#106 How To Increase Your Testosterone Levels Naturally | Derek from MPMD

Welcome back to the podcast. Today we're exploring one of the most influential hormones in human health and performance, testosterone. Joining me for this comprehensive conversation is Derek, founder of the popular YouTube channel More Plates, More Dates, and co-founder of Merrick Health, a company focused on personalized preventative health care. Derek and I recently spent an intensive eight-hour session together in Vancouver recording back-to-back podcasts where I joined him as a guest and he joined me. Today, you'll hear a deep dive into testosterone, addressing critical topics like testosterone's fundamental roles in men, including muscle mass, bone density, mood regulation, libido, cognitive function, and aging. How testosterone is accurately measured, interpreted, and optimized, including distinctions between total and free testosterone and why these nuances matter. identifying symptoms and underlying causes of low testosterone and understanding why two individuals with similar hormone levels may experience vastly different health outcomes. Lifestyle factors that significantly lower testosterone from chronic stress and poor sleep to environmental endocrine disruptors. Practical evidence-based strategies to naturally boost testosterone levels, emphasizing diet, exercise protocols, sleep optimization, and stress management. We also discussed an evidence-driven evaluation of popular testosterone-boosting supplements, vitamin D, zinc, magnesium, ashwagandha, fenugreek, tonga ali, and more. We highlight what truly works and what's hype. We also discussed the intricacies of testosterone replacement therapy, who should consider it, the expected benefits, potential risks, safe dosing practices, and responsible monitoring protocols. We also discussed testosterone's increasingly recognized importance for women's health, including impacts on libido, body composition, cognitive function, and athletic performance, alongside crucial considerations for therapeutic use and risk management. And finally, we have a focused exploration of testosterone's role in hair loss, the interplay with DHT, genetic predisposition, and also we discuss Derek's personal hair loss journey and proven strategies for mitigation. By the end of this episode, you will have a nuanced, scientifically robust understanding of testosterone and practical guidance on how to assess, optimize, and manage your levels effectively. 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And as always, my commitment is to deliver high quality evidence-based information free from advertising to support our continued work and to have access to exclusive content, including our members only podcast called the Aliquot monthly Q and A's that are live with me and also curated science digest that we send out twice a month. Please consider becoming a found my fitness premium member. You can learn more about that at foundmyfitness.com forward slash premium. Once again, that's foundmyfitness.com forward slash premium, P-R-E-M-I-U-M. And now on to my discussion with Derek on all things testosterone. I'm sitting here with Derek from More Place, More Dates. You may know him from his very large YouTube channel where he talks about all sorts of things, hormones, exercise, training. I became sort of aware of your work because you were on our mutual friends podcast, Peter Atiyah, a couple of times. Super interested in, you know, your own personal experience, but you also run a company that's a preventative health company that helps people optimize their hormones, among other things. And so, I mean, I'm excited to have a conversation with you. You've got a lot of this experience, you know, personal experience, but also experience just running this company where people are coming to your company to help optimize their hormones. And so it's a little bit of a different episode here. As you guys know, I cite everything on the podcast, and so I'm excited to kind of dive in and talk about all things hormones with you, Derek. So thanks for coming on the show. Thanks for having me. I really appreciate the invite. I'd love to kind of start. I want to talk about testosterone, as you know, kind of discussed this earlier. You're very knowledgeable in this area. In fact, we had a conversation and I was asking you some questions and your knowledge was very impressive in terms of the scope and depth. Thank you. All things testosterone, kind of just wanted to start with the role of testosterone in men. I mean, it's obviously fundamental for male health. But I'd love if you could kind of just outline some of the primary functions of testosterone in men. Yeah, I think at a basic level, it is the primary anabolic hormone men rely on for the sustainment or growth of muscle tissue, Bone health, bone integrity, inhibiting degradation, indirectly through some of those pathways as well, insulin sensitivity. If you have worsened body composition, it becomes more difficult to handle glucose adequately. Neurological health through the aromatization in the actual tissues themselves. There's an array of things that are supported critically by testosterone and its indirect metabolite activity as well through its aromatization to estrogen. And I guess notably but often overlooked, it's easy to forget, but in adolescence the 5-alpha reduction to DHT, so the conversion of testosterone to DHT is necessary for full maturation, sexual differentiation to basically reach full adult male maturity. And there's a myriad of examples where if DHT is either too low via genetic predispositions or through different means, then there is inhibited maturation. And that's where you get into some of these more unique intersex cases. But essentially, at a base level, this is the primary male, all but significantly impactful in females as well, hormone that is present at about 10x concentrations in males and kind of differentiates them in terms of sexual identity and male characteristics. I do. We are going to focus a lot on the role of testosterone in males and men. But I do kind of just briefly before we will eventually talk about females and women. But what is the major role of testosterone in women? I mean, women obviously don't make as much as men, but they do make testosterone, and it does play a functional role. Yeah, yeah. And, like, again, it's a non-exhaustive list that I just presented. Like, the list extends beyond into erythropoiesis, the production of red blood cells, intratesticular testosterone production, absolutely critical for fertility as well. and women all but not directly analogous intragonately but elsewhere in the body the activity of testosterone is still necessary for a lot of the same things cognitive health some level of cardiovascular support bone integrity as anabolic activity and muscle tissue all the same stuff is still the case in women just to a much lower magnitude so but similar as you would expect There's less of a concentration required to sustain a female musculature than a male. So the concentration differential is about 10x. But in women, the main function of testosterone still overlaps with males, but intergonadally it is more to facilitate as a substrate of estrogen production. So getting that sufficient amount of aromatization into estradiol, but also the conversion into estrone, which then turns into estradiol as well, to facilitate all of the female fertility-facilitated processes. So given the role of testosterone in all these important physiological processes that you just described, everything from muscle health, bone health, neurological health, red cell production, et cetera, what about the trade-offs of testosterone? And I mention this because of my interest in longevity, my long interest in, you know, life expectancy and looking at, you know, life expectancy between men and women. And you really see amongst like pretty much all mammal species that the females outlive the males. Obviously, there's a lot of differences going on there. But testosterone is something that does, you know, differentiate. there's a big difference between the levels of testosterone between males and females. So I'm kind of curious. I know you think about a lot of these things, and so I'm curious what your thoughts are with respect to the tradeoffs of testosterone with respect to longevity. I think it would be highly speculative because, obviously, I would love to just point to some clear-cut literature that says, based on these studies on, you know, inhibiting IGF-1 or having really low androgen levels equals lower body weight equals longer lifespan or something to that effect that could be a common kind of denominator, but it's not as cut and dry. I do think there is some level of metabolic resource demand that is needed to actually support the infrastructure of a male that is more intensive than a female. So I would, in general, like larger humans are going to die quicker than smaller ones, at least from what I've seen trend-wise. And in supporting that, it is something that requires more hormone production in general, which is also more intensive on all organ systems accordingly to actually facilitate and get that hormone production to the level it needs to sustain that larger human. So that's a highly speculative take on it, but that would be part of the reason. But at a high level, if you want to extrapolate to, you know, at higher levels, androgens will be neurotoxic in a dose-dependent manner past supra levels. It will cause cardiac remodeling in a negative manner, like all of the dyslipidemia, all of the negatives that you would hear about when it comes to anabolic steroid use, to some extent at supra levels are going to be present from testosterone, all but to a more muted extent because it's not a synthetic drug that is manipulated in a lab to create, you know, something that is not a substrate for aromatization and some of the other stuff that is protective. But that's a high-level speculative thing. Yeah, I mean, it's kind of a loaded question because there's probably a lot of factors at play here in terms of like the differences in life expectancy between males and females. You're pointing out the size difference is one, you know, maybe it's the lack of estrogen, right? Not the presence of testosterone, but not a lack of estrogen. Obviously, men make estrogen, but not to the same degree as women, premenopausal women. But have you looked at any of that literature? Are you aware of it? the male castrati, so the men that are castrated. They are osteoporotic as a consequence of a lack of sufficient aromatization into estrogen, and their growth plates, the epiphyseal growth plates, don't close fully because of that lack of aromatization in adolescents, which is facilitated essentially entirely by testosterone as a substrate, similar to what it is in women. But if you castrate a male in adolescence and he no longer has intratesticular testosterone production, he is now functioning off of solely adrenal production, which is like a drop in the bucket to what you actually need to function at a high level. Like you're not going to have sufficient bone development and you are going to suffer from osteoporosis inevitably. And those who don't know what the castratia are, it's really interesting. So it's individuals who had angelic singing voices. And I'm not sure where the last, who the last documented one was, but it was actually more recent than many would probably think. It's like within the last 100 to 200 years. But anyways, you can listen to them on YouTube singing and some of these old audios that were recorded. And it's, you know, a youthful, angelic singing voice that comes across as somewhat and like androgynous to some extent. And obviously going through male puberty and being subjected to male amounts of testosterone and DHT would, you know, like, quote, unquote, wreck that voice because it's going to be masculinized and get like fully, you know, the deepening that would happen. That's irreversible. So the castrati were individuals that were castrated in order to prevent them literally from going through puberty adequately. So they would actually grow into men without the full maturation that would come from androgen exposure in adolescence. And as a result, you know, they would have a lack of adequate sexual differentiation maturation, and their bones would reflect that as well via the osteoporotic outcomes they underwent. Did you happen to see that their life expectancy was increased, though? Yeah. I mean, it's like you're living longer, but not necessarily the quality of life. Notably, though, their estrogen levels are in the ground. So you saying a second ago about the estrogen. Right. So maybe, I don't know, it's interesting. Like, what is it? Well, it's definitely a lower capacity to build muscle and bone, which is less resource intensive and you're a smaller human. So maybe as a result, you are literally a walking, I don't know, like shell of a man, essentially. So you don't require as much to sustain, but your quality of life is dramatically hindered. Right. Yeah. So you live longer, but you don't necessarily want to. Right. Yeah. So that's kind of interesting. I just kind of wanted to get your perspective on that. So I'd love to kind of dive into an area that I know you have a lot of knowledge, you know, just based off of your company, Merrick Health, where you guys are really helping people optimize their hormone levels. And so I kind of want to talk a little bit about some of the best practices for measuring testosterone, interpreting the results. Because you kind of outlined some of the optimal best practices for actually measuring testosterone levels. So, you know, optimal timing, repeated measures, like free testosterone versus bound testosterone or total testosterone, right? Like what's the difference here? What should they consider? So total testosterone is the number that most people are familiar with, which reflects the total production that can be detected in your sample of blood that was taken. So floating around, how much testosterone is there, inclusive of the testosterone bound to binding proteins? So just because it's in your blood, though, it doesn't mean it's biologically active. If it's bound to these binding proteins produced by the liver, it could be either entirely inactive or, like, readily available to be dissociated, but not yet fully active as well. So you have, you know, SHBG is the primary one, sex hormone binding globulin produced by the liver. This acts as a regulator of androgenicity in the body, which is like how much androgen exposure systemically you would be exposed to. And the body has this kind of regulating mechanism to partly to make sure that, you know, females stay feminine, males stay male and regulate which tissues get which hormones when and transport it around the body. because these are hydrophobic, like they're fat-soluble and would not go through the blood to where you want them without some sort of carrier. So they have a hydrophilic vehicle similar to, like, how cholesterol will get moved around through its, you know, ApoB particles and whatnot. And these binding proteins, SHBG and albumin, comprise the vast majority of testosterone. I think SHBG is about 60% of your total T will be bound by SHBG, and then like 38% is albumin, and then 2% to 3% roughly, depending on how much SHBG you produce and some other factors, is actually free testosterone. So the free testosterone number is just like freely circulating, not bound to binding proteins, and it's like ready and readily available to be used by target tissues should it bind to the androgen receptor and cause the transcriptional activity. But in general, the two numbers you care about the most are going to be the total testosterone, which is like total production reflection. So like how much are you actually capable of making, which is important. A lot of people will just say, so look at your free, because that's like the number of the manners, because that's what's actually available to use, and that's true. But it still doesn't reflect total production capacity, capacity, which is important to assess the viability of the organ, response to the pituitary output, a myriad of things. So total testosterone, total production, including that bound to binding proteins, influenced by liver health, diet, a bunch of different factors, free testosterone, about two to 3% in an optimally healthy male. Typically, that is just freely available to be used. And then as far as measurement, kind of like best practices, typically in the morning, is the best. Testosterone is kind of, it's like a pulsatile secretion fashion. So you would see in a diurnal rhythm chart showing the secretions of testosterone throughout the day, it kind of pulses out in waves. So you would have like the biggest pulse early in the morning and then it kind of like goes, ebbs and flows throughout the day until it reaches this low point later at night. And then as you sleep, it starts to ramp back up again. So typically the best way to assess peak levels would be early in the morning, and ideally you would have not taken certain confounding variable supplements like biotin that can cross-detect as estrogens and whatnot. And typically labs will provide kind of like a guideline of what not to do, but in general the rule of thumb is, you know, go in fasted early in the morning, avoid your multivitamin probably if it has biotin in or biotin-containing supplements, and be hydrated to reflect your actual hematology profile correctly because some people incorrectly think they have an elevated hematocrit level when in reality they're just super dehydrated when they go in because they just got up, rolled out of bed, and are dehydrated from hours of sleeping and not hydrating properly when they wake up. And they just roll in and think that, oh, I'm going to have a heart attack and then I've got to donate blood now, which might not be the case. So I know that's a mouthful, but early in the morning and ideally you would get a repeat measurement before you make any sort of, especially before you make any sort of choices on a path forward, because you definitely want to get confirmation if you have a low reading or even one that's like mildly concerning. Because, again, these things can be so variable depending on so many factors that you might have a blip where it's a snapshot in time of your blood. You see, you know, a 495 total T and you think, well, that's not great. It should be closer to 1,000. That's what I hear is good in, you know, all these podcasts and whatnot. That's what my friends are at. They're at 900. Like, I only have 495. I should have way more than that. And some people have to really get on testosterone, jockingly, but it happens. And there are a lot of clinics that will tell you, like, oh, yeah, you can get that up. Let's get this up to, you know, 900. And that's all they need to give, you know, to justify it to themselves. So, yeah, you definitely don't want to go off of one reading. You want to go off of symptoms and repeat measurement to confirm your findings before you even decide what the path forward is for natural interventions and assessment of what is happening at the organ level and at the hypothalamic pituitary level. So you sort of alluded to this, like, talking about reference ranges, and I kind of want to get into that because, like, you know, there are these, like, reference ranges that you see, And I'm just kind of like curious, like how does a man navigate where their testosterone should be, what the reference ranges mean? How do you look at this? How does your company look at this with respect to age, with respect to like symptoms? Let's say someone's on the lower end of the reference range, but they have no symptoms. Or someone's at the higher end of the range, but they have symptoms. Like, how does one sort of interpret what their testosterone data shows, and how does the potential for someone who's actually hypogonadal, so people that are actually not making testosterone, right, how does that sort of complicate it? In general, I think it does get convoluted because people will see a reference range and assume, and understandably so, like there's a lot of things that people will just say, oh, target the top of the reference range because this is where you should be. And in general, it's not a bad recommendation often for things that modulate quality of life related outcomes. You know, like even when we talk about vitamin D, it's like, you know, you should probably be at like 60, even though the low end is like 30. Typically, if you were at 40, people would be like, you know, try and bump that up to 50 or 60. With the testosterone, people think similarly, and justifiably so sometimes. but often what is overlooked is the fact that the actual androgen receptor content, which is like how many androgen receptors you have in like a concentrated area, or also the sensitivity of it, like what kind of transcriptional activity do you get subsequent to binding, those things all factor into like how much of an impact the androgen has after binding to the receptor. So just because you have less testosterone than the next guy, It doesn't necessarily even mean that you have less muscle growth potential or less, you know, you know, bone support capacity or less neurological support. Like it's not guaranteed any of these things based on absolute values. It should be a combination of symptoms as well as blood values. But oftentimes, too, the blood values should be superseded by symptoms in some cases, too, because you'll have some individuals who have insensitivity at the AR. So it's not just about how sensitive are you and can you get away with lower testosterone. Some guys need higher testosterone to be able to actually function well, and they might otherwise be told, oh, you know, you don't need testosterone. Your total testosterone is 900, but they might have a, you know, super high sex hormone binding globulin that's gobbing it all up, and they have a low free testosterone. Or their actual receptor activity after binding is like subpar, or they have a, you know, gene mutation that inhibits the actual activity of it. And that's where you get into some of these convoluted cases with, like, you know, the Olympic boxer and, like, we're not going to go down that road. But some of these individuals who, like, you know, there's a spectrum of androgenic activity that is influenced not just by the total levels on paper, but it is very much dictated by your actual response to the hormone, too. Is that something that's measured readily? Like, can you measure your response to your androgen receptor activity? Or is that something that's not really known and you kind of have to do some? There are like proxies for it. In general, it's very crude the way they assess if you are one of the individuals on this like spectrum of androgen insensitivity. It's literally like manual assessments, essentially, of like your gonadal development, which is like kind of, you know, demeaning potentially if you're somebody who is like already obviously insecure about what's happening and then you're just subjected to some sort of like subjective analysis of like an expert who determines if you've had sufficient enough, like, male sexual secondary characteristic development. But in general, there are proxies for activity, and, you know, if you're somebody who has, like, if you looked at blood work, for example, some individuals think, oh, the guy with a natural, like, 1,300 total T, that's probably great. That guy is, like, an outlier genetic phenom. Oftentimes, it's a reflection of some sort of problem. Like they need to produce more to reach adequate activity. So like sometimes the body is screaming at the testes because it's not getting adequate production to do what it needs to do. And it's resulting in you shooting out more gonadotropins to make more testosterone. So typically you will see this reflected in some sort of symptom, either through actual development in adolescence being not adequate or through biomarkers. it becomes