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

25:38Derek:And you know, if you're somebody who has, like if you if you looked at blood work, for example, some individuals think, oh, the guy with a natural like 1300 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.

26:33Rhonda Patrick:What will, you mentioned the gonadotropins, like what would 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? I mean, it's...

26:48Derek: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? Are they 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 um 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 light excels 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.

28:19Derek: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. worry so you would if you're a primary hypergonadial you would see the reflection typically of high gonadotropins um 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 percent of males have a varicocele 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.

29:14Derek: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, you know, 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 like typically the first thing you would look to is like am i capable at the organ of responding to the signal and like is the signal adequate to begin with because if there's like a primary hypogonadal outcome it would be some sort of like structural response problem in the testes themselves if that's not an issue and you've ruled out all structural problems, you know, age-related decline is not a factor, and you're, you know, otherwise, you know, everything's all accounted for from that angle.

30:03Derek:You would look upstream to the pituitary, and it's like, 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 like a lot of men who are kind of like 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 uh 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.

31:08Rhonda Patrick:Yeah, we're going to get into a little bit, but okay. What about the sex-binding globulin hormone, S-B-G-H.

31:17Derek:S-H-B-G, sex hormone binding globulin.

31:20Rhonda Patrick:Sex hormone binding globulin. What about the sex hormone binding globulin? Like you're talking about like 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, can you like dial in looking at just that binding protein itself to help kind of solve some issues?

31:59Derek: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 you know 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 test versus total test 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.

33:06Derek: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 oral, 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.

33:45Derek:But you'll see in adolescent women or women who are, you know, in full adulthood that are taking combined oral contraceptives, their total testosterone will suppress upwards of 50 to 60 percent and free testosterone upwards of like 70 to 80 percent. So they're walking around like borderline asexual castrated by a pill, essentially.

34:05Rhonda Patrick:And that's only with oral contraceptives?

34:07Derek: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 levo-notrogestrel 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 gobbed up could be like the differential between you being symptomatic versus not, as well as your free tea.

34:56Derek:Even though it's proportionally less gobbed up, the DHT could be like nuked entirely essentially via the SHBG levels being high.

35:03Rhonda Patrick: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?

35:13Derek: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 1 % a year, your free test will decrease by up to 2 % 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.

35:58Derek: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, 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 were 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.

36:37Rhonda Patrick:so and this is also something that would be relevant for females too right yeah and these

36:41Derek: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 bound like the the total production looks okay but it's because it's factoring in all these like bound up hormones that are in use like

37:15Rhonda Patrick:unusable essentially is that something that's common like i mean would you say that's uh it

37:20Derek:depends on the person and lifestyle so but yeah probably especially among women because i 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

38:19Rhonda Patrick:libido is like totally down perhaps like they're having a harder time losing fat gaining muscle losing fat um it might it could come down to this right bone integrity bone integrity right

38:31Derek: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 impacts the fat impact of being you know obese and then if you have women who deal with all those same problems you're gonna 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.

39:14Like, you know,

39:15Derek: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. Like there are absolutely better ways to go about it. I'm just giving a examples that I see as commonplace.

39:42Rhonda Patrick:No, no, this is great. This is great information. You know, since we're kind of talking a little bit about symptoms, let's kind of circle back to talking about like, 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, mean, okay, this is testosterone or other things.

40:10Derek: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.

40:53Derek: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, it might be a combination of both. You no longer are able to hold muscle as easily or build muscle as easily. You're losing strength in the gym. Your recovery capacity is inhibited relative to what it was when you were younger.

41:16Derek: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.

41:56Derek: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.

42:09Rhonda Patrick:Right. Yeah. So then that in combination with the test and things that we just talked about is kind of like where.

42:14Derek:Yeah. You know, 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.

42:53And then you mentioned even in general, in general.

42:56Rhonda Patrick:Right. Right. On average. Like, yeah, exactly.

42:58Derek:There's and that's where I have absolutely seen seven year olds with 900 total T's.

43:03Rhonda Patrick:So 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, you know, its function essentially.

43:51Derek: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 uh output of signaling hormones which indirectly will also impact body composition which you know the whole downstream cascade of that um smoking obviously not helpful um how much alcohol is it is it like

44:30Rhonda Patrick:any amount or like light drinking moderate drinking i think like obviously the safe answer

44:37Derek: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, uh, 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 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.

45:18Derek:Like it all depends. 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 your way there is a, you know, it's a transition of, you know, shittiness as you arrive to that like worst case scenario. Um, so, uh, other things I could point to, um, 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. Um, also if you have a void of carbohydrate intake diet, it would also be something that would inhibit freely circulating hormones from liberating themselves.

46:01Derek:Um, 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 um 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.

46:41Derek:Or even like you mentioned in 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 vitamin 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 eight to ten 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 multivitamin so 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 debt like is a deterioration of, you know, 100 plus nanograms per deciliter per deficient micro potentially, depending on how severe the deficiency.

48:12Derek:Other things I get pointed 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.

48:56Derek:You don't need to make enough testosterone, more testosterone because I have enough estrogen. That's 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're 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.

49:34Derek: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, you know upwards of i would love to give hard and fast numbers but it could be like significant like half of a reference range maybe you know but it could be the differential between you being you know the quality of life of you're fine versus you're blatantly in you know severe deficiency and what else could i point to um what does weight loss do to to the to those levels like

50:13Rhonda Patrick:if you are someone that's obese and then you lose weight, does that bring you back?

50:18Derek: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 will 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.

50:59Derek:So there's a 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 it's 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 like 12 to 15 percent body fat ish will find that they have a increase in testosterone dramatically relative to when they were obese and it's like super significant and how much it will improve hormone status. So and then the sleep, I think I might have already mentioned that.

