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

23:56Dr. Jordan Feigenbaum:And I don't know where this was born out initially, you know, because we come from this like gym world, You know, it's like, look, you have all these individuals who are using anabolic steroids at very high doses, and there 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. 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.

24:39Dr. Jordan Feigenbaum:And this does seem to have spooked prescribers for years because at that time, prescription rates for testosterone therapy fell sharply, more than half between the years 2013 and 2016. 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 almost 10 years later. But a couple of other things happened during this timeframe. One, there were a number of lawsuits that came out against Androgel that started in 2014. This is a topical form of testosterone therapy that got combined to a single federal litigation case.

25:20Dr. Jordan Feigenbaum:There were 25 ,000 claims or more against various producers of topical therapy for testosterone, most of them alleging that heart attacks and strokes were tied to the drugs. 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. The advertising had been pretty substantial up until that point. AbbVie, for example, a pharmaceutical company, spent in the neighborhood of$75 million in 2012 and$65 million in 2013 promoting Androgel. and the testosterone market peaked around$1.6 billion in 2014 before the decline.

26:02Dr. Jordan Feigenbaum:So it seems like the FDA's position predated the scare. As far back as 2000, the FDA had told AbbVie that the marketing around Androgel for age-related low testosterone, which I don't really like that phrase. They said it was misleading. I'm not sure which part of that they said was misleading, but particularly because the drug at the time was only approved for testosterone deficiency from an identifiable cause. And so I guess the question to you, Austin, is do you agree that testosterone deficiency is genuinely undertreated? And if so, why do you think that's the case?

26:41Dr. Austin Baraki:I do think it is undertreated 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 overtreated and undertreated. It's essentially like misdirected. And, you know, interesting to review that history. It's almost like, you know, testosterone therapy. It's almost like the men's version of the WHI phenomenon of after that came out and like prescribing rates dropped 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. And so, you know, I obviously work in a general medical setting.

27:16Dr. Austin Baraki:I train junior doctors and residents. I work closely alongside colleagues. 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 nitty-gritty detail what are the clinical guidelines recommend and in particular, what sorts of populations are at risk and should be potentially tested in like a case-finding sort of way. So as an example, you mentioned the prevalence of this in patients who use chronic opioids 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.

27:58Dr. Austin Baraki: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, that 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 who would be very familiar with this or who would be actively doing this on a regular basis. 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.

28:34Dr. Austin Baraki:As I've described before, you know, I spent some time working with HIV, you know, 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. And I remember, you know, in retrospect, it's like that resonated so much for two reasons. One, that the level was so low, but number two, it's like, oh, I didn't see levels checked that often in any of these patients. It was like striking to me because I was so not used to seeing it checked. And there's like a lot of folks in this situation who, you know, had symptoms that could be compatible with the syndrome or who may have otherwise stood to benefit from, you know addressing it and so i do think it's undertreated i think there are populations who are at risk um where their clinicians this is not something that is a very high priority or that tends to come to mind and i think you know it's interesting that we have this series back to back with the menopausal hormone therapy sort of series just because of how much interesting you know overlap there is or some degree of commonality uh between the two of you know a lot of uh symptoms in that context uh that have either been glossed over brushed off not directly addressed treated with, you know, therapies that do not directly address the problem necessarily compared with, you know, just like using the hormone therapy appropriately, dosed properly when it is safe, properly monitored, things like that.

29:53Dr. Austin Baraki:Because in all those situations, it is like quite safe when it is being used properly. And so I think that that's kind of where our argument is, is that it is neither undertreated nor overtreated, but it is both. It's almost like this therapy overall is just kind of like misdirected. If we could just like shift the window of like who is on this, I think that overall, you know, the, the health of these populations would likely improve by 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?

30:25Dr. Austin Baraki:Um, and, and then helping those who are actually clinically, you know, deficient and who would stand to benefit from a replacement to physiologic levels, but not necessarily pushing them higher than that.

30:35Dr. Jordan Feigenbaum:Yeah, no, well said. I do wonder like how much of this is a training gap versus fears you know ultimately you think about what happens in clinical practice and why it happens people end up you know physicians end up doing things they're very comfortable with what they know they practice how they know otherwise you know what are you doing and it is interesting thinking back to our at least my own education i think we had obviously very similar educations given the fact we graduated a year apart same school whatever things like hypothyroidism hyperthyroidism diabetes are hammered into you and so as a primary care position, if that's what you went into, you feel like I have a pretty good lay of the land here.

31:11Dr. Jordan Feigenbaum:I feel comfortable for, um, non-complicated cases, you know, without additional training, you don't need to refer everyone to an endocrinologist when things get out of your belly, out of your area of comfort. Sure. Refer appropriately. That is not the same case when it comes to testosterone deficiency with menopause or whatever. 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. And so, you know, if you're a instructor, you're like, I really can't talk about testosterone deficiency to the same level as we can about hypothyroidism because there's just more unknowns.

31:44Dr. Jordan Feigenbaum:And like, you know, instead of half of the things you learn today, being out of date by the time you graduate 75%, we don't know. So 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, I don't know.

32:04Dr. Austin Baraki:what do you what's the cause here 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 whi take obviously now 20 plus years to really start to get shaken up a little bit more i think some of these things around testosterone especially as it relates to uh you know these concerns about cardiovascular risk which you know the more we look at carefully dosed uh trials we're starting to see less and less of that as a concern when it's being used properly, as well as probably hearkening 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.