pretty clear because there will be other factors that are clearly outlier oddities in blood work when you see somebody who is not responding adequately. You mentioned the gonadotropins. Like the luteinizing hormone or follicle-stimulating hormone, FSH, what would those kind of look like in the cases where it's kind of like a red flag? Like, I mean, it's like these are very outlier scenarios that I'd be deviating into where people are like, you know, overshooting to try and meet some sort of physiologic activity. Like most guys are going to be falling into the bucket of they have low gonadotropins or low response to it from age-related decline. That's more of like, you know, what most people will find relevant. So I'll start there. in general, the thing you would be looking to first is, okay, like what are your levels, your total and your free levels? Do they look good? Do you have any symptoms? And let's just say you do have symptoms and you're looking at these numbers and they look, you know, okay. At that point, you would be looking, the actual output from the pituitary is going to be dictating what the signal to your testes is to actually produce testosterone. So the LH from the pituitary signals to the Leydig cells to make the intratesticular testosterone. So is that signal adequate is one thing to assess, and that has a clinical reference range. But also individuals who are primary hypogonadal, similar to what we talked about when it comes to assessing, you know, when women are hitting menopause, like what kind of would you look to? in men if you are not responding and producing adequate testosterone at in the testes like you will be trying to make more luteinizing hormone typically to try and push that signal so it's your body's going to recognize i'm not getting enough testosterone out of this lh that i'm making so the signal isn't sufficient i'm not getting enough testosterone and or enough estrogen from that to provide the negative feedback that tells me to stop making gnrh and the other the pituitary hormones. So I would just, it would just keep shooting and trying to like probably overshoot you into adequate territory. So you would, if you're a primary hypergonadal, you would see the reflection typically of high gonadotropins. Or you would also see some sort of like structural defects. And that's where you would get into like, you know, ultrasounding for, I think the prevalence in males is like 15% of males have a varicose heel. I don't know if you know what that is, but it's like varicose veins in your testes essentially. And it looks like like twisted, kind of like the same thing you would see in varicose veins in your legs. It's like in the side of like the testes and it inhibits thermoregulation and significantly impedes testosterone production locally and fertility. So that oftentimes, well, 15% of men from what I recall is the number for prevalence, pretty significant though for something a lot of people don't know exists. and if you are doing all the lifestyle stuff and it's not working and you think you're doing everything correctly and you must need testosterone sometimes it can be overlooked that there are structural defects so typically the first thing you would look to is like am I capable at the organ of responding to the signal and is the signal adequate to begin with because if there's a primary hypogonadal outcome it would be some sort of structural response problem in the testes themselves If that's not an issue and you've ruled out all structural problems, age-related decline is not a factor, and otherwise everything's all accounted for from that angle, you would look upstream to the pituitary and say, okay, well, at that point, am I producing enough LH and FSH? And this is typically the outcome you would see in men, not always, but a lot of men who are kind of not sure if they need testosterone, they'll have like a relative proportional inadequate signaling driven through a myriad of factors, including but not limited to lifestyle, some age-related decline, toxins, exposures, a myriad of things. And that's kind of like where people have this opportunity to try and incrementally maximize all the areas in their life to try and improve the output. Because if you have sufficient functioning organs and your output is just insufficient, you might be able to get that up to snuff to where you need it just by getting leaner, losing body fat, fixing your diet, addressing micronutrient deficiencies, quitting smoking, not drinking anymore, fixing your sleep, you know, all the smorgasbord of things. Yeah, that we're going to get into a little bit, but okay. What about the sex-binding globulin hormone, S-B-G-H? S-H-B-G, sex hormone-binding globulin. Sex hormone-binding globulin. What about the sex hormone-binding globulin? You're talking about if you have a high level of that and it's bound up to your testosterone. So a couple of questions here. What regulates those levels? and what regulates, like, how much of that testosterone can then get away from that, you know, binding protein and then be used to, you know, obviously exert hormonal activity. So, you know, can you, like, dial in looking at just that binding protein itself to help kind of solve some issues? Yeah, and it gets really complicated in this regard because what a lot of people don't address is, So DHT, dihydrotestosterone, mentioned earlier how it's like the primary hormone that will determine if you reach full maturity in adolescence. It will still be markedly male probably if you have adequate testosterone production, but you won't get full maturation if you have, you know, zero DHT from a defect in the enzyme that encodes for 5-alpha reductase or something. But that hormone, the most androgenic hormone in the body that essentially determines if you fully masculinize or not, where you end up with a micropenis, that has a much higher binding affinity for SHBG than testosterone does, and then testosterone has a much higher binding affinity for SHBG than estrogen does. So even though on paper we're talking about the importance of free tests versus total tests, which is very important, also very important, which most people aren't going to test in their blood, is the DHT level that males will rely on through adolescence and to some extent in adulthood potentially, depending on their test levels, that is going to get gobbed up even more proportionally by SHBG. So if you have high SHBG, not only is your free test potentially inadequate despite adequate testosterone production, proportionally your free DHT, which is like the main androgenic hormone, is like way more gobbed up. And this gets really rough in females because they, a lot of them, are using things like combined oral contraceptives, which crank SHBG through the roof, through the liver interaction with the combined oral contraceptive pills, depending on which drug they're using. In general, ethanol estradiol plus some progestin, depending on how androgenic the progestin is, it'll depend on how much the SHBG goes up. But you'll see in adolescent women or women who are in full adulthood that are taking combined oral contraceptives, their total testosterone will suppress upwards of 50% to 60% and frees testosterone upwards of like 70% to 80%. So they're walking around like borderline asexual, castrated by a pill essentially. And that's only with oral? That's with oral, but like any sort of progestin that is synthetic will have negative feedback to some degree, all but much lesser so via a localized IUD releasing a level of nodrodestral or something, and you're not having to take that supporting estradiol that comes compounded into it. So it depends on the format, but a lot of girls are still using the combined pill. So it's just worth noting nonetheless that when these SHBG levels are skyrocketed or even like high on, you know, a clinical reference range, if you are somebody who is like moderate, you know, T production or low normal or whatever, like the proportional hit to your DHT getting gobbled up could be like the differential between you being symptomatic versus not, as well as your free T. Even though it's proportionally less gobbled up, the DHT could be, like, nuked entirely, essentially, via the SHBG levels being high. Since we're talking about the SBGH levels, I kind of want to, like, what is their lifestyle? So does age regulate that and also, like, lifestyle factors? Yeah, so, like, a common thing that people hear is when you get 30 years old, your total testosterone will decline by 1% per year. but the reality of what makes this even worse is your SHBG levels will increase year over year proportionally faster thus making the velocity of free testosterone decreases dramatically more so proportionally so even though total test decreases by one percent a year your free test will decrease by up to two percent per year and that's the one that you need to like do stuff in the body through like freely circulating activity so it's very important and very relevant for dictating what activity you have in different tissues in the body because it's ultimately the only one that can actually bind to the receptor and do what it's supposed to do. So the SHBG levels will be dictated by age, will be dictated by liver health to some extent, will be dictated by other medications, especially oral formulations. Insulogenic signaling as well is hugely implicated. If you're on a ketogenic diet, you can absolutely expect your SHBG levels to be through the roof and your free test to be much lower. So carnivore diet guys, there's a reason they eat fruit now. It's because their free test levels are all shit, and their total test levels were high, and they thought it was fine. But in reality, they had, like, borderline hypogonadal free test levels often because they were overlooking the fact that insulogenic signaling is needed to actually get SHBG to a meaningfully reasonable level for a male. And this is also something that would be relevant for females too, right? Yeah, and these binding proteins also exist for other hormones in the body because they all function in similar ways through cargo systems and transport mechanisms in the body. Like, you will have binding proteins for IGF-1. You'll have binding proteins for thyroid hormones. Like, it's not uncommon to see people with, like, normal on-paper levels for certain hormones, but then when you dig deeper, all the free hormones are, like, proportionally horrible because they're all bad. Like, the total production looks okay, but it's because it's factoring in all of these, like, bound-up hormones that are, like, unusable, essentially. Is that something that's common? Like, I mean, would you say that's? It depends on the person and lifestyle. So, but, yeah, probably, especially among women because, like, you know, a lot of them are, you only have so much androgens to work with to begin with. Like, your production is, you know, a tenth of males, typically. and then if you are occupying all of your androgens because you know essentially the shbg is going to with a much higher binding affinity mop up all your dht and testosterone not all of it but like a significant amount of it if it's high in any like higher than it should be like it will impact your like free androgenic signaling so significantly that might put you into like the you know female hypogonadal equivalent territory, essentially. So you could be like, it's not uncommon for girls to walk around borderline asexual or like literally no drive throughout their entire adolescence, 20s, 30s, and think it's normal, and it's just not what they're supposed to be walking around like. So in other words, like if they have, if their libido is like totally down, perhaps like they're having a harder time losing fat, gaining muscle, losing fat, it might, it could come down to this, right? Bone integrity? Bone integrity, right. Yeah, so that sounds like... A bit lesser so depending on if they're on, like, obviously, you know, if you're on a combined role contraceptive pill that has estrogen in it, you know, however much it does that to what dose, you know, you get into the nuance. But ultimately, like, you're inhibiting natural hormone production quite dramatically through a myriad of means. Like, think about guys who are just, like, natural having to deal with what they deal with as is, you know, the sleep impact, the cortisol impact, the fat impact of being, you know, obese. And then if you have women who deal with all those same problems, you're going to have all the suppressive results of all of those lifestyle things, the diet, the nutrition, the whatever. And then you also factor in medications on top of that, too, that maybe men don't typically have to take to, you know, achieve contraception. Like, you know, that's typically often, I think, the final blow that will, like, push women into, like, you know, closer to low-drive territory often and almost certainly lower quality of life for a lot of them. Now, that's not to say, because I think this gets misconstrued often, is it's not to say don't use contraceptives at all. There are absolutely better ways to go about it. I'm just giving examples that I see as commonplace. No, no, this is great. This is great information. Since we're kind of talking a little bit about symptoms, let's kind of circle back to talking about what are the symptoms of low testosterone. you know we're talking about men here but like we talked about libido muscle mass like what are what are like the classic symptoms that men should be looking out for is it something that's hard to differentiate between okay this is testosterone or other things it does get tough because as you would imagine a lot of the lifestyle related things that lead to low testosterone will come with the decrement to quality of life just via, you know, if you have poor sleep, like you're not going to feel great because you didn't rest enough. And then you add that on top of the inhibition of, you know, your output of gonadotropins, pituitary hormones, and response to them as well. Like it's like a one-two punch off in a lot of this stuff. So in general, I would look to things like libido, erection quality. Obviously, that's more, you know, circulatory often, but still notable nonetheless. If you suddenly, you know, if you're not mourning wood anymore, like you got to look into it regardless if it's circulatory or hormone mediated. Might be a combination of both. You no longer are able to hold muscle as easily or build muscle as easily. You're, you know, losing strength in the gym. Your recovery capacity is inhibited relative to what it was when you were younger, mood dysregulation, irritability. And these are all like really general vague symptoms. And I would love to just say, oh, look at, you know, this exact thing will happen. But in reality, it's often a constellation of things that comes as a vicious circle effect of the, you know, factors that led to that deterioration of testosterone to begin with. or if you were just, you know, never had reasonable testosterone to begin with, you would have probably not gone through puberty adequately to begin with. So, like, the genetic factors, like, some of these, like, more outlier cases become a bit more obvious because it's like you just never really, like, fully masculinize in adolescence. You may have a higher voice. You know, a lot of those things are less relevant for the average person. For the average person, it's going to be more of these general symptoms, and it's warranted to get a test at that point and just see what's up. Right, yeah. So then that in combination with the test and things that we just talked about is kind of like where. Yeah, like pre-diabetic, you know, progressing towards, you know, pre-diabetes, insulin resistance. A lot of this stuff is going to be ultimately determined by blood work, though, because a lot of people aren't going to be able to identify this autonomously reliably. So that's kind of where I'd point to the more vague stuff, like the quality of life. Like, do you notice a blatant deterioration with no other factors changed? erection quality, you know, libido, vigor, muscle mass, strength, fat, body composition, stuff like that. So you mentioned by age 30, total testosterone decreases by about 1% per year. And then you mentioned even... In general. In general. Right, right. On average. Like, yeah, exactly. And that's where I'm going to ask you. I've absolutely seen 70-year-olds with, you know, 900 total T's. So the question is then, like, there are lifestyle factors that really can sort of modulate that, you know, general decrease or not. So maybe you can accelerate it or maybe you can slow it, right? And I kind of want to dive into some of those lifestyle factors, like what should men avoid or try to minimize in terms of their environmental exposure or lifestyle factors that are known to accelerate the decline in testosterone and or increase the binding protein so there's less free testosterone, right? anything that's going to necessarily regulate the ability of testosterone to exert its function, essentially. I would love to bang out an exhaustive list, but forgive me, I guarantee we'll miss something. But, like, alcohol, you know, the direct toxicity effects of that does inhibit actual steroidogenesis in the testicles themselves. It will also impact sleep dramatically, which has the vicious back end effect of, you know, inhibited output of signaling hormones, which indirectly will also impact body composition, which, you know, the whole downstream cascade of that. Smoking, obviously not helpful. How much alcohol? Is it like any amount or like light drinking, moderate drinking? I think like obviously the safe answer for me is to say no drinking. I think it would be more like a dose-dependent toxicity effect, and what is your capacity to handle it? Because ultimately the testes are very affected by oxidative stress, and if you're not capable of handling that adequately, like it will reflect in your inadequate output of hormones locally. So I would love to give like hard and fast numbers, but there are a lot of people who will be able to get away with like murder and probably be okay. there are some guys who like you might be low normal uh function to begin with and like that you know couple drinks a week like you know throws off your sleep a bit and kind of pushes you over the edge like it all depends um it is very much a spectrum so like going from like optimal to like blatantly hypogonadal from a symptom perspective it's not like it's just on versus off like it's your way there is a you know it's a transition of you know shittiness as you arrive to that like worst case scenario. So other things I could point to, if you have a totally fat deficient diet, I think that's, you know, of a macro distribution that would be reflective of something that's almost certainly going to hinder your capacity to produce hormones. Also, if you have a void of carbohydrate intake diet, it would also be something that would inhibit freely circulating hormones from liberating themselves and lack of protein. Like you would not be able to produce, you know, get as robust of a response recovering from workouts and be able to build muscle, which indirectly is going to improve body composition and improve your hormones as well. So it's all kind of like balanced diet. Don't eat bad. Micronutrient intake. I could definitely point to if you're deficient and not every mineral or vitamin is going to be, you know, game changing, dramatic impact on your test levels. But things like zinc, magnesium, vitamin D, like these all have a marked impact on your testosterone, either response to it or capacity to produce it. Or even like like you mentioned our podcast, a conversion of vitamin D into active vitamin D. Like you might think you have adequate vitamin D status via your dose you're taking that's super high, but you're not actually utilizing it, but you think you are, and that's impacting your testosterone production and your response to it at the androgen receptor itself as well. So I think from a minerals and vitamins standpoint, the low-hanging fruits are typically going to be like B vitamins, but in particular like from a mineral side, you know, you have, you know, magnesium, zinc, and the vitamin D3 are going to be three things that specifically on top of the minerals and vitamins that everyone's familiar with from multivitamins and whatnot are more difficult to get in adequate doses. All but zinc is typically adequately in many multivitamins, but magnesium in particular almost never is because of the weight of it. You would be having to take a multivitamin that's like 8 to 10 capsules otherwise, which just nobody does. And then the vitamin D, it's fat soluble. Typically, you're going to have it in like a soft gel or something. and it's not always going to be at the dose you need in the multivitamins. It's just worth noting. So those are just some low-hanging fruits that are, if you don't look to those as part of your micronutrient optimization strategy, like you could be overlooking low-hanging fruit that, like, is a deterioration of, you know, 100-plus nanograms per deciliter per deficient micro, potentially, depending on how severe the deficiency. Other things I get a point to, being obese, like the worst one probably that I probably should have mentioned first, but is like so dramatically impactful on your negative feedback to the hypothalamic pituitary axis. So by that I mean men who are obese and women, if you have a significant amount of fat, it is going to elevate your aromatization, which is, you know, your conversion of testosterone to estrogen, and this is more impactful in males because of how the brain gets signaled from estrogen, not testosterone, directly as significantly. There's a bit of a nuance there. But in general, you need adequate estrogen to tell your brain, okay, we're good. You don't need to make more testosterone because I have enough estrogen. That kind of like the downstream cascade of these metabolite conversions is you produce testosterone in order to produce other things too And the estrogen is a very potent mediator of telling your brain we good And if you have a significantly elevated amount of estrogen being converted from your testosterone that you make because of how much fat you have, you are basically achieving the proportional increase in estrogen that is much higher than the amount of testosterone substrate that led to that conversion. So you have that signal telling your brain, okay, we're good, but the amount of testosterone you actually had to begin with was not good. So that's problematic. People who are obese have upwards of, I would love to give hard and fast numbers, but it could be like significant, like half of a reference range maybe. It could be the differential between you being the quality of life of you're fine versus you're blatantly in, you know, severe deficiency. And what else could I point to? What does weight loss do to those levels? Like if you are someone that's obese and then you lose weight, does that bring you back? Yeah, as long as you are losing ideally like visceral fat and like overall fat loss is going to be very supporting of getting that ratio back into balance of your estrogen and the amount that's converted to estrogen, estradiol in particular. And once that balance is favorable because you are leaner, you will have a balanced amount of feedback to the brain that then regulates, like, the perfect homeostasis between, okay, now we have adequate testosterone and estrogen. So you'll actually notice more testosterone being produced because it realizes to get this signal that we deem adequate, we had to produce more testosterone to get that amount of estrogen. So there's this Goldilocks zone, of course. You can't just, you know, become, you know, a malnourished, you know, low, like, bodybuilder, shredded person and just continue to get this elevation and proportion. At some point, you will end up essentially starving your body of the nutrients needed to actually support hormone production. But in general, you know, guys who