Male hormones and men's health

Male hormones and men's health

In this episode of A Whole New Level, Levels editorial director Mike Haney talks with Dr. Jesse Mills, a board-certified urologist and director of the Men's Clinic at UCLA. Dr. Mills specializes in male reproductive medicine and surgery, male sexual health, and male endocrinology, with nearly 20 years of experience in men's health.

This conversation is part of a series exploring different systems of the body---how to measure their health, how they relate to the rest of the body, and what we can do to improve them. The timing aligns with Levels expanding into comprehensive blood testing, giving members access to markers they may not have seen before.

They discuss the male hormone system from top to bottom: how testosterone is produced and regulated, what low testosterone looks like, when testosterone replacement therapy makes sense, and how to interpret blood test results. Dr. Mills also covers PSA testing and prostate cancer screening, explaining how modern diagnostic tools have transformed the landscape from overtreatment to more precise, personalized care. Throughout, he emphasizes the importance of lifestyle factors, the value of informed patients, and the evolving state of men's health as men become more willing to seek care and take ownership of their health.

How men's health evolved as a medical specialty

Mike Haney: So for context, you run the men's clinic at UCLA, and what we're going to talk about today, this show is part of a series we've been doing. I think we're going to do about a dozen shows on different parts of the body or different systems of the body, how we measure them, and how we improve them and how we make sense of those measurements. And this is inspired a little bit by our company's gotten into expanded blood testing. So we're going to have members or just folks who consume this podcast go get these expanded blood tests. They're going to start getting markers they haven't gotten before. And what we're really trying to do here is just talk to experts to help people figure out what to do when they get those back. And so today we're going to talk about male hormones. And then we're going to talk about PSA, which is another set of tests folks are going to get. But by way of starting, maybe just a little bit more about your background, how you came to focus on what you do and what you do at the men's clinic, what the men's clinic at UCLA is.

Dr. Jesse Mills: Men's health is probably the most rapidly evolving thing in medicine because I would argue it didn't even exist when I was in medical school. I was in medical school starting in 97-98, which is when the little blue pill came out. And I think that arguably started this idea that men's health is a thing because now we have a treatment for something that will bring guys into the doctor, whereas before we would not go to the doctor unless we had bone sticking out of us somewhere or some kind of sexual dysfunction, of which there was really no treatment.

So now you got this pent-up demand and we realized that guys that have this problem with erectile dysfunction, especially younger guys, we reverse engineered this physiology to say that they also probably have cardiovascular issues. And that really built the structure for men's health.

I had thought about going into a career in urology. I was transfixed with microsurgery and I thought the amazing ability to reconstruct somebody, to fix a problem using basically just your fingertips and a microscope, this is magical. The suture that I use to reconstruct the reproductive tract, which is really where my specialty is now, you can't see without a microscope. It's finer than hair.

Out of that, the idea of being a fertility surgeon comes this entire world of endocrinology and specifically male endocrinology because the reconstructive part is probably 20% of what I do. I do a lot of surgeries in sexual medicine as well, but bottom line is I have a lot of endocrine work I have to do that doesn't fall to the traditional endocrinologist.

That was right around the time that the testosterone revolution began in this country. Testosterone was isolated in the 1930s, won a Nobel Prize, but we had been experimenting with testosterone and animal derivatives of testosterone into the 1870s. But with the commercially available prescription for a transdermal product, which hit the markets right around 2000 in a brand called AndroGel, that had all this access to something that was easy to do. You didn't have to go in and get painful injections. Those two things hit at exactly the time I was making my decision to go into urology.

I did six years of urology training at University of Colorado and two years of general surgery. I did a fellowship in male reproductive medicine and surgery down at Baylor in Houston where I learned how to do microsurgery as well as do all the endocrine management. And that was almost 20 years ago. Since that time, I've been in practice since 2007, fully dedicated my entire career to just men's health.

Mike Haney: And what kinds of things are you treating nowadays at the men's clinic? What do you see folks coming to you for?

Dr. Jesse Mills: I was recruited out to UCLA about 10 years ago in 2015 to establish this men's health clinic. And we just opened up our brand new 11,000 square foot center on 2901 Wilshire. So right down the street from Erewhon, perfect marketing and brand placement for men's health.

The typical day for me is seeing a combination of men with low testosterone, with a history of any kind of sexual dysfunction, erectile dysfunction. Most of the practice on that side for me is surgical. So doing reconstructive urology to help restore erections in men. And then the other big thing is Peyronie's disease, which is often painful curvature of the penis that prevents men from being able to have normal intercourse. That's one of the things I've probably done the most research on.

And then a lot of men that are having difficulty initiating pregnancies, and a lot of those guys have some kind of endocrine disruption, some kind of problems with their testosterone or their pituitary hormones that govern the system. That keeps me busy from 8 to 5 every day other than when I'm in the OR.

Mike Haney: I'm curious what the difference is in either the things people are coming to you for or who's coming to you from when you started. You mentioned that pre-Viagra there was and certainly historically maybe for folks of our generation a real reticence to go to the doctor, especially among men. Have things changed over the 20, 30 years you've been doing this?

It is really fun to see men take ownership and be open about their process. The number of guys that are willing to share their story from sexual dysfunction to the fertility journey, those are conversations our dads would never have.

— Jesse Mills, MD

Dr. Jesse Mills: Things have even changed over the last two to three years and I think at some point I'm not going to have to say guys are reticent to go to the doctor because that has changed. And I feel a lot of gratitude and pride in the fact that men are doing this and a lot of it is because of the information that's out there. A lot of this is because of podcasts like this where you're arming the public to be informed and curious and interested, and those are really powerful weapons to come into the doctor.

So my practice has blissfully shifted more towards health optimization now and disease prevention, which is crazy. I went six years of training after medical school plus another year of fellowship to do fine, delicate reconstructive surgery, and still a big part of my day is teaching guys how to take better care of themselves now. And I'm okay with that trade-off. I'm still busy. I was still operating last night till 8 o'clock at night, so I still have a busy surgical practice. There's plenty of pathology out there, but it is really fun to see people and men particularly take ownership and be open about their process.

The number of guys that are willing to share their story, especially for what I do, anything from sexual dysfunction to the fertility journey, because that is so tied into our masculinity or machismo. So for a guy to be able to come to the doctor and say, "I have a problem with fertility or I have a problem with my testosterone, I have a problem with my penis," those are conversations our dads would never have. And probably even my generation, our generation is still reluctant to have. And so that's the cool thing is I'm seeing 26, 28, 30-year-old guys that just want to make sure they're doing okay.

Mike Haney: I wonder if the presence of a men's clinic is helpful there. I think about having this conversation with my general doctor versus knowing there is a place that is dedicated to these, and just that seems like it alone would get over the stigma of I don't want to talk about it.

Dr. Jesse Mills: I think that is it. They know walking in it's going to be an open, non-judgy space. Give you an example of a guy I saw yesterday in the afternoon who was 34 and he had spent pretty much since late adolescence getting testosterone from some guy at the gym or some guy on the internet somewhere and didn't even know where to source it from. And he was definitely somebody that used anabolic steroids as well.

But he came to me and said, "I finally wanted to do this legit and I felt like this would be the place. Because when I went to my primary doctor, you know, the minute you hear anabolic steroids, that guy's already been pre-judged. It's not real medicine." And these guys, I mean, they're deserving of care and actually they're incredibly good, compliant patients when you come up with a reasonable, rational, medically based, evidence-based regimen. Those guys would have never been in a doctor's office years ago and so they're kind of wandering the internet and wandering the back alleys of gyms to try to get that look or that feel. And there is real medicine in there.

And then trying to differentiate what I do, which is academic, evidence-based, we're writing the literature medicine, and then men's clinics that are really just kind of going to sell a product. That's the big differentiator I want your audience to know. If you walk into a men's clinic and they're automatically signing you up for a testosterone regimen without doing their due diligence, checking the levels, knowing what their labs are, knowing what's happening in their pituitary gland, all of those things are critical to a workup.

So it's not just a matter of going to a men's clinic, but going to the men's clinic, going to a place that really specializes in the academy of this. And that's the kind of patients that we're looking for, men that are willing to take charge and take ownership of their health as well. Because almost every relationship in my practice starts as a dialogue and a coach-player relationship before I even write a prescription. It's delving into their lifestyle, delving into their nutrition, their physical activity or lack of it, their sleep patterns, what are they doing on a global level before we get into the weeds of various precursors of testosterone.

How the male hormone system works

Mike Haney: Let's start with a little 101 around male hormones. We've done a couple episodes on female hormones and I feel like when we talk about hormones, particularly when we talk about female hormones, there's no way to escape fertility, menopause, sort of the context, right? When we talk about male hormones and what those are doing in the body, maybe just the highest level of how should we think about hormones and how they interact with the rest of our systems and our well-being.

Dr. Jesse Mills: Let's work from our head down. The control of male hormones starts up in the hypothalamus, which is kind of the lower level of the brain. And there is a signaling molecule called gonadotropin-releasing hormone or GnRH. It's not really clinically measurable, but it is what starts this system. It kind of ignites the spark to then send a signal down to the anterior pituitary gland, which sits right behind our nose and right between our eyeballs.

That puts out two hormones: luteinizing hormone and then something that was originally discovered in women called follicle-stimulating hormone. Why it's discovered in women? Because men don't have follicles, but it turns out that FSH is what governs sperm production. So it has the same function in a guy, it just governs sperm instead of ovarian function. So you have LH, FSH.

Now you travel all the way down to the testicle and that's the factory. So the testicle is pretty much the only organ that makes testosterone. There's just a small percent of testosterone that's made up in the glands that sit above the kidney called the adrenal glands. In men it's essentially negligible, but it has a higher role in women just because their testosterone sensitivity is so much greater, 10 to one. The testicle makes testosterone and makes sperm, and then that gets released into the system.

