[SPEAKER_01]: Last week, we introduced you to Mark, a 45-year-old partner at an architectural firm whose last 12 months had looked like a slow-motion collapse.
[SPEAKER_01]: Fatigue couldn't sleep off, a focus to kept slipping, and a marriage that was on the rocks.
[SPEAKER_01]: So we did what a lot of men in that position do.
[SPEAKER_01]: He went to a wellness clinic, one blood draw later, his total testosterone came back at 240 nanograms per desoliter.
[SPEAKER_01]: his first injection by the end of the week.
[SPEAKER_01]: If you stop the story right there, picture looks obvious.
[SPEAKER_01]: Low number, low T symptoms, prescribed testosterone, problem solved.
[SPEAKER_01]: Except 240 does not carry that story on its own.
[SPEAKER_01]: 240 means one thing in a man who slept three hours the night before his draw and got to pull it three in the afternoon.
[SPEAKER_01]: It means something different in a man who got to draw it 7am, fasted after a normal week of sleep.
[SPEAKER_01]: And it means something different again in a man who's as HBG is high, or who's LH and FSH suggests that the signal is breaking upstream at the hypothalamus, rather than at the testies.
[SPEAKER_01]: Now, the clinic that treated Mark didn't ask any of those questions.
[SPEAKER_01]: They saw a number below a cutoff and they treated the cutoff.
[SPEAKER_01]: This week, Altestosterone actually works.
[SPEAKER_01]: What the number on your lab report is actually measuring, the short list of symptoms that actually signal low testosterone, only three of the 32 that meant commonly attribute to it, and what a real evaluation of low testosterone actually looks like, because it's not what the wellness clinic on the street is doing.
[SPEAKER_01]: This is episode two of the Signal Book Launch Series.
[SPEAKER_01]: The book is where the full diagnostic and treatment picture lives.
[SPEAKER_01]: Today is the physiology behind the number in the standard that any evaluation should be held to before anyone picks up a prescription pad.
[SPEAKER_01]: I'm Dr. Jordan Feigenbaum, this is the Barbell Medicine podcast.
[SPEAKER_01]: and help us sort the signal from the noise on what that number actually means, which is sure to upset your local wellness clinic.
[SPEAKER_01]: It's the second most handsome doctor with American Dr. Austin Barackie.
[SPEAKER_01]: What's going on, man?
[SPEAKER_00]: I enjoy upsetting local wellness clinics.
[SPEAKER_00]: So look forward to getting into that.
[SPEAKER_01]: Well, let's start out here with how testosterone actually works, and before we get into anything else, here is the actual sort of diagnostic standard for testosterone deficiency, which is what we're going to call low testosterone or hypogonanism, and it requires two things together.
[SPEAKER_01]: One is specific symptoms, just not the long list that you've probably heard about, I'm much shorter one, we'll get into later in the episode, and it confirmed low number on a
[SPEAKER_01]: A man with symptoms and a normal number does not necessarily meet the guideline criteria for diagnosis, and a man with a low number and no symptoms does not meet the criteria either.
[SPEAKER_01]: The diagnosis lives at the intersection of those two things and most of what the current system gets wrong starts with treating one of them as if it were enough on its own.
[SPEAKER_01]: which is why a lab value is only ever a starting point.
[SPEAKER_01]: To know what a low number actually means, you have to know where the signal comes from, because the same total testosterone can point to three different problems depending on where in the signaling chain the break sits.
[SPEAKER_01]: Let's walk through it.
[SPEAKER_01]: This is the HPG axis, which stands for high-pithalamic pituitary gonaddle axis, and this is the sort of feedback loop that testosterone production runs on.
[SPEAKER_01]: Think of the hypothalamus as a sort of radio station at the base of the brain.
[SPEAKER_01]: It broadcasts a signal called GNRH, can add a trope and releasing hormone in pulses.
[SPEAKER_01]: The pituitary gland is a relay tower of sorts.
[SPEAKER_01]: It receives this GNRH pulse and rebroadcast two of its own hormones into the bloodstream, LH, which is luteinizing hormone, and FSH, which is follicle stimulating hormone.
[SPEAKER_01]: Then there are the testes, which act as local stations.
[SPEAKER_01]: LH tells the late Excel's in the testes to produce testosterone and FSH supports sperm production in a different cell population called Sirtoli cells.
[SPEAKER_01]: Now, this loop self regulates testosterone in circulation feeds back on the hypothalamus and the pituitary to quiet the broadcast.
[SPEAKER_01]: When there's more testosterone in the blood, there's less gnrh, less lh, less fsh, less production of testosterone.
[SPEAKER_01]: If there's less testosterone in the blood, the opposite occurs.
[SPEAKER_01]: Now, there are two clinical consequences that drive the rest of the episode.
[SPEAKER_01]: You've got to be familiar with them.
[SPEAKER_01]: One is that testosterone is an output of a pathway with at least three places the signal can break.
[SPEAKER_01]: A single low testosterone doesn't tell you where in the chain this break sits.
[SPEAKER_01]: It's a symptom with an unknown cause until you localize it.
[SPEAKER_01]: Your doctor needs to be at the helm of that.
[SPEAKER_01]: Low testosterone with high LH and FSH signifies that the break is at the level of the testes themselves, which we call primary hypogonatism.
[SPEAKER_01]: The Tuitary is working harder to push the signal through but the testes just aren't responding.
[SPEAKER_01]: Now, low testosterone with low or inappropriately normal LH and FSH tells you that the break is upstream in the brain at the hypothalamus or pituitary.
[SPEAKER_01]: This is called central or secondary hypogonenism.
[SPEAKER_01]: The testes are working just fine, but just not getting the signal.
[SPEAKER_01]: And so the work up then expands to include obesity, sleep disruptions, opioids, prolactin, pituitary imaging, and so on.
[SPEAKER_01]: From the last episode, this is why that large one million men met analysis matters.
[SPEAKER_01]: The LH decline that was seen alongside the testosterone decrease across the population, that signaled that there was a metabolic driver potentially like obesity or sleep disruption or visceral adiposity, which is our current theory, rather than some sort of generational defect in the testies themselves.
[SPEAKER_01]: Now, the second clinical problem is that the feedback loop runs in both directions.
[SPEAKER_01]: Testosterone put into the body from the outside, like a TRT prescription or a supplement that's spiked with actual animal exteroids, or a shot at a wellness clinic, that feeds back on the hypothalamus and put to a Terry the same way your own testosterone does.
[SPEAKER_01]: The broadcast quiets, your local stations stop producing, the moment exogenous testosterone enters the picture.
[SPEAKER_01]: and subsequently endogenous production of testosterone goes down.
[SPEAKER_01]: This is the mechanism behind episodes one contamination story.
[SPEAKER_01]: The 12% of muscle building supplements that are adulterated with undisclosed synthetic steroids do their damage precisely because your body cannot tell outside testosterone from its own, and it responds to the contamination by shutting itself down.
[SPEAKER_01]: It's also why TRT is this sort of commitment, not a casual intervention.
[SPEAKER_01]: Once you stop the TRT, the exogenous testosterone supplementation, the production doesn't immediately snap back.
[SPEAKER_01]: The signal takes a little bit to ramp back up.
[SPEAKER_01]: Now Austin, when you're teaching this to a medical trainee, so a medical student or resident, or maybe explaining this feedback loop for a curious patient for the first time, what's the piece that takes the longest to land?
[SPEAKER_01]: And what's the clinical scenario that might make it stick?
[SPEAKER_00]: Yeah, I think that having been through this process of medical training and then teaching trainees all the time.
[SPEAKER_00]: In the endocrine world, getting folks to really grasp the concept of feedback loops and interpreting the labs to help you localize things is a challenge that can take some time, especially with that one scenario that you describe where labs might be, quote, unquote, inappropriately normal, because a lot of folks, whether lay people or even, you know, trainees, even practice inclinitions, they might look at a lab or a lab report,
[SPEAKER_00]: And if nothing is flagged as abnormal, meaning everything is quote unquote in range, then the assumption is, oh, everything must be normal.
[SPEAKER_00]: And there are these complicated tricky situations where things might be normal when they should not be normal, meaning that if your body was responding appropriately to something,
[SPEAKER_00]: then you might actually appropriately have something go out of range.
[SPEAKER_00]: And that's a hard concept to grasp because it is easy and nice and neat and tidy for just like, oh, everything's green.
[SPEAKER_00]: I guess I'm good.
[SPEAKER_00]: And then conversely, if there's anything that's like what I'm quote red or like out of range, then that must signal a problem.