32:42Dr. Austin Baraki:But that was a, you know, not a clinical scenario that we were looking at there. And you're right that a lot of the clinical educators would have been trained in that era or earlier. And so you kind of need like, you know, 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. I think you're right that people have no concerns about throwing around thyroid hormone, throwing around insulin as another form of a hormone, but these other ones, a lot more apprehension and concern around. And there are some unique complexities to all of them, but not something that is like insurmountable.

33:13Dr. Austin Baraki:Like people can be trained, clinicians can be trained to do these assessments and to use these things properly. So it is very possible. But yeah, I think a long combination of historic events that get really burned into people's brains. 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 of years who are currently in residency, still being apprehensive about doing certain things for long debunked things. And I'm like, look guys, that is definitely not a thing. Let me pull up this paper from like a decade ago that I learned about back then that showed that this was not a concern that you needed to be worried about and try to erase that from your brain now also that you are practicing kind of up-to-date medicine moving forward.

33:58Dr. Austin Baraki:So 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.

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37:50Dr. Jordan Feigenbaum:Not the guy with a real disease, with real testosterone deficiency. The guy whose own production isn't broken, his level just sits on the low end of normal and he feels lousy. That's the patient and that's who they recruited to the study. So these guys started with a testosterone level around 310 nanograms per deciliter. That's on the low side of normal, but nowhere near what you'd see if the testicles or the pituitary had actually stopped working. The gel pushed them up to around 510, which is solidly into the healthy young man territory, right in the middle of the range. Their DHT went up, their estradiol went up, all the downstream stuff you'd expect.

38:24Dr. Jordan Feigenbaum:So the hormone was absolutely getting in and absolutely doing its job. But their symptoms, they didn't really change. The main thing they measured was each guy's own biggest complaint. Whatever brought them in scored over the past few weeks. Their energy levels, no real difference between testosterone and the placebo. Their sexual symptoms, same. No real difference between testosterone and the placebo. Then they ran the whole stack of quality of life questionnaires on top of that. Physical function, mood, sex, well-being, prostate problems, the works. 22 different measures. Exactly one of them favored testosterone.

38:57Dr. Jordan Feigenbaum:and the authors basically said, yeah, run 22 tests and one of them is going to look good by accident. That's not really a signal. That's just pee hacking. It's noise wearing a lab coat. And here's the part that makes this study matter. This was not some underpowered little pilot study that missed a real effect because each guy was his own control on the hormone and off of it. The design was actually really sensitive. It had over a 90 % power to catch even a moderate benefit of testosterone compared to placebo. It was sensitive enough to pick up the effects of age, body weight, where the guy started testosterone-wise.

39:32Dr. Jordan Feigenbaum:It picked up all of that. It just didn't find anything for testosterone because there wasn't anything to find. Now, there's one last nuance here. At the very end, they let each guy pick which gel he wanted to keep using, still totally blind to which was which. And more guys picked the testosterone, 26 out of 42. So you could squint at that and say, look, they liked the testosterone. but it wasn't even statistically significant, much less clinically significant. And the authors are honest that this phase was the weakest part of the study, way less powerful than the main trial. The solid finding is the big one.

40:04Dr. Jordan Feigenbaum: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. Now the caveats. The study was only six weeks long. It was only with 45 guys, all of them without actual testosterone deficiency. 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. For that guy, testosterone replacement can absolutely be life-changing, full stop. 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 and leaves you feeling just about the same.

40:43Dr. Jordan Feigenbaum:And that low normal guy, the one who feels nothing, is exactly who's getting a lot of the prescriptions.

40:50Dr. Austin Baraki:I can't say enough about how this type of clever design is exactly the kind of thing that can be super informative. And again, we're not here to debunk the idea that testosterone can help people. It's that when it is appropriately used and dosed properly in people who are clinically deficient, it certainly can be life-changing. I've seen it many, many times with folks. But there are those who are maybe influencers in this space. Maybe their entire career or practice is built around testosterone prescriptions. and of course they're going to have their own selection bias of seeing people who might be more likely to benefit 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 you like how i often frame these when when presented publicly it's like here's the design that we're going to do based on your understanding of this condition right 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 they're going to double from 300 to 600 or something like that what would you predict is going to result in terms of their symptoms and what would you predict is going to happen in terms of which therapy people opt to stay on and of course those who are very in favor of testosterone cures everything much like again i keep drawing these parallels to the menopause influencer space where it's like everyone needs estrogen estrogen fixes everything because there are similar types of studies in that context too right where they do this kind of thing and it's like what would you predict and of course they would say well obviously the people whose testosterone level doubled they're going to feel way better and they're going to opt for that therapy it's like okay let's see what happens and then when you see this it should just challenge you a little bit 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 maybe it doesn't fix everything.

42:46Dr. Austin Baraki:There are certainly some people who stand to benefit and those who don't. And if I were a responsible clinician, I would say, man, I would really like to be able to figure out a way or help to identify those who are more likely to benefit from those who are less likely to benefit. And then also in working with patients like this, let's say I decided I'm like, 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, I have no concerns about something like that. but also it being planned as a trial of like hey let's do this 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 and if not then we can also stop at that point that's also okay uh and that's the way i would

43:28Dr. Jordan Feigenbaum:negotiate this in practice yeah it is telling people are like okay you're saying that sometimes testosterone is helpful particularly if 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 Well, here's a telling statistic. Of individuals who start on testosterone replacement therapy, 70 % will stop using it within a year. 70 % will stop using it in a year. And that's not because testosterone is bad or poorly tolerated, generally speaking, but it just doesn't move the needle, pun intended, for a lot of these folks.