The two main conversion points for testosterone are into estradiol, where estrogen is an easier way to say it, and something called DHT or dihydrotestosterone. Those are the pathways that testosterone works, and those are all controlled by an enzyme that decides how much estrogen to make from testosterone, how much DHT or dihydrotestosterone to make from testosterone.

So that sets up the players. From there, the whole system runs. I look at the function of testosterone in the man into two big buckets. I've been made fun of for saying this before, but I like it: you have a sex bucket and then a non-sex bucket.

What testosterone does for sexual function

Dr. Jesse Mills: In the sex bucket, it's basically three things. It controls libido. It's not the only thing that controls libido, but testosterone is probably one of the main libido, sex drive hormones in men. And it really works up here in the prefrontal cortex and a little bit in the hypothalamus, our lizard brain, saying, "I want to have sex and I want to have it now." That's kind of a testosterone derivative thing.

It also controls the ejaculation and the amount of semen volume that comes out within an ejaculation. So it works on the prostate gland, which is what makes the majority of semen in the body.

And then it also has a pretty significant effect on erectile function, which is something we didn't really know forever. We thought they were separate, but the big thing that testosterone does is it controls nitric oxide synthesis, which is probably a whole other podcast. It won a Nobel Prize at UCLA about 30 years ago. But nitric oxide is what governs blood flow to the penis and the relaxation of the smooth muscle in the penis.

So guys with very low testosterone tend to not have as good erectile function. They almost never wake up with an erection in the morning, which is very physiologically important to us and is one of the great signs of testosterone deficiency. If I ask a guy, "Are you waking up in the morning with an erection?" and they say no, then the first blood test I'm going to get is a testosterone level.

What testosterone does beyond sexual function

Dr. Jesse Mills: And then in the non-sex bucket, it's like everything. I mean, it's so much that it's hard to just narrow it down to testosterone. And this is where things like the overlap between thyroid and testosterone are important because testosterone can control heat regulation. Guys that have really low testosterone can get hot flushes just like menopausal women. Well, that's also potentially a thyroid issue, so you have to be able to tease those out.

It's critical for cardiovascular function, critical for maintaining healthy body weight. So men that have very low testosterone tend to carry a lot of fat around their midsection. The balance of testosterone is critical for maintaining good lipid profiles, so good HDL levels. Men that have really low testosterone have really low HDL, which is our good cholesterol.

It's also super important for bone density. Those are the big things outside of even the mental health, which is where it really gets fuzzy. But for the most part, we know that guys that have normal testosterone tend to have more even moods. They tend to have faster, maybe more definitive decision-making capacity. So if your testosterone is really low, one of the signs is you can't decide. "Oh, I'm going to have the sandwich or the salad today." Believe it or not, that's partially testosterone function, how quickly you're going to make those decisions.

And just on and on and on from head to toe. There are functions that testosterone can be important for. But I think those are really the big things and those are things that get guys into the office when one of those systems is off.

Primary versus secondary hypogonadism

Mike Haney: So when you're looking at a blood panel, I'm going to get testosterone, I'm going to get free testosterone, I'm also going to get LH, I'm going to get FSH, I'm going to get DHEA. How should I make sense of those other kinds of hormones? You mentioned things like FSH and LH are precursors to testosterone. Are you looking at those kinds of levels as indicative of anything? Or rather, if those are off, does that tell me anything?

Dr. Jesse Mills: I love this. The detective work that goes into determining if a guy has low testosterone, you're right, it isn't just a blood test. It isn't just a total testosterone. If a guy, I mean, that actually is decent. If I had one test to get, of course I'd do a total testosterone and then correlate it to the symptoms the guy's having, some of the things we hit on.

But for me, we have to figure out why. It's especially important in a younger man, especially important in a guy that comes to me maybe with some degree of fertility questions. He may not be wanting to have kids yet, but he wants to keep that option open. And so we look at testosterone deficiency, or sometimes we call it hypogonadism, and we look at it in two different ways.

We say there's primary hypogonadism and there's secondary hypogonadism. Primary simply means the testicle is not working. So both means your testosterone is low, but primary means there's something wrong with the testicle intrinsically wrong. And it could be anything. It could be genetic. There are men that are born with a chromosomal abnormality where their testosterone levels never get very high and they will always need some kind of testosterone replacement.

There are things that are directly toxic to the testicles. Probably the most common one that we induce in the world of medicine is radiation. So if you need radiation therapy for any kind of pelvic cancer, that can affect the ability to make testosterone. There is trauma to the testicles. There are some things that are probably what we call mixed, but things like alcohol, marijuana use, for example, which, well one is on the dramatic rise, one sounds like alcohol use is kind of going down with the California sober movement. But the direct toxicity to the testicular tissue from some things we put in our body can all cause primary low testosterone.

Secondary means there's something wrong with either the hypothalamus or the pituitary gland. And it's super important because primary testosterone deficiency, meaning if the testicle is not working, there's no medication I can give a guy to reverse that. I can talk about lifestyle changes. You can say, "Hey look, your testicles aren't working. If you lost some weight, if you stopped drinking, if you cut down on your weed, all that kind of stuff," okay. But bottom line is the only prescription I can write a guy for primary hypogonadism is testosterone therapy. I have to give them some kind of testosterone.

Mike Haney: Can you restore function through lifestyle changes there?

Dr. Jesse Mills: Depending on why. The other big thing that can change in a guy with a testosterone level is they can have an anatomic problem as well. So the most common thing I see is something called a varicocele, which is a collection of veins that are really swollen around the testicle. And it's common in taller guys, common in athletes, common in bodybuilders. That actually can cause some degree of testosterone deficiency. And so sometimes we can reverse that by fixing it microsurgically.

But certainly, poor sleep is another cause of low testosterone, but again that will be more on the secondary side. So for primary, it's a little bit tougher to look at lifestyle. Secondary, we've got all day to talk about how you can reverse that with lifestyle issues. It's one of my favorite things to do is not write a prescription for testosterone if I can figure out how a guy can reverse it on his own.

But if the testicles aren't working, if they're absent from trauma, if they're crushed, if they had any kind of extrinsic deficiency, then we just got to replace the testosterone with a prescription.

How to read your blood test results

Dr. Jesse Mills: But secondary, something in the pituitary gland isn't working. That is a whole bucket of stuff that can go wrong from chronic fatigue, poor sleep. If a guy is not getting enough sleep, then the pituitary gland never really recovers at night. Shift workers, we have great data on guys that are working overnights and messing up that circadian rhythm. Their testosterone tends to be low because they're getting poor stimulation from the pituitary gland. So that's a huge issue with lifestyle modification. Sleep, sleep, sleep.

Obesity, another cause of secondary hypogonadism where the testicle is not getting the signal because the molecular markers are just getting kind of diluted and they're not getting to the testicle.

But secondary hypogonadism, the way we look at that in a lab, in a panel, is those pituitary hormones are going to be low. So if a guy comes in and his testosterone, I'll just make up a couple of guys just to drive this point home. A guy comes in, feels terrible, has all the symptoms of low testosterone. I examine him and his testicles are fine. They don't feel like there's no disease in them. They don't appear to be concerning at all to me. Then I'm thinking he probably has something wrong up here, secondary, which is far more common. I look at his pituitary levels. His LH and FSH are really low.

And if you kind of want to nail me down on levels, it's a little tricky because there are lab levels and then I think there's interpretive levels. But for a guy with low testosterone and his gonadotropins, which is the global term for LH and FSH, are less than six, then he probably has some degree of pituitary suppression where he's just not getting the signal. And that changes how I can manage this guy pretty significantly.

So if a guy comes in and has very high gonadotropins, so his LH and FSH are really high, that means that the pituitary gland is screaming to the testicle, "Dude, wake up. You've got to start making testosterone. I'm dying up here because I'm not getting the feedback." The testicle, for whatever reason, it was in an accident, it just is not responding. Then that's primary hypogonadism.

And the reason that the difference is important is that we can often reverse secondary hypogonadism. It has a much bigger implication for fertility treatment because there are medications I can give a guy to stimulate him to make his own testosterone and his own sperm production. So if a guy comes in with low testosterone, low sperm count, and low gonadotropins, low LH and FSH, that's a guy we may be able to reverse with medical therapy or again, lifestyle modification, sleep, exercise, better nutrition.

Mike Haney: Is there a sequence when we talk about that secondary hypogonadism? Is there a sequence to the testosterone is going to fall first and then the pituitary markers or the other direction?

Dr. Jesse Mills: Oh man, love this. I have a little pet hobby that I call forensic endocrinology where I try to recreate what happened to this guy. And the reason is that we really, we don't look at testosterone levels when a guy goes to the doctor at 18. He's an adult and he gets kind of his last hernia check and then he goes off to college or he goes off to his life outside of his parents' insurance. We don't do a testosterone level. And that's really important because the range of testosterone normal is huge.

I don't know where his T was. If he was 18 and he was firing on all cylinders and felt great, libido was good, morning erections were good, he was buff, he was doing everything right, and his testosterone was say 500, which is really kind of in the middle range of normal, that'd be really interesting information to know when he's in my office at 34 and the wheels have come off.

And the only way that I can kind of recreate that is to see what's happening in the gonadotropins. And if this guy comes in and his testosterone that used to be 500 is 300 now, then I would expect his gonadotropins would be high because the pituitary was used to seeing higher levels of T and now for whatever reason those numbers are down and the pituitary is like, "Dude, wake up. I need to get back up to 500 so that I can relax, so that I don't have to crank out an FSH or an LH of 10. I want to go back to chilling and just be down around four or five."

And so that's forensic endocrinology where I can actually interpret where a guy maybe was when he was ideal. What comes first, which is really what your question was, is more of an anecdotal thing. But I just happened to, somebody, a friend of mine who came to me maybe six months ago and said, "Hey, I'm just not feeling it anymore." He's 60, 61. "Not having the energy I used to have. My libido's a little down. I still feel fine. I'm getting up, going to work, doing everything right, but I don't quite feel like I used to."