[SPEAKER_00]: And there are scenarios, again, where it is appropriate and expected for things to be abnormal, quote unquote, and then also scenarios where that a value returns in a normal range, it is in fact, abnormal.
[SPEAKER_00]: And those require not just looking at a lab report, but actually like firing some neurons in your brain to think and analyze the problem before you and correlating it or contrasting it sometimes with the reported history and examination findings of the patient in
[SPEAKER_00]: And so that's why just having, for example, a single testosterone value is woefully insufficient to either make a diagnosis or to drive treatment decisions with great confidence, even though there are some places that, as we discussed last time, offer a treatment based on that single lab value, or in some cases based on no lab values at all, just based on certain symptoms alone, which, you know, as we'll get to, or can be quite non-specific.
[SPEAKER_00]: And so there's not just the single lab number that you need, but some additional context to help you localize, you have to be able to think about those lab results to think is this a pattern that I would expect with kind of so-called primary like testicular failure or is this problem up in the brain and then if so then as in a phrase that I think a lot of a lot of listeners might be fans of the root cause concept thinking about is there something identifiable that might be driving this that would be worth addressing.
[SPEAKER_00]: Or is this something that is unlikely to be addressable in any other way besides testosterone therapy?
[SPEAKER_00]: And there are certain situations where if I see a particular pattern, I'm like, yep, this just straight up needs the hormone.
[SPEAKER_00]: This is not going to get fixed by any other mechanism, which are a minority of cases compared with those where there's a great deal of things that might be able to be addressed to your point, things like obesity, metabolic disease, things like that.
[SPEAKER_01]: Yeah, that's what I'll said.
[SPEAKER_01]: And in overall, just kind of encapsulates why a single lab value is just a starting point in the diagnosis, not a sort of confirmatory.
[SPEAKER_01]: Oh, you've got it now.
[SPEAKER_01]: Here's the second.
[SPEAKER_01]: The total testosterone number itself is measuring something different than most men assume.
[SPEAKER_01]: The most of the testosterone flown around your blood is not free on its own, hanging out, ready to do stuff.
[SPEAKER_01]: It's bound to a carrier protein in the blood.
[SPEAKER_01]: About 40 to 45% is bound tightly to SHBG, which stands for sex hormone binding globulin.
[SPEAKER_01]: It's a protein made mostly in the liver.
[SPEAKER_01]: Another 50% is bound more loosely to albumin.
[SPEAKER_01]: It's another protein.
[SPEAKER_01]: And the remaining roughly 2% is circulating free unbound to anything untethered.
[SPEAKER_01]: Free to do its actions.
[SPEAKER_01]: When you order a total testosterone, the lab measures all three fractions together.
[SPEAKER_01]: Now, there are three ways to sort of get this free fraction if you were curious about that.
[SPEAKER_01]: And this has to do with the same sort of principle that we covered last week.
[SPEAKER_01]: The gold standard here is physically separating the free fraction in what's called a dialysis chamber, which is akin to the mass spec test that we talked about last week.
[SPEAKER_01]: Not that they operate the same, just that it's more accurate.
[SPEAKER_01]: It's a more direct method that actually measures the molecule of interest, in this case, free testosterone, and it's more reliable, especially at the lower end of the range, which is exactly where you would want to have this information if you were curious about what is the free testosterone level.
[SPEAKER_01]: The other option is a calculation.
[SPEAKER_01]: You plug in total testosterone, your SHBG levels, and albumin into a formula, and you get an estimated free value.
[SPEAKER_01]: It's cheaper, it's faster, it's available at every lab, and it's good enough when SHBG levels are behaving normally, but it's less reliable when it isn't, which happens to be when the answer actually matters most.
[SPEAKER_01]: What does this matter to the listener?
[SPEAKER_01]: Well, only the album and bound in the free fractions of testosterone are readily available to the tissues.
[SPEAKER_01]: S-H-B-G bound testosterone is locked up pretty tight and it's not effective at that when it's bound to S-H-B-G.
[SPEAKER_01]: So the bio-available testosterone is basically your free testosterone plus the album and bound testosterone.
[SPEAKER_01]: And that's closer to what the tissues actually see.
[SPEAKER_01]: from medical perspective, in most men with a normal SHBG level, total testosterone and bi-available testosterone levels move together.
[SPEAKER_01]: Ordering a free testosterone in the first draw, usually doesn't add any additional information here.
[SPEAKER_01]: But the cases where that relationship breaks are the ones that kind of matter to a physician who's trying to work somebody up for testosterone deficiency, basically if someone has abnormal SHBG in either direction.
[SPEAKER_01]: So, SHBG runs low in conditions like obesity, type 2 diabetes, hypothyroidism, people who are using exogenous androgens, corticosteroids, and so on.
[SPEAKER_01]: And this is sort of a falsely low testosterone ring, which is what you'll get on a total testosterone lab.
[SPEAKER_01]: Even though the bio-available testosterone may be adequate.
[SPEAKER_01]: S.H.V.G also runs high with advancing age, hyperthyroidism, chronic liver disease, and some other medications like anticovulsions, for example.
[SPEAKER_01]: And in this case, your total testosterone might be falsely reassuring.
[SPEAKER_01]: Oh, it looks normal, even though the bio-available testosterone is actually low.
[SPEAKER_01]: So both of these can produce the wrong sort of decision if the interpretation stops at the total testosterone lab.
[SPEAKER_01]: So you got to have more synapses as you alluded to to kind of interpret this.
[SPEAKER_01]: Now, Austin, here's a case that you probably see a lot.
[SPEAKER_01]: Guys, total testosterone is 230 nanograms per deciliter, and his SHBG comes back low.
[SPEAKER_01]: And then when you calculate his free testosterone, he's actually in the normal range.
[SPEAKER_01]: So how are you working through this and discussing it with him?
[SPEAKER_01]: And what do you do next?
[SPEAKER_00]: Yeah, there's probably going to be a continued familiar refrain in these situations of why did the guy walk in to get some additional context to that lab value?
[SPEAKER_00]: What was the person's signs or symptoms that led him to be concerned enough to get this check because that helps to contextualize things.
[SPEAKER_00]: And then if we have that total level 230, yeah, that definitely gets my attention.
[SPEAKER_00]: That is going to be flagged as low on pretty much every total testosterone lab out there for a man.
[SPEAKER_00]: If we have this additional data point with a low SHBG indicating that a greater fraction of that low total number is free or or bio available in some capacity, then it suggests that his tissues may well be seeing a sufficient amount of testosterone to do what they need to do.
[SPEAKER_00]: So the question here is how likely is it that this person needs additional testosterone to be dumped into the system compared with is there something that could be addressed that is contributing to that low SHB level now the SHB g being low itself is not necessarily harmful or pathologic in itself.
[SPEAKER_00]: It's not like the goal of therapy is to achieve a quote a quote optimal SHB g level.
[SPEAKER_00]: If the goal is to improve the person's quality and quantity of life, which is what we're aiming to do, and there might be, for example, a number of downstream consequences of a single upstream cause, for example, like obesity, that if we managed it might help to address a lot of things, so let me paint a different picture of, let's say this person came in and his primary symptom was fatigue.
[SPEAKER_00]: And he has this low total and he has this low SHBG with a, you know, suggesting a relatively normal bio available fraction, but his obesity is also contributing to obstructive sleep apnea, which is maybe a bigger contributor to his fatigue due to non restorative sleep well, if we address the obesity and we improve his obstructive sleep apnea and he sleeps better.
[SPEAKER_00]: and he manages to sustain some clinically significant weight loss.
[SPEAKER_00]: There's a decent chance that a lot of these things snap back into a happier normal place.
[SPEAKER_00]: So his total testosterone might improve.
[SPEAKER_00]: His SHBG might improve.
[SPEAKER_00]: His symptoms most importantly will likely improve and overall his long-term health will be improved as a result.
[SPEAKER_00]: So that's kind of a typical example that we might see here.
[SPEAKER_00]: Now, are there clinicians out there who might offer somebody like this testosterone therapy?
[SPEAKER_00]: Absolutely, because they might see that low number and treat it.
[SPEAKER_00]: And in some folks, that may actually be beneficial that they might weather due to placebo or due to physiological effects of the medicine they might report feeling better.
[SPEAKER_00]: But absent the additional kind of thinking, absent the additional thought process of what other contributors might be going on,
[SPEAKER_00]: And certainly looking for things like sleep apnea as a very common and under diagnosed issue in these types of scenarios, then you might miss the main problem that ought to be addressed, and you might be kind of bandating it with the hormone therapy.
