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    1. Testosterone and Appearance:

      • and discuss the minimal correlation between testosterone levels and physical appearance, emphasizing the role of training, nutrition, and psychological effects. Testosterone helps with muscle recovery and effort, but effort and training remain crucial for benefits 1.

      Transcript:

      **Andrew Huberman:** And the reason is, ever since going on podcasts and talking about this stuff and talking about it on this podcast, people will send me their numbers, they'll send me their charts, and then they'll send photos of themselves. And I can tell you, while I'm not a clinician and I haven't done fancy statistics on it, there is very little correlation between someone's absolute testosterone and how they appear. I mean, some of these guys look really lean, really strong, and they'll say, oh, total testosterone is 554 80. Right? And then other people testosterone is 860. But you'd look at them and you think, oh, they kind of gave kind of a doughy look to them. And so it's got to be this free testosterone thing. Plus estrogen, et, Peter training and nutrition too.
      
      **Peter Attia:** Right. For all this talk about testosterone, which I enjoy talking about, and I enjoy talking about the data on long term health consequences of testosterone because it's another controversial topic, I also think people kind of overstate its importance. I agree. And I think there's a group of people who think, if I could just fix my testosterone, everything will be better and it's sort of like no, actually, that's not true at all. Really, the only purpose in my mind of fixing testosterone is to give you the capacity to work harder. It's really going to help you recover more from your workouts. This should just give you a greater ability to experience muscle protein synthesis. So if I just give you a bunch of testosterone and you sit on the couch and your nutrition doesn't change and you're not exercising anymore, you're not going to experience any benefits of this thing? I mean, my testosterone level has fluctuated quite a bit throughout my life. And when I think about as an adult, not sort of including when I was sort of a fanatical teenager, but as an adult, when was I at my absolute most insane physique?
      
      **Peter Attia:** Like, my best performance on a Dexa scan would have been 30. I was 38 years old by Dexa. I was 7%. Body fat, my fat free mass index was like 23.223.3 kg/meter squared. I mean, I was huge, strong and totally ripped. My testosterone was in the toilet. I was over training like crazy. I was exercise probably 26 hours a week, killing it in the gym, swimming like a banshee, cycling like my life depended on it. Grossly overtrained, low t, but physically looked like twice the guy I am today. Today my tea is probably twice as high as it was then. Now, you could say, Well, Peter, what if you took tea back then? How much better could you have been? Sure, but but again, I think the take home is just giving somebody tea doesn't do much of anything. It probably helps on the insulin resistance front without any other thing. But to me that's a waste that's squandering the gift that it is giving you, which is the ability to do more work and capture the benefit of it via muscle protein synthesis.
      
      **Andrew Huberman:** I agree. And I think that the psychological effect of testosterone, whether or not it's exogenous or endogenous, is it makes effort feel good at some level, it really seems to do that. And Sepulski tells me the main reason, or mechanistically, the main reason that it can do that is by adjusting levels of activity in the amygdala.
      
      **Peter Attia:** Interesting.
      
      **Andrew Huberman:** And so there's some interesting imaging there. I'd love to chat more about the cholesterol pathway and I know this is a huge landscape as well, but I think we're doing a good job of diving in deep, but not getting stuck in the underlying currents at all.
      
    2. Testosterone and Competition:

      • describes how testosterone influences competitive behavior by reducing anxiety and promoting novelty seeking and effort, impacting mating dynamics by enhancing competitive willingness 2.

      Transcript:

      **Andrew Huberman:** So let's talk about competition, because it turns out that competition is a powerful influence on the sex steroid pheromones and the sextroid hormones powerfully influence competition. So most people don't realize this, but most males of a given mammalian species never get to reproduce. In fact, they never even get to have sex at all. And we don't often think about that. But testosterone plays a powerful role in determining which members of a given species will get to reproduce, which ones of that species will actually get access to females. And so here, I'm not talking about humans specifically, but it's well known in species like elephant seals, in species like antlerd animals and rams, for instance, that the higher levels of testosterone correlate with access to females. Now, one interpretation of this is that the females are detecting which males have high testosterone and selecting them, they're more receptive to them.
      