are, you know, like 12 to 15% body fat-ish will find that they have an increase in testosterone dramatically relative to when they were obese. And it's like super significant in how much it will improve hormone status. So, and then the sleep, I think I might have already mentioned that. Yeah. I definitely want to dive into some of the diet things in a minute. But I wanted to ask you about a couple of things with respect to maybe factors to avoid. what effect does excessive endurance training have on testosterone? Because I thought I came across some literature where it was a negative effect, and I wasn't sure how robust. I think it is pretty dramatic, pending, and exceeds your capacity to recover. So that sounds like a weird way to answer the question. Some people have a higher tolerance for stress, and that's reliant on a bunch of different factors. But if you are somebody who is not fueling yourself correctly to handle that amount of endurance training, like you were, let's just say you're in a calorie deficit and you're trying to be like, I don't know, six-pack shredded for the summer and like look as good as possible, but also fuel your like endurance event efforts, like you're probably like not doing two, you're not doing two birds one stone. Like you're doing two things like inadequately, almost certainly, and malnourishing yourself and ending up in a state of hormone deficiency as a result. Probably. Like you see in studies, there are cases that you can point to of what happened to natural bodybuilders as they diet for a show. And you can see in like as they start to get closer to stage ready, which is like the most shredded, basically any documented human gets, essentially. The requirement to get there is a state of malnourishment, essentially. and at some point, typically, once you start to cross into that, like, you know, single-digit body fat threshold, you start to become so malnourished that you are inhibiting your actual capacity to produce hormones adequately, and you almost enter into, like, you know, preservation mode slash, like, hibernation or something, and it's kind of just, like, save yourself. We're starving to death. Like, how do I stop everything metabolically taxing from happening? Let's shut down all systems, nor do we have the substrate to actually produce these hormones. hormones to begin with. That's kind of what happens when you get, like, really, really malnourished. And with endurance running, like, I've seen guys out eat, you know, 5,000-plus calorie per day diets when they're doing, like, really intensive endurance activity. So if you are not fueling adequately and with the right fuel, micronutrient density, macro allotment, how much of it is, like, carbs versus fat versus protein, yeah, you could absolutely exercise yourself into a state of hypogonagism easily. I kind of, like. I would caveat not easily. It's hard to train that hard. Right. Yeah. No, it's definitely not easily. Like, there's not a lot of people that are. Kudos to the people mentally strong enough to do that, I guess. Well, I kind of think of the analogy here for women. It would be like when women are excessively endurance training and in a severe caloric deficit and they become amenorrhetic, right? Exactly. So they're essentially not ovulating anymore. And, in fact, you mentioned, like, wanting to get shredded for the summer. Well, I actually in my 20s was doing this very thing where, I mean, I was running like 10 miles a day and I was eating like carrots and hummus. And that's it. You know, I was like not fueling myself, like hardly any fat. You know, it was very like very sort of like low protein, you know, low fat diet. And I definitely got shredded ish. But like I became a bernardic for several months, you know, where I just didn't get my period. and so it wasn't ovulating. And so I had to add back the calories in the food. It was like, and it took a while before my body kind of like recalibrated. But I feel like that's kind of like the analogy that like women, it is. It's like your body shuts down. It's like, okay, I'm not getting enough calories. Reproduction is not essential right now. Survival mode, right? Not reproductive, like happy growth mode. It's like survival mode. And, like, some people might not even realize how significant of a deterioration in hormone production I'm talking about. Like, to give context, men who are dieting for bodybuilding shows naturally, it is not uncommon to see the end result of a hormone profile on, like, the last week, them to look more female on paper than, like, their girlfriend. Like, that's how low their testosterone levels are. That's wild. Yeah. That's wild. Just to kind of sum up the, like, factors to avoid. Not always, but sometimes. I wanted to get your opinion on endocrine disrupting chemicals. Like, how have you or has your company looked or seen anything or do you have any speculation to, like, what the scientific literature has shown in terms of them affecting hormone levels? Yeah, I think we're pretty convinced that there is an effect. It's just the magnitude at which you often see hyped up, I think, maybe over-exaggerated. There are low-hanging fruit things to absolutely avoid, like don't use plastic Tupperware and heat it up and stuff like that. Try and use glass when you can. Try and ensure you have high-quality air, if possible. Pollution, I think, is a big factor for your body's capacity to deal with stress and, like, the allocation of resources to be chronically dealing with a toxic environment will inhibit systemic, like, broad systems. Water quality, like, if you can make sure you have, like, decent water, it's got to be solid. But as far as, like, the actual magnitude of impact of those things, for most people I think is going to be relatively negligible in contrast to, like, the obesity, the diet, the exercise, the sleep quality, the potential carcinogens that might be exposing themselves to, you know, some of the lifestyle stuff is, like, way more important to be addressing as, like, the base infrastructure before you start thinking about, like, oh, it must be my, like, shower that is, like, shooting chlorine on me. Like, it must be that. Or, sure, get a shower filter, but like it's not going to be the game changer. I do think avoiding like the basics though, like, you know, switch the glass where you can, don't use plastic water bottles, stuff like that. And there is blatant evidence showing interactions with estrogen receptors with some of these compounds as well as androgen receptors, which in turn will impede the ability of the actual hormones you produce to bind to those receptors and do what it needs to do. So you're like essentially competing with yourself for activity in the body. Like you're, you know, competing with these like, even if they're like moot activity compounds, they still act as like anti-androgens or anti-estrogens via their occupying of receptors. So to whatever degree they are, doing it at all is not ideal because it's inhibiting like space that could be occupied by actual endogenous hormones that you need to produce and need to work properly. And you don't want to be competing with like environmental toxins to like do things in the body. What do you hear? Like, I often hear from many people, popular, you know, media, as well as just people I speak to or comments that I read about testosterone levels being lower now in men than they have ever been. For one, like, is that true? Do you think that's true? And two, like, what are some of the major contributors? Is it obesity since obesity is rampant? I mean, or is it just like everything that you mentioned all sort of like compounding together and not necessarily just like increasing, you know, BPA and plastic, you know, endocrine disrupting chemicals that are now a lot more prevalent than they were, you know, 60 or 70 years ago? I did a video a while ago on like the earliest finding I could find of recorded testosterone levels in, I think it was like military soldiers or something. One thing that I think is notable is the actual detection sensitivity of testing is absolutely much different now than it was, you know, 60 years ago. So to contrast, like, oh, the total test of some guy 60 years ago versus now is equivalent even on, like, a testing methodology basis is, like, flawed to begin with because it's probably not an accurate comparison. But is there a trend downwards? I would say yes, and I think it is mostly dictated by the obesity, the diet, the lifestyle stuff. So, you know, like there's obviously things to deal with in the environment that are less favorable and are not supportive and probably not benign. But, like, in general, I think most people that worry about this stuff, they would be put their mind at ease by dialing in everything else, which is not that hard to do. It's often free or, you know, cost less money. You're eating less food. you know, go to the gym, et cetera. I'm not saying that's easy to do, but like dial in your basics. And once you do that, you have like an increase, you have your baseline. Let's just say you get a blood test and you see where you're at. From there, you can start doing some of the minute changes, like putting, you know, a chlorine filter on your shower head, do this, change your water source, whatever. Do you notice an incremental uptick in your gonadotropin output or your response to it at that point? If yes, like, okay, maybe it was a meaningful change. But like until you do that, like you're kind of just taking shots in the dark, assuming all of these things are, you know, occupying your mental bandwidth and concerning you that may not be worth your concern to that degree. Does chlorine have an effect on testosterone? I don't, I don't like. Maybe. Okay. Yeah, I think, I think more of like BPA, but, um, and consuming it like, or like you said, hot, like heating up the plastic or like hot beverages, like going into like something plastic. But, um, yeah, I, I agree. I think that these lifestyle factors are paramount. And I'd love to kind of get a little bit more into some of those, particularly like, so you've already mentioned the diet. And I'm kind of, you mentioned protein, fat, carbohydrate, you know, like, so what, what, what, why are some of these important? So fats are important to make, you know, the backbones of hormones. Maybe we can talk just a little bit about like why low-fat diets and why people should be incorporating fat into their diet to make sure that they're. Yeah, like in general, it's not like if you have, for example, if you ingest cholesterol, it doesn't necessarily mean you're going to have like a dose-dependent elevation in your like serum cholesterol, as I'm sure everyone knows here. But there are like certain baseline requirements to serve as the substrate for producing cholesterol-derived steroids in the body, and these are all ultimately derived from cholesterol and then get cleaved and manipulated through enzymatic processes to make all the hormones in your body, including but not limited to testosterone, estradiol, et cetera. So in general, it does seem like having a sufficient amount of fat is worthwhile and does seem to impact how much hormones you can actually produce. and the carbs for actually mediating, and this is going to depend on activity levels, how demanding of exercise you do, if you burn through them versus not, if you're sedentary versus not. But in general, the insulogenic signaling is somewhat necessary to facilitate a balance of free androgens, including free other hormones in the body that often go overlooked, to actually do what they're supposed to do, because a lot of people won't even measure the free levels of, you know, like the IGF-1, the, you know, the T3. Like, you know, some of this stuff gets, like, hyper-nuanced when you get into what hormones are actually bound up that you don't realize. Estrogens, DHT, et cetera. So having a balanced diet and then the protein, like you mentioned, from, like, a mechanistic perspective, like, I think in general these things all serve as building blocks is the simplest way I can put it. and having a deficiency entirely of one or the other, it's just like it's kind of the expected outcome. Like it's often not going to be ideal to be missing something entirely that your body utilizes for critical, you know, structural things. Well, it's interesting. I learned something from you because I, you know, I was aware of the importance for, you know, of fat, particularly like, you know, a certain amount of saturated fat, which is known to increase endogenous cholesterol production. but the carbohydrates and the insulin response and like having that insulin action or response like and I didn't realize that was also important and you know especially for the free you know hormones like the amount of free hormones so it's interesting to think about like a ketogenic diet you know as you mentioned like some people can really be in a problematic state if they're on a ketogenic diet and their free testosterone just kind of tanks. And it's not to say that it will absolutely happen. Like, I'm sure there are a lot of people that thrive on long-term ketogenic diets or may even clinically require them. So, like, I certainly don't want to come out here and suggest if you're on a ketogenic diet, stop doing it. Like, talk to your doctor first, obviously. It's just, like, mechanistically, this is what happens if you have a lack of insulin signaling, you will have less capacity to suppress the binding proteins. Well, what you're saying is, like, get your hormones measured. measure them right and make sure that you're monitoring that. Yeah, be informed before you freak out about anything. Right, yeah. With respect to other sort of lifestyle factors that can maybe boost testosterone, so we're talking about dietary factors here. What about exercise? Resistance training is one that comes to my mind when I think about trying to boost testosterone. I mean, is there merit to that? Is that something that moves the needle? Yeah, I think it's kind of like the simplest way I could put it is like descending order of intensity essentially so like you know weight lifting at the top and then you have like um some of your more like hit style workouts underneath that and then at the bottom of it would be like the most basic of i don't know barely exerting yourself but like getting out there and moving that is going to have the least impact in general and at the top it's going to be you know the muscle building facilitating processes the things that build bone etc resistance training that's going to be the most directly impactful, but ultimately it's also going to be what is the overall exercise regimen that you adhere to? Because a lot of people, the problem is not even necessarily like, oh, it's the perfect thing. It has to be something you enjoy enough that you'll adhere to it. So it's like adherence almost trumps optimal in some capacity. So like get the thing you can adhere to, the diet model that you can adhere to. Like a lot of people, the diet that on paper is the best, it won't be the one that you stick to for more than like six weeks. So like don't do that one if that's the case because you're not going to stick to it and then you're just going to end up where you were before. So calories trump everything, unfortunately, you know, or fortunately, because it gives you a lot more versatility with like your choices, I think. It's not like you're stuck in a myopic kind of, you know, box of I have to be on like the Mediterranean diet or I have to be on the carnivore diet or I have to be on the vegan, you know, the whatever. there are a lot of ways to skin a cat, and ultimately it's going to come in mainly from energy balance and then also from there optimizing for, you know, having adequate protein, fat presence, carbohydrate balance to support your, you know, whatever exercise you're doing and the intensity of it and all the things underlying that. With respect to some of the micronutrients, this kind of gets into the supplement area as well, but you mentioned some important ones that I've also kind of like come across in the literature and that being vitamin D, zinc, magnesium. Can we kind of just dive a little bit into their effectiveness? Like there's like, is there human data on it? Like, do you know anything about how they're working? I mean, I've seen, I've read some of the human studies, particularly on the vitamin D and like getting like higher dose vitamin D supplementation, improving testosterone. But I mean, I'd love to kind of just take a moment to kind of talk a little bit more about that if you want? Yeah, like in general, I think the most reliable things that move the needle if you were deficient is, I don't know if people are familiar with the ZMA. It was like the first combo supplement that was sort of seen as like a testosterone booster that was available on the market. And it's zinc, magnesium, and I don't remember if the A was something else, but vitamin D is the third thing. I don't remember what the A stands for. But those are the three things that move the needle most reliably that are natural. You, you know, otherwise would get through your diet, but likely non-sufficiently. Maybe zinc you might, but like magnesium, pretty difficult, I would say, for a lot of people. They don't realize how deficient they are. And then even like supplementing accordingly, it's like, you know, getting one that you respond, that you tolerate well with your digestive system, has the yield that actually produces enough magnesium from, like, the elemental weight of the supplement, which is not that complicated. I don't want to make it sound super complicated. Like, a lot of them are fine. Miranda has great articles on magnesium formats that are bioavailable and yield more than enough magnesium. And, yeah, the vitamin D, having an adequate amount, making sure you're converting it and actually getting the activity from it. But mechanistically, there is some level of, like, gene transcription capacity facilitated through these, like vitamin D is a hormone, for example, and it does also affect androgen receptor activity and some, like, the capacity for androgens to do what they do, not just, like, the production of the amount of them. So similar to what I talked about earlier where you have this kind of, like, receptor interaction, how well can you actually utilize these hormones to do the things it needs to do in the body, some of this is going to be facilitated by the adequate minerals and hormones for vitamin D supporting it. And it's not necessarily measurable as much like directly, but all you can really do is like backfill accordingly to hit your needs and then assess your kind of like proxies and your blood work and your symptoms and kind of go from there. In your opinion, like let's say someone is on the deficient range of vitamin D, their inadequate magnesium, perhaps their zinc is, you know, maybe okay or in the inadequate range, would getting to that sufficient status really move the needle with respect to, like, testosterone? I think if you were on the low end of the reference range or literally hypogonadal and you were clinically low or deficient for those, depending if it's all three or not, because obviously there'd be an additive effect. Most of them are. I mean, at least vitamin D, magnesium, pretty common. Yeah. Yeah. I would say, like, you're looking at probably a potential incremental difference of 100 to 150 total T, maybe. It kind of depends on the person, of course. Like, I've seen more robust response in some studies, but I also don't want to, like, over-exaggerate the expectations. But it is meaningful. Like, it's something that happens. And some of it can't be directly measured either. Like, we're talking about the total T number, but it's like, how do you know how much your deficient vitamin D is impacting your ability to, like, use it correctly? And then even if you had the sufficient vitamin D, the magnesium impact on all that and the DNA interactions and whatnot, it's like, you know, you'd be speculating at best. And then there are some other more, like, tangential supplements that are not as, like, obvious no-brainers that are helpful. They're just facilitating mechanisms that are not like this is the vitamin you need almost regardless of what your test levels were kind of thing. Yeah, I'd love to talk about those. I mean, you hear some of these herbal supplements and like some of the ashwagandha fenugreek with Tonga Ali. I mean, let's dive into that. Like, are they effective? Which ones are effective? Which ones are hype? Yeah. I think one that I would be worth mentioning, all but the literature isn't super robust. It is boron, so that potentially has a suppressive effect on SHBG levels. There's some literature that looks promising, all but I wouldn't hang my hat on it and say it's a guarantee. It's going to suppress your SHBG from, like, the hind of the reference range to something that's, like, much more, you know, much better. but like it may, it does seem to work for some people. And in general, it can be a supporting adjunct that some people are, it's not something you typically get through your diet and like significant quantities anyways. Like often people will, it'll come into multivitamin typically, but the quantity that moves the needle for SHBG, I believe it was like six to 12 milligrams and can be meaningful for actually liberating free testosterone, not for actually producing more total T. The other one that's probably worth mentioning, So ashwagandha, specifically extract that is standardized to a sufficient quantity of withanalyze and not just your standard run-of-the-mill generic ashwagandha. You want to look for ideally a patented, you know, Sensoryl or a KSM-66. These are patented formats of ashwagandha that are standardized to a target yield, so you know that what you're getting is what you're supposed to be getting rather than relying on certificates of analysis from China of a generic extract. What was that compound or standardized to again? With analytes. Okay. It'll show right on the label. It'll be like Aspragonda bracket standardized to X percentage with analytes. And depending on if you have KSM-66, that's 5%, Sensorial is 10%. the difference between why you would pick one or the other is the actual total dose. You could get away with using less milligrams of the case of the sensorial because it has more with analytes per milligram inclusion in your product. But they're both like impactful. Is that the active compound that affects testosterone? Yeah, it seems to be. And when I say testosterone, it's like the indirect effect via suppressing cortisol seemingly and kind of like the stress response manipulations that it can induce, which are favorable for people who are anxious, who have very stressful lifestyles, who could benefit from it, but it is not a catch-all supplement that will benefit everyone. And some people, it will push them into anhedonia territory, which is like a numbing of emotion. So you don't want to... Really? Yeah, if you overdo it, it will like literally suppress your stress response so significantly that everything is just like black and white. What's a dose that would be considered overdoing it, and what's a dose that would maybe be effective for suppressing the cortisol response and indirectly affecting testosterone by not having the cortisol decreasing the testosterone? Like, I would go with the clinically, like, supported dose for something that's efficacious. I wouldn't necessarily suggest somebody, you know, take something that's lower than what I've seen to actually work. But in general, it seems to be a cumulative effect over time. Maybe there are some people who might push you over the edge sooner. And, like, certainly it's something to be cautious of and be aware of as a disclaimer before you jump on any testosterone, own augmenting supplements just be aware of the mechanism of how it works based on your own individual biochemistry because it's not something like a vitamin d that you can just sequester into sub-q fat and just like get rid of