefit from treatment and which guy isn't.

1:25:02 [SPEAKER_01]: So this takes actual thinking and an actual workup. [SPEAKER_01]: It doesn't bend to one single cut off and it's really not a coupon code. [SPEAKER_01]: And one thing I should say before I point you anywhere. [SPEAKER_01]: We definitely have a financial interest here. [SPEAKER_01]: We sell coaching, we sell programs, and we sell this book, signal.

1:25:17 [SPEAKER_01]: That's the same conflict of interest as the TRT clinics. [SPEAKER_01]: We spent the last four episodes roasting. [SPEAKER_01]: Here's the thing, though. [SPEAKER_01]: We're trying to be honest, brokerage, or information here. [SPEAKER_01]: We're trying to do our best to just stick to the evidence.

1:25:27 [SPEAKER_01]: There's no subscription writing on this. [SPEAKER_01]: Nothing in this episode is gated. [SPEAKER_01]: And we don't make a dime off you believing any particular thing. [SPEAKER_01]: We don't profit from lying to you. [SPEAKER_01]: So what we're actually trying to do is give you enough information [SPEAKER_01]: That's it.

1:25:41 [SPEAKER_01]: With that in mind, if you want the free version of this, there's a testosterone action plan on our website. [SPEAKER_01]: It doesn't cost you anything. [SPEAKER_01]: It walks you through the evaluation, the levers you can actually pull, so if you want the whole thing, the full work up, the science, the history, the cases, that's in our book.

1:25:54 [SPEAKER_01]: It's called Signal. [SPEAKER_01]: And it's out right now. [SPEAKER_01]: If you've got a lab report sitting on your kitchen counter right now and you're trying to figure out what it means, the exact person we wrote this for. [SPEAKER_01]: Both are linked in the show notes and over at barbellmedicine.com.

1:26:06 [SPEAKER_01]: Before you go anywhere, please do us a favor and leave us a five star rating and review. [SPEAKER_01]: It really helps drive traffic to our podcast so we can keep bringing you all the latest nuance and health and fitness. [SPEAKER_01]: I'm Dr. Jordan Faganbaum. [SPEAKER_01]: That's Dr. Austin Baraki, and that's the series.

1:26:17 [SPEAKER_01]: We'll catch you next week, and every week right here on the Parbo Medicine podcast.