44:02Dr. Jordan Feigenbaum:And that's the whole thing. The goal of treatment here is to improve somebody's quality of life, their health trajectory, have them put more life in their years, so to say. And if it's not working, you don't have to just stay on it

44:14Dr. Austin Baraki:because you started it. 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. Yeah, right.

44:23Dr. Jordan Feigenbaum:Okay, say a guy genuinely does need testosterone therapy. What are you actually aiming for? You're aiming to help the person, not to hit some specific number on the lab. The current guidelines say the same thing here. Get them somewhere in the middle of the normal range, measured halfway between doses. You call it 450 to 600 nanograms per deciliter. So a guy sitting at 550 in the middle of his cycle is being treated correctly. But a guy who's sitting at 1 ,200 isn't being really treated. He's being juiced. And the we'll optimize you to 900 thing is mostly a sales pitch based on the assumption that higher is better, which isn't necessarily true.

44:59Dr. Jordan Feigenbaum:Here's something that almost no one tells you. The testosterone people actually get prescribed is often not the testosterone that's been studied. There's this regimen that's kind of fallen out of favor, for example. You get 200 milligrams of testosterone injected every two weeks, and it physically cannot hold you steady. You shoot up to like 1 ,400 in the first few days. You're super therapeutic. 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. It's a roller coaster, and you're basically microdosing a breakup with yourself every two weeks.

45:32Dr. Jordan Feigenbaum: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. Now, there was a real-world study of this in over 9 ,000 guys on testosterone, and their average levels landed around 800, way up near the tippy-top of the range, not the middle that the guidelines actually call for. That means that a significant number of these guys were super therapeutic, well above normal, kind of like a mild cycle of PEDs. And the monitoring is somehow even worse than the dosing. The VA looked at this, and only about 3 % of guys who started testosterone got the full recommended workup beforehand, 3%.

46:07Dr. Jordan Feigenbaum: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, potentially unchecked. So when some guy tells you that testosterone changed his life or that it did nothing for him, honestly, neither one tells you much by itself. Not unless you know his dose, you know why he started and you've seen his labs. Otherwise, all you're hearing is a story. So Austin, let's think about this. You got two different patients here.

46:39Dr. Jordan Feigenbaum:I want to kind of compare and contrast. First, you got a new patient. Total testosterone is 480. Pretty much in the center of the range. No specific symptoms, but they're like, look, I got to be 900 because that's the number he saw on the internet. He wants you to help him get there. Second, you get a second patient. It's a guy who's already on testosterone from some clinic who shows up wanting a second opinion. how do you run the sort of optimize me conversation without either one feeling like they're being

47:07Dr. Austin Baraki:dismissed yeah challenging conversations but certainly ones that i've 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 it almost becomes their identity of like this is just lower than i want it to be and therefore you know i 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 eject your dose and it's going to kind of gradually they'll spike and then gradually decline before before the next one but some of this depends on what their dosing interval looks like and when we're checking the lab 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 were treated you started on this what has been the result of that treatment did you have suggestive signs symptoms that are now better and like back to normal were you ever did you ever have any signs or symptoms like was this appropriate in the first place like what is the goal of therapy and then what are we trying to accomplish by achieving a level of 900 because hey i could potentially achieve a level of 900 by just like having you go in and get your level checked like an hour after your dose.

48:25Dr. Austin Baraki: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? What are the goals? Are we meeting those goals? And what remains to be achieved by hitting this number? 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 like just health and getting things to where I want them to be, they're generally on board with this sort of framing. These levels are not everything.

48:55Dr. Austin Baraki:Different people have different sensitivity to the same level of hormone. And if you're feeling well, doing well, performing well, recognizing that, hey, we're probably in a good enough spot. On the other hand, there are some people who are just gonna be ultra rigid and say, I really, I 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. And so then the question is like, well, how is that being measured? And is it gonna require you to get very super physiologic to get there, in which case you're just asking me if you can go on anabolics, go on PEDs.

49:24Dr. Austin Baraki:And it's like, well, you can do whatever you want. I'm not necessarily gonna recommend it or be the person who's prescribing you like PED level dosed 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 harms, some downsides, some of the side effects that you're hoping to avoid. There might be some mood disturbances, some acne that comes out, some you know other sorts of uh you know dose related toxicity i'll call it um 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 whether the blood counts the skin stuff the you know various other sorts of symptoms that people might experience from pushing things too high and so then it's like well if they want to try that they can on their own time um if they're able if they're sourcing it on their own already or getting it from someplace else it's like you can try but this is you know what you might look out for and if they experience the harms themselves then they might come to their own conclusions at that point.

50:17Dr. Jordan Feigenbaum:Yeah, no, good points. All right, so that's the story so far. When we come back from the break, we're going to talk about a trial of testosterone, the safety data, and what to do next. All right, welcome back to the Barbell Medicine Podcast. Before the break, we were talking about how more testosterone in a man who isn't deficient is unlikely to make him better. 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. And many men only get shown half of the equation. So you referenced earlier kind of running this as a trial.

50:52Dr. Jordan Feigenbaum:Just because somebody starts testosterone, for example, they don't need to persist in perpetuity on it. 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. They're like, well, look, if I take this exogenous testosterone from outside of the body, it's going to shut down my own production. So I'm just committing to lifelong therapy. But that's not necessarily true. People often will bounce back. And again, for a lot of people who start testosterone, apparently, it doesn't seem to get them what they want. With 70 % of men who start testosterone, stop it within the first year.

