The Peter Attia Drive - #274 - Performance-enhancing drugs and hormones： risks, rewards, and broader implications for the public

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.560 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:53.220 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.060 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Derek from

00:01:06.640 More Plates, More Dates. Derek is a fitness educator and entrepreneur behind the More Plates,

00:01:11.860 More Dates YouTube channel, podcast, and companion website. I've been following Derek now for a couple

00:01:17.460 of years, and I have always found him to be very thorough in his analysis and assessment of areas

00:01:25.480 that are very difficult to get insight into from the mainstream channels by which we would go about

00:01:32.900 searching for insights, for example, using published literature. Derek in particular has a lot of

00:01:39.440 expertise around molecules and the types of molecules that are both used and abused by bodybuilders

00:01:46.480 and athletes. A lot of our discussion today focuses on that. By way of background, Derek himself is

00:01:53.060 heavily into bodybuilding, fitness, and talks very openly about his past use with performance-enhancing

00:01:59.180 drugs and his real interest in understanding the science around these things. We really cover these

00:02:04.920 things in great detail. You might be asking, well, why is this relevant to a general audience? I think it's

00:02:11.120 because not a day goes by when I don't get at least one patient asking me a question about one of these

00:02:17.880 compounds. And the compounds I'm referring to, of course, include things like growth hormone,

00:02:22.320 testosterone, HCG, androgens, other hormones, SARMs, CERMs, peptides, oh my god, don't get me started on

00:02:29.700 peptides, clomid, estrogen, and much more. So throughout this conversation, we look a lot at how bodybuilders

00:02:35.660 are using these compounds because bodybuilders use them in the highest amounts. They also talk very openly

00:02:40.300 about these things. And then we ask the question, what can we learn about this for the general

00:02:46.380 population? Are these things all bad, carte blanche, or is there some nuance to this that we can understand?

00:02:52.860 This interview with Derek really is a part one because we just don't get through most of what I want to cover.

00:02:58.820 So we'll likely be doing this, and there'll be a part two, hopefully, in the not-too-distant future.

00:03:03.360 So without further delay, please enjoy my conversation with Derek.

00:03:12.280 Derek, awesome to have you here. Thank you for swinging by Austin. I know it's a little bit out

00:03:16.600 of the way for you. And great to meet you in person. We've had a lot of communications over

00:03:21.000 email and text, but... You as well. Thanks for having me.

00:03:24.340 Let's give people a little bit of background on you and maybe how you've come to know a lot about

00:03:29.120 stuff that's awfully technical, actually. So I don't know much about you, Earl. I'm going to

00:03:33.260 pretend I don't know much about you, other than that we share the same nationality and that you're

00:03:38.180 a fellow Canuck. So tell me about yourself growing up. Yeah. So I am from the West Coast of Canada,

00:03:44.680 born and raised Vancouver, British Columbia. How do you summarize? Like a childhood, how far do you

00:03:51.000 want me to go? First of all, when did you get interested in lifting weights, nutrition? When did the

00:03:55.720 topics that you now have pretty significant expertise in start to become a passion of yours?

00:04:01.920 Probably grade 11. I don't know if in the US there's like... We call it 11th grade or junior year,

00:04:09.180 but yes, continue. So that one. I can translate between the two. Yeah. So I was a rail, probably 130,

00:04:17.140 I think 138 pounds at my same height and basketball player. A lot of my friends were getting into working

00:04:23.240 out, putting on muscle, and I was the last one to get into it. And they were heavily encouraging me.

00:04:31.000 I was the only one who was left out if I didn't start. So I thought, okay, well, I might as well

00:04:35.460 join and I have nothing to lose by putting on some weight because I was pretty damn skinny at the time.

00:04:41.440 Got in the gym and a lot of people can relate to being bit by the iron bug where you start to get

00:04:47.200 the newbie gains and the quick progress becomes quite addicting. Then you get on a full-blown routine

00:04:55.080 thereafter. And I was kind of skewed away from actual sports like basketball because my three-pointer and

00:05:02.120 some of the muscle memory stuff really got thrown off when you start to gain 30 pounds in a matter of

00:05:08.220 months. All of a sudden your mechanics don't feel exactly the same anymore. So I got pretty into

00:05:13.140 working out and lifting weights. And as you get into lifting weights, it's kind of hard to avoid

00:05:19.740 some of the discussion around anabolic steroids, drug use, and bodybuilding. How are these insane

00:05:26.660 brontosaurus physiques you see on stage achieved and what goes into them? Because you often heard it

00:05:31.760 was, you know, that dare cell tech or some other supplement on the front of a cover or in a supplement

00:05:37.400 store sold by somebody. And then as I dug into it more, started to learn about hormones,

00:05:43.140 pharmacology. I actually had hair loss caused by androgens when I was experimenting with them as

00:05:51.020 a recreational bodybuilder. And then from there, I started to dig heavily into anti-androgens,

00:05:58.200 5-alpha reductase inhibitors, and had this weird broad spectrum pharma knowledge on weird niche stuff,

00:06:05.440 but it was all overlapping with the basis of androgen therapy, synthetic derivatives.

00:06:11.320 Just for sort of a timescale here, are you in college now or are you still in high school when

00:06:16.600 you're developing this level of interest? My initial interest peaked in 12th grade.

00:06:23.200 That grade, I developed my interest. When I get interested in something, I just go

00:06:27.480 hard. I just completely bury myself in reading whatever I can find. And back then it was a lot

00:06:34.160 of underground forums with Jim Burrows going back and forth talking about their experience with

00:06:39.020 fill in the blank compound, or this is what I did. And this is what I hear person X is doing.

00:06:44.880 And a lot of it was just anecdotal. Not that there's a lot of good literature anyways, but I mean,

00:06:49.100 just going on the forums, learning, digging into whatever science I could understand and

00:06:54.680 conceptualizing, getting a framework of understanding about how hormones impact physiology,

00:07:00.840 muscle growth potential, I don't know, genetic variability in response to that.

00:07:05.180 And as I got into university, in my first, second year, I got pretty hardcore into the

00:07:10.860 bodybuilding, got up to 260 plus pounds at my biggest. And that's when I actually discovered I

00:07:17.480 had sleep apnea that was severely exacerbated by getting that heavy that quickly. Sort of gave me

00:07:23.460 my first taste of side effects and what the potential downsides are of bodybuilding. Because a lot of

00:07:29.980 times when you're that young, it's like 20, 21 years old, you just think you're invincible and

00:07:35.440 you just think you can blast compounds. And at 260 pounds, how lean were you at that stage? Or were

00:07:42.260 you relatively unlean? Relatively unlean, I would say. And you were using lots of anabolic steroids or

00:07:48.820 just exogenous testosterone and calling it a day? We'll go into more detail about the nuances of this,

00:07:54.080 but just for reference. By our standards, a lot. But by bodybuilder standards, not really that much.

00:08:00.180 Probably at peak exposure, a combined weekly dosage of 1,500 milligrams to two grams or something.

00:08:09.240 So just for reference for the listener, when we prescribe testosterone, like when a physician is

00:08:13.480 prescribing testosterone to a patient for replacement, we're really only using testosterone. We're not using

00:08:18.180 nandrolone, oxandrolone. These are the things which we will talk about. But from a dose perspective,

00:08:22.960 I don't think I've ever prescribed more than 150 milligrams in a week of testosterone cipionate for

00:08:30.020 physiologic TRT. So you're already talking 10 to 12, 13 times more than that, more than what we would

00:08:38.480 consider a physiologic level. Yeah. And to conceptualize that, it does not equate to 12 to 13x the

00:08:45.500 results. That is something you learn pretty quick. There's a severe diminishing returns as you escalate

00:08:51.300 for sure. And you can even see this in the dose response studies. There is all, but it's still

00:08:56.220 pretty significant. There is slightly less each increment you go up proportionally. So that was my

00:09:04.220 first foray into extreme bodybuilding, I would say. And also my first taste of side effects and really

00:09:12.620 kind of led me down the rabbit hole of learning about, oh, what are the actual implications of using

00:09:17.340 this stuff, getting diagnosed with sleep apnea, getting a CPAP machine, correcting my sleep apnea,

00:09:23.340 but then also realizing that it's kind of a band-aid to the problem too. You should probably not be 260

00:09:28.480 plus pounds and taking all this shit. So the other question I have for you at this point in time is

00:09:35.620 how sophisticated is your understanding of managing the side effects of these hormones? Because obviously,

00:09:42.540 and again, we're going to talk about these in detail, but I think it's a great intro to the story of

00:09:46.180 you're learning this the hard way sometimes. But for example, like the estrogen effects,

00:09:50.480 the DHT effects, you've already alluded to them a little bit with hair loss. What is your degree

00:09:54.600 of sophistication around those in your early 20s when you're taking these doses?

00:09:59.800 Quite minimal. So back then you were told you take X amount of drug, has to be a base of testosterone

00:10:07.260 at this dosage relative to your other synthetic androgens that you're using alongside it,

00:10:11.600 based on what exactly? Arbitrary bro rules that are passed down the grapevine, essentially.

00:10:17.320 It's like your ratio of test to DECA must be two to one or else you get DECA-DEC, things like that.

00:10:22.580 I haven't even heard of DECA-DEC.

00:10:24.360 Well, back then they thought it was too little test compared to DECA, because if you had...

00:10:29.900 DECADRON being a synthetic hormone.

00:10:31.440 Yeah, so nandrolone is a progestin that is derived from testosterone, but it is quite different in

00:10:36.900 how it behaves. And interestingly enough, is the base for some of the synthetic progestins that

00:10:42.020 women use for oral contraception. That compound is riddled with certain side effects for people who

00:10:48.040 are prone to more the progesterone receptor interaction and its unique effects on cognitive

00:10:55.680 health, especially too, and even sleep quality. But back then, anyway, you were told random

00:11:00.880 things that were just passed down the grapevine and based on no real science. It was just anecdote.

00:11:07.280 I tried it and this is how I felt. My penis worked or it didn't work. Now it's working,

00:11:11.680 so this must be the correct way to do it. Stuff like that. And then also predetermined dosages of

00:11:16.880 aromatase inhibitors. You have to be on a milligram of Arimidex every day or every other day because

00:11:23.120 you're on 500 tests or more per week. Stuff like that was seen as acceptable and smart.

00:11:30.160 Taking preventative health measures by doing things like that is what we thought back then.

00:11:35.120 Minor attention is paid to blood pressure. If you have a bloody nose in the squat rack,

00:11:39.680 it's probably a sign that you should either lower the D-ball or think about something. But not much

00:11:45.120 talk about angiotensin receptor blockers or even how to choose a compound more intelligently. It was

00:11:52.160 often you must have estrogen side effects or something.

00:11:55.280 By the way, what was your monthly cost of drugs at that point in time?

00:12:00.400 When it comes to anabolics, it's actually not that expensive. Vial of test is probably 60 to 70 bucks.

00:12:07.680 So vial of testosterone is 2000 milligrams, right? It's two grams is a vial.

00:12:11.680 Usually underground labs dose it at 250 per milliliter. I don't know why. It's kind of interesting

00:12:17.280 because in pharma you're used to the 200 increments, but in UGL underground lab, it's almost always 250.

00:12:23.520 If it's test E, testosterone enanthate or testosterone cipionate, almost always 250.

00:12:30.000 Underground labs, tell me about that. Obviously you're not walking into the pharmacy and getting

00:12:34.080 branded depot testosterone, which is the FDA approved version of testosterone. Does that

00:12:40.800 mean these are compounding pharmacies that are doing this or how does this work?

00:12:43.760 No, no. It's literally just some guy who orders raws from China and then makes them in what you

00:12:50.400 hope to be a sterile and professional environment, but you have no idea if it's his bathtub or what.

00:12:56.320 So his only motivation to do this-

00:12:59.200 Financial.

00:12:59.440 Well, also is if I screw this up, people aren't going to come back to me to buy the drug.

00:13:03.280 Correct.

00:13:03.600 Wow. So when we talk about GMP, good manufacturing process,

00:13:07.680 which is what ensures sterility for injectable compounds, that's not the case. Recently, I did an AMA

00:13:13.360 on compounding pharmacies and the problems associated with them because they're not

00:13:18.880 subjected to the same GMP requirements, especially the community-based compounding pharmacies. They've

00:13:23.920 had a number of these awful incidents, including one where literally hundreds of people died from

00:13:30.400 compounded solumedrol because it was injected. So these were being manufactured without proper

00:13:35.840 sterile technique, sent to hospitals. So this was all being done legally. And then the hospitals were

00:13:40.560 using these to do, you know, facet blocks and things like that for people with back pain.

00:13:44.880 And literally in one outbreak, more than a hundred people died of meningitis,

00:13:50.160 of fungal meningitis due to this. So the stakes are very high when you're talking about injectable

00:13:54.480 compounds not being done sterile. So I guess we ought to come back to visiting the topic of what the

00:13:59.120 underground market looks like for these compounds.

00:14:00.880 Yeah, I guess what they bank on is the fact that with synthetic

00:14:05.280 anabolics, you don't have acute health issues. It's more chronic over a span of decades of abuse.

00:14:12.640 So even worst case scenario, if you get a badly compounded version of whatever,

00:14:18.160 if you can even call it that, you would have a elevated CRP from the carrier oils or solvents.

00:14:24.000 But most people weren't even checking blood work, let alone. And if you had a side effect,

00:14:27.920 you assumed it's the copious amounts of anabolics you're on, not necessarily

00:14:31.280 anything related to the manufacturing or anything. As long as the reputation of the lab

00:14:36.320 was maintained across the forums and the bros were happy, that meant this is high quality.

00:14:41.920 So some people would actually send it for third-party testing. There were certain people

00:14:45.280 who would come out with access to university labs and whatnot, and they would kind of under the table,

00:14:50.960 you would send a milliliter of your stuff in like a perfume atomizer, and they would test it for you

00:14:56.880 and send you HPLC results, and you would find out if the UGL underground lab has good stuff relative

00:15:02.800 to what it says on the label. But that was essentially it, as far as quality control.

00:15:06.720 How many of the guys that you were training with and yourself understood, for example,

00:15:11.040 the impact on fertility and long-term effects vis-a-vis gonadal function at that age?

00:15:16.800 Very few people ever brought concern to it, because we were always told,

00:15:23.440 when you come off, you will restore fertility in due time, once ester is cleared, etc. As long as you

00:15:31.280 had good baseline function, you weren't primary hypogonadal to begin with, you're going to be

00:15:35.440 good. You just have to get the compound out of your system, was what we were told back then. No

00:15:39.920 attention was paid to maintaining testicular volume, light excel stimulation to maintain things.

00:15:47.520 Nothing. It was just, come off your stuff. And the PCT regimens, post-cycle therapy to restore

00:15:53.120 fertility were just, made no sense when you look back on it. Back then, it made sense. But now,

00:15:58.320 in hindsight, the rule of thumb was literally, stop your drugs, wait two weeks, start a PCT of Novodex

00:16:06.240 plus Clomid for four weeks, you recover fully, you just assume, you don't actually check your blood work.

00:16:11.920 And then after that, as long as you are healthy, the responsible thing is wait time on equals time

00:16:17.680 off, and then you go time back on. But often it was just, come off two weeks, PCT, and then get

00:16:24.320 back on, or wait until some arbitrary amount of time has passed, or regardless of health markers,

00:16:29.040 and then get back on. What dose of Clomid were you guys taking in the PCT?

00:16:32.800 It was like 50 milligrams once or twice a day. 25 to 50 twice a day, depending. And it wasn't

00:16:40.720 based on anything scientific, it was just, you just choose. Amazing doses. Again, just so high

00:16:47.600 compared to what we would use clinically in traditional TRT. If we have time, we can come

00:16:52.320 back and talk about some of the risks associated with Clomid use, period. From a lipid perspective,

00:16:56.800 that is. So, you're in college, university, to be sensitive to the Canadians. You're obviously

00:17:01.920 studying, are you in biology, biochem? What are you studying?

00:17:05.040 Business. So, for me, I was pursuing a undergrad in the business faculty at Simon Fraser University,

00:17:12.960 and that was to lead me to a job as an accountant or something of that nature to be determined.

00:17:20.880 And I was working as a bouncer downtown while I was getting my degree, and then I kind of just

00:17:27.440 transitioned into posting online and then realized I could replace my income doing that on a computer,

00:17:33.920 rather than having to bounce, which is not like a sustainable job. I don't know. It was like,

00:17:38.400 I always felt like I should not be an accountant. This isn't something I find exciting. It's not

00:17:42.480 really where my interest lies. I'm okay with numbers, but it was kind of just from high school

00:17:47.920 thinking, oh, what's a good business job? Go downtown Vancouver, get a job as an accountant at a big

00:17:53.440 company, and you're good. That was the dream back then. Not that it was, but it was, you know,

00:17:58.240 the end goal in mind of getting your degree. Didn't end up doing that, fortunately, and started

00:18:04.160 making online content on a WordPress blog. It wasn't actually on YouTube for a couple months, but

00:18:10.560 started writing about, you know, dieting, how to bulk with not getting fat, how to cut, some basic stuff

00:18:17.520 about, you know, diet principles, bodybuilding, sort of talked about dating, social circle dynamics,

00:18:23.440 stuff I was super interested in at the time. And then it kind of transitioned from there into

00:18:28.080 discussion about my foray into anabolic side effect management, anything I could think of that was of

00:18:33.680 use that I thought I could impart on the viewer. Hey, don't screw yourself up. I've gone through this

00:18:39.680 and learned the hard way potentially. So let's go back to kind of your journey through that. So

00:18:45.360 you're in your early 20s, and you're kind of at peak anabolic steroid use. Are you using growth

00:18:51.920 hormone as well? I did try it periodically. I didn't notice a ton from it. And it seems to be

00:18:58.040 variable in how people respond. I think a lot of it is conflated with the effects on fluid dynamics.

00:19:05.280 So a lot of people that get a lot of edema, water retention that they perceive to be enhanced muscle,

00:19:11.800 and then they say, Oh, my, you know, genetic ceiling is higher now because of all the satellite

00:19:17.160 cell proliferation and hyperplasia that's happening. So I'm gonna keep using it. Or it makes me never get

00:19:23.880 fat, which is something I would hear quite often, which is not true. But I did try it up to I think

00:19:29.960 the most I use at a time is like, I might have tried six I use six to eight I use acutely.

00:19:35.800 Meaning six to eight I use daily. Yeah, which is quite a bit. That's a huge dose.

00:19:40.920 But it was for a span of like weeks, essentially, and didn't really notice a lot from it. So

00:19:46.440 decided it wasn't worthwhile to continue because it's super cost prohibitive. Like that's the thing

00:19:50.940 that drives costs mostly for bodybuilders. It's not the anabolics, it's the growth hormone,

00:19:55.720 typically, or health screening, because a lot of people don't want to pay for that. So they got to

00:19:59.660 have their budget for the anabolics and the food, but blood work out the window.

00:20:03.400 I mean, I think this probably for folks paints a picture of your empirical curiosity in the topic.

00:20:12.200 Whenever we have patients in our practice ask us questions about growth hormone, and we have our

00:20:18.380 research team go and look at answers, a lot of the times what we say both to the patients and what I

00:20:25.040 have to remind the research team is look, you're going to get very limited, very narrow information

00:20:30.800 from the literature. This is not like researching the question of what are the effects of physiologic

00:20:37.620 hormone replacement, you know, testosterone, estrogen, progesterone, things like that.

00:20:41.700 For that, we can turn to the literature and we can get a lot of information. But when you're trying

00:20:46.060 to ask the question, hey, what happens when you take growth hormone outside of its medically intended

00:20:51.020 purpose, such as low levels of growth hormone or things like that? I said, look, it's not an appealing

00:20:56.100 answer, but you're going to have to kind of go into bodybuilding forums. It sounds like the most

00:21:00.460 unscientific thing, but a bodybuilder with a good head on his shoulders or good head on her shoulders

00:21:06.620 will probably have more relevant observations about the good, the bad, and the ugly with these compounds.

00:21:13.880 What I find so interesting about your work, Derek, is that you've, in my mind, taken the best of both

00:21:19.360 worlds. So I think you've learned a lot through your own experience with these compounds,

00:21:23.980 coupled with obviously observing, you're being, you're, you're surrounded by a lot of bros who

00:21:28.500 maybe don't have your observational skills. And then you've coupled that with your own obsession

00:21:33.360 of going down the rabbit hole. And that's why I think if anybody can extract meaning from some of

00:21:38.260 this stuff, it's you. Maybe we'll start with going a little deeper on growth hormone, since I think

00:21:43.480 in many ways, that's the one for which we have, I believe, kind of the least insight outside of that

00:21:50.400 very narrow application, which is, you know, people who have growth hormone deficiencies,

00:21:54.980 where clearly replacing growth hormone is a good thing to do. Let's start with one application of

00:22:00.680 growth hormone. Now, I will admit, this is a question that has literally been asked of me more

00:22:06.100 than once. And the first time it was asked of me, I was shocked. And I don't say that to pass judgment,

00:22:12.040 but it never occurred to me that one would do this. But it's been asked enough times that I have to

00:22:18.220 believe it's a real thing. So a person approached me, a person I know, and said, look, my son is 12.

00:22:26.240 He's a very good athlete. He's an exceptional tennis player. But I'm 5'9". My wife is 5'5". He's

00:22:35.060 not going to be an inch above 5'10". He's never going to go anywhere in tennis, despite his remarkable

00:22:41.160 athleticism. Can we give him growth hormone to get him to be a 6'1", 6'2", kid, so he really has a

00:22:50.020 chance to be a pro tennis player? So when you hear that, do you think, I can't believe someone would

00:22:54.420 ask that? Or are you like, yeah, dude, welcome to the world? Yeah, I'm not surprised somebody would

00:22:59.860 ask that. To be honest, I've heard much worse. But it's not something that I believe you could look to

00:23:07.140 any literature and find, oh, you're going to completely surpass your otherwise predetermined

00:23:13.260 genetic ceiling. Some of the literature on idiopathic short stature is interesting because

00:23:17.700 they actually have prescription protocols that are even higher than GH deficiency. So you have an

00:23:24.220 unexplained lack of height velocity as you're growing up, but not necessarily, you know, IGF-1 deficiency or

00:23:31.480 anything you can point to in the blood work that looks odd. And they are prescribed upper end range,

00:23:36.980 even higher than GH deficient patients, which seems kind of odd to me. But for individuals who don't

00:23:43.320 have, they're not lagging behind significantly, and there's no indication for it, it's kind of hard to

00:23:47.980 justify, I imagine, especially as a doctor who's hearing that. I don't think this person was asking

00:23:53.820 me to do anything about it. I think he wanted to bounce the idea off me. I mean, I think he clearly

00:23:58.680 knew I would never have anything to do with this. And I wanted to sort of not get preachy, which I don't

00:24:03.200 think I did. But what I said was, look, it strikes me as a bad idea because you just don't know what

00:24:10.400 the risk associated with this is. And I'm not even talking about like, oh, what if your kid has cancer

00:24:14.940 and you make the cancer worse, which at that age, pretty small risk. We can talk about the risks of

00:24:20.040 cancer and growth hormone in terms of propagation. But I said, look, if you were asking me to come up

00:24:24.900 with a risk I would be worried about, I would be worried about bone health, for example. And I'm making

00:24:30.480 this up. But I'm saying, look, how do we know if these new elongated bones that your son is going

00:24:37.600 to develop that take him from being his natural or genetically predetermined 5'10 to 6'2, how do we

00:24:44.220 know if those bones are of the same caliber? And how do we know if we're not setting him up for

00:24:48.640 osteopenia when he's 50 instead of a normal life? I said, look, given all the unknowns, you just have

00:24:54.860 to ask yourself the question like, is it worth that risk? Have you seen some of the recent surgeries

00:25:00.960 to enhance height in adults? It's crazy. They like put screws in their knees and then they basically

00:25:07.560 increase their height by a millimeter every day and they crank it until they've got upwards of

00:25:12.280 half a foot and extra height. And then that area just fills in with new bone. They have to learn to

00:25:18.080 function with these new mechanics, both the femur and the apparently you pick if you want to do both

00:25:25.020 or if you do one or the other, but you put screws in. And if you want to max out your height, you can

00:25:30.740 basically crank upwards of half a foot and extra height. And there are people doing this and paying

00:25:36.220 for surgery and going to these facilities where you basically get manually stretched and then bone

00:25:45.180 forms in the space. And then you have to learn to move with those new mechanics. And this is becoming

00:25:50.580 a more, it's not a trend, I would say, but there's a lot of viral content surrounding it right now.

