#623: Testosterone Testing: What Do the Results Mean? When Does TRT Help? – Austin Baraki, MD

0:00Danny Lennon: Hello and welcome to Sigma Nutrition Radio. My name is Danny Lennon and you are listening to episode 623 of the podcast. You're very welcome. Today we're going to be taking a look at the topic of testosterone and specifically what do lab results from testosterone tests tell us? In what situations should they be done in the first place? Second, in what situation should they be acted on? and what are the potential pitfalls in malinterpretation of said results. And this has been a topic that has always been of interest, but has really captured a lot of people in recent times, owing to a number of narratives that we see within media, within social media, even within political discussion around the levels of testosterone we see generally across the population.

0:53Danny Lennon: and specifically most of this focus gets discussed in the context of men and what is an appropriate level of testosterone, what is too low, there's narratives about declining levels of testosterone over the last number of decades, etc. And to the point now where because of the ease of testing for this, people are able to go and get lab tests themselves even before thinking about probabilities or discussing with a medical professional the probabilities of having low testosterone. and then with a said test result people are looking for treatments most notably via testosterone replacement therapy or trt and so to go through this is a number of interesting questions we need to think about what those tests are measuring what they actually tell us and then how the context in which they're done actually adds an important layer to their interpretation and so how one result on its own doesn't really tell us everything because it could have different meanings depending on that context.

1:55Danny Lennon: And so to go through this, there's probably no better person than Dr. Austin Baraki, who has been on the podcast several times previously. In one of those, we specifically talked about issues related to testing and screening and so on. And that will raise its head again in this particular episode. And so we're going to go through all of this and hopefully by the end, you will have a clearer understanding around testosterone testing, interpretation of those results, etc. In the description box where you're currently listening or over on sigmanutrition.com, you will get a list of the resources related to this.

2:33Danny Lennon: So some papers that relate to what we might discuss, a bit more about Dr. Baraki and his background, where you can find him online, and then also previous episodes of the podcast that he has been on. So that will be linked in the description box where you're currently listening. If you are a Sigma Nutrition Premium member, then you will get a set of detailed study notes to accompany this episode. Again, available by clicking through to the episode page in the description box or finding that directly on sigmanutrition.com or you will have also received an email with it. If you are listening on the free public feed of the podcast and you're interested in getting more out of your podcast listening, including getting access to the detailed study notes we provide for each of the episodes, as well as a premium only episode each month, then check out all the benefits of being a premium member at the link in the description box where you're listening right now, or of course, again, over at sigmanutrition.com.

3:31Danny Lennon: So with that, let's get into this conversation between myself and Dr. Austin Doracki.

3:49Danny Lennon: and here we are welcome back to the podcast dr austin baracki how are you doing doing great i

3:55Austin Baraki, MD: think i've lost count it's been a handful of times we did some stuff on some some lab testing and iron deficiency are the main ones that i recall but good to be back nonetheless yeah i'll have

4:03Danny Lennon: to check this i'm gonna guess maybe this is your fourth appearance i could be wrong could be number or five, but I will double check that for people and I'll put links to those previous episodes in the description. I encourage everyone to go and check them out. I'm sure if you haven't heard any of those after listening to today's episode, you will be another Dr. Austin Baraki fan, just like me. So let's see how that goes. Very briefly before we get into this, Austin, before people who maybe haven't come across those episodes or for whatever reason, haven't come across your work before. What's the brief outline of who you are, what you do, what your work and interests are, and anything else that might be relevant to what we're going to chat about today?

4:44Austin Baraki, MD: Yeah, I am an internal medicine physician, often, I guess, labeled as a clinician educator. I work in an academic medical center teaching and mentoring junior doctors and medical students seeing acutely ill patients who need admission to the hospital and management on that front. but I also have a lot of other outside interests. I practice some telemedicine. I work in the weight management, kind of cardiometabolic risk management space as well. And then been working with barbell medicine for many years now over, I guess a decade or more at this point in the health fitness coaching performance sort of space as well.

5:20Austin Baraki, MD: So I think that has led to a host of downstream interests that have landed me here a few times in the past. We have our own podcast, website, resources, videos, and things like that. So a whole lot of interest spanning health and performance and fitness within the clinical realm. Again, for those who have either have heard those prior episodes or who are willing to suffer through them, you will learn about my interests in clinical diagnosis, clinical reasoning, testing, test interpretation, much of which is fortunately or unfortunately going to come through on this episode as well.

5:49Danny Lennon: Absolutely. And I think as people will see while this topic does get brought up in maybe fortunately or unfortunately in many of the general fitness general health type discussions people see online there is of course at the in the background a very clinical aspect to what we're going to be talking about specifically looking at testosterone and more specifically at the testing that goes on the numbers that someone might get from testing and then most importantly interpretations of that particularly now with the clamor that people have for maybe jumping on TRT, for example, and different incentives that they may see for people promoting this or otherwise.

6:29Danny Lennon: So maybe if we start at the beginning, so everyone gets on the same page here, when we talk about testosterone testing and typical testing, people may go and get typical labs. What is actually being measured? And then maybe after that, we can talk about for those typical measures, what are the current clinical cutoff points we might define as a normal range for those said measures?

6:52Austin Baraki, MD: I'm happy to answer those. I think that there is one critical element that should be asked before that, and that is, ought you be tested? And what are the sort of scenarios in which testing is recommended or justifiable? And so if anybody has heard some of our prior conversations around testing, the whole idea with medical testing is these two different paradigms. One is screening, where you may be attempting to identify a condition in somebody who has no symptoms whatsoever that may plausibly lead to downstream preventable complications, morbidity, mortality, early death. And if we detect it early and we're able to intervene on that thing, then we can substantially kind of alter that trajectory.

7:40Austin Baraki, MD: That's screening. Testing totally asymptomatic, well-appearing people to try to modify their lifespan, healthspan, things like that. The other arm of testing is diagnosis. And that is when a person has some sort of issue, a sign, a symptom, a complaint, and we are using our biomedical testing methods that could be testing any bodily fluid of your choice or imaging testing or anything like that to try to narrow down among the wide list of possibilities of diagnoses that could be causing that particular issue, and then with the hopes that we can intervene on that thing. And so testing really in that context aims at altering the probabilities of disease, and are we able to increase the likelihood of a disease or decrease the likelihood that a diagnosis is present to the point where we feel comfortable treating them for that condition, or we feel it is sufficiently unlikely that we can safely withhold treatment with no ill consequence.

8:45Austin Baraki, MD: I know this sounds super high in the clouds type of conversation, but that's really what we're doing with medical diagnosis. There are some things where the probability of a diagnosis being present is so high that you don't even need testing to make the diagnosis and to guide a treatment plan. If I have a young premenopausal, totally healthy woman who comes in complaining of absolutely textbook typical symptoms of a urinary tract infection. For example, I don't actually need to do a urine test. I don't need to do a urine culture. The probability of that being a standard urinary tract infection is so high that it has already crossed what is considered the treatment threshold, and we can just treat them with our empiric kind of antibiotic choice, and the overwhelming majority of those cases will resolve without any further complications.

