273 ‒ Prostate health: common problems, cancer prevention, screening, treatment, and more

1. 0:00 – 0:45

   Intro

   1. TSTed Schaeffer0:00

      I always talk about ancestry, and then I talk about all cancer risks, right? When I'm taking a family history, I say, "What's your personal history of prostate cancer?" And if you have a personal history of prostate cancer, you're meaning a father, uncle, or brother, so first-degree relative

   2. PAPeter Attia0:16

      Father, uncle, brother. Okay

   3. TSTed Schaeffer0:18

      Brother. The number of individuals and the age that they were diagnosed, and we'll put a link in the show note for the table, it increases your fold risk of being diagnosed with prostate cancer significantly. It doesn't mean you need to change-- You shouldn't have a prophylactic prostatectomy, but you should just have intensive f- intensive monitoring.

   4. PAPeter Attia0:36

      [upbeat music] Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Attia.

2. 0:45 – 5:56

   Changes to the prostate with age & problems that can develop

   1. PAPeter Attia0:46

      Ted, awesome to, uh, to be sitting down with you to talk about all things prostate, uh, related. Uh, it's been probably four years since we did this.

   2. TSTed Schaeffer0:54

      Yeah.

   3. PAPeter Attia0:55

      Yeah.

   4. TSTed Schaeffer0:55

      Thanks for having me.

   5. PAPeter Attia0:56

      So, um, I think probably it's worth assuming that there are a lot of people who didn't hear that first podcast, and those that did probably don't remember much anyway, and also a lot has changed in four years, so, um, I think never a bad idea to, to sort of start from the beginning. Um, so l- let's start with talking about what the prostate gland is, what it does, uh, before we get into any of the pathology associated with it.

   6. TSTed Schaeffer1:20

      Yeah. So the prostate's an exocrine gland, and it's part of the reproductive system. It sits just below the bladder in men. So it's a dimorphic organ. It does not exist in women. It develops in utero in response to fetal androgens. And so, um, it produces basically most of the components, or about fifty to sixty percent of the ponent- components of semen. So it's used in reproduction in all mammals, and we're a mammal, so we use it too.

   7. PAPeter Attia1:51

      And, um, I guess when you th- sort of think about, um, things that start to go wrong in the prostate, I, I'm guessing that most men listening to this, the first thing that they might think of is, you know, prostatitis, uh, c- certainly a- a- a- age-wise, right, before you get into prostate cancer, which of course we're gonna talk at length about. Um, so when I think, when... Just as a layperson thinking about the prostate gland, I sort of think about inflammation, infection, I think about benign enlargement that leads to obstruction, and then obviously we'll talk about neoplasm. Is that how you sort of think about the problems associated with it?

   8. TSTed Schaeffer2:28

      It's a, it's an organ that sits in line with the urinary tract, and it, and so the urinary tract in men has a dual purpose. General urinary tract has a dual purpose. One, it's used for reproduction. The other is used to kind of eliminate all, all the urine. And so because of that shared functionality, um, you can, you can develop problems in one or the other of those two s- disease systems, um, and they result in symptomatic issues. And a lot of the problems that men, even at a young age, but particularly as they age, will experience are related to the prostate. So in some ways, it's kind of the nexus of the lower urinary tract. So yes, it's absolutely true that in younger men you can develop infections in the urinary tract. They can be very problematic and difficult to solve and address if it's involving the prostate. Additionally, if you develop an infection, classic bacterial or potentially viral or other kinds of causes, you can get inflammation in the prostate, which can result in longstanding long-term pain. So that's one of the things I see when young men come in with prostatitis. Then as men evolve and age, as the prostate evolves and changes as we get older, um, different issues arise, and they can result in and impact, um, your urinary function because it's a shared kind of, it's a shared, uh, system of, uh, of elimination of semen and of urine. And so as we get older, fifty, fifty, fifty to sixty percent of men at age fifty and, and, and, and older will have, you know, issues with lower urinary tract dysfunction.

   9. PAPeter Attia4:06

      Hmm.

   10. TSTed Schaeffer4:07

       And those almost always directly relate to the prostate in some way or another. So, um, some of the s- some of the stats are pretty staggering. So at age fifty, it's probably fifty to sixty percent of men have lower urinary tract dysfunction, but by age sixty, it's seventy-five to eighty percent of men will have lower urinary tract symptoms.

   11. PAPeter Attia4:24

       So let's talk about what those are.

   12. TSTed Schaeffer4:25

       Typical ur- lower urinary tract symptoms, weak stream, um, hesitation or slowness in getting your urinary stream started, urgency to go to the bathroom, increased frequency to go to the bathroom, and they're related to two things. One, functional escruption, functional obstruction of the urethra. That's the tube that c- we urinate through, uh, the tube that comes out of the tip of the penis, and that tube, the first part of it passes right through the middle of the prostate. So as the prostate enlarges, it can compress that channel, and that can result in weak stream. It can result in dribbling and straining. Additionally, the muscle behind, above the prostate is the, is the bladder. The bladder is a, is a, a, a bag, a, a storage device that is, is muscular. And so that muscle, as the, um, as the diameter of the tube narrows with in- increasing size, for example, that muscle will have to work harder. Compliance will go down, and when the, the compliance of the bladder goes down, the capacity can go down, and the increased urgency to go to the bathroom will go up because it's less stretchy. So again, as we get older, the prostate, parts of the prostate will grow. Oftentimes, that growth of the prostate results in narrowing of the channel. That can concomitantly lead to thickening of the bladder wall, and then that results in a whole constellation of urinary symptoms, which can be managed, uh, but many, many men have them, and it's certainly something that we talk a lot about with almost all of our patients.

3. 5:56 – 15:08

   Behavioral modifications to help manage nocturnal urinary frequency & lower urinary tract symptoms

   1. PAPeter Attia5:56

      So maybe let's talk a little bit about, um, [clears throat] what the medical management is for those things, because, um, this is an area where The surgeon does both the medical management and the surgical management, right, typically?

   2. TSTed Schaeffer6:08

      Yeah, urologists are... It's one of the more unique specialties in that we do a lot of diagnosing and then managing medically and treating surgically and then survivorship for almost all the conditions that we take care of.

   3. PAPeter Attia6:21

      So what are the first steps in the medical management of lower urinary symptoms?

   4. TSTed Schaeffer6:27

      Yeah, so behavioral modifications. So, um, if you're an executive at a water company and all you do is drink water all the day, all day long, you're going to urinate a lot. So a, a lot of it is just education and behavioral modifications. So educating people that a lot of what you take in will come out. That, you know, that the idea that, you know, the kidneys are designed to maintain our body's fluid status in a kind of homeostasis. If you increase your fluid intake, you're going to have increased urinary output. And so just basic educational things about that is really, really helpful. In addition to regulating what you drink, it's when you drink it and what's in what you're drinking. So a lot of people will come and, and, and come in with symptoms of nighttime urinary frequency. And a lot of that is just you can modify with education, saying, "Hey, don't, you know, don't drink, you know, two glasses of water right before you go to bed. And if you get up in the middle of the night because you have to urinate, don't drink another glass of water right when you get up to, to urinate." So, so that kind of component of the education, timing of when you take in those fluids, and then what's in the fluids, specifically caffeine.

   5. PAPeter Attia7:36

      Mm.

