The Peter Attia Drive - #180 - AMA #28： All things testosterone and testosterone replacement therapy

00:00:00.000 Hey everyone, welcome to a sneak peek, ask me anything or AMA episode of the drive podcast.

00:00:16.500 I'm your host, Peter Atiyah. At the end of this short episode, I'll explain how you can

00:00:20.460 access the AMA episodes in full, along with a ton of other membership benefits we've created,

00:00:25.440 or you can learn more now by going to peteratiyahmd.com forward slash subscribe.

00:00:31.140 So without further delay, here's today's sneak peek of the ask me anything episode.

00:00:39.240 Welcome to ask me anything episode number 28. I'm joined once again by Bob Kaplan. In this episode,

00:00:46.060 we talk about all things related to testosterone and its replacement. So we talk about the

00:00:52.500 physiology of testosterone, how it works. We talk about the epidemiology of testosterone,

00:00:57.600 how it changes in level over the course of a person's life. We talk about what happens when

00:01:03.360 testosterone levels are low and what happens when it is replaced. So we talk about the benefits of

00:01:08.240 testosterone and we also talk about the risks of testosterone, mainly focusing on two risks,

00:01:13.280 cardiovascular and prostate cancer. Now, a couple of things to mention before we jump into this one,

00:01:18.700 this is a pretty important episode, whether or not you have low testosterone or not, because almost

00:01:24.440 everyone at some point in the course of their life will get to a point where their levels get to a

00:01:30.500 level that is defined as low. And we'll talk about what those cutoffs are. Therefore, I think that

00:01:35.540 whether it's something that pertains to you or something that pertains to someone that you care

00:01:39.800 about, whether it's a spouse or a family member, a relative or friend, I think it's worth getting

00:01:44.860 smart on this because there is a lot of misinformation out there on this topic, just as there is a lot of

00:01:50.980 misinformation out there on the topic of hormone replacement therapy for women. So yes, this is a

00:01:55.320 pretty male centric discussion because we focus on testosterone replacement therapy. And while

00:01:59.660 testosterone does play a very important role in women for this episode, we are focusing almost

00:02:05.880 exclusively on the role of testosterone in men. Now, this is not an episode where we get into case

00:02:12.860 studies. I'm not going to be going over clinical studies, though I do pepper in a lot of clinical

00:02:18.300 vignette, so to speak, all the way through it. So I talk a lot about the different ways in which

00:02:22.800 testosterone was replaced, the pros and cons of different ways it's replaced, injections versus

00:02:27.580 patches versus gels versus oral, and different manners in which it's dosed. So the frequency with

00:02:33.780 which you dose it and all of these things. Again, this podcast is probably much more geared towards

00:02:38.760 males. And we're, of course, aware that our audience is only half male. So that said, just as I suggested

00:02:45.400 to males when we did the HRT discussion, it's something that you ought to be aware of because

00:02:51.140 you undoubtedly know a female who is going to go through menopause. And similarly, if you're a female, 0.96

00:02:57.060 you undoubtedly know a male who is going to experience their own version of menopause,

00:03:03.600 which is to say their testosterone levels are going to go down. And the question will be,

00:03:08.740 should anything be done about it? So if you're a subscriber and you want to watch the full video

00:03:12.380 of this podcast, you can find it on the show notes page. I highly recommend that like many of the recent

00:03:18.920 AMAs, this one will be better served by watching it on video because there's just so much data that Bob

00:03:25.720 and I present and we do it in the form of graphs and figures. If you're not a subscriber, you can still

00:03:31.720 watch a sneak peek of this on our YouTube page. But again, you'll get more out of this by watching

00:03:37.960 it on video than listening it if you are a subscriber. So without further delay, I hope you

00:03:42.520 enjoy AMA number 28. Hey, Peter. Hey, Bob. Are you ready for another AMA? Sure am, man. Okay. I think

00:03:55.700 we're going to get to maybe one big topic here. We've got a bunch of questions around one topic,

00:04:02.060 but I think we can distill it down into, can you do a deep dive on testosterone or testosterone