at some point it's like it could impact your mood regulation quite significantly for a bit depending on like what your neurotransmitter balances at baseline like if you are already borderline like emotionally numb as a person and you take ash for a gun though like you might literally like cease to care about anything for all I know. That sounds awful. Yeah. But I mean, for someone who is more of an anxious phenotype, like 600 milligrams, I think is the dose, but double check on that because I might be misremembering. Right. I'm pretty sure. And that is impactful to the tune of upwards of another 100 points. Seemingly, I could be misremembering exactly, but it's like I think it's triple digits pretty reliably for those who can benefit from it. And for some people, it's like a game changer supplement that really improves their quality of life outside of just the testosterone enhancing capacity of it because some people deal with a lot of stress in their life and need that extra resilience or suppression of how much it's affecting their mental state like some people they can't even get to sleep because they're ruminating and they're constantly anxious and having that kind of suppressed uh stress response can be very very net beneficial and then on top of that improves their sleep and also improves their testosterone through the uh reduction of the kind of like glucocorticoid responses. And, yeah, so it works for sure. The literature seems sound on it. Some of it is funded by some of these companies that do have the patented extract, so just be aware of that. But at least from what I've seen, blood work anecdotally, too. It seems to work. Tonkat Alley, another very notable one. This is one that works for a different mechanism. It seems to be a bit more speculative how it works, but it seems to do a few things potentially. One being a minor CIRM activity potentially, and this is more speculative. CIRM is like a selective estrogen receptor modulator, so something that binds to estrogen receptors and either positively or negatively modulates them in selective tissues. So there are certain tissues that would be more favorable to have a selective inhibition of certain hormones versus others that would be detrimental. like you wouldn't want to inhibit estrogens of activity in bone, for example, because that would cause bone degradation. Having an inhibition at the hypothalamus level may, depending on the person, help increase testosterone via the inhibition of that feedback loop. Now, I don't necessarily think it is a CIRM. That's just like the tertiary potential mechanism, and it is speculative. The main mechanism that people seem to agree on that it does do, suppression of SHBG to some extent, as well as the upregulation of steroidogenesis intratesticularly. So like locally upregulating, I believe it's steroidogenic acute regulatory protein that basically incorporates cholesterol into the mitochondria to actually undergo these enzymatic cleaving sequences that result in the production of testosterone locally. So it seems to, like, help upregulate the process that actually enzymatically spits out testosterone, essentially, locally. So that one seems to work well for individuals who have high SHBG levels or potentially higher estrogen levels than they, you know, is otherwise fixable via basic lifestyle changes and whatnot. Because everyone has their own proportion of metabolism at the end of the day. It's not always going to be optimal, even if you have what is otherwise, like, a great diet and lifestyle. But also, it's just, like, I think it's for people who have adequate, everything looks on paper to be sufficient, but their SHBG might be a bit high, or they could use a little bit of a boost. And it seems to work to the tune of 100 to 200 nanograms per deciliter for some people. And it depends on how potent of a standardized extract you get. You want to look for one that is HPLC tested for urecominone. That's the active ingredient in Tonkat Ali that actually has the bioactive effect that you're looking for. There are a lot of Tonkat Ali supplements that just say Tonkat Ali or it'll say Tonkat Ali like 100 to 1 or like 10 to 1 or whatever. Like these are kind of meaningless numbers from what I understand. Like you're not going to get a 200 to 1 version of a Tonkat. And even if you did, there's no indication there's any urecominone in it. So similar to the ashwagandha, you want something that actually says this is how much of the literal ingredient that does what you're looking to get out of it in it, and here's a third-party test to verify it. And what was that ingredient called again? Uricominone. Got it. E-U-R-Y-A-C-O-M-A-N-O-N-E, I think. Now, how does Tonkat Ali compare to, like, boron? I mean, it sounds like for men it might be like you're getting a bigger bang because it's working in two different ways. Yeah, that's a good question. Boron is a mineral that seems to be something that is, mechanistically, I wouldn't be able to say for certain what the differential is and how they affect the SHBG binding complex. Like I would be trying to, I might misremember. I don't want to miss a peak. Okay. Well, yeah, it's just kind of interesting. Would the Tonkat LE work in women as well, just through the SHBG? Or maybe the, like, I don't know. Just for off the topic here, boron has also kind of been thought to potentially be a longevity molecule as well. There's some evidence that boron may be involved in, like, improving aging. So when you said boron, I was like, oh, really? That's interesting. Yeah, I feel like that's almost like a lower-hanging fruit thing because it's just typically part of a multivitamin that may just not be dosed high enough, and you can just, like, stack on top and see if it has an incremental decrease to SHBG. And then the Tonka is, like, more of a speculative one that you don't want to just, like, take until you've exhausted some of the other options, but it's, like, the more exotic kind of, like, hammer that you might want to take to the situation if it's, like, your last resort before, you know, I've tried everything. My lifestyle is perfect. My diet is dialed. My micronutrients are accounted for. My sleep is good. I don't drink. I don't smoke. And my total tea is still inadequate and I don't feel that great. Should I try some of this, like one of these exotic things that seems to have a reasonable safety profile and like an efficacious, you know, impact in men and young, healthy men at that? Like there are literature showing the effects in young, healthy men, not just like age-related, like declined men. So notable. notable. Now, as far as its impact on women, I would think mechanistically it would do a similar thing, but like, I don't have a study I could point to that says it's the same. So I would think, but I don't know. Are there any others? You know, I hear about, you know, the fenugreek and then the, some of these like de-aspartic acid, are there any others that are notable or would you say more hype? I think a lot of those have been disproven, like tribulus, de-aspartic acid, fenugreek. One that is notable that might do something is shilajit. If you get a high quality shilajit, it may provide enough, like the actual capacity of your organ to respond to hormones is partly conditional on its ability to tolerate stress and reactive oxygen species locally too. So if you have more than you can deal with and you introduce a potent antioxidant to the equation, you may be able to, like, attenuate and neutralize the kind of, like, decrement to performance and kind of, like, net out more local hormone yield. So Shilajit seems to be impactful on intratesticular antioxidant activity, but I wouldn't, it's another one that requires, like, careful sourcing, and it's also one that's, like, more speculative and indirect because, like, there are probably better ways to manage your antioxidant, like your antioxidant profile, I would think. So your top four supplements for testosterone would be? Zinc, magnesium, vitamin D, not in order, just the top three, I would say. And then I guess for impact, I would probably say like Tonkat Ali, but probably boron would be my safer next choice just for like safety profile. Okay, great. And then if you're like the anxious person at an astrogonda. Yeah, astrogonda, and just be like cognizant of how it works. Because you may be able to get the benefit at a lower dose. You may be able to cycle it depending on how you respond to it, like similar to you with caffeine. Like there's no hard and fast rules on all this stuff. Like there are studies you could adhere to like the protocols designed, but they're ultimately just designed by, you know, scientists who thought this was the way to do it. And like for you and your individual biochemistry, it may not be the ideal way. Right. I mean, I've been interested in ashwagandha. I kind of experimented with it, like, half-heartedly, like, years ago, and I think I'm going to now bring it back into circulation because I am interested in the stress management part of it, like, lowering some of the cortisol and stress, although I do that with exercise. But if there's, like, a side effect of, like, you know, just a little bit of testosterone boost, like, that would be great, you know, for me. Yeah, yeah. So I think that's going to be another experiment to mine that I try out. Shake your blood first, though. Yeah. No, that's – I already told you I want to get my hormones. I've had them measured, but, like, I don't feel confident. I haven't had repeated measurements. Because once you get that blood test, you're going to be like, fuck, I shouldn't have taken astragona because now I have no idea what this means. What the baseline was. Yeah. No, definitely, for sure. But let's talk about, like, let's say people are, you know, trying all these – If you do assess your cortisol stress response, I would highly recommend a Dutch test over a blood test. Why is that? Salivary cortisol levels are far more indicative of what's happening from a stress response standpoint than your transient serum cortisol levels will be. Oh, really? Yeah. And because? It's just like the snapshot in time and in the serum is just like not an accurate reflective measure. The salivary levels will fluctuate and they get like multiple readings and they create like an average curve for you and they should map out your day as opposed to with blood. You have like one big draw, the cortisol is measured one time and it's like, okay, you're like high end of normal. Like what do we do with that information? The salivary one's a little bit more indicative of like here are multiple time points of the day and like here's where we'd expect you to be at these points and like this is how you're responding to your day stressors kind of thing. Cool. All right. And it's like less intrusive to like spit in a tube, you know, or whatever. Right. And do you usually spit multiple times a day to kind of get that first? Yeah, I've actually not done a Dutch test personally, but I'm pretty sure it's just you spit in the tube. Yeah. Yeah. Okay. Good information. Let's kind of transition to, like, people that have, let's say, like, let's get back into the men category here, that have, like, exhausted these natural ways. They've like, you know, perhaps lost weight or done all the lifestyle factors that we've talked about to improve their testosterone. They're both total and free, all that above. Who should consider hormone replacement therapy? Like how does a man identify whether or not they're a good candidate? I mean, is it really just recommended for men with clinically low testosterone and symptoms? or like what we kind of touched on this a little bit earlier, but I kind of want to just go into this area now of actual testosterone replacement therapy. There are definitely scenarios in which it's more obvious because there is a structural issue that cannot be rectified via any sort of lifestyle change or like sleep hygiene manipulation or whatever. Like, if you have primary hypogonadism and you've ruled out the ultrasound, like, varicose, there's no issues. You're not, like, cooking your testes in, like, a hot tub every night. You're not, I don't know, like, your sleep is dialed. Your micronutrient intake is on point. Also, satisfactory amounts of calories, like, I think I might have probably indirectly touched on this, but, like, the getting to a good body fat, like, you still need to have an adequate amount of energy to actually meet the needs to produce hormones too. It's like adequate amount of calories, not overdoing it, not underdoing it. If you've done all of the stuff that we kind of like talked about and you've ruled out pituitary adenoma, you've ruled out any sort of like, I don't know, like structural defects and signaling is adequate or even supra physiologic and you're just not responding, Like, at that point, it's kind of like, okay, we could try hammering you with some HCG and see if we can stimulate a satisfactory response with, like, a manual, like, extra push at the Light Excel or use some of these other, like, augmenting, you know, steroidogenic supporting things like TongTat or whatever. But if that's not working either, like, your testes are cooked and you've got to be on test at that point because you're just not responding to any natural stimulation whatsoever. That is not typically the outcome of a lot of guys who end up on testosterone. A lot of guys end up on it through, like, secondary diet, like, hypogonadal symptoms through, like, the pituitary, either inadequate output or insufficient response to that output plus an insufficient amount coupled with it coming out of the pituitary. There's not a lot of people that are literally showing up with, like, your testes don't respond whatsoever. in those individuals, it's kind of like if you've exhausted all resources, you've tried the whole manual stimulation directly, because ACG is the way you would actually test that out, is you would actually look at, okay, if we actually hit your lighting cells directly with a signal, and we escalate that to like the maximum degree, and we use FSH too, exogenous. It's like if you're still responding to that, there's no saving it at that point, unless you have like such a significant amount of oxidative stress that you're just like not dealing with. but that would have been taken care of with the lifestyle stuff we mentioned. So primary hypogonadal, like you're going to probably be on exogenous testosterone, and it's literally like testosterone. You can't fix it with any clomiphene. You can't fix it with ACG. You can't fix it with HMG. There's no other way around it. Like you're taking the literal hormone because it's the only thing that will get you testosterone. Like you can't produce it. So there's that. And there's different ways you can take it, of course, which we could get into later. But the next situation that's a bit more relevant is, like, the secondary hypogonadism situation where somebody has, like, testes that function just potentially to, like, a suboptimal capacity. And there might be some level of, like, low gonadotropin output facilitated through some level of, like, lifestyle or diet or whatever. like Peter for example he's pretty dialed and like he did a lot of stuff to try and like fix it before he went to any sort of replacement sleep hygiene is on point like the guy like what else could you do when you're him right he's I think 50 years old so what he did was he used HCG which was assessing okay like are the testies responding to like a manual signal and they were and he like replaces hormones entirely by using a manual LH mimic essentially, why his pituitary wasn't shooting out enough LH to hit the amount, like the enough stimulation he would need to produce the same amount of tests that would hit his like optimal variety of factors, age-related decline, who knows, but probably a combination of multiple things. And at that point, it's kind of like, do you want to manually backfill the signal or do you want to take hormones pending? you've done all the exhaustive, you know, things to try and, like, check the boxes because, you know, some people don't care as much and don't want to check the boxes, but, like, in general, I would say it would be worthwhile to learn why you have the problem, even if your intention is to just end up on testosterone anyway. Like, I wouldn't delay treatment if you're symptomatic and it's, like, hurting your quality of life, but I also would, like, do some due diligence to just, like, assess, like, what's happening, And I think HCG for people who are like secondary hypogonadal is sometimes a good middle ground of assessing like, is this a testicle functionality problem or is it like my pituitary output is not sufficient? Because at that point you can kind of tell like which organ is it that's failing me here. So there's that. And then like upstream to that, there's the actual hypothalamus and the GNRH output, which is the thing that stimulates the pituitary to make the LH and the FSH. And throughout that whole cascade, you could have insufficient signal from that, insufficient response to that signal, and then insufficient pituitary output from that weakened signal and the response to it. Like it's a deteriorating thing that by the end of it, when it actually hits your test, these may just feel like suboptimal for your response to be adequate through often age-related decline. But it's a culmination of things. So certainly back to the original question, like, how do you make sense of all this and decide when is the appropriate time to be on hormones versus not? That's where you have to work with, like, a really highly educated medical professional in general. Like, I would not try and cowboy this yourself. Even trying to, like, learn it from, you know, online content, whatever. Like, I think it's good to learn how this stuff works mechanistically so you go in informed and don't end up putting on a haphazard regimen by a doctor who actually just wanted you on medications. Because if you know this stuff, it's pretty easy to identify who's like a shitty clinic who just wants to like get you committed and stuck on lifelong hormone support. And you can like weed it out really quick. Even if the doctor seems well-intentioned, he wants to help you, he wants to, you know, support your quality of life, says all the right things, seems professional, seems knowledgeable. If you don't know this stuff, it's kind of like you would be going in blind and assuming that's what you need to do. And a lot of people just end up on hormones and that's it. And sometimes there's nothing wrong with that. Sometimes that might be what you need, but sometimes people want to know what were the natural avenues I could have taken. Could I have, you know, done something else? Could I have maintained the signal from my brain to my testes this whole time? I'm just missing something. No, it's a really good point, you know, and also, like, talking about what any, you know, key risks and side effects are as well. So, I mean, that's kind of important. But, like, before we get to the risks, like, what kind of benefits can someone who is, you know, clearly, like, experiencing these symptoms of low testosterone expect from, you know, perhaps doing testosterone replacement therapy? I mean, you mentioned HCG, but I'm kind of here directing it more towards, like, actual testosterone replacement therapy. um yeah it would be in general if you are satisfactory in your replacement of these hormones to a physiologic replacement level like you should notice the amelioration of all symptoms that's the best way i could put it um now again it's uh obviously you should not expect that you're going to feel exactly the same as you did when you're like 20 years old like i think Some people think when they're 50, oh, I'm going to get on TRT and it's going to be, you know, like being 20 again. Like to some extent it could be because like on paper, like your test levels might be the equivalent. But it doesn't mean the way you metabolize the hormones into estrogen is going to be the same. It doesn't mean that the way you respond is going to be exactly the same. In general, though, the target is to ameliorate the symptoms and then like dial in from there kind of thing. so like I think what people should expect is like the intention of it is get rid of your symptoms similar to like menopausal therapy like you want to get rid of your hot flashes you want to ensure that you are not like your bone integrity is like actually supported like all these things are like your baseline requirements of why you're doing it is just like get rid of the negative and get to a baseline indirectly you will feel much better so it's like you will feel better from the result of it, but, like, don't expect to be Superman unless you're, you might feel like Superman relative to your state. It just depends how deficient you were to begin with. And it's all contingent on multiple things. So it's hard to put hard and fast generalities on this stuff, but, like, your target should ideally be symptom relief. Right. So you're not, like, necessarily going to be shredded in a couple of weeks. Exactly. Yeah, I mean, I think, you know, it's important to point out, like, some guys might see that their testosterone is, like, on the lower end of the normal reference range and, like, want to do something about it, like, with respect to, like, not skipping over the lifestyle factors and just, like, I'm going to go straight into, like, I'm just going to take some testosterone, right? And I think that would be the case to avoid, right, if you're not, especially if you're not really having symptoms, but you're just kind of, like, freaked out by the numbers, right? Yeah, I definitely wouldn't make any rash decisions based on numbers on a piece of paper because I know a lot of guys who like the best physiques in natural bodybuilding are like guys with 500 total testosterone. I know guys with three times the amount of testosterone production, much worse physiques. It's not always the number on a piece of paper. It's your genetics, your response to it, literally how many muscle fibers you have at birth. There are a lot of factors that determine what you're going to look like, how you're going to respond, the shape of your muscle bellies and how they appear to people, your body fat level especially. Like if you are leaner, you will just appear more muscular, you know, stuff like that. Right. Yeah. Okay. So let's talk about some of the important risks that, you know, people should keep in mind when they're going to start testosterone replacement therapy. I know you've like talked about this, heard about it, like the cardiovascular disease risk. I mean, for a while it was a controversy, right? Like doing testosterone replacement therapy is going to increase your cardiovascular disease risk. Like there's the TREVORS trial that's kind of we got some pre-publicated, like pre-data here where it seems as though this is a very large trial, placebo-controlled, where it seems as though men, these are older men that were at least it seems to be hypogonadal, like they were low testosterone. And if they were given testosterone replacement therapy to a normal like physiological restoration range there no really adverse effects on cardiovascular outcomes What are what the thought here with respect to cardiovascular disease risk I think the only issue is, like, defining what restoration of physiological testosterone production equates to is like when we were talking about like coffee and like how much caffeine is in a cup of coffee and like it could vary so much like some guy's replacement adequate physiologic replacement what he was when he was younger highly variable and in that traverse trial using androgel to bump your total t from like hypogonadal to like 400 is not necessarily indicative of what I would say a lot of people are looking to the data to see what the results were of testosterone therapy because a lot of guys are on injectable tests boosting to 1,000 total T with a disproportionately high free testosterone