#180 - AMA #28： All things testosterone and testosterone replacement therapy
Episode Stats
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Summary
In this episode, Dr. Bob Kaplan and I discuss the role of testosterone in men, the benefits and risks of testosterone replacement therapy, and what to do when your testosterone levels drop to a point where they need to be replaced.
Transcript
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Hey everyone, welcome to a sneak peek, ask me anything or AMA episode of the drive podcast.
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I'm your host, Peter Atiyah. At the end of this short episode, I'll explain how you can
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or you can learn more now by going to peteratiyahmd.com forward slash subscribe.
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So without further delay, here's today's sneak peek of the ask me anything episode.
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Welcome to ask me anything episode number 28. I'm joined once again by Bob Kaplan. In this episode,
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we talk about all things related to testosterone and its replacement. So we talk about the
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physiology of testosterone, how it works. We talk about the epidemiology of testosterone,
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how it changes in level over the course of a person's life. We talk about what happens when
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testosterone levels are low and what happens when it is replaced. So we talk about the benefits of
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testosterone and we also talk about the risks of testosterone, mainly focusing on two risks,
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cardiovascular and prostate cancer. Now, a couple of things to mention before we jump into this one,
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this is a pretty important episode, whether or not you have low testosterone or not, because almost
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everyone at some point in the course of their life will get to a point where their levels get to a
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level that is defined as low. And we'll talk about what those cutoffs are. Therefore, I think that
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whether it's something that pertains to you or something that pertains to someone that you care
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about, whether it's a spouse or a family member, a relative or friend, I think it's worth getting
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smart on this because there is a lot of misinformation out there on this topic, just as there is a lot of
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misinformation out there on the topic of hormone replacement therapy for women. So yes, this is a
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pretty male centric discussion because we focus on testosterone replacement therapy. And while
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testosterone does play a very important role in women for this episode, we are focusing almost
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exclusively on the role of testosterone in men. Now, this is not an episode where we get into case
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studies. I'm not going to be going over clinical studies, though I do pepper in a lot of clinical
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vignette, so to speak, all the way through it. So I talk a lot about the different ways in which
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testosterone was replaced, the pros and cons of different ways it's replaced, injections versus
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patches versus gels versus oral, and different manners in which it's dosed. So the frequency with
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which you dose it and all of these things. Again, this podcast is probably much more geared towards
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males. And we're, of course, aware that our audience is only half male. So that said, just as I suggested
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to males when we did the HRT discussion, it's something that you ought to be aware of because
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you undoubtedly know a female who is going to go through menopause. And similarly, if you're a female,
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you undoubtedly know a male who is going to experience their own version of menopause,
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which is to say their testosterone levels are going to go down. And the question will be,
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should anything be done about it? So if you're a subscriber and you want to watch the full video
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of this podcast, you can find it on the show notes page. I highly recommend that like many of the recent
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AMAs, this one will be better served by watching it on video because there's just so much data that Bob
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and I present and we do it in the form of graphs and figures. If you're not a subscriber, you can still
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watch a sneak peek of this on our YouTube page. But again, you'll get more out of this by watching
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it on video than listening it if you are a subscriber. So without further delay, I hope you
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enjoy AMA number 28. Hey, Peter. Hey, Bob. Are you ready for another AMA? Sure am, man. Okay. I think
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we're going to get to maybe one big topic here. We've got a bunch of questions around one topic,
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but I think we can distill it down into, can you do a deep dive on testosterone or testosterone
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replacement therapy? And can you do it in under six hours? I think it'll be tight, but I think we can do
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it. Yeah. Super interesting topic and one that probably just generates almost as much confusion
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as the hormone replacement therapy question does on the female side. So we've already had a great
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podcast that debunks a lot of the myths around hormone replacement therapy for perimenopausal and
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postmenopausal women. And I think in some ways this will be the equivalent podcast for testosterone
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replacement therapy in men. So with that said, what this will not be is kind of a review of,
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you know, nonstop case studies of how it's done in the real world. I think we'll reserve that for a
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subsequent podcast, probably in the form of an AMA, but you know, remains to be seen because I think
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sometimes there are multiple ways to go about doing this, but I think for the purpose of trying to get
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through an enormous body of literature, I think we'll reserve this to what testosterone is, how it
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works, what's the kind of epidemiology of testosterone deficiency, i.e. what does it look
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like by decade? What are the implications of that? What are the benefits of replacement and what are the
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risks of replacement? If we can get through that today, I will be delighted, but we'll see. I know it's