And I checked his testosterone and it was 500 and his gonadotropins were pretty normal. They were right like three, four. And so I said, "I don't really, you know, maybe sleep more, don't stress." And sent him on his way. And then about three months later he texts me and his testosterone's 100. Like he fell off a cliff. And his gonadotropins were really low as well.

But the point being is that I do see a fair number of guys where the symptoms precede the levels. And I think that's really important for clinicians to know and for patients to be persistent. If you feel like crap and the blood work isn't there yet, give it some time. It's almost as if we can compensate up to a certain level to keep our numbers where we think they should be and then we just crash and the data finally events themselves. And we say, "Oh, well now it makes sense. You felt crappy three, four months ago, but you were just punching and kicking and screaming all the way down into the pit." But now you're in the pit and the levels have caught up with you.

Mike Haney: What's going on physiologically in that guy's case? What happened? What was going on in his body when the symptoms were manifesting but the levels were normal? What systems were compensating?

Dr. Jesse Mills: I think it's probably what we call supra-neural. I think our brain is our most important endocrine organ and our brain is always going to be fighting to be on top of things and our brain can just do magical things to keep our levels up. Just as an anecdote, when we were doing the clinical trials for the AndroGel, for that gel therapy, this was a later version of it, about 2008, 2010 somewhere in there where they had a higher concentrated form of the same transdermal therapy. When we were putting hand sanitizer on guys, it was the gel without the testosterone, the placebo arm, their T levels still went up 30%.

So I think the brain can compensate and say, "No, I'm not okay with this. I am, I'm going to fight this." And at some point I think something craps out and it's probably, that's the pituitary gland that goes first and it just says, "I'm exhausted and I can't keep this up for so long and then that's it."

But I don't know. That's purely speculation because I don't even know how to come up with a study to look at that. You'd have to recruit a bunch of guys that feel okay but not great or maybe starting to feel bad that have normal levels and then follow them longitudinally and see what happens. And then see what else has changed. Is it a lifestyle thing? Is it sleep? Is it stress? And what starts it? We know that stress is a huge killer of testosterone. It's a huge endocrine disruptor in general. And so it could just be that you can compensate up to so much and then you're just done.

How testosterone levels fluctuate throughout the day

Mike Haney: How stable are levels of those pituitary hormones and even testosterone? Meaning if there's not an obvious sort of case of either primary or secondary, how normal is it for my levels to just vary say every six months when I go get them checked if I'm checking that often?

Dr. Jesse Mills: It's actually, even testosterone itself in a normal healthy younger guy up until age, I hate to say 50 because I'm north of there now, but up until that level, testosterone can actually fluctuate dramatically during the day, like up to between 50 and 100 points, which is a 30 to 50% change.

One of the rules of endocrinology is that you want to check early morning levels of testosterone because that's when the numbers are highest. And the reason for that is because it is so directly proportional to our deep delta sleep. So in other words, if you had an IV catheter in a lab in a guy, you put him to bed and you've got brain scanner on or EEG wave so that you can see when he gets into deep delta REM sleep, his eyelids are flapping, every time you see that you see a spike not only in his erection but also in his testosterone and his LH. And that's what we call pulsatile secretion.

So you get these pulses of LH to say, "Hey, make some testosterone. Hey, make some testosterone." And it's much more profound at night. And the highest peak of testosterone in a normal guy that's doing the graveyard shift at the hospital, it is somewhere between 4 a.m. and about 8 a.m. So that's why we always say try to get your levels before 10.

If you unpack that a little bit, which I argue is you also want to know what that delta is. What if you said, "Okay, great. So let's get your T at 6:30 in the morning." You just get up, haven't had your coffee yet, just happen to have a home tester and you get it and it's 600. You're like, "Cool, I'm great. Everything's good." But let's see what it is at 4 p.m. when you're starting to live in the real world and you've just been in front of your computer for seven hours. Is it still 600 or is it going to be 200? And what's more clinically significant?

And I don't think we have an answer for that. I think we've been so academically rigorous about, "Well, we know that this is where you should check," but I also want to meet guys where they're at. And so to me it's important to get a couple of readings and have them spaced on the clock so that they're not all at 8 a.m. but let's just see what the range is.

And more to your point, over a six-month period it can vary dramatically. If you just have one night in Vegas, if you have nights in Vegas, if you have one night where you're binging and you're not sleeping, your testosterone will be in the gutter by the morning because the half-life of a testosterone molecule that's naturally made in our body is about eight minutes. It does not last very long, which means we're cranking it all day long. Factory is producing T.

And so if you do something to insult either your brain, your pituitary, or your testicles, it doesn't take long for you to deplete what you're making and then it takes a little while to dig out of that pit. So the whole idea of, "Oh man, just wow, what a weekend, you know, Monday, am I right?" That's real. So binge drinking and staying up all night and partying is really bad for your testosterone. It's recoverable, but boy, it gets harder the older you get, which is why you don't see guys my age out clubbing that much.

Understanding total testosterone versus free testosterone

Mike Haney: So it sounds like the interpretation has to be not just the numbers, but also the symptoms, right? So that you have some sense of, is this a transient thing because the guy was just in Vegas for the weekend? Have you had symptoms that have been persisting for the last six months so we can sense that this might be a downward trend of some kind, whether age-related or some other sort of cause? Maybe before we get too much further, we should just talk about what are the testosterone blood tests you get, primarily testosterone and free testosterone and what those are.

Dr. Jesse Mills: Sure. When somebody comes to see me, I am doing exactly the panel that you said before. I don't spend a lot of time on DHEA in guys because it's not clinically that significant. It's the adrenal form of testosterone. It helps a little bit. But essentially I start up in the pituitary gland. So I do an LH, FSH.

I also like to check prolactin. Prolactin is a pituitary-secreted hormone. It's very important for men for sexual function. And guys that have an elevated prolactin, two things can happen. One is it suppresses LH and FSH, sometimes to the point where it becomes undetectable. In a rare, but not that rare---I probably diagnose about five a year in my practice---entity called a prolactinoma, where the pituitary can get so big with the prolactin-secreting cells that it squishes down on the LH and FSH-producing cells. And that's a very common, well not very common, but if a guy has a prolactinoma he is going to have low testosterone almost always. That's usually medically, sometimes surgically reversible. So I don't want to miss that because it's a cheap test. So I'll always look at FSH, LH, prolactin, and then testosterone.

The deal with free testosterone is that unless you're doing a really advanced free testosterone, which either has to be mass spec, so it's usually a send-out test where they're actually looking like the Olympic committee at that flash point for where free testosterone is, or you're doing something called equilibrium dialysis, which is a very expensive test, but it will actually be the only one that will truly give you a free.

Most free testosterones that you get in labs actually do what's called a calculated free testosterone. And what they do is they look at not only testosterone but something called sex hormone-binding globulin, SHBG, and albumin. And they come up with an algorithm for where you can relatively accurately assume what the free testosterone is based on a ratio of total testosterone to sex hormone-binding globulin using albumin as kind of your natural regulator. In other words, everybody should have an albumin somewhere around four.

There's an online calculator actually. If you just do T and SHBG, then that actually gets you pretty close to a free T. So to do a really good blood test if you don't do equilibrium dialysis or mass spec, then there is also something called an RIA or radioimmunoassay which is also cheaper and it does okay.

But I will tell you, and I'm not embarrassed to admit it as a guy that treats a lot of low testosterone, the amount of clinical decision-making I do based on free testosterone is pretty low. And the reason for that, and this goes a little bit in the face of what the FDA said about 15 or 12 years ago, which is you should not treat a guy for low testosterone based on his symptoms. That was kind of a big landmark change. And that was in response to the fact that the testosterone industry just kind of exploded and there's probably a lot of irresponsible therapy out there.

But I have always maintained that I want to treat a guy in the context of his symptoms using laboratories as my baseline for treatment and to justify treatment. So the most clinically significant way that I use free testosterone is exactly the way the FDA says I shouldn't do it. And that is if a guy comes in and his total testosterone is in the normal range but his free is low, whether I do the mass spec or equilibrium dialysis or even just the calculated, then that is a guy that could be functionally low in testosterone that I wouldn't have known had I just looked at his total.

So if a guy comes in, his total testosterone is say 375, which is in most labs we look at a level of less than 300 as being low. If he's 375 but his free testosterone is low, then he would be a guy that might benefit from therapy. So that's the most clinically useful way that I look at free testosterone.

The other two things that I will look at, one always, the other sometimes, are those peripheral testosterone conversion products which is estradiol and dihydrotestosterone or DHT. And the reason for that is that estradiol is a very important hormone in guys. And if it's too high it can cause some symptoms that you would almost confuse with low testosterone which is increased moodiness. Sometimes guys will have a lower libido if their estradiol is too high. But also it can lead to things that we wouldn't want in a guy, which is probably the most important physical one is something called gynecomastia where they can actually develop breast tissue. And sometimes that's an effect of testosterone therapy that's irresponsibly monitored.

So I always want to know what a guy's estrogen is or estradiol. And you also want to know what their testosterone to estradiol ratio is or the T to E ratio. And that's more important in fertility, but in general, we want a guy to have a T to E ratio of 10 to 1.

The dihydrotestosterone, the DHT, anybody that comes to me that's concerned with hair loss, DHT is really the two things most responsible for is prostate growth and the structure of our hair follicle. Our hair roots are very DHT-dependent. So if a guy comes in with a really high DHT and his testosterone is low, he's already probably on his way towards losing his hair if he hasn't. And then we would look at modulating products out there. The one that probably gets the most news is something called finasteride, which all it is is it's something that blocks DHT.

So it increases testosterone, but it decreases DHT. Now, just for fun, well not really for fun, but for clinical elucidation, if you block DHT and there's only two routes that testosterone can go, what do you think happens to the estradiol? It goes up. And that's where you get a lot of the symptoms of finasteride issues, is that a guy's estrogen spikes. And it goes back to what we just talked about: low libido, for example. So I like to know what all those balances are.