      **Andrew Huberman:** We're going to talk about receptivity for mating in a moment, but it's actually more so that the males that have higher testosterone forage further and will fight harder for the females. And this is really interesting because there's very good evidence now that testosterone can reduce anxiety, promote novelty seeking and promote competitive interactions. And so before you leap too far with this in your mind and think about all these human behaviors, just stay with me, because there's a little bit of biology here that makes it all make sense. And it turns out to be pretty simple. We have a brain region called the amygdala. In Latin, that just means almond. But the amygdala is most famous for its role in fear. We hear a lot about fear and the amygdala, but the amygdala is really involved in threat detection.
      
      **Andrew Huberman:** It sets our thresholds for anxiety and what we consider scary or too much testosterone secreted from the gonads and elsewhere in the body binds to the amygdala and changes the threshold for stress. So I've said before, on previous versions of this podcast and on other podcasts, that testosterone has this incredible effect of making effort feel good. But what I was really referring to is the fact that testosterone lowers stress and anxiety, in particular in males of a given species. Now, this is important because we often think of testosterone as creating whatever masculinization or it's viralization or all these terms are thrown around. But what's it really doing when it comes to mate, choice and competition, what it's doing is it's reducing the threshold for anxiety. And in doing so, it selects individuals of a given species to push further, being willing to suffer more, although it also reduces pain. So maybe they also suffer less in pursuit of reproduction in females.
      
    3. Testosterone and Aggression:

      Transcript:

      **Andrew Huberman:** But just as a final pass at examining the role between testosterone and aggressiveness, there was a very interesting study from Goetz, et al, G-O-E-T-Z published in 2014, that looked at serum, so in this case, blood levels of testosterone. 30 minutes after application of a gel-based testosterone that goes transdermal so that the testosterone can go very quickly into the bloodstream, and then did brain imaging to evaluate the activity of neurons in the so-called corticomedial amygdala, the cortico, the medial amygdala is one of the areas of the amygdala complex as we call it because it's complex, it's got a lot of different nuclei, you know, know what nuclei are, low clusters of neurons. It's got a lot of different ones, but that medial and that cortico medial amygdala in particular, is known to be associated with aggressive type behaviors.
      
      **Andrew Huberman:** It's linked up with as part of the larger circuit that includes the ventromedial hypothalamus and other brain areas that we referred to earlier, such as the PAG. What is remarkable about this study is that it showed that just 30 minutes after application of this so-called AndroGel, this testosterone that seeps into the bloodstream, there was a significant increase in of course, testosterone and corticomedial amygdala activation. So testosterone can have acute effects, immediate effects on the pathways related to aggression. And I think this is something that's not often discussed because many of the effects of steroid hormones like testosterone, and estrogen are very slow acting.
      
      **Andrew Huberman:** In fact, steroid hormones, because they have a certain biochemical composition can actually pass through the membranes of cells, so the outside of a cell and into the nucleus of the cell and change gene expression in the cell, you think about puberty, the kid that goes home for the summer and then comes back looking completely different. Well that's because of a lot of genes got turned on by steroid hormones like testosterone and estrogen, but the steroid hormones can also have very fast acting effects and with testosterone in particular, those can be remarkably fast acting and one of the most apparent and well documented fast acting effects is this effect: the ability to activate cells within the amygdala, so you might say, \"Well, I thought the amygdala was associated with fear?\" Wouldn't testosterone then cause fear? No.
      
