#274 - Performance-enhancing drugs and hormones: risks, rewards, and broader implications for the public | Derek: More Plates, More Dates

Hey everyone.

Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness and we've established a great team of analysts to make this happen. It is extremely important important to me to provide all of this content without relying on paid ads to do this. Our work is made entirely possible by our members and in return we offer exclusive member only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peterattiamd.com subscribe.

My guest this week is Derek from More Plates, More Dates. Derek is a fitness educator and entrepreneur behind the More plates, more dates YouTube channel, podcast and companion website. I've been following Derek now for a couple of years and I have always found him to be very thorough in his analysis and assessment of areas that are very difficult to get insight into from the mainstream channels by which we would go about searching for insights, for example using published literature. Derek in particular has a lot of expertise around molecules and the types of molecules that are both used and abused by bodybuilders and athletes, and a lot of our discussion today focuses on that. By way of background, Derek himself is heavily into bodybuilding fitness and talks very openly about his past use with performance enhancing drugs and his real interest in understanding the science around these things. So we really cover these things in great detail and you might be asking, well, why is this relevant to a general audience? I think it's because not a day goes by when I don't get at least one patient asking me a question about one of these compounds. And the compounds I'm referring to of course include things like growth hormone, testosterone, HCG, androgens, other hormones, SARMs, SERMs, peptides, oh my God, don't get me started on peptides, Clomid, estrogen, and much more. So throughout this conversation we look a lot at how bodybuilders are using these compounds because bodybuilders use them in the highest amounts. They also talk very openly about these things. And then we ask the question, what can we learn about this for the general population? Are these things all bad carte blanche or is there some nuance to this that we can understand? This interview with Derek really is a Part one because we just don't get through most of what I want to cover. So we'll likely be doing this and there'll be a part two hopefully in the not too distant future. So without further delay, please enjoy my conversation with Derek. Derek, awesome to have you here. Thank you for swinging by Austin. I know it's a little bit out of the way for you and great to meet you in person. We've had a lot of communications over email and text, but you as well.

Thanks for having me.

Let's give people a little bit of background on you and maybe how you've come to know a lot about stuff. That's awfully technical actually. So I don't know much about you or I'm going to pretend I don't know much about you other than that we share the same nationality and that you're a fellow Canuck. So tell me about yourself growing up.

Yeah, so I am from the west coast of Canada, born and raised, Vancouver, British Columbia. How do you summarize a childhood? How far do you want me to go?

First of all, when did you get interested in lifting weights, nutrition? When did the topics that you now have pretty significant expertise in start to become a passion of yours?

Probably grade 11. I don't know if in the US.

There'S like we call it 11th grade or junior year, but yes, continue that one. I can translate between the two.

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. 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 weight because I was pretty damn skinny at the time, got in the gym and a lot of people can relate to being bit by the iron bug where you start to get the newbie gains and the quick progress becomes quite addicting. Then you get on a full blown routine thereafter. And I was kind of 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 30 pounds in a matter of months, all of a sudden your mechanics don't feel exactly the same anymore. So I got pretty into working out and lifting weights. And as you get into lifting weights, it's kind of hard to avoid some of the discussion around anabolic steroids drug use and 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, dat Dare, Celtec or some other supplement on the front of a cover 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 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 androgen therapy, synthetic derivatives.

Just for sort of a timescale here, are you college now or are you still in high school when you're developing this level of interest?

My initial interest peaked in 12th grade. That grade I developed my interest. 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 Jim 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, but I mean just going on the forums, learning, digging into whatever science I could understand and conceptualizing, getting a framework of understanding about how hormones impact physiology, muscle growth potential, 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 sort of gave me my first taste of side effects and what the potential downsides are of bodybuilding. Because 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 blast compounds.

And at £260, how lean were you at that stage? Or were you relatively unlean?

And relatively unlean, I would say.

And you were using lots of anabolic steroids or just exogenous testosterone and calling it a day. We'll go into more detail about the nuances of this, but just for reference.

By our standards a lot, but by bodybuilder standards, not really that much, probably at peak exposure, a combined weekly dosage of 1500 milligrams to 2 grams or something.

So just for reference for the listener, when we prescribe testosterone, like when a physician is prescribing testosterone to a patient for replacement, we're really only using testosterone. We're not using nandrolone, oxandrolone or these are the things which we will talk about. But from a dose perspective, I don't think I've ever prescribed more than 150 milligrams in a week of testosterone cypionate for physiologic TRT. So you're already talking 10 to 12, 13 times more than that, more than what we would consider a physiologic level.

Yeah. And to conceptualize that it does not equate to 12 to 13x the results, that is something you learn pretty quick. There's a severe diminishing returns as you escalate for sure. And you can even see this in the dose response studies. There is all, but it's still pretty significant. There is slightly less each increment. You go up proportionally. So that was my first foray into extreme bodybuilding, I would say, and also my first taste of side effects and really kind of led me down the rabbit hole of learning about, oh, what are the actual implications of using this stuff. Getting diagnosed with sleep apnea, getting a CPAP machine, correcting my sleep apnea, but then also realizing that it's kind of a band aid to the problem too. He should probably not be 260 plus pounds and taking all this shit.

So the other question I have for you at this point in time is how sophisticated is your understanding of managing the side effects of these hormones? Because obviously, and again, we're going to talk about these in detail, but I think it's a great intro to the story of you're learning this the hard way sometimes. But for example, like the estrogen effects, the DHT effects, you've already alluded to them a little bit with hair loss. What is your degree of sophistication around those in your early 20s when you're taking these doses?

Quite minimal. So back then you were told you take X amount of drug has to be a base of testosterone at this dosage relative to your other synthetic androgens that you're using alongside it. Based on what exactly? Arbitrary bro rules that are passed down the grapevine. Essentially, it's like your ratio of test to Deca must be 2 to 1 or else you get DECA dick. Things like that.

I haven't even Heard of deca, Dick?

Well, back then they thought it was too little tests compared to deca because.

If you had Decadron being a synthetic.

Yeah. So nandrolone is a progestin that is derived from testosterone, but it is quite different in how it behaves and interestingly enough, is the base for some of the synthetic progestins that women use for oral contraception. That compound is riddled with certain side effects for people who are prone to more the progesterone receptor interaction and its unique effects on cognitive health especially too and even sleep quality. But back then, anyway, you were told random things that were just passed down the grapevine and based on no real science. It was just anecdote. I tried it and this is how I felt. My penis worked or it didn't work. Now it's working. So this must be the correct way to do it, stuff like that. And then also predetermined dosages of aromatase inhibitors. You have to be on, you know, a milligram of Arimidex every day or every other day because you're on 500 tests or more per week. Stuff like that was seen as acceptable and smart. Taking preventative health measures by doing things like that is what we thought back then. Minor attention is paid to blood pressure. If you have a bloody nose in the squat rack, it's probably, you know, a sign that you should either lower the D ball or think about something. But not much talk about, you know, angiotensin receptor blockers or even how to choose a compound more intelligently. It was often, you must have estrogen side effects or something.

By the way, what was your monthly cost of drugs at that point in time?

When it comes to anabolics, it's actually not that expensive. Vial of test is probably 60 to 70 bucks.

So vial of testosterone is 2000 milligrams, right? It's 2 grams is a vial.

Usually underground labs dose it at 250 per milliliter. I don't know why it's kind of interesting because in pharma you're used to the 200 increment, but in UGL underground lab, it's almost always 250. If it's test e testosterone nantate or testosterone cypionate, almost always 250 underground labs.

Tell me about that. Obviously you're not walking into the pharmacy and getting branded depot testosterone, which is the FDA approved version of testosterone. Does that mean these are compounding pharmacies that are doing this or how does this work?

No, no, 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 his only motivation to do this financial well, also is if I screw this up, people aren't going to come back to me by the drug. Wow. So when we talk about gmp, good manufacturing process, which is what ensures sterility for injectable compounds, that's not the case. You know, recently I did an AMA on compounding pharmacies and the problem associated with them because 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 from compounded Solu Medrol because it was injected. Right. So these were being manufactured without proper sterile technique, sent to hospitals. So this was all being done legally and then the hospitals were using these to do, you know, facet blocks and things like that for people with back pain. And literally in one outbreak, more than a hundred people died of meningitis, a fungal meningitis, due to this. So the stakes are very high when you're talking about injectable compounds not being done sterilly. So I guess we ought to come back to visiting the topic of what the underground market looks like for these compounds.

Yeah, I guess what they bank on is the fact that with synthetic anabolics you don't have acute health issues. It's more chronic over a span of decades of abuse. So even worst case scenario, if you get a badly compounded version of whatever, if you can even call it that, you would have a elevated CRP from the carrier oils or solvents. But most people weren't even checking blood work, let alone. And if you had a side effect, you assumed it's the copious amounts of anabolics you're on. Not necessarily anything related to the manufacturing or anything. As long as the reputation of the lab was maintained across the forums and the bros were happy, that meant this is high quality. So some people would actually send it for third party testing. There were certain people who would come out with access to university labs and whatnot and they would kind of under the table, you would send a milliliter of your stuff in like a perfume atomizer and they would test it for you and send you HPLC results and you would find out if the UGL underground lab has good stuff relative to what it says on the label. But that was essentially it as far as quality Control how many of the.

Guys that you were training with and yourself understood, for example, the impact on fertility and long term effects vis a vis gonadal function at that age.

Very few people ever brought concern to it because we were always told when you come off, you will restore fertility in due time, once ester is cleared, et cetera. As long as you had good baseline function, you weren't primary hypogonadal to begin with. You're going to be good, you just have to get the compound out of your system was what we were told. Back then, no attention was paid to maintaining testicular volume, lighting, cell stimulation to maintain things, nothing. It was just come off your stuff. And the PCT regimens, post cycle therapy to restore fertility were just made no sense. When you look back on it. Back then it made sense, but now in hindsight, the rule of thumb was literally stop your drugs, wait two weeks, start a PCT of Novodex plus Clomid for four weeks, you recover fully, you just assume you don't actually check your blood work and then after that, as long as you are healthy, the responsible thing is wait, time on equals time off and then you go time back on. But often it was just come off two weeks PCT and then get back on or wait until some arbitrary amount of time has passed, regardless of health markers, and then get back on.

What dose of Clomid were you guys taking in the PCT?

It's like 50 milligrams once or twice a day, 25 to 50 twice a day depending. And it wasn't like based on anything scientific, it was just, you just choose.

Amazing doses again, just so high compared to what we would use clinically in traditional trt. If we have time, we can come back and talk about some of the risks associated with Clomid use, period. From a lipid perspective, that is. So you're in college, University. To be sensitive to the Canadians. You're obviously studying. Are you in biology? Biochem? What are you studying?

Business. So for me I was pursuing a undergrad in like it's 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. 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, what's a good business job? Go downtown Vancouver, get a job as an accountant at a big company and you're good. 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 a couple months, but started writing about, you know, dieting, how to bulk with not getting fat, how to cut, some basic stuff about, you know, diet principles, bodybuilding, sort of talked about 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. 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.

So let's go back to kind of your journey through that. So you're in your early 20s and you're kind of at peak anabolic steroid use. Are you using growth hormone as well?

I did try it periodically. 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 fluid dynamics. So a lot of people that get a lot of edema, water retention that they perceive to be enhanced muscle. And then they say, oh, my genetic ceiling is higher now because of all the satellite cell proliferation and hyperplasia that's happening. So I'm gonna keep using it or it makes me never get fat. Which is something I would hear quite often, which is not true. But I did try it up to. I think the most I use at a time is like I might've tried six IUs, six to eight IUs acutely.

Meaning six to eight I use daily.

Yeah, which is quite a bit.

That's a huge dose.

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. Like that's the thing that drives costs mostly for bodybuilders. It's not the anabolics, it's the growth hormone typically, or health screening because a lot of people don't want to pay for that. So they got to have their budget for the anabolics and the food, but blood work out the window.

I mean, I think this probably for folks, paints a picture of your empirical curiosity in the topic. Whenever we have patients in our practice ask us questions about growth hormone, 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 going to get very limited, very narrow information from the literature. This is not like researching the question of what are the effects of physiologic hormone replacement, you know, of testosterone, estrogen, progesterone, things like that. For that, we can turn to the literature and we can get a lot of information. 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 low levels of growth hormone or things like that? I said, look, it's not an appealing answer, but you're going to have to kind of go into bodybuilding forums. It sounds like the most unscientific thing, but a bodybuilder with a good head on his shoulders or good head on her shoulders will probably have more relevant observations about the good, the bad and the ugly with these compounds. What I find so interesting about your work, Derek, is that you've, in my mind, taken the best of both worlds. So I think you've learned a lot through your own experience with these compounds, coupled with obviously observing, you're being. You're surrounded by a lot of bros who maybe don't have your observational skills. And then you've coupled that with your own obsession of going down the rabbit hole. And that's why I think if anybody can extract meaning from some of this stuff, it's, you know, maybe we'll start with going a little deeper on growth hormone, since I think in many ways 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. 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. 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, my son is 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 going to be an inch above 510. He's never going to go anywhere in tennis, despite his remarkable athleticism. Can we give him growth hormone to get him to be a 6162 kid so he really has a chance to be a pro tennis player? So when you hear that, do you think, I can't believe someone would ask that, or are you like, yeah, dude, welcome to the world.

Yeah, I'm not surprised somebody would ask that, to be honest. I've heard much worse, but it's not something that I believe. You could look to any literature and find, oh, you're going to completely surpass your otherwise predetermined genetic ceiling. Some of the literature on idiopathic short stature is interesting because they actually have prescription protocols that are even higher than GH deficiency. So you have an unexplained lack of height, velocity as you're growing up, but not necessarily, you know, IGF1 deficiency or anything you can point to in the blood work that looks odd. And they are prescribed upper end range, even higher than GH deficient patients, which seems kind of odd to me. But for individuals who don't have, they're not lagging behind significantly. There's no indication for it. It's kind of hard to justify, I imagine, especially as a doctor who's hearing that.

I don't think this person was asking me to do anything about it. I think he wanted to bounce the idea off me. I mean, I think he clearly knew I would never have anything to do with this. 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. And I'm not even talking about like, oh, what if your kid has cancer and you make the cancer worse? Which at that age, pretty small risk. 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 going to develop that take him from being his natural or genetically predetermined 5 foot 10 to 6 foot 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 a normal life? I said, look, given all the unknowns, you just have to ask yourself the question, like, is it worth that risk?

Have you seen some of the recent surgeries to enhance height in adults? It's crazy. They put screws in their 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, an extra height, and then that area just fills in with new bone. They have to learn to function with.

These new mechanics, both the femur and the.

Apparently, you pick if you want to do both or if you do one or the other, but you put screws in, and if you want to 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. It's pretty crazy.

How do you accommodate that from a muscle and tendon perspective?

That's the question. Proponents for it seem to assert that you eventually adjust to it with very intensive exercise routines, rehabilitation stuff, and you try and basically learn all your motor patterns again, and eventually everything adapts. I would assume that your athletic capacity would be inhibited pretty dramatically, permanently, potentially, and there's huge risk there. But it's just. Just showcases how extreme some people are willing to go.

