Peter Attia MD274 - Performance-enhancing drugs and hormones—risks, rewards, & broader implications for the public
EVERY SPOKEN WORD
150 min read · 30,008 words- 0:00 – 0:47
Intro
- DMDerek Munro
is often framed out to be like this fountain of youth elixir, you know, HGH. Oh, it's, you know, so cost-prohibitive. It's what all the pro athletes are using. This is the thing you need to be on to prevent any age-related decline in, you know, bone strength. Uh, you know, not, your ability to burn fat as you get older is gonna go down, so you need to be on growth hormone, et cetera, et cetera. And that is kind of, uh, like at a bird's-eye view, it's kind of responsible for the growth of, broad-spectrum growth of tissues as you grow up, and then as you get into adulthood.
- PAPeter Attia
[upbeat music] Hey, everyone, welcome to the Drive Podcast. I'm your host, Peter Attia. Derek,
- 0:47 – 10:28
Derek’s experimentation with anabolic steroids at a young age
- PAPeter Attia
awesome to have you here. Thank you for swinging by Austin. I know it's a little bit out of the way for you. Um, and great to meet you in person. We've had a lot of communications over email and text, but, uh-
- DMDerek Munro
You as well. Thanks for having me.
- PAPeter Attia
Yeah. So, um, let's give people a little bit of background on you and, um, maybe how you've come to, to know a lot about stuff that, that's awfully technical, actually. Um, so I don't know much about you, or I'm gonna pretend I don't know much about you-
- DMDerek Munro
[laughs]
- PAPeter Attia
... other than that we share the same nationality, uh, in that you're, you're a fellow Canuck. So, uh, tell me about yourself growing up.
- DMDerek Munro
Yeah, so I am from the west coast of Canada, born and raised, Vancouver, British Columbia. Um, I ... How do you summarize [laughs] a childhood? Like, how far do you want me to go?
- PAPeter Attia
Well, first of all, when did you get interested in lifting weights, nutrition?
- DMDerek Munro
Okay.
- PAPeter Attia
When did the, when did the topics that you now have pretty significant expertise in start to become a, a passion of yours?
- DMDerek Munro
Probably in my grade 11. Um, is, uh, I don't know if in the US there's like-
- PAPeter Attia
We call it 11th grade or, uh-
- DMDerek Munro
Yeah
- PAPeter Attia
... junior year, but yes-
- DMDerek Munro
Okay
- PAPeter Attia
... continue.
- DMDerek Munro
So that one. [laughs] So-
- PAPeter Attia
I can translate between the two.
- DMDerek Munro
Yeah.
- PAPeter Attia
Yeah.
- DMDerek Munro
So I was a rail, probably 130, I think 138 pounds at my same height, and basketball player. A lot of my friends were getting into working out, putting on muscle, and I was the last one to get into it, and they were heavily encouraging me. Almost, you know, I was the only one who was left out if I didn't start, so I thought, "Okay, well, I might as well join, and I have nothing to lose by putting on some, some weight," 'cause I was pretty damn skinny at the time. So got in the gym, and a lot of people can relate to being bit by the iron bug, where you start to get, you know, the newbie gains, and the quick progress becomes quite addicting. And then, you know, you get on a full-blown routine thereafter, and I was kind of, I kinda skewed away from actual sports like basketball, because my three-pointer and some of the muscle memory stuff really got thrown off when you start to gain, you know, if you gain 30 pounds in a matter of months, all of a sudden your mechanics don't feel exactly the same anymore. So I got, uh, pretty into working out and lifting weights. And as you get into lifting weights, it's kinda hard to avoid some of the discussion around anabolic steroids, drug use in bodybuilding, how are these insane brontosaurus physiques you see on stage achieved, and what goes into them, because you often heard it was, you know, D'Anabol, Cell Tech, or some other supplement on the, you know, front of a cover, uh, or in a supplement store sold by somebody. And then as I dug into it more, started to learn about hormones, pharmacology. I actually had hair loss caused by androgens when I was experimenting with them as a, you know, recreational bodybuilder. And then from there, I started to dig heavily into anti-androgens, 5-alpha reductase inhibitors, and had this weird broad-spectrum pharma knowledge on weird niche stuff, but it was all overlapping with the basis of kinda like androgen therapy, synthetic derivatives, and-
- PAPeter Attia
A- and just, just for sort of a timescale here, are you in college now? Or are you still in high school when you're developing this level of interest?
- DMDerek Munro
This is, my initial interest peaked in 12th grade. That's, yeah. So that, that grade, I developed my interest in it and started to ... When I get interested in something, I just go hard. I just completely bury myself in reading whatever I can find, and back then it was a lot of underground forums with-
- PAPeter Attia
Yep
- DMDerek Munro
... gym bros going back and forth, talking about their experience with fill-in-the-blank compound, or this is what I did, and this is what I hear person X is doing. And a lot of it was just anecdotal, not that there's a lot of good literature anyways.
- PAPeter Attia
Right.
- DMDerek Munro
But I mean, just going on the forums, learning, digging into whatever science I could understand, and kind of conceptualizing, you know, getting a framework of understanding about how hormones impact physiology, muscle growth potential, um, I don't know, genetic variability in response to that. And as I got into university, in my first, second year, I got pretty hardcore into the bodybuilding, got up to 260-plus pounds at my biggest, and that's when I actually discovered I had sleep apnea that was severely exacerbated by getting that heavy that quickly, and sort of gave me my first taste of side effects and what the potential downsides are of bodybuilding. 'Cause a lot of times when you're that young, it's like 20, 21 years old, you just think you're invincible, and you just think you can, you know, blast compounds and-
- PAPeter Attia
And at 260 pounds, I mean, how lean were you at that stage? Or were you relatively unlean and just-
- DMDerek Munro
Relatively unlean, I would say.
- PAPeter Attia
And you were using lots of anabolic steroids, or just, you know, exogenous testosterone and calling it a day?
- DMDerek Munro
By-
- 10:28 – 15:56
Acquiring steroids from underground labs & the potential long-term fertility concerns early in his bodybuilding career
- DMDerek Munro
or something.
- PAPeter Attia
By the way, what was your monthly cost of drugs at that point in time?
- DMDerek Munro
When it comes to anabolics, it's actually not that expensive. Like a vial of test is probably, you know, 60 to 70 bucks underground.
- PAPeter Attia
So a vial of testosterone is 200-- is 2,000 milligrams.
- DMDerek Munro
Yeah.
- PAPeter Attia
Right? It's two grams is a vial.
- DMDerek Munro
Usually underground labs dose it at 250 per milliliter. I don't know why.
- PAPeter Attia
Okay.
- DMDerek Munro
It's kind of interesting 'cause in pharma you're used to the 200 increments.
- PAPeter Attia
Yeah.
- DMDerek Munro
But in UGL, underground lab, it's almost always 250. If it's Test E, testosterone enanthate, or testosterone cypionate, almost always 250.
- PAPeter Attia
And so what, underground labs, tell me about that. This is... Obviously you're not walking into the pharmacy and getting-
- DMDerek Munro
No
- PAPeter Attia
... branded Depo testosterone-
- DMDerek Munro
Yeah
- PAPeter Attia
... which is the FDA-approved version of testosterone. So w- does that mean these are compounding pharmacies that are doing this, or how does this work?
- DMDerek Munro
No, no. But it's literally just some guy who orders raws from China and then makes them in what you hope to be a sterile and professional environment, but you have no idea if it's his bathtub or what. So there are certain labs that would-
- PAPeter Attia
So his only motivation to do this-
- DMDerek Munro
Financial
- PAPeter Attia
... It, well, also is, "If I screw this up, people aren't gonna come back to me to buy the drug."
- DMDerek Munro
Correct.
- PAPeter Attia
So, um.
- DMDerek Munro
Yeah.
- PAPeter Attia
But wow. So you know, when we talk about GMP, good manufacturing process, uh, which is what ensures-
- DMDerek Munro
Oh, out the window
- PAPeter Attia
... sterility for injectable compounds, that's not the case.
- DMDerek Munro
No.
- PAPeter Attia
You know, recently I did an AMA on compounding pharmacies-
- DMDerek Munro
Oh, nice
- PAPeter Attia
... and the problems associated with them. And, um, because, you know, they're not subjected to the same GMP requirements, especially the community-based compounding pharmacies, they've had a number of these awful incidents, including one where I mean, literally hundreds of people died-
- 15:56 – 21:23
Backstory on More Plates, More Dates & Derek’s unique ability to blend scientific knowledge with personal observation
- PAPeter Attia
Um, [clears throat] and maybe we've- if we have time, we can come back and talk about some of the risks associated with Clomid use, period. Um, no, from a lipid perspective, that is. So [clears throat] you're in college, university to be sensitive to the Canadians.
- DMDerek Munro
[laughs]
- PAPeter Attia
And, uh, you're, you're obviously studying s-some s- Are you in biology, biochem? What are you studying?
- DMDerek Munro
[laughs] No, business, so it's-
- PAPeter Attia
Oh, okay. I-
- DMDerek Munro
Yeah.
- PAPeter Attia
Yeah.
- DMDerek Munro
So for me, I was pursuing a undergrad in, like, the business faculty at Simon Fraser University, and that was to lead me to a job as an accountant or something of that nature to be determined. And I was working as a bouncer downtown while I was getting my degree, and then I kind of just transitioned into posting online and then realized I could replace my income doing that on a computer rather than having to bounce, which is not, like, a sustainable job, and I don't know. It was like I always felt like I should not be an accountant. This isn't something I find exciting. It's not really where my interest lies. I'm okay with numbers, but it was kind of just from high school thinking, oh, what's a good business job? Go downtown Vancouver, get a job as an accountant at a big company, and you're good. And that, that was the end ... That was the dream back then. Not that it was, but it was, you know, the end goal in mind of getting your degree. Didn't end up doing that fortunately and started making online content on a WordPress blog. I wasn't actually on YouTube for, I don't know, a couple months but started writing about, you know, dieting, you know, how to bulk with not getting fat, um, how to cut, s- basic stuff about, you know, diet principles, bodybuilding, sort of talked about, you know, dating, social circle dynamics, stuff I was super interested in at the time, and then it kind of transitioned from there into discussion about my foray into anabolics, side effect management, I don't know, anything I could think of that was of use that I thought I could impart on the viewer. Hey, don't screw yourself up. I've gone through this and learned the hard way potentially, you know.
- PAPeter Attia
So let's go back to kind of your journey through that. So y-you're, y-you're in your early 20s, and you're kind of at peak anabolic steroid use.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
Um, are you using growth hormone as well?
- DMDerek Munro
I did try it periodically. Um, I didn't notice a ton from it, and it seems to be variable in how people respond. I think a lot of it is conflated with the effects on like fluid dynamics. So a lot of people, they get a lot of edema, water retention that they perceive to be enhanced muscle, and then they, you know, say, "Oh, my, you know, genetic ceiling is higher now because of all the s- you know, the satellite cell proliferation and hyperplasia that's happening, so I'm gonna keep using it." And, or, "It makes me never get fat," which is something I would hear quite often, which, uh, which is not true. But it's, uh... I did try it up to... I think the most I used at a time is like, I might have tried six IUs, six to eight IUs acutely, but didn't notice anything more than-
- PAPeter Attia
Meaning six to eight IUs daily?
- DMDerek Munro
Yeah, which is quite a bit.
- PAPeter Attia
That's a, that's a huge dose.
- DMDerek Munro
But it was for a span of like weeks, essentially, and didn't really notice a lot from it, so decided it wasn't worthwhile to continue 'cause it's super cost-prohibitive. And like that's the thing that drives cost mostly for bodybuilders. It's not the anabolics, it's the, the growth hormone-
- PAPeter Attia
Yeah
- DMDerek Munro
... typically. Um, or health screening, 'cause a lot of people don't wanna pay for that, so they gotta have their budget for the anabolics and the food, but, you know, blood work out the window.