because when you inject infrequently too you drive your SHBG down proportionally. That is not the same as a guy who's using an androgel to get to like 430 total T. So taking that outcome and running with it as like no cardiovascular risk. I think that's a bit haphazard personally. Now it's obviously promising data and like, it's great that it came out. Like it's very, very promising. The only problem is, it's like how many guys are actually using that medium of therapy. Like, I don't know, none. Like I don't know a single guy using Androgel and that's fine. Like it's still data and it's still worthwhile and it's still good. It's just like, not, don't take that as like the, the sign off that like your, you know, 200 milligrams of testosterone and anathate per week that your like, you know, more aggressive protocol has been designed to do is like going to be the same outcome. Like it's not. You're going to have the erythropoiesis increase that might not be reflected in the TRIVERS trial. You're going to have the disproportionately high endogenic signaling. Like you're going to have a lot of things that you're looking to get the reassurance that won't happen, but you absolutely need to be cognizant of because it will probably happen still. No, this is so important. And that's kind of why I was like these are hypogonadal, and it's like I guess their normal physiological range is not really accurate if it's only going to like 400. So basically you're just making a non-hypogonadal. But it is important because you mentioned your erythroporesis, and so this is another kind of concern with testosterone, which does regulate red blood cell production. It does increase, you know, the thickness of blood. And polycythemia is, I would say, a risk factor, right? So, you know, how substantial is this? I mean, I think I've read studies where it's like almost 25% of men have thicker blood that are on testosterone replacement therapy. Now, it doesn't necessarily mean it's like to the point where it has to be treated, but it is thicker, right? It is like the hermetocra is thicker. So, you know, how should men weigh these risks for the cardiovascular disease risk, the polycythemia? So for people like listening or watching, that is a concern because it increases, you know, stroke risk. It increases the potential for, you know, cardiovascular events as well. So, like, what are your thoughts on sort of weighing those risks? to the opposite side of the coin on that androgel, you know, like it's not necessarily a physiologic replacement. The thing to note is it should be expected that if you use more testosterone, you're going to have more erythropoiesis. Like that's literally what it does. So to think that it would be a net negative because you have a 25% increase in that via your testosterone administration, if you were hypogonadal to begin with, which presumably is the reason you're getting on TRT, you know, depends on the person, but, like, going from hypogonadal, where you might be, like, borderline, like, anemic for all we know, and then having the 25% bump, like, maybe you need that to actually, like, have adequate oxygen-carrying capacity and, like, actually sufficiently fuel your body. So it's not to say it's, like, net bad, net good. It's all about where do you achieve, like, the problem is, like, the definition of symptom relief, too, is so vague, because you could achieve symptom relief at, you know, 450 total T, maybe, depending on the person, or it might be at, like, 800, or it might have been, like, even if it was 450, like, if you got up to 800, you're still in normal on paper, so, like, is that bad, you know? Like, who's to say? I think most people would say it's the high of normal, because that's literally what it is on a reference range, So it all is going to be just being cognizant of the fact that androgens will do what androgens do, which is they will, in a dose-dependent manner, derive rethropoiesis. They will induce cardiac remodeling if you push it too hard, not necessarily within physiologic limits, but, like, these are things to be aware of. Dyslipidemia will become more of a concern at a higher level, especially depending on the medium of administration. If you're dosing infrequently, like, once a week with a shot, it's going to be a different outcome than if you're doing like a daily, you know, little pulsatile cream administrations or like micro injections, like subcutaneously where you're bleeding out the effect more. It will all be impactful. So I think it's more about there is a risk, all but there's not going to be data that says directly if you replace to 800 total T, it's going to be dangerous, nor is there data that says it's safe either. Like, you can kind of take from the Taurus trial what they found and extrapolate out, like, what you know from graded dose response studies, which do exist, and, like, realize, okay, like, somewhere in the middle here, if you're one of those guys who, like, wants to hit that, you know, high normal because, I don't know, like, who's to say you're in the wrong for wanting to be, like, optimally vital, too? So it all kind of depends on the person. You have to weigh the risk accordingly because it's not risk-free. You're still going to have to keep an eye on your hematology panel. Is it getting out of whack to a degree that is, like, unsustainable? You're, like, looking at phlebotomies just to maintain something that looks normal. Or is it, like, adequate slash, like, optimal for you now to feel like you have enough energy to not, like, faint when you get up? I don't know. It depends on the person. yeah it's just like an understanding of all of the interplay of things and not taking the sign off you know the one the traverse trial is like you know you're get a jail free card like it's just you're still going to have to keep an eye on your blood work you're still going to have to have like a doctor who knows what they're talking about and is like very rigorous about this stuff you have to know how the different administration methods and frequency will impact things because like you're probably not going to be on androgel using a little dose that gets you to 420 nanograms per deciliter you're probably not on that protocol. And if you are, like, yeah, okay, look at the Traverse trial. Like, maybe you can get, like, a bit more reassurance. But, like, you're probably not that guy. And that's fine if you're not. It's just, like, being very realistic about what to expect. And, you know, there is dyslipidemia. There is an increase in blood viscosity to some extent. There will be a suppression of SHBG if you're doing injections infrequently, which will elevate your androgenic signaling beyond what is physiologic. Like, oh, most people are supra, at least transiently, without knowing it. And by that I mean, by supra, I mean, like, more than you would have produced physiologically, because it's not physiologic to have your hormones transiently shoot to, like, I don't know, 1,200 or 1,500 total T with a disproportionately high free testosterone from administering once or twice a week. Twice a week's quite a bit better, but once a week, for example. and then it crashing back down before you shoot again, like that's not physiologic really at all. So you need to be aware. That's going to cause more elevations in these like problematic biomarkers than would be if you tried to maintain what is reflective of like daily normal production. So like the ideal protocol would be literally replacing your daily testicular output, which is adherence problematic for a lot of people because not everyone wants to be using like a scrotal application of cream twice a day. A lot of people don't want to be injecting daily subcutaneously with like a micro amount of testosterone. They just want to be one and done one shot a week. Even some of the problem too is like the pharma has set it up so you might be forced to take it infrequently and at a high dose because they have these auto injector pens that are preloaded. So you like have to shoot it in one shot or you don't take it. Yeah. So like Zyastead is like the preloaded testosterone and antate pharma grade that is often prescribed and it's like, well, you either do the one shot, one kill, and take the whole dose, or you, like, don't take it. So you're touching on an important point here, that supra-physiologic level, like the amount that you wouldn't necessarily have in normal physiologically. I mean, I read a study where it was like 25% of men have this, and it seems like it might be due to this, like, dosing, this injection, you know, protocol. What's wrong with the cream? Like, is that something that doesn't get your levels high enough, or is it just, like, annoying to have to do every day? It kind of, well, it depends on the person, because it would be personal, subjective opinion for me to say, like, why I wouldn't want to do it. In general, the reason most people don't want to do it is adherence lifelong. Like, this is something you're going to do forever, typically. Somebody going to apply a cream to their scrotum twice a day, it's not that fun. Like, it's like something that you have to go out of your way to do wherever you are, you're traveling, whatever. Like, you will go hypogonadal with pretty quick if you don't get in the bathroom and wipe some cream on your balls. Yeah. I mean, I get that. But, like, you know, like, stroke risk, cardiovascular disease. If you want to be optimal, the problem is a lot of people will favor adherence and sustainability, similar to diet, over optimal. And that's fine. You just have to be accepting of the risk profile that comes along with it. Okay. What about other parts of the risk profile? So how does it affect the prostate? I read about fertility. I mean, being a big one, too. It's suppressing fertility. Yeah. Sleep apnea can be exacerbated as well. I mean, these are all, like, part of the risk profile things to consider. Yeah. When it comes to prostate, that is something that, at least based on the most recent literature that I'm aware of, is are you familiar with the androgen saturation model? Basically, if you go from hypogonadal. Oh, yes, yes. Okay. Go ahead. Please explain it. Yeah. So, essentially, from what I understand, based on the most recent literature, it shows that if you go from hypogonadal to eugenadal, or like the threshold of it, which is like, you know, on a reference range, roughly like 300 plus nanograms per deciliter, going from hypo to that, that differential will be positively stimulating of like prostate growth, you know, PSA levels will go up, etc. But beyond that, you are not necessarily in a dose-dependent manner like a muscle or something going to be inducing size increases. Like if you took even, if that were the case, you'd have bodybuilders who take, you know, thousands of milligrams of steroids per week. They would have prostates like busting out of their bodies at that point. So it's not necessarily the case, but it's not like it's still worth monitoring your PSA for trends and longitudinal patterns as you get older because like it will still have the same, you know, susceptibility to things that happen as you age. but the actual impact on prostate-related issues and, like, growing cancer from scratch. If you don't have preexisting cancer cells, like, you're not going to just, like, spawn cancer from taking testosterone. So I think that risk is a little bit overblown. Fortunately, we have data that seems to be pretty strongly indicating that you're not going to have to worry about that if you are somebody who is otherwise healthy, cancer-free, and you're just going from, like, you know, like you would probably have a small prostate to begin with if you were hypogonadal anyways. You're probably just going to where you would be if you had normal levels. So it's not like that growth is even bad either, getting to the eugenial state. So just keep an eye on the PSA and be aware of it, but it's not something that seems to just, like, dose-dependently escalate. The other stuff is worth mentioning. In general, like when I said testosterone does testosterone things in a dose-dependent manner, even if your protocol is dialed in, if you're producing more than you would physiologically, that your body can tolerate as well, like you will have the whatever backhand consequence of managing the extra estrogen, the extra DHT, you know, that could lead to extra acne, hair loss, gynecomastia if you have excessive aromatization locally in the tissue that is not antagonized sufficiently by the DHT and testosterone signaling, hair loss in the scalp, annoying body hair that sucks to get rid of if you care about that sort of thing. More facial hair growth, deepening of the voice, more than you already have as a male, surprisingly. There's, like, often, like, if you were low-T, you know, it's, like, typically guys who get on and then, like, push their test levels up to high normal, especially will notice, like, a little bit of a deepening. Like, these are all kind of, like, kind of like the maximization of the male secondary sexual characteristics being, like, pushed to the nth degree within physiologic parameters. Sleep apnea will get exacerbated pending your neck size increases, muscle increases in size, things that are contributing to the obstructive nature of your soft tissue falling into your airway will get worse pending you are dosing in a manner that pushes you there. So if you're physiologically replacing, like a lot of this stuff is probably a moot point. but a lot of people won't be they'll be pushing to optimal optimal quote unquote which is fine just be aware that you will potentially increase your risk of sleep apnea and keep an eye on it I would absolutely recommend anybody even before they get on TRT get their like a basic sleep study done it's a lot less intensive than you might think and they're actually pretty reasonable at home devices that measure like apnea episodes per hour that will like essentially put You want a chart of how many episodes of, like, ceasing breathing are you having per hour. And you could have a baseline there and see if that goes up when you get on TRT. So it's not like this is a questionable, like, what's going to happen to your sleep apnea susceptibility? Like, literally measure it. Like, you have your baseline when you're not on it. Now you're on it. What's the difference? And, like, you would see in real time the literal diagnostic metric either going up or not changing at all, and then you would have your answer kind of thing. But it is a possibility for sure, just like any of this stuff is. but if you're physiologically replacing like the risk is relatively low unless we're talking about that supra physiological level where it seems as though like one in four men don't even know they're in that level they are even transiently because i'm in blood work if you for example if i'm on zyastad and i'm shooting once a week an auto injector pen and i'm checking on trough day which means like typically you're a lot of physicians will say check your test levels on like the day where your test levels are lowest based on the pharmacokinetic profile of whatever the format of testosterone you're using. So if you're on a long ester testosterone formulation, like a testosterone cipionate or an enanthate, these are the typical prescriptions to make, allow you to get away with dosing only like once or twice a week for adherence. But the reflection of that in blood work is you would typically see because you're bolus dosing it at Once, your blood work would shoot into supra range, depending on the total dose, of course, but like a lot of people, this is what happens. They shoot into like, I don't know, 1,300, 1,400, 1,500 total T with the proportional 5-alpha reduction to DHT, suppression of SHBG, disproportionate freeing of free endogenic signaling via more DHT being free than would otherwise be normal, more free T than is proportionally normal, more aromatization than would be possible if that dose was like even spread out on an even curve throughout the week on micro injections. Increase in erythropoiesis acutely beyond physiologic, you know, capacity to, you know, an unhealthy acute level, at least for a periodic period of time. And then you're in like a slow or steep, depending on like the ester, crash essentially into like sort of normal looking territory until your next shot. That's the reality for a lot of guys. In Europe, they do testosterone undecanoate, maybe, or it's either a Sustanon formulation. Maybe it's undecanoate, and they'll do, like, one shot every, like, few weeks. It's crazy. So they'll, like, shoot their test into the stratosphere, and it'll, like, crash into hypogonadal territory, and then they pin again. Or shoot, inject. That's what I mean by pin. Yeah. I mean, so. It's like a roller coaster of, like, I can imagine it's, like, the equivalent of what females deal with times, like, some magnitude. I mean, it sounds – they must be, like, also just, like, they get aggressive and stuff and, like – Irritable. Irritable, yeah. The regulation would be, like, impossible to expect. You know, like, I don't know. Like, I wouldn't want to wish that on anyone. Like, that would suck. I mean, to me, so, like, let's say adherence, like, compliance, that's a whole issue, right, obviously. But let's just like, if we're just talking about risk profile, right? Like you're not wanting to really get into that supra physiological level. You're not like, you know, you're not like the bodybuilder. You're not like, you know, you're the person that just really wants to keep that risk low, but you want to get the benefits. Okay. Like that's what you want. You really don't want the risk. Like it's just not on the table for you. What would be the best? There's the different methods. You kind of mentioned a few. Maybe you could kind of just go through them again briefly, but, like, what would be the best method to get you to a more normal range? Maybe you're not someone that's totally hypogonadal, but, like, you know, low T symptoms, right, lower T and symptoms. You're aging when you're an age, you know, like a 50-year-old man or something. What would be the ideal delivery method that would really get you those benefits but lower that risk profile? Yeah. And one thing just to add before we entered that subtopic, I do want to clarify. If somebody was to take an amount of testosterone, even if it put them to like high normal of the reference range, but it was something you tolerated in youth and like your body was capable of handling, which a lot of people are. if you do it responsibly understand what you're taking know how to monitor your biomarkers are lean healthy have a good diet lifestyles dialed in you're aware of the risks um all that stuff is like overseen with a level of education some level of rigor and like obviously decreasing need over time as you start to dial it in you'll it's not as like rigorous of an oversight process because after you're in your dialed protocol, it's just kind of like living your life and you know what to expect from your blood work at that point and how it affects everything, you'll probably be fine. Probably. It's just being aware it's not zero risk. Like, it's just like that's the thing people need to accept if they want to be pushing, you know, to some level that is like just in general, like it's never going to be risk-free. But I could still also say with certainty that if you're hypogonadal, you're going to be healthier replacing to physiologic than you would staying hypogonadal for sure. Like you are a thousand percent in cardiotoxic, neurotoxic quality of life down the, you know, the toilet territory if you're like in hypogonadal levels almost certainly. So hopefully that's like somewhat of a consolidated wrap because I don't want to like sound too, it's worth being cautious and aware of all this stuff, but, like, it's certainly not to, don't dissuade yourself out of, like, fixing your levels, too. Like, it's critical that you have adequate hormone production, similar to women in menopause. Like, the benefit outweighs the risk. Like, essentially, every single time, essentially, and you just have to be responsible for your approach to what that is. Well, especially if you're monitoring biomarkers, and I'd love to, like, talk about some of those in a minute, but I think that's the key to, right, like monitoring, right? Yeah. Okay, so then circling back to administration, like, the ideal way to go about it, I can say off the rip I would not do pellets. I would probably not do androgel if you're a male. If you're a female, it's a bit different, which you can get into. The creams through compounding pharmacies, that's probably the only, like, tolerable way you're going to have something that you can apply scrotally to get the ideal absorption pharmacokinetic profile that would be reflective of something that's, like, more natural. So, like, that is probably on paper arguably the best way to go about it. It's just not necessarily something everyone wants to do, but it works well, and it will get you to the levels that are great and look pretty physiologic and, like, kind of reflect the pulsatile diurnal nature of normal testosterone and secretion. And it's also converting, like, locally, like, in the area you would actually be producing it, too. Like, there is a local effect, too, through, like, 5-alpha reduction in the skin and stuff like that, which can result in, that's why monitoring, like, DHT and some of this other stuff can be important, but it's, like, a whole more nuanced discussion. But in general, the crane scrotaly is reliable, good, produces a very favorable outcome, and a lot of guys will be quite happy with that method. the other method that I would say is worth considering and like the typical one that most guys do is injection which it's a bit more predictable typically in terms of like what you're going to get out of it in terms of adherence it's a lot easier because you don't have to shoot it daily you can also modulate the release pattern of it through either the ester so like you'll typically get prescribed like the longest bleed ester so cipionate has a half life of like I think it's like 10 days or something eight to ten days depending on how, depending on individual biochemistry and how you kind of like cleave the ester. But you can also change the way it absorbs via injecting subcutaneously into stomach fat or into any sub-Q fat versus intramuscularly where it's more quickly going to get absorbed and assimilated. So you can also bleed out the effect even more and make it even more stable in your blood levels. and it's pretty easy to adhere to a TRT protocol of like micro injections, even on like a relative frequent basis, like every other day is pretty damn stable. Subcutaneously is what a lot of guys do and works really, really well. And, you know, it keeps a very stable hormone concentration curve. It's pretty predictable in what's going to happen. You just kind of like got to be aware of the, you know, how hard you're pushing it and what that will do to your risk profile accordingly. The other way that's promising that I would say is oral testosterone undecanoate lymphatic absorption patented format. So there is three, I believe, Talando, Jotenzo, and Kaisotrix, and they've basically managed to make a lymphatically absorbed testosterone undecanoate. You can actually swallow orally, whereas back in the day they would have had to make it hepatotoxic to actually make it through the liver through a first-pass metabolism and actually, like, make it into circulation to any meaningful level. They'd have to, like, add, like, a 17-alpha alkylated group to it and make it, like, a terrible-for-you oral steroid, essentially. This does not have the same level of stress. It's not stress-free as far as I know, but it will get you a meaningfully significant, like get you replacement of total T levels to like mid to high range, depending on the person, likely achieve symptom relief for guys who are hypogonadal and is pretty sustainable because you're just popping something. So some people