      **Andrew Huberman:** Turns out that the amygdala harbors, both cortisol, corticosteroid receptors and testosterone receptors, and they each adjust the activity in the amygdala differently, such that testosterone tends to activate amygdala circuitry for inducing states of mind and body that are more action based and indeed in animals and in humans, testosterone application and activation of this corticomedial amygdala pathway will make animals and humans lean into effort. This is why I say testosterone makes effort feel good, or at least biases the organism toward leaning into challenge. So if you recall, there's not just one type of aggression, there's reactive aggression, which is triggered when one is confronted with something that sometimes is inevitable, right?
      
      **Andrew Huberman:** One needs to fight for their life or for somebody else's life, but also proactive aggression and proactive aggression involves activation of those go-pathways in the basal ganglia and a leaning into effort to overcome whatever state one happens to be in to begin with. And so this is very important because it points to the fact that yes, estrogen is activating aggression pathways that are in the ventromedial hypothalamus, but it's very likely the case that testosterone is acting to accelerate or to bias states of mind and body toward those that will lead to aggression. Again, aggression is not like a switch, on and off. It's a process. It has a beginning, a middle and an end. Remember that hydraulic pressure that Conrad Lorenz hypothesized? Well, think of testosterone as increasing the pressure toward an aggressive episode and then estrogen actually triggering that aggressive episode in the ventromedial hypothalamus. So if somebody tells you that testosterone, endogenous or exogenous makes people aggressive, tell them no, testosterone tends to make people lean into effort. And if that effort involves being aggressive, either reactively aggressive or proactively aggressive, well then it will indeed lead to aggression. But the actual aggression itself is triggered by estrogen, not testosterone.
      
    4. Testosterone Replacement Therapy (TRT):

      • TRT guidelines, emphasizing low-dose, frequent injections to manage side effects and maintain steady testosterone levels are detailed by 4.

      Transcript:

      **Andrew Huberman:** Very interesting. We haven't really talked about testosterone and optimizing testosterone in males, assuming someone is paying attention to the six pillars. There's kind of a gap, as I see it, between doing all those things and TRT hormone replacement therapy. And again, the R, the replacement in TRT is a little bit of in quotes nowadays because a lot of people who have testosterone in that 300 to 900 nanogram per deciliter range opt to take low dose testosterone. Anyway, my understanding is that there have been some new kind of movements in this area toward, for instance, not doing big large doses injected infrequently, but rather low doses, quite frequency, obviously prescribed by a doctor, monitored by a doctor, et cetera. Is that generally what you like to see in your patients? If they're going to take this route.
      
      **Dr Kyle Gillette, MD:** If they're a hypogonadal patient whose benefits outweigh risks of TRT, then you want to have a nice, even steady state. It's not going to be exactly the same as producing pulsatile testosterone. Release endogenously from your own body. When you have a steady state, you don't have a peak or a trough, and when you have a peak, that's when the androgen receptor gene is overactive. That's when you get more erythropoietin or EPO release. And that leads to a lot of the side effects of thick blood. So higher hemoglobins and hematocrites. And then when you have a crash, you don't feel good, so it's definitely not optimal. There's a lot of ways to get around this. So when you're doing testosterone replacement, if you're someone that needs it, you can have different types of esters or you could do topical testosterone. So the ester is basically something that's attached to increase the biological half life. The most common ones are cipionate and anthate.
      
      **Dr Kyle Gillette, MD:** There's also a very short acting proprieonate, which has almost no clinical relevance. And there's also very long acting ones, decannowate and undecannowate, and different mixtures of all those. So if you're someone who has a very, very low shbg, you're going to have trouble regulating your serum testosterone in the long run. If you do it topically, then the testosterone is absorbed, hopefully bound to SHPG, and then a lot of times you reapply twice daily or once daily, but you have lots of variations. So for most people, especially for people who can't absorb it, well, that's not going to be a great option.
      