- PAPeter Attia
All right. So I mean, I think this probably for folks paints a picture of your empirical curiosity in the topic.
- DMDerek Munro
Yeah.
- PAPeter Attia
Um, you know, whenever we have patients in our practice ask us questions about growth hormone, um, and we have our research team go and look at answers, a lot of the times what we say both to the patients and what I have to remind the research team is, "Look, you're gonna get very limited, very narrow information from the literature."
- DMDerek Munro
Mm.
- PAPeter Attia
This is not like researching the question of what are the effects of physiologic hormone replacement, [clears throat] you know, of testosterone, estrogen, progesterone, things like that. For that, we can turn to the literature and we can, you know, get a lot of information.
- DMDerek Munro
Mm.
- PAPeter Attia
But when you're trying to ask the question, "Hey, what happens when you take growth hormone outside of its medically intended purpose," such as hypo, you know, hype- hypo- you know, low levels of growth hormone or things like that, I said, "Look, it, it's not an appealing answer, but you're gonna have to kind of go into bodybuilding forums."
- DMDerek Munro
Yeah.
- PAPeter Attia
You're gonna ha- It sounds like the most unscientific thing-
- DMDerek Munro
Yeah
- PAPeter Attia
... but, um, a bodybuilder with a good head on his shoulders or good head on her shoulders will probably have more relevant observations about the, the good, the bad, and the ugly with, with these compounds. So I think what's kind of interesting... What, what I find so interesting about your work, Derek, is that you've, in my mind, taken the best of both worlds, right? So I think you've, you've learned a lot through your own experience with these compounds, coupled with obviously observing. You're be- you're, you're surrounded by a lot of bros-
- DMDerek Munro
Mm
- 21:23 – 29:34
Growth hormone—from extreme use-cases to the more typical—& the misconception that it’s the “elixir of life”
- PAPeter Attia
you. So maybe we'll start with going a little deeper on growth hormone since I think in many ways, [clears throat] that's the one for which we have, I believe, kind of the least insight outside of that very narrow application, which is, you know, people who have growth hormone deficiencies, where clearly replacing growth hormone is a good thing to do. So let's start with one application of growth hormone. Now, I will admit this is a question that has literally been asked of me more than once. And the first time it was asked of me, I was shocked. Uh, and I don't say that to pass judgment, but it never occurred to me that one would do this. But it's been asked enough times that I have to believe it's a real thing. So a person approached me, person I know, and said, "Look, um, my son is [clears throat] 12. He's a very good athlete. He's an exceptional tennis player. But I'm five foot nine, my wife is five foot five. He's not gonna be an inch above five ten. He's never gonna go anywhere in tennis, despite his remarkable athleticism. Can we give him growth hormone to get him, you know, to be a 6'1", 6'2" kid so he really has a chance to be a pro tennis player?"
- DMDerek Munro
Hmm.
- PAPeter Attia
So when you hear that, do you think like-
- DMDerek Munro
[laughs]
- PAPeter Attia
... I can't believe someone would ask that, or are you like, "Yeah, dude. Welcome to the world"?
- DMDerek Munro
The, yeah. I, I'm not surprised somebody would ask that, to be honest. Um, I've heard much worse. But it's, uh, not something that I believe you could look to any literature and find, oh, you're gonna completely surpass your otherwise predetermined genetic ceiling. Like it seems like if you had... Some of the literature on idiopathic short stature is interesting 'cause they actually have prescription protocols that are even higher than GH deficiency, so you have an unexplained, you know, lack of height velocity as you're growing up, but not necessarily, you know, IGF-1 deficiency or anything you can point to in the blood work that looks odd. And they are prescribed, you know, a upper end range even higher than GH deficient patients, which is, seems kinda odd to me. Um, but, uh, for individuals who don't have, you know, they're not lagging behind significantly-
- PAPeter Attia
Right
- DMDerek Munro
... there's no indication for it, it's kind of hard to justify. I imagine especially as a doctor who's hearing that.
- PAPeter Attia
Well, I mean, l- look, I mean, I don't think this person was asking me to do anything about it.
- DMDerek Munro
I agree.
- PAPeter Attia
I think he wanted to bounce the idea off me. I, I mean, I, I think he clearly knew I would never have anything to do with this.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
And I wanted to sort of not get preachy, which I don't think I did, but what I said was, "Look, it strikes me as a bad idea because You just don't know what the risk associated with this is.
- DMDerek Munro
Mm.
- PAPeter Attia
And I'm not even talking about like, oh, what if your kid has cancer and you make the cancer worse, which again, at that age, pretty small risk.
- DMDerek Munro
Mm.
- PAPeter Attia
We can talk about the risks of cancer and growth hormone in terms of propagation. But I said, "Look, if you were asking me to come up with a risk I would be worried about, I would be worried about bone health, for example." And I'm making this up, but I'm saying, "Look, how do we know if these new elongated bones that your son is gonna develop that take him from being his natural or genetically predetermined 5'10" to 6'2", how do we know if those bones are of the same caliber? And how do we know if we're not setting him up for osteopenia when he's 50 instead of, you know, a normal life?" Or something like that. So I said, I said, "Look, given all the unknowns, you just have to ask yourself the question like, is it worth that risk?"
- DMDerek Munro
Have you seen some of the recent surgeries to enhance height in adults? It's crazy. They like put screws in their n- knees, and then they basically increase their height by a millimeter every day, and they crank it until they've got upwards of half a foot in extra height, and then that area just fills in with new bone, and they have to learn to function-
- PAPeter Attia
Wait, wait, wait, wait
- DMDerek Munro
... with these new mechanics.
- PAPeter Attia
The, both the femur and the-
- DMDerek Munro
Depe- apparently you pick. You pick which, if you wanna do both or if you do one or the other, but you put screws in, and if you wanna max out your height, you can basically crank upwards of half a foot in extra height. And there are people doing this and paying for surgery and going to these facilities where you basically get manually stretched, and then bone forms in the space, and then you have to learn to move with those new mechanics, and this is becoming a more, it's not a trend I would say, but there's a lot of viral content surrounding it right now, and certain people that are showcasing before and afters as marketing material too, and it's pretty crazy.
- PAPeter Attia
What, how, how do, how do you accommodate that from a muscle and tendon perspective?
- DMDerek Munro
That's the [chuckles] that's the question. Uh, proponents for it seem to assert that you eventually adjust to it with very intensive, um, s- exercise routines, you know, rehabilitation stuff, and you try and basically learn all your motor patterns again, and eventually everything adapts. And I would assume that your athletic capacity would be inhibited pretty dramatically if permanently potentially, and there's huge risk there, but it's just, just showcases how extreme some people are willing to go.
- PAPeter Attia
All right. So if that's the most extreme story [laughs] I've heard about either the use of growth hormone or even surgical technique, let's talk about a far more typical story.
- DMDerek Munro
Sure.
- PAPeter Attia
So my patients, and probably most people listening to this, are not bodybuilders, but I think there is sort of a, a belief that growth hormone is the elixir of life.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
And there are no shortage of longevity doctors out there, which is why I, I, I bristle at the term [chuckles] when, when I'm looped into that group. Um, longevity clinics out there whose basically sole intervention is giving you growth hormone.
- DMDerek Munro
Mm.
- 29:34 – 41:43
Growth hormone 101: definition, where it comes from, & the challenges of measuring it
- PAPeter Attia
of measuring it. Let's, let's just do kind of a growth hormone 101.
- DMDerek Munro
Yeah, so growth hormone is, most people know it as like the primary hormone responsible for determining height as you grow in adolescence. Like, you know, androgens are more sexual differentiation, maturation, but, um, growth hormone and the subsequent growth factor production, IGF-1, will be a fairly significant determinant on if you grow to, I guess, like target height, whatever you could become. And it's pretty es- like during puberty especially, pretty important for the proper development of your infrastructure, bone, et cetera, connective tissue. As you get into adulthood, it becomes one of those things where It drops significantly, first off, as you reach adulthood, and as you get older, it drops precipitously as well. And that kind of begs the question, is this one of those things that you should be replacing to optimize, you know, function, fat loss, vitality, what have you? And it's tough because a lot of the proponents that assert such things have financial incentive, and it's kind of hard to wade through the nonsense and kind of figure out what is the truth here. And it is often framed out to be like this fountain of youth elixir, you know, HGH. Oh, it's, you know, so cost-prohibitive. It's what all the pro athletes are using. This is the thing you need to be on to prevent any age-related decline in, you know, bone strength. Uh, you know, not-- Your ability to burn fats as you get older is gonna go down, so you need to be on growth hormone, et cetera, et cetera. And that is kind of, uh, like at a bird's-eye view, it's kind of responsible for the growth of broad spectrum growth of tissues as you grow up. And then as you get into adulthood, it becomes, it's not irrelevant, but it's far less important because you're not trying to, you know, push a human from, you know, childhood into adulthood, essentially. And even when you have this push of exogenous growth hormone to manually manipulate your levels after, it's called epiphyseal plate closure, there does not seem to be any benefit to be gained from enhancing, like, the length of bones, for example. Like, you could still enhance, um, bone mineral density to some extent, and it seems to be, you know, you could enhance connective tissue integrity. It kind of depends on what your situation is and how IGF-1 deficient or lack thereof you are. But it's not gonna impact your height in adulthood. It's not gonna really do anything other than regulate, um, like lipolytic action, um-
- PAPeter Attia
How does it do that, by the way?
- DMDerek Munro
It just, like, liberates free fatty acids into circulation, so it's kind of seen as the opposing hormone to insulin. So it's like when grow-
- PAPeter Attia
Does it do that through lipoprotein lipase? I mean, what-- Is it actually acting on a substrate with, on the adipocyte?
- DMDerek Munro
That-- It seems to be driven through different, like, baseline, I don't know, states that you're in. Like, if you have, you know, ghrelin receptor agonism from being fasted, for example, a lot of people point to the literature on if you're deprived of calories, oh, growth hormone goes up. There are different situations in which it'll go up. Deep sleep obviously is super impactful on if you're gonna have release or not as well. But the main actions that I'm aware of, at least in a state of growth hormone pulsation, is kind of the underpinnings are you are trying to liberate free fatty acids for utilization as substrate for energy or anti-catabolic action. So the actual, like, mechanism enzymatically and whatnot, it's a bit fuzzy.
- PAPeter Attia
And what's the relationship then between GH and IGF in the liver? How does this all work? Because we don't really measure GH in people, right? Because it's pulsatile. So what are we stuck with as a proxy?
- DMDerek Munro
Yeah, even if you inject GH, like a, a large dose of it, you will only see a spike in serum for a transient period of time. And people who are trying to assess the quality of their growth hormone back in the, you know, with the underground stuff, they would be trying to time it very specifically down to the minute to assess the quality of their stuff. But the best proxy for GH production endogenously seems to be widely accepted as IGF-1, which is after you produce growth hormone from the pituitary, there is action in the liver, but also paracrine and autocrine action on, you know, muscle, especially if you are exercising or resistance training. But a lot of the serum IGF-1 is driven through liver production, and that is-- has its own implications in terms of its effects that seem to be more, it's like insulagenic in itself to some extent. And, um, yeah.
- PAPeter Attia
Which is kind of counterintuitive, right? Because if IGF-1 has insulagenic properties which are promoting a fat storage and GH is promoting lipolysis, don't those act at odds with each other? And how, how, how does, how does one sort of, uh, become more dominant?