prefer that. Pretty expensive though, and kind of like a newer medium of administration, but promising nonetheless. Typically what guys are doing though still is the injections or the cream. And the other method is intranasal, which I'm sure you've probably heard of for like, you know, hypoactive sexual disorder for women has a potential for that. As well as for men is like a different medium of getting like an erythro poiesis stimulating free version of tests because it's so acute. It's just like an unsustainable daily treatment. Unfortunately, like it's okay if you're trying to have like an on demand libido boost as a female or something. But for a guy using it like multiple times a day in snorting something, it's like not something any guy I think would want to do for. And even if they think it's cool to begin with, I think for once you get to like the month or couple month mark, the novelty would probably fade. A lot of guys are, you know, super excited when they start testosterone injections. Like it's like this roster using like this hormone and it's, you know, I'm replacing and it's, you know, I feel like this big significant thing. and then, you know, year in, it's just like, oh, I've got to do my injection. So it's like whatever you can most sustainably adhere to that is, like, the safest, will achieve the outcome you desire. The symptom relief is the one you should stick to. And the cream, I guess I didn't mention the obvious, but, like, transference. If you have children, you have pets, like, there are concerns with, you know, like what you are going to rub it off on and, like, how, like, your hygiene with it. So that's worth mentioning because, like, there are cases of transference issues that have been noted in media, you know. I think I did a video a while ago where some dad accidentally was, like, wiping residue on his kid without even realizing it, even after he, like, thought he cleaned it, and his kid was, like, starting to get masculinized from the testosterone residue or something. Wow. Yeah, crazy. because it's like the levels are so low, like any like significant amount will push things in like a significant incremental direction that is like going to cause problems. So that's a thing. Whereas injection, it's like you're in the bathroom, you do it and it's clean and done. Totally sterile. You don't have to worry about like, are my hands fully clean? You know, is somebody going to get into it? Like good luck accidentally like breaking into like a multi-dose vial or something. It's not going to happen. So, yeah, there's like different. different like logistical advantages to some of these administration methods that probably should not be understated but are worth mentioning um so yeah i think the three most viable cream scrotal application injection intramuscular or sub-q if you want to bleed out the effect or maybe the oral um all but i want to see more of the literature as it evolves right so it's kind and when it comes to the injections, it sounds like more frequent subcutaneous is where you're going to get more, less of the probability of having that supra-physiological peak versus if you're just doing it once a week, intramuscular, not bleeding out that response, their effect. But again, as you mentioned, compliance is definitely going to be better if you're doing it once a week. But, I mean, twice a week, three times like every other day. I mean, you know, for people that are really concerned about risk profile, perhaps they have already, like, you know, a family history of cardiovascular disease or stroke or whatever. They probably are more incentivized to, like, lower that risk for any potential side effects. Yeah, like in general, I think. Or fertility. What about men that are wanting to reproduce? Yeah, we got to talk about that, too. But one rule of thumb that's like to make it as easy to understand, at least for me, this is the easiest to understand, like how I remember it is the closer something is to what would be equivalent to what you would naturally make. Should you have had should you have healthy functioning test is producing natural testosterone. That's going to be the one that has the least impact on all of the unlike intentional consequences of like spikes in hormones. So, like, normally on a daily basis, you would pulse out, like, in ebbs and flows multiple times. So, like, the more you can get these, like, the more stable you can get it with the more micro administration spread throughout the week, the more stable everything will be. And as a consequence, less spikes into the territory that would produce things that are not representative of physiologic. And typically daily administration is the way to go, whether it's, like, cream is going to be twice a day, at least, but then for injection, it's like every day and every other day, there's diminishing returns, but you can kind of, like we said, bleed it out a bit. So, yeah. So as far as fertility goes, yeah, like you will absolutely crush your fertility pretty significantly, if not entirely, depending on some things. So intratesticular testosterone is the significant mediator of spermatogenesis, so it's not uncommon, even for bodybuilders who are on huge amounts of steroids, to still accidentally get their wives, girlfriends pregnant, thinking that they're sterile when in fact they have so much testosterone in their body that it's like, actually like, producing the spermatogenesis effect via the exogenous hormone. What that does, the epigenetics, all that stuff, no idea. Would freak me out a bit. Well, like, it happens. And it's like, on paper, these guys should be completely infertile, but still see accidental pregnancies all the time in the bodybuilding world. So I wouldn't rely on that as a means of contraception as a guy, first of all. But you will almost certainly have, like, inhibited to, like, horrifically low, if not azuspermic level fertility if you were on even just, like, baseline replacement because you are shutting down the signaling from your brain that otherwise dictates the intratesticular activity. So by that, I mean the hypothalamus releases the GnRH, the gonadotropin-releasing hormone. So it's the hormone that causes the release of gonadotropins, hence the name. At the pituitary gland, the pituitary responds to that GnRH to then produce the gonadotropins, metatropins, which are the luteinizing hormone, LH, and FSH follicle stimulating hormone, just like in women, goes down to the gonads. And the thing that happens is you produce intratusicular testosterone at the light cell. And women do too. It's just fecal cells instead of light cells. And that intratusicular testosterone mediates spermatogenesis in unison with the Sertoli cells, which are also supported by follicle-stimulating hormone. So if you have exogenous testosterone, so like you're administering it yourself synthetically, you have basically told your brain, I have enough estrogen and testosterone via this injection I'm doing or whatever it is. So you cannot produce any more GNRH. It's like, why would we need you to? We have enough hormones. It's like, okay, let's turn that off. Let's turn it off. As a result, we have no signal to produce pituitary hormones or the gonadotropin, so we turn that off. And now you have no signaling to your testes, so now you're just like literal organ atrophy is occurring because there's no signaling happening there. So the only thing you can really do at that point, if your HRT protocol is not built around replicating manual signal, because that is a means that some people do, if you have adequate organ function, you could theoretically do that instead of TRT. but if you're going to be on TRT like you either replicate that natural signal or you sustain organ atrophy to the point of potentially some permanent likely deterioration all but likely not inability to restore fertility. It's very rare that I see guys who are actually like not truly fully hypogonadal like their testes still work. that just had inadequate signaling or something via, like, secondary hypogonadism, if those individuals maintain the signaling, like, you can retain the structural integrity for the most part of the testes, and then if you want to get pregnant or whatever, you are either currently fertile still because you're manually stimulating it, or you could, like, you can basically manually manipulate how fertile you are in real time, essentially. So you could fully retain all fertility parameters, even push them to super levels if you wanted to. I don't recommend it, but, like, you can maintain everything while you're on testosterone via that manual signaling of HCG plus recombinant FSH. That's, like, the combo that basically replicates what would otherwise be the LH and FSH from your pituitary to your testes. You maintain structural, the size, the functionality, sperm production, et cetera. but then you also have to account for the extra testosterone you're producing because that's stacked on top of your exogenous test now. So now your dose might have to change. And the amount of estrogen, there's like local activity in the testes for how much aromatization happens and whatnot, which is different than if you're injecting it like in your butt or something. So you have to account for that differential too. Some people get highly estrogenic from ACG in particular, which is like a female, like literally in pregnant women's urine, to stimulate light excels. That's what it's like purified from. And, you know, there's some speculation as to if HCG is like healthy to be on. It's like, yeah, like you're taking like an extract of like women's urine. It's like a light excel stimulator similar to LH. It seems to mimic the effects of LH, but it's still not LH. It's HCG, which like human chorionic gonadotropin isn't what comes from your pituitary to your testes. It's just something that stimulates the light excels significantly. So do we see any, like, notable effects on, like, I don't know, epigenetic modifications from HCG plus FSH-mediated babies? Like, not that I'm aware of. Not that I've seen any literature point to, but it's worth noting, nonetheless, that HCG is not, like, a bioidentical gonadotropin for men that you would otherwise be using to shoot to your testes. It's, like, a replacement for it. And recombinant FSH is, like, it's FSH, but it's still, like, grown in a lab. It's not from your pituitary. Does that matter? I don't know for sure. But either way, you can maintain your fertility metrics to the literal baseline if you had an adequate adjunct therapy. It's just very cost prohibitive. Like the cost of recombinant FSH is insane, and HCG in itself is expensive, and then you're stacking that on top of your testosterone that you're using. It's not necessarily an affordable thing for everyone. So a lot of guys just let their testes atrophy because that's what they can afford to do, and they want to still get the symptom relief. And then once it comes time to have a kid, they have a bit of a more intensive protocol ahead of them to restore organ size and functionality, which is more intensive of a process than if you just sustained. I'm sure, like, you could speak to, like, it's easier to keep stuff where it is than it is to try and, like, regain health. So if you've literally atrophied an organ into, like, you know, a fraction of its functionality, trying to, like, bring it back from the – it's not dead, but it's, like, very compromised. It's likely not going to restore to, like, full functionality, and the road to getting there will require more aggressive intervention. You'll still probably get back to fertile, but, like, it might not be as good of health of the sperm, for all we know. It might not be the same capacity to produce the same volume. Who knows? So all that to say, yeah, you should expect your fertility to go down the toilet, and you should expect that you have an adjunct protocol in place if you want to sustain it, if you're on testosterone, and you want to sustain the fertility. But it's possible to sustain it. A lot of people thought until, like, relatively recently that if you're on testosterone, you just couldn't, and you're going to be infertile for sure. And it's unfortunate because there's a lot of guys, especially bodybuilders, who underwent severe atrophy and then had, like, more difficult roads to recovery because of just bad information. Wow. Yeah. Like, imagine finding out, like, for 10 years you've been on, like, hormone therapy and you could have kept your testicles where they were the whole time, and now you just have, like, these shriveled, you know, like, raisins that you have to, like, re-stimulate to baseline through, like, insane aggressive dosages of HCG and FSH. Like, not cool. At what point does that actually start to occur? I mean, like, how long do you have to be on, you know, TRT before that really starts to happen? It's pretty quick because, like, the suppression of the gonadotropins happens, like, within days. Like, once you start to inject that hormone, like, you've introduced an amount that is going to tell your brain, we have enough, don't make any more. And once the gonadotropins bottom out, you have no signal. Like, you will atrophy over, you know, the next months and get to some level of atrophy that is variable depending on the person. But regardless, you're not stimulating activity. So even if, like, the structural size isn't, like, as significant of a drop, like, there's a lack of activity entirely. So, like, you know, it's all kind of individual dependent. But, like, you should expect shrinkage within, you know, weeks to months. Wow. And so this is also kind of important to point out for, like, guys that are, you know, cowboying it and kind of, like, they want to get their T up for, like, maybe some muscular effects or something, right? and I just kind of like maybe not hypogonadal but like lower range. Yeah, I would treat it very seriously like you know that you want to be on it. It's not something to experiment with, in my opinion. If it's like the route of hormone therapy, like treat it as such, like you treat it like you are on it forever probably. And biomarkers to monitor, right? Let's say you are going to be on this. And so some of the biomarkers, you mentioned like lipids and we're talking about hematocrit, right? Like some of these biomarkers are important. Like what would be or what are some of the ones that your company measures or what you think are important to measure? PSA, right? Yeah, I think hematology, you know, this kind of like covers the basics of, you know, red blood cell count, hematocrit, hemoglobin, et cetera. metabolic parameters. There's a lot of stuff you want to incrementally assess, like how well it's working too, like how much more metabolically fit are you becoming in your blood work and insulin sensitive and whatnot, because these are metrics of progress you can use to actually determine how well this is going for you. So it's not just about like where did your total T and free T end up on paper. It's also about like the real health benefits that you're seeking, not just from a symptom relief aspect, but also from like, you know, what's your fasting insulin now? Is it, like, way better because you have more muscle mass on your body? Like, if not, like, you know, there's things to be had that are going to be net beneficial from a health standpoint, not just, like, a cosmetic and, like, I don't know, sexual health standpoint that should be monitored regularly. And I think one of the key things is just making sure you have a good baseline. Because it's, like, once you – a lot of people make the mistake of, like, this is kind of, like, mediated by default through us. Like, you have to get a baseline to even, like, see where you're at before you would get even recommended to do anything. but a lot of people that get on hormones before they have a baseline and then they just like, don't know what they're looking at after they're on it. And if you have a problem and you've shut down your system via hormones and you're trying to like retroactively figure out what happened and what went wrong, it's pretty difficult to see what like the change was that was marked and like significant that led you to where you are. That might be, you know, a problem. So if you have like a reasonably comprehensive baseline that assesses the hematology, a CMP that assesses your kidney status via Cystatin C estimated GFR, or a SDMA, which is like a symmetric, it's another marker, more progressive marker for kidney function that is a proxy for inulin clearance with relative accuracy, which is like the gold standard of actual GFR for kidney filtration capacity. I forget what it stands for, but you can just type in ADMA and STMA, and you'll see what the acronyms stand for. I think you've talked about it on your show, too. I don't know what they stand for either. Yeah. One of them is asymmetric dimethyl arginine. Yeah. So one of them assesses vasodilation potential, and one is more like for cardiovascular, and one is more of like a kidney marker. That is equivalent or slightly better than cystatin C estimated GFR, which is not influenced by muscle mass creatinine intake or the array of things that can cause transient, complete, like, to the point of it being unusable changes in the marker. Because creatinine calculated EGFR, the amount of guys I've seen think that they're on borderline, like, death's door of kidney failure from a creatinine that's high because they're, you know, a muscle-bound guy who takes creatinine and, like, works out hard or whatever, it's, like, it's startling that this isn't more widely known. So either of those two kind of like strong proxies for inulin clearance. You have your kind of like metabolic parameters to see your insulin sensitivity, hemoglobin A1C, you know, all the kind of basics. I think the lipid panel, definitely a baseline HDL to see how much it gets lowered by the dose of testosterone you're using because you will likely see a suppression if you are elevating your testosterone beyond what you were at. It doesn't mean that it's bad or good. It's just worth noting, like, how much of a deterioration it has based on your dose because that's one of the proxies for kind of, like, androgenic activity. SHBG, your binding proteins, like, what's your baseline relative to after? because if you are injecting infrequently or a dose that is significantly suppressive, like it might otherwise be a proxy for, like, using more than you might need, not necessarily the case always, but SHBG will get suppressed dramatically by exogenous androgens in a dose-dependent manner. So it's not uncommon to see with bodybuilders who are using full-blown steroid cycles, SHBG levels in the single digits, which is like you have essentially no regulation of androgenic signaling at that point. It's just like everything's flying around. So on DRT, it's like worth knowing where you stood to begin with and then how much it decreased because it's like if you didn't know the baseline too, any of your diet changes at that point, the carb manipulations, the exercise change, the calorie intake change, the sleep, you would have no idea what the impact thing was for sure that impacted the SHBG if you didn't have the baseline. So what else as far as assessing? Free T and total T measured through the accurate assays, which would be the gold standard for total testosterone, is liquid chromatography with tandem mass spectrometry. If you use an equilibrium, if you use an immunoassay test, which is like the cheaper version, often it will be relatively inaccurate especially at lower like more low levels it is like notoriously inaccurate because the the very low numbers like you need to be more specific so like with women especially like you don't want to be messing around with them you know assay tests you want to be using sensitive assay estradiol every single time sensitive assay testing for total t and for free testosterone you don't want to be using a calculation ideally you would want to be measuring through equilibrium ultrafiltration or equilibrium dialysis, which are like actual measurements, not estimates based on calculations. That's kind of what I would recommend. And then estradiol is LCMS as well, the same as what you use for total testosterone. And what else? I'm probably missing some stuff. Basic liver markers would be to have. So the stuff that's going to get directly affected the most by androgens, though, is going to be like your gonadotropins, LH and FSH. They're going to be in the ground. And if they're not, it kind of indicates that you don't have adequate either androgen or estrogen signaling. It would be odd if you're on testosterone replacement and your LH and FSH weren't like at the bottom of the barrel. It would almost be questioning at that point, like, am I having something inhibit the androgens from working or the estrogen? because it's like you could theoretically blunt estrogen-mediated feedback by using, you know, an aromatase inhibitor or a CIRM or something and, like, blunt that response. And you would see in your blood work it would be like your body still thinks it needs to make more natural testosterone and, you know, it's kicking up the gonadotropin. So if you're on, like, true replacement, those levels should be, like, not, like, even present essentially. Where's it odd? Like, seeking to have, like, a bottom note number as, like, what the target is. That would kind of indicate you've definitely kind of, like, satisfactory replaced to what you need to stimulate, like, the negative feedback. Yeah, and I mentioned the lipids. Yeah, I'm definitely missing something. But fast insulin, some of the insulin resistance markers. And there's some stuff you should probably check, like baseline, like clotting risks, predispositions, factor V laden, things like this. LP little a at baseline, especially because androgens suppress LP little a uniquely, which a lot of people don't realize is affected by androgens, which is typically not something that can be manipulated through anything really that I'm aware of through diet and lifestyle. So you might think you have a better LP little a then you actually had a baseline, so, like, your genetics might be, like, masked a bit by your androgen use. I don't know, thyroid balance. You know, thyroid levels are good to have. How much TSH do you have? You know, T4, T3, the free balance of those hormones. IGF1. None of these are, like, critical necessarily, but there's worth having for basic health assessments and to see where you land. But, like, yeah, it's basically, like, your total test, your free test, your estradiol, The free levels, sensitive assay measurements, LHFSH, hematology, HDL, kind of like the basics, metabolic health, insulin sensitivity metrics, I think are kind of like the critical baseline ones. It's pretty comprehensive. Yeah. I don't imagine everyone is doing that. Well, fortunately, a lot of good panels will just, like, have it for you. It's not like you would ever be expected to remember all that stuff. And I'm probably missing it. I'm sure I can't even remember it all. I'd have to go look at our own pre-designed panels to tell you I probably should have done that at the beginning of the thing rather than rambling nonsensically. So just briefly, women, you know, this is another. I'd love to know we've talked a lot already about, like, testing methodology, timing tests, you know, time of the day to test and all that stuff. but you know how how does a woman go about like determining whether or not she has low testosterone needs to kind of figure out dietary lifestyle wise like you know obviously that the first line of you know defense right you kind of address that first but I just would like to talk about like generally speaking clinical symptoms in women Sounds like it pretty similar to men We talked about that What females are a candidate for testosterone replacement therapy? Like, what's the actual reference range for women? Let's say they also have symptoms. Or maybe they just want to have some of the benefits of a little bit more testosterone as they're getting