Mike Haney: What explains that delta between a normal testosterone and a free testosterone that is off?

Dr. Jesse Mills: The biggest is that the guy's sex hormone-binding globulin is up. And SHBG, it's something we're really interested in. Years ago when we noticed so many men on testosterone replacement therapy, the liver is what makes SHBG and it, as a response to physiologically higher levels of testosterone, it senses, "Well, we got too much testosterone floating around. We got to put a bunch more SHBG." And as the acronym spells out, it binds sex hormones. So in men, your main sex hormone is testosterone. So if a guy has a high SHBG, he's driving down his bioavailable testosterone, the testosterone that the body sees.

And we're still trying to figure out, other than things like obesity and testosterone therapy directly that actually modulate SHBG levels, in other words, if you could figure out how to lower them, then you would make a more potent testosterone therapy, for example. And those are some of the things that we're trying to figure out on a research basis.

Mike Haney: So SHBG is essentially a homeostatic hormone. It's trying to keep, it's trying to watch those levels of testosterone in the body and keep them, or estradiol as well, right? It'll also bind to that.

Dr. Jesse Mills: Yep, exactly. It's a checkpoint regulator. And sometimes we override that checkpoint. So if a guy on therapy comes in and his total testosterone is going up, but he's not feeling the same symptoms, then it's probably because he's putting out too much SHBG. And so you got to kind of chase it a little bit and say, "Okay, well, no, I really want you to benefit. We're in for a penny, in for a pound here. We're going to up your testosterone prescription to overact or compensate for your elevated SHBG."

But we don't know the clinical significance of that yet. Maybe we are disrupting something else by doing that. So that's becoming a more interesting area of research to figure out why we do that, why our liver does that, and what is the clinical utility.

Mike Haney: Before we leave testosterone, free testosterone again, maybe just the 101 on what is free testosterone? What does it mean that it is free compared to normal testosterone?

Dr. Jesse Mills: So free testosterone is what is circulating in the bloodstream to do the job that testosterone does. I'll even 101 you a little bit further. I'll 99 you. So free testosterone, testosterone works mostly on a receptor basis. So what a receptor is, if you got a molecule of testosterone and on the surface of a cell you've got this little goblet, then the molecule of testosterone, free because if it's bound, it doesn't bind, it's already bound to SHBG, it makes this connection, right?

So once you have that receptor to androgen lock, that's when all of the cellular machinery opens up and does whatever it does. From if it's an androgen receptor in your bicep and you go to the gym and your T levels are good, you're going to get yoked. You're going to get bigger biceps. If it's in your prefrontal cortex and your libido sucks and all of a sudden now you're on testosterone and that receptor hits there, you have a better libido all of a sudden.

And so free testosterone is what is the workhorse. And total testosterone, if it is irreversibly bound, some of it is carried by albumin, for example, which carries a lot of different hormones. Then it is loosely bound and it can still be bioactive. But once it's bound to SHBG, it's essentially, as far as we know, irreversibly bound. So your total T is not as indicative of your overall sense of what am I doing, how are your receptors doing, than your free T. So it's the workhorse.

Mike Haney: I'm trying to understand that relationship and how you look at those levels to make sense of it. It sounds like total testosterone is telling you something about the mechanism by which your body is producing this hormone that you need. So your pituitary signals, your conversion machinery in your testicles, how that's working. Free testosterone is telling you something about how your body's homeostasis machinery is working. Is the SHBG at a normal level to bind what it should but not too much or not too little? And that's going to tell us the free T. And the free T then is going to affect those downstream functions of testosterone. Is that fair?

Dr. Jesse Mills: It's very fair. And again, it's very nuanced. In other words, the clinical significance of where you don't have enough free T is not that often, but when it is, then that's a guy that would still benefit from therapy is how I'd look at it. But yeah, I think from a laboratory standpoint, it allows for some clinical decision-making. From a physiologic standpoint, it's critical. I mean, this is how the body works and this is how it metabolizes testosterone.

It's just that the differences between free and total are usually not that dramatic, and usually you can overcome that by appropriate testosterone replacement. But that's where the details are and that's where we still have some research to do to figure that out.

Who should consider testosterone replacement therapy

Mike Haney: So let's talk about testosterone replacement therapy because I feel like this has been a hot topic, you know, as you mentioned when it came out. Most of my life people have talked about low T, something you see out in social media and influencers and third-party companies selling this. Testosterone naturally goes down as we get older, correct? And so we expect to see some kind of symptoms maybe over time, lower libido, etc. as we get older. But then there can also be these cases where for whatever reasons we have low testosterone when we're younger in life. Who should think about testosterone replacement therapy and why? That's sort of a broad way into it, but I'm just curious how you think about it and how you've come to think about it over the last 20 years.

Dr. Jesse Mills: I think there are at least two big groups of men with low testosterone. One that is absolutely pathologic. They have a chromosomal abnormality, they have a genetic abnormality, they've had a trauma. I mean, something that is absolutely not just because they're getting older. Those guys are going to be a whole different---that's sort of, there's no clinical decision-making necessary. They need testosterone in order to maintain healthy cardiovascular function, healthy muscle mass, healthy bone, cognition, plus all the sexual function that we talked about. That's easy. So we replete them however we do it, and we can talk about that here in a sec.

The other is the nuance between life optimization and clinically pathological low testosterone. And I don't even call it a gray area. It's more of a spectrum. And the reason for that is that you're right, testosterone levels decline about 10% every decade. And okay, sure, that's a normal part of aging. No question about it.

The other normal part of aging that I use a thousand times a day are my glasses. I'm 55 years old. I'm a microsurgeon. I need my eyes. I can't read without them. And I didn't need these when I was 45. So I optimized my eyesight. And so the question is if you have somebody that is aging but doing everything right. He's running marathons. He's lifting weights. He's sleeping. He's eating great diet and exercising. Everything he's doing right. And his testosterone comes back low, but even low normal. Is that somebody that would benefit from therapy even though he's not going to die from his low testosterone if it's not zero? That guy might benefit from therapy.

And I think that's the way that our guidelines are written. So if you look at the two major medical societies in this country that put out the literature, it's the Endocrine Society and the American Urologic Association Society. And we say in our guidelines that consider testosterone replacement for a man that has symptoms of low testosterone and has a total testosterone of less than 300 nanograms per deciliter. Consider therapy. So weigh the risks, weigh the benefits.

And that is how we wrote them, which is in direct contrast to what the FDA said again 12 years ago, which is never treat testosterone just because a guy's getting older. And I think that's where the clinicians have rebelled a little bit to say, "Well, that's ridiculous," because if I see that guy, I'm not just thinking about treating him because his erections aren't as good or his libido isn't as good. What if I do a bone density scan on him and his bone density is lower than it should be for his age even if he is running marathons?

So he's got osteopenia or bone loss. What if five years ago he was starting to see low muscle mass, which is the beginning of bone density loss is muscle density or sarcopenia? So you lose muscle. That stretch of muscle against when the muscle inserts into bone, that's the most medically active, bioactive part of the bone. And so if that starts to deteriorate with age, we can reverse that with testosterone therapy.

So I would always look at guys treating them with the lens on what can we do to optimize them and is there even a longevity benefit to consider for testosterone. Now, I will say what we do know is that guys that have normal testosterone have a higher longevity index. And there's this famous study about 30 years ago in a retirement community in the San Diego area that saw that guys that had normal testosterone had a much higher 20-year life expectancy than guys with low testosterone.

Testosterone is not only the critical hormone that we've just spent some time discussing, it's also a very good inflammatory biomarker. If a guy has low testosterone, it's a sign of some kind of inflammatory process in the body. The testicle basically just shuts down.

— Jesse Mills, MD

So I want to stop for a second because what has unfortunately I think happened in the industry of testosterone is they just assumed, "Okay great, so what we need to do then is we need to take every guy with low testosterone and jack him up and then he's going to live forever." But that's not what the study showed. And the reason this is critical is that testosterone is not only the critical hormone that we've just spent some time discussing, it's also a very good inflammatory biomarker.

Meaning that if a guy has low testosterone, it's a sign of some kind of inflammatory process in the body. The testicle basically just shuts down. So greatest example of this, COVID-19, pandemic and panic for that matter. But if you looked at guys that were in acute COVID phase, even the guys on a ventilator, their testosterones were basically undetectable. And we've known this for years that any guy in the ICU, especially somebody on a ventilator that is really sick, their testosterone is zero. And it's recoverable. You get them off the ventilator, you get them healthy again, their T comes back.

So it's not necessarily the testosterone itself. It's what we call in laboratory medicine a biochemical surrogate for inflammation, for disease. But having said that, there is still probably, we just don't have mature enough data, some evidence to show that appropriate testosterone replacement therapy probably has a longevity benefit, but I can't go on paper saying that.

Mike Haney: Yeah, this reminds me a bit of the hormone replacement therapy discussion for women, right? Where for years it was sort of assumed, "Look, menopause is normal. Your levels are going to change. Your cardiovascular risk is going to go up. Your diabetes risk is going to go up. You're going to have mood swings. You're going to have hot flashes. But hey, it's just a normal part of aging." And now we've come to believe, I think more, "Well, if we can do something about that and the downsides are low, why not do that?"

So when we talk about hormone replacement therapy for that older group, are we trying to, are we talking about people for whom that natural decline of about 10% a year is a steeper decline and we're trying to get them back up to what we would expect that age level to be? Or are we talking about trying to get a 60-year-old back to his 25-year-old levels and maintain those until something else kills him?

Dr. Jesse Mills: Yeah, I mean, we're talking about both. And I think that is the nuance. I mean, again, the whole "normal part of aging" is what I really have a problem with in general because a 40-year-old woman doesn't normally break her hip, right? But we know that as we age, men and women both, we have a much higher risk of what we call skeletal-related events or SRE from poor bone.