All right, so if that's the most extreme story I've heard about either the use of growth hormone or even surgical technique, let's talk about a far more typical story. So my patients, and probably most people listening to this, are not bodybuilders, but I think there is a belief that growth hormone is the elixir of life. And there are no shortage of longevity doctors out there, which is why I bristle at the term when I'm looped into that group longevity clinics out there, whose basically sole intervention is giving you growth hormone. It's like, here's a bunch of supplements that are proprietary and whatever, and growth hormone. There are two responses to that. So if you look at the traditional medicine approach to that, the what I call Med 2.0, what you might call just sort of the evidence based medicine guidelines. That group, which is the majority of medicine, would look at people doing that and say that's the most dangerous, careless, unethical thing you could ever do. Those people are not doctors. Shame on them. At the other end of the spectrum, you have the people that embrace that point of view, which is like the other people are idiots. This is modern medicine, this is the future. We should all be on growth hormone once we reach a certain age. And I find myself on neither side of that because I simply can't come up with an evidence based point of view. So my very naive point of view, which I'll acknowledge is naive, is given how many people are taking growth hormone and it is quite ubiquitous, especially in sports, which I think we'll talk about if there are really serious consequences to its use, even chronically, I feel like epidemiology would give us that answer. So it's possible that no one's looking. It's possible that there is a signal there, but it's not large. It's possible that not enough people take it for long enough. There's so many explanations for why this isn't happening, but there isn't a clear signal. Conversely, I think that there are probably a lot of reasons why growth hormone chronically given exogenously, especially if it's kind of supraphysiological, could be problematic. For example, if you have a tumor that is growth hormone or sensitive to growth hormone and it's already initiated, are you propagating it? So that would be kind of both sides of that. So let's go back to tell people about what growth hormone is, where it comes from, what are the challenges of measuring it? Let's just do kind of a growth hormone 101.

Yeah. So growth hormone is, most people know it as like the primary hormone responsible for determining height as you grow in adolescence, androgens are more sexual differentiation, maturation. But growth hormone and the subsequent growth factor production, IGF1 will be a fairly significant determinant on if you grow to I guess like target height, whatever you could become. And it's pretty 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. That kind of begs the question, is this one of those things that you should be replacing to optimize function Fat loss, vitality, what have you. And it's tough because a lot of the proponents that assert such things have financial incentive. 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, hgh. Oh, it's 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 bone strength. Your ability to burn fat as you get older is going to go down. So you need to be on growth hormone, hormone, et cetera, et cetera. And at a bird's eye view, it's kind of responsible for the growth, broad spectrum growth of tissues as you grow up and then as you get into adulthood. It's not irrelevant, but it's far less important because you're not trying to push a human from 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 the length of bones. For example, you could still enhance bone mineral density to some extent and it seems to be you could enhance connective tissue integrity. Kind of depends on what your situation is and how IGF1 deficient or lack thereof you are. But it's not going to impact your height in adulthood. It's not going to really do anything other than regulate lipolytic action.

How does it do that, by the way?

Liberates free fatty acids into circulation. So it's kind of seen as the opposing hormone to insulin.

Does it do that through lipoprotein lipase? Is it actually acting on a substrate within the adipocyte?

It seems to be driven through different baseline states that you're in. Like if you have 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 super impactful on if you're going to 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.

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?

Yeah, even if you inject GH 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 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 IGF1, which is after you produce growth hormone from the pituitary, there is action in the liver, but also paracrine and autocrine action on muscle, especially if you are exercising resistance training. But a lot of the Serum IGF1 is driven through liver production and has its own implications in terms of its effects that seem to be more intelligent in itself to some extent.

Which is kind of counterintuitive.

Right.

Because if IGF1 has insulinic properties which are promoting a fat storage and GH is promoting lipolysis, don't those act at odds with each other? And how does one become more dominant?

Yeah, it's this weird orchestrated feedback loop. And these feedback loops are present in the body in multiple different 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 IGF1, you will have negative feedback that will then lower your production of HGH while the IGF one is elevated. And as it declines, you have this decrease in inhibitory feedback that then tells your body, okay, now the IGF one is not present in significant quantities. It's okay to release GH again. So it's this finely tuned balancing act in your body where your body has counteracting things. It's not counteracting, but it's like the balance between anabolic or anti catabolic. Frankly, I don't even know how to elucidate like a super clear way that is completely accurate, but it seems to be 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, we have a.

Real sense of how to dose, for example, testosterone or estradiol in the case of 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 has a lot of sex hormone binding globulin or they don't or whatever the case might be 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 rejuvenation or longevity, the wastebasket term. How do they know? Because typically they're using about one to two units per day. Isn't that the typical dose?

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 IGF1 from seemingly lack of insulinic signaling because it also has a positive relationship with IGF1 production. But it can be difficult because you could have a person on a ketogenic calorie deprived diet model who has an IGF one 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. That's the best proxy we have as far as I'm aware, is that serum biomarker IGF1, but there's not really cut and dry away.

So people would use the Z score presumably of their IGF one as the output for determining how much GH to.

Yeah. My understanding is that regardless of its idiopathic short stature GH deficiency, they would use IGF1 as a metric to kind of dial in the dose. So if your IGF one is higher than the target, then you would dial the dose back accordingly. Or if it's not high enough, then you would increase it accordingly.

What did they target? A z score of 1 to 2, meaning 1 to 2 standard deviations above the mean is therapeutic. Or just being above zero, for example, which means you're above the 50th percentile the target.

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.

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. So we're gonna talk about this again when we talk about testosterone, of course. Cause that's a really obvious issue. What happens upstream of the pituitary, I. E. What happens to the signal from the 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?

Yeah. The negative feedback that I spoke about briefly, when you have elevated IGF1, it will give negative feedback. And there is an elevation, something called somatostatin 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 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.

And this is the same ghrelin hormone that plays an important role in management of hunger.

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 kind of 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 ibutamoran 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 kind of 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.

So if someone is just taking exogenous growth hormone, 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?

I think it's pretty quick. IGF1 elevations are not instant. In the serum, you would see GH spikes in a matter of minutes. Like, it's very transient in and out of your system. Very short half life. But the downstream IGF1 conversion can increase over days and then stay elevated for days. And this is why IGF1 as a biomarker has been asserted to be a potential way to catch people doping further out than the HGH isoform Differential immunoassay, which is the current accepted gold standard test that they use. Because IGF1 will stay elevated for a relatively long period of time.

Let's just say a person's on GH for two years and then they stop it. Does their pituitary go back to making gh?

Yes, seemingly. It seems pretty flexible in that.

In that sense, it's different than LH and FSH and the testes making testosterone.

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 going to atrophy in the same way, I would think. And this is just speculative, but, for example, people always want to 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 the maintenance of output of other hormones and things are at least maintaining its flexibility to some extent. But super speculative.

Let's talk a little bit about the use of GH in restoration of tissue during periods of healing. So I think there's some accepted medical use for GH in burn victims, for example. Right. So if a person sustains a significant enough burn, the body surface area is burnt. I mean, that's one of the Most catabolic activities a human can sustain, and therefore the reversal of that is one of the most anabolic demands that a human can sustain as an adult. What about during orthopedic injuries? So you look at a person who's having either elective or emergent surgery for an injury. So we've had patients who have had injuries. So like a torn bicep. We've looked at the literature, found, I would say, at best modest evidence suggesting maybe for that person an eight week course of anabolic steroids and growth hormone can aid in recuperation. The few times we've done this, we've seen great outcomes, but that means nothing. It's so anecdotal we'd have no contrapositive or opposite view there of what would have happened otherwise. So do you have any insight, either from literature or from just the underground world as to what the use of modest amounts of growth hormone would look like in periods of rehabilitation?

Yeah, it's more anecdotal because like you said, you could find very.

Yeah, there's just no counterfactuals to any of these stories.

Yeah. And oftentimes 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 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 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.

I think I may have told you this like a year and a half ago. I had shoulder surgery. And really this was an operation I had been postponing for 15 years until it got to the point where I sort of had to have it. And I really was so hesitant to give up so much because of the size of the tear in the labrum. It was going to be four months before I could really do anything again other than very light movements. My plan was to take. I did a little bit of homework and came to the conclusion that A certain cocktail of nandrolone and growth hormone was going to be the best cocktail.

So I found that so interesting that you didn't use a base of testosterone with the nandrolone because you could effectively wipe out your estrogen with that combination.

Interesting. Well, I ended up taking it for a total of one week.

Yeah, yeah, I noticed. Yeah, I saw that your post on Facebook where you mentioned how your. I think you had a blood pressure elevation and also blood glucose went up.

My blood pressure went up. My temperature was up at night. Now, in retrospect, what I realize is I think I was sick. I think I actually got an infection. So I don't get anything to do with the hormones, but I felt so bad on the hormones that I was like, well, I'm definitely not doing this. So I'm the counterfactual, I suppose, for not having done anything, which of course means I still know nothing. I still have no insight into what this is. But I do find this interesting and like you, I do find it frustrating that this is a question that isn't studied. Now, I understand that there isn't really a financial incentive to study this because of course it's not something that is a new drug recompentant. GH has been around for over 40 years now, hasn't it?

Yeah, it was like cadaver derived in the 80s and then soon they went to recombinant, I think late 80s or 90s.

Yeah. So over 30 years. It is a shame because I've talked to many orthopedic surgeons and to a person, they all say the same thing, which is, I really wish we knew the answer to this question. It would really be wonderful to study this rigorously and know, could we make a difference in the outcomes of patients by using these things in a very narrow opportunity. And the other question, I guess I'm wondering is because I can't find a clear answer to this in literature. Do you have a sense of the use of growth hormone in osteopenia?

Yeah. One thing I can say, circling back to the justifying, if it makes sense or not, I think there's certain things you can use to discern if it's a better idea, like baseline IGF1. Are you somebody who is in a ketogenic diet and you're trying to recover from an injury simultaneously? Are you calorie deprived? Like there are certain things that could otherwise be significantly influencing your recovery capacity from a growth factor standpoint that you may be able to manually backfill that for another person. Some people naturally have IGFs that are like top end of the reference range or if you were acromegaly, had acromegaly, you would not use gh obviously. So it's definitely context dependent. Or if you had insulin resistance at baseline or something like there are certain things that may otherwise sway you in the direction of the roi. Makes sense versus not. I feel like that should at least be said so people don't think it's a total blind roll the dice thing.

That's right. Yeah, that's a good point. And let's throw the same caveat in there. So let's say we're talking about an individual with osteopenia or osteoporosis. Let's assume further. You're going to do all the normal stuff you would do. So you're going to do all the things you would do nutritionally with respect to vitamin D, calcium, amino acids. You're going to increase load bearing activity, particularly strength training if necessary. You're even going to bring on Fosamax and the type of drugs that may help in that regard. But if in the context of all those things, an individual has a low IGF one, do you think, first of all, is there any evidence that in that setting GH administration will improve bone density?

Yes, I can say with almost near certainty that that literature exists. Even if it didn't, I would say almost without a shadow of a doubt that it would be worthwhile, especially in somebody with low igf. I'd have to circle back and make sure the literature was not rodent extrapolated. But I'm pretty sure that anybody, especially with lower igf, when you kind of get into the discussion of can you even sustain adequate bone integrity, especially in, I don't know, old age where you might have like, you're probably most prone to that to begin with. It's almost certainly justified, I would say in that scenario.

Yeah, it's interesting. I'd like to find that and maybe we can include that in the show notes. I feel like the last time I looked I didn't find anything that suggested not doing it, but I didn't find something that was a slam dunk home run. You mentioned a couple of peptides, so let's talk about these peptides that are upstream. So I can't even keep track of how many there are. There's like CJC, 1295, Samorelin.

What are the others 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 ipamerelin is often used in these like anti aging clinics and whatnot.

But sorry, the GHRP one are also.

Going to drive hyperphagia depending on the compound. 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 any reasonable magnitude within striking distance of MK677Ibutamoran. That difference is literally like you eating 2000 more calories a day. Not by choice, but you're just starving perpetually.

So it's almost like it's inducing Prader Willi syndrome or something, which is a condition where you have uncontrolled eating.

Yeah, like the willpower necessary to avoid overeating. On MK677 it's.

So what's the clinical use case for that? Is that used in aids wasting, cancer wasting and things like that?

Orally active. So adherence is much more reasonable to expect the application. It's not FDA approved by the way, but it is for GH deficient children, I believe. And we've seen restoration of IGF to the 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 going to push you into super physiologic territory because it's working through your endogenous capacity, but you can kind of max out what your pituitary output potential is. So similarly to a HCG or something, you can kind of manually at least stimulate natural production to the upper threshold of your capacity. It seems to be efficacious in that.

But not going to have a high application among adults who don't need an extra 2,000 calories a day.

No, but it also depends because some people, maybe you have low appetite and you want to gain weight or you're in a state of recovery and your appetite is suppressed from some other drug you're using, because that's fairly common. Depends on the context.

So what is the FDA approved indication.

For this drug, it is for GH deficiency in adolescents. I believe even though it's prescribed among clinics and whatnot, it's not. I don't even think it's achieved FDA approval yet. It's like in phase two or three.

So how is this oral? How does this peptide survive the gastric environment?

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 GHRP is to restore IGF1 to high end normal. So how the actual pharmacokinetic profile looks? All I know is the half Life is like 24 to 36 hours and.

It must just be enterically coated.

It's not hepatotoxic from what I remember. It's gotta be something that it just survives through coating like you said, or something of that nature.

Any other GHRPs that are worth discussing?

Yeah, I think Ipamorelin is probably the one most prescribed in clinics. And that one seems to be probably more targeted in the outcomes you'd want to see out of like a growth hormone releasing peptide. In that you get enhancement of sleep. Doesn't make you hungry. Really. Even though it operates through the same receptor pathway. Definitely increases IGF1. It is. Is it FDA approved? I believe it might be for lipodystrophy. It might be Tessa Moran. But These are the two. IPAMorelin is the primary one that is prescribed. And then there's a bunch like GHRP6, GHRP2 which significantly impactful on hunger. GHRP6 probably the worst one. That's what bodybuilders use when they reach a bottleneck of food intake and they can't eat anymore. They will. MK677 is around the clock. But GHRP6 after you inject it, it's like you can modulate acutely when you're hungry. So if you had an eating contest to win or you were going out for an all you can eat buffet, or you're just a bodybuilder who can't eat your 5,000 calories a day, that's when you would be. You'd look disgusted as I'm saying it.

No, I just. I mean it's. Yeah, there's so much to unpack there.

But ipammerillin is the one that is prescribed most often the other ones.

And that's a daily injectable.

Yeah.

And so is that used by athletes and bodybuilders?

Yeah, fairly often.

Is it cheaper than growth hormone?

Yes, yes. Depending on if you get the growth hormone underground or not through pharmacies, certainly. But there are generic growth hormone preparations that are pretty cheap. Now you could get 100ius of pretty high quality HGH from China for 150 bucks by comparison.

What would that cost at a pharmacy? I'm trying to think.

Thousands.

Yeah. I mean it's insane.

Yeah, especially if it's like a big brand name. Like back in the day, people would go to AIDS patients and convince them to sell their Serostim. That's what bodybuilders used to do decades ago.

Okay, so on the GHRH side, who were the big players?

Tessa Morlin and Samorelin. But I would say Tessa Moreland probably more commonly. Samorelin seems to just. People just don't really get the results they want out of it. And it's more anecdote than any kind of literature that points to it being sub efficacious. But Tessamorelin plus ipamerelin is kind of the primary combo utilized in clinics, especially nowadays.

So they combine them. They'll combine Tessamorelin with Ipamorelin?

Yeah, typically. And there's also, there's like the CJC 1295 and there's with drug affinity complex which is basically extends the half life significantly.

And CJC 1295 is which one of.

These GHRH receptor and then there's a shorter version of it. It's like mod grf129.