51:29Dr. Jordan Feigenbaum:As far as why, most of the studies don't really discuss the reasons. They just document that people do discontinue the therapy. It doesn't seem like it's medical complications, right, where they're just experiencing a ton of side effects. But it just seems like they're not experiencing the benefits that they thought they would or otherwise not experiencing the upside compared to either the financial cost. They don't like any injection. It's not something, right? Because you would expect, and again, we're taking a trip down speculation lane here, that if they were getting the benefits that they had originally been sold on or that they were expecting, that they would continue.

52:09Dr. Jordan Feigenbaum:See this in GLP-1 therapy, right? People who start it who do seem to respond well to them, they are very motivated to stay on them, generally speaking, if they can. whereas people who take them and don't get the same results you know that does happen a smaller smaller proportion they're kind of ambivalent about whether or not they continue um i think you know some of this has to do with timeline right so if somebody gets on testosterone replacement therapy because they were testosterone deficient and their main symptom or or motivation to investigate this was libido or or drive sexual drive 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 again very motivating for people to stay on on the other hand if it's more like this general sense of like well-being or even like body composition or like gains in the gym these things are generally longer term and so it may require a longer monitoring period to see if that that kind of shows up and now austin you've obviously treated a number of folks in this domain what's been your experience here as far as like, how do you frame the trial?

53:17Dr. Jordan Feigenbaum:And then do you tailor that based on like specific symptoms that originally led the person in, you know, to be worked up in the first place? Or yeah, how do you kind of frame that whole thing?

53:27Dr. Austin Baraki:Yeah, really getting a sense of what's bothering the person the most that's leading them to pursue care, and then seeing how confident am I that this is the therapy that is likely to benefit them? Of course, again, if I've done my proper diagnostic evaluation, my history, my exam, things like that, 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 wellbeing and they're sleeping poorly and they're drinking too much alcohol. Yeah. I don't have a great sense that testosterone is likely to fix that.

53:54Dr. Austin Baraki:Right. 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 suggestive 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. And part of the reasons why is 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 else 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 you know have a bit more immediate effects and so that variation makes it so that i'm not likely to say oh because you have this symptom then i would expect a benefit by this time frame i don't generally do that very much in practice.

54:40Dr. Austin Baraki:Rather, I just kind of negotiate, hey, how long would you be willing to try this for before there's a benefit? I really wouldn't expect there to be, you know, additional benefits beyond, you know, a relatively long time frame, we'll call it nine months or something like that. So somewhere within the realm of, we'll call it, you know, three to, you know, three to eight or nine or something like that would be somewhere. And it's like, if the person is willing to say, look, I'd be willing to keep doing this for, you know, six, seven, eight, nine months, it's like, okay, you know, we can do that. The longer you're on it and the higher the doses that you're on, the more challenging it can be to come off 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 but we see that more in the anabolic steroid use population than those who are just using like appropriate reasonable clinically dose testosterone for shorter periods of time so that's generally how i have the conversation it's like what are we trying to accomplish and how long would you be willing to try this to see a benefit 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 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 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 own conclusions which is i think what drives a lot of that 70 figure that

55:54Dr. Jordan Feigenbaum:you cited above yeah yeah i agree all right well so outside of like this monitoring um and setting expectations regarding running a trial, there are some concerns that need to be weighed and some risks and benefits. So first up is fertility. Now, the moment you put exogenous testosterone into a man, the brain will pick that up and say, well, look, man, I got a bunch of testosterone. I don't need to signal the testes to Bruce anymore. And you might think, well, cool. You got all this testosterone floating around. Everything else, save for the brain signal, should be working normally. Unfortunately, that is not the case because the shutdown happens at the level of the brain.

56:36Dr. Jordan Feigenbaum:You suppress the body's own production of FSH and LH, which means that that signal doesn't get to the testes. And so not only are the testes not going to produce testosterone, they're also not going to produce sperm. And so if fertility is a concern by a man who wants to start testosterone replacement therapy, well, you got to talk about fertility. Now, one thing, 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. Now you ask gym bros about testosterone and they're like, oh yeah, you get on testosterone, your balls shrink and you know, you're infertile for a period of time.

57:14Dr. Jordan Feigenbaum:You asked the same question to urologists in a survey, a quarter of them incorrectly believed that testosterone therapy would improve fertility, which is not the case. In fact, when you look at like male contraceptives, most of them are androgen-based, for example. So testosterone is one of the leading iatrogenic or medically induced causes of male infertility seen in clinical practice. Recovery after stopping testosterone replacement therapy is variable. Some people will bounce back relatively quickly. Other people will take a longer time. Some people won't bounce back at all. It depends on dosing.

57:53Dr. Jordan Feigenbaum:the duration of use and the individual, of course. So yeah, you know, it kind of runs, runs the gamut from six to 12 months, sometimes longer. And for men who want kids, this has to be a discussion. So Austin, how does this conversation go? You know, you have a person, let's say they have true testosterone deficiency, but they desire family. Like, how do you kind of weigh the benefits of testosterone replacement therapy on their life versus their life goals? I mean, this has got to be complicated.

58:24Dr. Austin Baraki:It really is. And it depends on what the symptoms are and how debilitating they are. But really, if once somebody says that they have a desire to maintain fertility, then the option of using testosterone therapy alone is generally not going to be recommended for that person. 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. 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 urology, kind of andrology, infertility realm, or endocrinologist, or things like that.