And is a hip fracture normal when you're 80? I hope not, but it's certainly almost expected. So what if we had something we could do to prevent that? And in women, we've known that HRT or hormone replacement therapy for years has been protective against hip fractures. And so in guys, we need to look at it from the same way.

So I don't, I mean, it's a very squishy question because I think that is where you go into this idea of lifespan, healthspan, optimization versus I'm just getting older. And I get it. My joints don't work as much as, I don't have that energy I used to have. And I think that almost has to be what I would put into the category of shared decision-making on the clinician and the patient together and say, "Here we have a therapy that may work."

But for me, the majority of the conversation is going to be first around what can you do to reverse this? So are you drinking too much? Are you not sleeping enough? Are you stressing too much? All of those things. If we can reverse that, which we know, I mean, the best longevity index is physical activity. And if you don't have the motivation to be physically active, but if I can write you a prescription and then the next time I see you, you're doing your 10,000 steps or you're back at the gym, then I think we've done some good.

Even though there was some pharmacological assistance to get that guy off the couch, we are still contributing, and he is most importantly contributing to his own longevity by doing that. So I think it's a spectrum and a very individualized decision rather than a longitudinal epidemiologic study.

Understanding the risks of testosterone replacement

Mike Haney: So maybe another way at this, folks are thinking about this, is to understand what the downsides are. And my sort of journalist-level read of the big studies over the past 10, 20 years is it doesn't seem like there's that much risk. It seems like the prostate risk, cardiovascular risk have kind of not really played out in the long-term studies. But what is the downside if I come to you and I go, "Look, I'm 65. I'm pretty healthy. I'm doing everything right, but I would like to continue to be muscular and have a really strong sex drive. So why not just give me lots of T?"

Dr. Jesse Mills: I think that's a reasonable argument, actually. You wouldn't have much pushback from me because of that. And I think you hit the two big ones that I think have finally been adjudicated. The prostate cancer risk, we know really good level-one data that if a guy's going to get prostate cancer, he's going to get it whether or not his T is zero, well, maybe not zero, but whether or not it's on the low side or the very high side.

It just actually what it does is it allows us to be much more screening and suspicion-based. So we can actually follow these guys a little closer by giving them testosterone replacement. We know if their PSA spikes or if their prostate screening scores spike that we got to really investigate it. And so I think that if anything, it allows for better scrutiny, better screening of the prostate.

Cardiovascular, thank goodness, I think has finally been put to bed with the largest randomized controlled trial. In fact, the FDA for the first time I believe in its history, in February of this year in 2025, has reversed its black-box warning on testosterone because of this landmark study, multi-institutional randomized controlled trial called the TRAVERSE trial, which has made headlines all over the place. It basically said there does not appear to be a signal that testosterone replacement increases anybody's cardiovascular risk of coronary disease or any kind of myocardial event or cerebrovascular event.

So I think you're right, that is a shorter conversation. When I was practicing at the beginning of this revolution, I had phrases and I had handouts. And in fact, I knew a lot of physicians that would make patients sign informed consent before they would take testosterone therapy, almost like a surgical procedure to say, "I'm going to give you this prescription, but I want you to know there could be a risk of cardiovascular disease." Because the data were bad, but the press was great. There were a couple landmark studies that showed this correlation, which has since been thrown out. So enough said, thank goodness.

The absolute risk, the biggest risk to a man with testosterone replacement therapy is it is a fantastic form of birth control. It will make a guy very quickly go to zero sperm such that in fact there's multiple clinical trials right now looking at a reversible form of male birth control that's essentially testosterone-based. And so it's a great way to diminish a guy's sperm count, usually to zero, because the majority of the volume of the testicle, most guys, their testicles are about 2.5 inches long by an inch and a half wide or so. So they're nice ovoid egg-shaped organs. 80% of the volume of a testicle, the mass of a testicle, is sperm production.

So if you put a guy on testosterone therapy without any other supplements or any other kind of medication, their testicles will shrink. And for some guys, they won't notice it. For some guys, they will be distraught, angry, especially if their physician didn't tell them, "Oh yeah, by the way, if I start you on this, you're going to lose testicular size." So that's actually the biggest risk. Is it a physical risk or a health risk? Not that we know of, but it certainly is a maybe a cosmetic and therefore a mood-altering risk.

The other thing that testosterone therapy, and it depends on the vehicle, whether it's a pill, a patch, a gel, an injection, a pellet, they all have varying risks of increasing your red blood cell count. So we always monitor guys for their red blood cell count, what we call hematocrit or hemoglobin. And it's a good way to stimulate bone marrow production of red cells in guys with anemia. That's kind of one of the off-label testosterone therapies. In fact, we look at it in men with kidney failure that are on dialysis where they're chronically anemic. Testosterone actually helps those men pretty significantly maintain better levels of red blood cell count.

But in a normal guy that's walking around with a perfectly normal hematocrit and they're on the most common form of testosterone therapy, which is some kind of injection, about 20% of them will have hemoglobin levels that will go up into the abnormal range. We don't know the clinical significance of that. We've looked at it. Is that why there was a signal for cardiovascular or cerebrovascular events? It never really correlated.

But in general, we don't love guys walking around with really high levels of hemoglobin because it does increase the viscosity of the blood or increases the sludgy factor of the blood. But again, the outcomes don't show that that increases anything. But most testosterone prescribers look at that and then even consider maybe doing phlebotomy or donating blood if it gets up to that, or stopping therapy if you cannot control it. That's the biggest in the injection. For the men that are on either the pill form of testosterone or the gel, it's a pretty low risk. It's around 2 to 4%.

The different forms of testosterone therapy

Mike Haney: And are there other differences among those delivery devices? I've only read that the injection is a heck of a lot cheaper than a lot of the gels.

Dr. Jesse Mills: Yeah, there's a lot. Let's start with pills, which for years, the pills that were delivering testosterone to guys were very dangerous. They had a lot of side effects. The most common one was liver issues that you would take this pill, it was metabolized in the liver, and it could even form liver tumors. So that was banned by the FDA even before my time, probably in the 80s, 90s, something like that. Still available overseas, and that's one of the biggest forms of testosterone abuse and anabolic steroid use is pill forms. So bad for the liver.

So they were a no-no for years until about 10, 12 years ago. There were a few companies that developed a way to deliver testosterone via pill that went through the liver, bypassed the liver, and was actually metabolized in the lymphatics. And it was pretty clever. So you take a pill, it goes right through the liver, and the lymphatics, because the way the pill is designed is a fatty-based pill, it gets absorbed into the lymphatic system and then gets into the bloodstream kind of through a back door.

And what that does is two things. One is it actually causes levels to be good right away. There's no delay. You take a pill and then boom, your levels are up in like an hour, two hours. The downside is it's also cleared right away. So you have to take the pill at least twice a day, sometimes even three times a day to maintain healthy levels. And so what you do is you get this giant peak and then really big trough, boom, boom.

But the pills are interesting in that it's easy. Guys are like, "Yeah, I can take a pill. I don't have to, I'm used to taking pills." And so there is definitely a newer market. There's three on-brand right now that are branded pharmaceuticals. So those are out there.

The next is really the gold standard of pharmaceutical testosterone, which is a gel. And it's something you rub on your shoulders usually in the morning. And the levels are good. They put you in kind of that mid to upper tercile range of where a guy should be, sort of in the 500, 600 range. You just put it on once a day and they are active for about 18 hours. So in other words, if you put it on in the morning, in the middle of the night it wears off and then you're ready for your next round of gel.

So you have to do it every day, otherwise your levels will be subtherapeutic and subphysiologic very quickly. So compliance with gels is a bit of a challenge because some guys don't remember to put it on and then their numbers are all over the place. And so injections have been around since the 1930s, and arguably even earlier in more what we would call bioidentical forms, which is usually animal extract of some kind.

And the injectable form of testosterone, there's multiple different what we call esters. So the testosterone molecule, again, very unstable, eight minutes. So you have to click it onto something that allows the body to not metabolize it like this. And those esters, what ester you conjugate it to will give you how long it lasts. And so the two big ones on the market that are all generic is something called testosterone enanthate, testosterone cypionate. And those last, if you do kind of a physiologic injection on say Monday, you will get a good bioavailable level of testosterone for about 10 days.

So that is not bad. And in fact, most of us that do a lot of testosterone prescribing, 10 days is kind of a strange number. You have to really set your alert to say, "Okay, this week it's Sunday, then next week it's Wednesday or whatever that is." So we actually usually do either weekly injections and then just back off on the dose so they're not getting quite as high a level, and then they never get too high and they never get too low. So we just have to adjust it. And then some guys even recommend doing two injections a week. And that's actually the most physiologic way to do it if you do two injections. But again, now you got a guy having to give himself a shot twice a week.

So they're the most labor-intensive, but also probably give you the best physiologic response. And then lastly, I think the other market which is really big and very convenient is a pellet. There's one FDA-approved testosterone pellet and that's something that the physician or the healthcare provider inserts usually into the fleshy part of the backside, so kind of upper buttock region, or if a guy has a little bit of extra heft around the midsection, you can put it in kind of the lateral abdomen.

And the pellets go in and they last about three to four months of nice sustained therapy. They have a very regulated degradation. So you can, based on a guy's level of where he comes in and his body weight and what you think his metabolics are going to be in terms of how active he is, you can judge how many pellets to put in. So it gives the physician, it gives the provider the most leeway in terms of how much testosterone a guy should get. And compliance is 100%, right? Because you're doing it. So the guy shows up, he gets his pellet, you check levels, and it's a great way to maintain really healthy levels of testosterone.

And so really, I'm having a conversation with you just like I would with a patient and say, "Here's your list." And because I'm in an academic medical center, I'm not selling anybody anything, so whatever works for them. If a guy says, "I can take a pill," great, here's a prescription.

The only downside with the gel that I have to tell everybody is it is bioactive drug on your skin. So if you're exposing your skin to somebody else that you don't want to give testosterone to, which would basically be nobody else, you have to be careful of skin-to-skin contact. So for the new dad that puts his testosterone gel in the morning and then goes in to change a diaper, that's the wrong therapy for that guy. So you just have to kind of figure out what, where a guy is going to be most compliant and get the most benefit out of therapy.