9:36Austin Baraki, MD: On the other hand, if I have somebody coming in with chest pain, I have a lot of possible causes of chest pain that I need to distinguish between, some very serious, some not so serious, and I may not be able to make that determination just by gathering a history on them alone or just by doing a physical examination, and that's where additional testing becomes useful. So for example, I might put some stickers on their chest and get an electrocardiogram, an EKG, and that will increase or decrease the probability of some sinister cause of chest pain related to their heart. Or I might image their chest, and that might increase or decrease the probability of some sinister cause of chest pain related to their lungs, or a rib fracture, or any number of other things.

10:20Austin Baraki, MD: It's all about altering these probabilities to make me feel more confident in a particular management plan that will either improve the symptom, the issue, or rule out ominous diagnoses. So that's like the preamble to this whole conversation. So when it comes to testing for testosterone, my first question, because I get these kind of consultations from people all the time, they're just like, here's my labs, tell me what you think. And before I even opened the PDF that they sent me, my question is, can you tell me some context? Tell me why these were done. Because there is a gulf of a difference between somebody who's like, I feel fine, I'm crushing it in the gym, I'm doing well.

11:01Austin Baraki, MD: and I just wanted to get these checked just to make sure everything's good. That's one possibility. You could say that's a screening situation, whether it's recommended or not as a separate topic, but that would be one scenario, and that would impact how I interpret those test results. The other scenario is somebody who says, I have been having substantial changes in my mood, in my sleep, in my erectile function. I've lost my libido that was previously very strong, all sorts of other changes that I've been experiencing, loss of body hair, like these various sets of symptoms or concerns, that substantially changes the probability that this person has a testosterone issue, even before I look at the blood test.

11:44Austin Baraki, MD: And then the blood test might be even more reinforcing. Or if it is very discordant, then again, I start to have to think like, what are the possibilities? This is a false positive, or this is a false negative, because I was so confident this would end up being that before I ever looked at the test. So it's kind of like this Bayesian probabilistic sort of reasoning. I need a prior estimation of how likely is there to be some pathology here. And then I use the test result to kind of move the needle there and determine what is my probability after seeing the test result. Why does all of this matter?

12:14Austin Baraki, MD: Because I'm trying to determine what is the probability that like giving this person testosterone helps them, for example. Because what we know, for example, is that person, the first scenario, the person who has no concerns, no complaints whatsoever, and is like, I just got it tested. And it turns out it's like a little lower than I wanted it to be because they listened and they heard on some bro podcast out there or saw in the media about this crisis and their levels need to be this high for them to do well. And they have no problems, but they're like, shouldn't it be higher? Should I get on testosterone?

12:43Austin Baraki, MD: The probability that person will benefit from testosterone is not very high. Whereas the probability that they will have adverse effects from it is meaningfully present. And that might inform our conversation and my ultimate recommendation. On the other hand, the person whose probability of clinically significant testosterone deficiency just by their history alone is at least moderate, and then I get a test result that further confirms that suspicion, now I am very confident that they both have this condition and that treating it is likely to benefit them. All of this, you know, preamble of setting my mental probabilities, it's not like I'm sitting here doing math, but through training and learning this stuff and clinical experience, you start to get a sense of what's the probability of this and how much does this test result move the needle for me in the probability of the diagnosis?

13:38Austin Baraki, MD: Because that's what then informs my conversation about how likely are you to benefit? Because that's what people really want to know is like, ought I pursue this thing or should I not? This ties into some of your other recent conversations we were talking about with my colleague about peptide. How do we know? What is the probability that this peptide is going to help my issue? The problem is nobody knows, right, for many of them. On the other hand, we could say, oh, I have clinically significant obesity with complications. What's the probability that taking a clinically significant dose of a GLP-1 receptor agonist is to benefit my condition?

14:11Austin Baraki, MD: Very high, based on abundant evidence. So to come back to this question now, what are we measuring when we do testosterone-based blood tests? It is measuring a few different things depending on exactly what's ordered, but you can measure a total blood testosterone level, just the total amount. And that's important because it circulates in differing forms. It circulates in a free form. That is a tiny fraction of the total amount of testosterone in the blood. And then it circulates in a protein-bound form. It can be bound to a handful of different proteins that is not readily accessible to your tissues for immediate action.

14:44Austin Baraki, MD: There's like this kind of equilibrium between the amount that's bound up and the amount that's free for action. And so you can, if you so order a total testosterone, you can also order a free testosterone, which can be measured in certain ways directly, or it can be estimated using certain other calculations. Those are the most common tests that are done relating to testosterone deficiency when applied clinically. Again, your second question had to do with the interpretation and the cutoffs and things like that. As we established in some of our previous episodes, establishing cutoffs for diagnostic tests is fraught.

15:20Austin Baraki, MD: It is challenging. There are lots of different ways that you can go about it that need to be specific to the test that you're looking at to kind of optimize its diagnostic performance. What do I mean by that? You would prefer that there be a nice, neat, tidy, single binary cutoff on a test that neatly separates the people who will benefit from treatment from those who won't benefit from treatment. That would be, what a utopia that would be. We could get this test result. If it's below this cutoff, boom, we know you're going to benefit. Treat them. If it's above this cutoff, we also know you're not going to benefit from treatment.

15:58Austin Baraki, MD: Move on to something else. There are almost no tests that offer that level of perfect discrimination between populations of who are or are not likely to benefit. This is also why we don't make, we should not make treatment decisions based on a single test result alone. This is not only because, again, that clinical context, all that history that I described that I would elicit from somebody beforehand to establish my probability, the person who feels 100 % fine and just set a PR deadlifted 300 kilos, the likelihood that they are to benefit from testosterone therapy if their testosterone level comes back at 385 or something like that, nanograms per deciliter, is not super likely compared with their likelihood of adverse effects.

16:52Austin Baraki, MD: On the other hand, the person with all of those signs and symptoms that I laid out, now my probability that they have clinically significant testosterone deficiency further supported by a testosterone level, even if it's kind of in this gray area range. Let's say it's around 300 or something like that. Some clinicians would say that's above the cutoff in my lab. I'm not treating that. If I see that kind of number and I have somebody who's checking like almost every box of symptom, my probability going into that test was so high that I'm like, it could be reasonable to offer a trial of treatment to this person and to see how well or whether they improve or not, while also thinking about other possibilities that they could have going on.

17:29Austin Baraki, MD: So that's why interpretation of these tests is also very challenging because you need to go into it with that probability and not thinking about it in such a discrete binary way. The problem is increased accessibility of lab testing to the general population. I'm not necessarily saying that is the problem, but rather that with that being the case, the way labs are reported to people when you look at a lab test, particularly with a direct-to-consumer sort of product, it is simply labeled as green or red. It is offered to you in binary terms. There are some companies that even sell it to you, the results with like a stoplight system or something like that.

18:08Austin Baraki, MD: And it implies that anything that's red is a disease that needs to be fixed. And anything that's red is not a disease that is perfect. That is also not the case. You can have labs that are normal, but are inappropriately normal that shouldn't be. You can also have labs that are abnormal, but like, yeah, you expect them to be abnormal because they should be. Just to give a couple examples of that, like, let's say that somebody chronically lives at very high altitude, They may well have a hemoglobin and a hematocrit that is reported on their lab as red, abnormal, but that is a physiologic adaptation to living at altitude, for example.