into perimenopause and such. So, yeah. Can we talk a little bit about, like, women? Yeah. So the reference range, I believe it's going to depend on the lab, of course, but in general I believe LabCorp is 15 to 70 nanograms per deciliter, so, like, the rough equivalent of, you know, a bit less than maybe, like, one-tenth that of men. and for them defining low T gets a bit more difficult because you're so close to like zero essentially that one if you're not doing sensitive enough testing like you're probably not going to be accurate so that's where it's super critical that you have these levels assessed accurately through the LCMS methodology that I mentioned but also like are they doing anything that is extra suppressive on top of all the stuff men already have to consider, like contraceptives, because it's like you could be artificially inducing a state of low T that you otherwise wouldn't have, and then maybe like self-diagnosing, thinking that you have it, like what you technically do, maybe on paper, but it's like self-mediated through something that you were also prescribed that's like a hormone too. So that gets a bit tough, but in general, to simplify, A lot of the stuff we just mentioned is directly analogous to what women should look to as well. It's the same micronutrients. It's the same, just a different scale and proportion. It's the same eating enough calories and not starving yourself and leading to amenorrhea. It's making sure you have a normal menstrual period, all this stuff. and then yeah the oral contraceptives is significant and worth noting if you're on that you almost certainly are artificially suppressing yourself into like the equivalent of hypo territory for women so if you're on it I would probably check where you stand and decide if that's the medium you want to continue moving forward and for some women it works it's not to say that's something you shouldn't be on at all some women like that Some women have, like, hyper-androgen-leaning, you know, phenotypes, and they might actually maybe benefit from some suppression. It kind of depends. Like, some women need to use, like, anti-androgens to maintain, like, a more neutral profile to not get, like, hirsutism and whatnot, which is, like, hair growth that would be reflective of, like, masculine characteristics. So, yeah, like, in general, I'd be looking to that. Basic symptoms and the biomarkers, while there is a reference range of 15 to 70, I don't think you're ever going to have a doctor who's not part of like, I don't know, like the more progressive kind of like preventive, really on the cutting edge. Tell them for sure just because they were low or like clinically low that they should replace because there's not really like a, there's no FDA approved medication for women for testosterone in the U.S. There is in Australia, apparently, which is kind of wild, considering it's like the most regulated place ever. There's like almost nothing is legal there, but somehow like testosterone is for women, shockingly. But in the U.S., everything is like off-label, so you're going to have to use like a male formulation, androgel, and like apply like a pea-sized amount to your arm or something if you use it. And even that would be done with the oversight of like a pretty rigorous doctor, ideally. And one of the things I can point to is if somebody was to go on TRT as a woman, one of the things that would be freaking most of them out is the side effect profile that are irreversible. Like for men, it's not a huge deal if you had a bit of a deeper voice. Like it might be a benefit and you get a bit of hair growth, whatever. For women, if you get irreversible voice deepening, like that is quality of life destroying for some of them. And you can't just fix it. So one of the things I would absolutely do, because there are a lot of doctors now that are, like, in the cutting edge that will overshoot women based on their more, like, liberal kind of, like, women should be optimal and, like, they should be at, like, 200 total T. And I had one doctor, even when I was, like, first getting into this industry, who's, like, really respected. I'm not going to necessarily put him on blast because hopefully he's kind of fixed his protocols. But he had a cookie-cutter protocol that was, like, way too aggressive. and, like, I could, he had my mom on the protocol, and I picked up the phone one day, and, like, I didn't even recognize her voice. I was like, what the hell? And fortunately, we, like, got her off it immediately, and it's sort of, like, self-regulated to some extent. But it was, like, fast and aggressive and blatant. And I was like, if I wasn't looking for this, like, she could have been, like, for sure viralized to the point of an unrecognizable voice within a matter of weeks. Yeah, yeah. So you got to be like hyper aware, even if you think you have like the most knowledgeable guy overseeing you. I would recommend downloading like a really vetted and highly reviewed app that monitors your actual like tone of your voice to assess any sort of change in inflection, tonality, deepness. Because that's the only thing that will assess in real time that change without just some subjective assessment from your like significant other or something. because eventually if you don't, when you're seeing yourself every day and it's like micro changes, you don't really notice, and then all of a sudden one day you notice in the mirror you have hair loss or all of a sudden you have like, you know, hair on your lip that you didn't have or somebody tells you like your voice sounds deeper and you didn't even realize it was happening. This stuff is insidious, but it will still creep up quick and you might not notice the change incrementally because you're so either, the changes are still like on a daily basis you might not notice it yourself but also a lot of women are kind of with even some of them are willing to like overlook it because they feel so good with the protocol it's like my quality of life is so great now i don't want to mess with anything and they'll just stay the course and then like fuck themselves up and they don't need to they could have got the same symptom relief at like a much lower dose so wow yeah you gotta be careful if you're a woman like replacing tests especially because it's uh there are a lot of doctors that like especially the ones that have cookie cutter protocols that are like you know everyone should get to a total team you know 200 to 300 like might be a bit aggressive maybe they should like you know yeah i mean especially as you're mentioning like the the range is so small for us right for women that like i mean i i'm concerned like even trying i mean i don't know if I need it right now, but, you know, I'm not saying that I'm going to, but, you know, for women that, like, do go and get a test, again, we don't even know that they got the right test. Maybe it wasn't even sensitive enough, right? And so now they're getting on testosterone replacement therapy, and then it's like, you know, it feels like kind of like the Wild West in a way, right? Like you mentioned, there's no FDA-approved TRT for women, so it's off-label. You're kind of just going, I don't know, it feels like uncharted territory. so you know I mean like there's definitely a way to go about it that I think is net beneficial for sure it's not like clinically like it's not like there's a guideline that says like at this level equals you know you're the equivalent of hypogonadal and you should be on testosterone like it's always going to be an off label recommendation based on an assessment of like what kind of net benefit you would hopefully get out of it which for a lot of people responsible use in menopause would probably be a net benefit it if they needed it, but your deterioration in testosterone production is not going to diminish to the same degree of velocity as your estrogen and progesterone that essentially plummet into nothingness. Like a lot of the testosterone is mediated through adrenal synthesis and like peripheral tissue conversion. It's not all ovarian. So like the proportion of how much testosterone you make in each area is not going to be equivalent woman to woman. It's going to change, you know, individual genetics. so you might not have that big of a drop in testosterone or even like the perceived impact of that drop relative to another woman it might not be nearly as significant like you might be totally fine in menopause just being on estrogen and progesterone micronized or whatever um it all depends and that's where like and a nuanced assessment and like no cookie cutter protocols like there are general guidelines of kind of like where to start with things but like that's the reason you have to be like insanely educated about this stuff going in especially if you're a woman using like an off-label prescription of something that is not FDA approved like there could be a huge quality of life bump but like you gotta know what you're doing when you go in and like it sounds bad you almost like gotta know what the ideal protocol is for you like before the doctor tells you you have to like find the doctor who like you know is responsible which is crazy. Yeah, you got to do your due diligence. You got to educate yourself. No, I mean, podcasts like this are for as well. And if you find that there's a way that you could get there, like, for example, if you found out you were, like, adrenal insufficient, for example, like there are natural things that you could do on the women's side, like DHEA, I'm sure at some point we would have ended up talking about, not meaningfully impactful for men's testosterone levels because the majority is driven through intratesticular testosterone production, but for women, because you only have such an amount, it's like, you know, 15 to 70 total, a significant chunk of that could be driven through DHEA-mediated conversion. And if that is the case in your low DHEA via an assessment of the biomarker DHEAS, typically as a proxy, sulfated DHEA, you may highly benefit from like a basic DHEA oral supplement that's like, you know, easier to predict what's going to happen. It's like an actual marker you can point to as deficient based on like a validated, you know, clinical biomarker. And you know exactly what happens when like, like there isn't a, it could convert technically to different metabolites, but in general women respond favorably to an adequate DHEA dose when warranted for testosterone conversion. Like I've seen pretty dramatic changes to the degree of women on combined oral contraceptives attenuating entirely the loss in testosterone production via the progestin and estrogen-induced suppression through the DHEA. So like by that, I mean starting off with like a 70 total T, getting suppressed down to like, you know, 30 or something on your combined oral contraceptive, taking DHEA and getting back up to 70 while you're still on the combined oral contraceptive. What kind of dose of DHEA? 25 to 50 would be like what you see in the studies, but I would start lower for sure just to see how you respond because it is, again, an androgen. And women, some of them respond pretty aggressively with acne flare-ups and androgenic side effects, and it should still be treated with the respect that it deserves because it's an androgen. It will still mediate similar side effects. And some women don't respond favorably to it, and, like, you know, testosterone could be warranted depending on the person. You just got to know, like, the dose is, like, really, really small. And, like, it's probably, like, a tiny little blip of cream or gel, like, whatever you're using, it's probably going to be, just be, like, aware of, you know, and extremely cautious about, like, who you're deferring to for information on it because it's not something you want to mess with without, like, knowing exactly where your dose should theoretically put you on, like, a reference range and, like, what that might yield in terms of symptom relief or, like, benefit quality of life via, an array of people that are trusted in the, you know, like widespread community for this kind of stuff. And, you know, multiple opinions, not just like one guy who, you know, is a cowboy doc. Totally. Yeah. No, this is great info. Kind of the last topic to get to, and we've already sort of touched on it, was like some of the side effects of maybe perhaps some of this androgen, you know, therapy or hormone replacement therapy hair loss. and this is something I know you've personally talked about. It's very interesting and I sort of just want to talk about it out of my own interest. Like why does hair loss occur? Like what is the role of DHT in that process? It's kind of a crazy thing how in this day and age we have like advanced AI stuff. We have like all these like cutting edge treatments for you can like literally completely get rid of the likelihood of ASCVDs you're crushing ApoB and, like, different things of this nature. But, like, hair loss, no one has a fucking clue what happened or how to prevent it without just crushing your DHT levels, essentially, which is wild that that's still a thing. But as long as I've been researching this stuff, there's been people that are like, oh, the solution's on the horizon. Like, every two weeks you'll see some viral article on Twitter. It's like, UCLA scientists found, like, Rodan regrew all his hair after shaved from, like, random thing. like oh my god D-ribos is the solution I'm going to go dump it on my head you should see the nutty shit that people on like Reddit and what not dump on their heads yeah I think so porophane was one too broccoli sprouts on the head didn't end up working though I'm sure it has like some indirect benefit for like systemic health but like at the end of the day the unfortunate reality inherently in the name of what it is is what is causing it which is androgenic androgen mediated alopecia. So the miniaturization of hair follicles mediated by androgens, primarily the one that is the most potent in its androgenic activity, which is DHT. And these hormones, it's not just like they convert and then have like in the blood or like at the liver or something. There is like tissue-specific concentrations of enzymes that are more prominent. And in particular, in the skin, in the scalp especially too, you will have, there's way more 5-alpha reductase density in men for converting testosterone to DHT. So that like local reaction where you're converting more testosterone into DHT is resulting in like a significantly high per surface area amount of DHT than like any, almost any other area in the body with exception of like other skin areas that They're hairy, you know, the prostate as well. Like the scrotum, when you apply the cream, like you actually get a bit of a disproportionate spike in DHT I mentioned earlier. But anyway, in the scalp, highly expressing 5-alpha reductase, and that conversion seems to be what mediates androgenic alopecia in essentially all cases. There are some fringe cases in men where, okay, you might have a, you know, nutrient deficiency, or you might have some weird genetic predisposition that was totally corrected by adding in fill-in-the-blank thing or you had undiagnosed hypothyroidism or what have you. Typically not the case. Typically it's pattern hair loss, miniaturization of the hair follicle, and if a lot of people unfortunately get misled by these like crazy, you know, wild stories like, oh, the solution's on the horizon, oh, just like wipe some broccoli on your head, oh, do this, And they just lose their hair and there's no recovery because, unfortunately, what happens is if you leave it for too long, the area starts to undergo fibrosis. So it's not like it's something that you can necessarily recover to baseline. If you're completely slick bald, the scalp environment is no longer habitable to, like, healthy hair follicles that are like, you know, your original hair. You're not going to really grow it back probably until they start, like, cloning hair follicles or something. So you kind of got to get in front of it, similar to ASCVD, as absurd as it sounds, like before it starts stacking because it's something that's cumulative and insidious and over time eventually all of a sudden it's a problem. So when you're young, you know, why is it? This is one of the stupidest things I hear. Why is it that when your DHT levels are at their highest when you're young, you have no hair loss, but then when you're old, you have hair loss? It's like the same reason that you've been stacking plaque in your artery since you were like a teenager, like it's cumulative. So being preventative and proactive is the name of the game when it comes to hair loss. And I'm not to say that, like, there isn't a solution that exists in the planet that somehow addresses the downstream cascade of, like, you know, TGF beta and, like, you know, the WNT pathway, all this fringe stuff that is a result of the androgen-induced transcriptional activity. but at the end of the day nothing seems to be potent enough to attenuate whatever is happening downstream so like the net result is the follicle literally like starves itself and miniaturizes like the follicle becomes weaker thinner and over time the antigen phase which is like the growth phase of the hair follicle shortens shortens shortens and over time you're just like shedding weaker and weaker hair and it's growing back thinner and thinner and eventually it's so thin sparse and insignificant cosmetically that you can't even see it. And it's just like these follicles have essentially died and undergone literal apoptosis because each one is an organ in itself individually. And once it dies, it's not going to just come back from the dead. And in that area, you know, fibrosis or undergoes fibrosis, and, like, you're screwed in that spot, essentially, unless you transplant non-AGA androgenic alopecia affected hair follicles into that dead zone. but like you need a lot of hair to offset like a completely bald head and it's like typically not possible if you've let yourself get too far gone so and it's really interesting too because these hair follicles they're not prone to the same miniaturization so like even if you transplant it from here to here like it's not going to undergo the same effect even though it's like in that area interestingly enough but these hair follicles are like highly prone to miniaturization if you are susceptible to hair loss. What makes you susceptible to hair loss? Genetics. But in general, are you going to bank on you being the one guy? Like how many guys do you know who 50 years old plus have like no visible hair loss whatsoever and it looks like they did when they were 19 years old? My dad, but his hair is gray, but it's essentially the same. Is it actually though? Yeah. Okay. Yeah. Full thick like head of hair, but it's just white. Okay. Very thick, yeah. But he's an outlier for sure. And you have a son, you said? I do. Oh, he's going to be thrilled then. Is it on the mom's side? Typically, it's thought to be the mom's dad. It doesn't always play out like that. Right, it doesn't play out always dead. But, like, that's a good, he might not have to take, you know, the hormone-crushing drugs. He might be one of the fringe lucky ones. Well, let's talk about the proactive. I mean, so, you know, what are these proactive measurements that can be done that do happen? Proactively, as unfortunate of reality as it is, you have to weigh the risk or reward on inhibiting DHT. So how far ahead you get of this kind of impacts how intensive of a protocol you have to use, as well as your, like, susceptibility to that androgenic stimulation, which is also going to be contingent on your hormone level. So if you're, you know, hypogonadal, and then you correct that and bump yourself up to, you know, high normal, like you might have just doubled your androgen load in your scalp for all you know. And the proportional increase is like magnified multiple fold because it's more 5-alpha reductase expression in the scalp than like anywhere else, essentially. So getting in front of it, the only thing like how they developed these drugs was they found that individuals that had a mutation in the gene that encodes for 5-alpha reductase seem to not undergo full sexual maturation in adolescence. and they would end up with, shockingly, the same amount of muscle mass as, like, you know, their, like, for example, siblings who weren't affected, but inhibited maturation of genitals, for example, like not full, but often end up with, like, a micropenis. That's, like, where that comes from typically. But also, no facial hair growth, really, and no temporal recession. It's, like, one of the hallmarks of, you know, they're called pseudo-hermaphrodites, which is like, I don't know, male pseudohermaphrodites. And maybe that's not like a correct term now, but that's what they are in the literature. And it is literally, these individuals have no inhibition in their capacity to produce testosterone. It is all the DHT. Now, it doesn't mean that testosterone doesn't also have a similar effect on hair follicles. It's just the magnitude of effect is so much less that if you get in front of it, like, you know, day one, unless you're highly susceptible, the inhibition via inhibiting that enzyme is likely going to be sufficient to offset loss visibly for your entire life because it's a progressive thing. And you won't even notice the cosmetic difference in hair density until you've lost like 25 plus percent of your hair. So like if I pull a hair out of my head right now, visibly it would look no different. If I pull two hairs on my head, it would look visibly no different. But once you start to get to, like, tens of thousands of hair follicles that you have on average, depending on the ethnicity, but, like, I think it's, like, 70,000 to, like, 80,000, upwards of 100,000 hair follicles on your head. Once you've gotten to the point that you're down, like, 10,000, 20,000, 30,000, all of a sudden you're starting to see visibly, like, in downlighting. You can see through your scalp and you couldn't before. You're starting to see yourself in pictures and you're like, oh, that's weird. Like, I don't remember seeing. I have to, like, part my hair weird now to cover this spot. Like, what the hell's going on? And then, like, one day it hits you, and it's devastating. And you're just like, shit, I guess I am prone to hair loss. I thought I was immune this whole time. That's not the case. Dude. Yeah, that's true. That's depressing. Yeah. Okay, so. No, I certainly don't want to leave a podcast saying, get on finasteride, we're detasteride, we're screwed. Like, there's an ROI calculation to be made similar to any sort of hormonal therapy that is not to be minimized. There are side effect profiles with these drugs, just as there is with any drugs, but I would compel you to look at the actual literature and assess what the prevalence was among those who were subjected to DHT deprivation in finasteride users and to tasteride, and it is not much different than placebo in very, very rigorous and significant high number of subject studies that were well-constructed studies. This is not something that a lot of it is media-driven. It's not to be ignored. Some people get devastated by these drugs, but it's a minority of individuals, and it's just kind of like, do you want to be one of those individuals who takes the risk or not? There are ways to assess if you're more likely to be one of those individuals. If you were a low androgen status individual to begin with, for example, I have low normal free testosterone with a borderline, you know, hypogonadal looking DHT level to begin with, and I'm still already having hair loss, like, and I already have symptoms, will crushing my DHT to nothing be more likely to result in a side effect than somebody who's, like, vital, no side, like, thriving, no issues whatsoever seemingly. Like, there is an androgen load component to assess, like, how significant of an impact it might have on your ability to support function-driven through androgens because it's like every person