[SPEAKER_00]: So I'm pretty flexible here with folks.
[SPEAKER_00]: If assuming I have done sufficient thinking about underlying causes, contributors address those to as much of a degree as the person is willing to.
[SPEAKER_00]: And if they wanted to, you know, attempt
[SPEAKER_00]: as long as it's a fully informed kind of decision with the plan, with goals, with outcome targets that we're looking to do.
[SPEAKER_00]: It's not always going to be that, you know, an absolute hard no from me, but rather I definitely want to do the hard work of all that thinking beforehand, before going down that path.
[SPEAKER_01]: and have that conversation.
[SPEAKER_01]: Yeah, well said, let us love physiology and the measurement to Stastron is the output of a long signaling loop and the number on your lab report is mostly measuring the fraction that your tissues can't really use.
[SPEAKER_01]: So the next question is how to read the number because the instinct that most men have.
[SPEAKER_01]: higher is always better.
[SPEAKER_01]: That more testosterone means more of whatever testosterone does, it's not really how this sort of Androgen receptor signaling behaves.
[SPEAKER_01]: And this is where the what we talk about in the book that earns its place.
[SPEAKER_01]: And when we come back from the break, the number on your lab report and why chasing a higher one is not what the receptor pharmacology actually supports.
[SPEAKER_01]: All right, welcome back, or we were asking about how to read a testosterone lab value when we left off on the first thing to understand is that a higher number is not automatically better and the reason has to do with a cellular mechanism that most of the online testosterone discourse ignores for decades, the prevailing belief was that testosterone fueled prostate cancer.
[SPEAKER_01]: Doctors were trained to never give a man with prostate cancer testosterone.
[SPEAKER_01]: If you're made sense, prostate cells are injured independent, more testosterone, more prostate signaling, more cancer growth.
[SPEAKER_01]: But when researchers measured what happens at the prostate as serum testosterone goes up, they found something that nobody had predicted.
[SPEAKER_01]: above a certain concentration, raising serum testosterone levels further produced no additional rise in PSA and no detectable increase in prostate cancer incidents over decades of follow-up.
[SPEAKER_01]: The cellular machinery had a ceiling and that ceiling has a name.
[SPEAKER_01]: Call it the saturation model, and the threshold sits at roughly 250 nanograms per deceler.
[SPEAKER_01]: Below that level, raising testosterone moves the downstream signal.
[SPEAKER_01]: Once you cross it, the receptors already occupied and adding more testosterone to the bloodstream produces no additional cellular response.
[SPEAKER_01]: Now, the prostate is one androgen dependent tissue, and the question worth asking is, which other tissues behave the same way?
[SPEAKER_01]: The answer is what most of the wellness clinic industry is built on getting wrong.
[SPEAKER_01]: So libido was the next tissue that researchers asked about.
[SPEAKER_01]: Now the framing him and HIM data sets show that it follows the same sort of plateau.
[SPEAKER_01]: libido rises with testosterone up until around the bottom of the reference range and then it flattens.
[SPEAKER_01]: That means a guy with a testosterone level 600 is not more libidinous than a guy at 400.
[SPEAKER_01]: I did everything in my power to avoid saying the word horny on air, but I just did it.
[SPEAKER_01]: So people know libidinous means.
[SPEAKER_01]: But a guy at 800 does not get better erections than a guy
[SPEAKER_01]: In those response trials going back to the late 1990s, researchers gave young men graded doses of testosterone up to 600 milligrams per week, this has to do with muscle, lean mass and strength climbed across the entire range tested, higher dose, more muscle, but there's a catch here.
[SPEAKER_01]: Those are superficial logical doses that cannot be achieved naturally.
[SPEAKER_01]: 600 milligrams per week of testosterone is roughly 3 to 6 times of what a standard TRT prescription delivers, but within the normal physiological range, which is the target that a good clinician tries to achieve when treating testosterone deficiency.
[SPEAKER_01]: The additive effect of testosterone a muscle is small to non-existent.
[SPEAKER_01]: A 12-week trial that will cover in the next segment tested exactly this.
[SPEAKER_01]: They did a standard transdermal dose of testosterone in men who were in the low to normal, low to low normal testosterone range.
[SPEAKER_01]: Adding testosterone to a structured exercise program didn't produce more lean mass, or more strengthening than exercise alone.
[SPEAKER_01]: And there's a reason at the level of the tissues for this finding.
[SPEAKER_01]: direct measurements of intramuscular androgen exposure don't scale with blood levels of testosterone in the way that most people assume.
[SPEAKER_01]: Muscle fiber sort of regulates its own local androgen environment, which is one of the reasons that men and women see the same relative improvement in strength and muscle mass in response to exercise.
[SPEAKER_01]: And it's one of the reasons that acute post-exercise testosterone spikes don't correlate with long-term hypertrophy.
[SPEAKER_01]: And within the physiological range, baseline testosterone levels also don't predict the train response that somebody's going to get.
[SPEAKER_01]: So despite a roughly 10-to-20-fold difference in circulating testosterone levels between men and women.
[SPEAKER_01]: Intramuscular androgen exposure is much closer between the sexes than serum levels would suggest.
[SPEAKER_01]: The muscle fiber sort of regulates its own androgen biology, including the capacity to produce androgens locally from precursors like DHEA.
[SPEAKER_01]: Now, a 2025 andhane's analysis of adult men found that serum testosterone didn't correlate with measured strength.
[SPEAKER_01]: There was a cross-sectional association with muscle mass, but that runs both directions in observational data sets like this.
[SPEAKER_01]: Men with more muscle tend to have less fat, and they have tend to have better metabolic health, and a higher SHBG, all of which raise the testosterone reading independent of any causal effect of testosterone on muscle.
[SPEAKER_01]: The finding that holds up is the strength dissociation, pushing the testosterone number higher does not push the strength number
[SPEAKER_01]: So Austin hears the patient this whole segment is aimed at.
[SPEAKER_01]: A guy walks in, his total testosterone is 480 nanograms per decelerator, right in the middle of the reference range, but he's convinced that 900 is the target to optimize.
[SPEAKER_01]: How do you walk him through the sort of saturation model, if at all, without making him feel like you're talking down to him?
[SPEAKER_00]: Yeah, challenging situation and I probably wouldn't get into the details or the weeds of a saturation model unless I can tell by the way the person is talking to me that they themselves are very much down in the weeds.
[SPEAKER_00]: And and some people, depending on their background or level of education, how hard they go on the nerding out on this stuff, they may actually want to converse on that level, but most people don't.
[SPEAKER_00]: And so once again, I'll begin with, hey, tell me the context here.
[SPEAKER_00]: Why was this checked in the first place?
[SPEAKER_00]: Did you have any symptoms that we're concerning to you?
[SPEAKER_00]: Like, what's the, what's the goal here that we're trying to achieve?
[SPEAKER_00]: And then from there, really I'm going through something else we've talked about on the podcast before, just like the concept of belief change.
[SPEAKER_00]: And I'm not here to like Neuralize this guy and like inception him with different beliefs about this but rather trying to get to the core of like what is driving him to believe that he has a problem right now what is driving him to believe that 900 would be better and what is the ultimate goal of you know pursuing that target and I may you know quote unquote win by getting him to grasp it hey if he feels well is performing well doesn't have any signs and symptoms of disease.
[SPEAKER_00]: Then this is probably like his natural equilibrium based on combinations of how much testosterone he produces, his receptor sensitivity, his SHBG levels, these things do tend to equilibrate out based on those variables in a given person and this is maybe his settling point so to speak.
[SPEAKER_00]: But if he does have signs or symptoms of disease, I might point out a few examples of, hey, what if this is something else entirely that is being missed here?
[SPEAKER_00]: Have we considered that there are other possible causes or contributors?
[SPEAKER_00]: And it would be foolish of me as the physician who's being here charged with, you know, your care, your health to just, you know, myopically look at one number and potentially miss other things that could be contributing.
[SPEAKER_00]: You know, I've had patients for example before who had some,
[SPEAKER_00]: you know, maybe some fatigue and maybe they were worried about their testosterone, which was definitively in the normal range, and then missed that they had as I've talked about before.
[SPEAKER_00]: Iron deficiency.
[SPEAKER_00]: It's like if you're a middle aged person and you're feeling that, oh my gosh, like what if there's a colon cancer leading you to have iron deficiency in anemia?
[SPEAKER_00]: And meanwhile, we're looking at just treating a testosterone number to make it look higher because bigger number sounds better.