00:25:55.060 And certain people that are showcasing before and afters as marketing material too. It's pretty crazy.

00:26:01.020 How do you accommodate that from a muscle and tendon perspective?

00:26:04.860 That's the question. Proponents for it seem to assert that you eventually adjust to it with

00:26:11.140 very intensive exercise routines, rehabilitation stuff. And you try and basically learn all your

00:26:18.900 motor patterns again. And eventually everything adapts. I would assume that your athletic capacity

00:26:25.540 would be inhibited pretty dramatically, permanently potentially. And there's huge risk there, but it's

00:26:30.560 just, just showcases how extreme some people are willing to go.

00:26:34.460 All right. So if that's the most extreme story I've heard about either the use of growth hormone or

00:26:40.640 even surgical technique, let's talk about a far more typical story. So my patients and probably most

00:26:46.220 people listening to this are not bodybuilders, but I think there is a belief that growth hormone is the

00:26:52.340 elixir of life. And there are no shortage of longevity doctors out there, which is why I bristle at the

00:26:59.940 term when I'm looped into that group. Longevity clinics out there whose basically sole intervention is

00:27:08.320 giving you growth hormone. It's like, here's a bunch of supplements that are proprietary and

00:27:11.960 whatever, and growth hormone. There are two responses to that. So if you look at the traditional

00:27:18.160 medicine approach to that, the, what I call Med 2.0, what you might call just sort of the evidence-based

00:27:24.340 medicine guidelines, that group, which is the majority of medicine, would look at people doing that

00:27:29.520 and say, that's the most dangerous, careless, unethical thing you could ever do. Those people are not

00:27:35.760 doctors, shame on them. At the other end of the spectrum, you have the people that embrace that

00:27:40.040 point of view, which is like, the other people are idiots. This is modern medicine. This is the future.

00:27:44.900 We should all be on growth hormone once we reach a certain age. And I find myself on neither side of

00:27:50.640 that because I simply can't come up with an evidence-based point of view. So my very naive point

00:27:56.560 of view, which I'll acknowledge is naive, is given how many people are taking growth hormone,

00:28:02.680 and it is quite ubiquitous, especially in sports, which I think we'll talk about.

00:28:08.040 If there are really serious consequences to its use, even chronically, I feel like epidemiology

00:28:15.620 would give us that answer. So it's possible that no one's looking. It's possible that there is a

00:28:22.280 signal there, but it's not large. It's possible that not enough people take it for long enough.

00:28:27.620 There's so many explanations for why this isn't happening, but there isn't a clear signal.

00:28:31.380 Conversely, I think that there are probably a lot of reasons why growth hormone chronically

00:28:37.120 given exogenously, especially if it's kind of super physiological, could be problematic.

00:28:42.880 For example, if you have a tumor that is growth hormone or sensitive to growth hormone,

00:28:47.460 and it's already initiated, are you propagating it? So that would be kind of both sides of that.

00:28:52.200 So let's go back to tell people about what growth hormone is, where it comes from,

00:28:56.620 what are the challenges of measuring it? Let's just do kind of a growth hormone 101.

00:28:59.680 Yeah, so growth hormone is, most people know it as like the primary hormone responsible for

00:29:05.720 determining height as you grow in adolescence. Androgens are more sexual differentiation,

00:29:12.760 maturation, but growth hormone and the subsequent growth factor production, IGF-1, will be a fairly

00:29:19.620 significant determinant on if you grow to, I guess, like target height, whatever you could become.

00:29:24.960 And it's pretty, during puberty especially, pretty important for the proper development

00:29:32.460 of your infrastructure, bone, etc., connective tissue. As you get into adulthood, it becomes

00:29:38.160 one of those things where it drops significantly, first off, as you reach adulthood. And as you get

00:29:43.820 older, it drops precipitously as well. That kind of begs the question, is this one of those things that

00:29:48.760 you should be replacing to optimize function, fat loss, vitality, what have you. And it's tough

00:29:56.160 because a lot of the proponents that assert such things have financial incentive. It's kind of hard

00:30:01.600 to wade through the nonsense and kind of figure out what is the truth here. And it is often framed out

00:30:06.860 to be like this fountain of youth elixir, HGH. Oh, it's so cost prohibitive. It's what all the pro

00:30:12.720 athletes are using. This is the thing you need to be on to prevent any age-related decline in bone

00:30:19.640 strength. Your ability to burn fat as you get older is going to go down. So you need to be on growth

00:30:24.220 hormone, etc., etc. And at a bird's eye view, it's kind of responsible for the growth, broad spectrum

00:30:31.020 growth of tissues as you grow up. And then as you get into adulthood, it's not irrelevant, but it's far

00:30:36.500 less important because you're not trying to push a human from childhood into adulthood, essentially.

00:30:43.320 And even when you have this push of exogenous growth hormone to manually manipulate your levels,

00:30:49.900 after it's called epiphyseal plate closure, there does not seem to be any benefit to be gained from

00:30:57.880 enhancing the length of bones, for example. You could still enhance bone mineral density to some

00:31:03.960 extent, and it seems to be, you know, you could enhance connective tissue integrity. It kind of

00:31:08.540 depends on what your situation is and how IGF-1 deficient or lack thereof you are. But it's not going to

00:31:14.800 impact your height in adulthood. It's not going to really do anything other than regulate lipolytic

00:31:20.740 action. How does it do that, by the way? Liberates free fatty acids into circulation. So it's kind of

00:31:26.620 seen as the opposing hormone to insulin. Does it do that through lipoprotein lipase? Is it actually

00:31:32.420 acting on a substrate on the adipocyte? It seems to be driven through different baseline states that

00:31:40.420 you're in. Like if you have ghrelin receptor agonism from being fasted, for example, a lot of people point

00:31:45.900 to the literature on if you're deprived of calories, oh, growth hormone goes up. There are different

00:31:51.000 situations in which it'll go up. Deep sleep, obviously, is super impactful on if you're going

00:31:55.880 to have release or not as well. But the main actions that I'm aware of, at least in a state

00:32:02.760 of growth hormone pulsation is kind of the underpinnings are you are trying to liberate

00:32:08.720 free fatty acids for utilization as substrate for energy or anti-catabolic action. So the actual

00:32:15.760 like mechanism enzymatically and whatnot, it's a bit fuzzy. What's the relationship then between

00:32:21.540 gh and igf in the liver? How does this all work? Because we don't really measure gh in people,

00:32:27.620 right? Because it's pulsatile. So what are we stuck with as a proxy? Yeah, even if you inject

00:32:32.940 gh, a large dose of it, you will only see a spike in serum for a transient period of time. And people

00:32:39.380 who are trying to assess the quality of their growth hormone with the underground stuff, they would be

00:32:44.720 trying to time it very specifically down to the minute to assess the quality of their stuff. But the

00:32:50.100 best proxy for gh production endogenously seems to be widely accepted as IGF-1, which is after you

00:32:59.420 produce growth hormone from the pituitary, there is action in the liver, but also paracrine and

00:33:05.580 autocrine action on muscle, especially if you are exercising resistance training. But a lot of the

00:33:13.280 serum IGF-1 is driven through liver production and has its own implications in terms of its effects.

00:33:19.960 that seem to be more intelligentic in itself to some extent. Which is kind of counterintuitive,

00:33:25.700 right? Because if IGF-1 has intelligentic properties, which are promoting a fat storage,

00:33:32.040 and gh is promoting lipolysis, don't those act at odds with each other? And how does one

00:33:37.040 become more dominant? Yeah, it's this weird orchestrated feedback loop. And these feedback

00:33:43.840 loops are present in the body and multiple different hormone substrates will reduce in

00:33:49.500 multiple different metabolites that then have negative feedback through different systems. And

00:33:53.760 this seems to be no different if you have GH at a certain level, and it results in a certain amount

00:33:58.180 of IGF-1, you will have negative feedback that will then lower your production of HGH while the IGF-1

00:34:05.220 is elevated. And as it declines, you have this decrease in inhibitory feedback that then tells

00:34:11.620 your body, okay, now the IGF-1 is not present in significant quantities, it's okay to release GH

00:34:16.820 again. So it's this finely tuned balancing act in your body where your body has counteracting things.

00:34:23.360 It's not counteracting, but it's like the balance between anabolic or anti-catabolic. Frankly, I don't

00:34:30.740 even know how to elucidate like a super clear way that is completely accurate, but it seems to be

00:34:36.400 when one is high, the other one would be low. And conversely, in order to kind of maintain a,

00:34:42.660 not necessarily at the same times, but to maintain like a balancing act in the body.

00:34:46.980 We have a real sense of how to dose, for example, testosterone or estradiol in the case of HRT for

00:34:53.420 women, because we know what physiologic normal levels are during various periods of a person's life.

00:34:59.840 And so if we're replacing testosterone to the level that we think is normal, either for your age or for

00:35:06.660 some earlier age, we can measure the hormone, we administer it, and we can do the calculation. Hey,

00:35:13.200 this person has a lot of sex, someone buying a globulin, or they don't, or whatever the case

00:35:16.340 might be. When people are administering growth hormone, and again, let's just talk about this

00:35:20.700 through the lens of the context you're talking about it now, which is rejuvenation or longevity,

00:35:27.520 the wastebasket term. How do they know? Because typically they're using about one to two units

00:35:33.120 per day. Isn't that the typical dose? Yeah, it depends largely on liver function too. So some

00:35:39.260 people with compromised function or type one diabetics, for example, they could have super high

00:35:44.300 GH production, but very low IGF-1 from seemingly lack of insulogenic signaling, because it also has a

00:35:52.060 positive relationship with IGF-1 production. But it can be difficult because you could have a

00:35:58.060 person on a ketogenic calorie deprived diet model who has an IGF-1 that is on the low end of the

00:36:03.680 reference range, be manually administering growth hormone and be using a higher dose than would

00:36:08.380 otherwise be necessary to get to high normal optimal function, put in quotation marks. That's the best

00:36:16.120 proxy we have, as far as I'm aware, is that serum biomarker IGF-1, but there's not really a cut and

00:36:23.940 dry way. So people would use the Z-score presumably of their IGF-1 as the output for determining how much

00:36:30.760 GH to administer. Yeah, my understanding is that regardless of its idiopathic short stature, GH

00:36:36.160 deficiency, they would use IGF-1 as a metric to kind of dial in the dose. So if your IGF-1 is higher than

00:36:44.240 the target, then you would dial the dose back accordingly, or if it's not high enough,

00:36:48.480 then you would increase it accordingly. What do they target? A Z-score of 1 to 2,

00:36:52.820 meaning 1 to 2 standard deviations above the mean is therapeutic, or just being above 0,

00:36:58.360 for example, which means you're above the 50th percentile? The target, I think it's mainly just

00:37:03.560 correcting, but as far as what is correct, I guess the reference range, if it's in the middle or

00:37:09.100 the high end of normal, I don't recall off the top of my head, but it's something in the neighborhood

00:37:13.780 of middle of a standard LabCorp reference range as far as I know. Could be off on that.

00:37:18.760 Okay, so let's talk about the physiology of this. So you give GH, there's a feedback signal,

00:37:25.260 because GH comes from the pituitary, but it's spoken to by the hypothalamus. So we're going to

00:37:30.560 talk about this again when we talk about testosterone, of course, because that's a really

00:37:33.760 obvious issue. What happens upstream of the pituitary, i.e. what happens to the signal

00:37:40.400 from the hypothalamus to the pituitary to make endogenous, to make your own growth hormone when

00:37:46.340 you take it from the outside? Does that get shut off as well? Yeah, the negative feedback that I

00:37:51.280 spoke about briefly, when you have elevated IGF-1, it will give negative feedback, and there is an

00:37:57.320 elevation, something called somatostatin, basically tells your body, don't make as much GH, essentially.

00:38:03.000 And there is different receptors, which gets a bit confusing as to how you produce the growth hormone

00:38:10.020 upstream. There's the ghrelin receptor, which super confusingly is also called the GH receptor,

00:38:16.440 I believe it's also called. And then you have the GHRH receptor and the production of GHRH endogenously,

00:38:23.020 as well as the agonism of ghrelin receptors, can both stimulate growth hormone and the way by which

00:38:31.240 they achieve your end output can be different. And that's why there's different drugs that target

00:38:37.440 different receptors for actual elevation. Typically, GHRH drugs are coupled with GHRPs to get like a 1

00:38:45.320 plus 1 equals 3 effect of sorts. But this is why also when you are fasted or malnourished, you could

00:38:52.840 have significantly more output via the ghrelin receptor agonism. And this is the same ghrelin hormone

00:38:58.660 that plays an important role in management of hunger. Yeah. So for people who don't know, ghrelin is like,

00:39:04.780 I don't know if it's the primary, but I think it's probably pretty accepted that leptin and ghrelin are

00:39:09.300 kind of like the signals that you're full versus hungry. So ghrelin and ghrelin receptor agonism is what

00:39:16.460 would tell your brain you're hungry. So for example, if you gave somebody a really potent ghrelin receptor

00:39:23.160 agonist like ibutamoran is a commonly orally bioavailable GHRP, you use that even if you're not

00:39:30.840 hungry, you'll want to eat your pantry like it's insane. So that compound plus a GHRH will seemingly

00:39:38.440 have a downward pressure on somatostatin activity and simultaneously increase the output from the

00:39:45.640 pituitary to produce more GH. So you can kind of like max out your endogenous production through these

00:39:51.480 peptides essentially. But those are the primary mechanisms involved. Like those three things is

00:39:58.880 the ghrelin receptor, GHRH, and then also somatostatin as a negative feedback.

00:40:04.820 So if someone is just taking exogenous growth hormone, how long would they need to take it

00:40:09.660 before they would start to compromise their own ability to make endogenous growth hormone once they

00:40:14.520 came off? I think it's pretty quick. IGF-1 elevations are not instant. In the serum,

00:40:22.040 you would see GH spikes in a matter of minutes. Like it's very transient in your system, very short

00:40:27.080 half-life, but the downstream IGF-1 conversion can increase over days and then stay elevated for days.

00:40:34.720 And this is why IGF-1 as a biomarker has been asserted to be a potential way to catch people doping

00:40:40.620 further out than the HGH isoform differential immunoassay, which is the current accepted gold

00:40:47.360 standard test that they use. Because IGF-1 will stay elevated for a relatively long period of time.

00:40:54.080 Let's just say a person's on GH for two years and then they stop it. Does their pituitary go back to

00:41:01.320 making GH? Yeah, seemingly. It seems pretty flexible in that. In that sense, it's different than LH

00:41:07.500 and FSH and the testes making testosterone. Yeah. And the reason for that, I can't help but

00:41:15.360 think because there's multiple actions of the pituitary, it's not going to atrophy in the same

00:41:20.920 way, I would think. And this is just speculative. But for example, people always want to know if I

00:41:26.100 take anabolics or testosterone replacement for years, but I don't take HCG or I don't take these

00:41:31.400 fertility drugs. Will I be able to restore fertility in short order? And it seems to be like a use it or

00:41:39.160 lose it kind of thing where not necessarily, but it's more difficult to restore fertility in somebody

00:41:44.140 with like severely atrophied organs that has not had stimulation directly for years versus the

00:41:51.780 pituitary does multiple different things. So I can only imagine that the maintenance of output of

00:41:57.380 other hormones and things are at least maintaining its flexibility to some extent, but super speculative.

00:42:03.340 Let's talk a little bit about the use of GH in restoration of tissue during periods of healing.

00:42:11.600 So I think there's some accepted medical use for GH in burn victims, for example, right? So

00:42:16.820 if a person sustains a significant enough burn, the body surface area is burnt. I mean,

00:42:22.020 that's one of the most catabolic activities that human can sustain. And therefore, the reversal of that

00:42:26.940 is one of the most anabolic demands that a human can sustain as an adult. What about during

00:42:32.140 orthopedic injuries? So you look at a person who's having either elective or emergent surgery for an

00:42:39.140 injury. So we've had patients who have had injuries, so like a torn bicep. We've looked at the literature,

00:42:46.080 found, I would say, at best modest evidence suggesting maybe for that person, an eight-week course

00:42:54.320 of anabolic steroids and growth hormone can aid in recuperation. The few times we've done this,

00:43:01.320 we've seen great outcomes, but that means nothing. It's so anecdotal. We'd have no contrapositive

00:43:06.440 or opposite view there of what would happen otherwise. So do you have any insight either from

00:43:11.640 literature or from just the underground world as to what the use of modest amounts of growth hormone

00:43:19.260 would look like in periods of rehabilitation? Yeah, it's more anecdotal because like you said,

00:43:24.920 you could find very... Yeah, there's just no counterfactuals to any of these stories.

00:43:28.860 Yeah. And oftentimes when I'm talking about this stuff, I want to say it's not necessarily founded

00:43:33.140 in literature, unfortunately. It's kind of a mix of extrapolations, rodent studies, anecdotes in humans,

00:43:41.000 stuff like that, which is unfortunate. I would love to be able to make hard-hitting factual statements

00:43:45.580 every time I say something on this stuff. But with GH, anecdotally, it seems to be quite effective

00:43:51.840 in rehabilitation. I think that it is worthwhile in an acute timeframe. That's where the ROI

00:43:57.860 makes sense, in my opinion. So I do see people... But again, it's not like you have a control of that

00:44:03.640 same guy with the injury not taking it. So we can only go by what you discern to be a reasonable,

00:44:11.120 I don't know, recovery period. And then, well, it seems like it's recovering quicker than you would

00:44:15.840 have expected. Good. Probably good. I think I may have told you this. Like a year and a half ago,

00:44:21.480 I had shoulder surgery. And really, this was an operation I had been postponing for 15 years

00:44:26.060 until it got to the point where I sort of had to have it. And I really was so hesitant to give up

00:44:32.160 so much because of the size of the tear in the labrum. It was going to be four months before I could

00:44:39.600 really do anything again other than very light movements. My plan was to take... I did a little

00:44:45.560 bit of homework and came to the conclusion that a certain cocktail of nandrolone and growth hormone

00:44:49.600 was going to be the best cocktail. So I found that so interesting that you didn't use a base of

00:44:54.140 testosterone with the nandrolone because you could effectively wipe out your estrogen with that

00:44:59.580 combination. Interesting. Well, I ended up taking it for a total of one week.

00:45:03.580 Yeah. I noticed. Yeah. I saw that your post on Facebook where you mentioned how you're... I think

00:45:10.380 you had a blood pressure elevation and also... Blood glucose went up. My blood pressure went up.

00:45:15.560 My temperature was up at night. Now, in retrospect, what I realize is I think I was sick. I think I

00:45:21.420 actually got an infection. So I don't think anything to do with the hormones, but I felt so bad on the

00:45:26.640 hormones that I was like, well, I'm definitely not doing this. So I'm the counterfactual, I suppose,

00:45:31.220 for not having done anything, which of course means I still know nothing. I still have no

00:45:36.080 insight into what this is, but I do find this interesting. And like you, I do find it frustrating

00:45:40.960 that this is a question that isn't studied. Now, I understand that there isn't really a financial

00:45:45.280 incentive to study this because of course, it's not something that is a new drug. Recombinant GH

00:45:50.400 has been around for over 40 years now, hasn't it? Yeah. It was like cadaver derived in the 80s. And

00:45:56.640 then soon they went to recombinant, I think late 80s or 90s. Yeah. So over 30 years, it is a shame

00:46:03.720 because I've talked to many orthopedic surgeons and to a person, they all said the same thing,

00:46:08.180 which is I really wish we knew the answer to this question. It would really be wonderful to study this

00:46:12.460 rigorously and know, could we make a difference in the outcomes of patients by using these things in a

00:46:18.640 very narrow opportunity? And the other question I guess I'm wondering is, because I can't find a clear

00:46:24.100 answer to this in literature. Do you have a sense of the use of growth hormone in osteopenia?

00:46:28.700 Yeah. One thing I can say circling back to the justifying if it makes sense or not,

00:46:32.840 I think there's certain things you can use to discern if it's a better idea, like baseline IGF-1,

00:46:40.360 are you somebody who is in a ketogenic diet and you're trying to recover from an injury

00:46:44.320 simultaneously? Are you calorie deprived? Like there are certain things that could otherwise be

00:46:49.620 significantly influencing your recovery capacity from a growth factor standpoint that you may be

00:46:55.160 able to manually backfill that for another person. Some people naturally have IGFs that are like

00:46:59.260 top end of the reference range. Or if you were acromegaly, had acromegaly, you would not use GH,

00:47:04.820 obviously. So it's definitely context dependent. Or if you had insulin resistance at baseline or

00:47:10.600 something, like there are certain things that may otherwise sway you in the direction of the ROI

00:47:14.840 makes sense versus not. I feel like that should at least be said so people don't think it's a total

00:47:18.800 blind roll the dice thing. That's right. Yeah. That's a good point. And let's throw the same

00:47:22.220 caveat in there. So let's say we're talking about an individual with osteopenia or osteoporosis.

00:47:28.020 Let's assume further, you're going to do all the normal stuff you would do. So you're going to do

00:47:32.400 all the things you would do nutritionally with respect to vitamin D, calcium, amino acids. You're

00:47:37.800 going to increase load bearing activity, particularly strength training. If necessary, you're even going

00:47:43.000 to bring on Fosamax and the type of drugs that may help in that regard. But if in the context of all

00:47:49.200 those things, an individual has a low IGF-1, do you think, first of all, is there any evidence that

00:47:57.460 in that setting, GH administration will improve bone density?

00:48:02.420 Yes. I can say with almost near certainty that that literature exists. Even if it didn't,

00:48:08.600 I would say almost without a shadow of a doubt that it would be worthwhile, especially in somebody

00:48:14.260 with low IGF. I'd have to circle back and make sure the literature was not wrote and extrapolated,

00:48:19.340 but I'm pretty sure that anybody, especially with lower IGF-1, you kind of get into the

00:48:23.680 discussion of can you even sustain adequate bone integrity, especially in, I don't know,

00:48:29.680 old age where you might have, I think you're probably most prone to that to begin with.

00:48:33.340 Like it's almost certainly justified, I would say, in that scenario.

00:48:38.020 Yeah. It's interesting. I'd like to find that and maybe we can include that in the show notes.

00:48:41.500 I feel like the last time I looked, I didn't find anything that suggested not doing it,

00:48:45.320 but I didn't find something that was a slam dunk home run. You mentioned a couple of peptides. So

00:48:50.980 let's talk about these peptides that are upstream. So I can't even keep track of how many there

00:48:58.200 are. There's like CJC1295, Samoralin. What are the others? On the GHRP side, the easiest way to

00:49:07.920 segregate these is by GHRP, GHRH. So GHRP are the ones that act on ghrelin receptor. GHRH are the ones

00:49:17.600 that look very similar to GHRH and act on that receptor. So like that's the easiest way to segregate

00:49:23.600 them in terms of categories. And then from there, they're pretty different in how they affect things.

00:49:28.920 Like for example, ipamaryllin is often used in these like anti-aging clinics and whatnot.

00:49:34.240 Sorry, the GHRP ones are also going to drive hyperphagia.

00:49:38.760 Depending on the compound, this is the weird thing about it. So even if you are stimulating the ghrelin

00:49:44.640 receptor, the effects on appetite are quite different. So for ipamaryllin, for example,

00:49:52.400 despite the fact that that's the receptor it's working through, and it is a ghrelin receptor

00:49:56.620 agonist, it does not influence hunger to even any reasonable magnitude within striking distance of

00:50:03.820 MK677 ibutamoran. That difference is literally like you eating 2000 more calories a day, not by

00:50:11.400 choice, but you're just starving perpetually. So it's almost like it's inducing Prader-Willi

00:50:15.640 syndrome or something, which is a condition where you have uncontrolled eating.

00:50:19.060 Yeah, like the willpower necessary to avoid overeating on MK677.

00:50:23.460 So what's the clinical use case for that? Is that used in AIDS wasting, cancer wasting,

00:50:27.820 and things like that?

00:50:29.020 Orally active. So adherence is much more reasonable to expect. The application, it's not FDA approved,

00:50:36.320 by the way, but it is for GH deficient children, I believe. And we've seen restoration of IGF to the

00:50:43.980 top end of the reference range when using it. So going from, I don't know, like a

00:50:47.620 low end IGF to a 200 to 300 or something. It's not going to push you into super physiologic

00:50:53.220 territory because it's working through your endogenous capacity, but you can kind of max

00:50:58.760 out what your pituitary output potential is. So similarly to a HCG or something, you can kind

00:51:05.980 of manually at least stimulate natural production to the upper threshold of your capacity. It seems

00:51:12.580 to be efficacious in that. But not going to have a high application among adults who don't need an

00:51:17.640 extra 2000 calories a day. No, but it also depends because some people maybe have low appetite and you

00:51:23.280 want to gain weight or you're in a state of recovery and your appetite is suppressed from some other drug

00:51:29.020 you're using because that's fairly common. Depends on the context. So what is the FDA approved indication

00:51:35.100 for this drug? It is for GH deficiency in adolescents, I believe. Even though it's prescribed

00:51:41.400 among clinics and whatnot, it's not, I don't even think it's achieved FDA approval yet. It's like in

00:51:46.460 phase two or three. So how is this oral? How does this peptide survive the gastric environment?