And then the levels change, but for the most part you can judge, you can change the prescription so that even if a guy on gel therapy is not where he needs to be, you can always increase it. But at some point, guys can only absorb so much of the stuff. And so the best kind of most predictable therapy is going to be some kind of injectable.

Testosterone replacement is long-term commitment

Mike Haney: And it's something that you will continue to take, right? This is not a short course.

Dr. Jesse Mills: Oh yeah. Well, that's a good point too, Mike. So one of the other sort of relative risks of testosterone replacement is that it is replacement. In other words, if a guy comes to me with a testosterone that is, say his testosterone is 600, and he says, "But I don't look like that guy at the gym. I want to look like that guy at the gym. Give me more testosterone." And I say, "Cool, I'll give you a shot of testosterone." What I've just done is I've taken his pituitary gland and sent it to Cabo. You are no longer working. And so you're completely dependent on my prescription to maintain even the testosterone of 600.

And usually I got to slingshot that guy. In other words, I got to take him to zero and then give him enough injection to get him above where he started, which is tricky to do. And by putting the pituitary on vacation, if you do it for a long enough period of time, years, two years, five years, 10 years, we don't know, that will never recover. And so then you are fully dependent on testosterone replacement.

So if I see a 25-year-old guy that has an irreversible cause of low testosterone, I've got no problem. I know that guy's never going to recover function. He has some intrinsic problem with his testicle. Great. We have the conversation. But if I see a 25-year-old guy that says, "I don't look like that guy at the gym and I want to look like that guy," he's not somebody that's probably going to get a prescription from me unless there's some overwhelming medical reason for doing it, just because of that fact that once you start testosterone, recovery is tricky.

It's not zero. In fact, we can do it through modulating the pituitary gland. There's a whole branch of medicine called selective estrogen receptor modulators or SERMs that actually can restore that pituitary function in guys that are on long-term testosterone. But there is a point of no return and we don't know what that is, but it's probably years.

Mike Haney: So I think you kind of alluded to the answer to this in that response, but why should I come see you if I'm interested in testosterone replacement, either because I'm aging or because I'm younger and I just want more? What's the, what are the downsides of some of the things I can buy off the internet?

Dr. Jesse Mills: I mean, I think you should see me if you want to have a really intellectual discussion and you want to be actively participating in your care to optimize everything you can for yourself and also run the risk of walking out of my office without a prescription. If you want to guarantee that you're going to be on testosterone replacement therapy, you should go to someplace that sells testosterone replacement therapy.

And I don't mean that in any disparaging way because a lot of those guys are doing pretty good medicine as well, but ultimately their business model is to sell drug. My business model is to take care of patients. And so there is a difference and there's a higher chance that you're going to come to me and we're going to have this discussion and I'm going to say there's other ways that we can treat the symptoms you have that are not going to commit you to testosterone forever.

So I think that's it. It's a longer road and I'm going to be much more academic and much more physiologic, but ultimately I think you're going to do better. And I know that because I see a lot of these guys from these direct-to-consumer places. And obviously I don't know the denominator. It's probably a very small percentage because a lot of those guys are just totally happy or whistling past the graveyard. In other words, they don't know what they don't know.

So they don't know what their hemoglobin levels are. They don't know that they're infertile until they come to me and say, "Whoa, nobody ever told me that I'm never going to have kids now if I stay on this regimen. And you have to do some kind of massive hormonal overhaul to get me to the point where I can have a biological child again."

So I think those are the risks, but I think it is, if you're going to come to my office, if you're going to come to a board-certified, academically trained physician, be prepared to work because that's what we want. We want to have this relationship where somebody is actually doing some of the heavy lifting when they're not in our office.

Monitoring testosterone therapy

Mike Haney: How delicate is the dosing? And maybe follow-up question, how important is the continued level of care?

Dr. Jesse Mills: Most of the time we can get a guy, we guess at the initial dosing, and I'll make up a favorable number, 90%, it's probably somewhere in there, of the time we get it right. We get the dosing right. We say, "Look, you're 220 pounds. You come in with a testosterone of 200. We really want you around 600, 700, and also feeling better is the main thing, is the symptomatic response. And I'm going to write for this or I'm going to give you this many pellets and you're going to come back in about three months and we're going to check labs before that and we're going to see where you're at and then we'll have data."

So a guy comes in, his T is 200. We start him on therapy. We see him in three months. It's 600. He says, "I feel amazing. This is, you've changed my life. I'm going to the gym three times a week. I'm sleeping better. Sex life is better. I feel stronger. Feel sharper." That's a home run. And that's usually what happens if we do it right.

Once we have that level and we know at 600 he is optimized and all his other blood, his liver functions are good, his hemoglobin, hematocrit, all else is good, then we typically can see that guy every six months. And as a controlled substance, testosterone is still what we call a Schedule III drug. We can't write for prescriptions greater than six months. We have to see those guys back. So it's an internal check to know that they are compliant with therapy. And it's a great time for me to check their blood pressure again and do all the doctoring stuff we should do that is, sad to say in this day and age, value-added over a DTC platform where they're not looking at all those other biometrics.

So most of the time it's great. Now, the guys I love taking care of are the ones that are coming in with some reversible lifestyle factors: obesity, cigarette smoking, too much alcohol. Those are sort of the big ones I would see. And they've done something to improve their lives. They took it to heart. They took a prescription and they ran with it.

Those are the guys I love dialing back their prescription a little bit and say, "Hey, you don't need that much anymore because you're actually doing better." Those are the most gratifying days in the clinic when I see a guy really taking ownership of his own health or in his sphere if his partners are helping out. It's just so fun to watch how you can change the dynamic of a relationship by just modulating one thing.

Mike Haney: So for a lot of folks, I mean whether it's, well, maybe it's particularly for the people that are getting older and are having that sort of natural decline, if there are lifestyle factors to be improved, is that generally where you start and say, "Let's get all of these, let's get the basics in line first and then we'll talk about giving you injections or something else?" Or does it again kind of depend on the person and their goals?

Dr. Jesse Mills: I rarely fully dichotomize because I do believe in value-adding and in forming good habits, giving guys the tool to form it. So the number one rule of this whole business of testosterone replacement and diagnosis is identify reversible causes. So if a guy comes into me, again, he just recovered from a massive fever and he feels, "Oh man, I'm so exhausted, I'm terrible, this is awful, I feel terrible," and I do testosterone and it's 100, I say, "Okay, we just got over a horrible fever and the flu. You've been in bed. Why don't we come back in six weeks and see what?"

So that's the only guy that has an identifiable, clearly reversible cause that he doesn't have to do too much work to get to. He just has to get better. That I wouldn't probably think about doing testosterone supplementation earlier on.

But if a guy comes in with some of those reversible lifestyle causes, I don't have a problem working with him and saying, "Look, you have to lose weight." I know that I can help him lose weight by initiating testosterone therapy. We know that if you put a guy on testosterone therapy, he can lose up to about five pounds of body fat and gain a couple pounds, two to three pounds of lean muscle in the first three months of therapy, which doesn't sound like a lot, but good gets better.

And so if he starts to feel better and he has that motivation which he didn't have to do the extra rep, to walk the extra hundred yards or 200 or 300, or I went from a mile to now I'm walking five miles a day, Dr. Mills, then that's because of his internal motivation and because of my prescription. I have no problem with that. I think that's good medicine, is that you're trying to give guys the tools to make themselves better. And so that's also really fine.

And then there are the guys that I know no matter what I do, they're never going to reverse their lifestyle. They can't. Somebody that maybe has some mobility issues where I know they're going to benefit from testosterone therapy and I can't tell them to move. If they have dramatic or irreversible mobility issues, then I'm going to supplement that guy.

Guys with chronic inflammatory conditions, chronic fatigue syndrome, neurologic, neurodegenerative disorders. A lot of these men are not being screened for low testosterone and they could benefit from therapy and they're doing everything right, but they have a chronic medical condition that is not reversible. That's a whole subgroup of men that are probably not being adequately treated that would benefit from testosterone therapy.

PSA testing and prostate cancer screening

Mike Haney: Well, I'm going to shift in the time that we have left to another set of markers that people are going to get when they go get one of these sort of big blood tests, and that's PSA. So PSA is a marker of prostate cancer. It's not really a hormone, not a hormone at all. And it's kind of the only thing, I think the only sort of cancer marker people tend to get unless they're getting the new sort of cancer tests that are out there. But in a normal blood panel, it's PSA and we get PSA, we'll get PSA free and we'll get PSA free percent. And these are all going to tell us something about our sort of cancer risk.

So I'll just share my anecdote as a way to get into this and then we can talk about the debate around this. I got one of these expanded blood tests last year, getting all my results back. Everything's nice and healthy. I'm feeling really good about myself and how healthy I am. And then I got one of the PSA markers was red and it was PSA free percentage and I didn't know what that was. So I went to ChatGPT and I plugged it in and I started asking and learned that, yeah, it's like an indicator that your PSA is normal, but if this is off, could mean something's wrong.

And so I also know that within the world of prostate, overdiagnosis is a problem and a lot of these things grow very slowly. And so you kind of have that debate. How much do I chase this down? I went to my GP and said, "Look, this is a thing I got." He said, "All right, send me the rest of the results when you get them and we'll see." I got impatient. I just scheduled an appointment with a urologist.

I went to the urologist. He said, "Yeah, you know, guy your age, healthy, normally I wouldn't worry that much about this, but let's do the DRE as long as you're here." And he felt a nodule. So now I'm going, "Oh God, no, all right, now it's cancer." He says, "All right, so we're going to do urine test and then we'll send you for the MRI. That's the best way to sort of tell."