   6. TSTed Schaeffer7:36

      Um, and there are some fluids that have natural diuretic properties, and so if you are taking or drinking, uh, something that's a diuretic, you're going to produce more urine, and that will result in more urinary symptoms within two to four hours after taking that fluid in. So caffeine, for example, uh, is a natural diuretic, and it will cause you to produce more urine over a certain amount of time than you would have if you didn't, if you took in, um, iced tea with no caffeine in, in, in it, for example. So a lot of educational things, a lot of, um, a lot of, um, education about what to do, when to do it. We often will have people do voiding diaries, um, but really it's a diary of what you're ta- what you're drinking and then when you're urinating. And actually, just having the patients just walk that, walk through that with them will, will be quite helpful.

   7. PAPeter Attia8:23

      Right. So they're measuring their input in timing-

   8. TSTed Schaeffer8:26

      Exactly

   9. PAPeter Attia8:26

      ... and, and volume-

   10. TSTed Schaeffer8:27

       Yeah

   11. PAPeter Attia8:27

       ... and output and timing and volume.

   12. TSTed Schaeffer8:29

       Yeah. And that simple task, which is, you know, easy, easy to do, will result in, A, a realization that, hey, I'm drinking, you know, 130, you know, ounces of water a day. Like, what... You know, and it's, it's all excessive. It's unnecessary. 'Cause you can show them that, yeah, you're urinating out the same basic amount of volume. 'Cause we also get in our foods, obviously, water too or f- or fluids. So, so mapping out, mapping out kind of behavioral modifications is the first step I always do. If it persists and they're bothered by it, then we'll talk about doing a voiding diary, particularly if their symptoms are a little bit unusual. For example, if you're sensing that they may be urinating much more at night than you would anticipate after they've done these different behavioral modifications. There are hormonal, hormonal, um, you know, uh, hormonal, uh, deficiencies that can result in increased urinary production at night, for example. So if we're suspicious of any of those things or if patients are still bothered by their urinary symptoms and they, um, they're, they want to not go on a medication, we'll do a voiding diary. We'll map out when they're drinking, when they're urinating, and then we'll kind of go from there.

   13. PAPeter Attia9:40

       Now, now what, what if a guy comes to you and, and is sort of upset about the frequency with which he's waking up to pee at night? The medical term for that, of course, is nocturia. Is there a norm, right? So you and I are 50 years old. Um, I would say five nights a week I don't get up to pee. Two nights a week I get up to pee once.

   14. TSTed Schaeffer10:01

       Yeah.

   15. PAPeter Attia10:01

       And obviously that's probably more tied to the timing of my fluid intake and what it was than, you know, necessarily prostate-specific symptoms. But what's normal, if there's such a thing as normal for a 50-year-old, a 60-year-old, et cetera?

   16. TSTed Schaeffer10:16

       Yeah, great question 'cause there's a lot of variability in terms of what you can expect based on, on the age of the individual. So there are, there's a, there's a naturally secreted hormone, antidiuretic hormone, and it, in younger decades of life, it has a, a surge of release around 7 or 8 o'clock at night. Antidi-diuretic hormone prevents you from diuresing or producing more fluid.

   17. PAPeter Attia10:40

       Alcohol, by the way, inhibits this hormone, which is why alcohol before bed is a great recipe for having to get up and pee for two reasons. You get the fluid-

   18. TSTed Schaeffer10:51

       Yes

   19. PAPeter Attia10:51

       ... in the drink.

   20. TSTed Schaeffer10:52

       Yes.

   21. PAPeter Attia10:52

       And then you get a molecule that inhibits the release of antidiuretic hormone.

   22. TSTed Schaeffer10:57

       Yeah. Absolutely. And, and so the classic one for that is beer because it's a higher volume-

   23. PAPeter Attia11:01

       It's high volume liquid

   24. TSTed Schaeffer11:02

       ... high, high volume intake.

   25. PAPeter Attia11:03

       Yeah.

   26. TSTed Schaeffer11:03

       So yeah. So y- we have natural diurnal release of antidiuretic hormone, and that diurnal variation is attenuated kind of per decade as we get older.

   27. PAPeter Attia11:15

       Mm.

   28. TSTed Schaeffer11:16

       So that peak of antidiuretic hormone goes down per decade, and that can then kind of normalize your 24-hour urine production, whereas when you're in your 20s or 30s, you would produce, let's just say, 80 or 90% of your urine during waking hours. During the nighttime when you have high levels of antidiuretic hormone, you're not going to produce as much urine, and your kidneys and your body will save that extra fluid for the morning when you get up.

   29. PAPeter Attia11:44

       So, so is there a biologic explanation for the attenuation of that hormone as we age?

   30. TSTed Schaeffer11:49

       You know, it's a good question. I don't know the, I don't know the answer to that, to, as to why that could be, but certainly we see it in general in aging populations, men and women.
4. 15:08 – 26:41

   Pharmacologic tools for treating nocturnal urinary frequency & lower urinary tract symptoms

   1. TSTed Schaeffer15:08

      behavioral.

   2. PAPeter Attia15:09

      Yeah.

   3. TSTed Schaeffer15:09

      That's-

   4. PAPeter Attia15:10

      So, so then let's talk about the pharmacologic tools. So you've already kind of alluded to one, and it's one that we use in our practice, um, which is when we have a guy who otherwise we don't have a clear explanation for why he's getting up to pee, um, and he doesn't appear to have a particularly enlarged prostate, and we c- we're gonna talk about, of course, all those things. A very low dose of desmopressin, which is this, uh, I get... is the synthetic version of the antidiuretic hormone, uh, typically 2... .2 milligrams before bed, uh, has profound effects.

   5. TSTed Schaeffer15:47

      Yeah.

   6. PAPeter Attia15:48

      Um, so talk a little bit about that and then maybe some of the other things. And, and also are there any contraindications to the use of that? I know certainly theoretically a contraindication or a concern would be hyponatremia, as you would sort of increase, uh, plasma volume, uh, and therefore dilute sodium. But maybe just talk a little bit about how you would use that.

   7. TSTed Schaeffer16:07

      Yeah. So there, there are very straightforward, you know, frontline medical management, um, me- med- uh, you know, pharmacologic agents to manage lower urinary tract symptoms. And generally speaking, the f- frontline ways that we manage it would be with an alpha blocker. So there are, um... That's a, a, a, uh, class of compounds that are nowadays very, very specific to prevent activation of, um, a set of smooth muscles that are really isolated mostly in the prostate and somewhat in the seminal vesicles. And so if you just take a step back and look at the embryology of the prostate, it obviously is a, um... it develops from ep- urogenital si- the urogenital sinus, and there's mesenchymal and epithelial components of that. So there's a lot of smooth muscle within the prostate. The smooth muscle exists within the prostate in part to help with ejaculation.

   8. PAPeter Attia17:01

      Mm-hmm.

   9. TSTed Schaeffer17:01

      It's, uh, effectively like-

   10. PAPeter Attia17:04

       It's like a pump.

   11. TSTed Schaeffer17:04

       It's a pump.

   12. PAPeter Attia17:05

       Yeah.