00:51:52.440 That is a great question, but it is the only one I know of that is often referred to as a

00:51:59.100 efficacious option in this laundry list of GHRPs to restore IGF-1 to high and normal. So how the

00:52:07.280 actual pharmacokinetic profile looks, all I know is the half-life is like 24 to 36 hours.

00:52:13.200 And it must just be enterically coded. It's not hepatotoxic from what I remember.

00:52:17.360 It's got to be something that it just survives through coding, like you said, or something of

00:52:22.340 that nature. Any other GHRPs that are worth discussing?

00:52:26.740 Yeah, I think ipamorelin is probably the one most prescribed in clinics. And that one seems to be

00:52:35.360 probably more targeted in the outcomes you'd want to see out of like a growth hormone

00:52:40.300 releasing peptide in that you get enhancement of sleep. Doesn't make you hungry, really,

00:52:47.160 even though it operates through the same receptor pathway. Definitely increases IGF-1. It is,

00:52:52.920 is it FDA approved? I believe it might be for lipodystrophy.

00:52:55.620 It might be tessamorelin. But these are the two, ipamorelin is the primary one that is prescribed.

00:53:02.120 And then there's a bunch like GHRP-6, GHRP-2, which significantly impactful in hunger. GHRP-6 is

00:53:07.720 probably the worst one. That's what bodybuilders use when they reach a bottleneck of food intake and

00:53:12.100 they can't eat anymore. They will, MK-677 is around the clock, but GHRP-6, after you inject it,

00:53:17.960 it's like you can modulate acutely when you're hungry. So if you had an eating contest to win,

00:53:23.280 or you were going out for an all-you-can-eat buffet, or you're just a bodybuilder who can't

00:53:27.840 eat your 5,000 calories a day, that's when you would be, you'd look disgusted as I'm saying it.

00:53:33.600 No, I just, I mean, it's, uh, yeah, there's so much to unpack there.

00:53:38.100 But ipamorelin is the one that is prescribed most often, the other ones.

00:53:42.560 And that's a daily injectable.

00:53:44.240 Yeah.

00:53:44.680 And so is that used by athletes and bodybuilders?

00:53:48.960 Yeah, fairly often.

00:53:50.500 Is it cheaper than growth hormone?

00:53:52.920 Yes, yes. Depending on if you get the growth hormone underground or not. Through pharmacies,

00:53:57.860 certainly, but there are generic growth hormone preparations that are pretty cheap now. You could

00:54:04.960 get a hundred IUs of pretty high quality HGH from China for 150 bucks.

00:54:11.040 By comparison, what would that cost at a pharmacy? I'm trying to think.

00:54:14.300 Thousands.

00:54:14.840 Yeah. I mean, it's insane.

00:54:16.300 Yeah. Especially if it's like a big brand name. Like back in the day,

00:54:20.400 people would go to AIDS patients and convince them to sell their serostin. That's what bodybuilders

00:54:24.960 used to do decades ago.

00:54:27.420 Okay. So on the GHRH side, who were the big players?

00:54:31.680 Tessamoralin and Samoralin, but I would say Tessamoralin probably more commonly. Samoralin

00:54:37.180 seems to just, people just don't really get the results they want out of it. And it's more

00:54:41.660 anecdote than any kind of literature that points to it being sub-efficacious, but Tessamoralin

00:54:47.640 plus Ipamrelin is kind of the primary combo utilized in clinics, especially nowadays.

00:54:53.100 So they combine them. They'll combine Tessamoralin with Ipamrelin.

00:54:56.400 Yeah, typically. And there's also, there's like the CJC-1295 and there's with drug affinity

00:55:03.680 complex, which is basically extends the half-life significantly.

00:55:07.520 And CJC-1295 is which one of these?

00:55:10.400 The GHRH receptor. And then there's a shorter version of it. It's like ModGRF-129.

00:55:17.580 These are not FDA approved compounds. These are literally the wild west of compounds.

00:55:22.000 Tessamoralin and Tessamoralin are FDA approved, I assume?

00:55:25.820 Yeah. Some of them have, I know one of them in particular is approved for lipodystrophy.

00:55:30.340 And there are some unique applications in which some of them have FDA approval, but most of them,

00:55:35.780 the GHRP-6, GHRP-2, Hexoralin, I believe. And a couple of the GHRHs on that list do not have FDA

00:55:42.740 approval. And MK-677, as far as I know, is like off-label prescribed. It's kind of weird because it's

00:55:48.320 like there's no company that makes a branded, you know, FDA approved version of it, but then

00:55:52.060 compounding pharmacies will still make it. There's a lot of questions as to, well, what are the

00:55:56.740 standards that go into making it then? And are you just ordering it from China similarly to an

00:56:01.280 underground lab?

00:56:02.360 Yeah, there are no standards. I mean, there are no standards. That's the whole point of compounding,

00:56:06.280 right? Is they can make anything. I mean, at this point, the real question is, where is the line

00:56:12.560 between, if something has a GRASC designation, it's generally regarded as safe by the FDA,

00:56:17.420 you can sell it on Amazon. It's an over-the-counter. What's the most potent GRASC thing out there?

00:56:22.400 It's probably DHEA. In other countries, DHEA is, I think, appropriately treated as a hormone.

00:56:27.800 I think it's like Schedule 1 in Canada.

00:56:29.740 Is it really?

00:56:30.320 Yeah.

00:56:30.980 Really? Wow. Interesting.

00:56:32.260 Why? I don't know. Because actual steroids are not as regulated.

00:56:36.720 That's amazing.

00:56:37.380 Yeah.

00:56:37.720 Yes. But in the US, DHEA, amazingly, is over-the-counter. So that means it has a GRASC

00:56:42.420 designation. I'm guessing that CJC-1295 does not have a GRASC designation. So that means you cannot

00:56:48.660 sell it without a prescription, but yet it doesn't have an IND. It's not an investigational new drug.

00:56:54.980 It hasn't gone down the pathway of an approval. I think it's just sort of in this gray area.

00:56:59.640 Some of them are abandoned. It'll be like a drug that was in a pipeline.

00:57:03.740 So maybe there was an IND and it got scrapped.

00:57:05.700 Yeah. So it's like, sometimes is it financial? Is it lack of efficacy? Is it some, like in some

00:57:10.920 cases, there's a drug called carterine. It's a PPAR delta agonist, which is actually pretty good

00:57:16.900 results on lipid management. It's kind of like one of those exercise mimetic drugs. But when you

00:57:22.460 look at the metrics that it improves, it looks great. But then there is some rodent study. It was

00:57:28.640 like every dose of carterine resulted in cancer in these rodents. And then I guess the response to

00:57:35.340 that was a public outcry of worry, concern, et cetera. And it just, no reason why publicly it

00:57:42.820 got scrapped, but it's weird because it was like preclinical rodent literature supposedly caused it

00:57:49.320 to get canceled after it was already in phase two in humans. So it's like some of this stuff

00:57:53.740 and carterine is prescribed through clinics too. But yet all the rodents who took it got cancer?

00:57:58.500 Yeah. Every dose. I mean, that would be disconcerting.

00:58:02.700 Yeah, for sure. Okay. So again, talking about this through the lens of,

00:58:08.720 I have one patient, by the way, who came to me having been prescribed some oral and from the

00:58:14.480 outside. I asked him to stop because I was like, look, I'm not going to take over the prescription

00:58:19.000 on that because I don't know anything about it. So he did. And like, I don't know, a year,

00:58:24.300 a year and a half later, he's like, look, I really want to be back on this. I've just never felt the

00:58:28.340 same since I was on it. You know, it just gave me such a feeling of vitality and hit a lot of

00:58:34.300 reasons why he felt it was the thing to be on. And I said, look, man, I'm not going to be that guy

00:58:39.420 who says no, just to say no, but I need to understand this a little bit more. And I think

00:58:44.800 we need to think through what are the risks and benefits of this. And so we kind of negotiated

00:58:49.140 this back and forth for six months where I said, look, I guess if we do a bunch of really good cancer

00:58:53.820 screening and can convince ourselves that you don't have cancer, you know, we do the PRNUVO,

00:58:58.800 we do a gallery blood test, check a colonoscopy, like basically to the level of detection

00:59:05.140 of our modern technology, you don't have cancer at the moment. I'll be happy to find an endocrinologist

00:59:11.700 who's more comfortable with the dosing. And we did. So we found a great endocrinologist and she was

00:59:15.600 like, okay. And he went and saw her and she's prescribing it to him and he's as happy as can be.

00:59:20.380 There's not a judgment around this. It's, I'm genuinely curious. I still can't make sense of,

00:59:26.500 would you want to be on samoralin, tesamoralin? It sounds like you're saying tes is better than

00:59:31.100 samoralin or, but that again, could just be anecdotal versus growth hormone. And then of

00:59:35.880 course, I never really understood the stacking where you would start to stack both compounds.

00:59:39.560 So do you get the sense that hitting both targets, both receptors is better than just using GH?

00:59:45.280 Does it give more specificity? One thing you could say for certain is when you push

00:59:49.580 endogenous production, you were fulfilling the full production of all spectrum of variants. So

00:59:56.040 there's different kilodalton isoforms of HGH and this is how they detected in doping. And these

01:00:03.120 variable like molecular weight growth hormone outputs that you get from the pituitary,

01:00:08.900 we don't know why they are put out in different formats, essentially. For all we know, they have

01:00:15.980 different actions in the body that may not be facilitated by the recombinant straight like 22.

01:00:21.860 So when you take a recombinant HGH, you are telling your brain don't make more essentially.

01:00:27.260 So you are actually losing the production of those other variants and you were relying entirely on this

01:00:33.100 one. So what the implications are of that from a health perspective or a performance, what have you,

01:00:39.640 obviously we can manually push your IGF to super physiologic, which you will not be able to do

01:00:44.660 with the endogenous kind of up regulators of sorts with the peptides. And you can kind of manually

01:00:50.320 just choose where you go with it. So there's certainly a case to be made just like with

01:00:54.480 testosterone. It's like, Oh, well, why would you use a GNRH agonist? Or why would you use a CIRM? Or

01:00:59.920 why would you use an aromatase inhibitor? What have you and modulate these upstream pathways when you

01:01:03.600 could just take the straight hormone and manually pick where you land. And oftentimes that could be the

01:01:09.880 reasonable answer, especially for somebody who wants like a very targeted end goal and knows

01:01:14.800 exactly where they want to land on their IGF or doesn't need or potentially has worse output relative

01:01:20.960 to the input of those peptides. Cause again, it's working off your natural capacity. So there's

01:01:25.700 definitely potential pros and cons. You can, if you have good functioning, entire hypothalamus pituitary,

01:01:34.200 all the output is satisfactory from an infrastructure standpoint to output natural hormones at an

01:01:40.200 adequate level. The natural peptides may be useful and you know, you're getting all the variants of

01:01:45.240 all the kilodalton molecular mass variants. But with exogenous, it's just like, you know, exactly what

01:01:50.740 you're getting. You can manually choose what you're getting out of it. And I think it's more could be

01:01:56.300 reserved for people who don't have the natural output that they are trying to get out of the peptides.

01:02:02.120 They don't respond that well, or there's just more data too.

01:02:07.160 So is there kind of an analogy here where taking growth hormone, exogenous common growth hormone

01:02:12.780 is like taking testosterone, whereas taking the peptides is like taking Clomid?

01:02:18.580 Yeah. I would say with exception that you're not blocking negative feedback, you are positively

01:02:24.940 modulating it. Correct. Clomid works by creating a block.

01:02:28.100 Yeah. So it would be like analogous to probably an HCG and recombinant FSH or more like a HCG probably

01:02:36.160 or combined HMG or something. What does the literature say and what does the non-literature

01:02:44.800 say about the role of GH alone, not in combination with anabolics, in terms of its capacity to help build

01:02:53.280 muscle and oxidized fat? The literature is so sparse on being able to say without a shadow of a doubt

01:03:02.620 that it is going to enhance muscle growth potential and performance especially. Like there are very

01:03:09.300 few studies that really show a clear enhancement of athletic performance. So I think what is clear

01:03:17.380 in the literature is the body recomp effects. You do gain lean mass. Part of that presumably is water

01:03:24.680 retention. You do lose fat mass, right? Yeah. And for like lipodystrophy, if you're able to,

01:03:30.100 I don't know, liberate free fatty acids and be able to actually improve your utilization of

01:03:37.760 substrate, you could absolutely improve your body comp fairly significantly with it. But when it comes to

01:03:44.740 actual protein synthesis, muscle accrual, it's very wishy-washy and certainly not something that

01:03:52.540 you should hang your hat on as the reason why you're taking it, in my opinion. So from a muscle

01:03:57.120 growth and athletic performance perspective, the jury is out in terms of if it does anything

01:04:00.760 significant enough to justify its use. Bodybuilders will claim to high heaven that it's, some think it's

01:04:06.680 an expensive fat burner and some think it's actually quite useful and they notice huge changes, but

01:04:12.540 it also very much depends on your response from a fluid dynamics perspective. It can definitely

01:04:19.080 increase sodium retention and things that you may interpret as muscle growth that may just be

01:04:24.680 volume. And with that said, the muscle is how much water at the end of the day. So is that to be ignored

01:04:30.020 from a cosmetic perspective, it certainly looks good on a bodybuilding stage. You might not have the

01:04:34.260 function. Yeah. So you may not get enhanced force production outcomes like you would be seeking

01:04:39.180 from like a true anabolic agent, but it doesn't improve cosmetic appearance of muscle, almost

01:04:46.720 certainly, and can help you improve your body composition, especially if you time it well with,

01:04:52.940 because if you just use it and liberate free fatty acids and sit around and do nothing, you could just

01:04:57.080 redistribute that and not necessarily get the benefit out of it that you're seeking. So do you

01:05:02.240 think that the liberation of fat is the more reproducible finding of GH use? Oh yeah. You

01:05:09.040 know, that's happening when you use it for sure. And you will become acutely insulin resistant as a

01:05:14.080 result of that too. So based on that knowledge, when is the ideal time to take it? Do people take

01:05:18.880 this once a day, twice a day? It depends on the dose because if you're using a very high dose and it

01:05:24.440 also depends on your lethargy from it, it is very lethargy inducing. You could feel sleepy all day. If

01:05:31.280 you're blasting a high dose of it. What would be a high dose? Like what you were taking six to eight?

01:05:35.720 Yeah. I would say when I took it, it was mostly in the two to four IU range. I only did six to eight

01:05:42.280 for like a very short period of time. Even that, the lower, lower, but still pushed me to like a 500 IGF

01:05:48.760 was lethargy inducing for me personally. For how long? Man, that was so long. I had tried it for

01:05:57.680 full durations of cycles. So, you know, upwards of a few months was probably the longest I had taken

01:06:03.680 that. Did you have lethargy the whole day or was it just like, if you took it in the morning,

01:06:07.400 you'd feel that way till noon, then you had to work out in the afternoon to get around it.

01:06:10.980 With the doses I was using and splitting it up the way I was, it was pretty around the clock.

01:06:17.100 Why is that? It seems to have a very intertwined connection with sleep. So you have your biggest

01:06:24.340 GH pulse when you're getting to sleep and people find seemingly pretty positively correlated with

01:06:31.780 aging. You have a decrease in IGF and seemingly deep sleep metrics also decrease precipitously too.

01:06:38.900 And I think this is the biggest case to be made on potential attenuation of cognitive decline is

01:06:44.340 its impact on sleep. If you're somebody who gets significant enhancement in deep sleep metrics,

01:06:50.120 however you want to track that, I can't imagine you can extrapolate from there that it's helpful.

01:06:54.340 For somebody who has, if you have a crashed IGF and you have horrible sleep as a result of it,

01:06:59.780 like there's clear literature to show that IGF deficiency will impair sleep. So if you're able

01:07:04.100 to correct that to some level, the minimum effective dose, you don't need to push it.

01:07:08.280 But you're saying with a higher IGF, you were more lethargic. You would think that you'd be

01:07:12.540 sleeping better based on that argument, right?

01:07:14.980 Yeah, probably. It's also gets conflated with bodybuilding diets too, because typically when

01:07:20.740 you're using it, you're in a calorie surplus trying to gain a bunch of muscles. So you could

01:07:23.740 definitely conflate those findings a bit and it is anecdotal. But in general, people using peptides

01:07:29.220 even and growth hormone will often find that their sleep is seemingly enhanced, like it's deeper,

01:07:36.920 more restful.

01:07:38.140 And yet they're more lethargic during the day.

01:07:39.900 Yeah, yeah.

01:07:41.120 Is it possible then that the GH is inducing too long asleep? So you sleep well, not at night,

01:07:46.700 but then it's carrying over to the day, like there's a hangover of sleep?

01:07:49.800 Potentially, for sure. Like it seems to be a hormone that is quite rejuvenative during your

01:07:55.800 sleep. And I can't imagine not that I really read into like ancestral history or how your body

01:08:01.700 functions relative to the ancestors that much. But it's like the time you are trying to recover and

01:08:08.580 rest the deepest, having the highest spike of GH, like it seems to be, I think it's something you could

01:08:14.940 at least extrapolate as a interesting anecdote, nonetheless, that I can understand why I might

01:08:20.820 be tired when the deepest point of rest is also the time that this is simultaneously the highest

01:08:26.440 endogenously. So if I'm manually creating at least half of the conditions that are associated with when

01:08:33.280 I would otherwise get the deepest sleep, maybe I can manually induce that myself, if I'm deficient,

01:08:39.440 or what have you. But as far as timing and the justification for it, it depends on if you were

01:08:44.620 trying to use it for lipolysis, or if you were trying to use it to enhance sleep, or what the

01:08:50.060 conditions are, because you are going to be suppressed at a certain level regardless. So

01:08:55.420 oftentimes, the logic would dictate, at least in my opinion, that you would probably put part of your

01:09:00.720 dose before bed, given that you're not going to get the same output when you're using exogenous GH.

01:09:06.200 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

01:09:12.160 and use the fat. Yeah, which is not a bad idea. There's definitely a, at least I think a justification

01:09:19.080 that part of that dose or potentially all of it when your IGF one or GH output is suppressed,

01:09:26.220 that you would actually allocate your dose to pre bed. So it depends on goals too. And if you notice

01:09:32.760 an enhancement of sleep or not, but you can say, without a shadow of a doubt, that feedback loop

01:09:37.060 will suppress your natural output, you're not going to just get the best of both worlds.

01:09:40.840 And so would you say more people today would be using the two receptor approach,

01:09:46.520 the two peptide receptor approach rather than GH? Is that a more common approach today?

01:09:50.660 I think among those in the clinics, for sure, because it's less cost prohibitive. That's what I think.

01:09:58.000 But in the underground bodybuilding world, they're typically pushing super physiological IGF one

01:10:03.640 levels. That's their goal. That's what they want to get out of it. So they typically try and find

01:10:08.300 pharma grade GH. And if they can't get it, they will go generic if they also can't afford it. And

01:10:12.380 that's what they're doing. They're pushing IGF to 500 and more.

01:10:16.220 Yeah, typically like that. It would be a minimum adequate amount for performance enhancement,

01:10:22.280 quote unquote performance enhancement, would be deemed higher than what is naturally achievable

01:10:28.620 based on typically a lab corp reference range is what most people would utilize.

01:10:33.460 Let's detour for a moment just to talk about bodybuilding before I want to kind of go back

01:10:37.380 and talk about anabolics. And then maybe this will be a nice dovetail into it. So in my gym,

01:10:42.640 I have a lot of pictures of bodybuilders, nice black and whites that I enjoy. And there's just a

01:10:46.880 real clear difference between Frank Zane, Arnold Schwarzenegger, Sergio Oliva to Jay Cutler and

01:10:56.080 Ronnie Coleman. And I don't know when that jump took place. Maybe Lee Haney, maybe Dorian Yates,

01:11:03.620 but somewhere in there, there was a real transition in physique. Not to debate which of those is the

01:11:09.780 best. I think everyone can have their own preference for which era of physique was their favorite.

01:11:14.140 But if you sort of think of the things that can impact your physique, genetics, okay, that's not

01:11:18.580 changing. Nutrition and knowledge of nutrition, that's clearly evolved. Training and knowledge

01:11:23.780 of training, that's clearly evolved. Drug use, that's clearly evolved. And then maybe just even

01:11:29.640 injection. I've talked to bodybuilders today who say that they're actually injecting compounds in

01:11:34.620 their muscles to alter the shape. They're injecting like fats into muscles to actually create some

01:11:40.560 sculpting. So again, that's probably something new. Let's put that one aside. Of the three,

01:11:45.760 evolution of training, evolution of nutrition, evolution of drugs, how would you rate the relative

01:11:52.060 balance of those three for the difference of a 1970s physique versus a physique today of the best

01:12:00.240 bodybuilders in the world? Probably drugs at the top, almost certainly, followed by I would say

01:12:08.040 nutrition probably, and then training at the bottom. How much emphasis on each of those,

01:12:12.740 like 50, 40, 10? That's tough because these get scrutinized to hell because it's like I'm going to

01:12:17.440 put a number on it. People will be like, how do you think diet is only 20%? A lot of these things don't

01:12:22.780 live without the other. So you could definitely lean heavier and say, well, if you eat nothing,

01:12:27.660 the drugs aren't going to do anything. So I would say just in order of importance,

01:12:31.800 if you did perfect diet, perfect training with all of the modern knowledge that we have now,

01:12:38.720 your ceiling for muscle growth potential could be as much as 50 to 100 pounds lower as a natural,

01:12:46.240 depending on height, depending on genetic response. And by the way, I don't want to forget on the GH

01:12:50.900 stuff. One thing that is interesting is even in acromegalic patients, the incidence of death seems to be

01:12:58.240 cardiovascular significantly more than cancer incidence. So if there's anything to discern

01:13:04.280 from actual human literature, significantly chronically elevated IGFs into even 40 years

01:13:10.600 old, these individuals are dying from congestive heart failure and things like that.

01:13:15.060 And that's really interesting. So not even atherosclerotic disease. I have to look into

01:13:18.480 this. Actually, that's a very good point. I should look at the acromegaly literature.

01:13:22.220 One of the interesting things is how much fluid retention they hold and the stress that has on the heart

01:13:27.220 too. Yeah. That's very interesting. They also probably would be, I'm guessing,

01:13:31.200 maybe more prone to aortic dissection because they probably have larger connective tissue,

01:13:35.460 things like that. Yeah. Okay. So you're putting drugs at the top of the list and then nutrition

01:13:40.800 and then training, I think was the order you had them in. So let's talk about the drug use.

01:13:45.380 So I've spoken to 70s bodybuilders and if they're being honest with me and I have no reason to believe

01:13:53.140 they're not. You would think. Yeah. Like what do they care? I was shocked at how little drug use

01:13:58.820 was going on back then amongst the best of the best. And we're talking like one to 200 milligrams

01:14:05.580 of testosterone a week, eight weeks at a time, eight on, eight off, eight on, eight off. In other words,

01:14:13.080 they're basically taking TRT. Yeah. They're not telling the truth. Okay. So that's your view?

01:14:17.820 Most of them almost certainly are not when you're saying you're taking a borderline female HRT

01:14:25.060 dianable dose. It's like back then that's what it was prescribed for or like muscle wasting in old

01:14:29.980 age or whatever. Some of the old like SEPA dianable ads are hilarious by the way, but those dosages are

01:14:36.400 almost impossible to wrap your head around producing outcomes that they are like, you might as well have

01:14:42.800 stayed natural almost at that point. So I too bought into the idea of, well, they seem to have

01:14:48.180 consistent stories. They seem to have all taken one shot of primo a week and you know, one to two

01:14:53.160 dianable or what have you. And it's just not an outcome that you see as reproducible ever in those

01:14:59.060 dosage quantities. So maybe on the hyper extreme outlier scenario, you might have a guy who a total

01:15:05.120 weekly dosage of a few hundred milligrams across everything he's using. He may hyper respond and get

01:15:11.080 huge. But I would say the majority of the guys competing at the Olympia level were still like,

01:15:16.120 I've heard of people slugging D ball by the bottles. Even back in the seventies. Yeah. It's

01:15:20.900 just certain people are more outspoken about their abuse than others seemingly. And it seems like the

01:15:27.340 ones that are outspoken are more like this guy, Pete Grimkowski. I don't know if you've heard of him

01:15:31.160 before, but looked incredible. But the guy used thousands and thousands and thousands of milligrams.