[SPEAKER_00]: You know, and so ultimately it's going to be a belief change sort of conversation.
[SPEAKER_00]: And when I say belief change again, my goal is not necessarily to change his belief, but rather to understand where these are coming from.
[SPEAKER_00]: And to see as part of the conversation, if we can kind of come into a little bit better alignment.
[SPEAKER_00]: If the person has no signs or symptoms whatsoever and has a testosterone level of 480, then they under no circumstance do they meet criteria for like testosterone deficiency that would merit, you know, hormone therapy.
[SPEAKER_00]: In which case, if the person is adamant and they really want to get that level of 900, then they're basically saying I would like to use antibiotics steroids based basically, right?
[SPEAKER_00]: And there are ways out there that people go and get that, but that would not be a scenario where I would recommend it or be be prescribing it for the like medical therapeutic purposes.
[SPEAKER_01]: Yeah.
[SPEAKER_01]: I think, and you probably see this all the time here.
[SPEAKER_01]: We live online chronically, you know, there are practitioners of varying levels of expertise.
[SPEAKER_01]: It is almost like an advertising hook.
[SPEAKER_01]: It's like we've got to optimize your testosterone level, whether they blatantly say, no, it's got to be high, you know,
[SPEAKER_01]: 800 to 900, or they say, well, it's for you, wherever you feel the best.
[SPEAKER_01]: But I think this misses a lot of the nuance around this.
[SPEAKER_01]: Like, not a, there's no single level that's best, right?
[SPEAKER_01]: And then the experiences you're attributing to a particular level are generally speaking, with a factorial, right?
[SPEAKER_01]: Especially the less specific the signs and symptoms, or the experience it is if we're talking about fatigue.
[SPEAKER_01]: For example, it's like, well, think of all the things that can make you tired or not.
[SPEAKER_01]: Right.
[SPEAKER_01]: For talking about performance in the gym, think about all the things that can go in of that, uh, same thing with sexual health, so on and so forth.
[SPEAKER_01]: Right.
[SPEAKER_01]: The more multifactorial the symptoms or signs are or the experience that you're trying to achieve, uh, the, the less that the single number is going to reflect that.
[SPEAKER_01]: But that's not a great advertisement for your services, particularly if it revolves around testosterone replacement therapy.
[SPEAKER_01]: They're like,
[SPEAKER_01]: We've got to optimize you, and it's like, in the back of your head, you're like, which is the optimal level.
[SPEAKER_01]: Yeah.
[SPEAKER_01]: After studying this for a long time, like, you know, we both know the general single level.
[SPEAKER_01]: So what do you think when you see an advertisement like that?
[SPEAKER_00]: Yeah, I mean, I think about it's like a, it's like this weird level that is put on a pedestal because imagine we just madlapped this and substitute it to stosterone with another physiologic parameter, like glucose or What is the optimal glucose level?
[SPEAKER_00]: And, you know, when I draw my lab tests and that's the glucose that I see and I want it to be lower and, you know, to most folks who are listening to like,
[SPEAKER_00]: Obviously your glucose is going to go up and down all the time based on a variety of things.
[SPEAKER_00]: You know, whether you're fast, did Fed, what's you ate your levels of activity, your sleep, all sorts of other things and it's like, yeah, turns out it's the same thing here.
[SPEAKER_00]: And so then we also see people, for example, seeking to quote unquote optimize their glucose levels and using things like CGMs to guide their behavior to, for unclear, you know, ultimate health outcomes, especially if they if they don't have a diagnosis of type 2 diabetes.
[SPEAKER_00]: I recognize
[SPEAKER_00]: like to use them for because they're, you know, geeking out on the data or they feel like it helps them make particular food choices.
[SPEAKER_00]: There's not really, you know, long-term evidence of concrete health benefits from such a thing.
[SPEAKER_00]: And so I'm not by any means suggesting that I would enjoy this or prefer it.
[SPEAKER_00]: In fact, it would probably more of a nightmare than anything else, but I can't help but think that if we had instead of CGMs like CTMs continuous testosterone level monitoring, like people might recognize at least how much more variability there are in these levels throughout the day, day to day, minute to minute hour to hour and maybe put a little bit less stock in like a single blood, you know, snapshot blood draw in that way, right, because.
[SPEAKER_00]: There's a lot of appropriate physiologic, and yes, sometimes pathologic fluctuations that can happen in these levels.
[SPEAKER_00]: And that kind of the net exposure to it over time within a reasonable physiologic range means you're probably fine.
[SPEAKER_00]: And so not over medicalizing it is something that I think we're both in favor of.
[SPEAKER_01]: Yeah, there's a lot of just I guess.
[SPEAKER_01]: I don't know if they're just conditioned beliefs and where those conditioning come from is a society, is it the medical establishment, is it, you know, whatever, that, again, hires better.
[SPEAKER_01]: And it four things that people really do seem to care about whether it's sexual health, whether it's games in the gym, and I just think over archingly.
[SPEAKER_01]: When you look at the normal physiological range, you know, that it is captured with a laboratory test, that if you're in that normal range and we're talking about non-specific symptoms here, there's really just not a good correlation between getting towards the higher level or trying to achieve that, specifically through like a medication, for example, where things get better, rather getting to a higher level generally reflects better health.
[SPEAKER_01]: And so,
[SPEAKER_01]: you don't need a testosterone lab value to get you to do that stuff where it is, you know, reducing this real adipose tissue, be more active, sleeping well, having good interpersonal relationships having a health promoting diet.
[SPEAKER_01]: Like you should have been doing that stuff already.
[SPEAKER_01]: We don't need a lab a testosterone test to motivate you.
[SPEAKER_01]: But if that functions as a behavior change sort of tool,
[SPEAKER_01]: Let testing testosterone's cheap.
[SPEAKER_01]: I'm just more concerned that people get a weird reading and then have to go down a further work up and maybe some inappropriate treatment.
[SPEAKER_01]: Does that make some rest of you?
[SPEAKER_01]: Yeah, I mean we see it all the time.
[SPEAKER_00]: So yeah, I agree with that.
[SPEAKER_01]: Yeah, so we'll talk about the number itself.
[SPEAKER_01]: Now, look, if the receptor saturates around 250 nanograms, predestice layer specifically for the prostate, and getting a normal man from like 500 to 900 doesn't change what the tissue is actually seen with respect to like libido, muscle, mass, and so on and so forth.
[SPEAKER_01]: The reference range itself is worth the closer look.
[SPEAKER_01]: What is the endocrine society 264 nanogram per deciliter cutoff actually defined?
[SPEAKER_01]: And what is within normal limits or low, actually mean on a lab report?
[SPEAKER_01]: Now, as you might remember, the endocrine society lowered their lower limit of normal from 300 to 264.
[SPEAKER_01]: This is basically a result of the testing change going from immunosays to mass spec.
[SPEAKER_01]: Basically, as we covered on last week's podcast or the first episode of this launch series,
[SPEAKER_01]: When researchers re-rand stored samples that they previously flagged as low using immunosatest, and they used the newer technologies, more accurate mass spec testing, more men fell below 300 than the older assays that said it's basically doubled.
[SPEAKER_01]: Now what the reference range actually is is a distribution of values that are observed in an apparently healthy men on a validized.
[SPEAKER_01]: test like this.
[SPEAKER_01]: It's not a target.
[SPEAKER_01]: A number inside the range doesn't rule out symptomatic testosterone deficiency.
[SPEAKER_01]: And a number below the range without symptoms and a confirmatory secondary draw, that doesn't establish a diagnosis either.
[SPEAKER_01]: So comparing a lab value to the established range is a starting point for interpretation.
[SPEAKER_01]: That's really the point we're trying to drive home here.
[SPEAKER_01]: The interpretation itself requires symptoms.
[SPEAKER_01]: A second confirmatory draw in the rest of the work
[SPEAKER_01]: So Austin, here's this scenario.
[SPEAKER_01]: You probably see very often the total testosterone of a guy comes back at 285 milligrams per deceler, technically above the endocrine societies cut off.
[SPEAKER_01]: Now a lot of clinicians would read that number right within normal limits in the chart and move on.
[SPEAKER_01]: What are you doing differently there?
[SPEAKER_01]: Outside of asking them, hey, why did you get this drawn and what is this?
[SPEAKER_00]: Yeah, you preempted me there.
[SPEAKER_00]: Yeah, I like to think that I'm firing some more neurons.
[SPEAKER_00]: Again, in this type of situation, I think it is poor practice insufficient to just look at the number, compare it to that reference range, say normal and move on abruptly.
