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So, without further delay, here's today's sneak peek of the ask me. Anything episode. Welcome to ask me anything
episode number 28. I'm joined. Once again by Bob Kaplan. In this episode. We talk about all things related to testosterone and its replacement. So we talked about the physiology of testosterone how it works. We talked about the epidemiology of testosterone how it changes in level, over the course of a person's life.
We talk about what happens when testosterone levels are low and what happens when it is replaced. So we talked about the benefits of testosterone and we also talked about the risks of testosterone, mainly focusing on to risks, cardiovascular and prostate cancer. A couple things to mention before we jump into this one. This is a pretty important episode whether or not you have low testosterone or not because almost everyone at some point in the course of their life will get to a point where their levels get to a level that is
Find is low and we'll talk about what those cut-offs are. Therefore. I think that whether it's something that pertains to you or something that pertains to someone that you care about whether it's a spouse or family, member or relative or friend. I think it's worth getting smart on this because there is a lot of misinformation out there on this topic just as there is a lot of misinformation out there on the topic of hormone replacement therapy for women. So, yes, this is a pretty male-centric discussion, because we focus on testosterone replacement therapy and well, testosterone does play a
very important role in women for this episode. We are focusing almost exclusively on the role of testosterone in men. Now, this is not an episode where we get into case studies. I'm not going to be going over clinical studies though. I do pepper in a lot of clinical vignette. So to speak all the way through it. So I talked a lot about the different ways in which to stas throne was replaced, the pros and cons of different ways. It's replaced injections versus patches versus gels versus oral and different.
Manners in which its dosed. So, the frequency with which you do sit and all of these things, again. This podcast is probably much more geared towards males and we are, of course, aware that our audience is only half male. So that said just as I suggested to males, when we did the HRT discussion, it's something that you ought to be aware of because you undoubtedly know, a female who is going to go through menopause and similarly, if you're a female, you undoubtedly know a male who is going to
To experience their own version of menopause, which is to say, their testosterone levels are going to go down and the question will be, should anything be done about it. So if you're a subscriber and you want to watch the full video, those podcast you can find it on the show notes page. I highly recommend that like many of the recent amas. This one will be better served by watching it on video because there's just so much data that Bob and I present and we do it in the form of graphs and figures if you're not a subscriber
Were, you can still watch a sneak peek of this on our YouTube page? But again, you'll get more out of this by watching it on video, then listening it, if you are a subscriber. So without further delay. I hope you enjoy. Am a
number 28. Hey Peter. Hey, Bob,
you ready for another? Am a sure em, man. Okay. I think we're going to get to maybe one big topic here. We got a bunch of questions.
Russians around one topic, but I think we can distill it down into. Can you do a deep dive on testosterone, or testosterone, replacement therapy? And can you do it in under?
Six hours, I think it'll be tight, but I think we can do it. Yeah, super interesting topic and one that probably just generates almost as much confusion, as the hormone replacement therapy question, does on the female side. So we've already had a great podcast that debunks a lot of the myths around hormone replacement therapy, for perimenopausal and postmenopausal women. And I think in some ways, this will be the equivalent.
Podcast for testosterone replacement therapy in men. So with that said, what this will not be is kind of a review of you know, non-stop case studies of how it's done in the real world. I think we'll Reserve that for a subsequent podcast, probably in the form of an AMA. But, you know, remains to be seen because I think sometimes there are multiple ways to go about doing this. But I think, for the purpose of trying to get through an enormous body of,
Literature, I think we'll Reserve this to what testosterone is, how it works. What's the kind of epidemiology of testosterone deficiency? IE. What does it look like, bye-bye decade? What are the implications of that? What are the benefits of replacement? And one of the risks of replacement, if we can get through that? Today, I will be delighted but we'll see. I know it's ambitious. Me too. Yeah, and I think that hormone replacement therapy is a good example here where I think with HRT, a lot of
Worry about it was breast cancer risk, and we've talked a lot about that. And here with trt. A lot of the questions were is trt right for me. If I'm worried about cardiovascular disease or prostate cancer, and there's a lot of call it controversy about that stuff, so we could to dig into it. Mmm, and I know that for this one, you sent me over some slides, the other day, that was helpful. And I think it will be helpful for the people. Hopefully, watching this. I think this is definitely another one of those things where it's fine to
Listen, but I think the level of detail will lend itself to being able to actually see what's going on both in figures and tables as we sort of draw, things out of the literature. So take it away Bob. Okay. So the first question is pretty basic. What what is testosterone? So testosterone is a hormone and it's a steroid hormones. So it's derived from the cholesterol family as many hormones are and it's synthesized in a number of steps.