59:00Dr. Austin Baraki:But it's something that can be done by somebody who, you know, wants to manage some of these other medicines. So again, testosterone alone, not ideal, should not be done on its own in this situation. That would worsen the fertility concern, but can be combined with the use of something like HCG, which can deliver direct stimulus to the testes to maintain fertility either on its own, or together with testosterone therapy. And then there are sometimes also folks who will instead of using testosterone or HCG, they'll use something like clomiphene, which is a selective modulator of some of these receptors in the body and can potentially improve testosterone levels a bit.

59:37Dr. Austin Baraki:And its impact on ultimate symptoms is a bit more weaker and more inconsistent than testosterone therapy, but can be a way to impact that in the meantime while preserving fertility. So that's an off-label use there. So those are some of the strategies that you'll sometimes see used relating to fertility preservation, either in somebody who has hypogonadism relating to testosterone therapy, HCG, clomiphene, and some other things that are getting even a little bit further into the weeds that we'll skip for now.

1:00:05Dr. Jordan Feigenbaum:Yeah, genuinely an interesting space. You would think with how many men desire testosterone replacement therapy, whether due to real symptoms or other perceived symptoms, right? 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. That also doesn't compromise fertility. But yeah, to date, not a lot of great options here. There are other safety concerns that often get brought up, some of them real, some overstated. Let's start with perhaps the most concerning one, maybe not the longest lasting one.

1:00:45That's going to be next.

1:00:45Dr. Jordan Feigenbaum:But the most concerning one has to do with cardiovascular disease, right? Now, for years, this space evidence-wise was a mess. Again, we talked about the FDA warning earlier on. There were some lawsuits. There was a 2010 trial on testosterone therapy. They got halted early because there was an increase in cardiac events and the people getting testosterone. A 2017 study suggested that testosterone therapy might increase non-calcified coronary plaque, which those soft plaques tend to be the cause of heart attacks, for example. But overall, you could sum it up and say, look, there was genuine uncertainty here.

1:01:20Dr. Jordan Feigenbaum:Now, you move forward to the TRAVERSE trial. This is 2023, New England Journal of Medicine. And 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 who were randomized to get either topical testosterone or a placebo. And 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. this sort of harm this threat that sort of haunted the field of testosterone replacement therapy didn't really show up uh there wasn't a benefit but this is more of like a safety finding not necessarily a win now there's some caveats here and i think this genuinely gets under discussed um most people will point out yeah there was slightly higher rate of atrial fibrillation um right a higher rate of pulmonary embolism not not large but but enough that the statistics picked it up.

1:02:20Dr. Jordan Feigenbaum:So here's the thing about the Traverse study that a lot of people skip. It used a gel, not the injections that many guys are actually on. And the treatment group only got up to about 375 nanograms per deciliter at the one year mark. And this tended to decline as the follow-up period went on. That's well below the middle of the range that the guidelines aim for. 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 to 900 because he went to a wellness clinic because that guy wasn't even in the study.

1:02:52Dr. Jordan Feigenbaum:Now, from that trial, it's fair to say that at two years in that specific group, the heart safety data looks pretty good. Long term, we still don't know. 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. I just don't see that being discussed very often. And so I'm still wanting for more data here. Does that kind of square with your current view on this? I mean, before you answer, like my thought is that I genuinely think people with low testosterone, testosterone deficiency 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 adiposity or whatever.

1:03:35Dr. Jordan Feigenbaum:And so I could see that holding up. I just don't know that replacing them necessarily reduces that risk unless all of those risk factors are otherwise corrected from the testosterone therapy. Does that make sense to you?

1:03:48Dr. Austin Baraki:To some extent. I do think it kind of matters how you got there in terms of the testosterone deficiency. You're right that there are a lot of these very high cardiovascular risk conditions that can increase the risk of visceral adiposity, insulin resistance, diabetes, et cetera. But we also know that the rate of cardiovascular complications rises, for example, in men who are receiving prostate cancer, androgen deprivation therapy. And it's like suddenly their testosterone is taken away and yeah, their cardiovascular risk goes up as well. So I do think that having like really rigorous trials to replace it and show reduction in cardiovascular risk.

1:04:19Dr. Austin Baraki:We would like to see some of that. That's not something that we have a ton of. That would be really nice to have. But I do think it kind of matters how you got there for sure. 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. In other words, you should not 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.

1:04:54Dr. Austin Baraki:Because then that was not something that would have been reflected. You can't say, well, this supports that. It's like, well, it literally doesn't. So you can't say that.

1:05:01Dr. Jordan Feigenbaum:Yeah. One of the longer lasting fears, perhaps the longest lasting fear, has to do with the prostate, right? Now, this dates back to 1941 where the study showed that castration actually shrank prostate tumors and then giving testosterone actually seemed to make them grow. Now, the finding was real, but the conclusion was incomplete. And the saturation model, which we detail heavily in the book, explains why. Austin, briefly, I know you're a big fan of the saturation model and you can probably say this more eloquently than I can. How would you describe the saturation model to the listener?

1:05:37Dr. Austin Baraki:I think calling me a big fan of it might be overstating it. It is something that is an interesting hypothesis, and it seems to comport with some of the observations that we have in the research. 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. And so those are clearly going to be tumors that are sensitive to the stimulus of testosterone for their growth. 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 now there are various kind of lines of evidence looking at this and one interesting one has been when testosterone is administered to folks what happens to their prostate-specific antigen levels or their PSA levels.