18:40Austin Baraki, MD: You might have, on the other hand, somebody who has some issues with their endocrine, there are various other endocrine feedback loops aside from testosterone or their calcium physiology or something like that. And then we might check a test that is normal when it actually shouldn't be normal. And that itself is the disease, right? So if somebody's calcium level is like a little bit higher than it should be, their parathyroid hormone should be very low. But if it is, and the red abnormal result would be the expected one there. But if it is green and labeled normal, then, oh, that is the disease.

19:15Austin Baraki, MD: And so that's why it takes clinical training to be able to interpret these things. And why when people just go out and get their labs done and they look at the result and then they send them to me and they're like, hey, doc, what do you think? What should I do? I'm like, we need a long conversation before I can tell you what we need to do. Because having that history, that context, the symptoms, the issues, if any, and if not, we can have a whole separate conversation about how useful are these labs? What is it actually telling us? What is it not telling us? Is your attention even in the best place for your health?

19:44Austin Baraki, MD: It may not be. So that was a much longer answer than I intended on giving you. But I think it set a lot of the stage for what is the test actually measuring? and how complex is it to interpret testosterone-related blood testing, but just like in general, it's all about what's the probability that treatment is going to help you or harm you. That's what I'm trying to get to the bottom of.

20:05Danny Lennon: That gives us the kind of perfect roadmap to walk through some of these. And whilst there are these distinct different contexts that you mentioned, maybe that first distinction that you laid out is really thinking about in a case where based on your assessment of a specific patient, there may be an indication that you want to go and test for their testosterone, whether to check something, rule something out, et cetera. And that's one area that we want to go down. Maybe later on, we can return to the other case that is now becoming this popular thing of someone off their own back goes and get a direct to consumer test, even though they're completely asymptomatic, they feel great.

20:42Danny Lennon: They're trying to optimize whatever the case may be and want to check their testosterone and then comes with a reported figure. So if we turn to the first case and if we think about, you mentioned some of the symptoms that may typically indicate someone may have a testosterone issue, but beyond some of those that you mentioned, and maybe to make it clear for people, what are some examples of cases where based on a patient profile, what they're reporting, some of their symptoms, where it would be indicated or something that you would go and check would be to order a testar strone lab for them.

21:14Austin Baraki, MD: Totally. So I like to break down the, what we call symptoms being the things that the patient experiences and reports to you, or what we call signs in medicine. Signs are not things that patients report, but things that we might find, be it on a physical exam or on some other testing. And that might also increase or decrease our suspicion and lead us to do additional testing. I can generally divide them into things that are very specific, meaning that if the person has these, it actually substantially alters the probability in my mind that they have clinically significant testosterone deficiency.

21:46Austin Baraki, MD: There are some symptoms that are non-specific, meaning that these are common in patients with testosterone deficiency, but also super common in like many other things. So those would be non-specific symptoms. And then I have this bucket that's kind of in between where they can be like suggestive. They're not very specific, but they're not like totally non-specific either. So I'll walk through some examples of those. So let's say that we have an adult male who actually never completed their secondary sexual development, like the normal sex development that happens, say, through puberty, for example, is incomplete, or they never actually went through it at all.

22:22Austin Baraki, MD: not a very common scenario that we run across but that's like pretty specific for a lack of testosterone if you never developed any of the secondary sex characteristics as an as an adult male if you have a loss of the normal pattern of male body hair that could be axillary hair pubic hair things like that that's lost or again never developed that would be suspicious if you have abnormally small testicular volume that's another example of something where i have concerns about the possibility of some testosterone deficiency. You can see that these are like not the most common things that people are out there complaining about, but these are some of the most specific things where when I say most specific, it means there's not too many other things.

23:02Austin Baraki, MD: There might be a couple, but not too many other things where I'm going to be testing for them as well. Let me contrast that with the other category, the non-specific symptoms. This is like somebody who says they have a depressed mood, they are fatigued, they have poor sleep, they don't really have too much muscle mass, or they have a lot of body fat. You're probably sensing it's like, yeah, all those things are super, super common and can happen for dozens to hundreds of different reasons. What are all the reasons why somebody might have a depressed mood, right? Endless sorts of things. Why might somebody be fatigued?

23:42Austin Baraki, MD: One of my favorite topics. What if they're iron deficient? That's another easy one. Or thyroid, or anemia for other reasons, or chronic infections, or chronic kidney disease, or cirrhosis, or all these undiagnosed sleep apnea. Extremely common things. So these are situations where if these are the predominant complaints or concerns that the person has, I might consider checking a testosterone level, but I am also very likely to be checking tons of other things. And many of those other things may be more likely, whether because of the nature of their symptoms or just because they're more common in general, right?

24:17Austin Baraki, MD: That's kind of the big distinction between the specific and the nonspecific. A few other things that you'll hear associated or that would get my attention are, again, I mentioned if somebody previously had a normal libido and it is lost, that actually definitely gets my attention. If there's issues with things like gynecomastia or male breast tissue development, infertility concerns, erectile dysfunction issues. If men start having kind of like what seem like menopausal hot flashes and things like that, that can also be a suggestive kind of in that in-between category. Because again, somebody, a guy, somebody tells me that they're having new onset drenching night sweats.

24:53It's like, yeah, you could have testosterone deficiency or you could have lymphoma or you could

24:57Austin Baraki, MD: have tuberculosis. Like, do you want me to start going down this list? You see how there's a handful of things that can cause this. So those are examples of the ranging from the most specific to the very nonspecific, where I still might consider testing, but there's a gulf between them in terms of what is the length of other things that could be going on and how far down that rabbit hole am I going to go with testing? Because many other things may actually be more probable or more common in the nonspecific category. And then the last thing I'll say here is that there could be scenarios where somebody has a bunch of the nonspecific symptoms and they're like, I'm really worried about having testosterone deficiency.

25:34Austin Baraki, MD: So they're tired, they're not sleeping well, they have mood impairment, things like that. But then when I assess their libido, for example, or their erectile function, they're like, no, no problem in that department because they want to make sure I know that's going great. I'm like, okay, well now the probability of testosterone deficiency being the issue is like plummeted just by the way you answered that question. And it's not to say, again, that we can't test or we shouldn't test, but it now changes the likelihood of that diagnosis. And it changes, in my mind, the likelihood that you would benefit from testosterone therapy.

26:04Austin Baraki, MD: And I'm going to be more reluctant to jump to that, given that I could be missing something else that's causing your symptoms. So that's why the details of that symptom category are very useful. So that's kind of how I break down some of the signs and symptoms. I think the only other one that immediately comes to mind that I didn't mention is a man who is diagnosed with low bone density or osteoporosis needs to have needs to have their testosterone level checked as well.