[SPEAKER_00]: And the main reason is that that number alone does not exclude the possibility that this person may benefit from some intervention, be it related to their health in general or to their testosterone level in particular.
[SPEAKER_00]: And ultimately, what is the point of a lab test in general?
[SPEAKER_00]: Like, we'll get in big picture philosophy here.
[SPEAKER_00]: What is the point of testing?
[SPEAKER_00]: It is to give us information that may plausibly lead to differences in management strategies.
[SPEAKER_00]: How we might do something, might lead us to do something differently.
[SPEAKER_00]: Then we may have otherwise done.
[SPEAKER_00]: by giving us that additional piece of information that we did not have before.
[SPEAKER_00]: And so here's a situation where if I have a symptomatic person and I have a lab level at 285 and perhaps they have other risk factors for testosterone deficiency.
[SPEAKER_00]: Maybe they have obesity, maybe they have some metabolic syndrome, maybe they have sleep apnea or they are at high risk of sleep apnea.
[SPEAKER_00]: And so this is a scenario where I could potentially pair it with a checking a SHBG level and getting a sense of, is this just a low total with a normal free or bio-available?
[SPEAKER_00]: Is this somebody who has definitively low free testosterone levels, which is the thing that tends to actually correlate a bit more closely with symptoms?
[SPEAKER_00]: and which symptoms in particular are they concerned about?
[SPEAKER_00]: Because the picture has to be coherent, it has to make sense what symptoms they're worried about, what signs they're worried about, are those even related to blood testosterone levels at all?
[SPEAKER_00]: And then other options that I might have would be just rechecking things.
[SPEAKER_00]: That's something I do pretty often when I have a lab test that is
[SPEAKER_00]: vague range or in a gray area, and I'm wanting to try to kind of adjudicate or get higher quality data overall to make my clinical decision.
[SPEAKER_00]: So I have a few options of next steps there, but the reason why I might not automatically say in range normal and move on is because of the concept of pretest probability.
[SPEAKER_00]: If I checked this test or a, what I would deem to be a valid reason, meaning I had suspicion that it might be low, and it comes in at this type of range, then my suspicion is kind of justified here to an extent, right, if I had no reason to check it, then, and I get this live value, it's harder to interpret there, right.
[SPEAKER_00]: But if my suspicion was high and it's in this range, then I'm not just going to dismiss it and move on because ultimately what I care about is not the number, but is this patient somebody who may plausibly benefit from intervention.
[SPEAKER_00]: And I have an array of interventions that I might offer, and that includes the potential of testosterone therapy, because when even when it comes to offering somebody the treatment, the question is like, what are you most afraid of?
[SPEAKER_00]: Like, what catastrophic risk are we being faced with?
[SPEAKER_00]: If I were to offer a particular trial of therapy to this person, and the risks as we'll get too later on are like,
[SPEAKER_00]: not insanely high, right?
[SPEAKER_00]: So if the person plausibly may benefit and I have enough supporting evidence, it may be worth a shot.
[SPEAKER_00]: If I have, you know, sufficiently thought about this underlying causes address those things.
[SPEAKER_00]: So that's why I would think a lot harder about this value, especially in somebody where what I call my like pre-test probability, where I had a high suspicion of like, oh, this person certainly at risk.
[SPEAKER_00]: of having testosterone deficiency.
[SPEAKER_00]: I'll think about a harder before just saying, app, in-range, move on.
[SPEAKER_00]: Because then you lose people.
[SPEAKER_00]: They feel dismissed.
[SPEAKER_00]: My doctor, you'd listen to me, and then they end up seeking care from other practitioners who may also not do very much thinking, but in a way that just leads them to write a script.
[SPEAKER_01]: Yeah, that makes sense.
[SPEAKER_01]: Yeah, I think over archially, again, a lab value is only the first piece of a workup.
[SPEAKER_01]: It doesn't make the diagnosis on its own.
[SPEAKER_01]: All right, so that handles the lab side of the diagnosis, the other side is symptoms.
[SPEAKER_01]: And there's a study that most men have never heard about, which symptoms actually point to low testosterone, in which ones they've been told, point to it, but don't.
[SPEAKER_01]: Here's what that is.
[SPEAKER_01]: We open the episode with the top line finding from the European male aging study.
[SPEAKER_01]: Three of 32 commonly attributed symptoms actually correlate with low testosterone, and all three are sexual.
[SPEAKER_01]: Let's walk through what that study actually tested because the finding only lands once you see
[SPEAKER_01]: More than 3,000 men across eight European centers, they were aged 40 to 79.
[SPEAKER_01]: The researchers cataloged 32 different complaints commonly attributed to low testosterone and correlated each one against total testosterone, free testosterone and LH.
[SPEAKER_01]: Three correlated at a statistically significant and reproducible level.
[SPEAKER_01]: decreased frequency of morning erections, decreased frequency of sexual thoughts, and erectile dysfunction.
[SPEAKER_01]: The other 29 symptoms did not survive the analysis.
[SPEAKER_01]: They either didn't reach statistical significance, or they disappeared when adjusting for age and medical comorbidities.
[SPEAKER_01]: Now, this isn't the same as saying those symptoms aren't real.
[SPEAKER_01]: They certainly are, and men experiencing fatigue, low mood, brain fog, etc.
[SPEAKER_01]: They're experiencing something, and it deserves attention.
[SPEAKER_01]: What this data does tell us is that those symptoms have many other possible causes besides low testosterone.
[SPEAKER_01]: A man who walks in saying, I'm tired, I can't focus.
[SPEAKER_01]: I don't feel like myself has symptoms that can be produced by at least a dozen other things before it even gets to testosterone.
[SPEAKER_01]: The usual suspects here are things we've talked about all the time.
[SPEAKER_01]: Poor sleep, untreated metabolic disease, depression, chronic stress, alcohol use, medication side effects, and so on.
[SPEAKER_01]: The wellness clinic funnel runs on that mismatch, though.
[SPEAKER_01]: The symptom profile that drives men through the door of one of these clinics is the profile least specific to the condition that they're being treated for.
[SPEAKER_01]: Now, the guidelines are stricter than that and they're what we should probably follow.
[SPEAKER_01]: The guidelines standard requires two different diagnostic elements.
[SPEAKER_01]: Thing one, symptoms that are consistent with testosterone deficiency, weighted towards the sexual symptoms because those tend to carry the highest or most robust diagnostic signal.
[SPEAKER_01]: The second is biochemical evidence on a correctly drawn morning sample with the confirmatory second draw on a different day.
[SPEAKER_01]: This is because the Massachusetts Mail Aging study data that we covered last week shows that roughly half of initially low values will normalize on repeat testing without any sort of treatment.
[SPEAKER_01]: So Austin, you got a patient that shows up with the list of 10 symptoms that is already convinced are due to low testosterone.
[SPEAKER_01]: How do you walk them through
[SPEAKER_00]: Yeah, totally validate what the person's experiencing first because these symptoms are extremely common and it's not that the person is like making up what they're feeling and based on the homework that they have done prior to their clinic visit perhaps they have you know been funneled down certain algorithmic routes on the internet that led them to kind of.
[SPEAKER_00]: uh, prefer a common cognitive error that we see in medical trainees called premature closure, and that cognitive bias leads you to just fixate on one possible cause to the exclusion of other possible causes and it leads to commonly diagnostic error and in like my world, um, in like say hospital medicine and things like that.
[SPEAKER_00]: a lot of harm can come from that.
[SPEAKER_00]: If somebody's like, oh, it has to be this, it can't be anything else, and then they just pursue that route.
[SPEAKER_00]: And then only on the back end when something goes really wrong, do you realize, oh, I missed this alternative possibility all along?
[SPEAKER_00]: The stakes here in the short term are not nearly as high in terms of like risk of death, as I might see from something like this in the hospital setting, but the long term stakes remain relatively high.
[SPEAKER_00]: If, again, somebody misses symptoms of an underlying malignancy, for example,
[SPEAKER_00]: and the tributes, the general non-specific symptoms to testosterone, as an example.
[SPEAKER_00]: And so I'm not waiting through the nuances of clinical research studies like this with the patient, but rather pointing out that, hey, totally valid what you're feeling and certainly will work together to try to get to the bottom of it, I would suggest that we kind of cast a wider net.
[SPEAKER_00]: It is possible that testosterone could be
[SPEAKER_00]: related to your symptoms, whether directly or indirectly because something else is causing both testosterone impacts and these other symptoms.