   13. TSTed Schaeffer17:05

       So once you have, when you're having an orgasm, the, the pump squeezes. The prostate will squeeze, and that will result in emission of the fluid. So what you can do for individuals who have lower urinary tract symptoms is that while you have this channel, this tube going right through the middle of it-

   14. PAPeter Attia17:21

       The urethra

   15. TSTed Schaeffer17:21

       ... that's the urethra.

   16. PAPeter Attia17:22

       Yep.

   17. TSTed Schaeffer17:22

       You can relax the smooth muscle within the prostate, and that will relax a little bit and, and theoretically it enhances the diameter of the, of the, uh, of the prostatic urethral channel. That's the thought for how it works, and that could then result in relaxation and improvement in urinary symptoms, and it works quite well for most people. Now, originally this was noted because of the kind of first class of, of, of alpha blockers were used for blood pressure control. And so one of the side effects of the first generation of these medications was just profound hypotension until you kind of titrated up the dose and so forth. But the more modern medi- more modern ones, um, really effectively treat specifically the, uh-

   18. PAPeter Attia18:06

       So they're selective in that they relax those muscles without dropping-

   19. TSTed Schaeffer18:10

       Yeah

   20. PAPeter Attia18:10

       ... blood pressure.

   21. TSTed Schaeffer18:11

       And, and the newest generation of ones will actually be more... are even selective to the smooth muscle within the prostate and not the seminal vesicles. So the seminal vesicles and the prostate kind of grow up right next to each other. For example, when you do a radical prostatectomy, you take out both organs. They're attached to each other.

   22. PAPeter Attia18:28

       Mm-hmm.

   23. TSTed Schaeffer18:28

       The seminal vesicles dump- Into the prostatic urethra. So the second generation, third generation, um, antimuscarinics, or I'm sorry, alpha blockers, would paralyze or prevent contraction of the prostatic smooth muscle, right? So you would have improved urinary symptoms, but would also have decreased-

   24. PAPeter Attia18:50

       But doesn't impede ejaculation.

   25. TSTed Schaeffer18:52

       It would, they would impede ejac- the, the kind of s- the first more targeted ones would.

   26. PAPeter Attia18:57

       Yes, 'cause-

   27. TSTed Schaeffer18:57

       Because they would in fact-

   28. PAPeter Attia18:58

       Paralyze both

   29. TSTed Schaeffer18:59

       ... paralyze both.

   30. PAPeter Attia19:00

       Yep.
5. 26:41 – 33:24

   Surgical tools for treating symptoms of the lower urinary tract

   1. TSTed Schaeffer26:41

      agonist. For me personally, though, it's always a balance because at some point you have to start saying, "Well, okay, how old is the patient? How significant are their symptoms?" Because there are highly effective ways to manage these issues surgically. These days, they can most of the time be done just as a simple outpatient.

   2. PAPeter Attia26:59

      Yep.

   3. TSTed Schaeffer27:00

      And so then you start saying, I, I usually begin to introduce the idea of, "Okay, well, if you're still bothered, we have outpatient surgical procedures that can basically fix this for life with no medications." And so I, that's kind of my stepwise process that I kind of lead patients through in terms of thinking about their urinary symptoms for men.

   4. PAPeter Attia27:18

      Let's talk about, let's talk about a surgical procedure.

   5. TSTed Schaeffer27:20

      Yeah.

   6. PAPeter Attia27:20

      So again, just kind of going back to my, where I, what I learned about 25 years ago, the, the TURP, right?

   7. TSTed Schaeffer27:26

      Yeah.

   8. PAPeter Attia27:26

      The transurethral resection of the prostate.

   9. TSTed Schaeffer27:29

      Yes.

   10. PAPeter Attia27:29

       Uh, uh, kind of a Roto-Rooter job.

   11. TSTed Schaeffer27:33

       Yeah. So the prostate develops from the urogenital sinus. The, uh, prostate as we mature in response to androgens and estrogens too, for that matter, will d- it develops into different zones or different regions. The peripheral zone, which is outlying the prostate, think about a orange and the orange peel, and the pulp of the orange is the transitional zone of the prostate. That gets bigger. Actually, it's not just a testosterone-driven thing. It's actually when there's more estrogens around that actually-

   12. PAPeter Attia28:03

       Mm

   13. TSTed Schaeffer28:03

       ... with testosterone that can result in hypertrophy, increasing in the size of the transition zone. That is what causes all the urinary symptoms in individuals, with rare exceptions with an aggressive cancer. That's what's causing it. In those situations, you can do what they call, there's a variety of MIST procedures, so minimally invasive surgical procedures that can address, um, these urinary symptoms. So you can do a variety of things. You can introduce steam into the transitional zone tissue. That can then, you know, kill that and effectively kill all the smooth muscle and reduce to some extent the kind of hypertrophy of the epithelial cells. You can surgically resect it. You can-

   14. PAPeter Attia28:46

       Transurethrally.

   15. TSTed Schaeffer28:47

       Transurethrally.

   16. PAPeter Attia28:48

       Yeah.

   17. TSTed Schaeffer28:48

       So no incisions.

   18. PAPeter Attia28:50

       Yeah.

   19. TSTed Schaeffer28:50

       So what we would, you could call a natural orifice procedure. Uh, you could suspend it surgically, so there's kind of tethers that you can put in place that kind of tent open the urethra. Uh, but the mainstay, the gold standard is to remove the tissue, uh, which can result in profoundly improved urinary symptoms. It is-

   20. PAPeter Attia29:09

       And, and is that done with, like, laser, electrocautery? I mean, what is-

   21. TSTed Schaeffer29:13

       Yeah

   22. PAPeter Attia29:13

       ... the gold standard today for the, the, the means by which you remove the tissue?

   23. TSTed Schaeffer29:19

       So the gold standard has always been the TURP procedure, which is what you described. Now, that procedure itself has evolved in that it can now be done with irrigation that is with normal saline. So pr- traditionally, to, uh, maintain a monopolar current, you had to use water 'cause you would not want the sodium to disrupt that current.

   24. PAPeter Attia29:39

       Mm.

   25. TSTed Schaeffer29:40

       So now a modern TURP is a bipolar TURP, a bipolar where you have, you, you, the, the, the-

   26. PAPeter Attia29:46

       Explain to folks why you need an irrigant when you're doing this procedure.

   27. TSTed Schaeffer29:50

       Yeah. So you're effectively, um, as you described it, this is a kind of Roto-Rooter procedure, but you're technically removing bulky tissue in the urethra that's kind of circumferentially surrounding the prostatic urethra.

   28. PAPeter Attia30:03

       Yeah, so you, you sort of have as, you know, you've got this thing here, and you, you, using the natural orifice of itself, you have to expand the diameter of this thing by actually getting rid of-

   29. TSTed Schaeffer30:14

       Yes

   30. PAPeter Attia30:14

       ... prostatic tissue in the transitional zone.
6. 33:24 – 42:06

   HoLEP surgery for reducing prostate size

   1. TSTed Schaeffer33:24

      My partner, Amy Kranbeck, is really one of the pioneers in modern HoLEP surgery. So this is different. So again, if you think about the orange analogy, a TURP or any of those other procedures is basically trying to scrape out the pulp one, one little chunk at a time. Amy will go in, and she'll get in the, the plane between the peel or the rind of the orange.

   2. PAPeter Attia33:45

      Yep.