26:24Danny Lennon: So if we walk through this, hopefully people are becoming aware that there's a kind of a chain along here. It's not the simplistic thing that sometimes is made out to be that first we might have this, these signs and symptoms that someone is coming with based on that. Let's say they do go and get some testing, maybe even multiple tests come back. And it is at that level that you would consider low or put them in this range for testosterone deficiency. From there, then it starts coming into two elements around the actual diagnosis you're going to come to, and then the kind of treatment you're going to get to.

26:56Danny Lennon: Because I think there's maybe a assumption, at least for some people, that it's as simple as, well, my doctor is going to flag that I've low testosterone. I'll jump on TRT, that will fix everything. As opposed to thinking, well, why might that be low? And how does that change your decision making about what to do about it? Can you maybe walk us through those two elements at the point of, okay, we've got now a patient that has actual symptoms. They have these test results come back. You see that the testosterone is low. From there, where are you going to try and work out what would be the next step and what you might need to do with this particular patient?

27:30Austin Baraki, MD: Yeah, this is super important because it is done so poorly in a lot of places. One of the, some of the shocking data points that we found when we were designing our testosterone course and the text that we wrote on this is there's been some kind of survey and registry data that have looked at this question and found that despite prescription testosterone increasing by like tenfold between say like 2000 to 2010, almost a quarter of patients didn't have a testosterone level even measured before they started therapy, which is wildly inappropriate. About a third of patients who were treated didn't actually meet diagnostic criteria for testosterone deficiency.

28:06Austin Baraki, MD: And then about half of patients didn't have subsequent rechecks of their levels after starting therapy. So like the whole testing and monitoring world is pretty poor. And so this is a bit of a hot topic for us to discuss is not just getting the level checked if it is appropriate to do so, but you need to complete a proper evaluation because there are significant implications for the person, both in treatment decisions and like long-term health decisions that need to be made. Because having clinically low testosterone deficiency, hypogonadism, These are all kind of interchangeable terms for the most part, as you might hear them in practice.

28:42Austin Baraki, MD: It is not, in my mind, a final diagnosis. And this might be reminiscent of, again, our prior episode where we talked about iron deficiency. And I said, look, iron deficiency is not a final diagnosis. You need to dig further to figure out what is the reason for this. And so the same applies with testosterone deficiency or hypogonadism. there are different possible, what I'll call lesions, to use a clinical term there, in the endocrine pathway that can lead to the ultimate phenotype of a low testosterone situation. That is based in knowing the underlying anatomy and the physiology from the hypothalamus, how that signals the pituitary gland, how that signals the gonads, how the gonads feed back to the hypothalamus and the pituitary, and how that whole system is not only intercommunicating and regulating, but also how other factors outside of that HPG axis, as it is known, how outside factors impact its function.

29:42Austin Baraki, MD: Because there are lots of other medical conditions that can impact it to where you might have low testosterone because of something totally outside of that system altogether. And while that might sound odd, it's actually the most common situation that we see is that the person does not have a specific, for example, structural or functional defect in their hypothalamus or their pituitary or even their gonads when they have testosterone deficiency, but more often it is due to outside factors that are impairing the function of that system. And so the way we divide this clinically is into what's called primary hypogonadism or primary testosterone deficiency, primary meaning that the source of the problem is in the testes.

30:25Austin Baraki, MD: The testes themselves are failing at their job. This is a minority of cases. This can happen for a variety of reasons that I'll set aside for now. We go through them in some detail in our material, but it is actually the distinct minority of situations. That is also more often characterized by not just low testosterone production, but impaired sperm production, infertility, and a variety of other things. The more common scenario is what we call secondary testosterone deficiency or secondary hypogonadism, where the problem is not in the testes, but it is actually in the brain. It is in the hypothalamus and the pituitary or somewhere in that territory that is impairing signaling to testes that are otherwise structurally and functionally normal.

31:06Austin Baraki, MD: Like the factory is there and it's ready to do its job, but the lights are off. It's not getting the signal from the brain to do its job. The question then is why? And this is where some of these outside factors come into play. Some of the most common issues that lead to testosterone deficiency are those that affect this brain signaling. Those include obesity, specifically the accumulation of visceral adiposity due to a variety of mechanistic kind of pathways relating to testosterone metabolism and leptin signaling and lots of other things that impair that signaling. So obesity, visceral body fat is a huge factor here.

31:42Austin Baraki, MD: The other is sleep, disrupted sleep, insufficient sleep restriction is another terrible one. Substance use, alcohol, chronic opioid use are a few examples of things that can significantly impair the function of that pathway. And then from there, we get into less and less common things. But you can see now when I mention what are the more common things, well, secondary, more common than primary. And then within secondary, the most common contributors to that are extremely common things of poor sleep, poor diet, activity, alcohol use, obesity, visceral body fat, this whole kind of syndromic kind of cluster are some of the most common contributors to clinically significant testosterone deficiency, as well as all of the other common conditions that we see, atherosclerotic disease, fatty liver disease, chronic kidney disease, et cetera, et cetera.

32:30Danny Lennon: Within those contexts, obviously, presumably, if we have some of these other factors that could be causing or contributing to someone's low testosterone, improving those would foreseeably likely have some benefit on testosterone. in what cases would that be the kind of primary clinical target versus using something like TRT or in what cases might you use a combination? What is that kind of calculus going on?

32:57Austin Baraki, MD: Yeah, this is where there's a lot of room for conversation with patients. You're going to hear if you talk to some clinicians out there, there's going to be hard liners on all sides. There's going to be some folks who say, look, if you have obesity, you should never be placed on testosterone therapy, you just need to fix the obesity and then the testosterone gets better. And we have data that weight loss tends to lead to clinically meaningful improvements in blood testosterone levels. Is that the case for everyone that it will return them to 100 % yugonatal or 100 % normal levels and function?

33:29Austin Baraki, MD: Not in everyone, but nothing works for everyone all the time. But some would say you need to do that first before I would consider testosterone therapy. I sort of understand where that thinking comes from, but I don't always practice that way. That to me is analogous to if you haven't quote unquote tried to lose weight on your own, I'm not going to offer the use of a GLP-1 receptor agonist to aid in that path, for example. So I think that we have treatments and tools. They just need to be targeted appropriately based on the person's clinical syndrome. Are they more likely to benefit than to be harmed?

34:01Austin Baraki, MD: And are they understanding of the potential pros and cons of that decision? So somebody who says, look, I am really not interested in testosterone therapy. if you're telling me that by losing some body fat, by improving my sleep, my diet, my exercise, things like that, that there's likely to be a meaningful improvement in this, I wanna give that 100 % of my effort for the next amount of time, four, six, nine, 12 months, something like that, and kind of reassess. I say more power to you, go for it. I'm happy to be here to help, to provide guidance, and we can always pivot our plan if that's something that you'd like to do.

34:32Austin Baraki, MD: On the other hand, somebody who says, I don't really wanna do any of that, I just wanna get on testosterone. Of course, we have to have a conversation about that too, because there are some other steps that need to be addressed. There are certain risks that ought to be assessed for. For example, does this person have undiagnosed sleep apnea that could be contributing that we ought to address if before or potentially at the same time? There are lots of other kind of holistic health sort of pieces that we need to think about here. But there are scenarios in this where it may be reasonable to offer a course of testosterone therapy or a trial of it, I should say, to somebody who's in this situation, even if they might have an otherwise reversible syndrome as part of a kind of what we call shared decision-making sort of process.

