Dr. Rhonda Patrick: You hear a lot about low T. Low T. And there's, like, this controversy around it. What defines low T? Is it levels? Is it a combination of levels and symptoms? So we're looking at menopausal women. We're talking about an average age of about 51 or something like that, right? Men, let's take the same period of life for men, okay, 50s. Do they start to experience like a decrease in testosterone around that time?

Dr. Peter Attia: Yeah, but it's more gradual, and it starts, frankly, in your 20s and 30s. So male testosterone probably peaks in the 20s and it's just a slow, steady decline. It's not like in the case of women where they go through puberty, they have these hormones that are cyclical and then fall off a cliff. With men, it's sort of you go through puberty, you kind of peak and then you're on a slow decline down. So you're right. Low T is really a combination of levels and symptoms and it's really important to remember that symptoms matter because levels are really, well, how can I put it delicately? I mean, just not as helpful as we'd like to believe they are. And it actually comes back to something you talked about a minute ago, right? Which is how do these hormones work?

Dr. Peter Attia: These hormones work by binding to androgen receptors and the testosterone androgen receptor complex has to make its way into the nucleus where it impacts transcription factors. Now, we know that not all men have the same density of androgen receptors and we know that not all androgen receptors function in the exact same way. So you have this problem which is we sit here and we measure testosterone levels in men and maybe we measure bioavailable or free testosterone, but those are just estimates. They aren't actually telling you your free testosterone level. You're measuring total testosterone, you're measuring sex hormone binding globulin, you're measuring albumin, you use those to estimate the free amount of testosterone, but that's still an estimate.

Dr. Peter Attia: Kind of like LDL-C calculated by the Friedewald formula is an estimate. And then you sort of have to guess, well, maybe their androgen receptors are saturated, maybe they're not. But if you're giving a guy testosterone in the presence of mild to low T, you're assuming his androgen receptors are not saturated and therefore giving him more testosterone will lead to an increased saturation of the AR and will lead to more nuclear transcription. But we have no way of measuring that. And so what I always say to patients is I've got to see a certain set of symptoms in combination with a biochemical set of labs that makes sense and then we have to test it out, but it's not going to be a placebo-controlled test, so we're going to have a placebo effect.

Dr. Peter Attia: And then if the response we see isn't a hell yes, I think we should pull it all off and see if we notice a response in the deficit. And I'm looking for symptoms as follows, right? So I'm looking for some signs and some symptoms. Most of it is symptoms. So it's, you know, reduction in libido, reduction in energy, mood. And then on the signs, we're kind of looking for insulin resistance, difficulty putting on muscle mass and difficulty recovering from exercise. Those are kind of your big ones. And some combination of those signs and symptoms coupled with a biochemical story that's plausible. So, you know, your total testosterone might be below the 30th percentile or even 40th percentile. And your free is commensurate with that, even though, again, that's an estimate. There's probably reason, in my book, to initiate treatment.

Dr. Rhonda Patrick: And is there a level that you decide to go to? Like, so, I mean, is there like a threshold where it's like, this is too much testosterone?

Dr. Peter Attia: Yeah, it's actually kind of like what we were talking about on the vitamin D front. Like, don't be too incremental. You're not going to get the answer. And again, each lab is going to have different scales. But in the lab, we use the fifth percentile of total testosterone. Well, let's do free testosterone because we actually, even though free is an estimate, we kind of look more closely at free. So approximately the fifth percentile is five nanograms per deciliter. And the 95th percentile is about 24 nanograms per deciliter. So call it five to 25, basically. So if a guy is at eight and we have a case to try TRT, I'm not going to take him to 12. That's incremental.

Dr. Peter Attia: I'm going to take him from eight to 20 and see if something changes. If he says to me at 20, “I don't feel any different,” and we take it away and he says, “I don't feel any different,” then I would say this guy might've already been saturated at eight nanograms per deciliter where he started, and all that additional testosterone may have done him no good. The exception is if we were only treating this for insulin resistance and muscle mass, in which case I would say we should still stay the course and see if those things get better. Whereas somebody else might've been woefully undersaturated. And when you increase him by 150%, you actually got benefit from it.

Dr. Rhonda Patrick: Does the injection versus like a gel, does that matter?

Dr. Peter Attia: We're very biased towards injections. I think they're far more consistent. I think, you know, you have variable absorption and it doesn't just vary by individual. It varies by time of day. So, you know, for example, if you just finished a workout and you're sweating, even if you go and have a shower, you're still kind of in a less absorptive state than maybe if you're cold. You know, what part of your body do you put it on? Do you have to exfoliate the skin first? Do you have hair on the skin? You know, you want to put it on an area that doesn't have hair. There's just more issues with it. So we recommend an injection. We also recommend instead of doing it every two weeks, which is standard, doing it twice a week at obviously a much lower dose.

Dr. Peter Attia: So typical dose would be somewhere between 80 and a hundred milligrams of testosterone a week. So it would be 40 to 50 milligrams twice a week. And that produces just a much more steady level because you're really trying to get the steadiest level possible. The every-two-weeks schedule was usually used in the days when people went to their doctor for the injection and wanted to minimize the inconvenience. But with that schedule, you're supraphysiologic for, you know, four or five days. Then you're kind of physiologic. And then you're actually back down to being very subphysiologic before the dose. So we'd like to avoid that.

Dr. Rhonda Patrick: Is there any like, what's the relationship between testosterone replacement therapy and like the prostate?

Dr. Peter Attia: Yeah, very well studied. So a couple of things we know as clear as day, right? So we know that the lower the testosterone, the higher the risk of high-grade prostate cancer. So again, contrary to popular belief, testosterone replacement therapy does not increase the risk of prostate cancer. But what it does do is potentially increase BPH, benign prostatic hyperplasia. So it does increase the size of the prostate potentially. So one, you know, needs to be mindful of that. And also there are side effects of testosterone, right? It will drive hair loss in an individual who's susceptible to hair loss through the sort of androgen pathways there. It can increase acne in a susceptible individual.

Dr. Peter Attia: Again, these things are typically more the type of side effects that people talk about when testosterone is being used in supraphysiologic levels. So I'm just trying to think the last time we saw a patient who had acne, I'll probably see it once a year. So these are really infrequent side effects. But we do have a lot of patients who, you know, are concerned about hair loss. And so we say, look, I mean, there are strategies around that. Of course, you can take a 5-alpha reductase inhibitor. So those are drugs that block the conversion of testosterone to dihydrotestosterone, which is a more potent androgen. And that's the androgen that's driving androgen-specific hair loss. Or they might say, you know, like I've had patients say, oh, you know what?

Dr. Peter Attia: Like my hair matters more to me than my testosterone. I don't want to take testosterone. So those are the things that we just kind of want to point out. The only other thing that's worth noting is I do believe that in a susceptible individual, in the short run, there's probably a slight increase in the risk of cardiovascular events with testosterone. And it's probably borne through an increase in blood pressure. So there was a very large study that looked at kind of high-risk men. And they were given testosterone. And at one year post-initiation of TRT, there was a slight increase in the risk of major adverse cardiac events in the testosterone group compared to the placebo group.

Dr. Peter Attia: That vanished at two and three years, almost suggesting that the highest risk men, probably those that were closest to having an event, were actually pushed over the edge a little bit. Again, I would probably attribute that to an increase in blood pressure as the thing that was potentially driving it. So, you know, we're not keen to put guys on testosterone until we have the house in order with respect to everything else.