I'll be honest with you. I don't actually remember anymore, how many steps it takes to create testosterone out of cholesterol, but what's really important is that it exerts its effect through binding to an androgen receptor. So because it is a hydrophobic molecule, it basically makes its way into the cell easily. It diffuses into the cell, quite simply opening. It doesn't require a Channel or a receptor on the cell membrane.
To make its way inside. So as we've talked about a lot with respect to lipids and lipoproteins cholesterol can't make its way through the bloodstream, the way glucose can or the way electrolytes can you know, for example, sodium potassium and those things because they're soluble in water. They're therefore soluble in the bloodstream and plasma and they don't need a chaperone or Carrier proteins, but cholesterol does. And that's, of course. Why it travels in things called lipoproteins and similarly testosterone.
Needs to be bound primarily to carrier proteins. And there are really two dominant carrier proteins that bind testosterone and carry it around one is called sex. Hormone-binding globulin or shbg for short and the other is albumin and directionally. Speaking shbg is responsible for about two-thirds of the carrying capacity. Whereas, albumin is about 1/3, but what's important is knowing that it's only,
Only the Unbound portion of testosterone that is able to actually exert the biological influence. So we pay very special attention to how much testosterone is quote, unquote free and free is defined as the testosterone that is neither bound to shbg or albumin. Whereas there's another term that many people who have had a blood test. May notice something called bioavailable testosterone, and that's the portion that is
To shbg but remains bound to albumin, or is free. In other words, free testosterone, which is a tiny amount. It's typically one to two, maybe three percent of total testosterone. Is that, which is completely Unbound. Whereas bioavailable includes that tiny fraction. Plus the much larger fraction that is bound to albumin. I would say from a clinical standpoint. I find that symptoms.
Rach more with free testosterone than bioavailable. But honestly, in there close enough in terms of their prediction of what's going on that if you're using a lab, that relies on one versus the other, it's probably. Okay. The lab that we use uses total testosterone, of course, but free testosterone and it's really the free number that we're paying most attention to. So let's go back to how testosterone works. So it makes its way into
The
cell and then it binds to an androgen receptor and this receptor is outside of the nucleus. It undergoes. This conformational change and it causes things called, heat shock proteins. To be dislocated. They get transported into the cell and then something called the dimerization takes place in it. And that's just a fancy way of saying, a new molecule is created by the fusion and it doesn't have to be covalent. It can be non-covalent but the fusion of two molecules that look
Look very much alike. So, this Androgen receptor dimer. Now makes its way into the nucleus, and, and binds with something called a hormone response element. And that's what actually turns on and off Gene transcription. And that's effectively what testosterone is doing. It is up or down regulating genes that are responsible for a number of things. But the most obvious of these are kind of the
Pollock or growth characteristics. Now there's something else I think worth mentioning here Bob which is the presence of another hormone here called dihydrotestosterone or DHT. Now, DHT is anywhere from oh, I don't know why. I think it's about three to six times more powerful than testosterone and by powerful. I just mean has a greater binding affinity for the Androgen receptor. And so DHT is something that is
Verted from testosterone using an enzyme called 5-alpha reductase, which I think we're going to get to that later Bob. So I'm probably not going to go into much detail on that. Now, I think that that's probably 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. It really adds much value to the clinical questions that we're going to want to get to, unless there's anything else that you have seen with respect to questions that people have about this. Not a lot of questions about that more around the Practical stuff. Like
What is low T. And you know what happens if you replace it? Okay, it's probably worth. Also saying, just something about how the body regulates this at a macro level and I think you have a slide on that. Do you mind pulling that up? Yes. So in this schematic, you can see basically the feedback loop that exists. So, obviously you have the central nervous system, but specifically, the hypothalamus and the hypothalamus in response to
Low, testosterone will secrete gonadotropin-releasing hormone. It secretes that to another part of the endocrine system, called the pituitary gland, which is divided into two pieces and anterior and a posterior. So in the anterior, pituitary gland in response to commodity open releasing hormone to other, hormones are released and these are hormones that most people might even be familiar with because you'll see them on the blood test when it's called Ella.