These are not FDA approved compounds. These are literally the wild west of compounds. Samorelin and Tessamorelin are FDA approved, I assume.

Yeah, some of them have. I know one of them in particular is approved for lipodystrophy. And there are some unique applications in which some of them have FDA approval. But most of them, the GHRP6, GHRP2 hex Arlen I believe, and a couple of the GHRHs on that list do not have FDA approval. And MK607, as far as I know, is like off label prescribed. It's kind of weird because it's like there's no company that makes a branded, you know, FDA approved version of it, but then compounding pharmacies will still make it. There's a lot of questions as to, well, what are the standards that go into making it then? And are you just ordering it from China similarly to an underground lab?

Yeah, there are no standards. I mean, there are no standards. That's the whole point of compounding, right, Is they can make anything. I mean, at this point the real question is where is the Line between if something has a grasp designation, it's generally regarded as safe by the fda. You can sell it on Amazon. It's an over the counter. What's the most potent grass thing out there? It's probably dhea. In other countries, DHEA is I think, appropriately treated as a hormone.

I think it's like Schedule 1 in Canada.

Is it really? Yeah, really. Wow. Interesting.

Why? I don't know. Because actual steroids are not as. As regulated.

That's amazing.

Yeah.

Yes. But in the us, DHEA amazingly is over the counter. So that means it has a GRAS designation. I'm guessing that CJC 1295 does not have a GRAS designation. So that means you cannot sell it without a prescription. But yet it doesn't have an ind. It's not an investigational new drug. It hasn't gone down the pathway of an approval. I think it's just sort of in this gray area.

Some of them are abandoned. It'll be like a drug that was in a pipeline.

So maybe there was an IND and it got scrapped.

Yeah. So it's like sometimes, is it financial, is it lack of efficacy? Is it some. Like in some cases there's a drug called Carterine, it's a PPAR delta agonist, which is actually get pretty good results on lipid management. It's kind of like one of those exercise mimetic drugs, but when you look at the metrics that it improves, it looks great. But then there is some rodent study. It was like every dose of Carterine resulted in cancer in these rodents. And then I guess the response to that was a public outcry of worry, concern, et cetera. And it just no reason why publicly it got scrapped. But it's weird because it was like pre clinical rodent literature supposedly caused it to get canceled after it was already in phase two in humans. So it's like some of this stuff and Carterine is prescribed through clinics too.

But yet all the rodents who took it got cancer.

Yeah, every dose.

I mean that would be disconcerting.

Yeah, for sure.

Okay, so again, talking about this through the lens of I have one patient, by the way, who came to me having been prescribed some Morellin from the outside. I asked him to stop because I was like, look, I'm not going to take over the prescription on that because I don't know anything about it. So he did and like, I don't know, a year, a year and a half later he's like, look, I really want to be back on this. I've just Never felt the same since I was on it. You know, it just gave me such a feeling of vitality. And he had a lot of reasons why he felt it was the thing to be on. And I said, look, man, I'm not going to be that guy who says no just to say no. But I need to understand this a little bit more and I think we need to think through what are the risks and benefits of this. And so we kind of negotiated this back and forth for six months where I said, look, I guess if we do a bunch of really good cancer screening and can convince ourselves that you don't have cancer, you know, we do the prenuvo, we do a gallery blood test check a colonoscopy, like basically to the level of detection of our modern technology, you don't have cancer at the moment. I'll be happy to find an endocrinologist who's more comfortable with the dosing. And we did. So we found a great endocrinologist and she was like, okay. And he went and saw her and she's prescribing it to him and he's as happy as can be. There's not a judgment around this. It's. I'm genuinely curious. I still can't make sense of would you want to be on Tessamorelin? It sounds like you're saying TESS is better than Samorlin or. But that again could just be anecdotal versus growth hormone. And then of course I never really understood the stacking where you would start to stack both compounds. So do you get the sense that hitting both targets, both receptors, is better than just using gh? Does it give more specificity?

One thing you could say for certain is when you push endogenous production, you are fulfilling the full production of all spectrum of variants. So there's different kill adult and isoforms of HGH and is how they detected in doping and these variable like molecular weight growth hormone outputs that you get from the pituitary. We don't know why they are put out in different formats essentially. For all we know they have different actions in the body that may not be facilitated by the recombinant straight like 22. So when you take a recombinant HGH you are telling your brain don't make more essentially so you are actually losing the production of those other variants and you were relying entirely on this one. So what the implications are of that from a health perspective or a performance, what have you. Obviously we can manually push your IGF to super physiologic which you will not be able to do with the endogenous kind of upregulators of sorts with the peptides. And you can kind of manually just choose where you go with it. So there's certainly a case to be made. Just like with testosterone, it's like oh well, why would you use a GNRH agonist or why would you use a serum or why would you use an aromatase neighbor or what have you and modulate these upstream pathways when you could just take the straight hormone and manually pick where you land. And oftentimes that could be the reasonable answer, especially for somebody who wants like a very targeted end goal and knows exactly where they want to land on their igf or doesn't need or potentially has worse output relative to the input of those peptides because again, it's working off your natural capacity. So there's definitely potential pros and cons. You can, if you have good functioning entire hypothalamus pituitary, all the output is satisfactory from an infrastructure standpoint to output natural hormones at an adequate level, the natural peptides may be useful. And you know you're getting all the variants of all the kilo Dalton molecular mass variants. But with exogenous it's just like you know exactly what you're getting. You can manually choose what you're getting out of it. And I think it's more could be reserved for people who don't have the natural output that they are trying to get out of the peptides. They don't respond that well. Or there's just more data too.

So is there kind of an analogy here where taking growth hormone, exogenous common growth hormone, is like taking testosterone, whereas taking the peptides is like taking Clomid?

Yeah, I would say with exception that you're not blocking negative feedback, you are positively modulating it.

Correct. Clomid works by creating a blockchain. Yeah.

So it would be like analogous to probably an HCG and recombinant FSH or more like a HCG probably or combined HMG or something.

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 oxidize fat?

The literature is so sparse on being able to say without a shadow of a doubt that it is going to enhance 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.

You do gain lean mass. Part of that presumably is water retention. You do lose fat mass, right?

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 utilization of substrate, you could absolutely improve your body comp fairly significantly with it. But when it comes to actual protein synthesis, muscle accrual, it's very 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 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. Some think 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 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 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.

Might not have the function.

Yeah. So you may not get enhanced force production outcomes like you would be seeking from like a true anabolic agent, but it doesn't improve cosmetic appearance of muscle, almost certainly, and can help you improve your body composition, especially if you time it well with. Because if you just use it and liberate free fatty acids and sit around and do nothing, you could just redistribute that and not necessarily get the benefit out of it that you're seeking.

So do you think that the liberation of fat is the more reproducible finding of GH use?

Oh, yeah, you know, that's happening when you use it for sure. And you'll become acutely insulin resistant as a result of that too.

So based on that knowledge, when is the ideal time to take it? Do people take this once a day, twice a day?

It depends on the dose. Because if you're using a very high dose, and it also depends on your lethargy from it, it is very lethargy inducing. You could feel sleepy all day if you're blasting a high dose of it.

What would be a high dose? Like what you were taking? 6 to 8?

Yeah, I would say when I took it, it was mostly in the 2 to 4 IU range. I only did 6 to 8 for like a very short period of time. Even that the lower, lower but still pushed me to like a 500 IGF. Was lethargy inducing for me personally.

For how long?

Man, that was so long. I had tried it for full durations of cycles, so upwards of a few months was probably the longest I had taken it.

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.

With the doses I was using and splitting it up the way I was, it was pretty around the clock.

Why is that?

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 want to track that, I can't imagine you can extrapolate from there that it's helpful for somebody who has. 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.

But you're saying with a higher IGF you were more lethargic, you would think that you'd be sleeping better based on that argument, right?

Yeah, probably. It's also gets conflated with bodybuilding diets too, because 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 yet.

They'Re more lethargic during the day.

Yeah.

Is it possible then that the GH is inducing too long a sleep so you sleep well, not at night, but then it's carrying over to the day, like there's a hangover of sleep?

Potentially, for sure. It seems to be a hormone that is quite rejuvenative during your sleep. And I can't imagine, not that I really read into 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 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. So if I'm manually creating at least half of the conditions that are associated with when I would otherwise get the deepest sleep, maybe I can manually induce that myself if I'm deficient or what have you. But as far as timing and the justification for it, it depends on if you were trying to use it for lipolysis or if you were trying to use it to enhance sleep or what the conditions are because you are going to be suppressed at a certain level regardless. So oftentimes the logic would dictate, at least in my opinion, that you would probably put part of your dose before bed, given that you're not going to get the same output when you're using exogenous gh. So if I'm using, let's just say all of my GH in the morning and then I'm going to exercise to.

Try and use the fat.

Yeah, which is not a bad idea. There's definitely a, at least I think a justification that part of that dose, or potentially all of it, when your IGF1 or GH output is suppressed, that you would actually allocate your dose to pre bed. So it depends on goals too. And if you notice an enhancement of sleep or not, but you can say without a shadow of a doubt that feedback loop will suppress your natural output, you're not going to just get the best of both worlds.

And so would you say more people today would be using the 2 receptor approach, the 2 peptide receptor approach rather than GH. Is that a more common approach today?

I think among those in the clinics for sure, because it's less cost prohibitive. That's what I think. But in the underground bodybuilding world they're typically pushing super physiological IGF1 levels. That's their goal, that's what they want to 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.

They're pushing IGF to 500 and more.

Yeah, typically like that. It would be a minimum adequate amount for performance enhancement, 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.

Let's detour for a moment just to talk about bodybuilding before I wanna kind of go back and talk about anabolics and then maybe this'll be a nice dovetail into it. So in my gym, I have a lot of pictures of bodybuilders, nice black and whites that I enjoy. And there's just a real clear difference between Frank Zane, Arnold Schwarzenegger, Sergio Oliva to Jay Cutler and Ronnie Coleman. And I don't know when that jump took place. Maybe Lee Haney, maybe Dorian Yates. But somewhere in there, there was a real transition in physique. Not to debate which of those is the best. I think everyone can have their own preference for which era of physique was their favorite. But if you sort of think of the things that can impact your physique, genetics, okay, that's not changing. Nutrition and knowledge of nutrition, that's clearly evolved. Training and knowledge of training, that's clearly evolved. 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. 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. 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 a 1970s physique versus a physique today of the best bodybuilders in the world?

Probably drugs at the top, almost certainly, followed by, I would say nutrition, probably, and then training at the bottom. Them.

How much emphasis on each of those? Like, 50, 40, 10.

That's tough because these get scrutinized to hell. Because it's like, I'm going to put a number on it. People will be like, how do you think diet is? Only 20%. A lot of these things don't live without the other. So you could definitely lean heavier and say, well, if you eat nothing, the drugs aren't going to do anything. So I would say, just in order of importance, 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 want to forget on the GH stuff. One thing that is interesting is even in acromegalic patients, the incidence of death seems to be cardiovascular, significantly more than cancer incidents. So if there's anything to discern from actual human literature, Significantly, chronically elevated IGFs into even 40 years old. These individuals are dying from congestive heart failure and things like that.

And that's really interesting. So not even atherosclerotic disease. I have to look into this. Actually. That's a very good point. I should look at the acromegaly literature.

One of the interesting things is how much fluid retention they hold and the stress that has on the heart too.

Yeah, that's very interesting. They also probably would be, I'm guessing, maybe more prone to aortic dissection because they probably have larger connective tissue, things like that.

Yeah.

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, and if they're being honest with me, and I have no reason to believe they're not, you would think, yeah, like what do they care? I was shocked at how little drug use was going on back then. Amongst the best of the best. And we're talking like 1 to 200 milligrams of testosterone a week, eight weeks at a time. Eight on, eight off. Eight on, eight off. In other words, they're basically taking TRT.

Yeah. They're not telling the truth.

Okay, so that's your view.

Most of them, almost certainly. Or not, when you're saying you're taking a borderline female HRT Diana Bol dose, it's like back then that's what it was prescribed for. Or like muscle wasting in old age or whatever. Some of the old like Seba Dianable ads are hilarious, by the way, but those dosages are almost impossible to wrap your head around, producing outcomes that they are like, you might as well have stayed natural almost at that point. So I too bought into the idea of, well, they seem to have consistent stories. They seem to have all taken one shot of primo a week and you know, one to two Diana Ball or what have you. And it's just not an outcome that you see as reproducible ever in those dosage quantities. So maybe on the hyper extreme outlier scenario, you might have a guy who a total weekly dosage of a few hundred milligrams across everything he's using. He may hyper respond and get huge But I would say the majority of the guys competing at the Olympia level were still like. I've heard of people slugging D Ball.

By the bottles even back in the 70s.

Yeah. It's just certain people are more outspoken about their abuse than others, seemingly. And it seems like the ones that are outspoken are more like this guy, Pete Grimkowski. I don't know if you've heard of him before, but looked incredible. But the guy used thousands and thousands and thousands of milligrams. And I can understand why you would arrive at that logic to take that, because there was nothing to tell you otherwise. So if you're competing against a guy at the highest level and there's relatively high stakes, you see a guy like Arnold getting movie roles and stuff, it's like the peak of achievement as a bodybuilder. Back then, you couldn't do social media. You couldn't do anything. You would try and emulate, presumably, what he was doing or something of that nature. To think that you're not going to escalate your dose past one to two, Diana Ball and a shot of Primo or what have you, or a shot of Nandrolone because you didn't want to hurt yourself, it's like, shut up, dude.

Yeah. I feel like I saw a video kind of recently of Tom Platts discussing.

He had changed the story. Yeah. With that said, his original breakdown was relatively conservative still, but he's done public presentations about drug use back in the 80s 90s, and you could tell he was pretty reserved even back then. He handled the situation very delicately. You could tell he was picking his words carefully as he spoke. But more recently, he came out and said his dose was like, I don't know, a third of that or something. It's like, okay, maybe like, you know, in 40 years or something. I don't expect you to remember exactly what you took, but to say your peak dose was one third of what it was, I don't know. Like, I just. I just don't really believe you.

Well, at the other end of the spectrum, I've spoken to one bodybuilder who. And I couldn't believe it, but he said at one point he was up to. Are you ready for it?

Yeah.

50 grams of testosterone in a week.

There's no way you would not inject that much.

I was like, how is that possible?

You would run out of injection.

How are you managing?

I think a lot of people just don't know what they take week too oftentimes. You ask people on trt, even what's your dose like, oh, I took like, you know, a half.

As we noodle with patients, between 100 and 120 milligrams a week. Like literally, we will make movements that fine. 20 milligrams a week?

Yeah. I think a lot of people, they just go by, oh, my doctor told me to take this much of a syringe and then they kind of just remember some rough number, but oftentimes they don't know how many milligrams per milliliter what they're using is. They don't know what their dosage is. They just take some scheduled protocol and they stay on it for years and then they don't even know what they're doing. But 50 grams is like, it's impossible. You would have to dedicate your life to injecting. Essentially that would be your full time job, just sitting there pinning like 5-10cc barrels of test all day.

Oh God. Given how remarkable the physiques were in the 70s at the top of the food chain in the Olympia, would you agree with me that something dramatically changed in the late 80s, early 90s?