- DMDerek Munro
Yeah, it's this weird orchestrated feedback loop, and these feedback loops are present in the body in multiple, you know, multiple different, uh, I don't know, hormone substrates will reduce in multiple different metabolites that then have negative feedback through different systems. And this seems to be no different if you have GH at a certain level and it results in a certain amount of IGF-1. You will have negative feedback that will then lower your production of HGH while the IGF-1 is elevated, and as it declines, you have this decrease in inhibitory feedback that then tells your body, "Okay, now the IGF-1 is not present in significant quantities. It's okay to, you know, release GH again." So it's this, like, finely tuned balancing act in your body where your body has kinda like counteracting things. It's not counteracting, but it's like the balance between anabolic or anti-catabolic. It's, it's kinda hard to... And frankly, I don't even know how to elucidate [chuckles] like a super clear way that is completely accurate. But it's, it seems to be kind of, uh, when one is high, the other one would be low, and conversely, in order to kind of maintain a, not necessarily at the same times, but to maintain like a balancing act in the body.
- PAPeter Attia
So we have a real sense of how to dose, for example, testosterone-
- DMDerek Munro
Mm
- PAPeter Attia
... or estradiol in the case of, uh, HRT for women, because we know what physiologic normal levels are during various periods of a person's life. And so if we're replacing testosterone to the level that we think is normal, either for your age or for some earlier age. We can measure the hormone, we administer it, and we can do the calculation. Hey, this person-
- DMDerek Munro
Yeah
- PAPeter Attia
... has a lot of sex hormone binding globulin, or they don't, or whatever the case might be. When, when people are administering growth hormone, and again, let's just talk about this through the lens of the context you're talking about it now, which is, you know, rejuvenation or, you know, whatev- ca- longevity, the, the wastebasket term. How do they know that... You know, 'cause typically they're using about one to two units per day. Isn't that the typical dose?
- DMDerek Munro
Yeah, it depends largely on liver function too. So some people with compromised function or type 1 diabetics, for example, they could have super high GH production but very low IGF-1 from seemingly lack of insulagenic signaling, 'cause it also has a positive relationship with IGF-1 production.
- PAPeter Attia
Mm.
- DMDerek Munro
But that is... I- it can be difficult because you could have a person on a ketogenic calorie-deprived diet model who has an IGF-1 that is on the low end of the reference range be manually administering growth hormone and be using a higher dose than would otherwise be necessary to get to high normal optimal function, put in quotation marks. Um, so it-- that's the best proxy we have as far as I'm aware is that serum biomarker IGF-1, but there's not really, you know, a cut and dry way to-
- PAPeter Attia
So people would use the Z-score presumably of their IGF-1 as the dosing, as the output for determining how much GH to administer?
- DMDerek Munro
Yeah, my understanding is that regardless if it's idiopathic short stature, GH deficiency, they would use IGF-1 as a metric to kind of dial in the dose. So if your IGF-1 is higher than it, the target, then you would dial the dose back accordingly, or if it's not high enough, then you would increase it accordingly.
- PAPeter Attia
And what do they, what do they target? A Z-score of one to two, meaning one to two standard deviations above the mean is therapeutic, or just being above zero, for example, which means you're above the 50th percentile?
- DMDerek Munro
The target for... I think it's mainly just correcting, but as far as what is correct, I guess the reference range, if it's in the middle or the high end of normal, I don't recall off the top of my head, but it's something in the neighborhood of middle of a standard LabCorp reference range as far as I know. Could be off on that, but.
- PAPeter Attia
Yeah. So, okay, so let's talk about the physiology of this. So you give GH. There's a feedback signal, because GH comes from the pituitary, but it's spoken to by the hypothalamus.
- DMDerek Munro
Mm.
- PAPeter Attia
So we're gonna talk about this again when we talk about testosterone, of course, 'cause that's a really obvious issue. So what happens upstream of the pituitary, i.e. what happens to the signal from the tho- hypothalamus to the pituitary to make endogenous, to make your own growth hormone when you take it from the outside? Does that get shut off as well?
- DMDerek Munro
Yeah. The negative feedback that I spoke about briefly, when you have elevated IGF-1, it will give negative feedback, and there is an elevation, something called somatostatin, which is like a, basically tells your body, "Don't make as much GH," essentially. And there is different receptors, which gets a bit confusing as to how you produce the growth hormone upstream. There's the ghrelin receptor, which super confusingly is also called, like, the GH receptor, I believe it's also called. And then you have the GHRH receptor and the production of GHRH endogenously as well as the agonism of ghrelin receptors can both stimulate growth hormone, and the way by which they achieve your end output can be different, and that's why there's different drugs that target different receptors for actual elevation. Typically, GHRH drugs are coupled with GHRPs to get, like, a one plus one equals three effect of sorts. But this is why also when you are fasted or malnourished, you could have significantly more output via the ghrelin receptor agonism as that is the-
- PAPeter Attia
And this is the same ghrelin hormone that plays an important role in management of hunger.
- DMDerek Munro
Yeah. So for people who don't know, ghrelin is like, I don't know if it's the primary, but I think it's probably pretty accepted that leptin and ghrelin are kinda like the signals that you're full versus hungry. So ghrelin and ghrelin receptor agonism is what would tell your brain you're hungry. So for example, if you gave somebody a really potent ghrelin receptor agonist, like ibutamoren is a commonly orally bioavailable GHRP. You use that, even if you're not hungry, you'll want to eat your pantry. Like, it's insane. So that compound plus a GHRH will seemingly have a downward pressure on somatostatin activity and simultaneously increase the output from the pituitary to produce more GH. So you can kinda, like, max out your endogenous production through these peptides essentially. But those are the primary mechanisms involved, like, those three things is the ghrelin receptor, GHRH, and then also somatostatin as a negative feedback.
- 41:43 – 43:51
Does exogenous growth hormone compromise one’s ability to make endogenous growth hormone?
- PAPeter Attia
So if someone is just taking exogenous growth hormone and, um, how, how long would they need to take it before they would start to compromise their own ability to make endogenous growth hormone once they came off?
- DMDerek Munro
Um, I think it's pretty quick. Like, IGF-1 elevations are not instant. Like, in the serum you would see GH spikes in a matter of minutes. Like, it's very transient in, out of your system, very short half-life. But the downstream IGF-1 conversion can increase over days and then stay elevated for days, and this is why IGF-1 as a biomarker has been asserted to be a potential way to catch people doping ... further out than the HGH isoform differential amino assay, which is the current accepted gold standard test that they use, um, 'cause IGF-1 will stay elevated for a relatively long period of time.
- PAPeter Attia
But let's just say a person's on GH for two years.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
And then they stop it.
- DMDerek Munro
Yeah.
- PAPeter Attia
Does their pituitary go back to making GH?
- DMDerek Munro
Yeah, seemingly. It seems pretty flexible in that.
- PAPeter Attia
So in that sense, it's different than LH and FSH and the testes making testosterone.
- DMDerek Munro
Yeah, and the reason for that, I can't help but think there's, because there's multiple actions of the pituitary, it's not gonna atrophy in the same way, I would think, and this is just speculative. But for example, people always wanna know if I take anabolics or testosterone replacement for years, but I don't take hCG or I don't take these fertility drugs, will I be able to restore fertility in short order? And it seems to be like a use it or lose it kind of thing, where not necessarily, but it's more difficult to restore fertility in somebody with, like, severely atrophied organs that has not had stimulation directly for years, versus the pituitary does multiple different things. So I can only imagine that, you know, the maintenance of output of other hormones and things are at least maintaining its flexibility to some extent.
- PAPeter Attia
Yeah.
- DMDerek Munro
But that, that super speculative.
- 43:51 – 51:45
Use of growth hormone in restoration of tissue during periods of healing
- PAPeter Attia
Let's talk a little bit about the use of GH in, uh, restoration of tissue during periods of healing. So, um, I think there's some accepted medical use for GH in burn victims, for example, right? So, um, if a person sub- sustains a significant enough burn, um, enough of their sur- the body surface area is burnt, I mean, that's one of the most catabolic activities-
- DMDerek Munro
Mm
- PAPeter Attia
... that a human can sustain, and therefore the reversal of that is one of the most anabolic demands that a, a human can sustain as an adult. Um, what about during, you know, orthopedic injuries? So you look at a person who's having either elective or emergent surgery for an injury. Uh, you know, I'll, I'll give you an example. So, so we've had patients who have had injuries, so like a torn bicep.
- DMDerek Munro
Mm.
- PAPeter Attia
And, you know, we've looked at the literature, found, I would say, at best modest evidence suggesting maybe for that person, um, you know, an eight-week course of anabolic steroids and growth hormone can aid in recuperation.
- DMDerek Munro
Mm.
- PAPeter Attia
You know, the few times we've done this, we've seen great outcomes, but that means nothing. It's so anecdotal. We'd have no, you know-
- DMDerek Munro
Mm
- PAPeter Attia
... we have no contrapositive, uh, or, or, you know, con- you know, opposite view there of what would happen otherwise. So do you have any insight either from kind of literature or from just kind of the underground world as to what the use of modest amounts of growth hormone would look like in periods of rehabilitation?
- DMDerek Munro
Yeah. It's more anecdotal 'cause like you said, you could find very-
- PAPeter Attia
Yeah, there's just no counterfactuals to any of these stories.
- DMDerek Munro
Yeah. And oftentimes when we're [chuckles] when I'm talking about this stuff, I want to say it's not necessarily founded in literature, unfortunately. It's kind of a mix of extrapolations, rodent studies, anecdotes in humans, stuff like that, which is unfortunate. I would love to be able to make, like, hard-hitting factual statements every time I say something on this stuff. But with GH, anecdotally, it seems to be quite effective in rehabilitation. I think that it is worthwhile in an acute timeframe. Like, that's where the ROI makes sense in my opinion. So I do see people... But again, it's not like you have a control of that same guy with the injury-
- PAPeter Attia
Yep
- DMDerek Munro
... not taking it, so we can only go by what you discern to be a reasonable, I don't know, recovery period. And then, well, it seems like it's recovering quicker than you would have expected. Good. Probably good.
- PAPeter Attia
Yeah, I, um, I, I think I may have told you this. Like a year and a half ago, I had shoulder surgery and, um, you know, I was so, I was... You know, really, this was an operation I had been dr- you know, postponing for 15 years-
- DMDerek Munro
Mm-hmm
- PAPeter Attia
... um, until it got to the point where I, I sort of had to have it. And I really was so hesitant to give up so much, you know, uh, because of the size of the tear in the r- in the, um, labrum. It was gonna be, you know, four months before I could really do anything again other than very light movements. So I, my plan was to take gr- I did, you know, I did a little bit of homework and came to the conclusion that a certain cocktail of nandrolone and growth hormone was gonna be the best cocktail.
- DMDerek Munro
See, I found that so interesting that you didn't use a base of testosterone with the nandrolone, 'cause you could effectively wipe out your estrogen with that combination.
- PAPeter Attia
Interesting. Well, I ended up taking it for a total of one week.
- DMDerek Munro
[chuckles] Yeah. Yeah, I noticed. Yeah. I lo- I saw that, uh, your, uh, post on Facebook where you mentioned how your, I think you had a blood pressure elevation and also-
- PAPeter Attia
Blood glucose went up.
- DMDerek Munro
Yeah, yeah.
- PAPeter Attia
My blood pressure went up. My temperature was up at night.
- DMDerek Munro
Mm.
- PAPeter Attia
Now, in retrospect, what I realize is I think I was sick.
- DMDerek Munro
Ah.
- PAPeter Attia
I think I actually got an infection.
- DMDerek Munro
Gotcha.