00:04:08.880 replacement therapy? And can you do it in under six hours? I think it'll be tight, but I think we can do

00:04:17.700 it. Yeah. Super interesting topic and one that probably just generates almost as much confusion

00:04:25.460 as the hormone replacement therapy question does on the female side. So we've already had a great

00:04:31.960 podcast that debunks a lot of the myths around hormone replacement therapy for perimenopausal and

00:04:38.420 postmenopausal women. And I think in some ways this will be the equivalent podcast for testosterone 0.78

00:04:45.860 replacement therapy in men. So with that said, what this will not be is kind of a review of,

00:04:54.780 you know, nonstop case studies of how it's done in the real world. I think we'll reserve that for a

00:05:00.780 subsequent podcast, probably in the form of an AMA, but you know, remains to be seen because I think

00:05:06.340 sometimes there are multiple ways to go about doing this, but I think for the purpose of trying to get

00:05:11.260 through an enormous body of literature, I think we'll reserve this to what testosterone is, how it

00:05:17.940 works, what's the kind of epidemiology of testosterone deficiency, i.e. what does it look

00:05:25.280 like by decade? What are the implications of that? What are the benefits of replacement and what are the

00:05:31.740 risks of replacement? If we can get through that today, I will be delighted, but we'll see. I know it's

00:05:36.980 ambitious. Me too. Yeah. And I think that hormone replacement therapy is a good example here where

00:05:42.020 I think with HRT, a lot of women worry about, I think it was breast cancer risk. And we've talked

00:05:47.020 a lot about that. And here with TRT, a lot of the questions were, is TRT right for me if I'm worried

00:05:52.900 about cardiovascular disease or prostate cancer? And there's a lot of, call it controversy about that

00:05:57.840 stuff. So it'd be good to dig into it. And I know that for this one, you sent me over some slides

00:06:04.160 the other day. That was helpful. And I think it will be helpful for the people hopefully watching

00:06:10.160 this. I think this is definitely another one of those things where it's fine to listen, but I think

00:06:15.360 the level of detail will lend itself to being able to actually see what's going on both in figures and

00:06:20.560 tables as we sort of draw things out of the literature. So take it away, Bob. Okay. So the first

00:06:28.140 question is pretty basic. What is testosterone? So testosterone is a hormone and it's a steroid

00:06:34.840 hormone. So it's derived from the cholesterol family, as many hormones are. And it's synthesized

00:06:42.560 in a number of steps. I'll be honest with you. I don't actually remember anymore how many steps it

00:06:47.740 takes to create testosterone out of cholesterol. But what's really important is that it exerts its

00:06:53.700 effect through binding to an androgen receptor. So because it is a hydrophobic molecule, it basically

00:07:03.680 makes its way into the cell easily. It diffuses into the cell quite simply, meaning it doesn't require

00:07:09.960 a channel or a receptor on the cell membrane to make its way inside. So as we've talked about a lot

00:07:17.780 with respect to lipids and lipoproteins, cholesterol can't make its way through the bloodstream the

00:07:23.660 way glucose can or the way electrolytes can, you know, for example, sodium, potassium, and those

00:07:28.060 things because they're soluble in water. They're therefore soluble in the bloodstream and plasma

00:07:32.800 and they don't need chaperone or carrier proteins, but cholesterol does. And that's of course why it

00:07:38.520 travels in things called lipoproteins. And similarly, testosterone needs to be bound primarily to

00:07:47.640 carrier proteins. And there are really two dominant carrier proteins that bind testosterone

00:07:53.660 and carry it around. One is called sex hormone binding globulin or SHBG for short. And the other

00:08:00.460 is albumin. And directionally speaking, SHBG is responsible for about two thirds of the carrying

00:08:06.720 capacity, whereas albumin is about one third. But what's important is knowing that it's only the

00:08:14.220 unbound portion of testosterone that is able to actually exert the biological influence. So we pay very

00:08:22.260 special attention to how much testosterone is quote unquote free and free is defined as the testosterone