   3. TSTed Schaeffer33:45

      And she'll take out the-

   4. PAPeter Attia33:46

      And just take all the pulp out

   5. TSTed Schaeffer33:47

      ... take it all out in one piece. She pushes it into the bladder, and then there's a morcellator that then chomps it into little tiny pieces that you then remove through the urethra. So there, the beaut- the benefits of HoLEP-

   6. PAPeter Attia33:58

      So, so just let's make sure people understand that, 'cause I love that. I think that, I think your orange analogy makes this so much easier to understand.

   7. TSTed Schaeffer34:04

      Yeah.

   8. PAPeter Attia34:04

      If you're doing a TURP, you're sticking a pe- you've got a pencil hole going through the orange.

   9. TSTed Schaeffer34:08

      Yeah.

   10. PAPeter Attia34:08

       You gotta put that, you gotta put a hollow pencil into that pencil hole, and literally one tiny, tiny thimble at a time-

   11. TSTed Schaeffer34:16

       Yeah

   12. PAPeter Attia34:16

       ... pull out little sacks of pulp-

   13. TSTed Schaeffer34:18

       Yes

   14. PAPeter Attia34:18

       ... one by one by one by one by one by one by one.

   15. TSTed Schaeffer34:21

       Yes. Additionally, remember that when you're doing that, you're disrupting the kind of architecture of the orange.

   16. PAPeter Attia34:26

       Yep.

   17. TSTed Schaeffer34:27

       And there's lots of blood vessels that exist within the transition zone itself.

   18. PAPeter Attia34:31

       Yeah. And so it's, now it's bleeding like a sieve.

   19. TSTed Schaeffer34:33

       Bleeds a lot.

   20. PAPeter Attia34:33

       Yeah.

   21. TSTed Schaeffer34:33

       When, when Dr. Kranbeck, when Amy does her procedures, she gets in that natural tissue plane.

   22. PAPeter Attia34:38

       She shaves into that natural plane.

   23. TSTed Schaeffer34:40

       The adenoma.

   24. PAPeter Attia34:40

       And it's not bleeding as much.

   25. TSTed Schaeffer34:42

       Yes.

   26. PAPeter Attia34:42

       And she somehow manages to take that whole pulp minus the peel, shove it into the bladder, and when it's in the bladder, now isolated, you can break it apart.

   27. TSTed Schaeffer34:51

       Yes.

   28. PAPeter Attia34:51

       And-

   29. TSTed Schaeffer34:52

       She'll morcellate it apart. So she'll, she is spectacular. So, um, HoLEP was a procedure developed, originally described in New Zealand, I believe, by a New Zealand urologist, and it was limited for a long time based on the technology that existed within the lasers. But, um, the laser technology, and Amy really helped develop the latest versions of these lasers that are just higher energy, more precise. Take that, and then you can then, you know, couple that with an experienced surgeon, and the outcomes for it are spectacular. So-

   30. PAPeter Attia35:22

       Uh, what are the, what are the, um, patients who would not be considered candidates for that procedure? Is there a, is there a contraindication to that?
7. 42:06 – 49:09

   Prostate size: correlation with cancer & considerations for small prostates with persistent symptoms

   1. TSTed Schaeffer42:06

      um, but yes, definitely runs in families.

   2. PAPeter Attia42:07

      Is there any correlation with prostate size and cancer?

   3. TSTed Schaeffer42:10

      Yes.

   4. PAPeter Attia42:10

      When you talk about those extremes.

   5. TSTed Schaeffer42:11

      Inverse correlation. So the bigger the prostate, the less your chance of developing aggressive cancer is.

   6. PAPeter Attia42:17

      Why is that?

   7. TSTed Schaeffer42:18

      Not sure. Um, and it, it may have to do with variations in the balance of hormones, for example. There's definitely a, um, large prostates i- grow in response to kind of a, not a increase in testosterone actually, but, but a, a, more of a even ratio of T to E, so testosterone to estrogens. So actually, as your testosterone declines, as you know, as you get older, the, the T can go down. Estrogens remain pretty stable or can go up ob- obviously with meta-

   8. PAPeter Attia42:49

      Especially if you have metabolic syndrome

   9. TSTed Schaeffer42:51

      ... metabolic syndrome.

   10. PAPeter Attia42:51

       Estrogen will rise.

   11. TSTed Schaeffer42:52

       So, so as men age, their prostates grow, and I believe that that's more hormonal. So-

   12. PAPeter Attia42:57

       In other words, if y- you're saying that You know, again, classic thinking that has clearly been proved false is that testosterone is causing prostate cancer. You're saying it's way more nuanced than that, and it's maybe if the endocrine component of prostate cancer may be more related to the relationship of testosterone and estrogen-

   13. TSTed Schaeffer43:15

       Yes

   14. PAPeter Attia43:15

       ... and a declining testosterone in the presence of a rising estrogen would be a more favorable endocrine milieu for prostate cancer than the younger phenotype, which is higher testosterone to estrogen.

   15. TSTed Schaeffer43:28

       Well, let's just take that back a second. So when you're t- when you're, as you're aging, your testosterone, and you-- let's say as you're aging and if you have metabolic syndrome, your testosterone levels will go down, your estrogen levels will go up, and that can result in prostatic growth, but it's typically more adenoma growth in the transition zone causing lower urinary tract symptoms. So-

   16. PAPeter Attia43:51

       So benign growth.

   17. TSTed Schaeffer43:51

       Benign growth. That somehow is protective. Either the-

   18. PAPeter Attia43:55

       I see

   19. TSTed Schaeffer43:55

       ... the size or just the ratio, that difference in ratio of T to E is somehow protective for developing kind of later onset prostate cancer. Remember, in my mind, you know, you're, you're locked in and, and your code is ef- is effectively set in stone in your 30s and 40s, in my opinion, for-

   20. PAPeter Attia44:14

       For development of prostate ca-

   21. TSTed Schaeffer44:15

       ... prostate cancer.

   22. PAPeter Attia44:16

       Wow.

   23. TSTed Schaeffer44:17

       Right. When your estrogen levels are very low, your T levels are higher. Now, we'll talk a lot about testosterone and what it's doing in prostate cancer later, but in my opinion, um, it's the T to E ratio that attributes t- uh, is responsible for prostatic enlargement much more than the development of any prostate cancer.

   24. PAPeter Attia44:37

       And just to kind of close the loop on the surgical procedures for lower urinary tract symptoms, two, two final thoughts. One is, what is the floor for the, uh, what's it called? The HoLEP.

   25. TSTed Schaeffer44:50

       HoLEP.

   26. PAPeter Attia44:51

       HoLEP.

   27. TSTed Schaeffer44:51

       Holmium laser enucleation of the prostate.

   28. PAPeter Attia44:54

       So what, what is the... In the hands of, as someone as talented as Amy, what is the smallest prostate she would do that procedure on?

   29. TSTed Schaeffer45:02

       Somewhere on, let's just call it twenty-five or thirty grams.

   30. PAPeter Attia45:05

       Oh, wow. So basically-
8. 49:09 – 1:02:28

   Prostatitis due to infection

   1. PAPeter Attia49:09

      Let's, before we get into some of the pathophysiology of how the hormones impact the prostate, which is a good lead-in, I think, to, to cancer, let's go back and talk a little bit about prostatitis, because I, I would guess that for many men, that is their first brush with pelvic floor discomfort and, uh, you know, a symptom associated with, uh, with this gland. So, so I, I remember, you probably don't remember this, but I remember having a brush with this about six years ago.