- PAPeter Attia
And, and anyway, so I don't think it had anything to do with the hormones, but my, I felt so bad on the hormones that I was like, "Well, I'm definitely not doing this."
- DMDerek Munro
Yeah.
- 51:45 – 1:07:12
Growth hormone-releasing peptides to increase endogenous GH: various peptides, risks, benefits & comparison to exogenous growth hormone
- PAPeter Attia
Um, you mentioned a couple of peptides. So let's talk about these peptides that are kind of upstream.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
So I can't even keep track of how many there are.
- DMDerek Munro
[laughs]
- PAPeter Attia
There's, like, CJC-
- DMDerek Munro
1295
- PAPeter Attia
... 1295, Semorelin.
- DMDerek Munro
Yeah.
- PAPeter Attia
Uh, what are the others? Uh-
- DMDerek Munro
So on the GHRP side, the easiest way to segregate these is by GHRP, GHRH. So GHRP are the ones that act on ghrelin receptor. GHRH are the ones that look very similar to GHRH and act on that receptor. So, like, that's the easiest way to segregate them in terms of categories. And then from there, they're pretty different in how they affect things. Like, for example, ipamorelin is often used in these, like, anti-aging clinics and whatnot.
- PAPeter Attia
But sorry, the GHRP ones are also going to drive hyperphagia.
- DMDerek Munro
Yeah. So the ... Depending on the compound, [laughs] this is the weird thing about it, so even if you are stimulating the ghrelin receptor, the effects on appetite are quite different. So for ipamorelin, for example, despite the fact that that's the receptor it's working through and it is a ghrelin receptor agonist, it does not influence hunger to even n- s- any reasonable magnitude within striking distance of MK-677 ibutamoren. The difference is literally, like, you eating 2,000 more calories a day, not by choice, but you're just starving perpetually.
- PAPeter Attia
So it's almost like it's inducing Prader-Willi syndrome or something, which is a condition where you have uncontrolled eating.
- DMDerek Munro
Yeah, like the willpower necessary to avoid overeating on MK-677, it's-
- PAPeter Attia
So what's the clinical use case for that? Is that used in AIDS wasting, cancer wasting, and things like that?
- DMDerek Munro
Orally active, so adherence is much more reasonable to expect. It's ... The application, it's not FDA-approved, by the way, but it is for GH-deficient children, I believe, and we've seen, you know, restoration of IGF to the, you know, top end of the reference range when using it, so going from, I don't know, like a low-end IGF to a 200 to 300 or something. It's not gonna push you into super physiologic territory 'cause it's working through your endogenous capacity, but you can kind of max out what your pituitary output potential is. So similarly to a, you know, an hCG or something, you can kind of manually at least stimulate natural production to the upper threshold of your capacity.
- PAPeter Attia
Yep.
- DMDerek Munro
So it seems to be efficacious in that, but it also is-
- PAPeter Attia
But not gonna have a high application among adults who don't need an extra 2,000 calories a day.
- DMDerek Munro
No. But it also depends, 'cause some people maybe you have low appetite and you wanna gain weight-
- PAPeter Attia
Yep
- DMDerek Munro
... or you're in a state of recovery and could ... Your appetite is suppressed from some other drug-
- PAPeter Attia
Yep
- DMDerek Munro
... you're using, 'cause that's, you know, fairly common. Depends on the context, and that's where unique kind of case-specific-
- PAPeter Attia
So what is the FDA-approved indication for this drug?
- DMDerek Munro
It is for GH deficiency in adolescents, I believe.
- PAPeter Attia
Okay.
- DMDerek Munro
Yeah. But it's also, like, even though it's prescribed among, you know, clinics and whatnot, it's not ... I don't even think it's a- achieved FDA approval yet, so, like, in phase two or three.
- PAPeter Attia
So how is this oral? How is, how does this peptide survive the gastric environment?
- DMDerek Munro
That is a great question. But it is the only one I know of that is often referred to as a efficacious option in this laundry list of GHRPs to restore IGF-1 to high and normal. So how the actual pharmacokinetic profile looks, all I know is the half-life is, like, 24 to 36 hours. It survives-
- 1:07:12 – 1:15:00
Role of growth hormone in building muscle & burning fat, as well as its effects on sleep & daytime lethargy
- PAPeter Attia
So what does the literature say and what does the non-literature say about the role of GH alone, not in combination with anabolics, in terms of its capacity to help build muscle and, uh, oxidize fat?
- DMDerek Munro
Yeah. The li- [laughs] the literature is so sparse on being able to say without a shadow of a doubt that it is going to enhance muscle potential, muscle growth potential, and performance especially. Like, there are very few studies that really show a clear enhancement of athletic performance. So I think what is clear in the literature is the body recomp effects, so being able to-
- PAPeter Attia
You do gain lean mass. Part of that presumably is water retention.
- DMDerek Munro
Yeah.
- PAPeter Attia
You do lose fat mass, right?
- DMDerek Munro
Yeah, and for, like, lipodystrophy, if you're able to, I don't know, liberate free fatty acids and be able to actually improve your, I don't know, utilization of substrate, like you could absolutely improve your body comp fairly significantly with it. But, you know, when it comes to actual protein synthesis, muscle accrual, it's very, uh, wishy-washy and certainly not something that you should hang your hat on as the reason why you're taking it, in my opinion. So from a muscle growth and athletic performance per- perspective, the jury is out in terms of if it does anything significant enough to justify its use. Bodybuilders will claim to high heaven that it's, you know, the ... Some think it- it's an expensive fat burner, and some think it's actually quite useful and they notice huge changes. But it also very much depends on your response from a, you know, fluid dynamics perspective. It can definitely increase sodium retention and things that you may interpret as muscle growth that may just be volume. And with that said, the muscle is, you know, how much water at the end of the day. So is that to be ignored? From a cosmetic perspective, it certainly looks good on a bodybuilding stage. It may not necessarily be-
- PAPeter Attia
It might not have the function.
- DMDerek Munro
Yeah. So you may not get enhanced force production outcomes like you would be seeking from, like, a true, you know, anabolic agent. But it doesn't improve cosmetic appearance of muscle almost certainly and can help you, uh, improve your body composition, especially if you, you know, time it well with ... 'Cause if you just use it and liberate free fatty acids and then sit around and do nothing, you could just redistribute that and not necessarily get the benefit out of it that you're seeking, so.
- PAPeter Attia
So do you think that the liber- the, the liberation of fat is the more reproducible finding of GH use?
- DMDerek Munro
Oh, yeah. Like, that, you, you know, you know that's happening when you use it, for sure. And you'll become acutely insulin resistant as a result of that, too.
- PAPeter Attia
So based on that knowledge, when is the ideal time to take it? Do people take this once a day, twice a day?
- DMDerek Munro
It depends on the dose, because if you're using a very high dose, you don't necessarily wanna ... And it also depends on your lethargy from it. It is very lethargy inducing. You could feel, you know, sleepy all day if you're blasting a high dose of it, you might say.
- PAPeter Attia
What, what would be a high dose? Like what you were taking, six to eight?
- DMDerek Munro
Yeah. I would say ... And in, when I took it, it was mostly in the two to four IU range. I only did six to eight for, like, a very short period of time. And even that, the lower, lower, but still pushed me to like a 500 IGF, was lethargy inducing for me personally.
- PAPeter Attia
For how long?
- DMDerek Munro
Um, pfft, man, that was so long [laughs] . Um, I had tried it for full durations of cycles. So, you know, upwards of a few months was probably the longest I had taken it.
- PAPeter Attia
But did you have lethargy the whole day, or was it just like if you took it in the morning, you'd feel that way till noon, then you had to work out in the afternoon to get around it?
- DMDerek Munro
With the doses I was using and splitting it up the way I was, it was pretty around the clock. But-
- PAPeter Attia
Why is that?
- DMDerek Munro
It seems to have a very intertwined connection with sleep. So you have your biggest GH pulse when you're getting to sleep, and people find seemingly pretty positively correlated with aging. You have a decrease in IGF, and seemingly deep sleep metrics also decrease precipitously, too. And I think this is the biggest case to be made on potential attenuation of cognitive decline is its impact on sleep. If you're somebody who gets significant enhancement in deep sleep metrics, however you wanna track that, it's, uh ... I can't imagine you couldn't extrapolate from there that it's helpful for somebody who has ... You know, if you have a crashed IGF and you have horrible sleep as a result of it, like, there's clear literature to show that IGF deficiency will impair sleep. So if you're able to correct that to some level, the minimum effective dose, you don't need to push it to the top end.
- PAPeter Attia
But you're saying with a higher IGF, you were more lethargic.
- DMDerek Munro
Yeah.
- PAPeter Attia
Does that mean you were ... You would think that you'd be sleeping better based on that argument, right?
- DMDerek Munro
Yeah, probably. But I was ... It also gets conflated with bodybuilding diets, too, 'cause typically when you're using it, you're in a calorie surplus trying to gain a bunch of muscle, so you could definitely conflate those findings a bit, and it is anecdotal. But in general, people using peptides even, and growth hormone will often find that their sleep is seemingly enhanced, like it's deeper, more restful and during the d-
- PAPeter Attia
And yet they're more lethargic during the day.
- DMDerek Munro
Yeah. Yeah. So th-
- PAPeter Attia
Almost ... Is it possible then that the That the GH is inducing too long a sleep, like-
- DMDerek Munro
Potentially
- PAPeter Attia
... you're, you're sleeping a lot during the day, but, uh, so you sleep till ni- at night, but then it's carrying over to the day, like there's a hangover of sleep?
- DMDerek Munro
Potentially, for sure. Like, it seems to be a hormone that is quite rejuvenative during your sleep, and I can't imagine, not that I really read into, like, ancestral history or how your body functions relative to the ancestors that much, but it's like the time you are trying to recover and rest the deepest, having the highest spike of GH, like, it seems to be ... I think it's, it's something you could at least extrapolate as a interesting anecdote nonetheless that I can understand why I might be tired when the deepest point of rest is also the time that this is simultaneously the highest endogenously.
- 1:15:00 – 1:27:01
Evolution of drug use in the sport of bodybuilding
- PAPeter Attia
common approach today?
- DMDerek Munro
I think among those in the clinics, for sure, 'cause it's less cost-prohibitive. That's what I think. But in the underground, you know, bodybuilding world, they're typically ... They're pushing super physiological IGF-1 levels. That's their goal. That's what they wanna get out of it. So they typically try and find pharma grade GH, and if they can't get it, they will go generic if they also can't afford it, and that's what they're doing. So d-
- PAPeter Attia
And they're pushing IGF to 500 and more?
- DMDerek Munro
Yeah, typically. Like, that it would be a minimum adequate amount for performance enhancement, you know, quote-unquote performance enhancement, would be deemed higher than what is naturally achievable based on typically a LabCorp reference range is what most people would utilize.
- PAPeter Attia
Let's detour for a moment just to talk about bodybuilding before I, I wanna kind of go back and talk about anabolics, and then maybe this will be a nice dovetail into it. So, um, in my gym I have a lot of pictures of kind of bodybuilders, nice black and whites that I enjoy. And y- there's just a real clear difference between-
- DMDerek Munro
Mm
- PAPeter Attia
... Frank Zane, Arnold Schwarzenegger, you know, Sergio Oliva, um, to, you know, Jay Cutler and Ronnie Coleman and, and, and, and I don't know when that jump took place. Maybe Lee Haney, maybe, um, Dorian Yates. But somewhere in there, there was a real transition in physique.
- DMDerek Munro
Yeah.