51:39Rhonda Patrick:Yeah. What 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 for with respect to maybe factors to avoid. What effect is like excessive endurance training have on testosterone? Because I thought I came across some literature where it was a negative effect. I wasn't sure like how robust.

51:59Derek:I think it is pretty dramatic pending and exceeds your capacity to recover. So that sounds like a weird way to answer the question. But like some people have a higher tolerance for stress. And that's, you know, reliance 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 all there are cases that you can point to of what happened to natural bodybuilders as they diet for a show.

52:56Derek: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 nourished that you are inhibiting your actual capacity to produce hormones adequately 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 to begin with that's kind of what happens when you get like really really malnourished and 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.

53:51Derek: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 hypogonadism easily.

54:08Rhonda Patrick:I kind of like.

54:09Derek:I would caveat not easily. It's hard to train that hard.

54:12Rhonda Patrick:Right. Yeah. Yeah, no, it's definitely not easily. Like there's not a lot of people that are.

54:16Derek:Kudos to the people mentally strong enough to do that, I guess.

54:19Rhonda Patrick: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? 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, it 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.

54:57And I definitely got shredded-ish,

55:00Rhonda Patrick:but like I became a broneretic for several months, you know, where I just didn't get my period and I wasn't ovulating. And so I had to add back the calories in the food. It was like, and it took a while. Yeah. Or my body kind of like recalibrated.

55:15Derek:Yeah.

55:15Rhonda Patrick: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, OK, I'm not getting enough calories. Reproduction is not essential right now. Survival mode. Right. Not reproductive, not reproductive, like happy growth mode. It's like survival mode.

55:30Derek: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.

55:54Rhonda Patrick:That's wild. Yeah. That's wild. Just to kind of sum up the like factors to avoid.

55:59Derek:Not always, but sometimes.

56:01Rhonda Patrick:I wanted to get your opinion on endocrine disrupting chemicals. Like how have you or has your, you know, your company looked or seen anything or do you have any speculation into like what the scientific literature has shown in terms of them affecting hormone levels?

56:22Derek: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, I think that'd be solid.

57:08Derek: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 at me. Like it must be that or it 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 to glass where you can, don't use plastic water bottles, stuff like that.

57:54And there is blatant

57:57Derek: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 uh 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 mental toxins to like do things in the body.

58:42Rhonda Patrick:What do you, 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, not necessarily just the increase in, 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.

59:26Derek: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.

1:00:13Derek:so you know like you 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 like eating less food you know go to the gym etc 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.

1:00:46Derek: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.

1:01:12Rhonda Patrick: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, and consuming it, like, or really, like you said, hot, like heating up the plastic or like hot beverages, like going into like something plastic. But yeah, 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.

1:01:50Rhonda Patrick: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.

1:01:57Derek: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 etc 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.

1:02:46Derek:And the carbs for actually mediating, and this is going to depend on, you know, activity levels, how demanding of exercise you do, if you burn through them versus not, if you're sedentary versus not. But in general, it's going to be 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'll, 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.

1:03:25Derek: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.

1:03:55Rhonda Patrick: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.

1:04:37Derek: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.

1:05:01Rhonda Patrick:Well, what you're saying is like, get your hormones measured, measure them right and make sure that you're monitoring. Yeah.

1:05:06Derek:Be informed before you like freak out about anything.

1:05:08Rhonda Patrick:Right. Yeah. With respect to other sort of like lifestyle factors that can maybe boost testosterone. So we're talking about dietary factors here. What about exercise? I, you know, 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?

1:05:28Derek:Yeah, I think it's kind of like in the simplest way I could put it is like descending order of intensity, essentially. So like, you know, weightlifting at the top and then you have like some of your more like HIIT 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 what's the perfect thing like 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.

1:06:23Derek: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.

1:06:56Derek: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. Yeah.

1:07:16Rhonda Patrick:With respect to some of the micronutrients, it kind of, 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

1:07:52Derek:more about that if if you want yeah like in general I think the most reliable things that move the needle if you were deficient what is I don't know people are familiar with the ZMA it was like a the first like combo supplement that was sort of seen as like a testosterone booster that was available on the market. And it's, you know, like 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 know, otherwise would get through your diet, but likely non-sufficiently.

1:08:32Derek: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 um which is not that complicated i don't want to make it sound super complicated like a lot of them are fine ronda has great articles on magnesium formats that are bioavailable and yield more than enough magnesium um and yeah the vitamin d having an adequate amount making sure you're converting it and actually getting the activity from it.

1:09:10Derek:Mechanistically, there is some level of like gene transcription capacity facilitated through these like like vitamin D to 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 through vitamin D supporting it.

1:09:47Derek: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.

1:10:01Rhonda Patrick: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?

1:10:19Derek: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.

1:10:35Rhonda Patrick:Most of them are, I mean, at least vitamin, vitamin D, magnesium, pretty common. Yeah. Yeah.

1:10:39Derek: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 would have, you'd be speculating at best.

1:11:18Derek:So, 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 a vitamin you need almost regardless

1:11:35Rhonda Patrick: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 tongat ali i mean yeah let's dive into that like are they effective which ones are effective which ones are hype

1:11:48Derek: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 the high end of the reference range to something that's much better. 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 was like 6 to 12 milligrams and can be meaningful for actually liberating free testosterone not for actually producing more total tea um the other one that's probably worth mentioning ashwagandha specifically uh extract that is standardized to a sufficient quantity of withanalyze not just your standard run-of-the-mill generic ashwagandha you want to look for ideally a patented you know uh sensorial 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 you know certificates of analysis from china of a generic extract so i would what was

1:13:24Rhonda Patrick:that compound they're standardized to again with analytes okay it's like the it'll show right on

1:13:29Derek:the label it'll be like ashwagandha bracket standardized to x percentage with with analytes and depending on if you have ksm 66 that's five percent sensorial is ten percent 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 and is that actual is that the active compound that affects testosterone yeah it seems to be and when i say testosterone yeah it's like the indirect effect via suppressing cortisol seemingly and kind of like the stress response manipulations that I 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.