1:06:30Dr. Austin Baraki:This is a marker, you know, related to the prostate and is used in various ways relating to prostate cancer screening, diagnosis, and monitoring over time. And certainly when you withdraw testosterone in that situation, it tends to drop. And when you replace testosterone, it tends to, you know, rise a bit. But then there's this really significant clear plateau in how PSA levels go. And even when you increase testosterone own levels to much higher levels, the PSA does not continuously increase to follow that trend indefinitely. So there does seem to be 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.

1:07:09Dr. Austin Baraki:I don't think that it's, you know, super slam dunk accepted among every clinician who's practicing in this space, but I found it interesting. And again, seems to reflect or comport with some of the other observations in this space that tissues have different levels of testosterone required to saturate their receptors 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 this is also something we see pharmacologically we know that when we give people certain medicines or drugs certain doses might saturate a given receptor and then it might kind of like spill over and start to hit other receptors 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.

1:07:56Dr. Austin Baraki:And so it's an interesting idea that beyond a certain level, you might have saturated all the testosterone receptors or the androgen receptors in the prostate. And so going up much higher than that would not necessarily confer much, much, much greater risk. 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. Now, it might be the case that somebody who has an existing tumor that is sensitive to androgens like testosterone, that they might benefit from, you know, withdrawal of that hormone to shrink the tumor, at least as far as the cancer outcomes go.

1:08:32Dr. Austin Baraki: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. Those things are not necessarily two sides of the same coin. Those are separate arguments. And the latter has not been proven or shown. While the former has, the latter has not, meaning that we do not see, for example, putting somebody on appropriately dosed testosterone replacement therapy for clinical hypogonadism, that it suddenly spikes the incidence of previously undiagnosed or not present prostate cancers in these individuals. And that may well be the result of this saturation model as a potential explanatory mechanism.

1:09:10Dr. Jordan Feigenbaum:Yeah. Yeah, the testosterone trials and the Traverse trial both found that men on testosterone had nearly identical prostate cancer rates compared to placebo. So that does seem to be a reassuring signal. But some new interesting data has emerged. I'll get your take on this. So the first has to do with men who have low testosterone levels. They do seem to have a higher incidence of aggressive types of prostate cancer. The thought here being that in that localized environment, having low testosterone levels may drive aggressive behavior of these sort of unregulated cells or additional mutations.

1:09:45Dr. Jordan Feigenbaum:Or, and or, because two things can be true, perhaps the disease states that cause the low testosterone in the first place may sort of be additional risk factors for these aggressive types of prostate cancers. So, for example, the 2026 retrospective study of over 900 men enrolled in an active surveillance program found that 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. Low testosterone was associated with the progression to this high-grade disease specifically, which I thought was interesting.

1:10:22Dr. Jordan Feigenbaum:Now, whether this additional mutations, more aggressive behavior, this is not really a study that was set up to identify that, but I found that interesting, particularly with the concern around testosterone on prostate cancer, it's like, well, look, having low testosterone could be a risk factor too, particularly with this kind of emerging evidence. And further, some people might be listening to this and like, well, look, I got a history treated prostate cancer. And I have some of these specific symptoms. I have testosterone deficiency. Is testosterone safe for me? Now, this isn't medical advice.

1:10:52Dr. Jordan Feigenbaum:This is for infotainment purposes only, but it does look like men who have already been treated for prostate cancer. The data is pretty reassuring here. A study of 850 men following radical prostatectomy, 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 that necessarily supports the saturation model in particular, just saying this is more complex and perhaps these risks that date back to 1941, you know, were a little bit misguided or maybe a little too simplistic.

1:11:32Dr. Jordan Feigenbaum:Either way, the PSA should be monitored on everyone just to sort of watch for this. What sort of gets your, you know, signals you like, ooh, I don't like this. What sort of change in PSA is something you're monitoring for?

1:11:44Dr. Austin Baraki: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 were 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 rates of increase is another thing that will tend to get your attention so if it is you know rapidly or like exponentially increasing or suddenly if there's a change in that trajectory sometimes you'll hear it described as like velocity 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 certainly if somebody has a history of prostate cancer then they're already working with you know a urologist and oncologist and things like that that's already getting outside of what i'm routinely managing 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

1:12:46Dr. Jordan Feigenbaum:safe yeah all right the last big sort of risk or thing to monitor has to do with the blood now We're going to talk about erythrocytosis, which is a fancy way of saying a rise in red blood cell production. As 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. But in up to 20 % of men, you can get a significant rise in that almost too high of levels if they're using injectable testosterone. um it seems to be worse with injectables compared to the the gels um that are used and so why does this happen well testosterone tells the kidneys to make more erythropoietin if you're not familiar with lance armstrong cycling at large erythropoietin or epo is a specialized protein that tells your bone marrow to ramp up uh red blood cell production amongst other formed elements or cells in in the blood.

1:13:41Dr. Jordan Feigenbaum:So if it gets too high, the blood can become more viscous, more thick. And so there are various levels here that seem to suggest either the dose of testosterone is too high, or the person has something else going on, like untreated sleep apnea, or potentially something else, even more nefarious, underlying the condition that's actually causing the high level of matocrit. 54 % or 54 seems to be that sort of threshold. This isn't like a proven, line in the sand where like, look, if you go at this level or above, you're going to have a blood clot, bad things are going to happen. It just seems to be more of like, yeah, we need to investigate this a little bit.