- PAPeter Attia
And, um, y- y- y- w- w- not to debate which of those is the best, I think everyone can have their own preference for which era of physique was the most, you know, was their favorite. But what, what is the ... Y- you know, if you sort of think of the, the things that can impact your physique. Genetics, okay, that's not changing. Uh, nutrition and knowledge of nutrition, that's clearly evolved. Training and knowledge of training, that's clearly evolved. Um, drug use, that's clearly evolved. And then maybe just even injection. I've talked to bodybuilders today who say that they're actually injecting compounds in their muscles to alter the shape.
- DMDerek Munro
Mm.
- PAPeter Attia
Um, they're in- they're injecting, like, fats into muscles to actually create some sculpting. So that, again, that's probably something new. Let's put that one aside. As far as the ... Like, a- when y- ... So of the three, evolution of training, evolution of nutrition, evolution of drugs, how would you rate the relative balance of those three for the difference of, you know, a 1970s physique versus a physique today of the best bodybuilders in the world?
- DMDerek Munro
Probably [chuckles] drugs at the top, almost certainly, followed by I would say nutrition probably, and then training at the bottom.
- PAPeter Attia
And how, how much emphasis on each of those? Like, 50, 40, 10?
- DMDerek Munro
Oh, [laughs] that's tough 'cause these get scrutinized to hell.
- PAPeter Attia
Yeah, yeah.
- DMDerek Munro
'Cause it's like I'm gonna put a number on it, people will be like, "How do you think diet is only 20%?"
- PAPeter Attia
Yeah, yeah, yeah, yeah.
- DMDerek Munro
So, um, [sighs] 'cause a lot of these things don't live without the other, so you could definitely lean heavier and say-
- PAPeter Attia
Yeah
- DMDerek Munro
... well, if you eat nothing, the drugs aren't gonna do anything. So I would say just in order of importance-
- PAPeter Attia
Fair
- DMDerek Munro
... if you did perfect diet, perfect training, with all of the modern knowledge that we have now, your ceiling for muscle growth potential could be as much as 50 to 100 pounds lower as a natural, depending on height, depending on genetic response. And by the way, I don't wanna forget on the GH stuff, one thing that is interesting is even in acromegalic patients, the incidence of death seems to be cardiovascular Almost, like, significantly more than cancer incidents. So if there's anything to discern from actual human literature-
- PAPeter Attia
That's a good point
- DMDerek Munro
... significantly chronically elevated IGFs into even f- you know, 40 years old, these individuals are dying from, um, congestive heart failure and things like that, as opposed to-
- PAPeter Attia
And that's really interesting. So not even atherosclerotic disease. It's, they're also probably... I, I have to look into this. Actually, that's a very good point. I should look at the acromegaly literature.
- DMDerek Munro
The a- one of the interesting things is how much fluid retention they hold and the stress that has on the heart, too.
- PAPeter Attia
Yeah. A- and that's very interesting. They also probably would be m- I'm guessing maybe more prone to aortic dissection 'cause they probably have larger connective tissue, um, and things like that.
- DMDerek Munro
Yeah.
- PAPeter Attia
Okay, so you're putting drugs at the top of the list, and then nutrition, and then training, I think was the order you had them in. So let's talk about the drug use. So I've spoken to '70s bodybuilders-
- DMDerek Munro
Mm
- 1:27:01 – 1:33:20
What explains the protruding abdomens on some bodybuilders & athletes?
- PAPeter Attia
Well, I was gonna say, so we have that issue going on. Um, you've also, um, talked a little bit about kind of what we see in... So, so, so my belief used to be all this GH and insulin use is why we're seeing these big abdomens on not just, uh, bodybuilders, but also on athletes.
- DMDerek Munro
Yeah.
- PAPeter Attia
So, you know, you, you, you'll see track and field athletes who are insanely muscular, insanely lean, but they have huge protruding abdomens-
- DMDerek Munro
Mm-hmm
- PAPeter Attia
... that do not appear to be fat because you still see a six-pack ripped on top of it, but from the side-
- DMDerek Munro
Yeah
- PAPeter Attia
... they look pregnant.
- DMDerek Munro
Yeah.
- PAPeter Attia
And again, the thinking was, well, is this just organomegaly, right? Are their organs just getting bigger? Now you've, you've talked a little bit about an, an alternative hypothesis, right?
- DMDerek Munro
Yeah. I think it is multifactorial, but there is seemingly... I think the largest cause of it now is significant distension caused by the excessive food intake and the result of significant gastrointestinal issues that result from the absurd diet models. 'Cause to get that many calories in, get that much protein and carbs often, and especially peri-workout when you're using insulin and you need to make sure you don't go hypoglycemic in your workout, they'll be slamming like, you know, 100 to 200 gram shakes that have hydrolyzed whey in them, uh, branched cyclic dextrin, plus, you know, aminos, plus creatine, plus glutamine, plus this. And oftentimes they're essentially in a state of... Like, I'm sure you've had a cheat day where your stomach was, like, incomparable to, you know, days when you're fasting, for example. It's a massive difference. You can't... You could, uh, fasting you could do a vacuum and see, you know, completely invert your stomach almost, versus when you have a giant cheat day and just go off the rails, you couldn't keep your stomach in for the life of you. You have to be flexing just to keep it not looking like you have a gut when you're sitting down. Like, that is a perpetual state of reality for bodybuilders who weigh that much to sustain that food intake and the physiques that they have, 'cause it's not a normal amount of muscle to hold, so it requires a not normal amount of food to accommodate the, the nutrients required to grow further or even, like, sustain it. Like, there's a... A good example of that is Ben Pakulski. He makes, you know, like, I think more health-focused content now, but he's a former high-level IFBB pro. I think he won the Arnold Classic even at one point, and one of his biggest criticisms was his distended gut, and you know for certain the guy was using all the same drugs everyone was using at the high level. But he was able to reverse it seemingly in a relatively short period of time in his l- like, the latter part of his career by reducing his food intake significantly seemingly, and he actually showed up one year later with, uh, a vacuum on stage. Which a vacuum for people who don't know, I don't even know if I [chuckles] could explain it, but it's like you suck your stomach in and it creates like an almost like an inverted-
- PAPeter Attia
Yeah
- DMDerek Munro
... it g- it kind of goes in. You can see your ribcage and, like, your serratus lines and stuff.
- PAPeter Attia
And most bodybuilders wouldn't be able to do that nowadays?
- DMDerek Munro
No. No. It's, that's a big notable, uh, differentiating factor of '70s and, like, '90s bodybuilders, the amount of people that could do a, a vacuum dramatically. So many could in the '70s and it looked great, and in the '90s you'd be hard-pressed to find somebody who has, like, an aesthetic vacuum. And I-
- PAPeter Attia
Except for presumably natural bodybuilders are more likely to, or?
- DMDerek Munro
Yeah. Yeah. 'Cause they don't have to-
- PAPeter Attia
They don't have, they don't have the food demands.
- DMDerek Munro
Yeah. It also depends on, like, what they're eating, 'cause people with gut issues could have issues too. But it's more common in people who are pushing food extremely hard. And then the drugs on top of that, like when you have hyperglycemia chronically, you might have impaired intestinal motility and, like, all these things that could compound the issue significantly. So and then you have people with SIBO and, you know, bacterial overgrowth and all this stuff that can influence the, um, distention that is kind of like a congregation of bad digestion, insane amounts of food, um, poor choices of food that don't agree with your body because it's simply the only way you can get the calories in to meet the demand of the muscle, um, et cetera. But anyway, Ben Pakulski, he, he showed up with less muscle, but he had completely reversed his gut distention. So it seemed as if the food was a large dictator of, okay, to get the biggest physique you ever got, you had to eat some diet that was not conducive to the most aesthetic-
- PAPeter Attia
Yeah
- DMDerek Munro
... non-distended appearance. And if he had organ growth, is it reasonable to assume that it-
- PAPeter Attia
He could've reversed that, yeah.
- DMDerek Munro
Yeah, like I, I don't think his intent-
- PAPeter Attia
And, and it's really, it, it is another example of something that's very frustrating to me. This is knowable. Like, literally take the bodybuilders, throw them into an MRI scanner. You can get organ volumes on everybody.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
Like, we can- and we could compare that to, you know, controls and, and also look at them off drugs, on drugs, all that stuff.
- DMDerek Munro
Yeah.
- PAPeter Attia
So again, it's just an example of there's so much, so many of the questions that we have here that we're, we're not getting resolution to are knowable. It's not like we're asking, is there life outside of the solar system?
- DMDerek Munro
Yeah.
- PAPeter Attia
We're, we're never gonna know the answer to that.
- DMDerek Munro
One thing I can say is on autopsied bodybuilders that did die young or what have you, oftentimes now with social media, those results are released publicly, and people dissect them and whatnot and kind of, you know, make, uh, I don't know, interpret what... Like, you learn things from bodybuilders-
- 1:33:20 – 1:42:15
Death of bodybuilders
- PAPeter Attia
wanna come back and do a long discussion onto anabolic steroids. But, um, w- what, uh... There was a bodybuilder that died kinda recently, right?
- DMDerek Munro
Yeah, yeah. That was a shocking one, too. He was, uh, 30 years old, one of the biggest social media influencers, too, and the s-
- PAPeter Attia
What was his name?
- DMDerek Munro
Uh, Jo Lindner.
- PAPeter Attia
Okay. Li- American or-
- DMDerek Munro
German.
- PAPeter Attia
German.
- DMDerek Munro
Lindner.
- PAPeter Attia
Oh, that's right. Yeah, yeah, yeah.
- DMDerek Munro
Yeah, yeah. So with him, the scariest part was he was one of the guys who was, um, doing all the right things, at least from a blood work standpoint. So he would get blood work done literally every two months, if not more frequent, and was very, very rigorous about trying to oversee his health status, and his blood work wasn't perfect always, but it certainly wasn't somebody who should be dying at 30 years old regardless of... You know, back in the day, or not that long ago even, it would be unheard of for somebody to be dying who's o- he wasn't a massive bodybuilder by industry standards for fitness, where we have this warped perception of what is big versus not. He was, like, you know, uh, probably, like, 50 pounds off of what you would consider a top-level open class bodybuilder who would compete with Ronnie Coleman or something. So he was more of, like, a jacked fitness model by fitness industry standards, and less drug use, significantly less drug use, less food intake. He was always in a calorie deficit, shredded year-round. The guy did lots of cardio, at least, like, 10,000-plus steps a day, ate clean. Like, there was no reason objectively at least why he should die at 30. Like, you might expect that his lifespan would be-
- PAPeter Attia
And what are the known circumstances of his death?
- DMDerek Munro
So apparently his... And this is the thing that's [laughs] ... I don't even know if you're gonna want this in the podcast, dude, but it's, he got apparently the vaccine and two boosters on top of it, I believe. Might have even been more. But after he got it done, apparently he went and saw... He got his blood work done just routinely, and they saw supposedly that the blood they pulled out was, like, really coagulated and weird-looking. And I forget exactly his terminology, but there was... He literally did a podcast maybe a week or two before his death how he got a blood test done, and they were telling him that he needs to get a plasmapheresis to clean his blood because it was so messed up from the, the vax. So he did it twice apparently, and then supposedly his D-dimer went back down 'cause it was super elevated in his blood work, and they said he was fine now. And he cleaned his blood and, you know, reintroduced it back into circulation. He would be good. He made a long trip to the U.S. I actually met him for the first time, like, a couple weeks before his death. Um, and then when he flew back to Thailand, which is a really long flight, and yeah, there's, you know, some, uh, uh, clotting risk-
- PAPeter Attia
Yeah
- DMDerek Munro
... you know, associated with that on top of all the other things, um, which is speculated to be something that's a, you know, another variable. But he got back seemingly fine, and then apparently a few days after he got back, he was complaining of neck pain.
- PAPeter Attia
Hmm.