35:15Austin Baraki, MD: As long as the person understands, what are you getting yourself into here? What are you willing to do? What are you not willing to do? And most importantly, and this is like ultra important here, is if you choose to go on testosterone therapy, you are not going to be fertile for very long. It will shut down your fertility. The reason I emphasize this is because this is actually shockingly poorly understood. There have been surveys of clinicians who prescribe this stuff, even surveys, published research surveys among attending urologists who were not fully aware that this is a risk to be discussed.

35:50Austin Baraki, MD: And so that is a super important key element of that conversation, because if I have somebody who's say in their 20s or their maybe 30s, and they have obesity or they have poor sleep, and they're concerned about their testosterone or their gains in the gym and they wanna get on test, but I also find out that they actually are intending or trying to have kids, then it's like, well, that is not gonna be the best move to go on testosterone therapy. Then we might talk about other strategies, alternatives, that gets further down into the weeds of the clinical decision-making here. So the big picture is laying out like how reversible is this to be?

36:26Austin Baraki, MD: And for some people, it is very reversible for them if we can address what might otherwise be pretty obvious secondary contributors like obesity and sleep and alcohol and things like that. I've seen shocking improvements in people's blood levels over time. And more importantly than improvements in their blood levels, improvements in how they feel and how they function, because just improving the blood level might improve some things, but not everything. They might feel way better if as part of the way that they got there was that they dramatically improved their aerobic capacity, if they doubled their strength, if they got much more consistent duration, high quality sleep.

37:01Austin Baraki, MD: That improves way more things than just taking testosterone. Of course, testosterone has its own role to play, but that's kind of the part of the conversation that I think is key is the person understanding what is likely contributing, what am I willing to do? And if I choose to, or if I'm a reasonable candidate for a trial of testosterone therapy to see if it helps me, what am I getting myself into? Because I don't want to be surprised by anything that hasn't been counseled on beforehand, mainly that fertility concern. I've also had plenty of guys seek me out for consultation who have, maybe they were like, I wasn't making the kind of gains in the gym that I wanted.

37:37Austin Baraki, MD: And I got my blood levels checked, and it was lower than I wanted it to be. And so I got on test. And I noticed that not only did I not feel better, but I started having worse acne, or I started having anxiety, I had panic attacks, I was irritable, I was one that I recall recently was like, this became most problematic, because I I had a radical increase in my libido and the discordance with my partner became a big source of problems. And we just could not carry that on anymore because the discordance itself became the problem. I wasn't even bothered by it before. And so there's all sorts of things that like guys don't really think about because these things aren't really talked about that much in the media and the conversation on podcasts and things like that.

38:14Austin Baraki, MD: It's just like higher number better. And it's like, depends how you got there, as I often like to say.

38:19Danny Lennon: And on that distinction you made a moment ago about differences in seeing a change in testosterone levels versus some of the things that we actually care about as outcomes. Of course, there's numerous situations where, again, we take a patient who truly does have an appropriate diagnosis, has low testosterone. They start on testosterone replacement therapy, levels come back up, and they see an improvement in a variety of symptoms. However, there's also reports of a similar type of patient who, again, with low testosterone, goes on testosterone replacement therapy. Their levels do come back up to a range that would be, let's just say, normal range.

38:56Danny Lennon: However, yet they don't see an improvement in some of those symptoms they were experiencing earlier. Why can this be happening? And what could be explaining this kind of disconnect between measured levels of testosterone versus the outcomes that we actually care about?

39:11Austin Baraki, MD: Totally, yeah. Not that unusual of a situation. There can be a variety of explanations. I would say the most common is depending on which symptom you're talking about, maybe that symptom falls into that nonspecific category, which means that it was a symptom that may have been caused by something else altogether that is not actually being improved by the increased level of testosterone. That's one thing. The others are related to, well, one I'll talk about is testing. I'll keep coming back to it. The easiest way that I can make your testosterone level go up is by first checking it in the evening and then rechecking it the next morning.

39:46Austin Baraki, MD: And that's because blood levels follow a diurnal rhythm. They go up in the early morning hours. That's why we typically check a total testosterone, say 7, 8, 9, 10 a.m., assuming a normal sleep schedule. And we don't tend to check it at 5 or 6 p.m. That diurnal rhythm tends to get a little bit blunted as folks get older, but it still is often present to some degree. And so that's another reason why testing can be problematic. Like, are you comparing apples to apples with your blood tests? Was your previous test done at the same time as your subsequent test, for example, or was there some other significant change that could have impacted your levels?

40:20Austin Baraki, MD: Even just having an acute illness, if you had went out and had some drinks the night before, and the alcohol itself, or poor sleep, or all sorts of other things could have suppressed your next day's level on the test, just lots of outside impacts. And so you want to have it under as kind of systematically controlled and similar conditions from tests to try to compare as much like to like as you can. But even then, there is an element of both biological variability and analytical variability between tests. I think on one of our prior episodes, I referenced the BMJ's Your Results May Vary tool that I often point people to.

40:54Austin Baraki, MD: And if you go to that website and you punch in a test result or two different test results, it'll give you a sense of like, are these tests actually meaningfully different or do they fall within the error bar of one another because of the combination of biological and analytical variability. And so that also informs my interpretation. If somebody is like, well, my testosterone level went from 380 to 450, I'm like, yeah, those are about the same. That's actually not that like clinically meaningful difference to me. If somebody tells me that went from 180 to 480, like, yes, that is a very clinically meaningful difference.

41:24Austin Baraki, MD: And so the more nuances to the element of test interpretation. Now the last, and this is perhaps one of the most interesting ones, is when we think about as far as your question of why might somebody have, say, objective improvements in these things, but not necessarily feel benefit, assuming that they are not just dealing with a nonspecific symptom and their symptom is coming again from a thyroid problem that's undiagnosed or sleep apnea that's untreated or iron deficiency. Again, all more common things. But if it's not those things, why might this happen? Testosterone functions by binding an intracellular receptor called the androgen receptor.

42:01Austin Baraki, MD: And that androgen receptor then has to translocate into the nucleus and it has to bind your DNA. And then, of course, the central dogma plays itself out, transcription and translation and subsequent kind of physiologic responses. There are also some independent mechanisms that can happen as well. The androgen receptor itself, as are most receptors, it is a protein that is encoded by our genes. And so there can be genetic polymorphisms or genetic differences between people in their androgen receptors. and those genetic differences can impact the sensitivity of that receptor to circulating testosterone levels.

42:37Austin Baraki, MD: So imagine a scenario where you are somebody who is set up with exquisitely sensitive androgen receptors. They are like magnetic force fields for any amount of circulating testosterone. You can see how somebody in that situation, they could probably have a relatively low blood level, not necessarily like clinically super, super deficient, but they could have a testosterone level on the quote unquote low end of normal. But because their receptors are so sensitive, they have completely normal function. That also is part of why I think we sometimes see that in people because the feedback system also relies on those androgen receptors.