1:14:17Dr. Austin Baraki:It's really extrapolated from other conditions that lead to abnormally high blood levels and where the concerns arise in those conditions. 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 erythrocytosis to this point having a direct causal relationship with like thrombotic complications meaning like clotting issues and things like that at least very very strong or nearly as strong as we do for example in patients with you know 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 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 yeah yeah so

1:15:04Dr. Jordan Feigenbaum:So not only monitoring, right? So monitoring a hematocrit when somebody's on therapy is part of the sort of a treatment algorithm here. But also like if it does seem to go up, investigating it further, you can manage it with smaller, more frequent doses, making sure the person's not inappropriately on something that 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. So there's a lot of complexities here, which we all cover in our book, Signal.

1:15:38Dr. Jordan Feigenbaum:Now, Austin, as we wrap this up, are there any sort of hard stops, any sort of do not pass go to 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? Any sort of like lines in the sand that you're drawing here?

1:16:00Dr. Austin Baraki: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. Another example would 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 relating to testosterone therapy. And when I say having conversations, that doesn't mean just with me. It should be with their, you know, oncologic specialist and things like that. So that's one. Definitely we've alluded to this already.

1:16:29Dr. Austin Baraki: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 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 not everybody but that's an example i mentioned the baseline psa as a reasonable thing to to look for there's certainly a level over four if there's certain other unexpected findings or trajectories.

1:16:57Dr. Austin Baraki:That's something that deserves evaluation before proceeding. Not necessarily like a hard, what we'll call contraindication 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. And then certainly anybody who has what we would consider like very dynamic, unstable health-related conditions. For example, you are not seeing me, you know, initiate testosterone therapy on people who I've admitted to the hospital for like you know ongoing active sort of evolving disorders be it heart failure or sepsis or something else like that those would be not the time to do something like that you want to be stable and in your usual state of health not only for like the safety of initiating this but like 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 you know admitted to the hospital in the vast majority of situations that's very very very few scenarios where i'm doing that there are a couple but very few.

1:17:49Yeah.

1:17:50Dr. Jordan Feigenbaum:Yeah. So I think, you know, we spent four episodes, 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 therapy. 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 PEDs at a relatively low level.

1:18:41Dr. Jordan Feigenbaum:And then people who don't have the signs and symptoms of testosterone deficiency, who have normal levels, are unlikely likely to benefit from true testosterone replacement therapy as well. They might feel differently about super physiological doses, but that's for an entire other podcast series. 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 this sort of therapy?

1:19:06Dr. Austin Baraki:Yeah, I like the way you described it there because really it's, you know, while you're framing it through the lens of testosterone, this whole podcast series, 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, right? And that probability varies based on the condition and it based on the stakes, right?

1:19:35Dr. Austin Baraki:So when somebody is critically ill, I might be willing to initiate or cross a treatment threshold and start treatment on them despite a lot of uncertainty, right? Because I'm trying to like save the person's life in the short term. For conditions that have very, very, very low stakes, then maybe you might want to be, and especially if the treatment has some potential risks or toxicities, then you want to have a very high level of confidence before you commit to a round of therapy. So an example of this might be, you know, somebody who has like a super indolent, possibility of a super indolent, slow growing, slowly progressive cancer.

1:20:06Dr. Austin Baraki:And you're talking about potentially treating them with some like form of chemo that has some toxicities. It's like, 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. And this is kind of in between. 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, 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.

1:20:41Dr. Austin Baraki:And we're trying to just match those. And so that's where there's a lot of gray area here. There's a lot of room for trial and error, some experimentation. It's not as clear cut as people would like to make it seem. 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. But somebody else might reasonably say, 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, 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.

1:21:14Dr. Austin Baraki:So hopefully that description of like, hey, this is medicine in general is a game of uncertainty, probabilities, risk management, benefits 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 and why there's a lot of room for like, you know, latitude for different approaches to practice here. And that's, I think, something that's taken 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 vagaries of day-to-day practice.

1:21:48Dr. Jordan Feigenbaum:Yeah, well said. All right, here's the one idea underneath this whole series and the core message of our book, Signal. Testosterone is an output. It's a readout of what the rest of your body's doing. And if we can fix the inputs, the output is gonna look a whole lot better. So if you think about what that means, the stuff that actually raises testosterone in most guys, losing the belly, fixing sleep apnea, sleeping enough, none of that happens by dumping hormone in from the outside. These things have to be addressed directly versus just chasing the number for its own sake. So we keep coming back to the same order of operations.

1:22:21Dr. Jordan Feigenbaum:Confirm that the low number is actually low. Figure out what's driving it down. Try to fix that first, if possible, and then reassess. Save the actual testosterone replacement for the guys who genuinely need it instead of trying to optimize to a particular level. The number itself is honestly the least interesting thing in the room, which brings us back to Mark. Remember Mark from episode one? He's 45. He's a partner at an architecture firm working 12-hour days, and over about a year, everything slid. His focus, his energy, his marriage, and he went to a wellness clinic, and they gave him one afternoon blood draw.

1:22:54Dr. Jordan Feigenbaum:Should have been done in the morning. And he walks out with a total testosterone level of 240 and a prescription for weekly injections. By month three, as you recall, he starts feeling worse than when he started. He's got morning headaches, his blood pressure's creeping up. 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. His airway was collapsing shut about 60 times an hour, once a minute, all night long. Plus a bunch of visceral fat suppressing his hormones from the other side. So Mark got a CPAP machine.