[SPEAKER_00]: So, you know, my job is to, you know, think about this really hard and try not to miss anything that could be going on to think comprehensively about this.
[SPEAKER_00]: And if there is some underlying kind of cause that we can identify to target that,
[SPEAKER_00]: while also, you know, addressing the person's concerns along along the way.
[SPEAKER_00]: So that would be kind of how I would go about it.
[SPEAKER_00]: And most people are really readily on board with something like that.
[SPEAKER_00]: Very few of them are like, no, I don't want you to look at anything else.
[SPEAKER_00]: Just look at this.
[SPEAKER_00]: But sometimes it takes a little bit of explaining of like, look, the list, you know, my job, my specialty is coming up with long differential diagnoses, which I'm very good at.
[SPEAKER_00]: And so I'm happy to do that for the person in point out that like, there's a lot of things that could be going on here.
[SPEAKER_00]: If it were me and if it were my health, I would want a more thorough look at those different possibilities rather than just fixating on one thing.
[SPEAKER_00]: But you're right, that the emphasis of emphasis is the right word, but the specificity in terms of symptoms, if somebody who has previously experienced a normal libido subsequently reports a loss of libido, that is one of the more suggestive and even more arguably specific symptoms that people can have,
[SPEAKER_00]: outside of like extremely early testosterone deficiency where somebody like never goes through puberty or something, but that's a more of a pediatric world type thing.
[SPEAKER_01]: Yeah.
[SPEAKER_01]: I imagine, you know, as you get more information on the persons, you know, history of press and illness, and you go through review systems and everything else, it's tending to lead you in a particular direction as far as how wide the net needs to be, right?
[SPEAKER_01]: And I assume, you know, things might pop up that would flag you to really, really broaden it and versus narrow it.
[SPEAKER_01]: But yeah, it would be very unusual.
[SPEAKER_01]: You got a person who says,
[SPEAKER_01]: and then you find out their blood pressure is elevated and they do have some some obesity for example and they're experiencing some of these what we would call like non-specific symptoms that could be attributed to testosterone efficiency but not necessarily only attributed to testosterone deficiency and you're like look it could be testosterone deficiency.
[SPEAKER_01]: But I'm leaning a little bit more strongly towards obstructive sleep apnea.
[SPEAKER_01]: And I think we need to evaluate you for that as well.
[SPEAKER_01]: And they say, no, I don't want any evaluation for that.
[SPEAKER_01]: That would be unusual.
[SPEAKER_01]: I suspect that hasn't happened to you personally that often because you're a clinical.
[SPEAKER_01]: Your bedside manner is better.
[SPEAKER_01]: But I imagine it has happened before.
[SPEAKER_00]: Yeah, it just depends on how you frame it.
[SPEAKER_00]: If the person feels dismissed and not listened to, then it's going to immediately set up an adversarial relationship, which I go out of my way to not establish with patients.
[SPEAKER_00]: I'm the person who asks an open-ended question at the beginning of the encounter and shuts up and lets them speak and I'm reading a lot of what they're saying and how they're saying it to get a sense of, has this person already come in with a bunch of prior negative experiences with other doctors, for example, and am I going to have to tread a little bit more carefully?
[SPEAKER_00]: Are they coming in, mistrusting right off the bat?
[SPEAKER_00]: Are they coming in, motivated to a particular end right off the bat?
[SPEAKER_00]: Or are they very open and want in a collaborative relationship?
[SPEAKER_00]: Do they already know anything about me and have expectations?
[SPEAKER_00]: From that standpoint.
[SPEAKER_00]: So there's all sorts of things that I'm trying to listen to.
[SPEAKER_00]: The words they choose, the way they say things, and see if I can glean that additional information from them.
[SPEAKER_00]: And if not, then sometimes I might just ask outright, like what if your prior experience has been with this working with other folks or have you worked with other folks about this?
[SPEAKER_00]: because that can all be valuable information to me to determine like what are this person's expectations and how can I best meet them to lead to, you know, benefit and not cause them harm.
[SPEAKER_01]: Yeah, it's hard to get good clinical outcomes when you have no therapeutic alliance because you just violated that immediately.
[SPEAKER_01]: Right.
[SPEAKER_01]: But let's say, yeah, you work with the patient and you've come to the conclusion it's reasonable to draw their testosterone because it is part of your broad net.
[SPEAKER_01]: So how do you go about doing that?
[SPEAKER_01]: Well, the first lab, when you're measuring testosterone, first thing it needs to be done in the morning.
[SPEAKER_01]: Ideally, between seven to 10 a.m., testosterone peaks in the early morning and falls across the day.
[SPEAKER_01]: The reference ranges are built off morning data.
[SPEAKER_01]: So you don't measure it in the afternoon.
[SPEAKER_01]: Now that's said, testosterone levels do go up a little bit not quite as high.
[SPEAKER_01]: They normally do in the morning about eight hours after waking.
[SPEAKER_01]: There's some thoughts with.
[SPEAKER_01]: Body temperature rhythms and things like that, but this is kind of the basis for why some individuals have said you should work out at this time in the afternoon to maximize results because your testosterone levels are a little higher.
[SPEAKER_01]: Interestingly, they tend to not recommend waking up working out first thing in the morning when the testosterone levels are going to.
[SPEAKER_01]: higher, but based on what you know about testosterone levels, intramuscular testosterone levels, and then ultimately how the difference is large differences, again, between men and women, and how they affect exercise outcomes.
[SPEAKER_01]: You already know, this is bogus.
[SPEAKER_01]: So part two, it doesn't need to just be in the morning.
[SPEAKER_01]: You also need to be fasting.
[SPEAKER_01]: Because eating a meal tends to raise your blood glucose transient leaf for a short period of time, which can lower total testosterone.
[SPEAKER_01]: It also should not be drawn while somebody is presently ill.
[SPEAKER_01]: Some sort of, you know, respiratory virus, other sort of illness, generally that will lower testosterone levels should not be coming off a run of bad sleep if that can be avoided.
[SPEAKER_01]: But just an imagine a scenario where a person's very motivated.
[SPEAKER_01]: to get a TRT prescription.
[SPEAKER_01]: And so they come in, they went on all night bender.
[SPEAKER_01]: Didn't sleep, drank a bunch, they might even be sick on top of that.
[SPEAKER_01]: I'm ready for this lab, and then you can record your hand.
[SPEAKER_01]: That'd be a way to artificially suppress your testosterone level.
[SPEAKER_01]: And I suppose if you did that twice on the repeat draw, and it would be some interesting, like LH and FSH data alongside of that, but you could have two low testosterone levels.
[SPEAKER_01]: But if the first one is low, then you sort of bought yourself, and in some cases, depending on the clinical context, a more expansive sort of hormonal work up related to that low level of testosterone.
[SPEAKER_01]: So you repeat the test on a separate morning under the same conditions.
[SPEAKER_01]: So between seven to 10 a.m. fasted, not sick, not under slept, et cetera.
[SPEAKER_01]: And then you add on LH, FSH, HBG, and potentially some other things like pro-lactin or whatever, depending on the clinical context.
[SPEAKER_01]: So you get a second trip to the lab with this more expansive diagnostic panel.
[SPEAKER_01]: Now again, we know that roughly half of initially low total testosterone levels will normalize on repeat testing without any sort of treatment.
[SPEAKER_01]: That's why this sort of confirmatory draw matters.
[SPEAKER_01]: Now, if the repeat draw confirms the first,
[SPEAKER_01]: LH and FSH can localize the problem, so is it located at the level of the testies?
[SPEAKER_01]: Or is it somewhere in the brain?
[SPEAKER_01]: Is it somewhere else?
[SPEAKER_01]: And if you get a SHBG, that can tell you whether the total testosterone value may be misleading because of the binding protein being abnormal.
[SPEAKER_01]: So, you may also choose to get a free or bi-available testosterone as a follow-up, sort of step.
[SPEAKER_01]: This is usually reserved for cases where the SHBG comes back abnormal or the total doesn't really match the clinical picture and you need that extra bit of information to make a decision.
[SPEAKER_01]: Although, again, as you mentioned, the sort of trial of testosterone replacement therapy is not really high stakes in the short term, but longer term is certainly can be.
[SPEAKER_01]: So why does this matter?
[SPEAKER_01]: Well, many wellness clinics default to prescribing TRT office single after noon total testosterone.
[SPEAKER_01]: People will go in the labs, 3pm, get a lab drawn.
[SPEAKER_01]: Oh, testosterone is low, boom, you're under self-prescription.