01:15:36.340 And I can understand why you would arrive at that logic to take that because there was nothing to

01:15:41.720 tell you otherwise. So if you're competing against a guy at the highest level, and there's

01:15:45.500 relatively high stakes, you see a guy like Arnold, getting movie roles and stuff. It's like the peak

01:15:51.520 of achievement as a bodybuilder back then you couldn't do social media can do anything you would

01:15:55.300 try and emulate presumably what he was doing, or something of that nature. To think that you're not

01:16:01.060 going to escalate your dose past one to two dianable and a shot of primo or what have you or a shot

01:16:05.780 of Nandrolone because you didn't want to like hurt yourself. It's like, shut up, dude.

01:16:10.580 Yeah. I feel like I saw a video kind of recently of Tom Platt's discussing this.

01:16:15.540 He had changed the story. Yeah. With that said, his original breakdown was relatively conservative

01:16:21.580 still, but he's done public presentations about drug use back in the eighties, nineties. And

01:16:27.160 you could tell he was pretty reserved. Even back then he handled the situation very delicately.

01:16:32.820 You could tell he was picking his words carefully as he spoke. But more recently he came out and said

01:16:38.560 his dose was like, I don't know, a third of that or something. It's like, okay, maybe like, you know,

01:16:43.420 in 40 years or something, I don't expect you to remember exactly what you took, but to say your

01:16:47.440 peak dose was one third of what it was. I don't know. Like, I just, I just don't really believe you.

01:16:53.120 Well, at the other end of the spectrum, I've spoken to one bodybuilder who, and I couldn't

01:16:58.860 believe it, but he said at one point he was up to, are you ready for it? Yeah. 50 grams of

01:17:08.160 testosterone in a week. There's no way you would not inject that much. I was like, how is that

01:17:14.580 possible? You would run out of injections. How are you managing? I think a lot of people just don't

01:17:19.500 know what they take too. Oftentimes you ask people on TRT even, what's your dose? They're like, oh,

01:17:24.660 I took like, you know, a half as. We noodle with patients between 100 and 120 milligrams a week.

01:17:31.100 Like literally we will make movements that fine, 20 milligrams a week. Yeah. I think a lot of people,

01:17:38.100 they just go by, oh, my doctor told me to take this much of a syringe. And then they kind of just

01:17:43.320 remember some rough number, but oftentimes they don't know how many milligrams per milliliter what

01:17:47.720 they're using is. They don't know what their dosage is. They just take some scheduled protocol

01:17:51.740 and they stay on it for years. And then they don't even know what they're doing. But 50 grams is like,

01:17:56.160 it's impossible. You would have to dedicate your life to injecting essentially. That would be your

01:18:02.420 full-time job. Just sitting there pinning like five to 10 CC barrels of test all day.

01:18:07.320 Oh God. Given how remarkable the physiques were in the seventies at the top of the food chain in the

01:18:12.380 Olympia. Would you agree with me that something dramatically changed in the late eighties,

01:18:18.100 early nineties? Yeah. And it seems to be the emergence of growth hormone and insulin abuse,

01:18:24.420 as well as the escalation of drugs to an even more extreme magnitude and the availability potentially

01:18:30.760 granted they were prescribed readily seemingly, but people also seemingly push the limit more. And

01:18:38.640 there's the emergence of underground lab preparations and things of this nature. So

01:18:42.660 my understanding at least is, and there's no literature to document like, Oh, you know,

01:18:47.960 this dosage equated to this and therefore this is why it happened. But it seems to be dose escalation

01:18:53.900 of anabolics to some extent, but more so the implementation of growth hormone coupled with

01:18:59.600 exogenous insulineus. They're using insulin because of how anabolic it is.

01:19:05.280 Well, the goal is what they think it is. And obviously if there's terminology that may not be

01:19:12.220 exact on that, but it's like what they believe it's doing is shuttling a super physiologic amount

01:19:18.500 of nutrients into the muscle. Cause also when you take GH, you're acutely insulin resistant. So

01:19:23.020 need a little insulin to overcome that. Yeah. They're almost like doing both things at the same time as

01:19:28.060 the goal. And often when you're using really high doses of GH, fortunately this isn't as problematic

01:19:34.680 and replacement dosages. So I don't want people to extrapolate out. Oh, GH equals chronic insulin

01:19:40.340 resistance necessarily. But at the dosages people are using, they could induce diabetes essentially.

01:19:45.760 Like you could end up a diabetic from just your GH abuse and oftentimes to relieve stress off the

01:19:51.660 pancreas and the beta cells, they will use exogenous insulin. So you don't have to produce as much

01:19:56.060 endogenously to actually accommodate the amount of carbohydrate intake and just overall nutrients.

01:20:02.200 Because these diets to maintain a 300 pound physique, you're pounding 5,000 calories a day

01:20:06.860 sometimes. So the introduction of growth hormone with all of its benefits, presumably, which we've

01:20:13.500 talked about. It's funny because right as we finished talking about how it's not performance

01:20:17.160 and saying now the thing that causes the 20 to 30 pound lean mass jump is supposedly GH and insulin.

01:20:23.500 It's interesting to say the least, but continue. Well, I was going to say, so we have that issue

01:20:30.220 going on. You've also talked a little bit about, so my belief used to be all this GH and insulin use

01:20:37.980 is why we're seeing these big abdomens on not just bodybuilders, but also on athletes. So you'll see

01:20:45.500 track and field athletes who are insanely muscular, insanely lean, but they have huge protruding

01:20:54.620 abdomens that do not appear to be fat because you still see a six pack ripped on top of it, but from

01:21:02.000 the side, they look pregnant. And again, the thinking was, well, is this just organomegaly? Are their organs

01:21:09.520 just getting bigger? Now you've talked a little bit about an alternative hypothesis.

01:21:13.100 Yeah, I think it is multifactorial, but there is seemingly, I think the largest cause of it now

01:21:22.620 is significant distension caused by the excessive food intake and the result of significant gastrointestinal

01:21:30.680 issues that result from the absurd diet models. Because to get that many calories and get that

01:21:35.240 much protein, carbs often, and especially peri-workout when you're using insulin and you need to make sure

01:21:40.540 you don't go hypoglycemic in your workout, they'll be slamming like 100 to 200 gram shakes that have

01:21:47.160 hydrolyzed whey in them, branch cyclic dextrin, plus aminos, plus creatine, plus glutamine, plus this.

01:21:55.460 And oftentimes they're essentially in a state of, like I'm sure you've had a cheat day where your stomach

01:22:01.080 was incomparable to days when you're fasting, for example, it's a massive difference. Fasting,

01:22:06.900 you could do a vacuum and see completely invert your stomach almost versus when you have a giant

01:22:12.680 cheat day and just go off the rails. You couldn't keep your stomach in for the life of you. You have

01:22:17.560 to be flexing just to keep it not looking like you have a gut when you're sitting down. That is a

01:22:21.500 perpetual state of reality for bodybuilders who weigh that much to sustain that food intake and

01:22:27.440 the physiques that they have because it's not a normal amount of muscle to hold. So it requires a not

01:22:32.580 normal amount of food to accommodate the nutrients required to grow further or even like sustain it.

01:22:38.900 Good example of that is Ben Pakulski. He makes more health focused content now, but he's a former

01:22:45.100 high level IFBB pro. I think he won the Arnold Classic even at one point. And one of his biggest

01:22:50.220 criticisms was his distended gut. And you know, for certain the guy was using all the same drugs

01:22:56.300 everyone was using at the high level, but he was able to reverse it seemingly in a relatively short

01:23:03.600 period of time in his latter part of his career by reducing his food intake significantly seemingly.

01:23:11.900 And he actually showed up one year later with a vacuum on stage, which a vacuum for people who

01:23:17.520 don't know, I don't even know if I could explain it, but it's like you suck your stomach in and it

01:23:21.100 creates like an almost like an inverted, it kind of goes in, you can see your rib cage and like your

01:23:25.420 serratus lines and stuff. And most bodybuilders wouldn't be able to do that nowadays. No,

01:23:29.480 no. And that's a big notable differentiating factor of seventies and like nineties bodybuilders,

01:23:36.480 the amount of people that could do a vacuum dramatically. So many could in the seventies

01:23:41.420 and it looked great. And in the nineties, you'd be hard pressed to find somebody who has like an

01:23:44.720 aesthetic vacuum. Except for presumably natural bodybuilders are more likely to, or. Yeah. Yeah.

01:23:50.900 They don't have the food demand. Yeah. It also depends on like what they're eating because people

01:23:54.400 gut issues could have issues too, but it's more common in people who are pushing food extremely

01:23:59.980 hard. And then the drugs on top of that, like when you have hyperglycemia chronically, you might have

01:24:05.980 impaired intestinal motility and like all these things that could compound the issue significantly.

01:24:11.500 So I think you have people with SIBO and bacterial overgrowth and all this stuff that can influence the

01:24:17.100 distension that is kind of like a congregation of bad digestion, insane amounts of food,

01:24:24.680 poor choices of food that don't agree with your body because it's simply the only way you can get

01:24:28.600 the calories in to meet the demand of the muscle, et cetera. But anyway, Ben Pakulski, he, he showed up

01:24:33.620 with less muscle, but he had completely reversed his gut distension. So it seemed as if the food was a

01:24:40.700 large dictator of, okay, to get the biggest physique you ever got, you had to eat some diet that was not

01:24:48.200 conducive to the most aesthetic, non-distended appearance. And if he had organ growth, is it

01:24:54.640 reasonable to assume that he could have reversed that?

01:24:57.460 Here's another example of something that's very frustrating to me. This is knowable. Literally take

01:25:01.700 the bodybuilders, throw them into an MRI scanner. You can get organ volumes on everybody. And we could

01:25:06.760 compare that to controls and also look at them off drugs, on drugs, all that stuff. So again,

01:25:12.220 it's just an example of so many of the questions that we have here that we're not getting resolution

01:25:16.700 to are knowable. It's not like we're asking, is there life outside of the solar system? We're never

01:25:22.580 going to know the answer to that. One thing I can say is on autopsy bodybuilders that did die young

01:25:28.280 or what have you, oftentimes now with social media, those results are released publicly and people

01:25:32.920 dissect them and whatnot. You learn things from bodybuilders that have died that you might have

01:25:37.520 not even known because not that long ago, 10 plus years ago, people were saying, where are the bodies?

01:25:42.440 No one's dying from steroid use, et cetera. But there are guys dying with hearts three times the size of

01:25:48.040 what they should be. So there's certainly organ enlargement systemically for sure. So we could

01:25:52.900 say that. I don't know if it's necessarily pushing on the stomach wall to actually cause-

01:25:58.760 Interesting. But I can say with near certainty, there is organ growth for sure. I just, again,

01:26:04.740 multifactorial. Maybe it's part of it. It's a great point. So let's talk about the death of

01:26:08.840 bodybuilders. And we're going to, again, I want to come back and do a long discussion onto anabolic

01:26:13.720 steroids. There was a bodybuilder that died kind of recently, right? Yeah. Yeah. That was a shocking

01:26:18.560 one too. He's a 30 years old. One of the biggest social media influencers too. What was his name?

01:26:25.100 Joe Lindner. American or? German. German. Oh, that's right. Yeah.

01:26:28.400 Yeah. Yeah. So with him, the scariest part was he was one of the guys who was doing all the right

01:26:35.880 things, at least from a blood work standpoint. So he would get blood work done literally every two

01:26:42.040 months, if not more frequent and was very, very rigorous about trying to oversee his health status

01:26:47.960 and his blood work. Wasn't perfect always, but it certainly wasn't somebody who should be dying at

01:26:53.020 30 years old, regardless of back in the day or not that long ago, even it would be

01:26:57.900 unheard of for somebody to be dying. If he wasn't a massive bodybuilder by industry standards for

01:27:03.500 fitness, where we have this warped perception of what is big versus not, he was like probably like

01:27:08.000 50 pounds off of what you would consider a top level open class bodybuilder who would compete with

01:27:14.000 Ronnie Coleman or something. So he was more of like a jacked fitness model by fitness industry standards

01:27:21.500 and less drug use, significantly less drug use, less food intake. He was always in a calorie deficit,

01:27:29.700 shredded year round. The guy did lots of cardio, at least like 10,000 plus steps a day,

01:27:35.380 ate clean. Like there was no reason objectively, at least why he should die at 30.

01:27:41.140 And what are the known circumstances of his death?

01:27:44.180 So apparently his, and this is the thing that's, I don't even know if you're going to want this in

01:27:48.860 the podcast, dude, but it's, he got apparently the vaccine and two boosters on top of it, I believe

01:27:55.740 might've even been more, but after he got it done, apparently he went and saw, he got his blood work

01:28:01.960 done just routinely. And they saw supposedly that the blood they pulled out was like really coagulated

01:28:09.800 and weird looking. And I forget exactly his terminology, but he literally did a podcast,

01:28:15.900 maybe a week or two before his death, how he got a blood test done. And they were telling him that he

01:28:21.000 needs to get a plasma pharesis to clean his blood because it was so messed up from the vex. So he

01:28:27.860 did it twice apparently. And then supposedly his D-dimer went back down because it was super elevated in his

01:28:34.580 blood work. And they said he was fine now. And he cleaned his blood and reintroduced it back into

01:28:39.780 circulation. He would be good. He made a long trip to the U S I actually met him for the first time,

01:28:45.800 like a couple of weeks before his death. And then when he flew back to Thailand, which is a really

01:28:50.560 long flight and yeah, there's clotting risk, you know, associated with that on top of all the other

01:28:55.600 things, which is speculated to be something that's another variable, but he got back seemingly fine.

01:29:02.280 And then apparently a few days after he got back, he was complaining of neck pain. His aunt

01:29:08.220 supposedly died from an aneurysm in her neck. That is what we have been told. We have yet to see a

01:29:16.580 autopsy report on his situation, but his girlfriend at least reported that his aunt died from the same

01:29:22.800 thing and had a aneurysm in her neck. In her neck or in her head?

01:29:26.900 It was apparently neck specifically, which I would think is unusual.

01:29:31.200 Yeah. I won't even speculate without an autopsy. I think again, tragic, obviously, but hopefully an

01:29:37.480 autopsy sheds light on that. I mean, it's not difficult to know if someone dies of an aneurysm

01:29:41.620 on autopsy. Would you scope that out with like a Prunuvo scan before you even?

01:29:46.980 Yeah. That's actually one of the reasons we really do like whole body MRI is the incidence of aneurysms

01:29:53.500 you'll see on a whole body MRI is about, depending on the series, I mean, somewhere between one and

01:29:58.480 seven cases per thousand. Now, not all of those are aneurysms that pose risk, meaning they're not

01:30:04.300 all aneurysms that if left alone would ultimately rupture, but a number of those require intervention.

01:30:11.540 So we've probably in the last seven years had two patients, if you think about how small our

01:30:17.500 practice is, two patients who have had incidental captures of aneurysms that were in one case large

01:30:24.800 enough, in another case, growing quickly enough to a large enough size that they needed to be coiled

01:30:29.880 preventatively. So the aneurysms that typically kill people are in the head, behind the stomach.

01:30:36.640 Those are the ones that you kind of want to look out for. Also, as far as if he had a deep vein

01:30:41.360 thrombosis, which would certainly be a risk factor on a long flight, that could obviously kill you with

01:30:46.380 a pulmonary embolism. Again, very easy to diagnose on autopsy. So by the way, what's your current

01:30:52.040 flight stack? So I don't fly that much anymore. And when I do, most of my stack is around sleep.

01:31:00.100 What I'm thinking about when I'm flying is how do I eliminate jet lag? So I went to London,

01:31:05.260 I don't know, a few months ago. So you don't control for like clotting potential anymore.

01:31:10.000 I take baby aspirin, although the literature suggests that it's not necessarily helpful

01:31:16.920 against DVT. I used to take something else. Nato kinase. Yeah, that's right. I used to take that

01:31:22.580 for DVT. Nowadays, I just use compression hose, hydrate like crazy. And basically, I've got straight

01:31:30.560 legs most of the flight because I'm like laying down. Honestly, I think like hydration probably

01:31:34.640 plays a greater role than most things. At one point, I was like so ridiculous. I was taking

01:31:39.600 Lovenox injections. So Lovenox is like an unfractionated, it's like a type of heparin

01:31:45.060 basically. But after one time I took it where I injected it and hit a blood vessel and had like

01:31:49.880 the biggest bruise on my head. And I was like, oh, this is just not worth the hassle anymore.

01:31:54.040 Most of my effort really focuses around how to not get jet lag, which I've turned into a science.

01:32:00.460 I'll have to ask you about that later.

01:32:01.580 Yes, yes. I can go to eight hour time zone away, be a hundred percent functional the minute I get off

01:32:06.840 the plane, get right into routine and rhythm. But traditional bodybuilder deaths, like this was

01:32:11.840 a bit of a unique one because a lot of people, well, until the autopsy comes out, no one really

01:32:16.020 knows. It might be that this is just a tragic death in someone who also happens to bodybuild and

01:32:20.540 it might have nothing to do with. Yeah. In general, what I've seen from the autopsies available on some

01:32:26.340 pretty young bodybuilders, it's almost always a cardiovascular issue. And not necessarily

01:32:32.580 atherosclerotic, but more cardiomyopathy type deaths. Yeah. Yeah. So like the left blood pressure

01:32:38.840 unchecked and had heart function just destroyed essentially. And hearts that are way larger than

01:32:45.260 they should be. I don't know if you've ever heard of Rich Piana, but he was a very famous and

01:32:50.340 influential bodybuilder in the fitness industry. And he died in his forties with, uh, I think it was

01:32:55.480 like a 660 gram heart. And then Dallas McCarver, probably the most notable one. He was like a

01:33:00.780 mass monster by IFBB pro standards, which is like one of the guys on the Olympia stage. Who's actually

01:33:07.400 the biggest of the guys on that stage. His heart was like 860 grams or something.

01:33:14.420 And I think an athlete heart is like what? One third of that or something.

01:33:19.080 Maybe a bit more than that. Okay.

01:33:20.660 Yeah. Mike Mencer died young as well, didn't he? Yeah. He had known atherosclerosis, didn't he have?

01:33:26.880 He was also, and I don't want to speak at a term, but I've heard he was pretty into amphetamines

01:33:32.440 on top of that. So it was like stimulant abuse on top of potential anabolic exposure.

01:33:39.060 I do think that that's one of the difficult things to ascertain with respect to bodybuilding is

01:33:44.220 so much polypharmacy. Well, it's the polypharmacy and there's also like,

01:33:47.840 there's the psychological component that's very difficult to disentangle. That's part of the

01:33:51.800 profession. So let's go on and talk about testosterone and androgens in general. You've

01:33:57.340 already thrown around a lot of names that are going to be foreign to people, but before we kind of get

01:34:01.320 into the different anabolic steroids, you want to just kind of do a quick review of the relationship

01:34:07.040 between the hypothalamus, the pituitary, Leydig cells, Sertoli cells, like what's the whole

01:34:13.360 relationship between those hormones, testosterone production, and maybe we can even talk about DHT

01:34:19.440 androgen receptors and estradiol for that matter. So the body has a pretty, it's complicated,

01:34:26.300 but it seems to be pretty well-regulated way to know how much hormone to produce based on needs

01:34:33.340 in tissues, especially too. So your hypothalamus will create something called gonadotropin releasing

01:34:39.480 hormone. Just like the name suggests, this is the hormone that goes to your pituitary to actually

01:34:44.600 stimulate the production and release of gonadotropins. Gonadotropins are the hormones that

01:34:50.900 work on your gonads to produce testosterone, as well as assist with spermatogenesis and sustain

01:34:58.180 fertility. So the gonadotropins that come out of the pituitary, they elevate upstream and GNRH as well

01:35:06.200 in response or lack thereof to adequate. And there's so many to lesser magnitudes, but primarily

01:35:13.440 androgen receptor activation and estrogen receptor activation. And then there's also like some

01:35:19.980 stimulation of progesterone receptors that causes negative feedback as well, among other things too.

01:35:25.540 But the primary that are to be noted probably for this discussion, androgen receptors, estrogen

01:35:30.240 receptors, when those are satisfactorily or in an adequate amount stimulated, it will tell your brain,

01:35:38.880 okay, we have enough testosterone, as well as DHT and estrogen that we don't need to make more

01:35:46.280 essentially because we have a satisfied amount of estrogen receptor activation in the body. So we need

01:35:52.020 to clamp down and not make as much hormones because we don't want to have too much. So that will give

01:35:57.340 negative feedback to the hypothalamus pituitary testicular axis to not produce as much GNRH and

01:36:04.240 LH and FSH until those levels fall to where there's a need to make more hormones. So it's this like

01:36:10.480 finely tuned system where your body regulates how much it assesses how much it needs, waits until it

01:36:17.480 needs to produce more, and then it produces more. So the top of that is the GNRH stimulates pituitary output

01:36:23.820 of LH, luteinizing hormone, which acts on latig cells in the testes, and follicle stimulating hormone

01:36:30.060 that acts on sertoli cells as well. And this is, we'll definitely get into that email you sent me

01:36:35.500 about fertility and whatnot. Those will go down to the testes and stimulate the production of

01:36:40.560 intratesticular testosterone, as well as assist with the production of sperm and maintenance of

01:36:47.740 fertility. So those levels, I think that's probably a good summation of how you end up with testosterone,

01:36:54.480 probably. So then what's the fate of testosterone? The fate of it in terms of metabolites? Yeah, like once

01:37:00.680 it gets out there, how much of it is converted into estradiol, DHT? Yeah, and this is where a lot of people

01:37:07.780 who neglect lifestyle and diet don't realize all of the backhanded consequences of being too obese or

01:37:15.240 something like that. You could have, for example, aromatase strongly expressed in adipose tissue.

01:37:20.700 So if you are too obese, and this is problematic, especially in adolescents too, if you have a

01:37:27.120 disproportionate amount of aromatase expression, because of how fat you are, essentially, you could

01:37:34.140 otherwise be producing more estrogen than you would have if you were lean, telling your brain in a

01:37:41.560 indirect way that, hey, we have enough estrogen, so don't make more testosterone.

01:37:47.020 Because I use testosterone to make estrogen. Yeah, and I probably should preface this with

01:37:50.740 testosterone converts primarily to two hormones through the 5-alpha-reductase enzyme, 5-alpha-reductase

01:37:57.980 to DHT, dihydrotestosterone, which has a significantly greater potency for binding and transcribing

01:38:05.920 activity at the androgen receptor, and estrogen, estradiol, that will be the primary estrogen

01:38:12.260 receptor agonist in estrogen receptors around the body. So those two hormones regulate kind of a

01:38:19.520 balance of androgenicity and estrogenicity in the body, and it's like a finely tuned system.

01:38:26.420 And this system is also regulated by binding proteins produced by the liver,

01:38:30.640 and the differential between females versus men. It also works in the same way. It's just the

01:38:38.160 difference in how much of these hormones are produced is quite different, and also the binding

01:38:42.800 proteins to regulate that you stay feminine versus you have a masculine profile. So ultimately,

01:38:48.520 the balance of free androgen to free estrogen in the body is almost the thing, essentially,

01:38:54.140 that dictates if you are feminine versus masculine. You could flip-flop back and forth almost manually if

01:39:00.300 you really wanted to, and we see this in bodybuilding where females will literally masculinize themselves

01:39:04.880 to hell in order to win a show by using super physiologic amounts of drugs, and also in people

01:39:10.760 trying to transition from male to female or vice versa. And some of these changes are permanent,

01:39:14.320 of course, on the masculinization front. If you have a deep voice, it's almost certain that you're

01:39:19.200 not going to get it high after going on female hormone therapy. But at the end of the day,

01:39:23.880 this is kind of like the primary hormones to understand as far as the spectrum of androgenic male

01:39:29.720 to estrogenic feminine-like. It's not a female hormone because they exist in both sexes, but

01:39:36.220 DHT, the primary. Androgen that dictates androgenicity and sexual differentiation and maturation.

01:39:44.560 Testosterone, the main anabolic hormone, and drives a lot of the neurology, kind of the psychoactive

01:39:50.440 effects. And then estrogen is kind of like, it's a big balancing act, essentially.