   2. TSTed Schaeffer49:39

      I remember. Yeah.

   3. PAPeter Attia49:40

      And of course, you, you helped me out. [smacks lips] And so what, this is part of the problem when you start to play doctor to yourself, right? So all of a sudden, I start having some, you know, discomfort when I'm peeing, and, um, you know, I, I do all the usual stuff. I, you know, check, oh, is it an infection? Da-da-da-da. None, none of the above, right?

   4. TSTed Schaeffer49:59

      Yeah.

   5. PAPeter Attia49:59

      So it's not like I have a urinary tract infection or, you know, an STD or anything like that. Um, and boy, does it... And it's not unbearable pain, to be... I don't wanna, I don't wanna over-dramatize this. It's not like razor blades are coming out, which I've heard people describe.

   6. TSTed Schaeffer50:14

      Yeah.

   7. PAPeter Attia50:14

      You know, that might be certain infections. No, no, it's none of that. It's just not comfortable.

   8. TSTed Schaeffer50:18

      Yeah.

   9. PAPeter Attia50:18

      It's really uncomfortable to void.

   10. TSTed Schaeffer50:21

       Yeah.

   11. PAPeter Attia50:21

       And, um, I, I gave you a call. I remember exactly where I was when I called you, by the way, and, and you were the one that said, "No, no, no, look," you know. And you started asking me a bunch of questions. "Hey, you've been traveling a lot. Are you a little constipated?" And one thing led to another, and the diagnosis in your mind was, "Look, playing doctor over the phone at least, I'm actually more likely thinking this is prostatic inflammation."

   12. TSTed Schaeffer50:41

       Yeah.

   13. PAPeter Attia50:41

       So walk us through the, the pathology of that.

   14. TSTed Schaeffer50:45

       Yeah, I mean, I w- I wish I could tell you in, in the next, uh, five minutes what the pathology was, 'cause we, the, the, the short answer is we do not know. We call this kind of constellation of symptoms chronic pelvic pain syndrome. So what that really ends up meaning is it's a bucket that you really, we put a lot of different things into. So you can have pelvic pain and discomfort if you have, uh, a large prostate and it's obstructing your urinary tract, okay? That one we talked about. You can manage that. That's pretty easy to do. But there are other things that can cause pelvic pain and discomfort. One would be a acute bacterial infection.

   15. PAPeter Attia51:20

       Mm-hmm.

   16. TSTed Schaeffer51:21

       And that's a classic. Frankly, if we find that, I feel good-

   17. PAPeter Attia51:25

       Yeah, you're lucky

   18. TSTed Schaeffer51:25

       ... because I know we c- we have a solution.

   19. PAPeter Attia51:26

       It's a quick fix. Yeah.

   20. TSTed Schaeffer51:27

       We can address it and so forth. You can address the infection. Now, the inflammation and the discomfort and pain that results after that may take much, much longer to resolve. You can have a n- a, a non-bacterial inflammation that could be viral, although no one's really ever isolated specific viral, viruses that are, you know, in an individual man tracks with that pain, but viral. And then there's pelvic floor, you know, dysfunction that is outside of the urinary tract. That pelvic floor function could be in the, in the anus and in the rectum, having to do with dysfunctional voiding or elimination in the rectum. It could have to do with dysfunctional elimination between the bladder and the ur- urinary or urethral sphincter. Those are common in kids.

   21. PAPeter Attia52:13

       Yeah, 'cause the other thing anatomically that maybe we failed to mention was the proximity of the rectum to the prostate.

   22. TSTed Schaeffer52:19

       Yeah. So the rectum and the prostate are adjacent to each other.

   23. PAPeter Attia52:23

       Yeah.

   24. TSTed Schaeffer52:23

       The rectum and the prostate effectively develop from the cloaca. The cloaca is the embryonic kind of sewer. That's where all the waste in a fetus would go into and out of, and then it's divided anteriorly and posteriorly into the urogenital sinus and then the, what becomes the anus and the rectum. And so yes, they're, they're intimately, um, they're intimately associated with each other, and the innervation between the two of them is actually, there's a lot of cross-innervation. So if you have inflammation in the gut, in the rectum and the anus, you can result in irritation and inflammation in the prostate. There also can be translocation of bacteria between the rectum and the prostate. So when we, when we are talking about your individual situation-

   25. PAPeter Attia53:06

       Yeah

   26. TSTed Schaeffer53:06

       ... I said, "Are you traveling? Are you constipated?" We think that that can result in maybe some increased transmural translocation of bacteria. But in general-

   27. PAPeter Attia53:15

       And by the way, to this day-

   28. TSTed Schaeffer53:16

       We don't really know what it was.

   29. PAPeter Attia53:17

       Yeah. But, but that said, like, any, for reason, I, I go to great lengths to make sure my bowel habits are regular when I travel.

   30. TSTed Schaeffer53:24

       Yeah.
9. 1:02:28 – 1:09:33

   Prostatitis caused by factors besides infection

   1. TSTed Schaeffer1:02:29

      Now, the issue is that there are, are many people who have discomfort that is not associated with bacterial infection. It could be viral. It could just be inflammation, and it's not necessarily within the urinary or genital tract. So I see a lot of patients, and when I do a rectal exam on somebody who's d- complaining of, of, of, uh, prostatic pain, I always wanna feel the muscles in the pelvic floor. And just like-

   2. PAPeter Attia1:02:53

      And how do you do that on the rectal? Is it just a broader exam?

   3. TSTed Schaeffer1:02:55

      So when you do a rectal exam and you feel kind of straight posterior-

   4. PAPeter Attia1:02:58

      Yeah

   5. TSTed Schaeffer1:02:58

      ... you're feeling just the prostate. If you just move your finger laterally-

   6. PAPeter Attia1:03:02

      You're into the pelvic floor, for sure

   7. TSTed Schaeffer1:03:03

      ... and you're in the pelvic muscle for sure.

   8. PAPeter Attia1:03:05

      Yeah.

   9. TSTed Schaeffer1:03:05

      And so oftentimes you won't feel much of anything.

   10. PAPeter Attia1:03:08

       Yeah.

   11. TSTed Schaeffer1:03:08

       But in a man who has pelvic pain syndrome, I, I feel all the ti- like at least-

   12. PAPeter Attia1:03:13

       Meaning it's just locked up?

   13. TSTed Schaeffer1:03:14

       It feels like a guitar string.

   14. PAPeter Attia1:03:17

       Yeah.

   15. TSTed Schaeffer1:03:17

       You'll feel bands of muscle. So, you know, think about when you, when you tweak your traps.

   16. PAPeter Attia1:03:22

       Yep.