1:14:26Derek: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's just like black and white.

1:14:39Rhonda Patrick: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?

1:14:54Derek: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, augmenting supplements, just be aware of the mechanism of how it works based on your own individual biochemistry. because this is not something like a vitamin D that you can just sequester into sub-Q fat and just like get rid of at some point.

1:15:32Derek:It's like it could impact your mood regulation quite significantly for a bit, depending on like what your neurotransmitter balance is at baseline. Like if you are already borderline, like emotionally numb as a person and you take astrogondra, like you might literally like cease to care about anything for all I know.

1:15:50Rhonda Patrick:That sounds awful. Yeah. But I mean, for someone who is more of an anxious phenotype, like.

1:15:54Derek:600 milligrams. 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 um 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.

1:16:29Derek: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 stress response can be very, very net beneficial. And then on top of that, improves their sleep and also improves their testosterone through the 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 extracts. Just be aware of that. But at least from what I've seen in blood work anecdotally, too, it seems to work. Tonkat Ali, another very notable one.

1:17:02Derek: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 like positively or negatively modulates them in selective tissues. So there are certain tissues where it 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 activity in bone, for example, because that would cause bone degradation.

1:17:43Derek:having an inhibition at the hypothalamus level 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 uh upregulation of steroidogenesis um intratesticularly so like locally upregulating i believe it's steroidogenic acute regulatory protein that basically incorporates um cholesterol into the mitochondria to actually undergo these enzymatic cleaving uh 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.

1:18:40Derek: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. um 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 nanogounds per deciliter for some people and depends on how potent of a standardized uh extract you get you want to look for one that is hplc tested for uricominone that's the active ingredient in tongkat ali that actually has the bioactive effect that you're looking for there are a lot of tongkat ali supplements that just say tongkat ali or it'll say tongkat 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 tongkat and even if you did there's no indication there's any uricominone 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.

1:20:02Derek:And here's a third party test to verify it. So.

1:20:05Rhonda Patrick:And what was that ingredient called again?

1:20:07Derek:Uricominone. Got it. E-U-R-Y-A-C-O-M-A-N-O-N-E, I think.

1:20:15Rhonda Patrick: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.

1:20:26Derek: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 and I don't want to misspeak. Yeah.

1:20:49Rhonda Patrick: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, which 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 sounds interesting.

1:21:14Derek: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 Tonkhead 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's 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 um 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 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 are there any others you know i hear about you know

1:22:22Rhonda Patrick:the fenugreek and then the some of these like diasporic acid or are there any others that are

1:22:29Derek:notable or would you say more hype um i think a lot of those have been disproven like tribulus D 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.

1:23:11Derek:So Shilajit seems to be impactful on intratesticular antioxidant activity, but I wouldn't, uh, it's another one that requires like careful sourcing. And it's also one that's like more speculative and indirect. Cause like there probably better ways to manage your antioxidant profile, I would think.

1:23:33Rhonda Patrick:So your top four supplements for testosterone would be?

1:23:40Derek: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.

1:23:56Rhonda Patrick:okay great unless and and then if you're like the anxious person at it yeah ashwagandha and just be

1:24:01Derek:like cognizant of what it's how it works because you you may be able to get the benefit at a lower dose you may be able to cycle it um 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.

1:24:26Rhonda Patrick: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 do, I am interested in, 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 so i think that's going to be another experiment of mine that i try out um check your blood first though yeah no i've that's already told you i want to get my my hormones it's i've had them measured but like i don't feel confident i haven't had repeated measurements

1:25:08Derek:because once you get that blood test you're gonna be like fuck i shouldn't have taken ashwagandha

1:25:11Rhonda Patrick:because now i have no idea what this means what the 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.

1:25:22Derek: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 like transient serum cortisol levels will be. Oh, really? Yeah.

1:25:39Rhonda Patrick:And because.

1:25:41Derek:it's just like the snapshot in time and it in the serum is just like not an accurate reflective measure um the salivary levels will fluctuate and they get like multiple readings they create like an average curve for you and they should map out your day as opposed to with blood you 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 it's like less intrusive to like spit in a tube you know or whatever right and do they and do

1:26:21Rhonda Patrick:usually you spit in multiple times a day to kind of get yeah i've actually not done a dutch test

1:26:26Derek:personally but i'm pretty sure it's just you spit in the tube yeah yeah okay um good information

1:26:33Rhonda Patrick:let's kind of transition to like people that have let's say like we're 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 um area now of actual

1:27:17Derek:testosterone replacement therapy so um like 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 yeah there's no issues you're not like cooking your testes in like a hot tub every night you're not uh 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 probably indirectly touched on this but like via 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.

1:28:05Derek:It's like adequate amount of calories, not overdoing it, not underdoing it. If you've done all 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 you're 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 lighting cell um or use some you know some of these other like augmenting you know steroidogenic supporting things like tongkat or whatever but if that's not working either like your your testes are cooked and you got to be on test at that point because you're just not responding to any natural stimulation whatsoever.

1:28:59Derek: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 hypogonadal symptoms through like the pituitary, either inadequate output or insufficient response to that output plus an insufficient amount coupled with it coming out to the pituitary there's not a lot of people that are literally showing up if like your testes don't respond whatsoever um in those individuals like it's app it's kind of like if you've exhausted all resources you've tried the whole manual stimulation directly because hcg 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 FSH2, exogenous.