01:39:54.760 Yeah. So let's, again, just make sure people understand the difference between androgenic

01:39:58.920 and anabolic, because we will come back to this more and more with other compounds as we talk

01:40:04.160 about the profile. Well, this one has slightly more androgenic behavior. This one slightly has

01:40:09.820 more anabolic behavior. Yeah. So the androgenicity or androgenic activity of a compound or your endogenous

01:40:17.520 hormones is essentially how masculinizing it is. So dihydrotestosterone, the 5-alpha reduced

01:40:25.180 metabolite of testosterone, is the most androgenic hormone in the body and can significantly inhibit

01:40:33.640 estrogen's activity, even in RNA transcription at the receptor site. It's very potent in what it does.

01:40:39.680 To frame how important it is, you could have a male. If you wiped out DHT before puberty,

01:40:44.660 basically, that's how you end up with a micropenis, essentially. You have individuals who will not

01:40:49.900 undergo full maturation unless you have the presence of this hormone. If you took a male

01:40:54.700 before puberty and just put him on detasteride or finasteride and zeroed out his DHT with making no

01:41:02.980 change on his testosterone. He would have the same amount of muscle, if not slightly more, but that's

01:41:08.600 debatable. But no temporal recession, probably not as much acne, not as much body hair, micropenis.

01:41:15.960 He would be probably visibly male voice, probably not as deep as it should be. And we see this in

01:41:22.240 pseudo hermaphrodites that have a mutation, the gene that encodes for 5-alpha reductase. So

01:41:27.220 this is kind of the advent of these enzyme inhibitors and how we even discovered how they work and

01:41:32.900 whatnot. But DHT, the most androgenic hormone in the body, the most masculinizing. Testosterone,

01:41:38.100 still very masculinizing too. And estrogen on the opposite side of the spectrum,

01:41:43.360 zero masculinization, very feminizing. I think that's the easiest way to kind of summarize.

01:41:48.700 So we talked a little bit, and I've discussed this on many previous podcasts, but just in case folks

01:41:52.880 haven't listened, right? So testosterone or DHT make their way into the cell, into the cytoplasm where

01:41:58.360 they bind to the androgen receptor. To your point, DHT does so with far, far greater affinity. I mean,

01:42:03.840 it's on the order of one order of magnitude more, maybe 20 times more binding efficiency to the

01:42:11.220 androgen receptor. This new complex of testosterone or DHT bound to the AR makes its way into the nucleus

01:42:17.880 where it acts as a transcription factor binding to DNA and imparting on it effectively transcription

01:42:24.180 translation. That's how we make stuff. It's how we make proteins. So that's how it

01:42:28.120 impacts muscle protein synthesis. I guess one thing I should have said is androgenic,

01:42:32.000 because you did actually ask me this, is not anabolic. So androgenic masculinizing,

01:42:37.020 but does not necessarily equate to muscle. So you could have severe masculinization with a relative

01:42:43.600 absence of actual muscle growth or translation to, I don't know, bone integrity and what have you.

01:42:49.720 By the way, how important is DHT post-puberty?

01:42:53.600 Seemingly, it depends because from a cognitive health perspective, from a balance of estrogen

01:43:01.020 standpoint, from a vasodilation in the penis standpoint, like there are certain things where

01:43:06.780 you could say it's pretty critical. But then there's also you could just as easily say it's

01:43:11.980 not necessary or mandatory, like you will survive and likely thrive just the same with a lack of DHT

01:43:19.340 almost entirely. A lot of people will demonize 5-alpha-reductase inhibitors and justifiably

01:43:25.640 so in some cases. But even when you look to literature that compares placebo versus finasteride

01:43:31.660 versus dutasteride, side effect profiles are pretty similar even.

01:43:36.880 Yeah, dutasteride and finasteride being two drugs that block 5-alpha-reductase used initially for

01:43:42.980 reducing prostate size because DHT disproportionately drives prostate growth, but also used, I would say,

01:43:49.240 used more for hair loss now. But yes, and we have talked about this on two podcasts previously about

01:43:54.040 post-finasteride syndrome, which is a debatable idea. In other words, there is not a clear consensus

01:43:59.900 in the urologic literature about even the existence of this, let alone the prevalence, let alone

01:44:07.920 the reversibility of it. All of these things are really unknowns. And actually, it's created quite

01:44:15.240 a bit of a conundrum for us because we have a number of patients who take finasteride or dutasteride

01:44:20.100 for hair loss. And what's your stance on 5-alpha-reductase inhibitors?

01:44:25.280 Yeah, I mean, look, I think I'll be honest with you. I never really paid enormous attention to it until

01:44:30.380 about a year ago. I think right now our stance is I probably wouldn't start somebody on it.

01:44:37.060 So in other words, if a person has BPH, we're not going to manage that anyway. But a urologist has

01:44:42.000 far better tools to manage BPH than 5-alpha-reductase inhibitors. So I feel pretty strongly that if you're

01:44:48.920 presenting with BPH, you should not be on a 5-alpha-reductase inhibitor. It's like if someone

01:44:54.340 came to me and said, my APO-B is too high and I gave them a bile acid sequester in circa 1981.

01:45:00.660 I mean, it's just not necessary. There's no upside. If you're talking about it from a hair loss

01:45:05.860 perspective, again, not something I obviously know much about, I would say, and they're going

01:45:11.340 to go and see a hair doctor who's going to try to give them 50 different proprietary compounds,

01:45:16.180 which by the way, I want to come back to that in a second. I would encourage them if they've never

01:45:21.040 taken it before, not to. Because I think there are enough other compounds, oral minoxidil,

01:45:27.480 topical minoxidil, topical 5-alpha-reductase inhibitors, PRP, transplants. I think there are

01:45:33.120 enough other tools that you can do to avoid the small but not necessarily zero risk of something

01:45:41.160 going wrong in terms of sexual side effects that in the worst case might not be reversible.

01:45:47.100 What about you? What do you think? I think that several of the drugs you just said

01:45:52.360 have either comparable side effect profiles like topical finasteride. You end up with the same

01:45:57.740 burden of 5-alpha-reductase inhibition systemically, despite the effect that it's marketed otherwise.

01:46:03.460 Topical dutasteride is interesting because it may have some capacity to stay local, especially if you

01:46:08.960 do mesotherapy. I wasn't aware of that difference. Yeah, it's thought to be the molecular-

01:46:15.100 Is it just hydrophobicity? It's more the molecular mass of the drug. So there's this like,

01:46:21.200 it's like an arbitrary rule, but if the molecule is greater or less than 500

01:46:26.020 daltons, I believe it is off the top of my head. It's been a while since I've revisited it, but

01:46:29.980 there is a lesser or greater ability to actually absorb it and get systemic circulation and

01:46:37.380 distribution across the body. With dutasteride, it's like, I think it's like 600 or 700. With

01:46:42.500 finasteride, it's like 300 or 200. I don't think that systemic minoxidil is necessarily

01:46:47.480 a benign drug. And the other thing is nobody really can give an explanation for what the

01:46:52.080 right dose is. If you look at how people- Oh yeah, like low-dose minoxidil.

01:46:55.280 Oral minoxidil, it's insane. So I don't like to be in the business of prescribing things for which

01:47:01.880 I don't have a great understanding, which is why I'm not in the business of treating hair loss.

01:47:05.680 Not because I don't think it's something worth addressing if it bothers someone, but I think the

01:47:09.980 bigger issue is it would be really awful if in trying to treat a cosmetic condition like hair loss,

01:47:16.740 you induced a devastating consequence on your endocrine system. That's really where I find

01:47:22.300 myself concerned. Now, it also appears that if you've been on finasteride for a long period of

01:47:28.740 time and you're not experiencing any of these side effects, you're probably fine. So I also don't

01:47:33.360 want this to turn into like someone listening to this who's been taking Propecia for 10 years,

01:47:38.740 who's never had an issue going like, oh my God, I got to stop this stuff. The literature would suggest,

01:47:43.400 and there is a pretty good review we'll link to, that if you're going to have these side effects,

01:47:48.380 you're going to have them in about six months. Yeah. In general, when it comes to hair loss,

01:47:52.380 the problem is oftentimes the treatments, if it doesn't actually interact with the AR or inhibit the

01:47:59.920 potential for stimulation or agonizing the AR through DHT reduction or even systemic antiandrogens,

01:48:08.240 it's not that I would recommend that, you are essentially just putting a Band-Aid on the issue.

01:48:12.040 So if you stimulate growth with minoxidil, you are still not preventing further loss. If you get a

01:48:16.980 transplant, you are putting hair on your head, but you're not preventing further loss of your actual

01:48:22.320 existing hair. So oftentimes it's like you're almost trying to row against a current or something,

01:48:29.460 and it's like you are continuously getting pushed back and eventually you're going to get to a point

01:48:33.100 where you have so few visible hair follicles even left that are healthy that it doesn't matter how

01:48:39.140 much you've been on minoxidil or what have you. And oral minoxidil, it's definitely effective,

01:48:44.720 but I think it should be reserved for people who have weak response topically, because topical seems

01:48:49.680 to be far more tolerated side effect wise and a lot more predictable with like hordes of literature and

01:48:56.500 great outcomes. And there are ways to enhance that and also turn yourself from a non-responder to a

01:49:01.280 responder, which we can get into. But finasteride in itself, it seems to be like, I don't want to

01:49:08.320 try and come out and say I'm a proponent necessarily. I try to take a balanced approach to

01:49:12.480 it, but the prevalence of side effects is not nothing, but it's quite overblown by the opposite

01:49:18.520 camp that wants to assert that why would you ever inhibit a hormone that is the primary androgen you

01:49:26.500 rely on. But similarly, why would you inhibit, I don't know, ApoB or something? Like there is a

01:49:31.980 clear outcome whereby there's benefit. And when there is DHT in somebody who's prone to hair loss,

01:49:37.980 it's hard to overlook that this is the primary thing dictating if you go bald or not. And some

01:49:43.800 people that hair loss, some people care a lot more than others, obviously.

01:49:47.640 So I do think there's a difference because I think ApoB serves no benefit.

01:49:51.480 If someone created an antisense oligonucleotide that knocked out ApoB,

01:49:56.200 all it would do is guarantee we don't have heart disease in our species. We would still be able to

01:50:00.280 use all the HDLs in the world for cholesterol transport, which we currently use LDL for.

01:50:06.100 But I think to take your analogy a step further, what you're basically saying is if a person cares

01:50:10.320 as much about hair loss as they do about heart disease, and by that logic, DHT is causal.

01:50:16.400 Which sounds absurd, but let's just run with it.

01:50:18.520 I would posit that there are lots of people who care more about hair loss than heart disease.

01:50:22.380 The psychological stress for some people is significant and should not be overlooked by

01:50:28.500 the silliness of, oh, just lose it and just shave it, bro. It's not a big deal. There's tons of

01:50:33.120 successful people who are bald. It's like, yeah, sure. Although I think there's a statistic that

01:50:38.000 no bald person has ever been president of the United States. So there you go. So there's a couple

01:50:43.140 of occupations you got to take off the list. Now you mentioned when you were going through your

01:50:48.140 insane anabolic steroid use, you at a very young age, if you're in your early 20s, we're already

01:50:52.900 starting to lose your hair. So how did you reverse that?

01:50:56.080 Part of it was just dropping the dose significantly and eventually just going down to replacement therapy.

01:51:02.680 But it was the introduction of 5-alpha reductase inhibitor, initially finasteride.

01:51:07.920 And then thereafter, I introduced a, and I wouldn't necessarily recommend this blindly,

01:51:13.380 but a topical antiandrogen that's experimental, never actually received FDA approval.

01:51:17.880 There are some that are in the FDA pipelines right now that actually look promising and have

01:51:23.520 safety data behind them and whatnot that I'm watching closely and hope one comes to fruition

01:51:28.300 because these are essentially compounds that compete for the androgen receptor locally,

01:51:33.540 but do not have systemic antiandrogenic activity. So you can maintain all systemic androgen levels

01:51:40.020 with just localized activity in the scalp essentially. So I use a topical antiandrogen coupled

01:51:45.700 with a 5-alpha reductase inhibitor. Those were the main two needle movers for me. I also use a

01:51:50.160 ketoconazole shampoo, but it's like a very mild antiandrogen. It's mostly just a good shampoo,

01:51:54.680 but those two things and decreasing the burden of androgen significantly were fairly effective at

01:52:01.720 getting me not to baseline. Meaning you never regain? No, no, no. And that's the thing with

01:52:06.320 hair. That's the sketchy thing is even if you're trying to decide, oh, you know, maybe I should

01:52:10.320 treat it. Maybe I shouldn't. I'll think about it for a bit. I'll see if it gets worse. The visual

01:52:14.220 representation of loss is typically not apparent until you've lost a lot of ground because you could

01:52:20.160 pull a handful of hair out of your head and see no difference whatsoever. Once you finally notice

01:52:25.860 diffuse thinning or recession, it's not something you've been looking for carefully because you've never

01:52:30.820 dealt with it. So oftentimes, once you actually notice it, picture or in heavy downlining or

01:52:35.340 something, you've already lost 20, 30% plus of your hair. And there's no guarantee that's coming back.

01:52:42.460 So did you regain hair that you had lost with this protocol or just completely stop some regrowth,

01:52:49.640 but expecting yourself to get back to baseline where you had, you know, like 17 year old immaculate

01:52:56.300 perfect hair. If you've been exposed to androgens at a level where you're visibly noticing it,

01:53:02.440 it's relatively unlikely. So that's not to say it's impossible. Like if I took minoxidil as well

01:53:08.260 as microneedle and did a bunch of other stuff, I could probably get a decent amount of the way

01:53:12.100 there. But the longer you wait and let hair follicles miniaturize, the more permanency you are

01:53:18.360 risking. So making back ground is way harder than preventing yourself from losing in the first

01:53:26.720 place. It's almost like maybe analogous to building muscle when you're younger. So then you don't have

01:53:32.280 to try and build it in old age when you have like anabolic resistance or what have you.

01:53:36.200 Let's make sure we give people the names of these compounds you're using.

01:53:39.040 So finasteride is like the main primary five alpha.

01:53:42.420 And you take one milligram of that daily?

01:53:44.320 I take dutasteride now.

01:53:45.580 So you take 0.5 milligrams. Is that 0.5?

01:53:48.580 Yeah, I take 0.5 a day. So that is a soft gel that essentially wipes out systemic DHT.

01:53:55.020 And your DHT level is?

01:53:56.420 It's like worse than a teenage girl. Yeah, it's terrible. But I smell okay. At least now.

01:54:00.420 I think one of the guys with the highest IQs on the planet has been on dutasteride for decades,

01:54:04.760 if that's notable for anyone.

01:54:06.840 Okay, so then what else are you taking besides dutasteride?

01:54:09.160 Dutasteride right now is the only thing I take more out of convenience.

01:54:12.420 Because a topical application schedule can be quite burdensome.

01:54:16.820 But when you were doing that big salvage effort in your early 20s, what was the rest of the stack?

01:54:21.700 Oh, it was topical application of something called RU-58841.

01:54:26.000 It was like an experimental antiandrogen.

01:54:28.860 So I don't necessarily recommend people use RU-58841

01:54:33.260 when there are actually alternatives with human safety data on the horizon.

01:54:38.180 With that said, it's also hard to tell me, however many years ago, that, wait,

01:54:43.960 because you only have so much time, right?

01:54:46.740 So I'm not going to sit around.

01:54:48.280 And what are these things that are on the, that have more safety data coming down the pipeline?

01:54:52.440 This company called Kintor has a compound called pyroludamide.

01:54:56.460 And it seems to be pretty well tolerated.

01:54:58.700 And comparable outcomes of hair count increase to dutasteride, if I recall off the top of my head,

01:55:07.480 which is pretty substantial, given that there are very few things that produce outcomes that are even make it worth taking another drug.

01:55:15.100 Right now, the most effective things are going to be 5-alpha reductase inhibitors and minoxidil.

01:55:19.360 On top of that, everything else is like little sprinkles on the cake, essentially.

01:55:24.940 Some people might get better benefit from PRP than another person or what have you.

01:55:28.860 But in general, the main meat and potatoes are going to be minoxidil,

01:55:32.280 potentially microneedling with minoxidil if you're not a good responder

01:55:35.120 or have low sulfotransferase enzyme activity in the scalp

01:55:38.300 and the inhibition of free androgenic signaling in the scalp.

01:55:42.640 Whether you do that through 5-alpha reductase inhibition or antiandrogen activity locally,

01:55:48.220 that's kind of up to you.

01:55:49.820 Or some people are going to couple both of them like I did.

01:55:52.220 But those are the main needle movers, ultimately.

01:55:54.880 And some people go super hardcore.

01:55:56.680 And the most crazy hair loss reversals you will see are always in men transitioning to women

01:56:01.740 who use female hormone therapy.

01:56:03.480 I would never recommend anyone do that, but it's a pretty interesting data set to pull from.

01:56:08.880 So estrogen and progesterone would promote hair growth.

01:56:11.380 I mean, we do see it in women, actually, during HRT.

01:56:13.840 Especially progesterone can really thicken hair.

01:56:16.520 But this is in women.

01:56:17.300 I mean, I have no idea.

01:56:18.560 Yeah, yeah, yeah.

01:56:19.040 I'm more talking about antiandrogen plus estrogen.

01:56:21.580 So somebody transitioning would typically use a cyproterone acetate,

01:56:26.140 bicalutamide, something of that nature, plus exogenous E2 or a synthetic estrogen.

01:56:31.420 And the first two, which I'm not even familiar with,

01:56:33.600 are drugs that just block the androgen binding to the androgen receptor?

01:56:38.660 Cyproterone is a very potently anti-genadotropic, I believe.

01:56:43.400 So it's like it will inhibit you from producing GNRH.

01:56:47.980 It's effectively a chemical castration.

01:56:49.460 That's like a steroidal antiandrogen.

01:56:51.360 And then there's a non-steroidal one.

01:56:53.020 And yet it's effectively chemical castration.

01:56:55.080 The non-steroidal variant, bicalutamide, seems to be a bit better tolerated.

01:57:00.180 It's not as liver toxic.

01:57:01.320 And it will actually raise your hormone levels on paper.

01:57:04.040 Your test levels go up.

01:57:05.140 It's just you can't actually interact with the receptor because it's occupied by bicalutamide.

01:57:09.040 So it's like a silent androgen receptor antagonist.

01:57:12.580 And those are like extreme options.

01:57:14.840 They're like essentially irrelevant for anyone watching.

01:57:17.500 So maybe I shouldn't have brought it up.

01:57:18.720 Yeah, yeah.

01:57:19.360 Let's go back to kind of TRT then.

01:57:20.960 So we've kind of established what's going on.

01:57:23.660 When are you starting?

01:57:25.460 Yeah, we're going to talk about that.

01:57:26.960 I'm actually doing my blood again next week.

01:57:28.700 So we'll see how far my levels have continued to fall.

01:57:31.660 So I was going to actually talk right about that, right?

01:57:33.400 Because let's talk about, quote unquote, what's normal?

01:57:35.620 I've never found a compelling table for normal levels of free testosterone that are stratified

01:57:43.240 by age.

01:57:44.080 You can find these data quite easily for total testosterone level.

01:57:48.320 But I've only really seen data for broad chunks, prepubescent, pubescent, post pubescent.

01:57:57.740 Here are the percentile ranks for free testosterone, whereas for total, I can show you by decade

01:58:04.420 or something like that.

01:58:05.740 I guess it's worth putting some context to this, right?

01:58:07.720 So if a person's total testosterone is 800 nanograms per deciliter, most of that is bound.

01:58:16.520 And sex hormone binding globulin and albumin probably do the lion's share of binding.

01:58:20.980 And if a guy's got 2% of that as free or unbound, that would translate to 16 nanograms per deciliter

01:58:32.220 of free testosterone.

01:58:34.340 That's estimated, by the way.

01:58:36.060 It's not calculated.

01:58:36.960 It's very important.

01:58:37.420 People understand this.

01:58:38.040 When you go to the lab and you get a test done, they're measuring testosterone.

01:58:42.800 That's direct measurement.

01:58:43.620 By the way, we should talk about ELISA versus LC-MS, but they're estimating the free based

01:58:50.040 on the measurement of the binding proteins.

01:58:52.620 So that's introduction of potential error number one.

01:58:55.420 So you don't really know how much free testosterone you have.

01:58:58.100 The other thing is you don't know how many androgen receptors you have.

01:59:00.500 So you really don't have any idea whatever amount of testosterone you have is saturating

01:59:05.060 your androgen receptors or not.

01:59:06.580 Are you playing below your weight or above your weight?

01:59:09.060 What do we know about the amount of total testosterone over time in a guy's life?

01:59:16.920 I know that after it peaks, you will have a steady, as opposed to women, where you see

01:59:23.360 a plummet after menopause.

01:59:25.680 For men, it's more gradual.

01:59:27.320 And you can expect, I believe it's about 1% drop in total tests per year with an approximate

01:59:33.700 2% to 3% drop in free each year as well.

01:59:38.240 So at the same time, you would have 1% total T drop, 2% to 3% free.

01:59:42.520 Depends on age, lifestyle, but in general, like post age 30, 35, you can kind of expect

01:59:48.920 a little bit of a decline to start.

01:59:51.000 But that's not to say I haven't seen 70-year-olds with like 1,000 total T sometimes.

01:59:55.640 So you can certainly retain high-level production.

01:59:59.520 I don't want anyone to think, oh, now that I'm 45, my levels have probably dropped 20 plus

02:00:04.620 percent at this point.

02:00:05.560 I should probably get on TRT.

02:00:06.820 It might not be the case.

02:00:08.580 So those are kind of general numbers of decline that you can expect based on literature.

02:00:14.800 But I think it's reasonable to assume that a lot of people can retain good production as

02:00:20.220 well.

02:00:20.520 It's just a matter of how well do you produce gonadotropins?

02:00:24.580 How well do you respond to them at your testes?

02:00:26.260 Because there is some level of function that declines with age 2, even in response to the

02:00:31.280 gonadotropins.

02:00:32.060 And that's an expected outcome, unfortunately.

02:00:35.000 But that's kind of where you get into the nuance of is TRT justifiable for this person

02:00:38.680 based on pituitary output, lifestyle, diet, nutrient intake, sleep hygiene, is there sleep

02:00:44.760 apnea, et cetera?

02:00:46.060 And then also actual testicular response.

02:00:48.400 Because there's an argument to be made if you have very good testicle response, like

02:00:52.280 why would you ever be on exogenous TRT too?

02:00:54.480 Because you could top out your natural signal even.

02:00:57.100 Is there an advantage to that?

02:00:59.040 Before we get to that, let's talk about the rationale for TRT.

02:01:02.720 So what do you think is the most compelling case for it?

02:01:05.740 And how often are people expanding that use case?

02:01:09.740 I think the most justified use for it is people who have primary hypogonadism.

02:01:17.140 So that is when you have gonadotropins going to your testes, but you're just not responding

02:01:22.320 to them.

02:01:22.640 So LH and FSH are, you will see these as high in your blood work, but your total T is still

02:01:27.680 bottomed out.

02:01:28.500 Like that could be somebody who is, you should probably check, do you have a varicocele?

02:01:32.280 Do an ultrasound in your testes?

02:01:33.460 See where things are at structurally, functionally, et cetera, before you make any rash decisions.

02:01:38.360 Because there could be something you're overlooking.

02:01:41.340 And I do think a lot of people do overlook certain structural abnormalities that may otherwise

02:01:45.500 be rectifiable.

02:01:47.060 Kind of depends.

02:01:47.660 But typically, testicular failure in response to adequate signaling would be the obvious

02:01:53.580 more no-brainer versus if you had low LH and FSH, maybe your testicles are fine.

02:01:59.980 So why are you hapazerally getting on testosterone when maybe it's a lifestyle thing?

02:02:06.120 And so typically when we see that pattern, the second pattern you've described, which is low

02:02:10.760 testosterone, but in the setting of low LH and FSH, the most obvious things that usually

02:02:16.520 show up there are poor sleep, basically high glucocorticoids, which can also suppress the

02:02:22.340 pituitary.

02:02:23.380 And you'd measure the glucocorticoids through like a Dutch test?

02:02:26.560 Yeah, usually urine actually.

02:02:27.880 We used to use saliva long ago, but yeah, so using a Dutch test.

02:02:31.400 Interestingly, those are not the easiest things to fix because people have to change behaviors,

02:02:35.760 which is a lot harder than taking a medication.

02:02:38.460 So let's just say we go down the path of we believe that TRT is the right thing to do and

02:02:46.100 we believe that it's primary hypogonadism.

02:02:49.660 What do we know about the dose response of testosterone?

02:02:53.320 And do we think that it makes sense to use fixed dosing and increased dosing or target

02:02:59.060 to certain levels?