00:08:29.120 that is neither bound to SHBG or albumin. Whereas there's another term that many people who have had

00:08:37.420 a blood test may notice something called bioavailable testosterone. And that's the portion that is unbound

00:08:43.740 to SHBG but remains bound to albumin or is free. In other words, free testosterone, which is a tiny

00:08:52.260 amount, it's typically one to two, maybe three percent of total testosterone is that which is completely

00:08:59.300 unbound. Whereas bioavailable includes that tiny fraction plus the much larger fraction that is bound

00:09:06.180 to albumin. I would say from a clinical standpoint, I find that symptoms track more with free testosterone

00:09:16.440 than bioavailable. But honestly, they're close enough in terms of their prediction of what's going on

00:09:24.560 that if you're using a lab that relies on one versus the other, it's probably okay. The lab that we use

00:09:31.460 uses total testosterone, of course, but free testosterone. And it's really the free number

00:09:35.960 that we're paying most attention to. So let's go back to how testosterone works. So it makes its way 0.97

00:09:43.120 into the cell and then it binds to an androgen receptor. And this receptor is outside of the nucleus.

00:09:50.020 It undergoes this conformational change and it causes things called heat shock proteins to be

00:09:55.540 dislocated. They get transported into the cell and then something called the dimerization takes place.

00:10:02.300 And that's just a fancy way of saying a new molecule is created by the fusion and it doesn't

00:10:09.040 have to be covalent. It can be non-covalent, but the fusion of two molecules that look very much alike.

00:10:14.820 So this androgen receptor dimer now makes its way into the nucleus and binds with something called a

00:10:23.760 hormone response element. And that's what actually turns on and off gene transcription. And that's

00:10:31.460 effectively what testosterone is doing. It is up or down regulating genes that are responsible for

00:10:40.460 a number of things, but the most obvious of these are kind of the anabolic or growth characteristics.

00:10:45.760 Now there's something else I think worth mentioning here, Bob, which is the presence of another hormone

00:10:51.260 here called dihydrotestosterone or DHT. Now DHT is anywhere from, oh, I don't know. I think it's

00:10:59.920 about three to six times more powerful than testosterone. And by powerful, I just mean has

00:11:06.300 a greater binding affinity for the androgen receptor. And so DHT is something that is converted from

00:11:14.440 testosterone using an enzyme called 5-alpha reductase, which I think we're going to get to that later,

00:11:20.280 Bob. So I'm probably not going to go into much detail on that now. I think that that's probably

00:11:25.160 as much as I want to say on this topic only because we could go a lot deeper into it, but I'm not sure

00:11:30.220 it really adds much value to the clinical questions that we're going to want to get to, unless there's

00:11:34.280 anything else that you have seen with respect to questions that people have about this.

00:11:40.160 Not a lot of questions about that, more around the practical stuff, like what is low T and what happens

00:11:45.960 if you replace it? Okay. It's probably worth also saying just something about how the body regulates

00:11:53.700 this at a macro level. And I think you have a slide on that. Do you mind pulling that up? Yes.

00:11:58.860 So in this schematic, you can see basically the feedback loop that exists. So obviously you have

00:12:06.420 the central nervous system, but specifically the hypothalamus. And the hypothalamus in response to

00:12:13.020 low testosterone will secrete gonadotropin releasing hormone. It secretes that to another

00:12:23.400 part of the endocrine system called the pituitary gland, which is divided into two pieces, an anterior

00:12:29.120 and a posterior. So in the anterior pituitary gland, in response to gonadotropin releasing hormone,

00:12:36.380 two other hormones are released. And these are hormones that most people might even be familiar

00:12:40.520 with because you'll see them on the blood test. One is called LH or luteinizing hormone. The other

00:12:45.700 is called FSH or follicle stimulating hormone. So LH and FSH are released from the anterior pituitary

00:12:53.120 gland into the bloodstream. And their targets are two specific types of cells in the testes.

00:13:00.020 One of them is called the Sertulli cell and one of them is called the Leydig cell.