is going to have some degree of impact. It just might not be perceivable in any noticeable way whatsoever. Like you might have like some like few percent deterioration to your nitric oxide capacity in your erection. Will you notice that? I don't know. It depends on the person. In the studies, it doesn't seem like the prevalence is very significant. And shockingly, dutasteride is a similar side effect profile to finasteride, even in studies comparing them where you have near full inhibition of systemic DHT versus only 60% to 70% via finasteride, which only inhibits two of the three isoenzymes in the scalp. So it's like it's not there's a side effect profile. It's just overblown by media, but it's not zero. And it's definitely worth reading the literal studies yourself before you come to an opinion because there will be people who try and plant their opinion and their subjective assessment based on their experience in your mind. Like, oh, I had no side effects. It's fine. Just get on it, bro. Don't worry about it. Or I had the worst experience ever and it ruined my life. It's going to fuck you up. Join my lawsuit to sue Merck. You know, that's like the kind of like disparity in these communities. And they all have like some, it's not like they're both wrong. Like everyone has their own individual drug response. And some people have like the most insane response to Tylenol. You know, like it's not like anything is risk-free in this world. So just be aware that these are ultimately hormone therapies that you're getting on. Like it's not, it will also not dramatically, but could suppress fertility metrics mildly because intratesticular androgenic signaling does dictate spermatogenesis. That includes DHT. So like if you're reducing the DHT a lot, that might impede your fertility to some extent too, even if you're natural and have no, you know, testosterone therapy and you're like a eugenadal male. But, yeah, the most impactful therapy for sure intervention-wise is going to be inhibiting DHT. The degree to which you inhibit it will be dictated on how susceptible you are. But if you nuke DHT into nothingness via high-dose deutasteride, it's pretty difficult, if not near impossible, to lose hair as a male. Now, the most susceptible might need to be on a topical antiandrogen, or maybe their side effect profile will be superior with a lower DHC inhibition and some sort of adjunct topical antiandrogen therapy with it or some topical 5-alpha rejectase inhibition with the topical antiandrogen. It's all kind of like a bit of a strategy approach based on your individual risk profile and what you want to take. But if you don't attenuate miniaturization potential, like you're not going to prevent hair loss. You could take minoxidol all day. you could take all the pumpkin seed oil, saw palmetto, dump sulfuric on your head, do whatever you want. Like it's not going to move the needle for inhibiting miniaturization mediated through androgens, which is ultimately what it is. And for females, PCOS females, like it doesn't take that much of an androgen burden to start to miniaturize. Like it's pretty quick and noticeable. And most hair loss outcomes with women come from autoimmune-related alopecia areata, Hashimoto's thyroiditis nutrient deficiencies things of this nature they're typically not in a pattern of like androgen related miniaturization but when it is it's like often pretty obvious why and it's just more rare so like you know when people want to speculate about what caused it what doesn't cause it it's like the largest anecdotal experiment plays out in real life every day with men versus women aging and it's like who's the ones with hair loss Like, the guys, like, I know the most dialed of biohackers with infinite resources who are still bald as hell, regardless of all the special stuff they tried that wasn't, like, the drugs that work, and it didn't work, unfortunately. I would love to have a natural therapy that moves the needle, but at least for me and what my knowledge, the extent of it, it's that DHT inhibition is almost a necessity if you're prone to hair loss. The capacity to which you do it is dictated by genetics, androgen load in the scalp, and free androgenic signaling, and your risk profile will be dictated by your own, you know, tolerance based on your interpretation of the scientific literature. And then there's some adjunct stuff. Like once you attenuate the miniaturization potential for the androgen-related activity in the scalp, that's where you can then look to, you can have a bit of a top-up, like ketoconsol shampoo, for example, with like a mild antiandrogen 2 that could add some additive protection on top of, let's just say you're on finasteride instead of the more nuclear duteasteride, and you felt like that risk profile was superior, for example. Getaconisle does help. There's studies showing it's equivalent to the hair growth results of 2% minoxidil via a totally different mechanism, which is like very significant for something that's like an over-the-counter shampoo, that also you can get that attenuated dandruff to some extent, syboric dermatitis can improve the scalp environment to your scalp environment to some extent, depending on, I don't know, if you're prone to, like, I don't know, fungal overgrowth, for example. But in general, it's like a mild 5-alpha reductase inhibitor and topical antiandrogen that's just, like, a good shampoo that doesn't require, like, the risk profile of a finasteride or dutasteride. But it's, like, typically for most people, not going to be sufficient to offset it unless you're like mildly, very lightly prone. That's where you need to like layer up with the 5-alpha reductase inhibition pharmaceutically. And then minoxidil is the growth stimulant that is FDA approved and works reliably. It's just hit or miss if it works based on your own enzymatic conversion capacity. So it needs to convert into minoxidil sulfate in the scalp to actually work. And if you have inadequate sulfo-transferase enzyme activity, it will not. You could be a total non-responder even though you're using the full drug dose every day. Those individuals either have a issue with the scalp environment, like they're not getting it into where it is, because with topicals, some of the problem often is just like your scalp either is unhealthy in the environment or it's not clean enough or like you're not using a high enough dose of the drug. It all depends on the person and the formulation that you're using. But in general, if you're using it properly and at a high enough dose, you will be limited by this enzymatic pathway, and there are ways to upregulate it. One is compounding the minoxidil with tretinoin, which can upregulate the sulfotransferase enzyme and allow more of that conversion to take place. And then there's microneedling, which also seems to be pretty dramatic, turning some non-responders into, like, significant responders or magnifying the results, like multiple fold for people who are responding, just not as well as they could be, either driven through lack of adequate absorption and or lack of adequate sulfotransferase enzyme activity that also seems to be upregulated via this, like, manual, like, micro damage, essentially. Like, there are some crazy studies with individuals who have, like, burned their scalps that had balding, and then they ended up, like, regrowing hair after, which is pretty weird. Via, like, the recruitment of growth factors that, like, you wouldn't have gotten if it wasn't for that, like, dramatic event. Now, obviously, no one's going to light their head on fire, hopefully, but that's the thing. So with respect to the topical, you know, strategies like the minoxidil, I mean, And obviously, what are the side effects of that? So it's like a very terrible blood pressure drug. So it was originally prescribed for high blood pressure as low anitin. Oral? Yeah. Oh, I thought it was topical. Yeah, so what they found when they prescribed it for blood pressure decades ago was that one of the side effects, besides people fainting when they're standing up or having low blood pressure or water retention, was hair growth everywhere, including their scalp significantly. So they're like, huh, maybe we can take this drug and repurpose it for a topical for hair growth because it's like essentially a really bad blood pressure drug with a black box warning on it. And they did successfully, and now it's known to be like the growth stimulant for your hair and seems to avoid a lot of that systemic side effect profile that comes with the oral formulation. Some people still use the oral formulation. Dermatologists have seemingly adopted it, I would say, a little bit haphazardly without really accepting the risk profile accordingly because it's like a pretty, it is a bit of a sketchy primitive drug, orally especially because the liver has so much sulfotransferase enzyme conversion, enzyme activity that leads to the minoxidil sulfate conversion that you get systemically. It leads to some people like pericardial effusion, like water retention, dysregulation of electrolyte balance. It's a potassium channel opener. That's how it works. And systemically, it has a much more significant side effect profile than topically, and it's not uncommon to see people even microdosing it, getting arrhythmias and talking about chest pains and freaking out and going to the hospital. And a lot of people just get chucked on it at low dose, but it's still high enough that it causes these problems in some people. It works really well, though. but topically it's like the most benign, at least entry-level way where you can not, you can get over the counter, like you can just buy it off Amazon or at Costco or whatever. Way more likely that you won't undergo side effects using it topically, and there are some studies, many studies that show like similar benefit profiles. It's just like a bit more of a nuisance because it's topical, and you have to adhere to the protocol. but like, you know, black box warning drug from like, you know, pre 2000 for blood pressure versus like the topical reiteration that is like likely not to cause that worst case scenario. You can elevate the efficacy profile by trying to threaten no one with it, trying to, the microneedling with it. And if it doesn't work, like maybe at that point, look at the, the oral if you want, but like, that's kind of like the escalation risk. Is the tretinoin oral or topical? You would get like a compounding pharmacy to formulate it with a minoxidil because you can't buy that over the counter. That would be like you would now have gone to the pharmaceutical route at that point because you would. Typically what I would do, like if it were me, is like I'd start with the minoxidil topically. If no response, I would probably look at microneedling to ensure there's actual absorption occurring and or the enzyme activity that can be manipulated via that manual. It's not an extra drug that I'm adding. It's just like manual, like micro damage, essentially, that I do once a week. And newest literature reveals that you might be able to get away with only doing a 0.6 millimeter depth, as opposed to the old studies had everyone doing 1.5, which was like guaranteed to draw blood. I have some of my old YouTube videos where like I have like a bloody scalp in the video because of like the depth that I would be going to to be, you know, using the devices. So 0.6 seems to be potentially as efficacious with less of a cosmetic issue, quicker recovery, et cetera. And it's not more drugs. It's something that, like, I recover from quick in my scalp seemingly. You know, is there some potential downstream issues to hitting my scalp with that once a week? I don't know. But, like, so far, so good from a lot of the data that I've seen and, like, for me using it. And then from there, I would escalate to, like, the pharmaceutical compounded route at that point if you needed to with, like, the tretinoin compounded minoxidil. It's funny, the microneedling, like, I'm interested in it for skin effects. Yeah, people use on their face, too. Yeah, so, you know, it is something I'm going to do. And when I went to my dermatologist and saw, like, some of the brochures with their studies, like, because my dermatologist does actual research, and it was funny, in their brochure, it was like, there's, like, this whole hair loss area to the microneedling and some of the stem cell growth factors that they use. And I was like, hmm, what's going on here? And I was like, oh, so it's like regrowing hair. And she was like, yeah, we've done like a small study, and we added some, it was like a combination of growth factors that are involved in like, you know, stem cell production and the hair follicle. And so I'm wondering if like you, but that's why I was like interested in the microneedling too with the hair. I was like, oh, so they're essentially just making it better absorbed. You're like, you're getting, whereas if you were to put some, you know, stem cell factors on just your scalp. Like, it's just not going to get absorbed, really. Yeah, I think the majority of the benefit is likely mediated via ensuring adequate absorption of the drug because when you do microneedling on its own, like, versus minoxidil on its own versus microneedling plus minoxidil, like, it's not a comparable outcome in terms of, like, you would expect the microneedling alone group to be very significant if it was recruiting some sort of local growth factors that were dramatic. it seems more like it's probably ensuring you're actually getting this to where it was supposed to go to begin with, but maybe wasn't getting fully assimilated, which is fine if that's what it does. It's just like that's what some people need in order to get the absorption. But it could be like the difference of four extra results I've seen in some studies. That seems like a legit pathway for some men that are like a little bit skittish about potential side effects with the oral drugs as well because, like, the finasteride and, what is the other one? Dutasteride. Dutasteride. You know, you mentioned the erection, but, like, are there any other serious side effects with those that are really cancer? Neurological, potentially, through the balance of, like, neurotransmitters and zealytic versus, like, there's a whole rabbit hole to go down of, like, inhibition of allopregnenolone, which is thought to be the main thing implicated in postpartum depression, being deprived of it. And there's a literal pharmaceutical that was developed to, like, manually restore that. And women that just had birth and have postpartum depression, it seems to be efficacious. And seemingly, by inhibiting 5-alpha reductase, you may be inhibiting that, like, GABAergic signaling through that, like, anxiolytic kind of, like, calming molecule, essentially. and it results in kind of like a, it depends on the person. Like, you can get pretty severe, I'm sure you've seen, or at least, you know, depending on if you've seen the podcast or if people will talk about it or not. I've heard of this, like, post-dutasteride syndrome. See, interesting. You'll never hear about post-dutasteride syndrome, though, even though it's a way more potent drug, because it's largely a media-driven construction. It's not to say it's not real. There's definitely side effects from these drugs. But, like, there's a huge nocebo effect that comes with these drugs where, you know, I have friends who get on it and they're like, dude, I swear, like, you know, my penis is not working like it used to. I'm like, dude, like, you're probably fine. Like, don't worry about it. And it's like they've read all the stuff that could happen, and they're convinced they just, like, killed their ability to, you know, have sex or something. And it's like, you know, the nocebo effect is absolutely real and significant. and I think is accounting for a large proportion of people who think they are affected. Because you can actually nocebo yourself into, like, real side effects by believing you have them. Oh, for sure. It's very real, yeah. And there's actually, believe it or not, there's genes that you can, there's SNPs that are known that you can look at. And even 23andMe does measure these SNPs for placebo versus nocebo. And so, like, some people are more, like, susceptible to a placebo effect where they, like, believe in something and it's going to happen. And I'm like, like, I'm taking all my creatine. I'm like, yes, I'm like, I'm not getting sleepy in the afternoon. And it could be placebo, but I don't care because it's a real effect, right? Nocebo effect is the same. And again, there's snips that like some people that have those snips are more susceptible to believing that something is harming them if they're like aware of those things. And so, yeah. Well, that's interesting to know. But clarifying quick on the minoxyl, though, it's a growth stimulant. It does absolutely nothing that we know of to attenuate the miniaturization caused by DHT. So, like, the only strategy that works is attenuating androgenic activity via either, like, the mild genoconazole, which probably is not going to be sufficient, but, like, over-the-counter, pretty benign, helpful, good shampoo regardless. That's why I use it. But finasteride or dutasteride or topical antiandrogen, probably going to be necessary for most people. Minoxidil is the thing you use to regrow hair. It's not the thing that prevents loss. You can cosmetically offset the visual perception of loss via the growing of hair, but it does absolutely nothing to prevent the further miniaturization. So at some point, if you just use minoxidil, you will have a net catch-up where you miniaturize to the point that you are caught up with what you've grown, and then you blast past it, and you still end up losing your hair. Okay. I see. But you can still delay the visual perception of it still, if you're somebody who wants to avoid inhibiting hormones entirely, you know, that's a strategy. It's still, like, biding time. Transplants, bide time, you know, it all makes a difference. Yeah, but essentially if you want to completely bypass it, you have to get, you have to inhibit. Essentially. You have to, like, turn your scalp into a female. Okay. Wow. Interesting stuff, and you're... Mild exaggeration, but, like, you get it. And you've been doing this yourself, right? Yeah, I've been on due task right now for years, and at least to date I have had no perceivable detriment to my cognitive state, to my sexual function, to anything that I would point to. And I know a lot of individuals that I respect in the anti-aging longevity community who also use it and think that it's a reasonable enough risk profile for them. And that's not to say that that means I endorse it or I don't endorse it. I just use it and I've been okay to date, knocking wood, because maybe something will happen. I don't know. Are there any long-term studies looking at? Yeah, because these are drugs that are used for benign prostatic hyperplasia and even at dosages up to 2.5 milligrams daily of dutasteride has been used with great success with individuals with a minority of prevalence of side effects and they're relatively minor. from what I've seen. The longest study that I know of off the top of my head, there's definitely studies assessing follow-ups of individuals who've been on it for like a decade plus, I think. Have they looked at like all-cause mortality or any of these? If any, okay, this is going to be a controversial one, but my speculation is that if anything, these would net, would increase your longevity because they're decreasing androgenic stimulation significantly. because DHT is literally the most androgenic hormone in your body, and if you're inhibiting it and you're just left with the testosterone and the anabolic activity, because DHT is entirely inactivated in muscle tissue, so you get no muscle growth benefit. Graded dose response studies using dutasteride alongside testosterone, even at super dosages, the dutasteride getting wiped out had no impact whatsoever on strength and muscular hypertrophy. So, like, there's no benefit muscularly to DHT in any capacity as an adult. which is notable because a lot of people think their physique is going to deteriorate if they use one of these drugs. Not the case. It has no impact on it whatsoever. So I would think, especially somebody who's on TRT, and, like, candidly, I don't take enough to put me at 400 total T. Like, I take enough to put me at, like, 800, and, like, my free T is, like, the high normal. I think that the dutasteride, like, probably whatever, like, excitotoxicity or cardiotoxicity that I might otherwise be like netting over into like an area I wouldn't want, I would anticipate and speculate that the DHT reduction is probably inhibiting that whatever detriment might be there to some magnitude. Could be wrong, but like I have a net increase in intratissue aromatization from the inhibition of the 5AR enzyme. So like in, you know, all the tissues that would otherwise be like pro-longevity from estrogen locally, you're getting a benefit. you're getting the proportional increase of 15% to 20% of intratissue estradiol. And if you don't have any side effects from that, if anything, you would think, okay, well, it's probably vasodilative. It's probably, like, more pro-antioxidant. It's probably less excitotoxic. It's probably less glutaminergic, like, all the stuff that is going to be potentially damaging of, I don't know, killing of brain cells. That's just a speculative thing, though. I wouldn't hang my hat on that or tell anybody that that is the case. I do think if there was some sort of direct study, though, that would be interesting. I was just going to say the same thing. I'm pretty sure there is some anti-aging studies on finaster and dutaster, though, that might. I wish we could pull it, but we don't have the. Yeah. Well, it's something to dive into later for sure. and maybe, you know, it'd be nice to have a study to see, like, people that are on TRT and, you know, doing these androgen, you know, blockers, like, how that affects life expectancy or cardiovascular-related disease, right? Yeah, and just, like, wrap it up on the hair loss front. Like, just because I do something, like, it does not mean I endorse it because it's a very controversial topic. Side effects are real, not to be ignored. some people they deem the risk profile worthwhile to the benefit they get the depression and mental anguish they endure from going bald might outweigh the risk profile it's all an individual decision don't listen to a guy on a podcast who tells you he uses something as your indicator if you should use a heavily hormone modulating drug like these are like very significant drugs that should be respected accordingly yeah yeah for real thank you um well this This has been a very interesting conversation, Derek. We've been talking for, I mean, just hours. I don't even know how many hours. Eight? Was that your first double pod? That was my first back-to-back. Oh, really? Yeah, especially like long podcasts, too long podcasts back-to-back. Oh, cool. So it's been a fun day talking to you. Thank you so much for coming on the show, talking all things hormones. Very informative. I've learned a lot. I have a lot to look into. I've made mental notes of things that I want to look into and I'll go back and when I read the episode again read the transcript of the episode I'll go back and look at some of these studies so thank you so much for coming on the show and you obviously have a big YouTube channel podcast called More Plates, More Dates where else can people follow you? You have your healthcare company, Merrick Health Yeah. I think Merrick Health on social media is just at Merrick Health, or the website is MerrickHealth.com if you want to check it out. Yeah, I think I'm more placed, more dates everywhere except Twitter. I don't think that was a handle I could get, so I think I'm just Derek Fitness there. But, yeah, that's me. Awesome. Well, thanks so much, Derek. Thank you for having me. I appreciate it. 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