[SPEAKER_01]: That's one draw the wrong time of day.
[SPEAKER_01]: No ancillary labs, no symptom work, no confirmatory repeat.
[SPEAKER_01]: The prescription comes out of the printer before the patient at a real evaluation, which is obviously part of the business model.
[SPEAKER_01]: I mean, we said this less than a quarter of people.
[SPEAKER_01]: actually had a testosterone level drawn before they received a TRT prescription and it gets worse.
[SPEAKER_01]: Half of people after they've been prescribed TRT don't have a level within the next year to confirm their at the right level.
[SPEAKER_01]: But with that in mind, let's ask a different question.
[SPEAKER_01]: When standard TRT is prescribed properly, to a man in this exact demographic at the right dose, with the correct work up behind it, does it actually deliver what the wellness clinic is promising?
[SPEAKER_01]: There's one trial that tested this directly with respect to muscle mass and strength outcomes.
[SPEAKER_01]: So in this 12-week study out of Australia, 80 men in their 50s and 60s, the exact demographic a wellness clinic is marketing to.
[SPEAKER_01]: They all had low normal testosterone, which admittedly is arbitrary.
[SPEAKER_01]: There is no specific cutoff for low normal.
[SPEAKER_01]: But in this particular study, the average testosterone level was 320 nanograms per deciliter.
[SPEAKER_01]: they all had a decent amount of visceral fat, right?
[SPEAKER_01]: That's the fat that surrounds your internal organs.
[SPEAKER_01]: They all had waste or conferences of 37 inches or more signifying they did have some visceral adiposity, and they were split into four groups.
[SPEAKER_01]: One group got testosterone alone, another group did exercise alone, a third group.
[SPEAKER_01]: This is the smiley face group, got both, and then the fourth group.
[SPEAKER_01]: This is the frowny face group.
[SPEAKER_01]: They got neither.
[SPEAKER_01]: The testosterone was the standard prescription dose, so not a higher PED level dose.
[SPEAKER_01]: Now, after 12 weeks, the exercise groups improves significantly, roughly a 10 to 13% improvement in aerobic capacity, the testosterone alone group.
[SPEAKER_01]: There was no improvement in aerobic fitness.
[SPEAKER_01]: So adding testosterone on top of exercise added nothing beyond what exercise was already doing.
[SPEAKER_01]: with respect to muscle mass, both testosterone and exercise produced gains independently and combining them looked directionally better than exercise alone, but it didn't achieve clear statistical significance at 12 weeks.
[SPEAKER_01]: For strength, exerciseer was, for strength, exercise was the driver across every measure tested.
[SPEAKER_01]: Testosterone alone did not move the strength needle and the combination didn't
[SPEAKER_01]: Now, the author's direct conclusion, exercise should be evaluated as an anti-aging intervention in preference to testosterone in middle-aged men with low normal testosterone levels.
[SPEAKER_01]: Now, there are a few caveats here, and this is the last point.
[SPEAKER_01]: I'm going to really get your take on this Dr. Barackie.
[SPEAKER_01]: So, this is one relatively well-designed trial, but the broader testosterone plus exercise literature is kind of a mess.
[SPEAKER_01]: Not a mess because people aren't doing these studies well, but they use different doses, different populations,
[SPEAKER_01]: This particular population was low normal, not testosterone deficient, but for a man with truly hypogonatal or testosterone deficient levels, the calculus is clearly different here.
[SPEAKER_01]: Next, 12 weeks is short.
[SPEAKER_01]: It may take longer for a significant difference between combined therapy, testosterone exercise, to show up compared to exercise alone.
[SPEAKER_01]: Also, they were using a standard prescription dose, not a super physiologic dose, where there is a dose response relationship between muscle and testosterone exposure.
[SPEAKER_01]: And testosterone alone did be placebo for lean mass and men who could not exercise.
[SPEAKER_01]: And so for that population, testosterone may have a real, if not modest, roll.
[SPEAKER_01]: But for the man who can train, the trial says that the training is doing most of the heavy lifting pun intended.
[SPEAKER_01]: Now, here's the final point I want to get your take on this.
[SPEAKER_01]: Hard training itself can suppress testosterone levels.
[SPEAKER_01]: This is deflies in the face of people saying, oh, you got to exercise to boost your testosterone levels.
[SPEAKER_01]: Now, to the extent exercise reduces somebody's visceral adipose tissue short.
[SPEAKER_01]: You can see an indirect increase in testosterone, but lifting weights itself or doing high-intensity interval training sprints, whatever, does not raise baseline testosterone levels on average.
[SPEAKER_01]: The exercise hypogonatal male condition EHMC is a well documented sort of example of this, particularly in endurance athletes, although there's similar adaptive suppression that likely shows up in people lifting weights for high volumes and specifically for not eating enough.
[SPEAKER_01]: Now, a man who's low, normal reading is an adaptation to their training load rather than just a sort of baseline deficit, that's a different patient than the men in the study we just discussed.
[SPEAKER_01]: And if they were to receive a standard prescription dose of testosterone replacement therapy, well, that might be like a PED for them rather than just replacement because it over rides the sort of trained down set point that the person is experiencing.
[SPEAKER_01]: We don't have a trial
[SPEAKER_01]: What do you think about that, Dr. Brocky?
[SPEAKER_00]: Yeah, I think you've made a good case for why this is so messy.
[SPEAKER_00]: And further supports the need to think, instead of just to look at the number and draw conclusions based on that number alone.
[SPEAKER_00]: Because to your point, taking people who are quote-unquote low normal, who may or may not have had clear associated signs or symptoms,
[SPEAKER_00]: meaning that if they were not, you know, confidently or clearly testosterone deficient, they may well have been unlike the flatter part of the curve in terms of the interaction between their testosterone levels and their physiology.
[SPEAKER_00]: And bumping them a little bit further up along the flat part of the curve is unlikely to have a substantial difference in their outcomes, which is kind of what was observed here.
[SPEAKER_00]: And this is not even to say anything about other
[SPEAKER_00]: you know, how strength testing is done in research and all sorts of things like that, right?
[SPEAKER_00]: But I think that the lower the testosterone level goes all the way down to levels of undetectable, which I've mentioned a few times before I've seen in practice, but usually in patients with like, you know, advanced HIV AIDS infection or something like that, the lower that level goes, the more suggestive and specific of symptoms the person has,
[SPEAKER_00]: the more likely they are to benefit from therapy.
[SPEAKER_00]: And that's about as far as I can go with this, it is a spectrum of likelihood of benefit.
[SPEAKER_00]: And it is, I know frustratingly, hedgy or like vague in a sense, but that's the clinical reality.
[SPEAKER_00]: Is we cannot always with 100% confidence, predict who is or isn't likely to benefit based on a single blood level.
[SPEAKER_00]: All right, that's why there has always been such controversy around like where should we set the cut off is some guidelines say 350 some say 300 some say 264 and it's like if there was a single cut off that reliably differentiated somebody who's likely to benefit from somebody who isn't that would be the cut off but that doesn't exist because not only are these cut off it's a it's a single point on a spectrum a continuous spectrum.
[SPEAKER_00]: but also different people get a rive at their blood level in different ways.
[SPEAKER_00]: And as we have also mentioned the blood testing itself is fraught of time of day and interfering factors and things like that.
[SPEAKER_00]: So that's why this is so messy.
[SPEAKER_00]: That's why this, you know, if you if you throw a bunch of people in a study and you give them.
[SPEAKER_00]: You know, a method of testosterone administration, I believe you said it was transformable here, which can be a little bit, you know, less reliable in terms of its effectiveness, then yeah, you're going to come out with a with a messy messy and mostly unhelpful result outside of reinforcing what we already knew training is good for you.
[SPEAKER_00]: Right.
[SPEAKER_00]: So I think that if you want to answer a very clear, concrete question, you need to have very rigid criteria for who you're going to put into a study, but then the downside of that is on the back end, your results can only be applied to that exact population and like it should not be extrapolated kind of beyond that right.
[SPEAKER_00]: So those are those are my thoughts here is it's just super messy and again reinforces the need to like think about these things beyond just a single blood test alone.
[SPEAKER_01]: Yeah, I think if you had like a hard training person and they were quote low normal wherever you wanted to arbitrarily make that cut off right and they didn't have any other symptoms outside of just this lot you know biochemical evidence of their testosterone level being maybe lower than you thought it was like for example if you had your testosterone level drawn and it came back at 300 right you have no other symptoms just have this low number low normal number right and then we put a person like you on TRT it's like well.