1:29:49Derek:It's like, if you're still not 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 hypergenital, like you're going to probably be on exogenous testosterone and it's literally like testosterone. You can't fix it with enclomiphene. You can't fix it with HCG. 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.

1:30:15Derek:like you can't produce it so there's that um and there's different ways you can take it of course which we could you know get into later but the next situation that's a bit more relevant is like the secondary hypogonadism situation where somebody has pro like testes that function just potentially to like a suboptimal capacity and there might be some level of like low gonadotropin output facilitate facilitated through some level of like lifestyle or diet or whatever um like peter for example like 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 testes responding to like a manual signal and they were and he's like replaced his 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 with signal or do you want to take hormones pending you've done all the exhaust of you know uh 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 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 um 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 testes may just be like suboptimal for your response to be adequate through often age-related decline, but it's a culmination of things.

1:33:02Derek: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'd 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 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.

1:33:42Derek:And you can like weed it out really quick. Even if the doctor seems well-intentioned, he wants to help you, he wants to 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 done something else? Could I have maintained the signal from my brain to my testes this whole time and I'm just missing something?

1:34:14Rhonda Patrick: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.

1:34:45Derek: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.

1:35:02Rhonda Patrick:That's the best way I could put it.

1:35:04Derek:Now, again, it's 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. And 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.

1:35:38Derek: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 uh 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 to like get rid of the negative and get to a baseline and indirectly you will feel much better so it's like you will feel better from a result of it, but like don't expect to be Superman unless you're, you might feel like Superman relative to your state.

1:36:13Derek: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.

1:36:24Rhonda Patrick:Right. So you're not like necessarily going to be shredded in a couple of weeks. And 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 gonna go straight into like i'm just gonna take some testosterone right and i think that would be the case to avoid right if you're not especially 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

1:36:57Derek: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. Like I know guys with three times the amount of testosterone production, much worse physiques. Like 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. Like 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.

1:37:33Rhonda Patrick: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. there's the the traverse trial that came that's kind of we got some pre pre public like pre pre data here where it seems as though this is 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's no really adverse effects on cardiovascular outcomes.

1:38:24Rhonda Patrick:What's the thought here with respect to cardiovascular disease risk?

1:38:31Derek: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. Like it could vary so much. So 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.

1:39:24Derek: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 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 you're you know 200 milligrams of testosterone enanthate per week that you're like you know more uh aggressive protocol has been designed to do is like going to be the same outcome.

1:40:09Derek:Like it's not. You're going to have the erythropoiesis increase that might not be reflected in the traverse trial. You're going to have the disproportionately high endogenic signaling. Like you're going to have a lot of things that you would or you're looking to get the reassurance that won't happen, but you have absolutely need to be cognizant of because will probably happen still.

1:40:31Rhonda Patrick:No, this is this is so important. And that's kind of why I was like, Like these are hypogonadal and, you know, 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 erythroparesis. And so this is another kind of concern, you know, 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 percent of men have thicker blood that are on testosterone replacement therapy.

1:41:18Now, it doesn't necessarily mean it's like to the point where it has to be treated, but it is thicker.

1:41:23Rhonda Patrick:Right. It is like the hermetocra is thicker. so um you know how how should men weigh these risks for the cardiovascular disease risk the polycythemia so for people like listening or watching that isn't a concern because it increases you know stroke risk it increases the the potential for um you know cardiovascular events as well so like what are your thoughts on sort of weighing those risks um to the opposite

1:41:55Derek:side of the coin on that androgel you know like it's not necessarily physiologic replacement the thing to note is it 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 hypogonial 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.

1:42:42Derek: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, is like the definition of symptom relief too is so vague because you could achieve some 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 yeah 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 drive rethropoiesis.

1:43:23Derek: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 daily you know little pulsatile uh 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 traverse 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 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.

1:44:38Derek: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 gonna have to keep an eye on your blood work you're still gonna 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 I get.

1:45:31Derek: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 most people are supra, at least transiently, without knowing it. And by that, I mean, by super, 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, 1200 or 1500 total T with a disproportionately high free testosterone from administering once or twice a week, twice a week's a bit quite a bit better, but once a week, for example, and then it crashing back down before you shoot again.

1:46:20Derek:like that's not physiologic really at all so you need to be aware that's going to cause more uh 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 the problem too is like the pharma 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 pre-loaded so you like have to shoot it in one shot or you don't take it yeah so like zyastat is like the pre-loaded testosterone and an anthate pharma grade that is often prescribed.

1:47:17Derek: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.

1:47:24Rhonda Patrick:So you're touching on an important point here, that supra physiologic level, like the amount that you wouldn't necessarily have in like a 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 what's what's wrong with the cream like is 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 I mean it depends on

1:47:56Derek: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 that's not i mean i get

1:48:30Rhonda Patrick:that but like you know like stroke risk cardiovascular disease oh yeah if you want to be

1:48:35Derek:optimal. The problem is a lot of people will favor adherence and sustainability similar to diet over optimal. And that's fine. You have to be accepting of the risk profile that comes along with it.

1:48:48Rhonda Patrick:Okay. What about other like parts of the risk profile? So like, how does it affect the prostate? I read about fertility. I mean, being a big one too, it's suppressing fertility. Sleep apnea can be exacerbated as well. I mean, these are all like part of the risk profile things to consider.

1:49:06Derek: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 hyper... Oh, yes.

1:49:19Rhonda Patrick:Yes.

1:49:19Derek:Okay. But go ahead.

1:49:20Rhonda Patrick:Please explain it. Yeah. So essentially, from what I understand, based on most recent literature,

1:49:27Derek:it shows that if you go from hypogonadal to eugonadal, or like the threshold of it, which is like, you know, on a reference range, roughly like 300 plus milligrams per deciliter going from hypo to that, that differential will be positively stimulating of like prostate growth, you know, PSA levels will go up, et cetera. 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 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 pre-existing cancer cells like you're not gonna just like spawn cancer from taking testosterone so So I think that risk is a little bit overblown.