43:16Austin Baraki, MD: So if the feedback system in your brain uses very sensitive androgen receptors, they're like, we're flush with testosterone. We have everything we need. We don't even need to crank out that much, right? Now imagine the other end of the spectrum. You have somebody whose genetics lead to androgen receptors that are not quite as sensitive. It's maybe a little bit harder, a little bit more challenging for testosterone to bind. It takes more of it to saturate those receptors to get the same clinical effect and importantly, the same feedback to the brain. You can see how somebody with that type of genetic makeup might naturally equilibrate to slightly higher blood levels.

43:51Austin Baraki, MD: This is not something that we're able to clinically measure in practice. They're androgen receptor polymorphisms. There are certain like kind of codon repeats and stuff like that have been characterized in the literature. And depending on how the length of this kind of repeated genetic segment in your androgen receptor genes, it impacts the sensitivity of your receptors. I find that to be a very plausible sort of explanation, differences in androgen receptor sensitivity for why some people feel better at certain thresholds upon testosterone replacement and conversely, why some people don't have symptoms at thresholds below which maybe you would otherwise expect them to.

44:25Austin Baraki, MD: Just kind of genetic variation between people.

44:28Danny Lennon: One final thing on testing that you mentioned right at the outset when we were talking about that within a certain panel that someone might get, they might see things like free testosterone, total testosterone, et cetera. You mentioned that in some cases, they may not track with each other. There may be this discordance between those types of measures. In those situations, what type of information is that giving you or do one or the other carry more weight for you in what you're thinking about? What comes up when you see discordance between some of those potential measures?

44:59Austin Baraki, MD: Yes. So the traditional kind of paradigm circulates around measuring total testosterone levels in the blood as like the preferred screening test. And when I say screening test, meaning like the initial pass, if you're going to do this test in somebody, I think there is a reasonable case to be made to also measure free testosterone levels. The accuracy of test assays, particularly the more modern ones, has improved. And based on some data sets that we kind of cite in some of our material on this, they basically tested and stratified four different cohorts. They identified people who had compared the total testosterone and the free testosterone, and how did that correlate or not correlate with their symptoms.

45:42Austin Baraki, MD: And what has been observed is that free testosterone levels tend to be a better correlate for people's symptoms. They are more predictive of people's symptoms. Now, that's not to say that means that we should just only ever test free testosterone and only make all of our decisions based on that, because this is, again, a complex picture, but the mediating variable between those two has to do with that protein binding. Remember I described that testosterone circulates, there's the total amount, and then And there's the free amount, which is tiny, like 1%, 2%, 3%, something like that, of total is actually unbound and free.

46:16Austin Baraki, MD: And then the rest is all bound up by proteins, various proteins, but importantly, one called sex hormone binding globulin. And there are lots of different factors that can impact the levels of sex hormone binding globulin. These include things like age, obesity, liver disease, thyroid disease. If somebody is on hormones to include if they're taking anabolic steroids, lots of things can impact levels of sex hormone binding globulin. And so the higher your levels of SHBG are, the more you are going to bind up of your circulating testosterone pool, and the lower your free is going to be. Conversely, the lower your sex hormone binding globulin goes, that tends to lead to a little bit greater proportion of free.

47:02Austin Baraki, MD: And so there are implications for this, again on that feedback system, how much total testosterone you even produce, because if the free is what's doing most of the signaling and is kind of quote unquote physiologically active, there's some nuance around that, but it's good enough for our purposes, then it might be the case that you have all the free you need because a greater proportion of a lower total amount is actually liberated and able to do that. And so if you just look at the total, you're like, that's a little lower than I'd like it to be, so to speak. But if enough of it is free, And that is a scenario where when it's studied, those people don't tend to have clinical symptoms.

47:37Austin Baraki, MD: On the other hand, somebody might have a total testosterone level that looks apparently normal, but because for whatever underlying reason, they have very high levels of SHBG. More of it is bound, less of it is free. And with very low free levels, they're actually more likely to have symptoms. Now that might raise the question, is the answer in that situation just to put them on testosterone? Again, it's like, it kind of depends. There's a lot of reasons why their SHBG levels might be high in that situation. and maybe those things deserve some attention as well. Maybe. It might be modifiable. It might not be modifiable.

48:07Austin Baraki, MD: There are even some situations where clinically, and this is kind of taking a mild detour, but just for the purposes of education in women, particularly those who have kind of androgenic symptoms in what was previously known as like PCOS, now known as PMOS, they have acne and various other sorts of complications of hyperandrogen. They have elevated androgen levels. one of the common treatments that you see used, not an ideal treatment for every case, but a common treatment in that situation is to use like standard hormonal oral contraceptives. Why? Because they increase levels of sex hormone binding globulin in women.

48:45Austin Baraki, MD: And by increasing SHBG, it binds up more of those androgens and then it addresses the androgenic symptoms that they have. So the physiology, there's some kind of analogies and some similar physiologic implications between between even the sexes here.

48:57Danny Lennon: With that, I wanted to take a turn back to that other case that sometimes is coming more and more prevalent of someone who hasn't came with symptoms, someone who maybe is relatively what we deem average healthy person in the population that is interested in getting their testosterone measured, goes off their own back and does that now some type of testing and notes that their result is somewhere based on depending on the lab's reference range somewhere maybe at as you mentioned that low end of normal or maybe even tipping over into what that cutoff point for this particular lab reference range may be for low in those situations and again you've already mentioned this but to really hammer this home in what is number one the implication of that, if anything?

49:45Danny Lennon: And then second, for someone who maybe their testosterone, presuming it truly is at that level, would there be any expected benefit of that person, let's say, increasing that through testosterone replacement therapy or otherwise, and pushing that up where it's maybe still within that range of normal, but is much higher now than previously. What is that likelihood? Because I think that's for many people, the thought process that I hadn't really noticed anything, but given what I've seen now, would I receive a benefit from it? Because it's so relatively straightforward for many people to get access to this, unfortunately.

50:23Danny Lennon: So what would be the likelihood of them receiving any type of noticeable benefit?

50:28Austin Baraki, MD: Yeah. Honestly, totally reasonable questions for most people who are coming into this conversation without all of this background that we've just gone to, because it would seem on its surface to be a very simple sort of thing, right? You get all this stuff marketed to you. You're like, oh, I can just get a blood test. It'll tell me if I'm good or if I'm not. Again, this nice, neat, binary sort of thing. If I'm low, should it be high? I understand where the question's coming from. Now, hopefully we've clarified and unpacked some of the complexity here. And so it is, to your point, a little bit of a matter of degree of how low are we talking.

51:00Austin Baraki, MD: I often recall and cite a story that I recall from my residency training of seeing a gentleman who had an actually undetectable blood testosterone level. This was not somebody who was undergoing deliberate androgen deprivation therapy for prostate cancer, anything like that, but they had actual AIDS. And that was part of why they had such severe testosterone deficiency. And they were in fact, a candidate for treatment because they understandably felt terrible. Now, did they feel terrible because exclusively they had no testosterone in their body? No, that was part of it, but they also had AIDS and we had to reconstitute their immune system and make sure they didn't have any chronic infections that were hiding.