[SPEAKER_01]: You didn't need the replacement, so is this actually like a PED for you because you were previously like, again, turned down and now it's a little higher.
[SPEAKER_01]: I mean, that's plausible.
[SPEAKER_01]: We'd have to test it right to say it with confidence, but it does seem plausible to me.
[SPEAKER_00]: Yeah, I think that's part of why because I see patients for this sort of thing all the time and do these consultations with folks who have either either you know testosterone therapy curious or who have been on it and wanted to get my my input on things and I have lost count of the number of times I have a guy who maybe has followed you know in the in the lifting space.
[SPEAKER_00]: who maybe got inundated probably again algorithmically at this point with messages around this and decided to give it a shot maybe he is in his 30s or 40s and he got his level checked and it was yeah like 380 or 400 and he's like I'm under the impression that my levels at this age are supposed to be 800 so I actually tried.
[SPEAKER_00]: and went and got on some testosterone therapy because it's not terribly difficult to find.
[SPEAKER_00]: And then the end up, I can think of many cases off the top of my head.
[SPEAKER_00]: They're like, I had this like debilitating anxiety.
[SPEAKER_00]: I had severe acne outbreaks.
[SPEAKER_00]: I disrupted my sleep.
[SPEAKER_00]: I felt way worse.
[SPEAKER_00]: And it's like, well, you were probably on like very super physiological levels because you may not have actually needed it in the first place, which makes much more sense compared with people who are clinically deficient, truly testosterone deficient who feel substantially better.
[SPEAKER_00]: when they're replaced to appropriate levels compared with feeling like way, way worse, which I've seen many times enough to where they would discontinue therapy.
[SPEAKER_00]: And those are the people who kind of get dissolutioned with things.
[SPEAKER_00]: But it can certainly go in that direction.
[SPEAKER_00]: And that is a plausible explanation for me of like they were at their kind of natural equilibration standpoint based on their life, their training, their sleep, their receptor sensitivity, their intramuscular levels, all those sorts of things that are play a role in the ultimate feedback cascade.
[SPEAKER_00]: And so getting on therapy for them was just like straight up going on antibiotics instead of, you know, replacing to a physiological level that they didn't actually need.
[SPEAKER_01]: Yeah.
[SPEAKER_01]: I think we're both coming, you know, at this and arriving at the same point where if a person is overtly low,
[SPEAKER_01]: And we're talking, whatever outcome we're talking about, whether it's libido, whether it's muscle mass, strength, et cetera, replacing the testosterone to get it to what would be the normal physiological range is going to they're going to see improvements there then there's a big flat spot within this sort of normal physiological range with the where where the reference range of the lab there's a big overlap there's not a perfect circle right but the venn diagram there's a lot of overlap there.
[SPEAKER_01]: in that range adding more testosterone to shift you to the high normal versus in the right in the middle versus low normal probably is not going to have a big effect but when you go above that range now you're frankly super physiological levels the calculus changes yes there is now a dose dependent relationship between testosterone exposure and muscle mass and strength but it incurs a whole another set of risks and you know that also come along with that so
[SPEAKER_01]: sort of like a three different levels if you if you will here.
[SPEAKER_01]: But overall, I think we're saying the same thing.
[SPEAKER_01]: A real diagnosis takes the symptoms, weighted towards the sexual complaints, a correctly drawn morning testosterone level confirmed on repeat, and a work up for reversible drivers, not a list of non-specific symptoms at a single afternoon draw that the wellness clinics seem to thrive on.
[SPEAKER_01]: Austin, anything else you want to add before we wrap this up?
[SPEAKER_00]: Yeah, just to reiterate that final point that you made of it being kind of like a venn diagram again that there is not a single isolated blood level that can reliably distinguish the person who stands to benefit from those from from someone who doesn't that's why I remit retain kind of an open mindedness around those sort of borderline levels depending on my pre test probability and what the person symptoms are.
[SPEAKER_00]: So if their level is above that, you know, say it's slightly above that 264th threshold, but they have like very suggestive symptoms.
[SPEAKER_00]: Then yeah, maybe it may be a trial is perfectly reasonable sort of thing.
[SPEAKER_00]: Maybe there's somebody who, if you, you know, bump them up a bit.
[SPEAKER_00]: And they end up reporting that they feel dramatically better.
[SPEAKER_00]: It's like, okay, then we're probably on the right track, but I've also again seen people who work.
[SPEAKER_00]: You know, in similar ranges, say in like, you know, load of 300s or something like that who thought it was lower than they wanted to be who tried treatment and actually felt substantially worse.
[SPEAKER_00]: And it stands to reason that that person probably was not clinically low beforehand.
[SPEAKER_00]: And they ended up super physiologic and dealing with some negative consequences of that.
[SPEAKER_00]: And so, you know, I'm not overly rigid about this in practice.
[SPEAKER_00]: but I definitely, you know, I think the take-home point here is like understand why you're testing and then if you do get testing, you have to be able to think really hard about it to try to interpret it and then rule out other possibilities or incorporate other possibilities in your management planet at the very least.
[SPEAKER_01]: Years would a man worried about his testosterone should take away from the episode.
[SPEAKER_01]: One, testosterone is produced by a signaling loop with at least three places it can fail.
[SPEAKER_01]: A single total testosterone value tells you almost nothing about where and the loop the problem is.
[SPEAKER_01]: Without LH and FH to localize it, low total testosterone is a symptom with an unknown cause.
[SPEAKER_01]: 2.
[SPEAKER_01]: The number on your lab report will mostly measure in the fraction of testosterone that your tissues can't use.
[SPEAKER_01]: About 2% of circulating testosterone is free.
[SPEAKER_01]: The rest is bound to proteins.
[SPEAKER_01]: And the interpretation of total testosterone versus free testosterone depends on SHBG.
[SPEAKER_01]: And SHBG is the binding protein routine ignored by the wellness clinic workup.
[SPEAKER_01]: 3.
[SPEAKER_01]: The antigenorceptor has a ceiling on what serum testosterone can do for it.
[SPEAKER_01]: For prostate function, libido, and erectile function, the gains plateau within the lower end of the reference range.
[SPEAKER_01]: Push in a man's total testosterone from 500 to 900 doesn't produce more effect on the things he's chasing.
[SPEAKER_01]: The chase-a-hire number framing sells treatment without delivering at the receptor.
[SPEAKER_01]: 4.
[SPEAKER_01]: Of the 32 symptoms commonly attributed to low testosterone in the largest prospective study we have, only 3 reliably correlate with it, all through your sexual fatigue, brain fog, irritability, and low meat are real, and they deserve attention, but they're not reliably produced by low testosterone specifically, which means that treating them as if they are produces the wrong decision most of the time.
[SPEAKER_01]: 5.
[SPEAKER_01]: A real diagnosis takes symptoms weighted towards sexual complaints, a correctly drawn morning total testosterone that's confirmed on repeat, and a workup for reversible causes.
[SPEAKER_01]: The current system often stops at non-specific symptom list and a single afternoon draw.
[SPEAKER_01]: If the single number is not the diagnosis, and most of the symptoms men blame on their testosterone are not actually produced by it, the next obvious question is, what is producing them?
[SPEAKER_01]: And when testosterone really is low, what drove it down?
[SPEAKER_01]: Next week, we get into the causes.
[SPEAKER_01]: The specific, modifiable reasons, I mean, it's testosterone ends up where it is.
[SPEAKER_01]: And we come back to Mark, because the thing that produced is 240 nanogram per deciliter level is not a testosterone problem at all.
[SPEAKER_01]: It is a condition that's wife has been complaining about every night for years.
[SPEAKER_01]: As well in this clinic, probably never asked.
[SPEAKER_01]: You probably know someone who has it.
[SPEAKER_01]: Episode 3 of 4 in our Signal Book Launch Series.
[SPEAKER_01]: We'll see you next week.
[SPEAKER_01]: Everything we covered today, the HPG Access, the Saturation Model, the EMAS data, the Chaslin Trial, the evaluation standard, comes from our upcoming book Signal.
[SPEAKER_01]: The podcast gives you the conclusions and the key evidence.
[SPEAKER_01]: The book is where the complete diagnostic approach, the case studies, and the decision trees live.
[SPEAKER_01]: If you have a lab report on your kitchen counter right now, and you're trying to figure out what it means, this book is the thing we wrote for you.
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[SPEAKER_01]: I'm Dr. Jordan Viagamam, that's Dr. Austin Baraki, we'll catch you next week and every week right here on the Barble Medicine podcast.