- DMDerek Munro
And his aunt supposedly died from a aneurysm in her neck. That is what we have been told. We have yet to see a, you know, autopsy report on his situation, but his girlfriend at least reported that his aunt died from the same thing and had a aneurysm in her neck, whether it, like, you know-
- PAPeter Attia
In her neck or in her head?
- DMDerek Munro
Yeah, y- it, it was apparently neck specifically-
- PAPeter Attia
Hmm
- DMDerek Munro
... which I would think is kind of unusual.
- PAPeter Attia
I mean, uh, yeah, I won't even speculate without an autopsy, I think, but a- again, uh- Tragic obviously
- DMDerek Munro
Yeah
- PAPeter Attia
... but, um, hopefully an autopsy sheds light on that. I mean, it's, th- there's, um, it's not difficult to know if someone dies of an aneurysm on autopsy.
- DMDerek Munro
Would you scope that out with like a Prenuvo scan before you even... Like, hypothetically if somebody wa-
- PAPeter Attia
Y- yeah, that's actually one of the reasons we, we really do like whole body MRI is you do... I mean, the incidence of aneurysms you'll see on a whole body MRI is about, depending on the series, I mean, somewhere between one and seven cases per thousand.
- DMDerek Munro
Wow.
- PAPeter Attia
Now, not all of those are aneurysms that pose risk, meaning they're not all aneurysms that if left alone would ultimately rupture. But, um, a number of those require intervention.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
So we've probably in the last f- seven years had two patients, and you, if you think about how small our practice is, two patients who have had incidental captures of intracerebral, intracerebral hemor- uh, pardon me, um, aneurysms that were both large enough, one, in one case large enough, in another case growing quickly enough to a large enough size that, um, they needed to be coiled-
- DMDerek Munro
Hmm
- 1:42:15 – 1:52:23
Complex interplay of hormones, & the conversion of testosterone into metabolites like DHT & estrogen
- PAPeter Attia
So-
- DMDerek Munro
Yeah.
- PAPeter Attia
Um, all right. So let, let's go on and talk about testosterone and androgens in general. You've already thrown around a lot of names that are gonna be foreign to people, but before we kinda get into the different anabolic steroids, um, you wanna just kinda do a quick review of the relationship between the hypothalamus, the pituitary, Leydig cells. You know, basically, you know, Sertoli cells, like what's the whole relationship between those hormones, testosterone production, and uh, and, and maybe we can even talk about DHT androgen receptors for-
- DMDerek Munro
Sure. Yeah
- PAPeter Attia
... and, and estradiol for that matter.
- DMDerek Munro
So the body has a pretty, it's complicated, but it seems to be pretty well-regulated way to know how much hormone to produce based on needs in tissues especially too. So your hypothalamus will create something called gonadotropin-releasing hormone. And just like the name suggests, this is the hormone that goes to your pituitary to actually stimulate the production and release of gonadotropins. Gonadotropins are the, uh, hormones that work on your gonads to produce testosterone, um, as well as assist with spermatogenesis and kind of sustain fertility. So the gonadotropins that come out of the pituitary, they elevate upstream, and GnRH as well, in response or lack thereof to adequate, and there's so many, to lesser magnitudes, but primarily androgen receptor activation and estrogen receptor activation. Um, and then there's also, like, some stimulation of progesterone receptors that causes negative feedback as well, um, among other things, too. But the primary that are to be noted probably for this discussion, androgen receptors, estrogen receptors. When those are satisfactorily or in a, a adequate amount, um, stimulated, it will tell your brain, "Okay, we have enough testosterone as well as DHT and estrogen that we don't need to make more essentially 'cause we have, you know, a satisfied amount of estrogen receptor activation in the body, so we need to, like, clamp down and not make as much hormones 'cause we don't want to have too much." So that will give negative feedback to the hypothalamus pituitary testicular axis to not produce as much GnRH and LH and FSH until those levels fall to where there's a need to make more hormones. So it's this, like, finely tuned system where your body regulates how much ... it assesses how much it needs, waits until it needs to produce more, and then it produces more. So the top of that is the GnRH stimulates pituitary output of LH, luteinizing hormone, which acts on Leydig cells in the testes, and follicle-stimulating hormone that acts on Sertoli cells as well. And this is the, and this we'll definitely get into that email you sent me about, you know, fertility and whatnot. Those will go down to the testes and stimulate the production of intratesticular testosterone as well as assist with the production of sperm and maintenance of fertility. So those levels, I think that that's probably a good summation of-
- PAPeter Attia
Yeah
- DMDerek Munro
... how you end up with testosterone probably.
- PAPeter Attia
Yeah. So then what's the fate of testosterone?
- DMDerek Munro
The fate of it in terms of metabolites and-
- PAPeter Attia
Yeah, like, o- once it gets out there, you know, it's, it's how much of it is converted into estradiol, DHT.
- DMDerek Munro
Yeah. Yeah, and this is where a lot of people who neglect lifestyle and diet don't realize all of the backhanded consequences of being too obese or something like that. You could have, for example, aromatase strongly e- expressed in adipose tissue. So if you are too obese, and this is problematic especially in adolescents, too, if you have a disproportionate amount of aromatase expression because of how much, you know, how fat you are essentially, you could otherwise be producing more estrogen than you would've if you were lean, telling your brain kind of in a indirect way that, "Hey, we have enough estrogen, so don't make more testosterone 'cause we don't need-
- PAPeter Attia
Because I use testosterone to make estrogen.
- DMDerek Munro
Yeah. And to, I probably should preface this with testosterone converts primarily to two hormones through the 5-alpha-reductase enzyme. 5-alpha-reductase to DHT, dihydrotestosterone, which has a significantly greater potency for binding and transcribing activity at the androgen receptor, and estrogen, estradiol, that will be the primary estrogen receptor agonist in estrogen receptors around the body. So those two hormones regulate kind of a balance of androgenicity and estrogenicity in the body, and it's like a finely tuned system, and this system is also regulated by binding proteins produced by the liver. And the differential between, you know, like, females versus men, it also works in the same way. It's just the difference in how much of these hormones are produced is quite different and also the binding proteins to regulate that you stay feminine versus you have, like, a masculine profile. So ultimately, the balance of free androgen to free estrogen in the body is almost the thing essentially that dictates if you are feminine versus masculine. You know, and you could flip-flop back and forth almost manually if you really wanted to, and we see this in bodybuilding where females will literally masculinize themselves to hell in order to win a show by using, you know, super physiologic amounts of drugs. So, and also in, you know, transition, people are trying to transition from male to female or vice versa. And some of these changes are permanent, of course, on the masculinization front. If you have a deep voice, it's almost certain that you're not gonna get it, you know, high after going on female hormone therapy. But at the end of the day, this is kinda like the primary hormones to understand as far as the spectrum of androgenic male to estrogenic feminine-like. It's not a female hormone 'cause they exist in both sexes. But DHT, the primary androgen that dictates androgenicity and sexual differentiation and maturation. Testosterone, the main anabolic hormone and drives a lot of the, uh, neurology, kind of the psychoactive effects. Um, and then estrogen is kinda like ... it's a big balancing act essentially.
- PAPeter Attia
Yeah. So let's again just make sure people understand the difference between androgenic and anabolic-
- DMDerek Munro
Mm-hmm
- PAPeter Attia
... because we will come back to this more and more with other compounds-
- DMDerek Munro
Yeah
- PAPeter Attia
... as we talk about the profile. Well, this one has slightly more androgenic behavior. This one slightly has more anabolic behavior.
- DMDerek Munro
Yeah. So the androgenicity or androgenic activity of a compound or your endogenous hormones is essentially how masculinizing it is. So dihydrotestosterone, the 5-alpha, 5-alpha-reduced metabolite of testosterone is- The most androgenic hormone in the body and can significantly inhibit estrogen's activity even in RNA transcription at the receptor site. Like, it's very potent in what it does, and even if you had... Like, to frame how important it is, you could have a male, if you wiped out DHT before puberty, he would basically... That's the, how you end up with a micropenis essentially. Like, you have individuals who will not undergo full maturation unless you have the presence of this hormone.
- PAPeter Attia
So in other words, if you, if you took a male before puberty-
- DMDerek Munro
And put him on dutasteride
- PAPeter Attia
... and just put him on dutasteride or finasteride-
- DMDerek Munro
Yeah
- PAPeter Attia
... and zeroed out his DHT, but with making no change on his testosterone
- DMDerek Munro
He would have the same amount of muscle, if not slightly more, but that's debatable, but no temporal recession, probably not as much acne, not as much body hair, micropenis. He would be probably visibly male.
- PAPeter Attia
And his voice?
- DMDerek Munro
Probably not as deep as it should be.
- PAPeter Attia
Yep.
- DMDerek Munro
But that is, uh... And we see this in pseudohermaphrodites that have a mutation in the gene that encodes for 5-alpha reductase. So this is kind of the advent of, you know, these enzyme inhibitors and how we even discovered how they work and whatnot. But yeah, DHT, the most androgenic hormone in the body, the most masculinizing. Testosterone, still very masculinizing too, and estrogen on the opposite side of the spectrum, zero masculinization, very feminizing. I think that's the easiest way to-
- 1:52:23 – 2:07:55
Post-finasteride syndrome & how Derek successfully treated his hair loss
- DMDerek Munro
almost entirely. Like, even when you... A lot of people will demonize 5-alpha reductase inhibitors, and justifiably so in some cases. But even when you look to literature that compares placebo versus finasteride versus dutasteride, side effect profiles are pretty similar even.
- PAPeter Attia
Yeah, dutasteride and finasteride being two drugs that block 5-alpha reductase-
- DMDerek Munro
Yeah, yeah
- PAPeter Attia
... used m- initially for reducing prostate size-
- DMDerek Munro
Mm
- PAPeter Attia
... 'cause DHT disproportionately drives prostate growth, uh, but also used for h- u- I think would s- I would say used more for hair loss now.
- DMDerek Munro
Yeah.
- PAPeter Attia
Um, but yes, and we have talked about this on two podcasts previously about post-finasteride syndrome-
- DMDerek Munro
Mm
- PAPeter Attia
... um, which is a debatable idea. In other words, there is not a clear consensus in the urologic literature about even the existence of this-
- DMDerek Munro
Yeah
- PAPeter Attia
... let alone the prevalence, let alone the reversibility of it. All of these things are really unknowns, and, um, a- actually it's created quite, quite a bit of a, a, a conundrum for us because we have a number of patients who take finasteride or dutasteride-
- DMDerek Munro
Mm-hmm
- PAPeter Attia
... uh, for hair loss. And, um...
- DMDerek Munro
What's your stance on 5-alpha reductase inhibitors, just at a...
- PAPeter Attia
Yeah, I mean, look, I think, uh, I, I'll, I'll be honest with you, I never really paid enormous attention to it until about a year ago.
- DMDerek Munro
Mm.
- PAPeter Attia
Um, and I, I think right now our stance is I probably wouldn't start somebody on it.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
Um, and if a person... So in other words, if a person has BPH, we're not gonna manage that anyway.
- DMDerek Munro
Yeah.
- PAPeter Attia
But a urologist has far better tools to manage BPH than 5-alpha reductase inhibitors. So I feel pretty strongly that if you're presenting with BPH, you should not be on a 5-alpha reductase inhibitor. It's simply unnecessary. It's like if someone came to me and said, you know, "My ApoB is too high," and I gave them a bile acid sequester in circa 1981.
- DMDerek Munro
Yeah.
- PAPeter Attia
I mean, it's just not necessary. There's no upside.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
If you're talking about it from a hair loss perspective, again, not something I obviously know much about, I would say... And they're gonna go and see a hair doctor who's gonna try to give them 50 different proprietary compounds.