51:36Austin Baraki, MD: And so that's when I, the reason I bring this story up is again, it's a matter of degree. So even if this person tells me that they don't really notice any concerns or have any, any problems, if they do choose to pursue this testing, which wouldn't necessarily be recommended for them, but if they choose to pursue it and they're like, I got a testosterone level back and it was like 90, I'm like, okay, that's much lower than I would expect anybody who is eugonadal, quote unquote, to be. And so I will first make sure that the testing was done properly, that it was done at the proper time. I will very likely repeat it because the best, this is a theme in endocrinology in particular, but medicine in general, if you see a test result that is unexpected, then the first step is probably to repeat it for confirmation.

52:22Austin Baraki, MD: And so assuming that the testing was all done properly, and we're not in this situation of like just unexpectedly severe apparent deficiency that would actually still lead me to launch an investigation and scan their brain and do other things like that. But let's say he's more in this kind of gray area range. Let's say his level's like, again, 375 or something like that, 350. The conversation around this is really getting a sense of what is the person's understanding and what are their goals by doing this? And a fair amount of them are going to say, look, I just to be healthy and I want to make sure I'm getting the best results that I can out of the gym or whatever the case is.

53:01Austin Baraki, MD: And so I might talk and do an assessment of their general kind of lifestyle habits. Tell me about your sleep. Tell me about your nutrition. Do you drink? Tell me about your physical activity habits, assess for obesity, things like that. What are their risk factors for sleep apnea if present, any other kind of health conditions, any chronic medicines that they use that could be impacting this, things like that. And if that ends up kind of turning up empty, like they're good, they're lean, they're active, they don't drink, they sleep well, they feel well, they're performing well, the likelihood with each of those questions being answered in that way, the likelihood that they are to benefit from going on testosterone therapy is diminished less and less to the point where after a certain point, I no longer am calling it testosterone therapy or testosterone replacement therapy for somebody in that situation.

53:47Austin Baraki, MD: If they choose to pursue it, it's called going on anabolic steroids. Because physiologically, maybe you're one of these people who has exquisitely sensitive androgen receptors, and your system has kind of equilibrated, and this is your normal, to where if you go on, you're essentially going on, as they say, a cycle of anabolics, right? It might not be that different. And sure enough, that has been reflected, again, in many of the consultations that I've done with folks, where they were in this kind of gray area, they're like, I was okay, but it was like, I wondered if I could do better if I got it up a little bit higher, and they went on.

54:21Austin Baraki, MD: And of course, I think that testosterone therapy, when it is dosed reasonably and monitored properly, it is quite safe and safer than it has historically been thought. That is like my current take, just for the record. I'm not demonizing it or saying that it's ultra risky for a lot of people. Again, if it's dosed reasonably, we're not shooting them up to very super physiologic levels and things like that. But that's also a scenario where I've had conversations with guys who not only didn't feel that much better, but maybe they're like, gosh, I started to have a lot of anxiety or I started this mood irritability or the acne issues or various other sorts of things, some of which can be modified with dosing adjustments and split frequency and things like that.

55:00Austin Baraki, MD: But again, if we're going to go through all that, it's like, why? Like, what are we getting out of this if you're not actually feeling that much better from the higher levels? And are there higher yield kind of areas that we can work on to improve your health, longevity, performance more in line with your goals. And maybe this is like kind of a side quest that may not end up being worthwhile for you. So that's really what the conversation looks like. There are again, scenarios where if I'm in that gray area and there's something that I think could be related that could plausibly benefit, assuming that they're okay with the fertility implications, I may well say, look, it'd be reasonable to try this because the other kind of misconception, and this is something that was thought more strongly in the past.

55:39Austin Baraki, MD: I still think a lot of people think of it this way, that like, you better be sure because as soon as you take that first dose, it's a lifelong commitment. That's something that's often, it's often been framed that way. Like it is a decision with that level of gravity, which is not true. That is not the case. Now, if you go on therapy, it will have some of these implications for, as I mentioned, on fertility and things like that, among others. However, it is not a crazy idea to say, if there are some things that could plausibly be improved. I'm going to try it for four to six months. And if those things don't improve to discontinue the therapy, totally fine.

56:16Austin Baraki, MD: Assuming it is being done again in an appropriate, reasonable, like monitored way and things like that. And there are, it's very unlikely for there to be long-term detrimental effects from that kind of thing. Even for the fertility implications, a pretty substantial fraction. And the other concern that people have is I'm just going to shut down my endogenous production, and that's going to be permanent. For a pretty sizable fraction of people, that endogenous production and fertility will likely improve over the subsequent 9 to 12 months. Now, what percentage? There are data sets looking at this.

56:52Austin Baraki, MD: There is some scientific research examining this question, and it is not 100 % whose systems will fully wake back up. However, I think that is more often going to be the case for people using very high doses for very long periods of time, potentially multiple agents in the polypharmacy performance enhancing kind of space, where it can be more problematic. Somebody who is taking a totally reasonable clinical dose, monitored, not going super physiologic for a few months, and then decides to stop, very unlikely to have like permanent shutdown of anything in that sort of situation. So that's the other aspect of the conversation is like, how likely are you to benefit.

57:29Austin Baraki, MD: If it is very low, probably not worthwhile, honestly. You may well have more downsides than upsides. If there is some possibility of benefit and you're accepting of the potential downsides and you want to try it and you decide ultimately not to continue, you'll probably also be okay, assuming we do it in a safe and monitored, reasonable way.

57:45Danny Lennon: So speaking of those downsides, the side effects, the safety profile, there's probably two extremes of this that you've mentioned. One is, I suppose, where that reasonable question you mentioned earlier of someone thinking well my test results coming back a bit low it there's no harm in trying it because they've heard that it's it's safe and as you know generally that has a good safety profile in the context of appropriate prescription management etc that is distinct from someone just doing whatever and thinking there's no problem but that idea for many people that it is essentially so safe that it's a kind of free shot at i may as well try it is maybe misguided from understanding what the actual potential side effects are for them.

58:29Danny Lennon: At the other end, then there's maybe historically been some concerns that were thought to be much more grave than they actually have turned out to be on subsequent research. Can you maybe give us an idea on the two ends of that from a side effects and safety profile perspective from the use of something like TRT? How does that, what type of side effects are we potentially talking about? And then for some of those historic ones, for example, cardiovascular safety was one of the big ones. What do we know that might actually be the most reasonable take on that right now?

59:04Austin Baraki, MD: Yeah, definitely an actively evolving field for a variety of reasons. I think in the early 2010s, there was some data that started to come out looking at this question and finding some concerns of increases in cardiovascular risk. And so that led to not only like FDA black box warnings and things like that, but also a mandate or a that some randomized trials be run on this very question. And over the subsequent years, there's been some increasing randomized trials getting run some updated meta analyses and things like that looking at this question. And if I could paint with a perhaps excessively broad brush, I think that the case for very significant cardiovascular safety concerns, that has been weakened.