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ambitious. Me too. Yeah. And I think that hormone replacement therapy is a good example here where
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I think with HRT, a lot of women worry about, I think it was breast cancer risk. And we've talked
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a lot about that. And here with TRT, a lot of the questions were, is TRT right for me if I'm worried
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about cardiovascular disease or prostate cancer? And there's a lot of, call it controversy about that
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stuff. So it'd be good to dig into it. And I know that for this one, you sent me over some slides
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the other day. That was helpful. And I think it will be helpful for the people hopefully watching
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this. I think this is definitely another one of those things where it's fine to listen, but I think
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the level of detail will lend itself to being able to actually see what's going on both in figures and
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tables as we sort of draw things out of the literature. So take it away, Bob. Okay. So the first
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question is pretty basic. What is testosterone? So testosterone is a hormone and it's a steroid
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hormone. So it's derived from the cholesterol family, as many hormones are. And it's synthesized
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in a number of steps. I'll be honest with you. I don't actually remember anymore how many steps it
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takes to create testosterone out of cholesterol. But what's really important is that it exerts its
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effect through binding to an androgen receptor. So because it is a hydrophobic molecule, it basically
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makes its way into the cell easily. It diffuses into the cell quite simply, meaning it doesn't require
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a channel or a receptor on the cell membrane to make its way inside. So as we've talked about a lot
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with respect to lipids and lipoproteins, cholesterol can't make its way through the bloodstream the
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way glucose can or the way electrolytes can, you know, for example, sodium, potassium, and those
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things because they're soluble in water. They're therefore soluble in the bloodstream and plasma
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and they don't need chaperone or carrier proteins, but cholesterol does. And that's of course why it
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travels in things called lipoproteins. And similarly, testosterone needs to be bound primarily to
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carrier proteins. And there are really two dominant carrier proteins that bind testosterone
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and carry it around. One is called sex hormone binding globulin or SHBG for short. And the other
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is albumin. And directionally speaking, SHBG is responsible for about two thirds of the carrying
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capacity, whereas albumin is about one third. But what's important is knowing that it's only the
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unbound portion of testosterone that is able to actually exert the biological influence. So we pay very
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special attention to how much testosterone is quote unquote free and free is defined as the testosterone
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that is neither bound to SHBG or albumin. Whereas there's another term that many people who have had
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a blood test may notice something called bioavailable testosterone. And that's the portion that is unbound
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to SHBG but remains bound to albumin or is free. In other words, free testosterone, which is a tiny
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amount, it's typically one to two, maybe three percent of total testosterone is that which is completely
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unbound. Whereas bioavailable includes that tiny fraction plus the much larger fraction that is bound
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to albumin. I would say from a clinical standpoint, I find that symptoms track more with free testosterone
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than bioavailable. But honestly, they're close enough in terms of their prediction of what's going on
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that if you're using a lab that relies on one versus the other, it's probably okay. The lab that we use
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uses total testosterone, of course, but free testosterone. And it's really the free number
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that we're paying most attention to. So let's go back to how testosterone works. So it makes its way
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into the cell and then it binds to an androgen receptor. And this receptor is outside of the nucleus.
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It undergoes this conformational change and it causes things called heat shock proteins to be
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dislocated. They get transported into the cell and then something called the dimerization takes place.
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And that's just a fancy way of saying a new molecule is created by the fusion and it doesn't
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have to be covalent. It can be non-covalent, but the fusion of two molecules that look very much alike.
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So this androgen receptor dimer now makes its way into the nucleus and binds with something called a
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hormone response element. And that's what actually turns on and off gene transcription. And that's
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effectively what testosterone is doing. It is up or down regulating genes that are responsible for
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a number of things, but the most obvious of these are kind of the anabolic or growth characteristics.
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Now there's something else I think worth mentioning here, Bob, which is the presence of another hormone
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here called dihydrotestosterone or DHT. Now DHT is anywhere from, oh, I don't know. I think it's
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about three to six times more powerful than testosterone. And by powerful, I just mean has
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a greater binding affinity for the androgen receptor. And so DHT is something that is converted from
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testosterone using an enzyme called 5-alpha reductase, which I think we're going to get to that later,
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Bob. So I'm probably not going to go into much detail on that now. I think that that's probably
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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
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it really adds much value to the clinical questions that we're going to want to get to, unless there's
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anything else that you have seen with respect to questions that people have about this.