Yeah. And it seems to be the emergence of growth hormone and insulin abuse as well as the escalation of drugs to an even more extreme magnitude. And the availability potentially granted, they were prescribed readily, seemingly, but people also seemingly push the limit more and there's the emergence of underground lab preparations and things of this nature. So. So my understanding at least is, and there's no literature to document like, oh, you know, this dosage equated to this, and therefore this is why it happened, but it seems to be dose escalation of anabolics to some extent, but more so the implementation of growth hormone coupled with exogenous insulin use.

They're using insulin because of how anabolic it is?

Well, the goal is what they think it is and obviously if there's terminology that may not be exact on that, but it's like what they believe it's doing is shuttling a super physiologic amount of nutrients into the muscle. Because also when you take GH you are acutely insulin resistant, so need a.

Little insulin to overcome that.

Yeah, they're almost like doing both things at the same time is the goal. And often when you're using really high doses of gh, fortunately this isn't as problematic in replacement dosages. So I don't want people to extrapolate out, oh, GH equals chronic insulin resistance necessarily. But at the dosages people are using, they could induce diabetes essentially, like you could end up a diabetic from just your GH abuse. And oftentimes to relieve stress off the pancreas and the beta cells, they will use exogenous insulin. So you don't have to produce as much endogenously to actually accommodate the amount of carbohydrate intake and just overall nutrients. Because these diets to maintain a 300 pound physique, you're pounding 5,000 calories a day sometimes.

So the introduction of growth hormone with all of its benefits, presumably, which we've.

Talked about, it's funny because right as we finish talking about how it's not performance tensing now the thing that causes the 20 to 30 pound lean mass jump is supposedly GH and insulin. It's interesting to say the least, but continue.

Well, I was gonna say. So we have that issue going on you've also talked a little bit about. So my belief used to be all this GH and insulin use is why we're seeing these big abdomens on not just bodybuilders, but also on athletes. So you'll see track and field athletes who are insanely muscular, insanely lean, but they have huge protruding abdomens that do not appear to be fat because you still see a six pack ripped on top of it, but from the side they look pregnant. And again, the thinking was, well, is this just organomegaly? Are their organs just getting bigger? Now you've talked a little bit about an alternative hypothesis.

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. Because to get that many calories in, get that much protein 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 100 to 200 gram shakes that have hydrolyzed whey in them. Branch cyclic dextrin plus 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 incomparable to days when you're fasting, for example. It's a massive difference. Fasting, you could do a vacuum and see 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. That is a perpetual state of reality for bodybuilders who weigh that much to sustain that food intake and the physiques that they have because it's not a normal amount of muscle to hold. So it requires a not normal amount of food to accommodate the nutrients required to grow further or even like sustain it. Good example of that is Ben Pikulski. He makes, 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 latter part of his career by reducing his food intake significantly. Seemingly. And he actually showed up one year later with a vacuum on stage, which. A vacuum for people who don't know. I don't even know if I could explain it, but it's like you suck your stomach in and it creates like an almost like an inverted. It kind of goes in. You can see your rib cage and like your serratus lines and stuff.

And most bodybuilders wouldn't be able to do that nowadays.

No, no. And that's a big notable differentiating factor of 70s and like 90s bodybuilders. The amount of people that could do 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.

Except for presumably natural bodybuilders are more likely to. Or.

Yeah, yeah.

They don't have the food demand.

Yeah. It also depends on like what they're eating, because people's 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, things that could compound the issue significantly. So then you have people with sibo and bacterial overgrowth and all this stuff that can influence the distension. That is kind of like a congregation of bad digestion, insane amounts of food, 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, et cetera. But anyway, Ben Pukulski, he. He showed up with less muscle, but he had completely reversed his gut distension. 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, non distended appearance. And if he had organ growth, is it reasonable to assume that he could.

Have reversed that is another example of something that's very frustrating to me. This is knowable. Literally, take the bodybuilders, throw them into an MRI scanner, you can get organ volumes on everybody. And we could compare that to controls and also look at them off drugs, on drugs, all that stuff. So again, it's just an example of so many of the questions that we have here that we're not getting resolution to are knowable. It's not like we're asking, is there life outside of the solar system? We're never going to know the answer to that.

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, you learn things from bodybuilders that have died that you might have not even known, because not that long ago, 10 plus years ago, people were saying, where are the bodies? No one's dying from steroid use, et cetera. But there are guys dying with hearts three times the size of what they should be. So there's certainly organ enlargement, systemically for sure. So we could say that. I don't know if it's necessarily pushing on the stomach wall to actually.

Cause I see what you're saying, but.

I can say with near certainty there is organ growth for sure. I just. Again, multifactorial, maybe it's part of it.

It's a great point. So let's talk about the death of bodybuilders and we're gonna. Again, I want to come back and do a long discussion onto anabolic steroids. There was a bodybuilder that died kind of recently, right?

Yeah, yeah. That was a shocking one too. He was 30 years old. One of the biggest social media influencers too.

What was his name?

Joe Lindner.

American or German? German. Oh, that's right.

Yeah, yeah, yeah, yeah. So with him, the scariest part was he was one of the guys who was 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 back in the day or not that long ago even. It would be unheard of for somebody to be dying if he wasn't a massive bodybuilder by industry standards for fitness, where we had this warped perception of what is big versus not. He was like 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.

And what are the known circumstances of his death?

So apparently his. And this is the thing that's. I don't even know if you're going to 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 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 vax. So he did it twice apparently. And then supposedly his D dimer went back down because it was super elevated in his blood work and they said he was fine now and he cleaned his blood and reintroduced it back into circulation. He would be good. He made a long trip to the US I actually met him for the first time like a couple weeks before his death and then when he flew back to Thailand, which is a really long flight and yeah, there's clotting risk, you know, associated with that on top of all the other things, which is speculated to be something that's another variable. But he got back seemingly fine and then apparently a few days after he got back, he was complaining of neck pain. His aunt supposedly died from aneurysm in her neck. That is what we have been told. We have yet to see a 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.

In her neck or in her head?

It was apparently neck specifically, which I would think is unusual.

Yeah, I won't even speculate without an autopsy. I think, again, tragic, obviously, but hopefully an autopsy sheds light on that. I mean, it's not difficult to know if someone dies of an aneurysm on autopsy.

Would you scope that out with like a pernuvo scan before you even.

Yeah, that's actually one of the reasons we really do, like, whole body MRI is 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. Now, not all of those are aneurysms that pose risk, meaning they're not all aneurysms that, if left alone, would ultimately rupture. But a number of those require intervention. So we've probably in the last seven years had two patients. If you think about how small our practice is, two patients who have had incidental captures of aneurysms that were, in one case large enough, in another case growing quickly enough to a large enough size that. That they needed to be coiled preventatively. So the aneurysms that typically kill people are in the head, behind the stomach. Those are the ones that you kind of want to look out for. Also, as far as if he had a deep vein thrombosis, which would certainly be a risk factor on a long flight, that could obviously kill you with a pulmonary embolism. Again, very easy to diagnose on autopsy.

So, by the way, what's your current flight stack?

So I don't fly that much anymore. And when I do, most of my stack is around sleep. What I'm thinking about when I'm flying is how do I eliminate jet lag? So I went to London, I don't know, a few months ago.

So you don't control for, like, clotting potential anymore?

I take baby aspirin, although the literature suggests that it's not necessarily helpful against dvt. I used to take something else.

Natokinase.

Yeah, that's right. I used to take that for dvt. Nowadays I just use compression hose, hydrate like crazy. And basically I've got straight legs most of the flight because I'm, like, laying down. Honestly, I think, like, hydration probably plays a greater role than most things. At one point I was like, so ridiculous. I was taking lovenox injections. So Lovenox is like an unfractionated. It's like a type of heparin basically. But after one time I took it where I injected it and hit a blood vessel and had like the biggest bruise on my abdomen, I was like, oh, this is just not worth the hassle anymore. Most of my effort really focuses around how to not get jet lag, which I've turned into a science.

I'll have to ask you about that later.

Yes, yes. I can go to 8 hour time zone away, be 100% functional the minute I get off the plane, get right into routine and rhythm.

But traditional bodybuilder deaths, this was a bit of a unique one because a lot of people, well, until the autopsy comes out, no one really knows.

It might be that this is just a tragic death in someone who also happens to bodybuild.

And it might have nothing to do with, in general what I've seen from the autopsies available on some pretty young bodybuilders. It's almost always a cardiovascular issue and.

Not necessarily atherosclerotic, but more cardiomyopathy type dance.

Yeah. So like left blood pressure unchecked and had heart function just destroyed essentially. And hearts that are way larger than they should be. I don't know if you've ever heard of Rich Piana, but he was a very famous and influential bodybuilder in the fitness industry. And he died in his 40s with I think it was like a 660 gram heart. And then Dallas McCarver probably the most notable one. He was like a mass monster by IFBB pro standards, which is like one of the guys on the Olympia stage who's actually the biggest of the guys on that stage. His heart was like 860 grams or something. And I think an athlete heart is like, like what, one third of that or something?

Maybe a bit more than that.

Okay.

Yeah. Mike Menser died young as well, didn't he? Yeah, he had known atherosclerosis. Didn't he have.

He was also, and I don't want to speak out of turn, but I've heard he was pretty into amphetamines on top of that. So it was like stimulant abuse on top of potential anabolic exposure.

I do think that that's one of the difficult things to ascertain with respect to bodybuilding is so much polypharmacy. Well, it's the polypharmacy and there's also like, there's the psychological component that's very difficult to disentangle. That's part of the profession. So let's go on and talk about testosterone and androgens in general. You've already thrown around a lot of names that are going to be foreign to people. But before we kind of get into the different anabolic steroids, you want to just kind of do a quick review of the relationship between the hypothalamus, the pituitary, Leydig cells, Sertoli cells, like what's the whole relationship between those hormones, testosterone production, and maybe we can even talk about dht, androgen receptors and estradiol for that matter.

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, 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 hormones that work on your gonads to produce testosterone as well as assist with spermatogenesis and 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. And then there's also like some stimulation of progesterone receptors that causes negative feedback as well, 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 adequate amount 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 because we have a satisfied amount of estrogen receptor activation in the body. So we need to clamp down and not make as much hormones because 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 accent Sertoli cells as well. And this is. We'll definitely get into that email you sent me about fertility and whatnot. Those will go down to the testes and stimulate the production of intra testicular testosterone as well as assist with the production of sperm and maintenance of fertility. So those levels, I think that's probably a good summation of how you end up with testosterone. Probably.

So then what's the fate of testosterone?

The fate of it in terms of metabolites?

Yeah, like once it gets out there, how much of it is converted into estradiol? Dht.

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 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 fat you are, essentially you could otherwise be producing more estrogen than you would have if you were lean, telling your brain in a indirect way that hey, we have enough estrogen, so don't make more testosterone. Because I use testosterone and 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 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 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 super physiologic amounts of drugs. And also in people who 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 going to get it high after going on female hormone therapy. But at the end of the day, this is kind of like the primary hormones to understand as far as the spectrum of androgenic male to estrogenic, feminine. Like it's not a female hormone because 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 neurology, kind of the psychoactive effects. And then estrogen is kind of like it's a big balancing act, essentially.

So let's again, just make sure people understand the difference between androgenic and anabolic because we will come back to this more and more with other compounds as we talk about the profile. Well, this one has slightly more androgenic behavior. This one slightly has more anabolic behavior.

Yeah. So the androgenicity or androgenic activity of a compound or your endogenous hormones is essentially how masculinizing it is. So dihydrotestosterone, the 5alpha 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. It's very potent in what it does to frame how important it is. You could have a male if you wiped out DHT before puberty. Basically that's how you end up with a micro penis. Essentially you have individuals who will not undergo full maturation unless you have the presence of this hormone.

If you took a male before puberty and just put him on dutasteride or finasteride and zeroed out his DHT with making no change on his testosterone.

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, voice probably not as deep as it should be. 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 these enzyme inhibitors and how we even discovered how they work and whatnot. But 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 kind of summarize.

So we talked a little bit, and I've discussed this on many previous podcasts, but just in case folks haven't listened, Right. So testosterone or DHT make their way into the cell, into the cytoplasm, where they bind to the androgen receptor. To your point, DHT does so with far, far greater affinity. I mean, it's on the order of one order of magnitude more, maybe 20 times more binding efficiency to the androgen receptor. This new complex of testosterone or dht, bound to the ar, makes its way into the nucleus where it acts as a transcription factor, binding to DNA and imparting on it, effectively, transcription, translation. That's how we make stuff. It's how we make proteins. So. So that's how it impacts muscle protein synthesis.

I guess one thing I should have said is androgenic, because you did actually ask me. This is not anabolic. So androgenic masculinizing, but does not necessarily equate to muscle. So you could have severe masculinization with a relative absence of actual muscle growth or translation to, I don't know, bone integrity and what have you.

By the way, how important is DHT post puberty?

Seemingly it depends, because from a cognitive health perspective, from a balance of estrogen standpoint, from a vasodilation in the penis standpoint, like, there are certain things where you could say it's pretty critical, but then there's also, you could just as easily say it's not necessary or mandatory, like you will survive and likely thrive just the same. With a lack of DHT almost entirely, 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.

Yeah, dutasteride and finasteride being two drugs that block 5 Alpha Reductase. Used initially for reducing prostate size because DHT disproportionately drives prostate growth growth, but also used, I would say used more for hair loss now. But yes, and we have talked about this on two podcasts previously about post finasteride syndrome, which is a debatable idea. In other words, there is not a clear consensus in the urologic literature about even the existence of this, let alone the prevalence, let alone the reversibility of it. All of These things are really unknowns and actually it's created quite a bit of a conundrum for us because we have a number of patients who take finasteride or dutasteride for hair loss.

And what's your stance on five alpha reductase inhibitors?

Yeah, I mean, look, I think, I'll be honest with you, I never really paid enormous attention to it until about a year ago. I think right now our stance is I probably wouldn't start somebody on it. So in other words, if a person has bph, we're not going to manage that anyway. But a urologist has far better tools to manage BPH than five 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 like if someone came to me and said, my APOB is too high and I gave them a bile acid sequester in circa 1981, I mean, it's just not necessary. There's no upside. 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, which, by the way, want to come back to that in a second. I would encourage them, if they've never taken it before, not to, 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. What about you? What do you think?

I think that several of the drugs you just said have either comparable side effect profiles like topical finasteride. You end up with the same burden of 5 alpha reductase inhibition systemically, despite the fact that it's marketed otherwise. Topical dutasteride is interesting because it may have some capacity to stay local, especially if you do mesotherapy.

I wasn't aware of that difference.

Yeah, it's thought to be the molecular.

Just hydrophobicity.

It's more the molecular mass of the drug. So there's this like. It's like an arbitrary rule, but if the molecule is greater or less than 500 Daltons, I believe it is off the top of my head. It's been a while since I've revisited it, but. But there is a lesser or greater ability to actually absorb it and get systemic circulation and distribution across the body. With Dutasteride, it's like, I think it's like 600 or 700. With finasteride, it's like 300 or 200.

I don't think that systemic minoxidil is necessarily a benign drug. And the other thing is nobody really can give an explanation for what the right dose is. If you look at how people low dose minoxidil, oral minoxidil, it's. It's insane. So I don't like to be in the business of prescribing things for which I don't have a great understanding, which is why I'm not in the business of treating hair loss. Not because I don't think it's something worth addressing if it bothers someone. But I think the bigger issue is it would be really awful if in trying to treat a cosmetic condition like hair loss, you induced a devastating consequence on your endocrine system. That's really where I find myself concerned now. It also appears that if you've been on finasteride for a long period of time and you're not experiencing any of these side effects, you're probably fine. So I also don't want this to turn into like someone listening to this, who's been taking Propecia for 10 years, who's never had an issue going like, oh my God, I gotta stop this stuff. The literature would suggest, and there is a pretty good review we'll link to that. If you're gonna have these side effects, you're gonna have them in about six months.