Get the urine test back, the ExoDx. It's in the unclear range, right? It's not like you're off somewhere in there. It was maybe 22. So it was a little higher than what was considered the sort of lowest risk range. So then I had another couple weeks of sitting around doing, and at this point I'm doing a lot of chatting with ChatGPT about prostate cancer treatment, life after prostate cancer. What happens when you lose the prostate? I'm looking up what kind of underwear do you wear when you can't control your urination anymore because this is a side effect. And I'm really in my head going, "All right, what is life going to be like if this happens?"

Finally go get the MRI because it takes about a month to schedule that. MRI comes back with like a score of one, like PI-RADS one. It's like we don't see cancer. You're fine. Great. Talked to the urologist. He goes, "Look, we could biopsy it, but at this point probably not worthwhile to do."

So I feel like I've lived the sort of case of the reason we have these questions around should we be testing this, at what ages should we be testing this, how should we make sense of the testing, and what do we do with results from each one of these sort of stages of PSA. So maybe I'll just sort of start broadly with how do you think about PSA testing and the kind of recommendations which are out there, which I primarily read now as "talk to your doctor." I see things like shared decision-making, informed decision-making, which feels to me like the opposite of a guideline, which should be to sort of put some rules around what we do so it's not so fuzzy. But instead what I'm seeing a lot of is, "Well, that didn't really work. We probably overdiagnosed people and so now informed decision-making. Go talk to your doctor, learn a little more." How do we make sense of this?

Dr. Jesse Mills: Yeah. Well, I mean, I think a little history is critical to this and also a gratitude towards the lowly and much-maligned PSA. And the reason is that in the 80s and prior, we didn't diagnose prostate cancer until you had a nodule or until you were peeing blood, until you had something where you couldn't pee at all because the tumor had grown to the point where there was no urine coming out of the bladder.

And so we saw a lot of guys die from prostate cancer. It's the leading solid organ cancer death. And it still is even today, even after all these years of diagnosis and purported overtreatment. PSA came around late 80s. And you're right, it is actually a normally occurring protein. It's called a serine protease and what it does is it dissolves other proteins and it's a fertility hormone is what it does.

So when a guy ejaculates, semen turns out very thick. And in order to liquefy so that little sperm can figure out how to get up and make a baby, PSA goes in and liquefies it. So it actually is a delivery vehicle for semen to have one big cohesive blob of sperm delivered to its source. So it's kind of an interesting molecule in that form because it has a functional purpose.

So somewhere in the late 80s, early 90s, we started to measure PSA and correlate it to prostate cancer as what we call a biochemical marker. So it's not cancer-causing and everybody has PSA. Even women have very low levels of PSA because it's a very conserved protein. So what we did is we established a number of ranges for where PSA was if it were elevated. And the original number was four. So if a guy had a PSA of four or greater, it showed that his risk of prostate cancer was about 25%.

Which as a screening test is pretty horrible if you think about it because that means that at the time, every guy that had an elevated PSA, we would do a biopsy on, which sucks. I mean, a biopsy is painful. It leads to infection, blood loss, all kinds of things. Now we've gotten much better at doing those and the risks are way down. But thankfully we don't have to do as many because of some of these more advanced prostate cancer screening.

So that was the history of PSA. We didn't want to miss a prostate cancer because we saw way too many guys die of a disease that now we knew with early detection and surgical or radiologic intervention we could cure. So that was a win. I mean, careers were made purely based on PSA and getting really good at doing one of the signature surgical procedures for a urologist, which is to do a radical prostatectomy. And we were doing them when I was in training in the 90s and early 2000s. We were doing probably five to six, seven times as many as we do now because we were detecting so much prostate cancer.

And as you said, what we're finding is that not all prostate cancer is as aggressive as other kinds of prostate cancer. So you can have ones that are smoldering and never cause anybody a problem. And of course, this came up in the news recently with President Biden's diagnosis of advanced cancer. So we know there are some bad players out there. We also know that there are some ones that it's a cancer you die with, not die from.

But to that point, all we had was PSA. It's high, you biopsy. Now with the advent around the mid-teens, so 2012, 13, 14, 15, what we did was we realized that we could detect with a high-resolution MRI, we could detect a lot of clinically significant prostate cancers. And so all of a sudden now, massive change in how we do this.

Now we do exactly what happened to you. And we'll get into ExoDx in a second, but we do the PSA, it's elevated. Now we've screened a hundred guys, only 25% of them are going to be prostate cancer. Instead of biopsying a hundred guys and finding cancer in 25 and causing 75 guys to pee blood for two to three weeks afterwards and a few guys going into the ICU for a blood transfusion, now we've gone way down on that and we can do an MRI.

And the MRI, a lot of the research done at UCLA has come up with being able to say, "No, how dense the prostate is, if there are pockets that look really, really dense," it very nicely correlates to cancer. So then what do we do? If your PI-RADS came back high three, four, five, really four or five, then you would get a biopsy. And in the old days, like when I even started in medicine, we used to biopsy guys blindly without ultrasound. We would literally have one finger in the rectum to feel the prostate and then our needle would go up over our finger to just kind of feel if there was a tumor there. We would try to biopsy it.

And then we got ultrasound and now we can actually fusion biopsy. So we look at the MRI, we correlate that to the ultrasound at the time of the biopsy, and we can target biopsy all of those MRI-suspicious lesions and give guys the best diagnosis. And it has dramatically cut down on the number of cancers that are clinically significant.

So now as a screening, what we think about or what we do is PSA first of all, it's probably a $30 or $50 blood test, so it's cheap. And prostate exam is free, although we're getting kind of, I applaud your urologist actually for even doing the prostate exam and going along the pathway they did, because most prostate cancers are detected through a blood test or now some kind of advanced genetic marker.

And so that's where the role of ExoDx comes in and is this whole concept of exosomes, which all cells have exosomes. It's kind of the cellular text messaging basically. If a cancer cell makes an exosome, it's a little pocket of genetic material it sends out to the next cell. And then it becomes kind of cellular peer pressure where it's like, "Hey, you should develop cancer too." And then it's just another exosome going to another cell to another cell, and that's how cancer grows.

And so we know in the urine that prostate cancer will release exosomes that we can detect. And it kind of goes back to looking at the percent of exosomes within the urine that are abnormal gives us a risk stratification that even can further guide our screening. And so the ExoDx has changed. You have an elevated PSA or suspicious PSA or a prostate exam. You do the ExoDx. If it's confirmatory, so if it's higher, and again, that's where the clinical interpretation goes in, but well over 20, then that guy definitely needs an MRI and probably a biopsy based on that.

And so now we are way not overtreating prostate cancer. Now we are realizing who the bad players are and we can even do genetics on the biopsy specimen that's even more advanced to say what the likelihood is that that cancer is going to go rogue and really cause that guy a problem. And so that is the modern era of prostate cancer detection. And so it wouldn't have been here without PSA.

So PSA gets maligned and there was a period of time where no doubt everybody got a PSA, everybody got a biopsy, a lot of people got surgical treatment that maybe didn't need it, but we were still saving a lot of lives. And the reason I know that is that in about 2010, our U.S. Preventive Services Task Force came out with a recommendation that we probably shouldn't screen for prostate cancer. And we are still seeing the mop-up from that.

One of those may even be our former president. They said, "No, the risk of prostate cancer screening is worse than the treatment. So the number of guys that you would need to treat to save one life," and I don't remember what the number that came up was, but it was something like 30 guys. And so they're like, "We should never do this anymore."

But if you're one of those guys that is dying of a preventable disease, that doesn't seem like too high of a risk. And you get enough of those guys because it's so common, you're seeing hundreds of thousands of men that are now presenting with advanced cancer that weren't screened 10 years ago because of that advice, because we did not have the molecular machinery in place to be much more scrutinizing to find who the guy is that needs to go to the ExoDx, that needs to go to the MRI, that needs to go to the biopsy, that then needs to go to treatment.

So we have all these checkpoints in our screening now that allow for that much higher level of accuracy when we actually go to treatment decision-making.

Understanding overtreatment and active surveillance

Mike Haney: So we should probably clarify here what overtreatment means, right? Because you think, as you just said, if I have a cancer in me, I want it out. So what would be overtreatment of that? And as I understand it, the risks are with biopsy because you're essentially sticking a needle in there and you can get infection, you can get bleeding, it can be pretty uncomfortable. So there are risks associated with the actual biopsy itself. As you said, maybe down now because we can do smarter ultrasound-guided biopsies.

And then if we go all the way to treatment level, it is a highly treatable cancer, but there are going to be side effects that a lot of folks are going to have to live with: erectile dysfunction, loss of urinary control. And so when we talk about overtreatment, what we're talking about is either a screening tool like a biopsy that maybe you didn't need to do if we had better tools in place to tell you this is not an aggressive cancer or maybe not a cancer at all, we wouldn't need to go all the way to that biopsy step which has a risk.

Or if it's a slow-growing tumor, which a lot of the prostate ones are, maybe it doesn't need the surgical treatment or radiological treatment that's going to cause you those downstream side effects. Is that the primary sort of, those are the things we want to avoid in this march to catching a cancer that does end up killing a lot of guys.

Dr. Jesse Mills: Yes. You brought up a very good point which is that there are certain men, or people in general, that when they hear the C-word, they just want it out. And so even if we say, "Look, this is such a long conversation to have with you because really we're even starting to reclassify some of the very, very low-grade prostate cancer to try to get away from that C-word."

Because if a guy comes in and says, "Doc, just do what you tell me is best," and I say, "Well, if it were me, if it were my brother, if it were my dad, I wouldn't get treatment," and he says, "Great, I'll see you next year," that's active surveillance where we're checking in with those men very regularly to make sure that their prostate cancer isn't getting worse, both through either another biopsy in a year, MRI following. But we're watching those guys.

And we know that there are certain characteristics of the pathology from that biopsy that allow us to predict who can stay in active surveillance. And those are great patients to take care of because again, you're seeing them for their prostate cancer, but you can make sure that they're exercising and all the other men's health things. They're still getting their colonoscopies, for goodness sake. I mean, there's so many other ways that we can die other than prostate cancer that can be prevented if they're having regular follow-ups with a physician.