1:50:31Derek: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 eugonadal 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 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're if you were low t to be 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 um like these are all kind of like the kind of like the maximization of the male secondary sexual characteristics being like pushed to the nth degree um within physiologic parameters um 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.

1:52:36Derek: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 there are actually like pretty reasonable at home devices that measure like apnea episodes per hour that will like essentially put you on a chart of how many episodes of like ceasing breath.

1:53:12Derek: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 in 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 um just like any of this stuff is um but if you're physiologically replacing, like the risk is relatively low.

1:53:41Rhonda Patrick: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.

1:53:49Derek:Even transiently. Transiently. In blood work, if you, for example, if I'm on Zyested 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 cypionate 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.

1:54:26But the reflection of that in blood work is you would

1:54:30Derek: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, 1300, 1400, 1500 total tea with the proportional five alpha reduction to DHT suppression of SHBG disproportionate freeing of free androgenic signaling via more DHT being free than would otherwise be normal. More free tea 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.

1:55:06Derek: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 i think that's the reality for a lot of guys even in europe they do testosterone, uh, undecanoate maybe, or it's either a sustenone 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 tassi into the stratosphere and then they'll like crash into hypogonadal territory and then they pin again or shoot inject.

1:55:46Derek:That's what I mean by pin.

1:55:47Rhonda Patrick:Yeah. I mean, so it's like a roller

1:55:50Derek:coaster of like, I can imagine it's like the equivalent of what females deal with times like

1:55:56Rhonda Patrick:some magnitude i mean it it sounds they must be like also just like are they get aggressive and

1:56:03Derek:stuff and like what irritable regulation would be like impossible to expect you know like i don't know like i wouldn't want to wish that on uh anyone like that would suck i mean to me so

1:56:16Rhonda Patrick: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 you're 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?

1:57:01Rhonda Patrick:Maybe you're not someone that's totally hypogonadal, but like, you know, low T symptoms, right? Lower T and symptoms. What would, what you're aging when you're an aged, 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?

1:57:22Derek: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.

1:58:17Derek: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, uh, quality of life down the, you know, the toilet territory. If you're like in hypogonadal levels, almost certainly.

1:58:57Derek:So hopefully that's like somewhat of a consolidated to wrap because I don't want to like sound too, uh, 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 to like, it's critical that you have adequate hormone production, similar to women in menopause. Like the, the benefit outweighs the risk. So, like, essentially every single time, essentially, and you just have to be responsible for your approach to what that is.

1:59:28Rhonda Patrick: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.

1:59:38Derek: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 we 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 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 um 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 cream 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 uh 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 uh 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.

2:01:45Derek: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, 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.

2:02:28Derek: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.

2:03:17Derek:Likely achieved 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 as 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 as like a different medium of getting like an erythropoiesis stimulating free version of tests because it's so acute.

2:03:54Derek: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 you the novelty would probably fade um like a lot of guys are you know super excited when they start testosterone injections like it's like this rush you're using like this hormone and it's, you know, I'm replacing and it's, you know, it feels like this big significant thing.

2:04:30Derek:And then, you know, year in, it's just like, oh, I 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 thought he cleaned it.

2:05:12Derek:And his kid was like starting to get masculinized from the from the testosterone residue or something. Wow. Yeah. Crazy. because it's like the levels are so low like any like significant amount will like 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.

2:05:46Derek:So yeah, there's like different like logistical advantages too to some of these administration methods that probably should not be understated but are worth mentioning. 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, all but I want to see more of the literature as it evolves.

2:06:15Rhonda Patrick:Right. So it's kind of a newer thing. And when it comes to the injections, it sounds like more frequent sub-Q is like subcutaneous is like where you're going to get more less of the probability of having that supra physiological peak versus like if you're just doing it once a week, intramuscular, not bleeding out that like 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 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 fertility what about men that are wanting men that are wanting to reproduce yeah we gotta

2:07:06Derek:talk about that too but one rule of thumb that's like to make it as easy to understand at least for me this was 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 testes producing natural testosterone that's going to be the one that has the least impact on all of the un like intentional consequences of like spikes and hormones so like 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.

2:07:49Derek: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 a significant mediator of spermatogenesis.

2:08:32Derek: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's 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.

2:09:14Derek: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 response to that gnrh to then produce the gonadotropins which are the luteinizing hormone lh and the fsh follicle stimulating hormone just like in women goes down to the gonads and the thing that happens is you produce intratesticular testosterone at the lytic cell um and women do too it's just uh theca cells instead of you know lytic cells um and that intratesticular testosterone mediates spermatogenesis in unison with the Sertoli cells, which are also supported by follicle-stimulating hormone.

2:10:21So if you have exogenous testosterone,

2:10:24Derek: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 can not produce any more GnRH because like, why would we need you to? We have enough hormones. It's like, okay, well, let's turn that off. Let's turn 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.

2:11:06Derek: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 and it's very rare that I see guys who are actually like not truly fully hypogonadal like their testes still work they just hit inadequate signaling or something via like secondary hypogonadism. If those individuals maintain the signaling, you can retain the structural integrity for the most part of the testes.

2:11:48Derek:And then if you want to get pregnant or whatever, you are either a 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 fs from your pituitary to your testes you maintain structural uh the size the functionality sperm production etc 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 hcg 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 um and you know there's some speculation as to if hcg is like healthy to be on as a guy like you're taking like an extract of like women's urine it's like a light excel stimulator similar to lh and 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 lighting cells 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 uh therapy it's just very cost prohibitive Like the cost of recombinant FSH is insane and HCG in itself is expensive.