1:23:25Dr. Jordan Feigenbaum:He says wearing it is like sleeping with a leaf blower strapped to his face, which fair. But within about six weeks, the morning headaches were gone. He was actually sleeping through the night for the first time in years. And once he was sleeping, everything else got easier. He had the energy to train, so he started doing that. Three days a week, nothing crazy. His relationship with food also got a lot better. Now that he was sleeping, he had less cravings for junk food and he had the energy to cook. So he started eating better, more protein, real meals made at home. And over a few months, the training and the food brought his weight and waist down and subsequently he felt better.

1:23:57Dr. Jordan Feigenbaum:And then something happened that the TRT clinic never would have done. He agreed to try coming off of the testosterone. Now, here's the thing that people get wrong about this. 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. So you stop, and then you wait, and then you find out what your body can do on its own. There's no guarantee. Now, in Mark's case, he'd spent those months clearing the stuff that was actually driving his testosterone levels down.

1:24:27Dr. Jordan Feigenbaum: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. That's the whole series in one guy. His body was sending the signal the entire time. It just took someone reading it correctly instead of immediately reaching for a prescription pad. Okay, before we wrap the whole series, let me give you five things to take away from today. Number one, the healthcare system gets testosterone wrong in both directions at the same time. About a quarter of prescriptions get written without even testing the guy's levels first.

1:24:59Dr. Jordan Feigenbaum:And even among the guys who do get tested, roughly one in five get the script without actually meeting the criteria. Meanwhile, on the other side, among guys who genuinely have low testosterone, only about one in 10 are actually being treated. So the problem isn't too much or too little, the problem is aim. Number two, if you're in that low normal gray zone, more testosterone moves the number, but it doesn't really change symptoms. That Sydney study we walked through, they got guys up to a higher testosterone level and the symptoms didn't budge versus placebo. And the guys couldn't reliably tell which gel was which.

1:25:31Dr. Jordan Feigenbaum:Now, if you're genuinely deficient, replacement can absolutely change your life. But for the low normal guy chasing a number, you're mostly just buffing the chart. Number three, about 70 % of guys who start testosterone are off of it within a year. That's usually not side effects that are chasing them off. It's 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. Number four, testosterone can be considered a contraceptive. 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.

1:26:04Dr. Jordan Feigenbaum:And coming back can be slow. 6 to 12 months sometimes, and for a small group, it never fully recovers. So if kids are anywhere in your future, that conversation should happen before the first dose, not after. This is the one I really don't want you learning the hard way. Number five. The two big scary fears have actually been walked back, but with caveats. On the heart, the TRAVERSE trial found basically identical rates of cardiac events in both groups. So no sign of harm at two years, though remember, those guys only got up two levels in the mid to upper 300s, and they used the gel. 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.

1:26:47Dr. Jordan Feigenbaum: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 this stuff needs to get their blood checked. Bottom line here is that while testosterone replacement therapy is relatively safe, 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. All right, let me tie the whole series together. Episode 1, the testosterone crisis is mostly manufactured. 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.

1:27:21Dr. Jordan Feigenbaum:Increased 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. Over the last 10 years, testosterone levels have actually been rising at the level of the population. Episode 2, testosterone is the output of a complex feedback loop. The number itself is often a reflection of what's going on health-wise, assuming that it's drawn correctly. And a real diagnosis takes actual symptoms plus a confirmed low level, not an automated checklist and one blood draw at 3 p.m. Episode 3, what actually drives the number down in most men is their body composition getting worse and a lack of high-quality sleep.

1:28:00Dr. Jordan Feigenbaum:Less commonly, men who do a ton of training can also see their levels go down, though this doesn't always cause symptoms. And today, who actually needs replacement, what the safety and fertility data really say, and how testosterone is both under and over-prescribed. We still can't draw a clean line from a single blood level and tell you which guy is going to benefit from treatment and which guy isn't. So this takes actual thinking and an actual workup. It doesn't bend to one single cutoff. It's certainly not a coupon code. And one thing I should say before I point you anywhere, we definitely have a financial interest here.

1:28:31Dr. Jordan Feigenbaum:We sell coaching, we sell programs, we sell this book, Signal. That's the same conflict of interest as the TRT clinics we've spent the last four episodes roasting. Here's the thing, though. We're trying to be honest brokers of information here. We're trying to do our best to just stick to the evidence. There's no subscription writing on this. Nothing in this episode is gated. And we don't make a dime off you believing any particular thing. We don't profit from lying to you. So what we're actually trying to do is give you enough information to make an informed decision for yourself. That's it. With that in mind, if you want the free version of this, there's a testosterone action plan on our website.

1:29:03Dr. Jordan Feigenbaum:It doesn't cost you anything. It walks you through the evaluation, the levers you can actually pull. So if you want the whole thing, the full workup, the science, the history, the cases, that's in our book. It's called Signal. And it's out right now. If you've got a lab report sitting on your kitchen counter right now and you're trying to figure out what it means, it's the exact person we wrote this for. Both are linked in the show notes and over at barbellmedicine.com. Before you go anywhere, please do us a favor and leave us a five-star rating and review. It really helps drive traffic to our podcast so we can keep bringing you all the latest nuance in health and fitness.

1:29:31Dr. Jordan Feigenbaum:I'm Dr. Jordan Feigenbaum. That's Dr. Austin Baraki, and that's the series. We'll catch you next week and every week right here on the Barbell Medicine Podcast.

1:29:43Thank you.