59:46Austin Baraki, MD: I would not say that it has been eliminated. There's some, and that's also because cardiovascular disease is not all one thing. There are various types of cardiovascular disease and examples of it. You can have myocardial infarction or heart attack. You can have heart failure. You can have pulmonary embolism. You can have atrial fibrillation. And I'm not saying that you can have all these things as a direct result of going on reasonably dosed testosterone therapy, but these would all fall under the category, for example, in a research study of cardiovascular disease kind of endpoints. And sure enough, for example, in one of the more recent trials that was called the TRAVERSE trial that's often cited on this, they took a population deemed at elevated cardiovascular risk and they randomized them to transdermal, actually a form of testosterone therapy versus placebo, did kind of a poor job at dramatically increasing the blood levels you would have like to, as you will be familiar from like the nutrition research world, see a bigger contrast between your groups to get a sense of some of the differences in exposure to the testosterone levels.

1:00:42Austin Baraki, MD: But ultimately, it was a mostly reassuring finding as far as impact on their cardiovascular risk, although there still were some signals for in terms of pulmonary embolism and atrial fibrillation and things like that. How strongly I view those risks in, again, a reasonably screened and managed population, still probably more safely and more modest than it would have been viewed, I think, 20 years ago, when anybody assumed that anybody who goes on testosterone therapy is going to die of a pulmonary embolism, which is not really the case. So I think that if I had somebody who was at elevated cardiovascular risk, this would certainly factor into the conversation, but it would not, in my mind, be what we call an absolute contraindication.

1:01:23Austin Baraki, MD: It would probably make me want to be extra diligent about being confident in my diagnosis, being confident if we choose to pursue it in my dosing, in my monitoring, things like that, and making sure that as many of their other risk factors are under control as possible, like not putting somebody on testosterone therapy who has active uncontrolled hypertension, who has uncontrolled dyslipidemia, something like that, like addressing all of the, but that's just called good doctoring, is handling all of those things appropriately. So the cardiovascular risk piece is one that non-zero in my mind at this point, but weaker than it had been viewed in the past.

1:01:56Austin Baraki, MD: The other is prostate cancer. It's historically been thought of as something that quote unquote, like causes prostate cancer. And this was tracing back now the better part of 70, 80 years when we started to recognize that lowering testosterone levels through processes like what's called androgen deprivation therapy actually led prostate tumors to shrink. Therefore, the seemingly logical implication being that giving or increasing testosterone levels would cause them to grow. There's a difference, however, between androgens stimulating growth or causing new incident prostate cancer that was not already there.

1:02:30Austin Baraki, MD: That's one kind of wrinkle in this argument. And the other, and this is kind of more in the current hypothesis realm, is this idea of a saturation point for the androgen receptor, that above, below a certain level, it will indeed lead to cancer shrinking and maybe going up to that threshold. It may actually lead to, say, stimulation or growth of the prostate in general. But above that saturation point, which has been proposed at being at around a level of 250, which is like relatively modest, that there is not actually further implications on prostate growth and things like that. So that's the current state of the argument there.

1:03:05Austin Baraki, MD: Now, it is still clinically kind of guideline recommended if you're going to be pursuing this therapy to have a PSA level checked before initiation. if it is elevated before you even start, you should probably hold off on starting until you get that evaluated. And it's something that could be reasonably monitored over the course of your therapy. And if it starts to increase at an unacceptable rate or velocity, that's also something that ought to be investigated. But in my mind, the concern that by going on therapy, that is again, appropriate for the patient, dosed, monitored, et cetera, that I'm going to cause a new incident to prostate cancer is not a very high concern in my mind.

1:03:41Austin Baraki, MD: I would say that those are the two biggest ones that people have historically associated with testosterone therapy. I've already touched on and hammered on multiple times. I think our audience now knows the fertility implications. That's one that was underappreciated and ought to be part of the conversation. And then aside from those big three, there are a variety of what I would deem less severe, less serious sorts of things, although they can certainly be distressing to the person. So I've alluded to a few of them so far. Impacts on mood. People are super variable. Some irritability, some kind of depressed mood, some anxiety, some panic.

1:04:12Austin Baraki, MD: I've just seen all sorts of different things. Everybody's different. Skin-related changes, particularly acne, and that's more associated with super physiologic blood levels. So the dosing seems to matter there quite a bit. It stimulates blood production. So if the doses are too high or the cumulative exposure is too high, you can get high hemoglobin and hematocrit levels. It's called a condition called polycythemia, which there's some controversy around how likely is that to increase the risk of clotting. There have been historically, it's just been assumed that increases the risk of clotting, although that's based more on other conditions that lead to high blood hemoglobin and hematocrit levels rather than direct evidence of it.

1:04:49Austin Baraki, MD: I find it plausible, but kind of unproven at this time and remains also primarily a dosing related phenomenon. You'll sometimes see impacts on elevations in blood pressure in addition to blood volume and those things can even be related. There can be some changes on lower urinary tract symptoms as well as a handful of, again, progressively less concerning sorts of things from like an absolute safety standpoint, although it can be very bothersome to the person if they experience them. So a lot of that is part of the conversation that I have with people up front as far as what are the things that we're like legitimately concerned about and what are the things that you may experience that we might be able to work around if this is something that may still benefit you.

1:05:28Austin Baraki, MD: But again, if you're somebody who is very unlikely to benefit. So like, let's say you're in a scenario where you have absolutely no, what I'll call clinical benefit. And when I say clinical benefit, I'm meaning this to separate it from, you're not intending on just going on performance enhancing drugs because that's a whole separate conversation and not one that I'm going to be having with you because I don't do that. I don't recommend it. I don't manage that for people. But if there's no clinical benefit to be had, that means that you are only exposing yourself to potential downsides. And I think that's a reasonable way to frame that question so that you understand what you're potentially getting yourself into and then just like be honest with yourself.

1:06:04Austin Baraki, MD: It's like, are you just trying to be on steroids or not?

1:06:06Danny Lennon: That's a good sanity check for most of these.

1:06:09Austin Baraki, MD: I think people could use.

1:06:10Danny Lennon: Dr. Bracky, before I let you go, for people who either want to dive more into this topic and some of the resources you've got on that, please let them know where they can find that or for your work more broadly, where some place on the internet they should go.

1:06:23Austin Baraki, MD: Yeah. So I think we, this conversation was prompted by some work that we've done relatively recently. So I had created a whole kind of web-based educational course on this topic at Barbell Medicine. This has now been paired with a text that we have written that is now, I believe, available in ebook and in published book form, like hard copy. If people want to use that traditional method of acquiring knowledge, that's available at this time. You can find me and a lot of this stuff at Barbell Medicine, where we have our podcast, YouTube articles, et cetera. And then I'm also on Instagram, Austin underscore Barbell Medicine.

1:06:56Austin Baraki, MD: You can find me there as well. I think that's probably the best places to find what we do.

1:07:00Danny Lennon: Fantastic. With that, Dr. Austin Baraki, thank you so much for taking all this time out to come and talk through this topic, for the excellent information you shared and for giving up your time to come and talk to me again.

1:07:11Austin Baraki, MD: Anytime. Happy to be here.

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