2:14:19Derek: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. And I'm sure like you could speak to like it's easier to keep stuff where it is than is to try and like regain health. So if you've literally atrophied an organ until 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.

2:15:01Derek: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 uh health of the sperm for all we know um 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

2:15:31Rhonda Patrick:you're on testosterone and you want to sustain the fertility but it's possible to sustain it a lot of

2:15:36Derek: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 really more difficult roads to recovery because of just bad information wow i mean that's 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 the baseline through like insane aggressive dosages of hcg and fsh like

2:16:11Rhonda Patrick:not cool so at what point does that atrophy start to occur i mean like how long do you have to be on you know trt before that really starts to happen um it's pretty quick because like the suppression of the gonadotropins happens like within days like once you start to inject that

2:16:32Derek: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

2:17:07Rhonda Patrick:so this is also kind of important to point out for like guys that are you know cowboying it and trying to like they want to they want to get their t up for like maybe some muscular effects or something right and they're just kind of like maybe not hypogonadal but like lower range yeah

2:17:23Derek:very seriously like it's a 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.

2:17:40Rhonda Patrick: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?

2:18:01Derek:Mm-hmm. Yeah.

2:18:02Rhonda Patrick:I think hematology, you know, this kind of like covers the basics of, you know, red blood

2:18:10Derek:cell count, hematocritic 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 like 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 tea and free tea 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 they 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 like 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.

2:19:36Derek: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 could 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.

2:20:18Rhonda Patrick:I don't know what they stand for either.

2:20:19Derek:Yeah, one of them is like asymmetric dimethyl arginine. One's a, yeah. So one of them assesses vasodilation potential and one is more of 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 creatine 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 creatine 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 um you have your kind of like metabolic parameters to see your insulin sensitivity hemoglobin a1c you know all the kind of basics um i think uh the lipid panel definitely a baseline htl to see how much it gets lowered by the dose of testosterone you're you're using because you will likely see a suppression if you are elevating your testosterone beyond what you were at 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 it's one of the proxies for kind of like androgenic activity shbg and 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 with guys on trt 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 to 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.

2:22:47Derek:So what else as far as assessing free tea and total tea 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 a 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 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 immunoassay tests. You want to be using sensitive assay estradiol every single time, sensitive assay testing for total T.

2:23:32Derek: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.

2:23:57Derek:And what else?

2:24:01Rhonda Patrick:I'm probably missing some stuff. Basic liver markers would be to have like,

2:24:04Derek: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.

2:24:41Derek:And you would see in your blood work, it'd 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. Which is 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 then I mentioned the lipids. Yeah, I'm definitely missing something. But fasting insulin, some of the insulin resistance markers.

2:25:22Derek:and there's some stuff you should probably check like baseline like clotting risks you know predispositions factor five laden you know things like this

2:25:34Derek: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 can be manipulated through anything really that i'm aware of through like diet and lifestyle so you might think you have like a i don't know you might have like a think you have a better lp than you actually had at baseline so like your genetics might be like masked a bit by your androgen use um 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 they're just 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.

2:26:36Rhonda Patrick:It's pretty comprehensive.

2:26:38Derek:Yeah.

2:26:38Rhonda Patrick:I don't imagine everyone is doing that.

2:26:41Derek: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. Like, I'm sure I like I can't 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.

2:26:58Rhonda Patrick: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's the first line of 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's pretty similar to men. We talked about that.

2:27:36Rhonda Patrick: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?

2:27:55Derek: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 gonna 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?

2:28:46Derek: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, like a lot of the stuff we just mentioned is like directly analogous to like what women should look to as well. Like 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, you know, amenorrhea.

2:29:22Derek:It's making sure you have like a normal, you know, menstrual period, all this stuff. um and then yeah like you know the the oral contraceptives is significant and worth noting if you're on that like you almost certainly are artificially suppressing yourself into like the equivalent of hypo territory for women so if you're on it like i would probably check where you stand and you know decide if that's the medium you want to continue moving forward and for some women it works like it's not to say that that's something you shouldn't be on at all some women like that some women have like hyper androgen leaning you know uh 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 like hair growth that would be reflective of like masculine characteristics um so yeah like in general i'd be looking to that um basic symptom and symptoms and the biomarkers while there is a reference range of 15 to 70.

2:30:26Derek: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 US. There is in Australia apparently, which is kind of wild considering And it's like the most regulated place ever that is like almost nothing is legal there. But somehow like testosterone is for women, shockingly. But in the U.S., everything's like off label.

2:31:03Derek:So you have to use like a male formulation, androgel and like apply like a pea size 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.

2:31:42Derek: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 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 uh 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 uh 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.

2:33:24Derek: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 and 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 have cookie cutter protocols that are like you know everyone should get to a total t of you know 200 to 300 or like might be a bit aggressive.

2:34:11Derek:Maybe you should like, you know.

2:34:13Rhonda Patrick:Yeah. I mean, especially as you're mentioning, like the range is so small for us, right? For women that like, I mean, I'm concerned like even trying. I mean, I don't know if I need it right now, but so, 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.

2:34:48Rhonda Patrick:So it's off label. You're kind of just going, I don't know, it feels like uncharted territory. So, you know.

2:34:55Derek: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 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 a assessment of like what kind of net benefit you would hopefully get out of it, which for a lot of people with responsible use in menopause would probably be a net benefit 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.