Yeah. In general, when it comes to hair loss, the problem is oftentimes the treatments, if it doesn't actually interact with the AR or inhibit the potential for stimulation or agonizing the AR through DHT reduction or even systemic anti androgens. Not that I ever recommend that you are essentially just putting a band aid on the issue. So if you stimulate growth with minoxidil, you are still not preventing further loss. If you get a transplant, you are putting hair on your head, but you're not preventing further loss of your actual existing hair. So oftentimes it's like you're almost trying to row against a current or something. And it's like you are continuously getting pushed back. And eventually you're going to get to a point where you have so few visible hair follicles even left that are healthy that it doesn't matter how much you've been on minoxidil or what have you and oral minoxidil, it's definitely effective, but I think it should be reserved for people who have weak response topically because topical seems to be far more tolerated, side effect wise and a lot more predictable with hordes of literature and great outcomes. And there are ways to enhance that and also turn yourself from a non responder to a responder which we can get into. But finasteride in itself, it seems to be like, I don't want to try and come out and say I'm a proponent necessarily. I try to take a balanced approach to it. But the prevalence of side effects is not nothing, but it's quite overblown by the opposite camp that wants to assert that why would you ever inhibit a hormone that is the primary androgen you rely on? But similarly, why would you inhibit, I don't know, APOB or something like there is a clear outcome whereby there's benefit. And when there is DHT in somebody who's prone to hair loss, it's hard to overlook that this is the primary thing dictating if you go bald or not. And some people that hair loss. Some people care a lot more than others, obviously.

So I do think there's a difference because I think APOB serves no benefit. If someone created an antisense oligonucleotide that knocked out apob, all it would do is guarantee we don't have heart disease in our species. We would still be able to use all the HDLs in the world for cholesterol transport, which we currently use LDL for. But I think to take your analogy a step further, what you're basically saying is if a person cares as much about hair loss as they do about heart disease, and by that logic DHT.

Is causal, which sounds absurd, but let's just run it through.

I would posit that there are lots of people who care more about hair loss than heart disease.

The psychological stress for some people is significant and should not be overlooked by the silliness of, oh, just lose it and just shave it, bro. It's not a big deal. There's tons of successful people who are bald. It's like, yeah, sure, but although I.

Think there's a statistic that no bald person has ever been President of the United States. So there you go. So there's a couple of occupations you gotta take off the list. Now you mentioned when you were going through your insane anabolic steroid use, you at a very young age, if you're in your early 20s, were already starting to lose your hair. So how did you Reverse that part.

Of it was just dropping the dose significantly and eventually just going down to replacement therapy. But it was the introduction of 5 alpha reductase inhibitor, initially finasteride, and then thereafter I introduced a. And I wouldn't necessarily recommend this blindly, but a topical antiandrogen that's experimental never actually received FDA approval. There are some that are in the FDA pipelines right now that actually look promising and have safety data behind them and whatnot that I'm watching closely and hope one comes to fruition. Because these are essentially compounds that compete for the androgen receptor locally but do not have systemic antiandrogenic activity. So you can maintain all systemic androgen levels with just localized activity in the scalp, essentially. So I use a topical anti androgen coupled with a 5 alpha reductase inhibitor. Those were the main two needle movers for me. I also use a ketoconazole shampoo, but it's like a very mild anti androgen. It's mostly just a good shampoo. But those two things and decreasing the burden of androgen significantly were fairly effective at getting me not to baseline.

Meaning you never regain.

No, no, no. And that's the thing with hair. That's the sketchy thing, is even if you're trying to decide, oh, you know, maybe I should treat it, maybe I shouldn't, I'll think about it for a bit, I'll see if it gets worse. The visual representation of loss is typically not apparent until you've lost a lot of ground because you could pull a handful of hair out of your head and see no difference whatsoever. Once you finally notice diffuse thinning or recession, it's not something you've been looking for carefully because you've never dealt with it. So oftentimes once you actually notice it, picture or in heavy downlining or something, you've already lost 20, 30% plus of your hair and there's no guarantee that's coming back.

So did you regain hair that you had lost with this protocol or just.

Completely stop some regrowth, but expecting yourself to get back to baseline where you had, you know, like 17 year old immaculate perfect hair? If you've been exposed to androgens at a level where you're visibly noticing it, it's relatively unlikely. So that's not to say it's impossible. Like if I took minoxidil as well as microneedle and did a bunch of other stuff, I could probably get a decent amount of the way there. But the longer you wait and let hair follicles miniaturize the more permanency you are risking. So making back ground is way harder than preventing yourself from losing it in the first place. It's almost like maybe analogous to building muscle when you're younger, so then you don't have to try and build it in old age when you have anabolic resistance or what have you.

Let's make sure we give people the names of these compounds you're using.

So finasteride is like the main primary five alpha inhibitor.

You take one milligram of that daily.

I take dutasteride now.

So you take 0.5 milligrams. Is that 0.5?

Yeah, I take 0.5 a day. So that is a soft gel that. That essentially wipes out systemic dht.

And your DHT level is.

It's like worse than a teenage girl. Yeah, it's terrible. But I smoke. Yeah. At least now I think one of the guys with the highest IQs on the planet has been on dutasteride for decades, if that's notable for anyone.

Okay, so then what else are you taking besides Dutasteride?

Dutasteride right now is the only thing. I take more out of convenience because a topical application schedule can be quite burdensome.

But when you were doing that big salvage effort in your early 20s, what was the rest of the stack?

Oh, it was topical application of something called RU58841. It's like a experimental antiandrogen. So I don't necessarily Recommend People use RU58841 when there are actually alternatives with human safety data on the horizon. With that said, it's also hard to tell me, however many years ago, that wait, because you only have so much time, right? So I'm not going to sit around.

And what are these things that are on the hue that have more safety data coming down the pipeline?

This company called Kintor has a compound called pyrolutamide, and it seems to be pretty well tolerated. And comparable outcomes of hair count increase to dutasteride, if I recall off the top of my head, which is pretty substantial, given that there are very few things that produce outcomes that even make it worth taking another drug. Right now, the most effective things are going to be five alpha reductase inhibitors and minoxidil on top of that. Everything else is like little sprinkles on the cake, essentially. Some people might get better benefit from PRP than another person or what have you, but in general, the main meat and potatoes are going to be minoxidil, potentially microneedling with minoxidil if you're not a good responder or have low sulfotransferase enzyme activity in the scalp and the inhibition of free androgenic signaling in the scalp. Whether you do that through five alpha reductase inhibition or anti androgen activity locally, that's kind of up to you. Or some people are going to couple both of them like I did. But those are the main needle movers ultimately and some people go super hardcore. And the most crazy hair loss reversals you will see are always in men transitioning to women who use female hormone therapy. I would never recommend anyone do that, but it's a pretty interesting data set to pull from.

So estrogen and progesterone would promote hair growth. I mean we do see it in women actually during HRT especially progesterone can really thicken hair. But this is in women. I mean, I have no idea.

Yeah, I'm more talking about anti androgen plus estrogen. So somebody transitioning would typically use a cyproteronacetate, bicolutamide, something of that nature, plus exogenous E2 or a synthetic estrogen.

And the first two, which I'm not even familiar with, are drugs that just block the androgen binding to the androgen receptor.

Cyproterone is a very potently antigonadotropic, I believe, so it's like it will inhibit you from producing GnRH.

It's effectively a chemical castration that's like.

A steroidal antiandrogen and then there's a non steroidal one. And yeah, it is effectively chemical castration. The non steroidal variant, bicolutamine seems to be a bit better tolerated. It's not as liver toxic and it will actually raise your hormone levels on paper. Your test levels go up, up. It's just you can't actually interact with the receptor because it's occupied by bicolutamine. So it's like a silent androgen receptor antagonist. And those are like extreme options though, like essentially irrelevant for anyone watching. So maybe I shouldn't have brought it up.

Yeah, yeah, let's go back to kind of TRT then. So we've kind of established what's going on.

When are you starting?

Yeah, we're going to talk about that. I'm actually doing my blood again next week, so we'll see how far my levels have continued to fall. So I was going to actually talk right about that. Right. Because let's talk about quote unquote, what's normal. I've never found a Compelling table for normal levels of free testosterone that are stratified by age. You can find these data quite easily for total testosterone level, but I've only really seen data for broad chunks. Prepubescent, pubescent, post pubescent. 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, most of that is bound and sex hormone binding, globulin and albumin probably do the lion's share of binding. And if a guy's got 2% of that as free or unbound, that would translate to 16 nanograms per deciliter of free testosterone. That's estimated by the way, it's not calculated. It's very important people understand when you go to the lab and you get a test done, they're measuring testosterone. That's direct measurement, by the way. We should talk about ELISA versus LC ms, but they're estimating the free based on the measurement of the binding proteins. So that's introduction of potential error. Number one, 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. So you really don't have any idea whatever amount of testosterone you have is saturating your androgen receptors or not. Are you playing below your weight or above your weight? What do we know about the amount of total testosterone over time in a guy's life?

I know that after it peaks you will have a steady as opposed to women, where you see like a plummet after menopause. For men it's more gradual and you can expect, I believe it's about 1% drop in total tests per year with an approximate 2 to 3% drop in free each year as well. So at the same time you would have 1% total tea drop 2 to 3% free. Depends on age, lifestyle. But in general, like post age 30, 35, you can kind of expect a little bit of a decline to start. But that's not to say I haven't seen 70 year olds with like a thousand total tea sometimes. So you can certainly retain high level production. I don't want anyone to think, oh, now that I'm 45, my levels have probably dropped 20 plus percent at this point I should probably get on TRT. Might not be the case. So 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 how well do you produce gonadotropins, how well do you respond to them at your testes? Because there is some level of function that declines with age 2, even in response to the gonadotropins. And that's an expected outcome, unfortunately. But that's kind of 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? Because there's an argument to be made if you have very good testicle response, like, why would you ever be on exogenous TRT too? Because you could top out your natural signal even.

Is there an advantage to that? Before we get to that, let's talk about the rationale for trt. So what do you think is the most compelling case for it, and how often are people expanding that use case?

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. That could be somebody who is. You should probably check. Do you have a varicose seal? Do an ultrasound of your testes, see where things are at structurally, functionally, et cetera, before you make any rash decisions. Because 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. Kind of depends. But typically, testicular failure in response to adequate signaling would be the obvious. More no brainer versus if you had low LH and fsh, maybe your testicles are fine. So why are you hapazardly getting on testosterone when maybe it's a lifestyle thing?

And so 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, basically high glucocorticoids, which can also suppress the pituitary.

And you'd measure the glucocorticoids through like a Dutch test?

Yeah, usually urine. Actually, we used to use saliva long ago, but. But yeah. So using a Dutch test, interestingly, those are not the easiest things to fix. Because people have to change behaviors, which is a lot harder than taking a medication. 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. 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? Because again, most of the studies, and we might talk about the traverse trial, they kind of just use fixed dosing, which is at least for me. One of the criticisms of that approach, by the way, is especially when you're using something topical and you have variable absorption. But what do we know about this?

I think in general, if you're going to be treating with exogenous testosterone, an accepted entry level dose that is on average safe and well tolerated and will get you to a reasonable total tee that provides symptom relief for the majority of people is, I can't see a more logical start point than for example, like 100 to 120 migs a week or something of that nature. And just seeing what happens to the guy's total T free T. This could also be variable based on does he have a super high shbg? Should we be evaluating that? Because maybe he just has a low free T instead of his total is fine. In that case, you could have brutal symptoms, but your production is still good. It's just being bound up severely. And why is that the case? Do you have severe liver issues or something? So after you flesh all that out and you determine the guy needs tea, I would imagine a reasonable starting place is typically like 80 to 120 a week and then go from there. See how you respond to that.

And any advantage to dosing it once weekly, taking that dose and dividing it by two and doing it twice a week, taking that dose and dividing it by seven and doing it every day.

I don't necessarily know that. Like for example, when patients come to you, I'm sure they're looking for the highest level of optimization, hence why they're with you. So maybe it's more reasonable to expect them to pin more frequently. When I say pin, I mean inject. But there is a half life with the drug depending on the ester chosen. Typically testosterone cypionate will be prescribed, at least in the US that's the most prescribed one, which is a half life of 10 days, if I recall off the top of my head. Depends on the person, of course, where it's injected, blah, blah, blah. But that half life, you could extrapolate out from that. Okay, it's going to take 50 days to achieve steady state serum concentrations in the blood. And that's going to look on like a steroid plotter. You could check online and see this kind of like spiking until all of a sudden there is the same amount of dropping of the drug clearing out of your system. You're getting an equal amount of spike back up. Like there is no accumulation of drug burden after you've achieved steady state serum concentrations. So the advantage to injecting more frequently, and this is going to be determined largely by patient adherence more than anything, because some people simply refuse to inject even more than I've seen some insane stuff where people will let themselves drop to literally hypogonadal territory and then remember based on their dick not working. I'm gonna. Okay, now I take my test. But in general, once a week is like bare minimum, I would say, but that's certainly not optimal. And I would say that two times a week, at least for somebody seeking good quality oversight, you know, preventative medicine, whatever, if they're coming to you or to somebody who believes in the same things you do, twice a week I think is kind of minimum for decent steady hormone concentrations.

We've sort of arrived at the same conclusion that that's the sweet spot. We do have a couple patients who do daily injections. And interestingly, in these patients we see much less for the same dose of testosterone. So you take 15 milligrams injected a day, which is actually very difficult to do. You have to be very thoughtful about what kind of needles you're using to actually get such a small volume in. But they will have much less FSH LH suppression, which suggests to me that the higher the peak, the more the FSHLH suppression. I don't know that there's anything physiologically relevant to that.

The studies, when you look at trough level T levels and when I say trough, I mean like the lowest point of hormone concentrations after an injection. Oftentimes these studies assessing dose response will look a week after your injection. So what you see in the literature isn't necessarily reflective of what's going to be in patients trying to optimize anyways. But what I see personally and in Marek Health and through all my blood work that I've seen over the years, et cetera, the more frequent you get, there's a diminishing returns for sure. But you can lower the aromatization spike and 5 alpha reduction by going more frequent so if you have a bolus administration of, I don't know, 150 milligrams once a week, you are literally spiking your T into super physiological territory acutely and concurrently, you are getting super physiologic conversion to estradiol dht. You also have a very, very aggressive spike in free androgenic signaling which can crank your sympathetic nervous system up, impair your sleep quality. There's so many consequences.

And you'll see more hematopoiesis. So when I had Mo Cara on here, he was talking about Natesto, which is the nasal formulation, which has such a short half life that it's actually a TID dosing schedule. So it's 7 milligrams of testosterone.

I want to see somebody take three times a day for more than a year and still tell me it's cool and fun to take. So if you end up doing that for trt, you go to.

I probably will not. But two interesting points with Natesto. The first is they don't have the hematopoiesis. So these are not people who are making too many red blood cells that you have to actually be careful of and have to go and get them therapeutically phlebotomized to take blood off them as their hematocrit gets over 50. Secondly, it's a FDA formulation that women can use because if a guy is taking 7 milligrams in each nostril three times a day, clearly a woman could take one of those every other day. And by the way, it's sort of an on demand libido tool for women in particular. So there are lots of interesting things around that. Also, they're doing a clinical study and we're sort of observing what they're doing where women are using intravaginal use one application of that intravaginally before sex to enhance orgasmic function. It's always desirable to have an FDA formulated product when you can kind of avoid the dark side of compounding, is my view.