      **Andrew Huberman:** So injections would be preferred.
      
      **Dr Kyle Gillette, MD:** Most people end up injecting because they have either side effects from too high, too low, or just too much of a varied dose. When they do topical, there's also a capsule with a special lymphatic absorption, so it's not being absorbed through the liver, it's not hepatically metabolized, but it's absorbed through the lymph and it's essentially testosterone undecannowed and then put into a capsule. And that's taken twice daily. It has fairly steady half lives, but you have to take it at specific times of the day. So that being said, and it's new enough to where there isn't a huge amount of data on it, but it is FTA approved, so it is brand name now. It's called jutenzo. But the injectables in general, the lower your Shbg, the longer of an ester you want, because when you inject it, whether it's intramuscular or subcutaneous, just talk to your doctor about the risks and the benefits of those.
      
      **Dr Kyle Gillette, MD:** Subcutaneous has slightly longer active half life because the ester races take longer to reach that cipionate or an anthester to cleavage. So most men, a lot of people ask me about what a usual dose is. For most people, it would be a total of about 100 to 120 per week. For an actual replacement dose.
      
      **Andrew Huberman:** Milligrams.
      
      **Dr Kyle Gillette, MD:** Milligrams. 120 to 100 milligrams per week, administered two to three times per week.
      
      **Andrew Huberman:** So you're saying dividing that into two or three? Right, because I'm sure there's a bunch of people out there thinking, oh, yeah, 103 times a week, which is actually quite high dose yeah, there really does seem to be a shift toward spreading these dosages out into dividing them into two or three smaller doses. And then along those lines.
      
    5. Sperm Development:

      • A discussion on the role of testosterone and androgen-binding protein in sperm development, highlighting the importance of these hormones in maturing healthy sperm 5.

      Transcript:

      **Andrew Huberman:** In fact, the concentration of intratesticular testosterone is at least 100 times higher than the concentration of testosterone anywhere else in the body, even though it's being secreted into the rest of the body. And that's because there are a number of different so-called binding proteins and enzymes that sequester the testosterone within the testes. So the Leydig cells are making testosterone, and a lot of that testosterone is acting on and is restricted to the testes. And that turns out to be very important because testosterone within the testes acts in concert with a different biological program that starts with FSH, follicle-stimulating hormone, that also travels to the testes and acts on a very specific set of cells that are called supporting cells or, more specifically, the Sertoli cells. The Sertoli cells are the cells that generate something called ABP, or androgen-binding protein. And it is the combination of testosterone from the Leydig cells and ABP from the Sertoli cells that is necessary for spermatogenesis.
      
      **Andrew Huberman:** It's necessary for those spermatocytes to become what will eventually be healthy, mature sperm that have really nice shaped oval heads, have a mid region, chock a block through mitochondria, and can generate a fast whipping motion of the tail to swim from the cervix, or up the vagina into the cervix, and from the cervix to the egg to fertilize the egg. So it's really a basic set of chemical players that are involved here and so basic, in fact, that if you were to disrupt any one of these chemical players-- either the luteinizing hormone, the FSH, the testosterone from the Leydig cells, or androgen-binding protein-- you would observe pretty marked disruption in spermatogenesis or the elimination of sperm entirely. We'll get into a few deficits in sperm development and sperm number and sperm function a little bit later. But just keep in mind-- or I should say, maybe sit back and just appreciate that the exact same players generate from the hypothalamus, which causes luteinizing hormone and follicle-stimulating hormone released from the pituitary, which travels to the gonad, which in this case is the testicle, which triggers the release of testosterone from Leydig cells, which triggers the action of the supporting cells, the Sertoli cells, which make androgen-binding protein.
      
      **Andrew Huberman:** Testosterone and androgen-binding protein combine and create a chemical and actually a structural milieu in which those little spermatocytes can go from the walls, from literally the walls of the tubes of the seminiferous tubules, can mature into healthy, well-developed sperm, and can hop into those ducts, those little tubes, and then head off to the epididymis, where they will reside-- the epididymis is the tissue nearby the testicles or surrounding one portion of the testicle-- and then eventually fuse with the vas deferens, can combine with or be contained with, rather, the seminal fluid, and then can be ejaculated via the urethra into the female, where then they can swim very quickly, effectively the distance, for them anyway, from Los Angeles to San Francisco, over the course of a very short period of time, and fertilize the egg. So that's the process of spermatogenesis, the maturation of sperm, which is ongoing throughout the lifespan from puberty onward. And in doing so, we talked about some of the hormonal elements-- coming from the hypothalamus and coming from the pituitary, and within the testes themselves the Leydig cells, which produce testosterone, the Sertoli cells, which are the support cells that allow spermatogenesis to occur.
      