And so to me, that longitudinal relationship is so critical. And that's a great branch of medicine and a great position to be in as a patient. But if a guy comes in and says, "I don't care what you tell me. You say this isn't really that bad of a cancer to me. It's cancer. Cut it out. I'll deal with the risks later," then you have to respect that decision as a physician.

Because even what you told me about yourself is real. I mean, that you had to wait a month. I mean, that's agonizing to wait a month when it's information that you could have had and been able to make a decision and either say, "Okay, I'm going forward, I'm going to go take care of this," or "I don't have to worry about it." But with cancer, if your mind goes to that, then it sometimes it's hard to sleep at night. And even if your doctor's reassuring you that you're probably going to be okay, doesn't matter. You still have to deal with the ramifications of what happens in your mind at night when you try to go to sleep.

And then there's a group of guys that have, "Wow, you're 50 and we found a horrific cancer that is going to spread like wildfire," which is rare in prostate cancer. It is a very slow-growing condition, but there are ones that can be aggressive and can grow if not on a month-to-month, at least a year-to-year basis. And if you're 50 and five years later, you already have advanced cancer, that's a young dude, because that just happens to be my age. And so that's a problem.

So you want to stay on top of those guys. You want to find the really aggressive cancers through appropriate screening, biopsy, treatment, and get those guys treatment. And so those are really your three groups: the guys that have no cancer at all that have been screened appropriately and are off and living their lives, thank goodness. And then the guys that, "Ah, you know, we have something that probably is going to be okay and we can definitely have time before we need to intervene." And then we got the bad dudes that we got to take care of.

Just as a side note, not only has screening got better, but our treatment for prostate cancer has also improved dramatically. So our surgical outcomes are better. The world of prostate cancer surgery is essentially almost 100% done with a robotic approach now, often through just one incision. You can do an incredibly delicate, incredibly elegant operation under high-power magnification so that the two big side effects that you discussed, loss of erectile function, loss of urinary continence, can be dramatically reduced or even avoided.

And as a shameless plug to the men's clinic and just reconstructive urologists in general, if a guy is going through prostate surgery, we know one of the papers I put out in the literature years ago, about 10 years ago now, if we intervene on those guys before their surgery and we start them on a regimen of nerve preservation and lifestyle management and everything else, their chance of recovering erectile function with a nerve-sparing prostatectomy, which is mostly the standard of care these days, their chance of developing erectile dysfunction is down dramatically over historical controls.

So I always tell guys when I see them prior to their surgery, at UCLA we have an amazing urologic oncology staff of many surgeons. Most of them will come into my office and see me or one of my colleagues and we walk them through the quality of life aspect of their prostate cancer care. And in fact, we always say that visit, guys worry about the three C's. They worry about cure, continence, and coitus.

And the continence and coitus are what keep a lot of guys up at night worrying, especially if you're in the prime of your life and you're running marathons and you're doing great and you have a cancer that has no symptoms and now somebody's telling you you need surgery and, "Oh by the way, it could affect your sexual function, your urinary function." That is a hard stop and that leads a lot of guys to some really anxiety and surgical decision-making.

But we have amazing ways to steward men through this care so that they have actually incredible not only quantity of life from our brilliant oncology surgeons, but quality of life from guys like me.

When to start PSA screening

Mike Haney: Right. So what I'm hearing is given where we've come to with both the screening tools and the actual treatment itself, that we maybe don't need to be as afraid of PSA and that people, and I'm curious your take on at what ages you should start testing and how frequently you should test, but that doing the actual, doing that as a first-level screen isn't necessarily going to lead you to the downsides that we would have cautioned against before, be that anxiety, be that some of these other rushing into procedures that have some kind of side effects. That we've got enough checkpoints along the way that don't have side effects like MRI, which was easy to do, probably the easiest MRI I've ever had because I didn't have to go all the way in the tube.

Dr. Jesse Mills: Right.

Mike Haney: Or the ExoDx, which is a urine test and there are other things like that, that you've got some of these tools along the way that you can do so you don't have to be afraid that, "Well, this is going to, the next step from a high PSA is going to be while I'm in surgery."

If you walk into an office, you get a PSA, it's elevated, and the clinician says you need a biopsy, you need to walk out of that office most likely, unless you have something on your prostate exam that is really concerning. Because the standard of care these days would be to go through those checkpoints.

— Jesse Mills, MD

Dr. Jesse Mills: Right. I think the take-home point for the audience is if you walk into an office, you get a PSA, it's elevated, and the clinician says you need a biopsy, you need to walk out of that office most likely, unless you have something on your prostate exam that is really concerning. And because the standard of care these days would be to do, to go through those checkpoints. So elevated PSA, most likely next you would do ExoDx, some kind of urinary marker, give you a better idea. And then probably the MRI, especially if the ExoDx is high. So those are your checkpoints before you get to it.

And so PSA is a great screening tool in terms of if you look at it as a giant fish net you throw it out, you're going to catch a lot of fish. You also may catch a lot of dolphins that you want to throw back. PSA is good at that. You're going to get most prostate cancers, but you got to figure out who you're going to throw back and who you're going to pursue. And that's where all of these advanced diagnostic either imaging or blood and urine tests can help us out.

So I would say everybody should get a PSA. The age, our guidelines now are somewhere in mid-50s, unless you have a family history of prostate cancer, you should get screened a decade sooner. I actually, if a guy comes into my office, back to what we initially were talking about, and is thinking about testosterone replacement therapy, even if they're in their 40s, I would do a baseline PSA because there is an effect if a guy's testosterone is very low, the PSA can be inappropriately low because one of the things we know happens is if somebody comes in with a testosterone incredibly low, less than 200, then his PSA may actually not be appropriate for what his prostate cancer risk is. And that's super important to think about.

So if a 49-year-old guy comes into me, he's below screening ages for prostate cancer, no family history, and he has a testosterone of 100, say something crazy low, and I said, "Well, I'm going to get your PSA," and the PSA is say two, I'm worried about that guy. I'm not worried that I'm going to give him prostate cancer if I start him on testosterone, but I will tell him, "Look, if I start you on testosterone, your PSA could go up to the point where we're probably going to do some kind of more advanced screening." I don't want to miss that guy and miss that opportunity to have the conversation and be able to have early intervention on him.

So those are the guys that I look at PSAs. I do use a lot of screening PSAs and the number of them that I have to act on is thankfully very low, but it's not zero.

Separating good information from myths

Mike Haney: Maybe the last thing before we leave off in this age of people getting a lot of health information on the internet and on their social media. Are there any bits of misinformation that you see a lot, people coming and that are out there, things that are being propagated that you find yourself dispelling in folks that are coming to you that you want to, in any of the topics we've talked about or anything else related to male health?

Dr. Jesse Mills: I think there are a lot. But I think it's having a good conversation with people and I'm not one of those physicians that's so dogmatic that I don't want to hear about what alternative therapies they're trying. I think we got nowhere near enough time to talk about supplements, for example. I mean, I think supplements, in traditional medicine, we think none of them work. If a guy's on supplements, he's wasting his money. And then we have guys that are on 200 supplements and trying to live forever.

And that's a classic example of where there's not one myth. I mean, there are supplements that have good randomized, placebo-controlled data that they work, especially in the world of sexual function, but most don't, right? But I think the myth is that, "Look, I want to try something natural and I want to just, I want to do this without any help." So for example, "I won't take a medication like tadalafil or Cialis or Viagra because they're medications, but I'd rather take 40 of these supplements."

Well, as you know, supplements, especially taken in high quantities, I mean, there's the big thing just on turmeric, right? That you think turmeric is great, but if you take enough of that, you'll end up in liver failure and it's now regulated. And if nobody's really prescribing it, you don't know what an adequate dose is. Whereas if you look at a traditional medication, if it's prescribed responsibly and indicated on-label, then even if it's not exactly natural, it may still be therapeutic.

And I think the dichotomy between prescriptions and supplements needs to stop because if a supplement works, it's going to work like a medication. Otherwise you wouldn't take it. So I think that is the biggest myth, is that if it's natural, it's okay. It's not. And a lot of times, in fact, it can be very dangerous and more dangerous than pharmaceuticals. So that's myth number one.

I think myth number two is just the idea that you can do this alone and that you can biohack, and no offense to ChatGPT or anything else, but that you can biohack your way out of a doctor's office. But there are great reasons for maintaining regular checkups with people that are very well trained to take care of you. And you don't miss stuff. And I think we tend to be away from the sensationalization of medicine and the clickbait.

Because for every time a guy comes in and says, "I want to try ashwagandha or I want to do this extract or I want to do this," and he's already malignantly hypertensive, I'm going to worry about his blood pressure, which is not very sexy to worry about. And we've known about blood pressure for 200 years, but that still is one of the leading causes of death of men in this country is hypertension, kidney failure, erectile dysfunction, vision loss. And it's a vital sign.

And so I think sometimes we just have to get back to the basics and realize that there is a lot of good medicine that's based on years and years of randomized data, placebo-controlled studies that work and they work for a reason. And they're not sexy and they're not going to sell this and they're not going to sell that. But I think we need to come into that union where people are getting a good high-level consumer level of information, much like what we're doing here. I mean, this conversation is very high-level, very approachable. And I think the work that you do is critical for this mission of saying, "Hey, we should be working on this together."

And the best thing that I do in my clinic, one of the things I'm most gratified by is when somebody does come in with, "I just saw this. What do you think of that?" And I will tell them. And then sometimes I learn. I mean, that's always fun too if there's something I learn about from a patient that I don't know because I'm not spending hours looking at my own medical condition. But I love the informed patient, someone that's so invested in their care that they can teach me.

Mike Haney: All right, I think that's a great place to end it. So Dr. Mills, thanks so much.

Dr. Jesse Mills: I got 10 minutes on the meter. It's perfect. Thank you.