I think the best way to conceptualize for the listener to why this frequent protocol or getting a more stable level, why does it result in a lower side effect burden? The closest you can replicate natural function, the more you will replicate natural side effect profile, which should be nothing if you are physiologic. So with Natesta, which is like in and out acutely, like so fast, you were not getting this huge spike to like 15002000 nanogram per deciliter total T, there is no situation ever in which your testes would Just blast you once a week with a hammer of test and all of the associated metabolites and back end and consequences of that, you would have little pulsations over the diurnal rhythm. And this is why you would test your blood as a natural. In the morning when your testosterone is spiking and it's going to ebb and flow over the day, your test level in the morning could be 300 nanograms per deciliter higher than later in the day. Like it fluctuates. So to expect that it's reasonable to jam yourself with an absurd amount of test in one go and then hang on that as it declines at your body and then crank it to the stratosphere again once a week, it's just not representative of physiologic state whatsoever. So the more you can replicate that diurnal rhythm through the synthetic administration route, the closer you're going to get to a lower side effect burden. I've seen some guys that get gynecomastia from TRT dosages, go to ED everyday dosing and get off their AI.

Just to translate that into English, sorry. You've seen guys who can take a weekly dose of testosterone and in doing so they make so much estrogen that they have to take an aromatase inhibitor to prevent them from getting breast tissue gynecomastia. And if they take that same dose and divide it daily, they can come off their aromatase inhibitor altogether.

Yeah, and some people, it's problematic because they will give feedback to their doctor or just give a judgment to what hormone therapy was like for them based on what is maybe not the right dose, but also just not even close to an ideal dosing regimen and injection frequency.

When I got back into the practice of medicine and was learning about hrt, I couldn't find doctors who weren't prescribing anything different than every two weeks. That was the standard.

Have you seen the European sustenance?

No, I have not. But the standard dose was 200mg every two weeks. I remember going through Llewellyn's pharmacology and looking at the pharmacokinetics and being like, this is an awful idea. Any difference clinically between cypionate and ananthate? Obviously, one of the advantages of ananthate is there's a commercial product called Zyostead for people who are squeamish about injecting that comes in a preloaded pen. So we have some patients who just don't like the idea of having to draw up a syringe and they just kind of want something that's a little more turnkey. So Zyostat, which is a slightly different form of testosterone, but clinically I sort of remember at one point there was some difference that might be age specific, but I don't recall.

Now ananthate is often thought to be a long ester, which it is relative to like propionate or phenyl propionate. But it's kind of like an in between of cypionate and propionate. It's like a half life of could be as short as four and a half to five days, I believe off the top of my head. Whereas cypionate could be twice as long in some people. So it depends on your individual metabolism of the drug often. And also if you're pinning sub Q or im like you could bleed out the effect more. So I would say if you're injecting frequently enough, it's essentially irrelevant.

The xiaosted protocol from the FDA is once weekly. We still recommend people do it twice a week. Just use a lower dose.

The difference of what you're supposed to take versus using it, like obviously frequency is of a lesser concern than you walking around with no test. So if it's the difference between a guy taking it versus not okay, take your once a week if that's what it's going to take. Is the preloaded dose. Can you modulate?

You can't meter it. That's what's so annoying about it.

It's annoying with the GLPs too.

Yeah, it's such a racket. And I always tell patients, I'm like, look, if you're completely cost insensitive, I guess fine. But otherwise getting sipionate in a jar is a fraction of the cost if you're just willing to be the guy that meters it out. But the ananthate, I think only comes in three loaded doses of zyostat. You also have less wiggle room if you're not happy with the output.

I would assert with near certainty that you are not optimizing your hormone status. If you are, I want to say optimize. I mean, just dialing in the stability of it and the side effect profile and potentially quality of life as much as you could if you did a more frequent schedule, especially with ananthate, meaning.

The more frequent you're giving it, the better better.

Yeah, I think the diminished returns are. There's a significant drop off when you go from every other day to every day. But one week to twice a week. I'd say there's a pretty dramatic difference. That's worthwhile.

Let's talk about the difference between sub q&im. I have always advised patients to do sub Q for the belief that it has, as you point out, kind of you bleed out the effect a little bit longer. I have to be honest, I don't think I've seen data to support that.

I have seen, and I think this is an extrapolation, but I believe it to be true, is when you look at sub Q dosing, you'll notice the total T levels are higher and then people take away from that. Oh, sub Q is like you get more out of your test. But the reality is when they measure total test levels, it's often a week after your shot.

I see. So it just lasts longer.

So I think you are almost giving yourself a sustained release through administering into the fat tissue rather than intramuscular, which is more readily absorbed, quicker blood flow, et cetera. Just like if you did like an IV administration, it would be in your blood immediately. Not that you would ever do that, of course, but the difference in pharmacokinetic profile of IV to IM to sub Q, like you can change the same drug dramatically in onset of action through that.

You think that sub Q is probably a better administration.

I think once you get to every other day dosing, it's almost.

Doesn't almost matter.

Yeah, but I think especially for people who are doing, and again, it depends on the amount, because if you're doing once a week, is that going to be too much of a bolus to sit in Stomach fat depends on the person. But I would say especially for infrequent, you'd be better sub Q. Ideally if the volume of oil isn't significant enough that it's creating lumps and stuff.

Let's talk about aromatase inhibitors. There was a study that I don't think gets enough attention. I think it was 2014, might have been 2013 in New England Journal of Medicine that looked at 10 groups. So it took a group of men, chemically castrated them, 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 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 erectile functional things. The punchline was you were better off with more estrogen and more testosterone. So the best outcome group was the high T, high E group. Now, the high E group wasn't that high. I'd have to go back and look how high the E was. I think it was probably in the ballpark of 50 picograms per milliliter. 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, I guess let's start with normal physiology. And then I'm kind of curious to hear what the bodybuilders are doing.

Back in the day, we thought that regardless of the dose of androgen, you should lower your estradiol to 20 to 30 because it's in the middle of the reference range. Ish for a man. And that's where you get the best. There was no thought of balance. It was kind of like, this is a bad hormone to have above the reference range. Even though our androgens are literally like 10x the reference range.

What would your testosterone levels when you were back in the heyday?

I never got LC Ms. Testing when I use my highest dosages, so it would get capped at like 1500 or something. But it was, you know, in the thousands for sure. But yeah, with estradiol there is, and I've seen these 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. 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 so many things that regulate mood as well. I think even, like temperature control, too, is going to be variable based on that. It kind of ties into the postmenopausal stuff. But for men, it is certainly important. And to crush it arbitrarily based on a reference range is kind of like old bro lore. And I think most people even in the bodybuilding space are pretty aware now that estrogen is important for cardio neuro Protection.

And I think another thing it's really important for is bone health. And by the way, you asked me earlier about when am I ready to start my TRT protocol? I think I'm more troubled by the fact that my estradiol is so low because my T is routinely between about 3 and 400 nanograms per deciliter and my estradiol is never above 25 picograms per milliliter, which is normal. That would be normal for such a low T. But to me, one of the big advantages of having a t of 1000 would be that I'd hopefully.

Have an estradiol of 40, 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, by 15 to 22% on finasteride or dutasteride. Some people who are very low aromatizers and have like a hyper androgenic state, those people, that's where unique individual variability comes into the consideration for drug implementation. So a guy like that, even for actual quality of life, sometimes that like modulation.

Interesting.

Yeah.

I'm actually going to do both tests side by side next week where I'll do enzyme based test plus lcms for dht, testosterone and estradiol. So I'll probably have a better sense of what they look like. Because we can talk about how often enzyme based testing gets estradiol wrong.

No. Yeah, I've seen some brutal overestimations using eclia when it was like single digit.

Yeah, we've seen guys come back with estradiol levels of. We're using like say Boston Heart, which is using an enzyme based system. And they'll come back and they'll have an estradiol of 100 and we're like, this can't be right. And then you send them to LabCorp and specify LC MS, they're at 31.

Yeah. And this is especially important, I think, in especially hypogonadal men who have relatively low estrogen to begin with. Like, actually identifying where it stands is pretty important for sure.

Okay, let's talk a little bit about the other hormones. So for most of the medical needs, is there any reason to be considering a hormone beyond testosterone for male sex hormone replacement?

I think it depends on the person for sure. That's like such a general answer.

Well, let's say this. If you're just talking about health benefits and not performance benefits, we're going to talk. I'm sure. About lots of others. And I'll give you one example. So way back I used to be a little bit more liberal and creative. So one of the things I used to do was if guys had normal testosterone. The example used a minute ago, a guy who's got a testosterone of a thousand nanograms per deciliter, but his SHBG is a hundred for a guy is very high and his free t is like 8 nanograms per deciliter. So he's like 8/10 of a percent free. Instead of say 2, you could use a very, very low dose of oxandrolone and you could eradicate his SHBG because it has such a high binding affinity for oxandrolone. 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. You knock that SHBG down and you double his free testosterone. You haven't given him any testosterone. I don't do that sort of thing anymore. I feel like it's just not worth the hassle. Truthfully. That's one example of an area where you can manipulate another part of the system without having to go beyond that. But, but if you maybe take examples like that out, if you're just talking about the use of these other steroids, what's the case?

In some individuals, adrenal hormone replacement sometimes may be justified, but it's going to be based on blood work.

When you say adrenal, do you mean DHEA? Yeah.

So like DHEA, if you have like a bottom DHEAs, maybe you would look to a DHEA replacement if you had low pregnenolone. That might make sense, but it's more for like, like neurological, cognitive, perceived quality of life effects. Not necessarily because there's any evidence to support that it's necessary. In general, the main needle mover is going to be your test and how much a 5 alpha reduces or aromatizes into the two metabolites. And from there 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 storiedogenesis cascade where might other stuff stuff plug in. I've seen progesterone use in men on trt, actually reasonably effective in sleep quality.

How much progesterone? The same amount as women, 1-200mg you.

Don'T have any HPTA suppression because you're shut down anyway. So it can be impactful on quality of life because you get the downstream conversion to some of those neurosteroids that may be inhibited in post finasteride patients.

I'd never heard of that. That's super interesting.

Not common or why would it work in women and not work in men? If you had a reasonably low progesterone level, yeah, you're not expected to have a sky high progesterone anyway. But it's some of the downstream neurosteroid metabolites that you make through five alpha reduction and whatnot that are very GABAergic and anxiolytic and can help certain people. And maybe that's useful for a specific guy who has a low SHBG and is in a state of high sympathetic drive on his test and needs to calm down. Or there are certain use cases that are more individual dependent for sure and not necessarily dictated solely by let's lab result it out and anywhere. We just look for red and then replace it.

I don't really know the history at all of anabolic steroids. Guessing testosterone's probably been around since the 30s or 40s, right? Presumably, yeah.

I think when it was first synthesized remains up for debate. Maybe it goes back back nearly 100 years at this point.

And so what was the first anabolic derivative of testosterone?

The first one I can think of off the top of my head is Diana Bowl. There might have been like methyl test or something I could be misremembering. But essentially what they did was they took the testosterone molecule and found they could finagle it, manipulate it in ways to create testosterone derivatives like Diana Ball Methandrostenolone, which is supposedly the breakfast of champions, according to Arnold. It's one of his famous quotes. Boldenone is a very commonly used drug as well. Still. 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 Halo Testin, which I think famously one of the presidents the United States was on some aggressive dose of Halo Testin for I forget what it was, maybe fertility or androgen therapy. But some of the protocols back then made almost no sense. Halo testing. 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. 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 going to give a child testosterone who has a burn patient. You're not going to give them tests because 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, keep somebody from wasting away in a state of fill in the blank without causing extreme viralization. So the 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 the Diana balls, the bulldanones, and on the DHT derivative side you had oxandrolones, one of the more refined, more recent, although decades ago at this point, Primobolin, also a very refined one, metenolone proviron I think still used actually to interact with shbg. It's probably one of the most potent drugs at binding. SHBG is master alone. But yeah, the ideal scenario would be you're trying to segregate the anabolic from androgenic activity because 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, 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. But an array of compounds, if sort.

Of one to ten it would be. Let's just make this a scale up. So five is testosterone. So it is halfway between completely anabolic and completely androgenic. DHT would be closer to 1. It's much more androgenic than it is anabolic. What is the furthest example you have that's closest to 10, meaning the most anabolic?

Primobolan probably.

So one would think that that would be like the drug of choice.

If you're a bodybuilder, it often is too. So typically men will take. I'm not saying it's the only drug because it depends on what else you're trying to get because sometimes the side effects, as absurd as it sounds, are desired. So with Diana Ball, for example, heavily water retentive, so that could help cushion your joints when you're doing heavy lifting, for example, if you have better leverages on like 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 Primobol and is extremely refined and specific in its action. Like, it's like a pure protein accretion compound with a relatively less burdensome androgenic profile. But the side effects of it, it doesn't interact with aromatase because it's a DHT derivative. So it's not a substrate from 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 want to look cosmetically inflated with water. Some people want to lift more weights or prevent injury. And sometimes that water can be helpful. Depends on the person. But yeah, that's like skewing the furthest direction of anabolic relative to anergenic. You'd probably have like Primobol and Anavar.

Yeah, and I remember again, just sort of reading like Anavar, also highly prized.

Among athletes, technically, SARMs are actually even further if I was to give the most extreme anabolic relative.

So let's talk about SARMs then. Tell folks what those are.

Okay, so selective androgen receptor modulators. These were kind of designed. Some people might be more familiar with serms. You've talked about Clomid Tamoxifen on this podcast before. 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 inhibition of estrogen receptor activity in the breast for somebody who has breast cancer, for example, versus you would have 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 antiandrogens actually to make these compounds that would interact with the androgen receptor in a way that was tissue specific. And try and get 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, beta blockers, for example, as you get higher and higher, they become less receptor selective and you get more like broad spectrum.

What are the typical SARMs or what are the most potent or commonly used SARMs?

LGD4033, probably. It's called Ligandrol. 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 two trial for hip fracture patients. Osterine, also known as Inobo. Sarm 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 Austrian and they don't viralize themselves when they take it.

It's funny, I always thought that was a serm. I didn't know it was a sarm. Are these banned compounds in natural bodybuilding?

Yep. And they're super detectable because they're not supposed to be in your body at all.

So how does one get these? Are these. If they're in phase two compounding pharmacies?

Some of them make them.

Yeah, that's true.

I've heard some wild, nutty stuff just like, oh, yeah, I'm prescribed Tren. How does your pharmacy make Tren?

Yeah, let's talk about Tren. Where does that fit into?

So that's actually classified as a steroidal sarm, interestingly enough. So it was prescribed to women in the 80s, I believe, and was also used to beef up cattle and might even still be. But it is super anabolic. But it also has very odd progestogenic activity. So it interacts with the progesterone receptor, causes severe night sweats. It's called Trend Sweats. It also has this weird side effect called Trend Cough. No one can be sure of what is causing it, but it's one of the only drugs associated with a prevalence of a severe coughing fit. Like you're having an allergic reaction or something after you take it. So you inject it and you feel all of a sudden this tightness. In your chest and then within 20 seconds you're on the floor hacking up a lung for two minutes.

I had a patient come to me a little while ago who was seeing some fancy doc in LA who had him on a pretty high dose of Trenin gh. Again, there's always like, how do you get people off these things? Luckily he wasn't on it for very long.