02:03:00.320 Because again, most of the studies, and we might talk about the TRAVERSE trial, they kind

02:03:04.400 of just use fixed dosing, which is at least for me, one of the criticisms of that approach,

02:03:08.600 by the way, is especially when you're using something topical and you have variable absorption.

02:03:12.480 But what do we know about this?

02:03:14.100 I think in general, if you're going to be treating with exogenous testosterone, an accepted

02:03:18.800 entry-level dose that is on average safe and well-tolerated and will get you to a reasonable

02:03:25.560 total T that provides symptom relief for the majority of people is I can't see a more logical

02:03:32.680 start point than, for example, like 100 to 120 migs a week or something of that nature.

02:03:37.720 And just seeing what happens to the guy's total T, free T, this could also be variable based

02:03:43.660 on does he have a super high SHBG?

02:03:46.940 Should we be evaluating that?

02:03:48.200 Because maybe he just has a low free T instead of his total is fine.

02:03:51.260 In that case, you could have brutal symptoms, but your production is still good.

02:03:55.440 It's just being bound up severely.

02:03:57.240 And why is that the case?

02:03:58.140 Do you have like severe liver issues or something?

02:04:00.620 So after you flesh all that out and you determine the guy needs T, I would imagine a reasonable

02:04:06.040 starting place is typically like 80 to 120 a week and then go from there.

02:04:09.880 See how you respond to that.

02:04:11.500 And any advantage to dosing it once weekly, taking that dose and dividing it by two and

02:04:17.600 doing it twice a week, taking that dose and dividing it by seven and doing it every day?

02:04:22.040 I don't necessarily know that, like, for example, when patients come to you, I'm sure they're

02:04:25.980 looking for the highest level of optimization, hence why they're with you.

02:04:30.080 So maybe it's more reasonable to expect them to pin more frequently.

02:04:33.720 I would say pin, I mean inject.

02:04:35.640 But there is a half-life with the drug, depending on the ester chosen, typically testosterone

02:04:41.180 cipionate will be prescribed, at least in the US, that's the most prescribed one, which

02:04:46.120 is a half-life of 10 days, if I recall off the top of my head.

02:04:48.900 It depends on the person, of course, where it's injected, blah, blah, blah.

02:04:51.920 But that half-life, you could extrapolate out from that, okay, it's going to take 50

02:04:58.140 days to achieve steady state serum concentrations in the blood.

02:05:01.800 And that's going to look on like a steroid plotter.

02:05:04.140 You could check online and see this kind of like spiking until all of a sudden there is

02:05:08.960 the same amount of dropping of the drug clearing out of your system.

02:05:12.180 You're getting an equal amount of spike back up.

02:05:14.660 Like there is no accumulation of drug burden after you've achieved steady state serum

02:05:19.620 concentrations.

02:05:21.060 So the advantage to injecting more frequently, and this is going to be determined largely by

02:05:27.380 patient adherence more than anything, because some people simply refuse to inject even more

02:05:33.020 than I've seen some insane stuff where people will let themselves drop to literally hypogonadal

02:05:39.660 territory.

02:05:40.220 And then remember, based on their dick not working, I'm going to, okay, now I take my

02:05:45.380 test.

02:05:45.980 But in general, once a week is like bare minimum, I would say, but that's certainly not optimal.

02:05:52.520 And I would say that two times a week, at least for somebody seeking good quality oversight,

02:05:59.940 you know, preventative medicine, whatever, if they're coming to you or to somebody who believes

02:06:03.200 in the same things you do twice a week, I think is kind of minimum for decent, steady

02:06:08.100 hormone concentrations.

02:06:10.320 We've sort of arrived at the same conclusion that that's the sweet spot.

02:06:13.660 We do have a couple patients who do daily injections.

02:06:18.000 And interestingly, in these patients, we see much less for the same dose of testosterone.

02:06:23.360 So you take 15 milligrams injected a day, which is actually very difficult to do.

02:06:28.600 You have to be very thoughtful about what kind of needles you're using to actually get such

02:06:31.660 a small volume in, but they will have much less FSH-LH suppression, which suggests to

02:06:38.040 me that the higher the peak, the more the FSH-LH suppression.

02:06:43.000 I don't know that there's anything physiologically relevant to that.

02:06:45.680 The studies, when you look at trough level, T levels, and when I say trough, I mean like

02:06:50.840 the lowest point of hormone concentrations after an injection.

02:06:54.080 Oftentimes, these studies assessing dose response will look a week after your injection.

02:06:59.160 So what you see in the literature isn't necessarily reflective of what's going to be in patients

02:07:04.220 trying to optimize anyways.

02:07:05.600 But what I see personally and in Merrick Health and through all my blood work that I've seen

02:07:11.040 over the years, etc., the more frequent you get, there's a diminishing returns for sure,

02:07:17.020 but you can lower the aromatization spike and 5-alpha reduction by going more frequent.

02:07:24.280 So if you have a bolus administration of, I don't know, 150 milligrams once a week, you

02:07:30.220 are literally spiking your T into superphysiological territory acutely, and concurrently, you are getting

02:07:37.020 superphysiologic conversion to estradiol, DHT.

02:07:40.880 You also have a very, very aggressive spike in free androgenic signaling, which can crank your

02:07:46.320 sympathetic nervous system up, impair your sleep quality.

02:07:49.260 There's so many consequences.

02:07:50.920 And you'll see more hematopoiesis.

02:07:53.480 So when I had Mo Cara on here, he was talking about Netesto, which is the nasal formulation,

02:07:59.360 which has such a short half-life that it's actually a TID dosing schedule.

02:08:04.140 So it's 7 milligrams of testosterone injected intranasally three times a day.

02:08:09.880 I want to see somebody take that for more than a year and still tell me it's cool and fun to take.

02:08:13.860 So if you end up doing that for TRT, you've got to keep me posted.

02:08:16.420 I probably will not.

02:08:17.520 But two interesting points with Netesto.

02:08:20.020 The first is they don't have the hematopoiesis.

02:08:22.740 So these are not people who are making too many red blood cells that you have to actually be

02:08:27.140 careful of and have to go and get them therapeutically phlebotomized to take blood off them as their

02:08:32.660 hematocrit gets over 50.

02:08:34.420 Secondly, it's a FDA formulation that women can use because if a guy is taking 7 milligrams in

02:08:42.860 each nostril three times a day, clearly a woman could take one of those every other day.

02:08:47.960 And by the way, it's sort of an on-demand libido tool for women in particular.

02:08:52.580 So there are lots of interesting things around that.

02:08:55.200 Also, they're doing a clinical study and we're sort of observing what they're doing where women

02:09:00.880 are using intravaginal use, one application of that intravaginally before sex to enhance

02:09:06.800 orgasmic function.

02:09:08.240 It's always desirable to have an FDA-formulated product when you can kind of avoid the dark

02:09:12.400 side of compounding, is my view.

02:09:15.340 I think the best way to conceptualize for the listener to why this frequent protocol or getting

02:09:21.680 a more stable level, why does it result in a lower side effect burden?

02:09:25.060 The closest you can replicate natural function, the more you will replicate natural side effect

02:09:32.260 profiles, which should be nothing if you are physiologic.

02:09:36.020 So with Natesta, which is like in and out acutely like so fast, you are not getting this huge

02:09:42.500 spike to like 1,500, 2,000 nanogram per deciliter total T.

02:09:46.400 There is no situation ever in which your testes would just blast you once a week with a hammer

02:09:52.380 of test and all of the associated metabolites and back end and consequences of that, you would have

02:09:58.260 little pulsations over the diurnal rhythm.

02:10:00.960 And this is why you would test your blood as a natural in the morning when your testosterone is

02:10:04.720 spiking and it's going to ebb and flow over the day.

02:10:07.260 Your test level in the morning could be 300 nanograms per deciliter higher than later in the day,

02:10:12.340 like it fluctuates.

02:10:13.280 So to expect that it's reasonable to jam yourself with an absurd amount of tests in one go and

02:10:21.980 then hang on that as it declines at your body and then crank it to the stratosphere again

02:10:25.880 once a week, it's just not representative of the physiologic state whatsoever.

02:10:30.460 So the more you can replicate that diurnal rhythm through the synthetic administration route,

02:10:36.040 the closer you're going to get to a lower side effect burden.

02:10:39.300 Like I've seen some guys that get gynecomastia from TRT dosages, go to ED everyday dosing

02:10:45.500 and get off their AI.

02:10:48.140 Just to translate that into English, you've seen guys who can take a weekly dose of testosterone

02:10:53.840 and in doing so, they make so much estrogen that they have to take an aromatase inhibitor

02:10:59.460 to prevent them from getting breast tissue gynecomastia.

02:11:02.600 And if they take that same dose and divide it daily, they can come off their aromatase inhibitor

02:11:07.560 altogether.

02:11:08.140 Yeah, and some people it's problematic because they will give feedback to their doctor or

02:11:13.540 just give a judgment to what hormone therapy was like for them based on what is maybe not

02:11:21.540 the right dose, but also just not even close to an ideal dosing regimen and injection frequency.

02:11:28.080 When I got back into the practice of medicine and was learning about HRT, I couldn't find doctors

02:11:34.160 who weren't prescribing anything different than every two weeks.

02:11:38.680 That was the standard.

02:11:40.360 Have you seen the European sustenon?

02:11:42.600 No, I have not.

02:11:43.400 But the standard dose was 200 milligrams every two weeks.

02:11:47.800 I remember going through Llewellyn's Pharmacology and looking at the pharmacokinetics and being

02:11:52.100 like, this is an awful idea.

02:11:53.560 Any difference clinically between cipionate and enanthate?

02:11:58.520 Obviously, one of the advantages of enanthate is there's a commercial product called Zyested

02:12:05.880 for people who are squeamish about injecting that comes in a preloaded pen.

02:12:10.620 So we have some patients who just don't like the idea of having to draw up a syringe and

02:12:16.760 they just kind of want something that's a little more turnkey.

02:12:18.880 So Zyested, which is a slightly different form of testosterone, but clinically, I sort

02:12:24.400 of remember at one point there was some difference that might be age specific, but I don't recall

02:12:28.560 now.

02:12:29.420 Enanthate is often thought to be a long ester, which it is relative to like propionate or

02:12:35.900 phenopropionate, but it's kind of like an in-between of cipionate and propionate.

02:12:40.960 It's like a half-life of, could be as short as four and a half to five days, I believe, off

02:12:46.460 the top of my head, whereas cipionate could be twice as long in some people.

02:12:49.720 So it depends on your individual metabolism of the drug often.

02:12:55.680 And also if you're pinning sub-Q or IM, like you could bleed out the effect more.

02:13:00.220 So I would say if you're injecting frequently enough, it's essentially irrelevant.

02:13:05.600 The Zyested protocol from the FDA is once weekly.

02:13:09.560 We still recommend people do it twice a week.

02:13:11.660 Just use a lower dose.

02:13:12.660 The difference of what you're supposed to take versus using it, like obviously frequent

02:13:16.440 frequency is of a lesser concern than you walking around with no test.

02:13:20.800 So if it's the difference between a guy taking it versus not, okay, take your once a week if

02:13:25.280 that's what it's going to take.

02:13:26.560 Is the preloaded dose, can you modulate?

02:13:28.740 You can't meter it.

02:13:29.620 That's what's so annoying about it.

02:13:31.720 It's annoying with the GLPs too.

02:13:33.140 Yeah, it's such a racket.

02:13:34.860 And I always tell patients, I'm like, look, if you're completely cost insensitive, I guess

02:13:39.380 fine.

02:13:39.900 But otherwise, getting cipionate in a jar is a fraction of the cost if you're just willing

02:13:45.240 to be the guy that meters it out.

02:13:47.180 But the enanthate, I think, only comes in three loaded doses of Zyested.

02:13:51.660 You also have less wiggle room if you're not happy with the output.

02:13:54.800 I would assert with near certainty that you are not optimizing your hormone status if you

02:14:00.120 are, I'm going to say optimize.

02:14:01.160 I mean, just dialing in the stability of it and the side effect profile and potentially

02:14:06.000 quality of life as much as you could if you did a more frequent schedule, especially with

02:14:10.900 enanthate.

02:14:11.680 Meaning the more frequent you're giving it, the better.

02:14:13.900 Yeah.

02:14:14.480 I think the diminished returns are, there's a significant drop off when you go from every

02:14:19.280 other day to every day, but one week to twice a week, I'd say there's a pretty dramatic

02:14:24.140 difference that's worthwhile.

02:14:25.480 Let's talk about the difference between sub-Q and IM.

02:14:28.120 IM, I have always advised patients to do sub-Q for the belief that it has, as you point out,

02:14:34.960 kind of you bleed out the effect a little bit longer.

02:14:37.160 I have to be honest, I don't think I've seen data to support that.

02:14:41.240 I have seen, and I think this is an extrapolation, but I believe it to be true, is when you look

02:14:47.800 at sub-Q dosing, you'll notice the total T levels are higher and then people take away

02:14:52.540 from that, oh, sub-Q is like, you get more out of your test.

02:14:56.920 But the reality is, is when they measure total test levels, it's often a week after

02:15:01.100 your shot.

02:15:01.680 I see.

02:15:01.820 So it just lasts longer.

02:15:02.980 So I think you are almost giving yourself a sustained release through administering into

02:15:09.760 the fat tissue rather than intramuscular, which is more readily absorbed, quicker,

02:15:14.240 blood flow, et cetera.

02:15:15.600 Just like if you did like an IV administration, it would be in your blood immediately.

02:15:19.280 Not that you would ever do that, of course, but the difference in pharmacokinetic profile

02:15:22.440 of IV to IM to sub-Q, like you can change the same drug dramatically in onset of action

02:15:27.260 through that.

02:15:28.360 You think that sub-Q is probably a better administration?

02:15:31.320 I think once you get to every other day dosing, it's almost...

02:15:34.040 Doesn't almost matter.

02:15:35.080 Yeah.

02:15:35.380 But I think especially for people who are doing, and again, it depends on the amount,

02:15:39.620 because if you're doing once a week, is that going to be too much of a bolus to sit

02:15:43.940 in stomach fat?

02:15:45.080 Depends on the person.

02:15:45.880 But I would say, especially for infrequent, you'd be better sub-Q, ideally, if the volume

02:15:52.200 of oil isn't significant enough that it's creating lumps and stuff.

02:15:55.740 Let's talk about aromatase inhibitors.

02:15:58.460 There was a study that I don't think gets enough attention.

02:16:02.520 I think it was 2014, might've been 2013 in the New England Journal of Medicine, that looked

02:16:07.140 at 10 groups.

02:16:08.900 So it took a group of men, chemically castrated them, divided them into two first.

02:16:14.440 Half of them get an aromatase inhibitor, half of them don't.

02:16:17.700 And then within each of those groups, there were four escalating doses of testosterone

02:16:21.380 plus a placebo.

02:16:23.120 So what you have are five groups times two, one with estrogen inhibition, one without,

02:16:31.280 and five escalating doses of testosterone.

02:16:33.640 So you end up with 10 outputs, which are ranging from low to high testosterone with high and

02:16:39.440 low estrogen.

02:16:40.080 And the outputs were body composition, mood, libido, a whole bunch of, you know, erectile

02:16:46.140 function, all these things.

02:16:47.100 The punchline was you were better off with more estrogen and more testosterone.

02:16:53.680 So the best outcome group was the high T, high E group.

02:16:57.780 Now, the high E group wasn't that high.

02:16:59.440 I'd have to go back and look how high the E was.

02:17:01.900 I think it was probably in the ballpark of 50 picograms per milliliter.

02:17:05.300 But this was an important study because I think it suggested that estrogen is not the

02:17:09.300 bad guy, right?

02:17:09.980 I think there was probably a lot of people out there thinking, if you're taking testosterone,

02:17:14.840 you need to be taking an aromatase inhibitor.

02:17:16.960 And while that might be true at some doses, I guess let's start with normal physiology.

02:17:22.020 And then I'm kind of curious to hear what the bodybuilders are doing.

02:17:24.300 Back in the day, we thought that regardless of the dose of androgen, you should lower your

02:17:31.740 estradiol to 20 to 30 because it's in the middle of the reference range-ish for a man.

02:17:37.300 And that's where you get the best.

02:17:39.280 There was no thought of balance.

02:17:41.360 It was kind of like, this is a bad hormone to have above the reference range, even though

02:17:45.520 our androgens are literally like 10x the reference range.

02:17:49.380 What were your testosterone levels when you were back in the heyday?

02:17:52.420 I never got LCMS testing when I used my highest dosages, so it would get capped at like 1,500

02:17:57.480 or something, but it was in the thousands for sure.

02:18:01.300 But yeah, with estradiol, there is, and I've seen these studies too, where it shows neurotoxicity

02:18:07.160 when you add it in versus you take it out and there's a protective effect.

02:18:11.940 So neurotoxic outcomes are higher when aromatase is inhibited and less neurotoxicity when it's

02:18:17.700 taken out on the exact same input of testosterone.

02:18:20.580 I think it's pretty clear at this point that there is a role of estrogen in the body,

02:18:26.260 not just from a cardiovascular standpoint, but from a neurological standpoint too.

02:18:30.360 There's like serotonergic activity.

02:18:32.100 There is so many things that regulate mood as well.

02:18:35.860 I think even like temperature control too is going to be variable based on that.

02:18:40.000 It's kind of ties into the post-menopausal stuff.

02:18:42.600 But for men, it is certainly important and to crush it arbitrarily based on a reference

02:18:48.160 range is kind of like old bro lore.

02:18:51.060 And I think most people, even in the bodybuilding space, are pretty aware now that estrogen is

02:18:55.740 important for cardio and neuroprotection.

02:18:58.160 And I think another thing that's really important for is bone health.

02:19:00.700 And by the way, you asked me earlier about when am I ready to start my TRT protocol.

02:19:04.520 I think I'm more troubled by the fact that my estradiol is so low because my T is routinely

02:19:10.760 between about 300 and 400 nanograms per deciliter.

02:19:14.140 And my estradiol is never above 25 picograms per milliliter, which is normal.

02:19:19.740 That would be normal for such a low T.

02:19:22.660 But to me, one of the big advantages of having a T of 1,000 would be that I'd hopefully have

02:19:28.540 an estradiol of 40.

02:19:29.620 Not to derail, but 5-alpha reductase inhibition, when you don't have conversion to DHT, you

02:19:37.340 branch off more T to estradiol and estradiol will reliably increase by 15 to 22% on finasteride

02:19:46.140 or dutasteride.

02:19:47.280 Some people who are very low aromatizers and have like a hyperandrogenic state, those people,

02:19:54.520 that's where unique individual variability comes into the consideration for drug implementation.

02:19:59.620 So a guy like that, even for actual quality of life, sometimes that like modulation.

02:20:05.600 Interesting.

02:20:06.300 Yeah.

02:20:06.820 I'm actually going to do both tests side by side next week where I'll do enzyme-based

02:20:12.120 test plus LC-MS for DHT, testosterone, and estradiol.

02:20:16.580 So I'll probably have a better sense of what they look like because we can talk about how

02:20:19.500 often enzyme-based testing gets estradiol wrong.

02:20:23.200 No, yeah.

02:20:23.900 I've seen some brutal overestimations using ECLIA when it was like single digit.

02:20:28.700 But yeah, we've seen guys come back with estradiol levels of, we're using like say Boston

02:20:33.840 Heart, which is using an enzyme-based system.

02:20:36.620 And they'll come back and they'll have an estradiol of 100.

02:20:38.960 And we're like, this can't be right.

02:20:40.440 And then you send them to LabCorp and specify LC-MS.

02:20:43.560 They're at 31.

02:20:45.060 Yeah.

02:20:45.440 And this is especially important, I think, in especially hypogonadal men who have relatively

02:20:51.180 low estrogen to begin with.

02:20:52.860 Like actually identifying where it stands is pretty important for sure.

02:20:56.140 Okay, let's talk a little bit about the other hormones.

02:21:01.520 So for most of the medical needs, is there any reason to be considering a hormone beyond

02:21:09.000 testosterone for male sex hormone replacement?

02:21:13.280 I think it depends on the person for sure.

02:21:16.820 That's like such a general answer.

02:21:18.880 Well, let's say this.

02:21:19.840 If you're just talking about health benefits and not performance benefits, we're going

02:21:24.540 to talk, I'm sure, about lots of others.

02:21:27.420 And I'll give you one example.

02:21:28.620 So way back, I used to be a little bit more liberal and creative.

02:21:32.560 So one of the things I used to do was if guys had normal testosterone, the example used a

02:21:37.960 minute ago, a guy who's got a testosterone of a thousand nanograms per deciliter, but his

02:21:42.780 SHBG is a hundred for a guy is very high and his free tea is like eight nanograms per deciliter.

02:21:50.600 So he's like eight tenths of a percent free instead of say two.

02:21:55.040 You could use a very, very low dose of auxandrolone and you could eradicate his SHBG because it has

02:22:03.660 such a high binding affinity for auxandrolone.

02:22:07.100 And of course, it also will inhibit, if you give too much, you'll inhibit testosterone production.

02:22:11.300 So there's a very fine balance where you might give him like 10 milligrams twice a week or three

02:22:17.100 times a week of auxandrolone.

02:22:18.680 You knock that SHBG down and you double his free testosterone.

02:22:22.300 You haven't given him any testosterone.

02:22:24.260 I don't do that sort of thing anymore.

02:22:25.620 I feel like it's just not worth the hassle, truthfully.

02:22:28.220 That's one example of an area where you can manipulate another part of the system without

02:22:32.620 having to go beyond that.

02:22:33.760 But if you maybe take examples like that out, if you're just talking about the use of these

02:22:38.760 other steroids, what's the case?

02:22:41.220 In some individuals, adrenal hormone replacement sometimes may be justified, but it's going to

02:22:48.260 be based on blood work.

02:22:50.660 When you say adrenal, do you mean DHEA?

02:22:52.400 Yeah.

02:22:52.760 So like DHEA, if you have like a bottom DHEA-S, maybe you would look to a DHEA replacement.

02:22:58.080 If you have low pregnenolone, that might make sense, but it's more for like neurological,

02:23:01.640 cognitive, perceived quality of life effects, not necessarily because there's any evidence

02:23:06.800 to support that it's necessary.

02:23:08.600 In general, the main needle mover is going to be your test and how much of 5-alpha reduces

02:23:12.200 or aromatizes into the two metabolites.

02:23:15.020 And from there, you would never manually use more DHT.

02:23:19.100 You would never, almost never probably manually use estradiol on top, although it's not impossible.

02:23:24.500 So it's like upstream to that in the storiogenesis cascade, where might other stuff plug in?

02:23:28.960 I've seen progesterone use in men on TRT actually reasonably effective in sleep quality.

02:23:34.840 How much progesterone?

02:23:35.960 I think the same amount as women.

02:23:37.360 One to 200 milligrams?

02:23:39.280 You don't have any HBTA suppression because you're shut down anyway.

02:23:41.880 So it can be impactful on quality of life because you get the downstream conversion to some of

02:23:47.260 those neurosteroids that may be inhibited in post-finasteride patients.

02:23:51.140 I'd never heard of that.

02:23:52.460 That's super interesting.

02:23:53.500 Not common, or why would it work in women and not work in men if you had a reasonably

02:23:58.080 low progesterone level?

02:24:00.300 Yeah.

02:24:01.220 You're not expected to have a sky-high progesterone anyway, but it's some of the downstream neurosteroid

02:24:06.080 metabolites that you make through 5-alpha reduction and whatnot that are very GABAergic

02:24:10.680 and anxiolytic and can help certain people.

02:24:13.520 And maybe that's useful for a specific guy who has a low SHBG and is in a state of high sympathetic

02:24:18.660 drive on his test and needs to calm down, or there are certain use cases that are more

02:24:23.400 individual-dependent for sure and not necessarily dictated solely by, let's like, lab resulted

02:24:30.160 out and anywhere we just look for red and then replace it.

02:24:33.420 I don't really know the history at all of anabolic steroids.

02:24:36.240 Guessing testosterone's probably been around since the 30s or 40s, right?

02:24:39.940 Presumably.

02:24:40.840 Yeah.

02:24:41.180 I think when it was first synthesized, it remains up for debate maybe.

02:24:45.920 It goes back nearly 100 years at this point.

02:24:49.400 And so what was the first anabolic derivative of testosterone?

02:24:54.280 The first one I can think of off the top of my head is dianabol.

02:24:58.100 There might have been like methyl test or something.

02:25:01.180 I could be misremembering.