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Not a lot of questions about that, more around the practical stuff, like what is low T and what happens
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if you replace it? Okay. It's probably worth also saying just something about how the body regulates
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this at a macro level. And I think you have a slide on that. Do you mind pulling that up? Yes.
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So in this schematic, you can see basically the feedback loop that exists. So obviously you have
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the central nervous system, but specifically the hypothalamus. And the hypothalamus in response to
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low testosterone will secrete gonadotropin releasing hormone. It secretes that to another
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part of the endocrine system called the pituitary gland, which is divided into two pieces, an anterior
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and a posterior. So in the anterior pituitary gland, in response to gonadotropin releasing hormone,
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two other hormones are released. And these are hormones that most people might even be familiar
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with because you'll see them on the blood test. One is called LH or luteinizing hormone. The other
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is called FSH or follicle stimulating hormone. So LH and FSH are released from the anterior pituitary
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gland into the bloodstream. And their targets are two specific types of cells in the testes.
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One of them is called the Sertulli cell and one of them is called the Leydig cell.
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Now the Sertulli cell is responsible for secreting growth factors that further stimulate the Leydig
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cell. And LH directly acts on the Leydig cell. And the net result of this is the production of
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testosterone. And as you can see in this figure, it's actually a little more sophisticated, right?
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There's more going on here. So the androgens that are produced by the Leydig cell testosterone
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can undergo what's called aromatization, which is the process by which they are turned into
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estrogens using specific enzymes that we'll sort of not get into at the moment. But an obvious
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byproduct of testosterone creation is the co-creation of estradiol. I guess the most important thing I
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want to say on this figure is that when testosterone is low, the feedback cycle to the brain ultimately
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is to ramp up the secretion of LH and FSH. Conversely, when testosterone is high, the signal
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that's sent back is to inhibit the production of these things. So this is a very important point
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to understand clinically. If a person is supplementing with testosterone, it is usually very obvious to tell
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this from their blood work because they have unmeasurable levels of LH and FSH and usually
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high levels of testosterone. Now, at some point, this becomes a permanent issue. In other words,
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at some point, if a person is taking exogenous testosterone for long enough, their body will
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lose the ability to make its own. Now, I think we'll come back to that a little bit later, but I just want
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to point out that this is a regulated process through a feedback loop. Another way to look at this sort of
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clinically is when you see patients who have relatively high LH and high FSH, but low testosterone. So in
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that situation, high LH, high FSH, low testosterone, the problem is usually in the testes. Conversely,
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when you see low testosterone, but low LH and low FSH, the problem is usually central, meaning there's
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something in the brain that isn't working. And of course, I'm being a little tongue in cheek when I
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say that because it's not really the brain that's not working, but there's something in that pathway
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either at the GNRH level or at the pituitary level. And I will say that the most common thing that we
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see clinically that results in that picture, i.e. low testosterone, but with an inappropriately low
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LH and FSH is sleep deprivation and hypercortisolemia, i.e. lots of stress. So those are
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unfortunately kind of ubiquitous clinical situations. We see a lot of people that have insufficient sleep or
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insufficient quality of sleep and or high levels of cortisol and stress, which by the way, are
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difficult to disentangle sometimes from poor sleep. And that can result in the brain not sending the
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right signal to the testes. But that's important from a clinical perspective because how we treat
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low testosterone when we do make the decision to treat it is highly dependent on being able to
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differentiate between those two paths. Any other questions that have come up on that particular topic,
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no, I think that's it. Okay. So where to next? So next we have the questions of, okay, so what
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constitutes low testosterone? And I think you just made a distinction there, but maybe just from a
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clinical level for looking at, you know, numbers wise, if somebody is looking at a panel, what is
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low testosterone? Well, so this is interesting. I will say that most of the literature focuses on low
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total testosterone. And I think that's probably because it's more commonly measured. It's easier
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to measure. And it's basically the one thing that's always going to be measured. Whereas I think not
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all the time are physicians also measuring free testosterone or bioavailable testosterone. Again, my bias
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is to measure free testosterone because that's actually the testosterone that makes its way into the
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cell. But if you pull up the table that looks at total testosterone levels, we'll get a sense at how
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wide the range is across all age groups. Thank you for listening to today's sneak peek AMA episode of
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