Those compounds are more suppressive too because they interact with the progesterone receptor significantly. So it's like you get the negative feedback not just to AR ER but prime as well.

So let's just kind of recap where you were on some of those. So did you talk about Deca and Androlone?

Yeah, Deca is close to the more pure anabolic side. It's not near the selectivity of a SARM at a therapeutic dose, but it is probably the. Interestingly enough, the only steroid that you can probably use at a dose that is will result in bodybuilder level results without hair loss because it has unique interaction where it's. It gets so complicated when you think of the pharmacology of this stuff because it's like it will 5 Alpha reduce into a dihydronandrolone, which is almost no androgenic activity. So in the muscle where you have a relative absence of 5 AR, you will retain the anabolic properties of nandrolone where you want it. But then in your scalp it'll 5 Alpha reduce into this metabolite dihydronandrolone, where it has almost no androgenicity. So you get like the muscle building without the hair loss.

So do bodybuilders even take testosterone at this point?

Almost always.

So why are they taking testosterone when they have all of these more designer anabolics that seem to have an advantage over testosterone in every way.

Testosterone is the base because it provides your estrogen base layer of neural protection.

Because none of these things provide aromatization.

The only other compounds that could act as replacements for test are things that are potent substrates for aromatase too. But even then you get these synthetic estrogen metabolites that have less predictable activity. So for example, D ball converts to methyl estradiol, which the potency of it at the estrogen receptor, it's not as predictable and your body doesn't really know exactly. It doesn't have as predictable of outcomes in terms of providing the base layer of what you want from like a broad spectrum perfectly balanced. Androgenicity converts to estrogen where you want it in tissues. You know, it protects the brain to some extent. Granted, at super physiologic dosages you're in neurotoxic territory. Certainly you're not going to protect yourself with a base of test, but it's better than no test for sure. Or no estrogen.

When you're saying it's super physiologic doses, you mean supraphysiologic doses of all of these other hormones?

Yeah, because I guess there's no actual physiologic level of them. But it's more just like the androgen burden on your body is exceeding what it would be from a natural testosterone production standpoint.

So what is a bodybuilder? Let's just talk about an IFBP, top 50 bodybuilder in the world. What percentage of the year is he on some anabolic steroid?

Oh, anabolic steroid including testosterone, presumably 90 to 100%.

They basically have accepted the fact that they've completely suppressed and lost any endogenous production for life. And it's now just a question of how they cycle up the testosterone plus or minus the other anabolic sort of.

I've seen firsthand multiple bodybuilders who've been shut down for decades come off and restore natural function.

And they're using presumably FSH and some.

Of them just HCG and just coming off the drugs and waiting long enough. But it begs the question, would they have been there had they not used the drugs until then? Is that just what is representative of where they declined to naturally? Or is it like a permanently lower ceiling potential because you've inhibited organ function for so long? You can't really say for certain.

Do we have data on people who have been on anabolic steroids for five years or greater and the ability to forget spermatogenesis, just regain endogenous testosterone production?

Yeah, it's sparse, but it exists.

The data are sparse or the frequency of people who do it is sparse.

There's almost no literature on it. I believe there's a study that shows the recovery capacity and there are people who recover function. It's just relatively arduous if you don't know what you're doing too, when it comes to post cycle therapy, because you might have clearance of hormones and go to a crashed hypogonadal level that you're dealing with until you hopefully kick in gonadotropins and hopefully respond to those well and hopefully restore production to a level that provides symptom relief. And that process isn't instant, like you have to bleed these hormones out of your system if you're using long acting compounds too, which most people are. So there requires a lot of thought around bridging into your recovery and how you go about doing that. People have to be implementing as the androgens clear, they'd be implementing. Well, you'd hopefully be on HCG to begin with to preserve testicular function.

Are these guys taking HCG the entire time they're on these other drugs to just maintain some testicular volume?

Nowadays it's becoming more understood that it's probably important. But back in the day, and even me, I didn't do it because I was just told it doesn't matter, you will just recover fine when you want to, when you want to come off. I think more people are becoming aware though that stimulating activity in the Leydig cells is of reasonable importance, almost certainly to retain an easier transition back into recovery while you're on drugs.

So at their lowest time throughout a year, they'd be on how much testosterone? They'd be only on testosterone and they would be on.

Yeah, some people, they think that they're cleaning out by taking like a month off, but in reality it's like, like the drugs have almost some of them worked their way out of their system by then, but they've been on grams of stuff that's achieved steady state and you're just clearing 80% of it or something. And then you've never actually gotten out of your system and recovered function, which could take months. So oftentimes they have either residual androgens in their system for the time they're trying to clear, or most of them are staying on a base of TRT to bridge between blast phases which are like your high exposure points. So those bridges though of TRT, typically it's not actual TRT, it's like fitness industry TRT where everyone's dose is 200 minimum.

They cycle up during contests. Obviously professional bodybuilding is not tested, so the understanding is you're going to take anything and everything as often as you want. Do they take a more middle of the road set of compounds as their bulking up and then move to the more pure anabolic, Less water retention as they're leaning out or. There just must be so much nuance.

To this in general in an off season when your goal is protein accretion building muscle, they are using as they still use a ton of stuff, but they will use less than when they are preparing for a contest. And the thought is when I am trying to diet down aggressively when I'm.

In A calorie deficit. I need more help on the anabolic.

Even though it's like what threshold, threshold is it to preserve tissue at the end of the day? Typically a fraction of what they're using. But to build muscle, they will typically be using a base of testosterone plus one or two anabolic agents. In general, it's going to be a primobolin and anandrolone or something.

And how many total milligrams because they're about one to one to one, right?

No, it depends on the person how sensitive they are to estrogen because there's also interaction with, for example, DHT derivatives. They also compete for aromatase. Seemingly. I've seen people on the same dose of testosterone with and without a synthetic DHT derivative have significantly lower estrogen without an aromatase inhibitor. So they're actually lowering their estrogen input through competing for aromatase simply by using a synthetic anabolic on top. So it's like you have to modulate that accordingly too. So it's like oftentimes if you're a very estrogen prone individual or you get gynecomastia easily, the male breast tissue development, these are things you are concerned of when you are pushing your dosages to levels that your body cannot regulate on its own to prevent tissue formation at TRT levels. Most people will have no issues with gynecomastia development if they have a good protocol in place and they're not obese or whatever. But at super physiological doses of tests, not necessarily the case. But you might be able to modulate that activity down by actually competing for aromatase with your primobolin or your drostanolone. And then you get to the progestins like nandrolone, which seem to have a additive effect because progesterone receptor agonism seems to be a stimulation. It actually provides stimulative input on breast tissue development too. There's other things besides estrogen that stimulate breast tissue. So you have gh, also an IGF one, stimulate breast tissue development, estrogen, progesterone, prolactin. These are all things you have to consider when you're using which drugs.

How do these guys navigate this?

Not well, typically.

Even at the pro level.

Yeah, they just take random shit. Often.

I mean, when you look at the guys on the Mr. Olympia stage, responding.

Well does not equate to health. Often there's multiple ways to skin a cat and you can still gain similar amounts of muscle with all these compounds in general. But the way you arrive, there just might be more side effect. Burdensome or problematic and fill in the blank area.

How many of these guys require surgery for gynecomastia?

Most. They proactively do it to make sure they don't have to because one of the things that's brutal is guys who choose their drug protocol based on how gyno prone they are to those drugs. So I've seen people use abusive dosages of aromatase inhibitors, SERMs, just to tolerate the androgen input, some of the drugs that are substrates for aromatase. So it's like to use the drugs I need to gain the muscle. I'm going to get gynodevelopment, which I can't have on stage because it looks cosmetically not pleasing and I'll get marked down for it. So I'm going to use aggressive Novodex and aromatase inhibitors while I'm using the androgens to prevent gyno. So I can gain the muscle without the estrogen. But it's like you can just imagine the androgenic signaling plus no estrogen and it's like a horrible constellation of negative problematic factors.

Just seems like such a complicated regimen. I'm really surprised there aren't more health consequences of this.

We see early deaths all the time in the bodybuilding world. Granted, we see early deaths in all places, but these individuals are at least, you can say lean. They're typically following meticulous diets and training regimens. So at that point it's kind of just body weight and drug exposure because their sleep is usually dialed too, at least as much as it can be relative to their drug related side effects. But yeah, when people say where are the bodies? I'm surprised we don't see more deaths. I think it just hasn't been as documented as it should be. There are a lot of people that you will never hear about because they're not a big name in the industry that had heart failure at 27 or something.

Let's talk a word about how you measure this stuff. So if you're taking testosterone, you can check testosterone, but which of these other compounds show up on a testosterone check?

Many of them through immunoassay testing. So if you use, for example, testosterone plus nandrolone, it is derived from testosterone and often you will see a cross detection. So you might have an elevated testosterone level through a standard immunoassay that is not reflective of your testosterone dosage you're using. And similarly we see things like estrogen metabolites that are synthetic, artificially inflating your estradiol on ECLA as well.

And there are certainly a group of supplements that seem to aggravate this problem, although it's not been clear to me which ones aggravate which. The artificial reading of enzyme based testing of estradiol.

Yeah, yeah. There's certain things that you shouldn't take before a blood test, even like. Like biotin. Yes, Biotin being one of the basic stuff that really messes up readings in general. If you're not getting liquid chromatography with tandem mass spectrometry, it's like the highest sensitivity of testing you can get for total testosterone and free testosterone. This is something I haven't revisited in a while, but I recall equilibrium dialysis was the gold standard and if you don't use those, you will end up with cross detection. I've seen on immunoassay for total test and then the calculation for free tests, numbers showing that I'm in the reference range for testosterone. When I did nandrolone monotherapy, which for you, if you stayed on that deca almost for sure your test would have ended up in the gutter, Estradiol in the gutter, and you would have just had nandrolone. There's no nandrolone test, so you should have just had a hypogonadal looking testosterone profile and estradiol. But if you got the cheap entry level immunoassay testing, it probably would have been, oh, look at that, my test is in range still. I'm not suppressed on nandrolone. I guess 100 mgs of nandrolone isn't that enough? Yeah, yeah, yeah. So that's like what some people might conclude. So it's very nuanced and it's not like you're taught to look for this stuff often. Most people aren't going to be prescribed this stuff to begin with, so it's a bit less relevant. But in the bodybuilding world especially, pretty important, I would say, to know especially where your estrogen is at, thinking that you're good when you might have a DHT derivative competing for aromatase. And your E2 on paper looks in range and it's actually like crashed into single digits, problematic brain damage, cardiovascular disease, bad bone loss.

Let's talk a little bit about Clomid and hcg, maybe tell folks how they're used and we can talk about some of the pluses and minuses of each.

Human Chorionic gonadotropin is presence in pregnant women's urine, significant quantities and often it is pulled out, as absurd as that sounds. And Purified because it can be used to stimulate the luteinizing hormone receptor similarly to what endogenous LH does. So it looks similar. Some people say it's a memetic essentially I think is the best way to put it. Like it mimics the effects of luteinizing hormone in the body. And this is why it is commonly used in fertility regimens for men, because you can essentially replicate the LH signal to your testes that may be suboptimal if you have low gonadotropin output or non existent if you have HBTA suppression from your exogenous testosterone you're using. So if you use TRT you can pretty reasonably expect that your LH and FSH will go down to either non detectable or close to there depending on what you're using and the dose.

Dose.

And replacing that LH I would say is of pretty high importance if maintaining fertility is important to you. So you will experience testicular atrophy if you do not replace the LH somehow, whether it's through recombinant LH which is almost never used or HMG which is typically not used either. The most cheapest, lowest barrier to entry predictable thing is HCG which still is.

Not that cheap if you're using the branded HCG is much more expensive.

Yeah, there's a clamp down on it recently too in the compounding world. And then Clomid, I guess the primary clinical use is in women for fertility, for IVF prep in men it acts. This is how it works in women too, but it's just for fertility purposes in men it's a selective estrogen receptor modulator. So we talked about SARMs earlier and I mentioned serums and, and how they use that idea. For SARMs, it interacts with the estrogen receptor in either a positive or negative way in that it could stimulate activity or prevent estrogen from binding to it and interacting and providing estrogen related activity in certain tissues. And it's selective in the way it does this. So Clomid has anti estrogenic activity in the hypothalamus. So it tricks your brain into thinking it's estrogen deprived. So the response to that is, is we have low estrogen so we need to make more testosterone to aromatize into estrogen. So you uptick your GNRH output to the pituitary which will increase LH and fsh, which increases test and then you can intervene with that compound to trick your body to make more tests. I think yes, is the best way to put It. And interestingly, I don't know if you want to go down the rabbit hole of enclomiphene versus Clomid. Clomid has two stereoisomers, I believe. Yeah.

One is basically a mirror image of it. Yeah.

So it's like zoo Clomiphene and enclomiphene. And enclomiphene is seemingly the more selective and actually antagonistic in the hypothalamus. So it's kind of like doing the thing you want from the Clomid. Whereas the zoo Clomiphene is like antigonad. Like, it's providing almost like a antiandrogenic type activity in a way that is not. Not as selective as like a pure serum. So when you think serum, you're thinking something that antagonizes estrogen receptors purely in the hypothalamus, but then leaves estrogen activity everywhere else. Bone integrity is maintained, cardiovascular, et cetera. Everything is kind of backfilled accordingly, except for right there in your brain where you want your brain tricked into thinking, make more testosterone. So. And clomiphene, it also has a shorter half life, significantly less. I think it's 10 hours off the top of my head. And zoo Clomiphene is like days or something. So the actual ability to maneuver the drug, like pharmacokinetically too, if you have a bad side effect or something, can't even get off it as easily with Clomid because you have this big chunk of it as zoo Clomiphene. So the idea, and presumably creation of trying to get FDA approval on N Clomiphene was this is a more pure version of the drug that does what we want. And there's been at least one study that showed immediately improved outcomes in women who took enclomiphene, but it never made it through FDA approval. But despite that, it doesn't stop people from prescribing it and people from using it. I don't think that's a sustainable treatment protocol for your entire life. Probably. I think the reality, and it's not as easy to adhere to, but I would probably assert that stimulating exactly what you want to do directly with an HCG + recombinant FSH is a superior outcome rather than perpetually inhibiting estrogen activity. There's no drug that's purely selective exactly where you want and is perfect.

And that's the only issue I would also have with it where I think if you took two individuals and one of them you put on exogenous testosterone, and one of them you put On Clomiphene, they were identical in every way. In terms of readout, equal testosterone, free testosterone and estradiol. I think there's still an argument to be made that the guy who's getting it from exogenous testosterone has a better outcome because he's not getting the central inhibition of estrogen. So his libido is better, his mood is better, his sleep is better.

Oh, some of the mood dysregulation on Clomid Wild.

Yeah. I mean, we never saw this stuff, but again, I think we're a very small sample size. We're not running like a clinic on this stuff, and we're using microdoses compared to where I think people are going. If you're not asking those questions, you also might not get it.

Even when people report that these are often people who are on the precipice of hypogonadism already with very low quality of life, as is, presumably to even get on the therapy, going on something and then noticing a decrease in vitality and notable antietrogenic activity, you are going from a baseline that is not good to begin with. So it's like comparing that to the outcome of trt, I feel like, is often a misrepresentation just for the sake of you're maintaining adequate function or you're maintaining the testicular axis at the end of the day. A thing that I need to maintain in perpetuity just for the sake of having an LH and FSH that comes from my pituitary instead of just manually doing it. It probably not if it's at the burden of permanently antagonizing one of the most important receptors in your body, I would say.