- DMDerek Munro
Yeah.
- PAPeter Attia
W- which, by the way, wanna come back to that in a second. I would encourage them, if they've never taken it before, not to.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
Because I think there are enough other compounds, oral minoxidil, topical minoxidil, topical 5-alpha reductase inhibitors, PRP transplants. I think there are enough other tools that you can do to avoid the small but not necessarily zero risk of something going wrong in terms of sexual side effects that in the worst case might not be reversible.
- 2:07:55 – 2:28:56
Testosterone replacement therapy: compelling use-cases, side effects, & optimal dosing schedules
- DMDerek Munro
for anyone watching. [chuckles]
- PAPeter Attia
Yeah.
- DMDerek Munro
So maybe I shouldn't have brought it up.
- PAPeter Attia
Yeah, yeah. Um, okay, so let's, let's go back to kinda TRT then. So we've kind of established what's going on. Um-
- DMDerek Munro
When are you starting?
- PAPeter Attia
Uh [laughs] , yeah, we're gonna talk about that. My, my little, my hor- I'm actually doing my blood again next week, so we'll-
- DMDerek Munro
Oh, good
- PAPeter Attia
... we'll see how, how far my levels have continued to fall. So I was gonna actually talk right about that, right, which is let's talk about, quote-unquote, what's normal.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
So I've never found a compelling table for normal levels of free testosterone that are stratified by age. So you can find these data quite easily for total testosterone level.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
Um, [clears throat] but I've only really seen data for broad chunks, you know, prepubescent, pubescent, post-pubescent.
- DMDerek Munro
Yeah.
- PAPeter Attia
Here, here are the, here are the percentile ranks for free testosterone, whereas for total I can show you by decade or something like that. I guess it's worth putting some context to this, right? So if a person's total testosterone is 800 nanograms per deciliter, um, most of that is bound, and sex hormone binding globulin and albumin probably do the lion's share of binding. Um, and if a guy's got 2% of that as free or unbound, that would translate to 16 nanograms per deciliter of free testosterone. Um, that's estimated, by the way. It's not calculated. It's very important people understand this. When you go to the lab and you get a test done, they're measuring testosterone. That's a, that's direct measurement. By the way, we should talk about ELISA versus LC-MS. Um, but they're estimating the free based on the measurement of the binding proteins. So that's introduction of potential error number one, is you don't really know how much free testosterone you have. The other thing is you don't know how many androgen receptors you have.
- DMDerek Munro
Mm.
- PAPeter Attia
So you really don't have any idea how much whatever amount of testosterone you have is saturating your androgen receptors or not. Are you playing below your weight or above your weight? Um, so what, what do we know about the amount of total testosterone over time in a guy's life?
- DMDerek Munro
Um, I know that after it peaks, you will have a steady... As opposed to women where you see, like, a plummet in, after menopause, for men it's more gradual, and you can expect, I believe it's about 1% drop in total test per year with, at a, an approximate 2 to 3% drop in free each year as well. So at the same time you would have 1% total T drop, 2 to 3% free, and this occurs, well, it depends on age, you know, lifestyle, but in general, like post age 30, 35, you can kinda expect a little bit of a, the decline to start. But that's not to say I haven't seen 70-year-olds with like 1,000 total T sometimes. So you can certainly retain high level f- uh, production. I don't want anyone to think, "Oh, now that I'm 45, my levels have probably dropped, you know, 20-plus percent at this point. I should probably get on TRT." Might not be the case. So in general, those are kind of general numbers of decline that you can expect based on literature, but I think it's reasonable to assume that a lot of people can retain good production as well. It's just a matter of, you know, how well do you produce gonadotropins, how well do you respond to them at your testes, 'cause there is some level of function that's declines with age too, even in response to the gonadotropins. Um, and that's an expected outcome unfortunately. But that's kinda where you get into the nuance of is TRT justifiable for this person based on pituitary output, lifestyle, diet, nutrient intake, sleep hygiene, is there sleep apnea, et cetera, and then also actual testicular response. 'Cause there's an argument to be made if you have very good testicle response, like why would you ever be on exogenous TRT too? 'Cause you could top out your natural signal even.
- PAPeter Attia
Is there an advantage to that? So I guess maybe before we get to that, let's, let's talk about the rationale for TRT. So what, what do you think is the most compelling case for it, um, and, and how often are people, you know, expanding that use case?
- DMDerek Munro
I think the most justified use for it is people who have primary hypogonadism, so that is when you have gonadotropins going to your testes but you're just not responding to them. So LH and FSH are... You will see these as high in your blood work, but your total T is still bottomed out. Like, that could be somebody who is, you know, you should probably check do you have a varicocele, do an ultrasound of your testes, see where things are at structurally, functionally, et cetera, before you make any rash decisions, 'cause there could be something you're overlooking. And I do think a lot of people do overlook certain structural abnormalities that may otherwise be rectifiable. Kinda depends, but typically testicular failure in response to adequate signaling would be like the, the obvious more no-brainer, versus if you had low LH and FSH, maybe your testicles are fine, so why are you haphazardly getting on testosterone when maybe it's a lifestyle thing, you know?
- PAPeter Attia
And so, you know, typically when we see that pattern, the second pattern you've described, which is low testosterone but in the setting of low LH and FSH, the most obvious things that usually show up there are poor sleep, uh, and, you know, basically high glucocorticoids.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
Um, which can also suppress the pituitary.
- DMDerek Munro
And you'd measure the glucocorticoids through like a Dutch test?
- PAPeter Attia
Saliva or... Well, you would, yeah, usually urine actually.
- DMDerek Munro
Okay.
- PAPeter Attia
We used to use saliva long ago.
- DMDerek Munro
Okay.
- PAPeter Attia
But yeah, so using a Dutch test.
- DMDerek Munro
Cool. Yeah.
- PAPeter Attia
Um, [clears throat] interestingly, those are not the easiest things to fix because people have to change behaviors, which is a lot harder than, you know, taking a medication. Um- So let's just say we go down the path of we believe that TRT is the right thing to do, and we believe that it's primary hypogonadism. Um, what do we know about the dose response of testosterone? And do we think that it makes sense to use fixed dosing and increased dosing or target to certain levels? 'Cause again, most of the studies, and we might talk about the Traverse trial, um, you know, they kinda just use fixed dosing.
- 2:28:56 – 2:34:38
Aromatase inhibitors to suppress estrogen, & the misconceptions around estrogen in men
- PAPeter Attia
Let's talk about aromatase inhibitors. So there was a, a study that I don't think gets enough attention, um, I think it was 2014, might have been 2013, in the New England Journal of Medicine, that looked at, um, 10 groups. So it took a, it took a group of men and, um, chemically castrated them, and then gave, uh, divided them into two. First, half of them get an aromatase inhibitor, half of them don't, and then within each of those groups, there were four escalating doses of testosterone plus a placebo. So what you have are five groups times two, one with estrogen inhibition, one without, and f- and five escalating doses of testosterone. So you end up with 10 outputs, which are ranging from low to high testosterone with high and low estrogen. And the outputs were body composition, mood, libido, a whole bunch of, you know, erectile function, all these things. And the punchline was you were better off with more estrogen and more testosterone. So the best outcome in the, the best outcome group was the high T, high E group.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
Now, the high E group wasn't that high. I'd have to go back and look how high the E was. But you know, I don't, I think it was probably in the ballpark of 50 picograms per milliliter.
- DMDerek Munro
Hmm.
- PAPeter Attia
Um, but this was an important study because I think it suggested that estrogen is not the bad guy, right? I think there's probably a lot of people out there thinking if you're taking testosterone, you need to be taking an aromatase inhibitor. And while that might be true at some doses, um, what... I guess let's start with normal physiology, and then I'm kinda curious to hear what the bodybuilders are doing.
- DMDerek Munro
Yeah. So back in the day, we thought that regardless of the dose of androgen, you should lower your estradiol to 20 to 30 'cause it's in the middle of the reference range-ish for a man, and that's where you get the best... Uh, like there was no thought of balance. It was kinda like this is a bad hormone to have above the reference range, even though our androgens are literally like 10X the reference range. So it's like how we concluded that-
- PAPeter Attia
Yeah, what, what were your testosterone levels when you were back in the heyday?
- DMDerek Munro
I never got LCMS testing when I used my highest dosages, so it would get capped at like 1,500 or something.
- PAPeter Attia
Hmm.
- DMDerek Munro
But it was, you know, in the thousands for sure. Um, but yeah, with estradiol, there is, and I've seen these, you know, studies too where it shows neurotoxicity when you add it in versus you take it out and there's a protective effect. So like neurotoxic outcomes are higher when aromatase is inhibited, and less neurotoxicity when it's taken out on the exact same input of testosterone. And I think it's pretty clear at this point that there is a role of estrogen in the body, not just from a cardiovascular standpoint, but from a neurological standpoint too. There's like serotonergic activity. There is, um, so many things that regulate mood as well. Um, I think even like temperature control too is gonna be variable based on that. It's kinda ties into the post-menopausal, um, stuff. But for men, it is certainly important, and to crush it arbitrarily based on a reference range is kinda like old bro lore, and I think most people, even in the bodybuilding space, are pretty aware now that estrogen is important for cardio and neuroprotection.
- PAPeter Attia
And I think another thing it's really important for is bone health.
- DMDerek Munro
Yeah.
- PAPeter Attia
And so that's the other thing that I think worries me when I see... And by the way, when I, you know, you asked me earlier about when am I ready to start my TRT protocol, I, I think I'm more troubled by the fact that my estradiol is so low.
- DMDerek Munro
Oh, yeah.
- PAPeter Attia
Because, you know, my T is routinely between about three and 400 nanograms per deciliter.
- DMDerek Munro
Okay.
- PAPeter Attia
And my estradiol is never above 25 picograms per milliliter.
- DMDerek Munro
Hmm.
- PAPeter Attia
Which is normal, right? That would be, you know, normal for such a low T.
- DMDerek Munro
Yeah.
- PAPeter Attia
But to me, one of the big advantages of having a T of 1,000-
- DMDerek Munro
Mm-hmm
- PAPeter Attia
... would be that I'd hopefully have an estradiol of 40.
- DMDerek Munro
And this is not to derail, but 5 alpha-reductase inhibition, when you don't have conversion to DHT, you branch off more T to estradiol, and estradiol will reliably increase by 15 to 22% on finasteride or dutasteride. Some people who are very low aromatizers and have, like, a hyperandrogenic state, those people, that's where, like, unique individual variability comes into the consideration for drug implementation. So a guy like that, even for actual l- you know, quality of life, sometimes that, like, modulation may-
- PAPeter Attia
Interesting.
- DMDerek Munro
Yeah. That's just an aside.
- PAPeter Attia
Yeah. I, I mean, I'm, I'm actually gonna do both tests side by side next week, where I'll do, um, like, enzyme-based test plus LC-MS for DHT, testosterone, and estradiol.
- DMDerek Munro
Oh, nice.
- PAPeter Attia
So I'll probably have a better sense of what they look like. 'Cause we can talk about how often enzyme-based testing gets estradiol wrong.
- DMDerek Munro
Yeah. No, yeah, I've seen some brutal est- overestimations using ECLIA when it was, like, single digit.
- 2:34:38 – 2:38:45
Other hormones beyond testosterone for male sex hormone replacement
- PAPeter Attia
let's talk a little bit about the other hormones, right? So for most of the medical needs, is there any reason to be considering a hormone beyond testosterone for male sex hormone replacement?
- DMDerek Munro
Um, I think it depends on the person, for sure. That's, like, such a [chuckles] general answer, but-
- PAPeter Attia
Well, well, l- let's say this, not... If you're just talking about health benefits and not performance benefits, 'cause I... We're gonna talk, I'm sure, about lots of others.