   17. TSTed Schaeffer1:03:23

       You have those bands of muscle you can feel with your hands, but the good thing about that is you can go get a massage and you can work it out. And, and that same thing happens in the pelvic floor muscles. So when I'm dealing with a patient who has chronic pelvic pain syndrome, or pelvic pain I should say, maybe not chronic, but oftentimes we'll see them after a while, this discomfort and pain, I try to be- I try to treat their symptoms based on where the, where the pain is coming from. So is it prostatic? If it's prostatic, I try to do things like, um, you know, alpha blockers, uh, potentially Cialis is another one, to treat the symptoms that are associated with that discomfort. If I pick up that they have a lot of tightness in their pelvic floor, I send them for myofascial release. So it's transrectal-

   18. PAPeter Attia1:04:08

       Yep

   19. TSTed Schaeffer1:04:08

       ... myofascial release. It sounds barbaric-

   20. PAPeter Attia1:04:11

       No, no, but I've-

   21. TSTed Schaeffer1:04:12

       ... but it is a game changer

   22. PAPeter Attia1:04:12

       ... I've seen this make, like change a guy's life.

   23. TSTed Schaeffer1:04:15

       100%. And so I feel great.

   24. PAPeter Attia1:04:17

       And the same for women.

   25. TSTed Schaeffer1:04:18

       Yes. True.

   26. PAPeter Attia1:04:19

       Yeah.

   27. TSTed Schaeffer1:04:19

       So I feel, you know, um, great when I can, when I, if I'm examining somebody and they have that, it makes me feel good 'cause I have a solution. The ones that are difficult are the ones that we just don't know what's causing it. Can be related to food, too. So if somebody has pelvic discomfort or pelvic pain, you do a very thorough kind of diary of what they're eating and, and it's more classic in women with what the kind of female equivalent of this would be interstitial cystitis.

   28. PAPeter Attia1:04:44

       Mm.

   29. TSTed Schaeffer1:04:44

       Where you'd say, "Well, what foods trigger it for you?" 'Cause it can be triggered and irritate the bladder, and that's causing the pelvic discomfort. So again, you, you take a thorough history. The NIH has a very good online questionnaire to help you kind of tease out where the symptoms are coming from. Then once you-

   30. PAPeter Attia1:05:00

       And that's, that's under NIH's website, or is it under-
10. 1:09:33 – 1:15:00

    How to minimize risk of urosepsis in Alzheimer’s patients

    1. PAPeter Attia1:09:33

       Okay. So we've talked now at length about two of the big problems associated with the prostate, and while both of these can be an enormous threat to the quality of a man's life, um, they're, they're not often a threat to the length of life, though I guess one point I'd make before we leave these is one of the questions I get asked a lot is, "How does somebody actually die from Alzheimer's disease?" And, you know, what I usually explain to people is they usually don't die from Alzheimer's disease. They usually die from something else that is brought on by the Alzheimer's disease, and one of the classic, sad, tragic cases you see is urosepsis.

    2. TSTed Schaeffer1:10:12

       Yeah.

    3. PAPeter Attia1:10:13

       So you see a, a man with Alzheimer's disease, and he is simpl- So one, he might have a catheter in him because he's unable to void on his own, and that dramatically increases his risk. But even if he doesn't, he's simply less responsive to the signs of an infection. He's not attentive to the fact that it's burning when he pees.

    4. TSTed Schaeffer1:10:31

       Mm-hmm.

    5. PAPeter Attia1:10:31

       And because of his age and his immunologic reserve, what starts out as a urinary tract infection on day one is a lethal case of urosepsis on day four.

    6. TSTed Schaeffer1:10:43

       Yeah.

    7. PAPeter Attia1:10:43

       And so, uh, you know, I do think of this as kind of one of the grim reapers, uh, o- of, of older men.

    8. TSTed Schaeffer1:10:49

       Yeah, I mean, um, as men age, and particularly if you have con- you know, concomitant other significant medical issues, your frailty goes way up, and so any little insult to your body can do it, and obviously classic things are aspiration, aspiration pneumonia.

    9. PAPeter Attia1:11:06

       Yep. The smallest cellulitis if you're not moving around.

    10. TSTed Schaeffer1:11:08

        Exactly.

    11. PAPeter Attia1:11:09

        And yeah, yeah, so it's-

    12. TSTed Schaeffer1:11:09

        And, and so I think it's a lack of awareness and, and absolutely it requires a very astute kind of caregiving family or, or cohort of individuals to notice subtle changes because obviously if you can pick up an infection early, then it doesn't necessarily have to spread, and it won't be so symptomatic.

    13. PAPeter Attia1:11:28

        I- if you could speak to someone listening to this who's caring for an elderly patient, male or female, who is in the throes of dementia, what can a caregiver do on this particular front? Is there anything they can do to minimize the risk of a kidney infection or a bladder infection turned into systemic sepsis? Is there anything they can do?

    14. TSTed Schaeffer1:11:54

        Yeah, good hygiene is obviously key. Uh, and I think in general, um, if you're monitoring the individual, uh, their, their voiding, you know, uh, their voiding history. So we, we obviously would prefer for people to void on their own, and many people can. Many times people have catheters in place for convenience of the caregiver, right? And so if you can keep hardware out of somebody, that's obviously very effective. And if you, if the individual can't void, and they're having trouble with that, then intermittent catheterization is what we obviously endorse and recommend, where you just place a catheter temporarily, empty the urine-

    15. PAPeter Attia1:12:33

        And intermittent catheterization poses less of an infectious risk-

    16. TSTed Schaeffer1:12:37

        Absolutely

    17. PAPeter Attia1:12:37

        ... than constant catheterization. Little counterintuitive, right? You would think, gosh, if three times a day you have to cath somebody, that's three times you're introducing it. But you're saying if it's done with-

    18. TSTed Schaeffer1:12:46

        Dwell time

    19. PAPeter Attia1:12:46

        ... perfectly sterile technique-

    20. TSTed Schaeffer1:12:48

        Dwell time, right?

    21. PAPeter Attia1:12:48

        Yeah.

    22. TSTed Schaeffer1:12:48

        So three times a day for 60 seconds each for... So that's 180 seconds versus 24/7 for the bacteria to be there. And we know if you leave a catheter in place, by 48 hours, the c- the bacteria has crawled-

    23. PAPeter Attia1:13:01

        They've colonized the whole thing

    24. TSTed Schaeffer1:13:02

        ... crawled up the, the tubing and is in the bladder. So yes, if you can minimize the dwell time of the foreign body-

    25. PAPeter Attia1:13:09

        Okay

    26. TSTed Schaeffer1:13:09

        ... the better. So yes, it is a little counterintuitive, but for men and for women, if you can do intermittent catheterization, that's a profound way to reduce the chances that you develop any, you know, urosepsis. Will you develop or will you have bacteria in the urine if you do intermittent catheterization? It's possible. Does that mean that you've failed with that technique? No, because if you're continuously emptying the bladder, you never can get overgrowth, and you can never get enough urine with bacteria in it to cause or pose a problem. And, and that, that leads to another point, which I often see, which is in individuals- As they're aging, you know, I think dehydration is a key underappreciated contributor to all these medical conditions. So remember-

    27. PAPeter Attia1:13:51

        Yeah, especially because older people lose their re- re- relationship between thirst and hydration status. That, that's another one of those things that deteriorates with age.