Sure, luteinizing hormone. The other is called FSH or follicle-stimulating hormone. So LH and FSH are released from the anterior, pituitary gland into the bloodstream and their targets are two specific types of cells. In the testes. One of them is called the sertoli cell and one of them is called the latex L. Now. The sertoli cell is responsible for secreting growth factors that further stimulate the latex L + LH directly Acts.
On the latex cell and the net result of this is the production of testosterone and as you can see in this figure, it's actually a little more sophisticated, right? There's more going on here. So the androgens that are produced by the late Excel testosterone can undergo, what's called aromatization, which is the process by which they are turned into estrogens, using specific enzymes, that will sort of not get into at the moment. But an obvious byproduct of testosterone creation is the co-creation
Of estradiol. I guess the most important thing I want to say on this figure is that when testosterone is low the feedback cycle to the brain ultimately is to ramp up the secretion of LH and FSH. Conversely, when testosterone is high the signal that's sent back is to inhibit the production of these things. So this is a very important point to
First and clinically. If a person is supplementing with testosterone. It is usually very obvious to tell this from their blood work because they have unmeasurable levels of LH and FSH and usually high levels of testosterone. Now, at some point, this becomes a permanent issue. In other words, at some point, if a person is taking exoticness testosterone for long enough,
Their body will lose the ability to make its own. Now. I think we'll come back to that a little bit later. But I just want to point out that this is a regulated process through a feedback loop. Another way to look about. Look at this, sort of clinically is when you see patients, who have relatively High, LH, and high, FSH, but low testosterone. So, in that situation, hi, LH High FSH, low testosterone. The problem is usually, in the testes.
Conversely, when you see low testosterone but low LH and low FSH. The problem is usually Central. Meaning there's something in the brain that isn't working. And of course, I'm being a little tongue-in-cheek. When I say that because it's not really the brain, that's not working. But there's something in that pathway either at the GnRH level or at the pituitary level. And I will say that the most common thing that we see clinically that results in that picture. IE load.
Testosterone. But with an inappropriately low LH and FSH is sleep deprivation, and hypercortisolism Mia. IE lots of stress. So those are unfortunately, kind of ubiquitous clinical situations. We see a lot of people that have insufficient sleep, or insufficient quality of sleep and or high levels of cortisol and stress, which by the way, are difficult to disentangle, sometimes from poor sleep, and that can result in the
Rain, not sending the right signal to the testes, but that's important from a clinical perspective. Because how we treat low testosterone. When we do make the decision to treat, it is highly dependent on being able to differentiate between those two paths. Any other questions that have come up on that particular topic pop? Now, I think that's it. Okay, so where to next
So next we have the questions of. Okay. So what constitutes low testosterone? I think you just made a distinction there but maybe just from a clinical level. If we're looking at your numbers wise, if somebody's looking at a panel, what is low testosterone? Well, so, this is interesting. I will say that most of the literature focus is on low, total testosterone and I think that's probably because it's more commonly measured. It's easier to measure and it's
We've been one thing that's always going to be measured. Whereas, I think not all the time or Physicians also measuring free testosterone or bioavailable testosterone. Again, my bias is to measure free testosterone because that's actually the testosterone that makes its way into the cell. But if you pull up the table that looks at total testosterone levels will get a sense at how wide the range is across all
age
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