2:35:34Derek:Like a lot of the testosterone is mediated through adrenal synthesis and like peripheral tissue conversion. It's not all ovarian. So like you're 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 depending on individual genetics. so like 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 and menopause just be on estrogen and progesterone micronized or whatever um it all depends and that's where like an 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 got 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 got to know what you're doing when you go in and like it sounds bad but you almost like got to know what the ideal protocol is for you like before the doctor tells you and you have to like find the doctor who like you know is responsible which is crazy but yeah you got to do your due diligence you got to

2:36:46Rhonda Patrick:Educate yourself. No, I mean, this with podcasts like this before as well.

2:36:50Derek: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 uh 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 role contraceptives attenuating entirely the loss in testosterone production via the progestin and estrogen-induced suppression through the DHEA.

2:38:19Derek: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.

2:38:31Rhonda Patrick:What kind of dose of DHEA?

2:38:33Derek: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.

2:39:09Derek: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 like widespread community for this kind of stuff. and you, you know, multiple opinions, not just like one guy who, you know, is a cowboy doc.

2:39:44Rhonda Patrick: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 my own interests like why why does hair loss occur like what is the role of dht in that

2:40:13Derek:process you know 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 ascvd for crushing apob and like different things of this nature but like hair loss no one has a fucking clue what happens 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 you know the solutions on the horizon like every two weeks you'll see some viral article on twitter like ucla scientists found like rodent regrew all his hair after shaved from like random thing like oh my god d ribose is the solution i'm gonna go dump it on my head you should see the nutty shit that people on like

2:41:03Rhonda Patrick:reddit and whatnot dump on the belletonin right yeah i think sulforaphane was one too at one point

2:41:07Derek:broccoli sprouts on the head didn't end up working though um i'm sure it has like some like 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 in the blood or like at the liver or something. There is like tissue specific concentrations of enzymes that are more prominent.

2:41:51Derek: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 test Osterone 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 like other other skin areas that are 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 and 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 um 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.

2:43:02Derek: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 gonna grow it back probably until they start like cloning hair follicles or something.

2:43:44Rhonda Patrick:So you kind of got to

2:43:45Derek: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 arteries 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 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 gone undergone literal apoptosis because each one is an organ in itself individually and once it dies like 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?

2:46:17Rhonda Patrick:My dad, but his hair's gray, but it's essentially the same.

2:46:21Derek:Is it actually though?

2:46:22Rhonda Patrick:Yeah. Okay. Yeah. Full thick, like head of hair, but it's just white.

2:46:27Derek:Okay. Very thick, yeah.

2:46:28Rhonda Patrick:But it's, it's an out, he's an outlier for sure.

2:46:31Derek:And you have a son, you said?

2:46:33Rhonda Patrick:I do.

2:46:33Derek:Oh, he must, he's gonna be thrilled then.

2:46:35Rhonda Patrick:Is it, is it on the mom's side? Typically,

2:46:37Derek:it's thought to be the mom's dad. It doesn't always play out like that.

2:46:40Rhonda Patrick:Right, it doesn't seem like it always does. But like, that's a good,

2:46:44Derek:he might not have to take, you know, the hormone crushing drugs. He might be one of the fringe lucky ones.

2:46:48Rhonda Patrick:Well, let's talk about the proactive. I mean, so, you know, what are these proactive measurements that can be done that do happen?

2:46:56Derek:So proactively, as unfortunate of reality as it is, you have to weigh the risk to 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.

2:47:33Derek: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 seemed 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 they're like for example siblings who weren't affected but inhibited uh maturation of uh genitals for example like not full that 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 is like one of the hallmarks of uh you know the uh they're called pseudo hermaphrodites which is like i don't know male pseudo hermaphrodites 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 for 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 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 down lighting 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.

2:49:50Derek:I thought I was immune this whole time. That's not the case. Dude. Yeah, that's rough.

2:49:55Rhonda Patrick:That's depressing.

2:49:56Derek:Yeah.

2:49:58Rhonda Patrick:Okay, so.

2:49:59Derek:No, I certainly don't want to leave a podcast saying,

2:50:03Rhonda Patrick:get on finasteride, we're dutasteride, the rest are screwed.

2:50:06Derek: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 dutasteride. And it is not much different than placebo in very, very rigorous and significant high number of subject studies that were well, well constructed studies. Like this is not something that a lot of it is media driven. in. It's not to be ignored.

2:50:48Derek: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?

2:51:30Derek:Like, there is an androgen load component to assess, like, how significant of an impact it might have on your ability to support functions 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 a 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 percent 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.

2:52:36Derek: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.

2:53:08Derek: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 inhibitor 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.

2:53:49Derek:Now, the most susceptible might need to be on a topical antiandrogen, or maybe their side effect profile would be superior with a lower DHT inhibition and some sort of adjunct topical antiandrogen therapy with it, or some topical 5-alpha reductase 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 sulfur on your head, do whatever you want.

2:54:25Derek: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 dhd 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.

2:55:55Derek: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 ketoconazole shampoo, for example, is like a mild antiandrogen too, that could add some additive protection on top of, let's just say you're on finasteride instead of the more nuclear dutasteride. And you felt like that risk profile was superior, year for example ketoconazole does help there's studies showing it's equivalent to the hair growth results of two percent 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 seboric dermatitis um can improve the scalp environment to your 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 anti-androgen that's just like a good shampoo that doesn't require like the risk profile of a finasteride 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.

2:57:17Derek: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.

2:57:34Rhonda Patrick:Those individuals either have a

2:57:38Derek:This issue with the scalp environment, like they're not getting it into where it needs because with topicals, some of the problem often is just like your scalp either is unhealthy 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 were 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's some crazy studies with individuals who've like burned their scalps that had balding and then they ended up like a 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 a thing.

2:58:56Rhonda Patrick:So with respect to the topical, you know, strategies like the minoxidil, I mean, obviously, what are the side effects of that? Is that...

2:59:04Derek:So it's like a very terrible blood pressure drug. So it was originally prescribed for high blood pressure as a low in its end. Oral? Yeah.