00:13:03.940 Now the Sertulli cell is responsible for secreting growth factors that further stimulate the Leydig

00:13:11.440 cell. And LH directly acts on the Leydig cell. And the net result of this is the production of

00:13:17.820 testosterone. And as you can see in this figure, it's actually a little more sophisticated, right?

00:13:22.460 There's more going on here. So the androgens that are produced by the Leydig cell testosterone

00:13:27.340 can undergo what's called aromatization, which is the process by which they are turned into

00:13:32.540 estrogens using specific enzymes that we'll sort of not get into at the moment. But an obvious

00:13:39.820 byproduct of testosterone creation is the co-creation of estradiol. I guess the most important thing I

00:13:46.400 want to say on this figure is that when testosterone is low, the feedback cycle to the brain ultimately

00:13:56.720 is to ramp up the secretion of LH and FSH. Conversely, when testosterone is high, the signal

00:14:06.780 that's sent back is to inhibit the production of these things. So this is a very important point

00:14:13.260 to understand clinically. If a person is supplementing with testosterone, it is usually very obvious to tell

00:14:22.740 this from their blood work because they have unmeasurable levels of LH and FSH and usually

00:14:30.060 high levels of testosterone. Now, at some point, this becomes a permanent issue. In other words,

00:14:38.380 at some point, if a person is taking exogenous testosterone for long enough, their body will

00:14:44.200 lose the ability to make its own. Now, I think we'll come back to that a little bit later, but I just want

00:14:50.440 to point out that this is a regulated process through a feedback loop. Another way to look at this sort of

00:14:57.920 clinically is when you see patients who have relatively high LH and high FSH, but low testosterone. So in

00:15:06.360 that situation, high LH, high FSH, low testosterone, the problem is usually in the testes. Conversely,

00:15:13.860 when you see low testosterone, but low LH and low FSH, the problem is usually central, meaning there's

00:15:22.860 something in the brain that isn't working. And of course, I'm being a little tongue in cheek when I

00:15:27.420 say that because it's not really the brain that's not working, but there's something in that pathway

00:15:31.620 either at the GNRH level or at the pituitary level. And I will say that the most common thing that we

00:15:38.700 see clinically that results in that picture, i.e. low testosterone, but with an inappropriately low

00:15:46.700 LH and FSH is sleep deprivation and hypercortisolemia, i.e. lots of stress. So those are

00:15:54.880 unfortunately kind of ubiquitous clinical situations. We see a lot of people that have insufficient sleep or

00:16:02.260 insufficient quality of sleep and or high levels of cortisol and stress, which by the way, are

00:16:08.380 difficult to disentangle sometimes from poor sleep. And that can result in the brain not sending the

00:16:14.380 right signal to the testes. But that's important from a clinical perspective because how we treat

00:16:19.520 low testosterone when we do make the decision to treat it is highly dependent on being able to

00:16:25.960 differentiate between those two paths. Any other questions that have come up on that particular topic,

00:16:31.560 no, I think that's it. Okay. So where to next? So next we have the questions of, okay, so what

00:16:41.480 constitutes low testosterone? And I think you just made a distinction there, but maybe just from a

00:16:46.760 clinical level for looking at, you know, numbers wise, if somebody is looking at a panel, what is

00:16:51.560 low testosterone? Well, so this is interesting. I will say that most of the literature focuses on low

00:16:58.460 total testosterone. And I think that's probably because it's more commonly measured. It's easier

00:17:05.700 to measure. And it's basically the one thing that's always going to be measured. Whereas I think not

00:17:13.040 all the time are physicians also measuring free testosterone or bioavailable testosterone. Again, my bias

00:17:19.360 is to measure free testosterone because that's actually the testosterone that makes its way into the

00:17:26.040 cell. But if you pull up the table that looks at total testosterone levels, we'll get a sense at how

00:17:33.760 wide the range is across all age groups. Thank you for listening to today's sneak peek AMA episode of

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The Peter Attia Drive - October 18, 2021

#180 - AMA #28： All things testosterone and testosterone replacement therapy

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