    6. Testosterone in Women:

      • and explore testosterone's role in women, its production, and its importance alongside estrogen and progesterone for health optimization 6.

      Transcript:

      **Andrew Huberman:** I want to touch on testosterone in women because there is testosterone in women. I'd like to know where that testosterone comes from, which tissues. I'd like to know whether or not testosterone replacement therapy makes sense in women. I'm hearing more and more about women using testosterone and I'd like to know whether or not knowing a woman's testosterone for her to know her testosterone is of equal, less than, or more value than knowing, for instance, progesterone and estrogen levels. Because I think there are a lot of misconceptions about the roles of testosterone in women.
      
      **Dr Kyle Gillette, MD:** For health optimization, testosterone is just as important to know. For pathology prevention, for example, breast cancer, osteoporosis, estrogen and progesterone are more important to know. So when you're thinking about women, women think that they have such a tiny amount of testosterone because you test it. Most people test a free testosterone. So a testosterone that's unbound, which is by far the smallest proportion of testosterone any androgen is bound by lots of different steroid binding proteins. But the ones that are most pertinent are called Shbg or sex hormone binding globulin. And that binds the androgenic steroid, for example, Dht or dihydrotestosterone, it's associated with prostate enlargement, it's associated with male pattern baldness. It binds that the most strongly. And then it binds testosterone next most strongly. And then it binds things like Andersonidione or Dhea dehydroepi androne and then it binds the estrogens, the weakest like estrodiol. So if you look at the total amount of testosterone women actually have, almost all women, not all women, but almost all of them have significantly more testosterone than estradiol. But it's because it's in different measurements. So estradiol a lot of time is peak grams per mill as opposed to nanograms per deciliter. So women have more testosterone than estrogen and significantly more Dhea than either.
      
      **Dr Kyle Gillette, MD:** Interesting.
      
      **Andrew Huberman:** Do women make dihydro testosterone?
      
      **Dr Kyle Gillette, MD:** Yeah.
      
      **Andrew Huberman:** Where does this testosterone come from? Because they don't have testes.
      
      **Dr Kyle Gillette, MD:** Yeah, so most testosterone in women that are pre menopausal can come from theca cells T-H-E-C-A. So theca cells are cells in the ovaries that can produce testosterone. And a lot of people have actually heard about hyperthycosis, not the term itself, but a lot of Olympians that are their chromosomes are x y. They're females and they are not taking any XY, but they're females. Sorry. They're Xx. Yeah. Thank you. So they're Xx, they're not x y, and they have never transitioned or been on any sort of hormone replacement or testosterone, but they naturally produce a huge amount of testosterone, as much as many men. And some of these women, I believe they were from Botswana, were banned from competing in the Olympics in certain distances. I believe they were banned from the 400 meters and 800 meters because their natural testosterone was deemed to be too high.
      
      **Andrew Huberman:** So they mistakenly thought that they were using steroids.
      
      **Dr Kyle Gillette, MD:** They actually knew they were not using steroids. They knew it was their thea cells were just genetically gifted, I suppose, and they still made them change distances. Wow. So one or two of these athletes changed to, I believe it was the three K or the five K, and they still did quite well, but it was not their best event.
      
      **Andrew Huberman:** Interesting. Yeah. That's turning out to be a very interesting and controversial area of this notion of hormone therapies and natural variation in hormones on different chromosomal backgrounds. Fascinating. We should probably do a whole episode about that because it's very much of the times.
      
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