2:59:13Rhonda Patrick:Oh, I thought it was topical.

2:59:15Derek:Yeah. So what they found when they prescribed it for blood pressure decades ago was that one of the side effects besides like people like 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.

2:59:52Derek: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 like talking about like chest pains like freaking out

3:00:42Rhonda Patrick:and going to the hospital and it's a lot of people just get chucked on it at like low dose but it's

3:00:49Derek:still low enough it's still high enough that it causes like these problems in some people 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.

3:01:32Derek:worst case scenario you can elevate the uh efficacy profile by trying the tretinoin with it trying the microneedling with it and if it doesn't work like maybe at that point look at the the oral

3:01:43Rhonda Patrick:if you want but like that's kind of like the escalation risk um is the tretinoin oral or

3:01:49Derek:top 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 minoxyl topically if no response I would probably look at micro needling to ensure there's actual absorption occurring and or the enzyme activity that can be manipulated via that manual because 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.

3:02:33Derek:Like 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, etc. 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.

3:03:18Rhonda Patrick:It's funny, the microneedling, like I'm interested in it for skin effects. And so

3:03:21Derek:people use on their face too. Yeah.

3:03:22Rhonda Patrick:So I, 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.

3:03:55Rhonda Patrick: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

3:04:08Derek: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 in 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 4x the results I've seen in some studies.

3:04:51Rhonda Patrick: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 concerned?

3:05:14Derek: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 angiolytic kind of like calming thing uh uh molecule essentially and it results in kind of like a depends on the person like he can get pretty severe i'm sure you've seen um or at least you know depending on if you've seen the podcasts where people talk about it or not but

3:06:03Rhonda Patrick:i've heard of this like post dutaster or post finasteride interesting you'll never have you

3:06:08Derek:you'll never hear about post dutasteride syndrome though yeah 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 Nasebo effect that comes with these drugs where, you know, I have friends who get on it and they're like,

3:06:29Rhonda Patrick: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.

3:06:35Derek:And it's like, they've read all the stuff that could happen and they're convinced they It just like killed their ability to, you know, have sex or something.

3:06:43Rhonda Patrick:And it's like, you know, the nocebo effect is absolutely real and significant.

3:06:48Derek: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.

3:06:58Rhonda Patrick:Oh, for sure.

3:06:59Derek:It's very real.

3:06:59Rhonda Patrick: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 SNPs that like some people that have those SNPs are more susceptible to believing that something is harming them if they're like aware of those things.

3:07:34Rhonda Patrick:And so, yeah, well, that's interesting to know.

3:07:37Derek: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 ketoconazole, which probably is not going to be sufficient, but like over the counter, pretty benign, helpful, good shampoo regardless. list. 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.

3:08:16Derek: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.

3:08:34Rhonda Patrick:Okay. I see.

3:08:35Derek: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.

3:08:48Rhonda Patrick:Yeah. But essentially, if you want to completely bypass it, you have to get, you have to inhibit.

3:08:54Derek:Essentially. You have to like turn your scalp into a female.

3:08:59Rhonda Patrick:Okay. Wow.

3:09:02Derek:interesting stuff and you're mild exaggeration but like you get it and you're and you're you've been doing this yourself 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 you know the anti-aging longevity community who also use it and think that it's you know a reasonable enough risk profile for them and that's not to say that i 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 i'll something will happen i don't know are there any long-term studies looking at uh yeah because like these are drugs that are used for benign prostatic hyperplasia and even at dosages up to like 2.5 milligrams daily of due to asteroid has been used with great success with individuals with like no, you know, like a minority of prevalence of side effects and like they're relatively minor from what I've seen.

3:10:08Derek: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.

3:10:17Rhonda Patrick:Have they looked at like all cause mortality or any of these like outcomes? If any, okay, this is gonna be a

3:10:21Derek: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.

3:10:56Derek: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 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.

3:11:43Derek: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 uh vasodilative it's probably like more pro um 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 this is 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's some sort of direct study though that would be interesting that i was just going to say the same thing i'm pretty sure there is some anti-aging studies on finasteride and dutasteride though that

3:12:40Rhonda Patrick:might i wish we could pull up but we don't have the yeah well 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 these androgen you know blockers like how yeah how that affects life expectancy or cardiovascular related disease right yeah and just like wrap it up on the hair

3:13:04Derek: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 is 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.

3:13:36Rhonda Patrick:Yeah. Yeah. For real. Thank you. Well, 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.

3:13:46Derek:Was that your first double pod?

3:13:48Rhonda Patrick:That was my first back to back. Yeah. Especially like long podcast back, too long podcast back to back.

3:13:54Derek:Oh, cool.

3:13:55Rhonda Patrick:So it's been 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 learned, you know, I've made mental notes of things that I want to look into and I'll go back. And when I look at the, 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 uh your your health care company merrick health yeah um i think merrick health on social media is just

3:14:34Derek:at merrick health or the website is at merrick is merrick health.com if you want to check it out and um yeah i think i'm more plates 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 uh that's me

3:14:48Rhonda Patrick:Awesome. Well, thanks so much, Derek.

3:14:50Derek:Thank you for having me. I appreciate it.

3:14:53Rhonda Patrick:Thank you for listening and a huge thank you to Derek for joining me today. If you enjoyed this conversation, be sure not to miss out on my free weekly email newsletter. My team and I dive into cutting edge topics each week. We translate the latest health, fitness, and scientific research into practical tools that you can use. Last week, we explored the anti-cancer effects of strength training and high intensive interval training. We've covered lots of really interesting subjects, including the creatine's effects on cognition, how indoor exercise influences vitamin D levels, why the proximity to golf courses might actually impact your Parkinson's disease risk, and so much more.

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