- DMDerek Munro
Yeah.
- PAPeter Attia
And, and I'll give you one example. So way back, I used to be, um, I used to sort of be a little bit more liberal and creative. So one of the things I used to do was if guys had normal testosterone-
- DMDerek Munro
Mm-hmm
- PAPeter Attia
... the, the example you used a minute ago, a guy who's got a testosterone of 1,000 milligrams, or nanograms per deciliter, but his SHBG is 100-
- DMDerek Munro
Mm
- PAPeter Attia
... which for a guy is very high, and his free T is, like, eight nanograms per deciliter. So he's, like, you know, eight tenths of a percent free instead of, say, two.
- DMDerek Munro
Yeah.
- PAPeter Attia
So you could use a very, very low dose of oxandrolone.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
And you could eradicate his SHBG because it has such a high binding affinity for, uh, oxandrolone.
- DMDerek Munro
Mm.
- PAPeter Attia
And of course, it also will inhibit... If you give too much, you'll inhibit testosterone production, so there's a very fine balance where you might give him, like, 10 milligrams twice a week or three times a week of oxandrolone.
- DMDerek Munro
Yeah.
- PAPeter Attia
You knock that SHBG down, and you double his free testosterone, and you haven't given him any testosterone.
- DMDerek Munro
Mm.
- PAPeter Attia
I don't do that sort of thing anymore. I feel like it's just not worth the hassle, truthfully. And, um, but, but, you know, that's one example of an area where you can manipulate another part of the system without having to, to go beyond that. But i- if you maybe take examples like that out, if you're just talking about the use of these other steroids, what's the case?
- DMDerek Munro
In some individuals, adrenal hormone replacement sometimes may be justified, but it's going to be based on blood work more. And-
- PAPeter Attia
When you say adrenal, do you mean DHEA?
- DMDerek Munro
Yeah. So, like, DHEA, if you have, like, a bottom DHEAS, maybe-
- PAPeter Attia
Mm
- DMDerek Munro
... you would look to a DHEA replacement. Um, if you had low pregnenolone, that might make sense, but it's more for, like, neurological kind of cognitive perceived quality of life effects, not necessarily 'cause there's any evidence to support that it's necessary. Um, in general, the main needle mover is going to be your test and how much of 5 alpha reduces or aromatizes into the two metabolites. And from there, like, you would never manually use more DHT. You would never, almost never probably manually use estradiol on top, although it's not impossible. So it's, like, upstream to that in the steroidogenesis cascade, where might other stuff plug in. I've seen progesterone use in men on TRT actually reasonably effective in sleep quality. Kind of depends on the person though.
- PAPeter Attia
How much progesterone?
- DMDerek Munro
Like, the same amount as women.
- PAPeter Attia
Like, 1 to 200 milligrams?
- DMDerek Munro
You don't have any HPTA suppression 'cause you're shut down anyway, so it can be impactful on quality of life 'cause you get the downstream conversion to some of those neurosteroids that, you know, may be inhibited in post-finasteride patients.
- PAPeter Attia
Wow.
- DMDerek Munro
Yeah.
- 2:38:45 – 2:44:24
History of anabolic compounds, & the differing effects of various anabolic testosterone derivatives & related drugs
- PAPeter Attia
yeah. Um, so I don't really know the history at all of anabolic steroids, so I'm- I'm guessing, like, testosterone's probably been around since the '30s or '40s, right, presumably?
- DMDerek Munro
Yeah, I think the, when it was first synthesized is, remains up for debate maybe, but I know it was, uh ... It- it goes back nearly 100 years at this point.
- PAPeter Attia
And so what was the first anabolic derivative of testosterone?
- DMDerek Munro
The first one I can think of off the top of my head is Dianabol. Um, there might've been, like, methyltest or something, but, you know, I'm, I could be misremembering. But essentially what they did was they took the testosterone molecule and found they could finagle it and re- you know, manipulate it in ways to create testosterone derivatives like Dianabol, methandrostenolone, which is, you know, supposedly the breakfast of champions according to Arnold. It's one of his famous quotes. Um, boldenone un- uh, is a very commonly used drug as well still. Um, it was prescribed to horses, I believe, for a while, and then I don't think it ever had a human use, but that is a testosterone derivative as well. And there's other ones that came thereafter, like halotestin, which I think famously one of the presidents of the United States was on some aggressive dose of halotestin for, I think, I forget what it was, maybe fertility or androgen therapy, but some of the protocols back then made almost no sense. But halotestin, um, and through there they also found, oh, if we take the 5 alpha-reduced DHT, testosterone converts to DHT. You would take that DHT molecule, you can manipulate it and create more anabolic compounds that are tissue-selective. Like, the idea of actually tweaking and modifying it to begin with came from the utility clinically to implement in muscle wasting in androgen-sensitive individuals. So you're not gonna give a child testosterone who has, you know, like a burn patient, you're not gonna give him tests 'cause you might masculinize the hell out of a female child, for example. So you have to come up with novel alternatives that are going to be anti-catabolic, preserve tissue, um, keep somebody from wasting away in a state of, you know, fill in the blank, without causing extreme, um, viralization. So the kinda like arms race of creating the best anabolic agent was from numerous pharmaceutical companies and came an array of compounds that you know now to be, you know, the Dianabols, the boldenones. On the DHT derivative side you had, you know, the, uh, oxandrolone's one of the more refined, more recent, although decades ago at this point. Um, primobolan, also a very refined one. It's, uh, metenolone. Um, proviron I think's still used actually to interact with SHBG. It's probably one of the most potent drugs at binding SHBG is mesterolone. Um, but yeah, the ideal scenario would be you're trying to segregate the anabolic from androgenic activity 'cause testosterone is essentially equal, at least based on rodent studies. You would find an equal amount of anabolic activity in muscle relative to androgen-like activity and masculinization. So you would try and take the compound, manipulate it to give maximum anabolic outcomes with a relative lack of androgenic outcomes to create something that men, women, children, anybody could take for muscle-wasting purposes and preserve tissue. And they never successfully did it. Um, but an array of compounds have come out.
- PAPeter Attia
But if- if- if sort of 1 to 10 would be testos- let's just make this a scale up.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
So 5 is testosterone.
- DMDerek Munro
Sure.
- PAPeter Attia
So it is halfway between completely anabolic and completely androgenic.
- DMDerek Munro
Mm-hmm.
- PAPeter Attia
DHT would be closer to 1, right? It's much more-
- DMDerek Munro
Sure
- PAPeter Attia
... androgenic than it is anabolic.
- DMDerek Munro
Yep.
- PAPeter Attia
What, what is the furthest example you have that's closest to 10? Meaning the most anabolic-
- DMDerek Munro
Primobolan probably.
- PAPeter Attia
So I mean that-
- DMDerek Munro
I don't know
- PAPeter Attia
... so, so one would think that that would be, like, the drug of choice if you're a bodybuilder, right?
- DMDerek Munro
It often is, too. So typically men will take ... I'm not saying that's the only drug 'cause it depends on what else you're trying to get, 'cause sometimes the side effects, as absurd as it sounds, are desired. So with Dianabol, for example, heavily water retentive. So that could help, like, cushion your joints when you're doing heavy lifting, for example. If you have better leverages on, like, a, I don't know, a max out, you're going to be better with more water retention around your muscle belly than if you ... or in your muscle belly, than you would if you had, like, a dry compound that is not a substrate for aromatase. And, like, primobolan is extremely refined and specific in its action. Like, it's like a pure, like, protein accretion compound with a relatively less burdensome androgenic profile. But the side effects of it, it doesn't interact with aromatase 'cause it's a DHT derivative, so it's not a substrate for aromatase. It does not 5 alpha reduce into a bunch of different things, too, so it's more predictable in its outcomes. But that's not always the desired outcome. Some people wanna look cosmetically inflated with water. Some people wanna lift more weight or prevent injury, and sometimes that water can be helpful. Depends on the person. Um, but yeah, that's like skewing the furthest direction of anabolic relative to androgenic. You'd probably have, like, primobolan and Anavar.
- PAPeter Attia
Yeah. And I remember, um, again, just sort of reading, like, Anavar also highly prized among athletes because-
- DMDerek Munro
T- technically SARMs are actually even further if I was to give-
- 2:44:24 – 2:51:53
Use of SARMs by bodybuilders
- PAPeter Attia
Okay
- DMDerek Munro
... the most extreme anabolic relative to-
- PAPeter Attia
So let's talk about SARMs then. What are ... Tell, tell folks what those are.
- DMDerek Munro
I guess, uh, selective androgen receptor modulators. These were kind of designed ... Some people might be more familiar with SARMs, which are, you've talked about Clomid-
- PAPeter Attia
Yeah
- DMDerek Munro
... Tamoxifen on this podcast before. Um, selective estrogen receptor modulators, so these will interact in a tissue-specific way with estrogen receptors in various areas of the body. So you might have a, you know, inhibition of estrogen receptor activity in the breast for somebody who has, you know, breast cancer, for example, um, versus you would have, like, pro-estrogen activity in other areas of the body like bone, which is what makes the selective action of it desirable because you can actually sort of choose where you get the activity you want, but also don't impact the health of other tissues and other areas of the body. So the same idea was kind of adopted for SARMs, and they tweaked and modified anti-androgens, actually, to make these compounds that would interact with the androgen receptor in a way that was tissue-specific and try and get s- like, pure anabolic activity with almost no androgenic. And proportionally, it's more successful probably than anabolic steroids, but the ceiling of anabolic activity seems to be lower. So when people use SARMs, they do not gain as much muscle as when they use anabolic steroids. And oftentimes in their quest for achieving a similar muscle-building outcome, the higher and higher the dosage gets, the less selective it becomes. So almost like certain, I don't know, uh, like, uh, beta blockers, for example. As you get higher and higher, they become less, uh, receptor selective, and you get more, like, broad-spectrum, you know.
- PAPeter Attia
What d- what are the typical SARMs, or what are the most potent or commonly used SARMs?
- DMDerek Munro
LGD 4-0 th- 4033 probably. It's called, uh, Ligandrol. It was actually ... It's ... These compounds often get traded around companies so often that they have new code names every time I check. I think the most recent one was, I think it turned into VK5211 by Viking Therapeutics was the last company I'm aware of who had it, and it was in, I think, a phase 2 trial for hip, hip fracture patients. Um, Ostarine, also known as Enobosarm, was probably the most well-known SARM, but it has not been FDA-approved and seems to have not hit their target endpoints that they wanted, although it looked effective. And oftentimes women who are trying to achieve, like, a physique to step on stage to try and, like, bridge the gap between not using anything and using steroids, they will go for something like an Ostarine, and they don't viralize themselves when they take it.
- PAPeter Attia
And, um, yeah, I ... It's funny, I always thought that was a SERM. I didn't know it was a SARM. These are, um, are these banned compounds in-
- DMDerek Munro
Yeah
- PAPeter Attia
... natural bodybuilding?
- DMDerek Munro
Yeah.
- PAPeter Attia
So they're considered-
- DMDerek Munro
And they're super detectable 'cause they're not supposed to be in your body at all.
- PAPeter Attia
So how does one get these? Are these ... If they're in phase 2, uh-
- DMDerek Munro
Same way you would get-
- PAPeter Attia
So it's all underground.
- DMDerek Munro
But compounding pharmacies, some of them pr- make them-
- PAPeter Attia
Yeah, that's true
- DMDerek Munro
... crazy.
- PAPeter Attia
I, I've seen compounding pharmacies make a lot of things that are not yet approved.
Episode duration: 3:30:34
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