    28. TSTed Schaeffer1:13:58

        Yeah, and if you have Alzheimer's, you forget to drink-

    29. PAPeter Attia1:14:01

        Yeah

    30. TSTed Schaeffer1:14:01

        ... frankly. And so if you have bacteria in the urine, but you keep the concentration at 10, you know, 10 bacteria per ML, well, that's not gonna be a problem. But if you're dehydrated-
11. 1:15:00 – 1:24:10

    Prostate cancer: 5-alpha reductase inhibitors & how androgens factor into pathogenesis

    1. PAPeter Attia1:15:00

       Okay. So Ted, let's, let's, let's kinda put those two aside and now pivot to the third, uh, major source of pathology associated with the prostate, which is prostate cancer. So, so prostate cancer is the second leading cause of cancer death, uh, for men, uh, behind only lung cancer. Um, and so in order, right, it goes for men, uh, it's, it's lung, prostate, colon, pancreas. Um, the thing that kinda stands out to me is we have great tools of detection for prostate cancer, and based on that, I guess it's a little surprising to me that it is still the second leading cause of cancer death in men. So one of the things I hope to be able to do by the end of this final part of our discussion is get a better sense of what an individual can do to flip the odds in their favor, because you've probably heard me say this before, I don't think anybody should ever die of colon cancer-

    2. TSTed Schaeffer1:15:58

       Right

    3. PAPeter Attia1:15:58

       ... for the same reason. We have remarkable tools of detection, and, um, and we also have a very predictable pathogenesis, where we must go from a polyp. We must go from an adenoma to a carcinoma.

    4. TSTed Schaeffer1:16:13

       Yes.

    5. PAPeter Attia1:16:14

       And we can detect the presence of the adenoma because it is outside the body effectively.

    6. TSTed Schaeffer1:16:19

       So just to bring it back old school to where we first met, obviously, that would be the Halstedian theory for how cancer would spread, right? And that would be a stepwise from a localized non-invasive to an invasive tumor, to a regionally advanced, and then metastatic lesion.

    7. PAPeter Attia1:16:35

       Metastatic, yeah.

    8. TSTed Schaeffer1:16:35

       And colon follows that algorithm pretty well. There are obviously always, you know, the cases that you can't, you know, that, that are outliers.

    9. PAPeter Attia1:16:42

       Yeah, sure. There are sessile polyps-

    10. TSTed Schaeffer1:16:44

        But-

    11. PAPeter Attia1:16:44

        ... that are very difficult to detect and things like that.

    12. TSTed Schaeffer1:16:46

        But in general, I would say that yes, I, I agree with everything you're saying, and I would agree that on average, prostate cancers follow a similar Halstedian spread, Halstedian theory of spread, as opposed to Bernard Fisher and the Fisherian spread, which I think is-

    13. PAPeter Attia1:17:02

        Which is the breast cancer model

    14. TSTed Schaeffer1:17:03

        ... breast cancer.

    15. PAPeter Attia1:17:03

        Yep.

    16. TSTed Schaeffer1:17:03

        Exactly. So yes, 100% agree with you that prostate cancer is on average, um, 250 to 260,000 new diagnoses this last year, so a lot, um, will follow a, a, uh, more of a Halstedian spread. Now remember, um, if you keep that in mind, and you're the math guy, not me, if you do this, just model it, 250 to 260,000 new diagnoses, 34,000 deaths. So yes, on average, we are picking up cancers. But on average, if you look at the ratio of cancers diagnosed to cancer deaths, that ratio is pretty favorable.

    17. PAPeter Attia1:17:42

        It's much better-

    18. TSTed Schaeffer1:17:44

        Yes

    19. PAPeter Attia1:17:44

        ... than the other cancers.

    20. TSTed Schaeffer1:17:45

        That's right.

    21. PAPeter Attia1:17:45

        Conversely, to put pancreatic cancer in terms like that, of the people diagnosed with adenocarcinoma of the pancreas, about 95% of those people will experience lethality within five years.

    22. TSTed Schaeffer1:17:58

        Exactly. So we have that in our favor.

    23. PAPeter Attia1:18:00

        Yes.

    24. TSTed Schaeffer1:18:01

        And so yes, what keeps me up and gets me up in the morning and excited is to understand and identify what it is about the individuals who develop prostate cancer that is, you know, localized and, you know, doesn't have a lethal potential, and how do we better attack those subset of individuals that will ultimately die from their prostate cancer? So lots of progress, even since when we last talked. But yes, big picture, it is still a real issue.

    25. PAPeter Attia1:18:27

        Okay. We've already touched on, um, testosterone. We touched on estrogen. We peripherally discussed dihydrotestosterone. Let's explain how androgens work. Where are androgen receptors? What are these hormones doing? And for the purpose of this discussion, how do they factor into the pathogenesis of this condition?

    26. TSTed Schaeffer1:18:54

        Yeah. So if you go back, and I actually think it's a really good exercise for, for an individual, uh, to go back and understand where the prostate actually comes from. It comes from the urogenital sinus. This is a sexually dimorphic organ, and in the response to androgens around week 10 or 11 in a developing fetus, human fetus, there's a surge of testosterone from the gonad, and that surge of testosterone results in the development of this ductal network. It's an exocrine gland, and it develops in, out of the structure. And it turns out-

    27. PAPeter Attia1:19:29

        By the way, how big a surge in testosterone? I know that it's much more significant than the levels that a little boy is b- a little boy is born with very low testosterone, but he did experience a lot of it in utero, right?

    28. TSTed Schaeffer1:19:39

        Yeah, lots in utero, lots in, in really at birth, and then puberty. Those are the three-

    29. PAPeter Attia1:19:44

        Yeah

    30. TSTed Schaeffer1:19:44

        ... peaks. And they're, um- Similar, I think, to obviously puberty is the highest.
12. 1:24:10 – 1:33:33

    Post-finasteride syndrome

    1. TSTed Schaeffer1:24:10

       w- we'll talk about because there's s- s- there's significant pathology associated with taking finasteride. And so we, we used to think that it was predominantly in those main structures, follicles of your hair, prostate, et cetera, but now we know it actually has pr- there's profound potential impact of, of that neural... You know, centrally in your nerve system, right? And it can affect your sex drive, it can affect your sex performance, et cetera. So-

    2. PAPeter Attia1:24:32

       So let's talk about this, 'cause I had never heard of this until a few months ago: post-finasteride syndrome.

    3. TSTed Schaeffer1:24:39

       Yeah.

    4. PAPeter Attia1:24:40

       So we talked earlier about finasteride. When it's taken in a drug called Proscar, five milligrams a day. It has a cousin called dutasteride or Avodart.

    5. TSTed Schaeffer1:24:50

       Yeah.

    6. PAPeter Attia1:24:50

       I think that's .5 milligrams per day?

    7. TSTed Schaeffer1:24:52

       Yeah. That one theoretically is more potent because it blocks 5-alpha reductase I and II.

    8. PAPeter Attia1:24:58

       Okay.

    9. TSTed Schaeffer1:24:58

       But, but their effe- the efficacy is equivalent in the human body.

    10. PAPeter Attia1:25:02

        Okay.

    11. TSTed Schaeffer1:25:03

        And then lower dose finasteride, so not five milligrams.

    12. PAPeter Attia1:25:05

        Lower dose, one milligram per day is called Propecia.

    13. TSTed Schaeffer1:25:08

        Yeah.

    14. PAPeter Attia1:25:08

        And that's the branded version that's used for hair loss.

    15. TSTed Schaeffer1:25:10

        Yes.

    16. PAPeter Attia1:25:11

        Okay. The first thing I remember you telling me about this was it's a little bit of a scam that these drugs are taken daily because their half-life is quite long, right?