02:25:02.760 But essentially what they did was they took the testosterone molecule and found they could

02:25:07.120 finagle it, manipulate it in ways to create testosterone derivatives like dianabol, methandrostenolone,

02:25:15.040 which is supposedly the breakfast of champions, according to Arnold.

02:25:18.900 It's one of its famous quotes.

02:25:20.920 Boldenone is a very commonly used drug as well still.

02:25:24.420 It was prescribed to horses, I believe, for a while.

02:25:27.040 And then I don't think it ever had a human use, but that is a testosterone derivative as

02:25:31.640 well.

02:25:32.420 And there's other ones that came thereafter like halotestin, which I think famously one of

02:25:38.520 the presidents of the United States was on some aggressive dose of halotestin for,

02:25:42.940 I forget what it was, maybe fertility or androgen therapy, but some of the protocols back then

02:25:47.720 made almost no sense.

02:25:49.560 Halotestin.

02:25:50.480 And through there, they also found, oh, if we take the 5-alpha reduced DHT, testosterone

02:25:55.460 converts to DHT, you would take that DHT molecule, you can manipulate it and create more

02:26:00.560 anabolic compounds that are tissue selective.

02:26:04.080 Like the idea of actually tweaking and modifying it to begin with came from the utility clinically

02:26:09.560 to implement in muscle wasting in androgen-sensitive individuals.

02:26:16.020 So you're not going to give a child testosterone who has, you know, like a burn patient, you're not

02:26:21.500 going to give them tests because you might masculinize the hell out of a female child,

02:26:24.920 for example.

02:26:25.500 So you have to come up with novel alternatives that are going to be anti-catabolic,

02:26:31.180 preserve tissue, keep somebody from wasting away in a state of fill-in-the-blank without

02:26:36.300 causing extreme viralization.

02:26:38.980 So the arms race of creating the best anabolic agent was from numerous pharmaceutical companies

02:26:45.240 and came an array of compounds that you know now to be the dianabols, the boldenones.

02:26:50.260 On the DHT derivative side, you had oxandrolone, one of the more refined, more recent, although

02:26:55.500 decades ago at this point.

02:26:57.460 PrimaBolin, also a very refined one.

02:26:59.720 It's a metenolone.

02:27:01.220 Proviron, I think still used actually to interact with SHBG.

02:27:04.420 It's probably one of the most potent drugs at binding SHBG is mysterolone.

02:27:09.120 But yeah, the ideal scenario would be you're trying to segregate the anabolic from androgenic

02:27:13.340 activity because testosterone is essentially equal.

02:27:15.660 At least based on rodent studies, you would find an equal amount of anabolic activity in

02:27:19.940 muscle relative to androgen-like activity, masculinization.

02:27:25.920 So you would try and take the compound, manipulate it to give maximum anabolic outcomes with a relative

02:27:32.360 lack of androgenic outcomes to create something that men, women, children, anybody could take

02:27:37.480 for muscle-wasting purposes and preserve tissue.

02:27:40.700 And they never successfully did it, but an array of compounds.

02:27:44.220 If sort of 1 to 10 would be, let's just make this a scale up.

02:27:49.360 So 5 is testosterone.

02:27:51.360 So it is halfway between completely anabolic and completely androgenic.

02:27:58.200 DHT would be closer to 1.

02:28:00.840 It's much more androgenic than it is anabolic.

02:28:04.060 What is the furthest example you have that's closest to 10?

02:28:08.260 Meaning the most anabolic.

02:28:10.100 Premabolin probably.

02:28:11.580 So one would think that that would be like the drug of choice if you're a bodybuilder.

02:28:15.540 It often is too.

02:28:16.640 So typically men will take, I'm not saying it's the only drug because it depends on what else

02:28:20.460 you're trying to get, because sometimes the side effects, as absurd as it sounds, are desired.

02:28:24.220 So with Dianabol, for example, heavily water-retentive.

02:28:29.040 So that could help cushion your joints when you're doing heavy lifting, for example.

02:28:34.440 If you have better leverages on like a max out, you're going to be better with more water retention

02:28:39.800 around your muscle belly than if you, or in your muscle belly than you would if you had like a dry

02:28:45.800 compound that is not a substrate for aromatase and premabolin is extremely refined and specific

02:28:51.800 in its action.

02:28:52.680 Like it's like a pure protein accretion compound with a relatively less burdensome androgenic

02:28:59.400 profile.

02:29:00.220 But the side effects of it, it doesn't interact with aromatase because it's a DHT derivative.

02:29:04.700 So it's not a substrate for aromatase.

02:29:06.520 It does not 5-alpha reduce into a bunch of different things too.

02:29:09.660 So it's more predictable in its outcomes.

02:29:11.320 But that's not always the desired outcome.

02:29:13.520 Some people want to look cosmetically inflated with water.

02:29:16.720 Some people want to lift more weight or prevent injury.

02:29:20.840 And sometimes that water can be helpful.

02:29:22.840 Depends on the person.

02:29:24.560 But yeah, that's like skewing the furthest direction of anabolic relative to androgenic.

02:29:28.860 You probably have like premabolin and anivar.

02:29:31.160 Yeah.

02:29:31.380 And I remember, again, just sort of reading like anivar, also highly prized among athletes.

02:29:38.500 Technically SARMs are actually even further.

02:29:40.660 If I was to give the most extreme anabolic relative.

02:29:44.200 So let's talk about SARMs then.

02:29:45.900 Tell folks what those are.

02:29:47.240 Okay.

02:29:47.440 So selective androgen receptor modulators.

02:29:49.840 These were kind of designed.

02:29:52.220 Some people might be more familiar with SARMs.

02:29:54.780 You've talked about Clomid, Tamoxifen on this podcast before.

02:29:58.300 Selective estrogen receptor modulators.

02:30:00.140 So these will interact in a tissue-specific way with estrogen receptors in various areas of

02:30:06.460 the body.

02:30:06.800 So you might have inhibition of estrogen receptor activity in the breast for somebody who has

02:30:11.780 breast cancer, for example, versus you would have pro-estrogen activity in other areas of

02:30:17.380 the body like bone, which is what makes the selective action of it desirable.

02:30:21.680 Because you can actually sort of choose where you get the activity you want, but also don't

02:30:28.340 impact the health of other tissues in other areas of the body.

02:30:31.960 So the same idea was kind of adopted for SARMs.

02:30:33.900 And they tweaked and modified anti-androgens, actually, to make these compounds that would

02:30:39.980 interact with the androgen receptor in a way that was tissue-specific and try and get pure

02:30:45.580 anabolic activity with almost no androgenic.

02:30:48.600 And proportionally, it's more successful probably than anabolic steroids, but the ceiling of anabolic

02:30:54.540 activity seems to be lower.

02:30:56.920 So when people use SARMs, they do not gain as much muscle as when they use anabolic steroids.

02:31:02.820 And oftentimes, in their quest for achieving a similar muscle-building outcome, the higher

02:31:08.880 and higher the dosage gets, the less selective it becomes.

02:31:11.380 So almost like certain, I don't know, beta blockers, for example, as you get higher and

02:31:15.600 higher, they become less receptor-selective, and you get more broad-spectrum.

02:31:20.200 What are the typical SARMs, or what are the most potent or commonly used SARMs?

02:31:24.140 It's LGD-4033, probably.

02:31:27.400 It's called a ligandrol.

02:31:29.160 These compounds often get traded around companies so often that they have new code names every

02:31:33.560 time I check.

02:31:34.320 I think the most recent one was, I think it turned into VK5211 by Viking Therapeutics,

02:31:40.480 was the last company I'm aware of who had it.

02:31:42.780 And it was in, I think, a phase two trial for hip fracture patients.

02:31:46.700 Osterine, also known as Enobo SARM, was probably the most well-known SARM.

02:31:52.260 But it has not been FDA-approved and seems to have not hit their target endpoints that

02:31:59.200 they wanted, although it looked effective.

02:32:01.540 And oftentimes women who are trying to achieve a physique to step on stage to try and bridge

02:32:09.380 the gap between not using anything and using steroids, they will go for something like an

02:32:13.580 Osterine, and they don't viralize themselves when they take it.

02:32:17.680 It's funny.

02:32:18.000 I always thought that was a SARM.

02:32:19.160 I didn't know it was a SARM.

02:32:20.440 Are these banned compounds in natural bodybuilding?

02:32:23.160 Yeah.

02:32:23.660 And they're super detectable because they're not supposed to be in your body at all.

02:32:27.400 So how does one get these?

02:32:29.020 Are these, if they're in phase two, compounding pharmacies, some of them make them.

02:32:33.960 Yeah, that's true.

02:32:34.860 I've heard some wild, nutty stuff just like, oh yeah, I'm prescribed Tren.

02:32:39.900 How does your pharmacy make Tren?

02:32:42.240 Yeah, let's talk about Tren.

02:32:43.740 Where does that fit into?

02:32:44.600 So that's actually classified as a steroidal SARM, interestingly enough.

02:32:48.480 So it was prescribed to women in the 80s, I believe, and was also used to beef up cattle

02:32:53.420 and might even still be, but it is super anabolic, but it also has very odd progestogenic activity.

02:33:00.860 So it interacts with the progesterone receptor, causes severe night sweats, it's called Tren

02:33:06.000 sweats.

02:33:06.720 It also has this weird side effect called Tren cough.

02:33:10.680 No one can be sure of what is causing it, but it's one of the only drugs associated with

02:33:15.580 a prevalence of a severe coughing fit, like you're having an allergic reaction or something

02:33:20.200 after you take it.

02:33:21.100 So you inject it and you feel all of a sudden this tightness in your chest.

02:33:24.540 And then within 20 seconds, you're on the floor hacking up a lung for two minutes.

02:33:28.600 I had a patient come to me a little while ago who was seeing some fancy doc in LA who

02:33:35.260 had him on a pretty high dose of Tren and GH.

02:33:39.400 Again, there's always like, how do you get people off these things?

02:33:43.120 Luckily, he wasn't on it for very long.

02:33:45.260 Those compounds are more suppressive too, because they interact with the progesterone receptor

02:33:48.520 significantly.

02:33:50.020 So it's like you get the negative feedback, not just through AR, ER, but PR as well.

02:33:54.700 So let's just kind of recap where you were on some of those.

02:33:57.320 So did you talk about Deca and Androlone?

02:34:00.080 Yeah, Deca is close to the more pure anabolic side.

02:34:05.640 It's not near the selectivity of a SARM at a therapeutic dose, but it is probably the,

02:34:12.780 interestingly enough, the only steroid that you can probably use at a dose that is, will

02:34:18.360 result in bodybuilder level results without hair loss, because it has unique interaction

02:34:23.800 where it gets so complicated when you think of the pharmacology of this stuff, because

02:34:27.540 it's like, it will 5-alpha reduce into a dihydronandrolone, which is almost no androgenic

02:34:35.960 activity.

02:34:37.080 So in the muscle, where you have a relative absence of 5-AR, you will retain the anabolic

02:34:43.860 properties of nandrolone where you want it, but then in your scalp, it'll 5-alpha reduce

02:34:48.060 into this metabolite dihydronandrolone, where it has almost no androgenicity.

02:34:52.520 So you get like the muscle building without the hair loss.

02:34:55.960 So do bodybuilders even take testosterone at this point?

02:34:59.680 Almost always.

02:35:00.560 So why are they taking testosterone when they have all of these more designer anabolics that

02:35:05.280 seem to have an advantage over testosterone in every way?

02:35:08.960 Testosterone is the base, because it provides your estrogen base layer of neuroprotection.

02:35:14.920 Because none of these things provide aromatization.

02:35:17.860 The only other compounds that could act as replacements for tests are things that are

02:35:24.000 potent substrates for aromatase too.

02:35:25.800 But even then, you get these synthetic estrogen metabolites that have less predictable activity.

02:35:33.100 So for example, D-ball converts to methyl estradiol, which the potency of it at the estrogen receptor,

02:35:40.780 it's not as predictable.

02:35:42.400 And your body doesn't really know exactly.

02:35:44.120 It doesn't have as predictable of outcomes in terms of providing the base layer of what

02:35:48.380 you want from like a broad spectrum, perfectly balanced androgenicity, converts to estrogen

02:35:53.460 where you want it in tissues.

02:35:54.840 You know it protects the brain to some extent.

02:35:57.400 Granted, at super physiologic dosages, you're in neurotoxic territory.

02:36:01.940 Certainly, you're not going to protect yourself with a base of test, but it's better than no

02:36:06.480 test for sure, or no estrogen.

02:36:08.680 When you're saying it's super physiologic doses, you mean super physiologic doses of

02:36:13.120 all of these other hormones?

02:36:15.100 Yeah, because I guess there's no actual physiologic level of them, but it's more just like the

02:36:19.780 androgen burden on your body is exceeding what it would be from a natural testosterone production

02:36:24.660 standpoint.

02:36:25.700 So what is a bodybuilder?

02:36:27.260 Let's just talk about an IFBP, top 50 bodybuilder in the world.

02:36:30.960 What percentage of the year is he on some anabolic steroid?

02:36:35.800 Oh, anabolic steroid, including testosterone, presumably?

02:36:39.540 90 to 100%.

02:36:40.760 They basically have accepted the fact that they've completely suppressed and lost any

02:36:45.440 endogenous production for life, and it's now just a question of how they cycle up the

02:36:51.420 testosterone plus or minus the other anabolic.

02:36:53.860 Sort of.

02:36:54.920 I've seen firsthand multiple bodybuilders who've been shut down for decades come off and restore

02:37:00.660 natural function.

02:37:01.660 And they're using presumably FSH and...

02:37:04.960 Some of them just HCG, just coming off the drugs and waiting long enough.

02:37:07.880 But it begs the question, would they have been there had they not used the drugs until then?

02:37:13.880 Is that just what is representative of where they declined to naturally?

02:37:16.880 Or is it like a permanently lower ceiling potential because you've inhibited organ function for

02:37:22.800 so long?

02:37:23.540 You can't really say for certain.

02:37:25.080 Do we have data on people who have been on anabolic steroids for five years or greater and the ability

02:37:31.980 to forget spermatogenesis, just regain endogenous testosterone production?

02:37:36.600 Yeah.

02:37:37.060 It's sparse, but it exists.

02:37:39.340 The data are sparse or the frequency of people who do it is sparse.

02:37:43.240 There's almost no literature on it.

02:37:45.020 I believe there's a study that shows the recovery capacity and there are people who recover function.

02:37:49.480 It's just relatively arduous if you don't know what you're doing too when it comes to post-cycle

02:37:53.340 therapy because you might have clearance of hormones and go to a crashed hypogonadal level

02:38:00.360 that you're dealing with until you hopefully kick in gonadotropins and hopefully respond

02:38:05.100 to those well and hopefully restore production to a level that provides symptom relief.

02:38:09.800 And that process is an instant.

02:38:11.280 You have to bleed these hormones out of your system if you're using long-acting compounds

02:38:14.660 too, which most people are.

02:38:16.420 So there requires a lot of thought around bridging into your recovery and how you go about doing

02:38:23.100 that.

02:38:23.740 People have to be implementing as the androgens clear, they'd be implementing, well, you'd

02:38:28.380 hopefully be on HCG to begin with to preserve testicular function.

02:38:31.920 Are these guys taking HCG the entire time they're on these other drugs to just maintain

02:38:35.800 some testicular volume?

02:38:37.020 Nowadays, it's becoming more understood that it's probably important.

02:38:41.640 But back in the day, and even me, I didn't do it because I was just told it doesn't matter.

02:38:47.000 You will just recover fine when you want to, when you want to come off.

02:38:49.960 I think more people are becoming aware though that stimulating activity in the latin cells

02:38:55.760 is of reasonable importance, almost certainly to retain an easier transition back into recovery

02:39:02.480 while you're on drugs.

02:39:04.420 So at their lowest time throughout a year, they'd be on how much testosterone?

02:39:08.620 They'd be only on testosterone and they would be on...

02:39:10.620 Yeah.

02:39:10.840 Some people, they think that they're cleaning out by taking like a month off.

02:39:15.600 But in reality, it's like the drugs have almost some of them worked their way out of their

02:39:20.080 system by then, but they've been on grams of stuff that's achieved steady state and you're

02:39:25.200 just clearing 80% of it or something.

02:39:27.560 And then you've never actually gotten out of your system and recovered function, which

02:39:30.640 could take months.

02:39:31.820 So oftentimes they have either residual androgens in their system for the time they're trying

02:39:36.400 to clear, or most of them are staying on a base of TRT to bridge between blast phases,

02:39:43.440 which are like your high exposure points.

02:39:45.580 So those bridges though of TRT, typically it's not actual TRT.

02:39:50.880 It's like fitness industry TRT where everyone's dose is 200 minimum.

02:39:56.540 They cycle up during contests.

02:39:57.920 Obviously, professional bodybuilding is not tested.

02:40:00.560 So the understanding is you're going to take anything and everything as often as you want.

02:40:04.880 Do they take a more middle of the road set of compounds as they're bulking up and then

02:40:10.980 move to the more pure anabolic, less water retention as they're leaning out?

02:40:15.240 There just must be so much nuance to this.

02:40:18.600 In general, in an off season, when your goal is protein accretion, building muscle, they

02:40:25.960 are using it as, I think they still use a ton of stuff, but they will use less than when

02:40:31.400 they are preparing for a contest.

02:40:32.860 And the thought is when I am trying to diet down aggressively.

02:40:37.180 When I'm in a calorie deficit, I need more help on the anabolic side.

02:40:40.260 Even though it's like, what threshold is it to preserve tissue at the end of the day?

02:40:43.620 Typically, a fraction of what they're using.

02:40:46.260 But to build muscle, they will typically be using a base of testosterone plus one or two

02:40:51.600 anabolic agents.

02:40:52.980 In general, it's going to be a primabolin and an androlone or something.

02:40:58.000 And how many total milligrams?

02:40:59.200 Because they're about one to one to one, right?

02:41:01.140 No, it depends on the person how sensitive they are to estrogen.

02:41:03.460 Because there's also interaction with, for example, DHT derivatives, they also compete

02:41:09.060 for aromatase, seemingly.

02:41:11.480 I've seen people on the same dose of testosterone with and without a synthetic DHT derivative have

02:41:17.700 significantly lower estrogen without an aromatase inhibitor.

02:41:21.620 So they're actually lowering their estrogen input through competing for aromatase simply

02:41:28.200 by using a synthetic anabolic on top.

02:41:30.460 So it's like you have to modulate that accordingly too.

02:41:32.540 So it's like oftentimes if you're a very estrogen prone individual or you get gynecomastia easily,

02:41:39.320 the male breast tissue development, these are things you are concerned of when you are

02:41:43.200 pushing your dosages to levels that your body cannot regulate on its own to prevent tissue

02:41:50.480 formation.

02:41:51.680 At TRT levels, most people will have no issues with gynecomastia development if they have a

02:41:55.620 good protocol in place and they're not obese or whatever.

02:41:58.500 But at super physiological doses of tests, not necessarily the case.

02:42:02.540 But you might be able to modulate that activity down by actually competing for aromatase with

02:42:07.640 your primabolin or your drostanilone.

02:42:11.160 And then you get to the progestins like nandrolone, which seem to have like a additive effect because

02:42:16.540 progesterone receptor agonism seems to be a stimulation.

02:42:20.160 It actually provides a stimulative input on breast tissue development too.

02:42:25.300 Like there's other things besides estrogen that stimulate breast tissue.

02:42:28.080 So you have GH also and IGF-1 stimulate breast tissue development.

02:42:33.280 Estrogen, progesterone, prolactin.

02:42:36.320 These are all things you have to consider when you're using which drugs.

02:42:39.180 How do these guys navigate this?

02:42:41.580 Not well, typically.

02:42:43.120 Even at the pro level?

02:42:44.220 Yeah, they just take random shit often.

02:42:46.180 I mean, when you look at the guys on the Mr. Olympia stage...

02:42:49.680 Responding well does not equate to health often.

02:42:53.060 There's multiple ways to skin a cat and you can still gain similar amounts of muscle with

02:42:56.840 all these compounds in general.

02:42:58.960 But the way you arrive there just might be more side effect burdensome or problematic and

02:43:04.220 fill in the blank area.

02:43:05.780 How many of these guys require surgery for gynecomastia?

02:43:09.460 Most.

02:43:10.060 They proactively do it to make sure they don't have to.

02:43:13.100 Because one of the things that's brutal is guys who choose their drug protocol based on

02:43:18.400 how gyno-prone they are to those drugs.

02:43:21.900 So I've seen people use abusive dosages of aromatase inhibitors, CIRMs, just to tolerate

02:43:27.500 the androgen inputs, some of the drugs that are substrates for aromatase.

02:43:31.600 So it's like, to use the drugs I need to gain the muscle, I'm going to get gyno development.

02:43:35.780 Which I can't have on stage because it looks cosmetically not pleasing and I'll get marked

02:43:39.600 down for it.

02:43:40.420 So I'm going to use aggressive Novodex and aromatase inhibitors while I'm using the androgens

02:43:45.880 to prevent gyno.

02:43:47.460 So I can gain the muscle without the estrogen.

02:43:49.520 But it's like, you can just imagine the androgenic signaling plus no estrogen.

02:43:54.760 It's like a horrible constellation of negative problematic factors.

02:44:00.720 It just seems like such a complicated regimen.

02:44:02.840 And I'm really surprised there aren't more health consequences of this.

02:44:06.280 We see early deaths all the time in the bodybuilding world.

02:44:08.660 Granted, we see early deaths in all places.

02:44:10.800 But these individuals are at least, you can say, lean.

02:44:14.760 They're typically following meticulous diets and training regimens.

02:44:17.500 So at that point, it's kind of just body weight and drug exposure because their sleep is usually

02:44:22.520 dialed to, at least as much as it can be relative to their drug-related side effects.

02:44:26.920 But yeah, when people say, where are the bodies?

02:44:28.400 I'm surprised we don't see more deaths.

02:44:30.060 I think it just hasn't been as documented as it should be.

02:44:33.420 There are a lot of people that you will never hear about because they're not a big name in

02:44:36.460 the industry that had heart failure at 27 or something.

02:44:41.080 Let's talk a word about how you measure this stuff.

02:44:43.240 So if you're taking testosterone, you can check testosterone.

02:44:46.740 But which of these other compounds show up on a testosterone check?

02:44:51.400 Many of them through immunoassay testing.

02:44:54.320 So if you use, for example, testosterone plus nandrolone, it is derived from testosterone

02:44:59.360 and often you will see a cross detection.

02:45:02.460 So you might have an elevated testosterone level through a standard immunoassay that is

02:45:08.600 not reflective of your testosterone doses you're using.

02:45:11.700 And similarly, we see things like estrogen metabolites that are synthetic, artificially

02:45:17.640 inflating your estradiol on ECLA as well.

02:45:21.360 And there are certainly a group of supplements that seem to aggravate this problem, although

02:45:27.560 it's not been clear to me which ones.

02:45:30.040 Aggravate which?

02:45:31.040 The artificial reading of enzyme-based testing of estradiol.

02:45:36.000 Yeah, yeah.

02:45:36.520 There's certain things that you shouldn't take before a blood test, even like biotin.

02:45:41.140 Yes, biotin being...

02:45:42.000 Yeah, there's some basic stuff that really messes up readings.

02:45:45.140 In general, if you're not getting liquid chromatography with tandem mass spectrometry, it's like the

02:45:50.220 highest sensitivity of testing you can get for total testosterone and free testosterone.

02:45:55.860 This is something I haven't revisited in a while, but I recall equilibrium dialysis was

02:46:00.660 the gold standard.

02:46:02.480 And if you don't use those, you will end up with cross detection.

02:46:06.280 I've seen on immunoassay for total tests and the calculation for free tests, numbers showing

02:46:12.980 that I'm in the reference range for testosterone when I did nandrolone monotherapy, which for

02:46:18.680 you, if you stayed on that DECA, almost for sure, your test would have ended up in the

02:46:22.620 gutter, estradiol in the gutter, and you would have just had nandrolone.

02:46:26.780 There's no nandrolone test, so you should have just had like a hypogonadal-looking testosterone

02:46:30.120 profile and estradiol.

02:46:31.740 But if you got the cheap entry-level immunoassay testing, it probably would have been, oh, look

02:46:36.300 at that.

02:46:36.500 My test is in range still.

02:46:37.600 I'm not suppressed on nandrolone.

02:46:38.780 I guess 100 mg of nandrolone isn't that suppressed?

02:46:40.560 Isn't enough?

02:46:40.920 Yeah, yeah.

02:46:41.280 Yeah.

02:46:41.760 So that's like what some people might conclude.

02:46:43.400 So it's very nuanced, and it's not like you're taught to look for this stuff.