Yeah. I think as a general rule, if you start to muck around with receptors in the brain, you should have a pretty good idea what you're doing. Let's talk a little bit about fertility. So let's compare a guy who's on testosterone versus a guy who's on hcg. So if you're on a high enough dose of hcg, you're going to see FSH and LH suppression.

Yeah, this is what I found. I dug into this specifically based on that case that you mentioned.

So what does it mean? So you've got two guys, one guy's on testosterone, one guy's on hcg, and they both have a very high testosterone. They both have completely suppressed LH and fsh. Obviously, in the case of the guy on high testosterone, his Leydig cells are doing nothing, and the guy on the high HCG his Leydig cells are cranking out testosterone. But in both cases, there's enough testosterone being made that the pituitary has stopped making LH and fsh. So what happens to these guys when you stop testosterone? Let's assume they've both been on their protocol for several years.

The guy who has sustained organ function is almost certainly going to have a smoother transition because he has maintained the natural function and output of the organ responsible for intratesticular testosterone the entire time versus the other guy has literally deprived the tissue so significantly that it's a fraction of the size. So trying to compare a guy recovering with testes half the size or less compared to a guy who has fully functioning testes that have been maintained, that guy just needs to discontinue and get rid of that feedback inhibition, and he's likely going to return to natural function within short order, pending his gonadotropin output from the pituitary is satisfactory. So it's to be determined if that guy is going to have adequate pituitary output, given a bunch of other factors, lifestyle, et cetera. But probably that guy is going to be okay. I would say the question then is, why did that guy go on HDD to begin with? Because it's presumably because he had low LH output. So maybe if that guy got on with low LH outputs on hcg, because that's probably the main reason he would have. He's probably gonna go back to low LH output unless something dramatic has changed in his baseline lifestyle, diet, and he's older now with less testicular function just as a result of age. So there's that for sure. That is a major factor. But he at least has more potential to recover to whatever his baseline was than the other guy, in my opinion, who's gonna have a longer, more arduous road with, okay, you have to have enough. You have to not only get the testosterone out of your system to stop having negative feedback now you have to get the pituitary output back, hopefully to some satisfactory amount, which, if your baseline was low, because presumably it was, if you got on trt, why else would you. Unless you had, like, testicular failure. And that guy would have never got off test because that's the only option he has. Essentially, that guy is going to have to have enough LH output to stimulate him back to a baseline testicle size to match the capacity of the other guy, just from a morphologic standpoint. So I would assert that the HCG guy is almost certainly going to be Better off than the test guy.

Do you think that there's a way around it on the HCG guy if you dose him more frequently like you take the same dose. We typically dose HCG twice a week. So kind of starter dose would be like 750 units twice a week or 6:25 I think makes the math easier. I think 6:25 twice a week allows him to, to go whatever eight weeks with a vial or something like that and then generally we just stop. If you're not getting an amazing response at 2000 twice a week, which we would never go above that, you're wasting your time and you're wasting money. Curious by the way, what doses are bodybuilders using?

Most aren't using it, but the ones that are are typically. Well even the ones that are using it aren't following like a literature recommended dosages, but at least from what I've seen to maintain intrathecicular testosterone at 100% while suppressed on exogenous androgens, I think the dose is about like 375 IU every other day approximately.

Okay, so not her doses at all.

But this is also assuming you're starting at full function and you're not trying to get back up from zero to a hundred. So that'll be a bit of a difference on that. That guy who was on hcg I would assert probably have an easier transition for sure. But we can definitely get into the FSH suppression and the frequency of administration. That's what you asked. So if you pin more frequently versus twice a week, half life of HCG I believe is 24 to 36 hours. Off the top of my head I'd have to double check. But if you are going to an everyday schedule you're probably going to maintain more stable serum concentration so you're not going to get as aggressive spikes in light Excel activation. So you're going to have probably more representative of natural output of test. But at the same time, if that level of test is satisfactory to achieve the hormone levels that your body needs from an androgen, you should shut down. Yeah, then you should shut down. So the only way you wouldn't is either A HCG was too low, B your response to the HCG was too low, or C your dosage frequency was so not ideal that you had little blips of time that you had deprivation essentially and your body reacted to it, which is not an ideal outcome either. So the frequency thing I think it's more so I would recommend more frequent probably for just stability and Side effect profile, but it's based on the adherence of the patient. How realistic is that?

Yeah, A couple more random things before we wrap up. We've been going a while, and I feel like I'm about halfway through the stuff I wanted to talk about, but there was one peptide we didn't talk about, which is BPC157. Do you know anything about that peptide?

Yeah, yeah. One thing I should say before we get off the hcg, though, because you had this specific example of if FSH is suppressed, how do you know if the negative feedback is through the HCG dose amplitude, et cetera, versus the testosterone that comes from it? I found a really good study that was. It used HCG at 4000ius in men who had normal gonadal function and those who are poor non responders to hcg. So you can discern from that if.

It'S the testosterone or the hcg.

Yeah, but in addition, the people who responded, they use Clomidon after. So this is the interesting thing. So it suppressed FSH in the people who responded to the hcg, but not in the individuals who don't respond. So from that you can discern it's not necessarily the LH interaction and more so the downstream androgen receptor activation and subsequent to that, E2 estrogen receptor activation, the negative feedback.

So that's pretty elegant. So that actually tells us that it's not that you've shut off lh, it's that you've ramped up testosterone that is turning the system down.

Yeah, basically.

Sorry. It's not that HCG is mimicking too much lh. Yeah.

The LH receptor doesn't tell your brain, stop making tests. It's the testosterone output.

Yep, yep, yep.

And to confirm, they applied Clomid in the responders to HCG to see if they could attenuate the FSH suppression, and they could. So in that, you can assert that an estrogen is obviously a huge negative feedback regulator. If you can maintain FSH at baseline with a high 4,000 IU dose of HCG with pushing your total T way up and use the CIRM concurrently and prevent FSH suppression, it's like, okay, it's really downstream to the LH activation because it's literally the testosterone output and the estrogen because you're still maintaining FSH with the same androgen signal and the LH receptor signal. So from there, you kind of then need to discern. Okay. One thing I can say from the literature I've seen, too, is intratesticular androgenic Signaling seems to be the primary determinant on spermatogenesis far and above FSH receptor activation. So one of the ways you can kind of conversely assess this too is finasteride and dutasteride. Reliably kill, don't kill, but it decreases significantly sperm quality and count. It's something that is just reliably decreases all metrics of fertility from a semen parameters aspect. So the intra testicular free androgen signaling seems to be the main dictating variable on spermatogenesis. And you can find even in people who have minimal or no FSH at all, getting them fertile on HCG only and maintaining it. Now, there are certain people who don't seem to respond as well off 5.

Alpha reductase inhibitor though, or, well, still on.

I'm just saying in general, like people who are on five IR inhibitors, you're diminishing your possibility of fertility, almost certainly. So again, it's not just intratesticular testosterone, it's also presumably, and this is how you confirm what the 5alpha reductase inhibitor applied is, when DHT goes down, t goes up 15 to 22%. There's nothing changing about output of testosterone production other than DHT goes down when you have a 5 alpha reductase inhibitor. So if fertility goes down, when DHT goes down, it's not just the testosterone, it's just broad androgenic signaling. So the more androgenic of environment you have intra testicularly seemingly is the main dictating variable.

When DHT goes down, testosterone goes up by how much?

If it's finasteride, about 15% and you are inhibiting upwards of at best, if you use a 5 milligram Proscar tablet for benign prostatic hyperplasia, you're getting a 70% systemic DHT inhibition, which pushes your T and estrogen up by 15%, which.

Is so interesting because regular T conversion to DHT is not that high. I mean, it's rarely more than 10%. So it's like you're disproportionately getting a bump in T to the inhibition.

Yeah, yeah. And I'm sure this is probably something I'd have to almost like write out. But I'm sure if you get into the modulation of how much DHT occupies SHBG and then how much free testosterone.

There is, that's a free increase in testosterone, not total testosterone.

That's total. But DHT also, the activity of it is going to be inhibited dramatically more proportionally. To test because of its affinity for SHBG is like 5x. So I'm sure there's something there. If I wrote it out, it would make more sense than me just trying to think all the way upstream. But in general, the takeaway that I've seen is having high intra testicular androgenic signaling is the only thing that's mandatory for spermatogenesis and FSH receptor activation. With some level of fsh, you can still maintain or achieve spermatogenesis with minimal to almost no fsh. And in those individuals that still need a push, they either lack androgenic signaling or there's too much oxidative stress. Potentially they need to utilize things like ubiquinol, nac, like, I don't know, like sometimes supplements actually make a difference. Carnitine, creatine, or get off their 5 alpha reductase inhibitor or a myriad of things. But a little bit of FSH recombinant on top of that base of ensuring you have adequate intra testicular testosterone can be the differentiating factor on fertility for a minority of people, but it's not mandatory. And at the end of the day, when I hear people talking about, well, maybe we should get back to, we should use Clomid instead of hcg because we're seeing FSH suppression, I'm like, I'm thinking a little bit of fsh. It's cost prohibitive, but it's probably a much better alternative.

Yeah. What's the cost of recombinant fsh?

Depends on the pharmacy. But I heard the other day there was a pharmacy in Texas that prescribes 1500 IU vials for like a couple hundred bucks, which. Which to me sounds cheap. I've heard it's extremely cost prohibitive. And I think it depends if you're getting like, gonal or if you're getting like, which brand you're getting.

A typical dose would be what, 50.

IU every other day? It depends. You can go as high as 75 every day if you need to.

So it's still significantly cheaper than growth hormone.

Oh, yeah, probably.

I mean, everything is okay. All right, a word on BPC157, which is a peptide.

Yeah. Yeah. So body protection compound, I think is what the acronym stands for. 157. It's like a peptide that's produced endogenously in your gut. And it seems to have some angiogenic properties that can be useful for certain injuries. But it's like, I've seen some pretty remarkable improvements in minor, not complete tears and certain injuries that are of lesser. I'm not overly familiar with it to a point that I could say with any certainty that it's going to be efficacious for fill in the blank tank thing. But it seems to be something that if I had an area with low blood flow, like a tendon issue or something, that's when I would be looking to something that's pro angiogenesis because it's like I also worry about cancer cell proliferation from something that's pro growing blood vessels. So that is a concern with BPC for sure.

And does it need to be injected locally for it to have maximum efficacy? So let's just assume you tear your rotator cuff.

This was one of the bro myths we were taught back in the day is inject it right into the injury site. And. And I now don't believe that to be the case. It seems, at least the last I heard, that you don't need to do that.

Do we hold out any semblance for hope that we might get a study that would shed light on this? Because how could we ever possibly know the counterfactuals here? And how could we possibly disentangle the single user experience on all these things?

I don't think so. I think it's something that so many people use at this point. I imagine you can't patent anything or make any money off of studying it. You'd probably know better than me off of how pharmaceutical pipelines work. But I imagine it's kind of at a point where so many compounding pharmacies sell it. The problem I see mainly I don't really think it's not good to use. I would probably use it if I had a minor injury to somewhere I needed more blood flow. But I do think a lot of people use it proactively far too often for something that is directly intertwined with. With increasing. I think it's VEGF and is like super correlated with cancer growth. Like to me that would freak me out. People who are using it like preventatively. A lot of athletes use it as a preventative measure to avoid injury or rehabilitation when it's not necessary. And I think that's overkill and risky as hell.

Personally, I think because there are so many other things I want to talk about that we should just.

We can do it.

Wrap this up and hit a part two.

Sure.

Because we haven't talked about any of the stuff I want to talk about around nutrition, around appetite, appetite suppression. Again, I think we've talked a lot about how bodybuilders use drugs. And I think for many people that's a pretty foreign idea. But bodybuilders also, I think in a way, through their own very empirical study, have really figured out the science of how to get lean and how to do it with the maximum preservation of muscle. This is something that diet wild, they really do. And that's why I can't imagine a demographic that better understands how to do that, even if it's not necessarily the healthiest way to live. But I think we could all take a page out of the book if we're saying, you know, God, I could stand be 10 pounds lighter. Wouldn't it be cool if I only lost 1 to 2 pounds of muscle in the process?

When you see a guy with 50 pounds more metabolically active tissue, demanding nutrients, starve himself to 5% body fat and step on stage, it's like, okay, I can cut my calories by 300 or find some way that is more satiating to hit my goals. Like, it's definitely something to take from that.

Yeah, I want to dive deep into that. I also think we could spend some time talking about ways that people can prevent themselves from being fooled by all the charlatans out there. But these people wouldn't be as popular as they are. They wouldn't be making tens, if not hundreds of millions of dollars if there weren't people who were falling for what they're talking about. So probably there's something to talk about as far as, like, what are signs that maybe what this person is telling you might be too good to be true. Maybe there's a bit of a buyer beware. Anything else you want to add to a round two when we do it, which maybe we can do in the fall or something.

Off the top of my head, I think the fertility discussion, I think we kind of scratched the surface on what, what an ideal protocol might look like and things to be mindful of, banking sperm concerns that people might have getting on TRT beforehand, how to vet if you need it, even, like, criteria that would be worthwhile to know because discerning oftentimes people are told, especially at the clinics, oh, your total T is 400.

That's low.

Get on tests and it's like, you might have high AR content and expression. You don't know that you need more tests to actually achieve. I've seen some of the most jacked guys I know. I have 450 total tees and feel fine. There's a lot of nuance that goes into that too. And knowing, not just identifying content charlatans, but medical providers, even your own doctor potentially knowing who is looking out for your best interest. Educating yourself at a base level I think is almost a necessity nowadays to wade through the nonsense, so I would love to dive deeper.

Sounds awesome man. I look forward to it. Derek. This was a ton of fun and I look forward to continuing the discussion.

Awesome. Thank you for having me.

Thank you for listening to this week's episode of the Drive. It's extremely important to me to provide all of this content without relying on.

Paid ads to do this.

Our work is made entirely possible by our members and in return we offer exclusive member only content and benefits above and beyond what is available for free. So if you want to take your knowledge of this page space to the next level, it's our goal to ensure members get back much more than the price of the subscription. Premium membership includes several benefits. First, comprehensive podcast show notes that detail every topic, paper, person and thing that we discuss in each episode. And the word on the street is nobody's show notes rival ours. Second, monthly Ask Me Anything or AMA episodes. These episodes are comprised of detailed responses to subscriber questions, questions typically focused on a single topic and are designed to offer a great deal of clarity and detail on topics of special interest to our members. You'll also get access to the show notes for these episodes, of course. Third, delivery of our premium newsletter, which is put together by our dedicated team of research analysts. This newsletter covers a wide range of topics related to longevity and provides much more detail than our free weekly newsletter. Fourth, access to our private podcast feed that provides you with access to every episode, including AMAs, sans the spiel you're listening to now and in your regular podcast feed. Fifth, the Qualys, an additional member only podcast we put together that serves as a highlight reel featuring the best excerpts from previous episodes of the Drive. This is a great way to catch up on previous episodes without having to go back and listen to each one of them, and finally, other benefits that are added along the way. If you want to learn more and access these member only benefits, you can head over to Peterattiamd.com subscribe. You can also find me on YouTube, Instagram and Twitter, all with the handle Peterattiamd. You can also leave us a review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Users should not disregard or delay and obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or Advise, please visit PeterAttiamD.com about where I keep an up to date and active list of all disclosures.

SA.