02:46:48.480 Often, most people aren't going to be prescribed this stuff to begin with, so it's a bit less

02:46:51.340 relevant.

02:46:51.800 But in the bodybuilding world especially, pretty important, I would say, to know, especially

02:46:56.220 where your estrogen is at, thinking that you're good when you might have a DHT derivative competing

02:47:02.120 for aromatase, and your E2 on paper looks in range, and it's actually like crashed into

02:47:07.080 single digits.

02:47:08.860 Problematic.

02:47:09.520 Brain damage.

02:47:10.880 Cardiovascular disease.

02:47:12.080 Bad.

02:47:12.380 Bone loss.

02:47:13.960 Let's talk a little bit about Clomid and HCG.

02:47:17.320 Maybe tell folks how they're used, and we can talk about some of the pluses and minuses

02:47:21.040 of each.

02:47:22.140 Human chorionic gonadotropin is present in pregnant women's urine, significant quantities, and

02:47:29.580 often it is pulled out, as absurd as that sounds, and purified because it can be used to stimulate

02:47:35.460 the luteinizing hormone receptor similarly to what endogenous LH does.

02:47:40.640 So it looks similar.

02:47:42.880 Some people say it's a mimetic, essentially, I think is the best way to put it, like it

02:47:45.680 mimics the effects of luteinizing hormone in the body.

02:47:47.780 And this is why it is commonly used in fertility regimens for men, because you can essentially

02:47:53.140 replicate the LH signal to your testes that may be suboptimal if you have low gonadotropin

02:47:59.360 output, or non-existent if you have HBTA suppression from your exogenous testosterone you're using.

02:48:06.360 So if you use TRT, you can pretty reasonably expect that your LH and FSH will go down to

02:48:13.360 either non-detectable or close to there, depending on what you're using and the dose.

02:48:18.660 And replacing that LH, I would say, is of pretty high importance if maintaining fertility is

02:48:26.020 important to you.

02:48:26.880 So you will experience testicular atrophy if you do not replace the LH somehow, whether

02:48:33.500 it's through recombinant LH, which is almost never used, or HMG, which is typically not

02:48:39.600 used either.

02:48:40.220 The most cheapest, lowest barrier to entry, predictable thing is HCG.

02:48:45.120 Which still is not that cheap if you're using the branded HCG.

02:48:48.800 It's much more expensive than testosterone.

02:48:50.280 Yeah, there's a clampdown on it recently, too, in the compounding world.

02:48:53.220 And then Clomid, I guess the primary clinical use is in women for fertility.

02:48:59.060 Fertility for IVF prep.

02:49:00.420 In men, it acts, this is how it works in women, too, but it's just like for fertility purposes

02:49:05.000 in men, it's a selective estrogen receptor modulator.

02:49:07.960 So we talked about SARMs earlier, and I mentioned SARMs and how they use that idea for SARMs.

02:49:13.260 It interacts with the estrogen receptor in either a positive or negative way in that it could

02:49:19.160 stimulate activity or prevent estrogen from binding to it and interacting and providing

02:49:24.620 estrogen-related activity in certain tissues.

02:49:27.360 And it's selective in the way it does this.

02:49:29.140 So Clomid has anti-estrogenic activity in the hypothalamus, so it tricks your brain into

02:49:34.780 thinking it's estrogen-deprived.

02:49:36.360 So the response to that is, we have low estrogen, so we need to make more testosterone to aromatize

02:49:41.980 into estrogen, so you uptick your GnRH output to the pituitary, which will increase LH and

02:49:48.260 FSH, which increases tests.

02:49:50.300 And then you can intervene with that compound to trick your body to make more tests, I guess

02:49:55.360 is the best way to put it.

02:49:56.900 And interestingly, I don't know if you want to go down the rabbit hole of N-clomiphene versus

02:50:00.120 Clomid.

02:50:01.200 Clomid has two stereoisomers, I believe.

02:50:05.260 Yeah.

02:50:05.440 One is basically a mirror image of it.

02:50:07.840 Yeah.

02:50:08.140 So it's like zoo-clomiphene and N-clomiphene.

02:50:11.180 And N-clomiphene is seemingly the more selective and actually antagonistic in the hypothalamus.

02:50:19.880 So it's kind of like doing the thing you want from the Clomid, whereas the zoo-clomiphene

02:50:23.820 is like anti-gonadic, like it's providing almost like a anti-androgenic type activity in a way

02:50:32.260 that is not as selective as like a pure serum.

02:50:34.940 So when you think serum, you're thinking something that antagonizes estrogen receptors

02:50:38.480 purely in the hypothalamus, but then leaves estrogen activity everywhere else.

02:50:42.660 Bone integrity is maintained, cardiovascular, et cetera.

02:50:46.620 Everything is kind of backfilled accordingly, except for right there in your brain where you

02:50:50.020 want your brain tricked into thinking, make more testosterone.

02:50:53.680 So N-clomiphene, it also has a shorter half-life, significantly less.

02:50:57.180 I think it's 10 hours off the top of my head and zoo-clomiphene is like days or something.

02:51:01.920 So the actual ability to maneuver the drug like pharmacokinetically too, if you have a

02:51:08.380 bad side effect or something, you can't even get off it as easily with Clomid because you

02:51:12.440 have this big chunk of it as zoo-clomiphene.

02:51:14.980 So the idea and presumably creation of trying to get FDA approval on N-clomiphene was this

02:51:21.680 is a more pure version of the drug that does what we want.

02:51:23.980 And there's been at least one study that showed improved outcomes in women who took N-clomiphene,

02:51:29.920 but it never made it through FDA approval.

02:51:32.760 But despite that, it doesn't stop people from prescribing it and people from using it.

02:51:36.940 I don't think that's a sustainable treatment protocol for your entire life, probably.

02:51:41.980 I think the reality, and it's not as easy to adhere to, but I would probably assert that

02:51:48.480 stimulating exactly what you want to do directly with an HCG plus recombinant FSH is a superior

02:51:54.660 outcome rather than perpetually inhibiting estrogen activity.

02:51:58.960 There's no drug that's purely selective exactly where you want and it's perfect.

02:52:02.960 And that's the only issue I would also have with it where I think if you took two individuals

02:52:08.460 and one of them you put on exogenous testosterone and one of them you put on Clomiphene, they were

02:52:14.740 identical in every way in terms of readout, equal testosterone, free testosterone, and

02:52:20.200 estradiol.

02:52:21.660 I think there's still an argument to be made that the guy who's getting it from exogenous

02:52:25.920 testosterone has a better outcome because he's not getting the central inhibition of estrogen.

02:52:31.660 So his libido is better, his mood is better, his sleep is better.

02:52:34.980 Some of the mood dysregulation on Clomid, wild.

02:52:40.100 Yeah, I mean, we never saw this stuff, but again, I think we're a very small sample size.

02:52:45.100 We're not running like a clinic on this stuff and we're using micro doses compared to where

02:52:50.780 I think people are going.

02:52:52.200 If you're not asking those questions, you also might not get it.

02:52:55.000 Even when people report that, these are often people who are on the precipice of hypogonadism

02:53:00.000 already with very low quality of life as is, presumably to even get on the therapy, going

02:53:07.700 on something and then noticing a decrease in vitality and notable anti-estrogenic activity.

02:53:13.020 You are going from a baseline that is not good to begin with.

02:53:16.940 So it's like comparing that to the outcome of TRT, I feel like is often a misrepresentation

02:53:22.680 just for the sake of you're maintaining adequate function or you're maintaining the testicular

02:53:28.040 axis.

02:53:28.500 At the end of the day, a thing that I need to maintain in perpetuity just for the sake

02:53:34.860 of having an LH and FSH that comes from my pituitary instead of just manually doing it,

02:53:38.840 probably not if it's at the burden of permanently antagonizing one of the most important receptors

02:53:45.000 in your body, I would say.

02:53:45.940 Yeah, I think as a general rule, if you start to muck around with the receptors in the brain,

02:53:49.980 you should have a pretty good idea of what you're doing.

02:53:52.180 Let's talk a little bit about fertility.

02:53:53.920 So let's compare a guy who's on testosterone versus a guy who's on HCG.

02:53:57.540 So if you're on a high enough dose of HCG, you're going to see FSH and LH suppression.

02:54:02.560 Yeah, this is what I found.

02:54:03.720 I had dug into this specifically based on that case that you mentioned.

02:54:07.700 So what does it mean?

02:54:08.700 So you've got two guys, one guy's on testosterone, one guy's on HCG, and they both have a very high

02:54:14.800 testosterone, they both have completely suppressed LH and FSH.

02:54:18.940 Obviously, in the case of the guy on high testosterone, his Leydig cells are doing nothing.

02:54:26.660 In the guy on the high HCG, his Leydig cells are cranking out testosterone.

02:54:32.700 But in both cases, there's enough testosterone being made that the pituitary has stopped making

02:54:40.080 LH and FSH.

02:54:41.780 So what happens to these guys when you stop testosterone?

02:54:44.500 Let's assume they've both been on their protocol for several years.

02:54:48.080 The guy who has sustained organ function is almost certainly going to have a smoother

02:54:54.080 transition because he has maintained the natural function and output of the organ responsible

02:55:02.000 for intratesticular testosterone the entire time versus the other guy has literally deprived

02:55:08.320 the tissue so significantly that it's a fraction of the size.

02:55:12.040 So trying to compare a guy recovering with testes half the size or less compared to a guy who has

02:55:19.020 fully functioning testes that have been maintained, that guy just needs to discontinue and get rid of that

02:55:25.440 feedback inhibition.

02:55:26.580 And he's likely going to return to natural function within short order pending his gonadotropin output from the

02:55:33.380 pituitary is satisfactory.

02:55:35.420 So it's to be determined if that guy is going to have adequate pituitary output given a bunch of other factors,

02:55:40.600 lifestyle, etc.

02:55:41.380 But probably that guy is going to be okay, I would say.

02:55:44.580 The question then is, why did that guy go on HCG to begin with?

02:55:47.740 Because it's presumably because he had low LH output.

02:55:49.900 So maybe if that guy got on with low LH output on HCG, because that's probably the main reason he would have,

02:55:57.180 he's probably going to go back to low LH output unless something dramatic has changed in his baseline lifestyle diet.

02:56:02.780 And he's older now with less testicular function just as a result of age.

02:56:06.780 So there's that for sure.

02:56:08.640 That is a major factor.

02:56:10.020 But he at least has more potential to recover to whatever his baseline was than the other guy, in my opinion,

02:56:15.200 who's going to have a longer, more arduous road with, okay, you have to have enough.

02:56:19.840 You have to not only get the testosterone out of your system to stop having negative feedback.

02:56:23.560 Now you have to get the pituitary output back, hopefully to some satisfactory amount,

02:56:29.240 which if your baseline was low, because presumably it was if you got on TRT,

02:56:33.960 why else would you unless you had like testicular failure?

02:56:36.200 And that guy would have never got off test because that's the only option he has.

02:56:40.420 Essentially, that guy is going to have to have enough LH output to stimulate him back to baseline testicle size

02:56:48.300 to match the capacity of the other guy just from a morphologic standpoint.

02:56:53.480 So I would assert that the HCG guy is almost certainly going to be better off than the test guy.

02:56:58.780 Do you think that there's a way around it on the HCG guy if you dose him more frequently?

02:57:02.940 Like you take the same dose.

02:57:04.200 We typically dose HCG twice a week.

02:57:06.200 So kind of starter dose would be like 750 units twice a week or 625, I think makes the math easier.

02:57:12.960 I think 625 twice a week allows him to go whatever, eight weeks with a vial or something like that.

02:57:18.280 And then generally we just stop.

02:57:20.840 If you're not getting an amazing response at 2000 twice a week, which we would never go above that,

02:57:26.280 you're wasting your time and you're wasting money.

02:57:28.780 Curious, by the way, what doses are bodybuilders using?

02:57:31.580 Most aren't using it, but the ones that are typically, well, even the ones that are using it aren't following like literature recommended dosages.

02:57:40.900 But at least from what I've seen to maintain intratesticular testosterone at 100% while suppressed on exogenous androgens,

02:57:49.380 I think the dose is about like 375 IU every other day approximately.

02:57:54.900 Okay, so not Herculian doses at all.

02:57:56.900 But this is also assuming you're starting at full function and you're not trying to get back up from 0 to 100.

02:58:03.820 So that'll be a bit of a difference on that.

02:58:06.880 But that guy who is on HCG, I would assert probably have an easier transition for sure.

02:58:13.240 But we can definitely get into the FSH suppression and the frequency of administration.

02:58:18.780 That's what you ask.

02:58:19.380 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.

02:58:27.160 I'd have to double check.

02:58:28.260 But if you are going to an everyday schedule, you're probably going to maintain more stable serum concentration.

02:58:35.160 So you're not going to get as aggressive spikes in light excel activation.

02:58:39.380 So you're going to have probably more representative of natural output of tests.

02:58:44.460 But at the same time, if that level of test is satisfactory to achieve the hormone levels that your body needs from an androgen.

02:58:52.260 You should shut down.

02:58:53.260 Yeah, then you should shut down.

02:58:54.320 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.

02:59:13.280 So the frequency thing, I think it's more so, I would recommend more frequent, probably, for just stability and side effect profile.

02:59:21.420 But it's based on the adherence of the patient.

02:59:23.860 How realistic is that?

02:59:25.240 Yeah.

02:59:25.540 A couple more random things before we wrap up.

02:59:27.640 We've been going a while, and I feel like I'm about halfway through this stuff I wanted to talk about.

02:59:31.580 But there was one peptide we didn't talk about, which is BPC-157.

02:59:35.540 Do you know anything about that peptide?

02:59:37.320 Yeah, yeah.

02:59:38.080 One thing I should say before we get off the HCG, though, because you had that specific example of if FSH is suppressed, how do you know if the negative feedback is through the HCG dose, amplitude, etc., versus the testosterone that comes from it.

02:59:51.620 I found a really good study that was, it used HCG at 4,000 IUs in men who had normal gonadal function and those who were poor non-responders to HCG.

03:00:01.920 So you can discern from that.

03:00:03.380 If it's the testosterone or the HCG.

03:00:04.860 Yeah, but in addition, the people who responded, they used clomid on after.

03:00:08.300 So this is the interesting thing.

03:00:09.260 So it suppressed FSH in the people who responded to the HCG, but not in the individuals who don't respond.

03:00:16.640 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.

03:00:29.200 So that's pretty elegant.

03:00:30.000 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.

03:00:39.280 Yeah, basically.

03:00:40.260 Sorry, it's not that HCG is mimicking too much LH.

03:00:44.500 Yeah, the LH receptor doesn't tell your brain, stop making tests.

03:00:47.620 It's the testosterone output.

03:00:49.300 Yep, yep, yep.

03:00:49.840 And to confirm, they applied clomid in the responders to HCG to see if they could attenuate the FSH suppression, and they could.

03:00:58.660 So in that, you can assert that an estrogen is obviously a huge negative feedback regulator.

03:01:04.780 If you can maintain FSH at baseline with a high 4000 IU dose of HCG with pushing your total T way up, and use the serum 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.

03:01:23.900 Because you're still maintaining FSH with the same androgen signal and the LH receptor signal.

03:01:30.280 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.

03:01:44.460 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.

03:01:56.420 It's something that is just reliably decreases all metrics of fertility from a semen parameters aspect.

03:02:01.420 So the intratesticular 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.

03:02:20.000 Now, there are certain people who don't seem to respond as well.

03:02:22.960 Off 5-alpha reductase inhibitor though, or well still on?

03:02:25.520 I'm just saying in general, like people who are on 5-IR inhibitors, you're diminishing your possibility of fertility almost certainly.

03:02:32.880 So again, it's not just intratesticular testosterone, it's also presumably, and this is how you confirm what the 5-alpha reductase inhibitor applied is when DHT goes down, T goes up 15 to 22%.

03:02:44.060 There's nothing changing about output of testosterone production other than DHT goes down when you have a 5-alpha reductase inhibitor.

03:02:51.720 So if fertility goes down, when DHT goes down, it's not just the testosterone, it's just broad androgenic signaling.

03:02:59.280 So the more androgenic of an environment you have, intratesticularly seemingly is the main dictating variable.

03:03:06.120 When DHT goes down, testosterone goes up by how much?

03:03:09.700 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%.

03:03:26.380 Which is so interesting, because regular T conversion to DHT is not that high.

03:03:31.380 I mean, it's rarely more than 10%.

03:03:33.040 So it's like you're disproportionately getting a bump in T to the inhibition.

03:03:37.860 Yeah, yeah.

03:03:39.500 And I'm sure, this is probably something I'd have to almost 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.

03:03:49.380 Oh, is that a free increase in testosterone, not total testosterone?

03:03:52.100 No, that's total.

03:03:52.960 But DHT also, the activity of it is going to be inhibited dramatically more proportionally to tests because of its affinity for SHBG is like 5X.

03:04:02.080 So I'm sure there's something there.

03:04:04.340 If I wrote it out, it would make more sense than me just trying to think all the way upstream.

03:04:08.220 But in general, the takeaway that I've seen is having high intratesticular androgenic signaling is the only thing that's mandatory for spermatogenesis and FSH receptor activation.

03:04:21.440 With some level of FSH, you can still maintain or achieve spermatogenesis with minimal to almost no FSH.

03:04:28.600 And in those individuals that still need a push, they either lack androgenic signaling or there's too much oxidative stress, potentially.

03:04:37.440 They need to utilize things like ubiquinol, NAC, like I don't know, like sometimes supplements actually make a difference.

03:04:42.120 It's carnitine, creatine, or get off their 5-alpha reductase inhibitor or a myriad of things.

03:04:47.400 But a little bit of FSH recombinant on top of that base of ensuring you have adequate intratesticular testosterone can be the differentiating factor on fertility for a minority of people, but it's not mandatory.

03:05:01.500 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.

03:05:09.140 I'm like, I'm thinking a little bit of FSH, it's cost prohibitive, but it's probably a much better alternative.

03:05:15.900 Yeah.

03:05:16.000 What's the cost of recombinant FSH?

03:05:18.380 Depends on the pharmacy.

03:05:19.560 But I heard the other day there was a pharmacy in Texas that prescribes 1,500 IU vials for like a couple hundred bucks, which to me sounds cheap.

03:05:29.020 I've heard it's extremely cost prohibitive.

03:05:31.560 And I think it depends if you're getting like Gonal or if you're getting like which brand you're getting.

03:05:36.180 A typical dose would be what?

03:05:37.520 50 IU every other day.

03:05:40.080 It depends.

03:05:40.680 You can go as high as 75 every day if you need to.

03:05:43.040 So it's still significantly cheaper than growth hormone.

03:05:45.260 Oh yeah, probably.

03:05:46.300 I mean, everything is.

03:05:47.140 Okay.

03:05:47.960 All right.

03:05:48.620 A word on BPC-157, which is a peptide.

03:05:52.960 Yeah.

03:05:53.580 Yeah.

03:05:54.160 So body protection compound, I think is what the acronym stands for, 157.

03:05:58.660 It's like a peptide that's produced endogenously in your gut and it seems to have some like angiogenic properties that can be useful for certain injuries.

03:06:07.400 But it's like, I've seen some pretty remarkable improvements in like minor, not complete tears and certain injuries that are like of lesser.

03:06:19.900 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 thing.

03:06:26.960 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.

03:06:37.140 Because it's like, I also worry about cancer cell proliferation from something that's pro-growing blood vessels.

03:06:43.380 So that is a concern with BPC for sure.

03:06:45.560 And does it need to be injected locally for it to have maximum efficacy?

03:06:48.520 So let's just assume you tear your rotator cuff.

03:06:51.160 This was one of the bro myths we were taught back in the days, inject it right into the injury site.

03:06:55.400 And I now don't believe that to be the case.

03:06:58.500 It seems at least the last I heard that you don't need to do that.

03:07:02.260 Do we hold out any semblance for hope that we might get a study that would shed light on this?

03:07:07.220 Because how could we ever possibly know the counterfactuals here?

03:07:11.220 And how could we possibly disentangle the single user experience on all these things?

03:07:17.400 I don't think so.

03:07:18.320 I think it's something that so many people use at this point.

03:07:21.600 I imagine you can't patent anything or make any money off of studying it.

03:07:25.980 You'd probably know better than me off of how pharmaceutical pipelines work.

03:07:29.040 But I imagine it's kind of at a point where so many compounding pharmacies sell it.

03:07:32.820 The problem I see mainly, I don't really think it's not good to use.

03:07:36.780 I would probably use it if I had a minor injury to somewhere I needed more blood flow.

03:07:40.340 But I do think a lot of people use it proactively far too often for something that is directly

03:07:47.360 intertwined with increasing, I think it's VEGF, and is super correlated with cancer growth.

03:07:54.880 To me, that would freak me out.

03:07:56.160 People who are using it preventatively, a lot of athletes use it as a preventative measure

03:08:00.720 to avoid injury or rehabilitation when it's not necessary.

03:08:04.080 And I think that's overkill and risky as hell, personally.

03:08:06.800 I think because there are so many other things I want to talk about that we should just wrap

03:08:13.060 this up and hit a part two.

03:08:15.600 Sure.

03:08:15.980 Because we haven't talked about any of the stuff I want to talk about around nutrition,

03:08:20.100 around appetite, appetite suppression.

03:08:22.680 Again, I think we've talked a lot about how bodybuilders use drugs.

03:08:26.420 And I think for many people, that's a pretty foreign idea.

03:08:29.480 But bodybuilders also, I think, in a way, through their own very empirical study, have really

03:08:37.900 figured out the science of how to get lean and how to do it with the maximum preservation

03:08:42.960 of muscle.

03:08:43.840 This is something that I think most-

03:08:44.840 Oh, yeah, they've got that dialed.

03:08:46.080 They really do.

03:08:46.940 And that's why I can't imagine a demographic that better understands how to do that, even

03:08:51.920 if it's not necessarily the healthiest way to live.

03:08:54.200 But I think we could all take a page out of the book if we're saying, God, I could stand

03:08:58.900 to be 10 pounds lighter.

03:09:00.360 Wouldn't it be cool if I only lost one to two pounds of muscle in the process?

03:09:05.360 When you see a guy with 50 pounds more metabolically active tissue demanding nutrients starve himself

03:09:13.280 to 5% body fat and step on stage, it's like, okay, I can cut my calories by 300 or find some

03:09:19.420 way that is more satiating to hit my goals.

03:09:22.460 It's definitely something to take from that.

03:09:23.840 Yeah, I wanted to dive deep into that.

03:09:25.920 I also think we could spend some time talking about ways that people can prevent themselves

03:09:32.000 from being fooled by all the charlatans out there.

03:09:34.700 But these people wouldn't be as popular as they are.

03:09:37.400 They wouldn't be making tens, if not hundreds of millions of dollars if there weren't people

03:09:42.280 who were falling for what they're talking about.

03:09:44.620 So probably there's something to talk about as far as like, what are signs that maybe what

03:09:48.900 this person is telling you might be too good to be true?

03:09:51.640 Maybe there's a bit of a buyer beware.

03:09:53.840 Anything else you want to add to a round two when we do it, which maybe we can do in the

03:09:57.500 fall or something?

03:09:59.100 Off the top of my head, I think the fertility discussion, I think we kind of scratched the

03:10:04.440 surface on what an ideal protocol might look like and things to be mindful of.

03:10:09.820 Banking sperm, concerns that people might have getting on TRT beforehand, how to vet if you

03:10:16.620 need it, even like criteria that would be worthwhile to know, because discerning, oftentimes people

03:10:22.640 are told, especially at the clinics, oh, your total T is 400.

03:10:26.520 That's low.

03:10:27.380 Get on tests.

03:10:28.080 And it's like, you might have high AR content and expression.

03:10:31.860 You don't know that you need more tests to actually achieve.

03:10:34.280 I've seen some of the most jacked guys I know.

03:10:35.880 I have 450 total T's and feel fine.

03:10:38.300 There's a lot of nuance that goes into that too.

03:10:40.440 And knowing, not just identifying content charlatans, but medical providers, even your

03:10:46.300 own doctor potentially, knowing who is looking out for your best interest, educating yourself

03:10:51.340 at a base level, I think is almost a necessity nowadays to wade through the nonsense.

03:10:55.080 So I would love to dive deeper.

03:10:57.300 Sounds awesome, man.

03:10:58.100 I look forward to it.

03:10:59.140 Derek, this was a ton of fun and I look forward to continuing the discussion.

03:11:03.180 Awesome.

03:11:03.620 Thank you for having me.

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The Peter Attia Drive - October 09, 2023

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

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