    17. TSTed Schaeffer1:25:21

        Yeah. They all have a very long half-life. So if you took a, a single, uh, finasteride five milligram dose, it's generic, so it costs nothing anyway.

    18. PAPeter Attia1:25:28

        Yeah.

    19. TSTed Schaeffer1:25:29

        But if you took that, it would hang around in your system for a week or two.

    20. PAPeter Attia1:25:31

        [laughs] Okay.

    21. TSTed Schaeffer1:25:32

        So, so the idea that, that, you know, the reason it was reformulated at one milligram versus five milligrams was for a new patent, new indication.

    22. PAPeter Attia1:25:40

        Yes, of course.

    23. TSTed Schaeffer1:25:40

        Uh, but you could take, you c- I, I haven't worked it out. You could probably just take a single five milligram of finasteride once a week, and that would be the same as one milligram of the other stuff every day. It's, it has a much longer half-life than anyone appreciates. Um, and, um, It's, you know, that's the least of the problems that I think is associated with this drug

    24. PAPeter Attia1:26:01

        Yes. So let's get to, let's get to the issues, because this is also a very controversial topic, right? There are people that get up in arms on both sides of this discussion. So describe what post-finasteride syndrome is.

    25. TSTed Schaeffer1:26:13

        Well, it, it's a variety of symptoms that men will complain of after taking either, you know, uh, the BPH dosing or the kind of hair loss dosing of these medications. Decreased sex drive, impotence, um, anejaculation, um-

    26. PAPeter Attia1:26:32

        Inability to ejaculate

    27. TSTed Schaeffer1:26:33

        ... inability to ejaculate, depre- more so-- those are obvious and apparent things for any young man trying to do it, but there's a lot of other associated, uh, findings with it like, uh, depression, you know, uh, dec- you know, just general, uh, change in your affect. So those are harder, in my mind, to attribute to the, the medication, but patients do complain about it. But when you have a patient who's young, healthy, has a great interest in sex, et cetera, and they take this medication for hair loss and they can't get an erection, they have no interest in sex, they can't have any orgasm, those are real, and those are directly, in my opinion, definitely related to the drug.

    28. PAPeter Attia1:27:13

        And what do you think is the approximate frequency of this post-finasteride syndrome?

    29. TSTed Schaeffer1:27:19

        Yeah, that's probably where there's more debate, right? I think, and some people would say 5%, some people would say 15%. I mean, you-

    30. PAPeter Attia1:27:27

        Wow
13. 1:33:33 – 1:43:21

    The relationship between testosterone & DHT & the development of prostate cancer over a man's lifetime

    1. PAPeter Attia1:33:33

       Okay. Now let's talk about the relationship between testosterone and DHT and the development of prostate cancer over a man's lifetime. So one of the, you know, obvious statements is when a man has the most testosterone and presumably DHT in his body, so let's just take out the case of guys who are taking, uh, 5-alpha reductase inhibitors.

    2. TSTed Schaeffer1:33:58

       Yeah.

    3. PAPeter Attia1:33:58

       So when a man is in his 20s, you know, call it 18 to 20, 18 to 30, his testosterone and DHT are through the roof. We don't see guys getting prostate cancer.

    4. TSTed Schaeffer1:34:08

       Yes.

    5. PAPeter Attia1:34:08

       Um, similarly, by the way, we don't see women getting breast cancer-

    6. TSTed Schaeffer1:34:12

       High estrogen

    7. PAPeter Attia1:34:12

       ... when their estrogen is at their highest either.

    8. TSTed Schaeffer1:34:14

       Yeah, yeah.

    9. PAPeter Attia1:34:14

       So, so we know there's-- we know that the story is more complicated than the caricature is.

    10. TSTed Schaeffer1:34:19

        Yes.

    11. PAPeter Attia1:34:19

        Which is not to say that these hormones don't matter, because to your point a moment ago, when you have men with metastatic prostate cancer or untreatable prostate cancer, hormone deprivation therapy is a core treatment.

    12. TSTed Schaeffer1:34:31

        Yes.

    13. PAPeter Attia1:34:32

        So how do we reconcile those two observations?

    14. TSTed Schaeffer1:34:36

        Well, it has to just-- there's a time-dependent covariable here, right? So you, you will-- When you have-- There's lots of things that testosterone does at a cellular level, right? It impacts, um, damage to the DNA, repair of that damage to the DNA, all these different things that people I don't think really fully appreciate. But, um, I think when you have, when you go through your surge of testosterone, whatever that may be, if your puberty, you know, your peak in, in is at age, age 18 or age 25, wherever your peak is, I think you begin to reset, um, the functional code, right? So you're born with your DNA, but it's not really, for the most part, what's in your DNA that matters. It's the epigenetic, you know, changes that result in the tr- RNA trans- trans, you know, location, transition that really is the most important thing. So I think that you begin to m- mark and see differences in terms of the epigenetics of different genes within a test- an androgen-responsive organ that then sets the stage for your potential risk for developing prostate cancer, right? So I think that there's a correlation between testosterone and, and subsequent, you know, future diagnosis of prostate cancer, but it's just one of the many factors that plays a role. So if you don't have any testosterone, you're not gonna get prostate cancer 'cause you won't have a prostate, right? That's the obvious one.

    15. PAPeter Attia1:36:03

        Yeah.

    16. TSTed Schaeffer1:36:03

        But I do think that there's a correlation between T and A being a healthy male, and part of being a healthy male is a potential risk for developing prostate cancer. Does that, does that make sense? I mean...

    17. PAPeter Attia1:36:13

        It does, and then, and then there's this other very interesting observation, and I don't know if this has been subsequently refuted, but I remember this probably when we were in residency, Ted, that there was that paper that came out that found that men with lower testosterone, this was in the New England Journal of Medicine-

    18. TSTed Schaeffer1:36:29

        Yeah

    19. PAPeter Attia1:36:29

        ... were at risk for higher grade prostate cancers.

    20. TSTed Schaeffer1:36:33

        Yes.

    21. PAPeter Attia1:36:33

        The, the sort of teleologic explanation was, [clears throat] at least this was my teleologic explanation, if you are developing prostate cancer in the presence of low androgens, you have a very sensitive-- You have a cancer that's very sensitive and therefore is probably much higher grade. Is that still kind of the thinking, or has the thinking evolved significantly?

    22. TSTed Schaeffer1:36:57

        Yeah. So we just published a paper on this. We, we looked at one hundred thousand prostate cancer transcriptomes, and we did-

    23. PAPeter Attia1:37:05

        Where did you get so much data?

    24. TSTed Schaeffer1:37:07

        We did this in partnership with a company, originally it was called Decipher, now it was, it's owned by a company called Veracyte.

    25. PAPeter Attia1:37:13

        Okay.

    26. TSTed Schaeffer1:37:13

        And I did this with, uh, the, the founder of the company. I've had a-

    27. PAPeter Attia1:37:16

        You, you did this with-

    28. TSTed Schaeffer1:37:17

        Eli Di Vincenzo.

    29. PAPeter Attia1:37:18

        Okay.

    30. TSTed Schaeffer1:37:18

        And, uh, we looked at their database of... Now, they now have one hundred and forty thousand plus prostate cancer transcriptomes.
14. 1:43:21 – 1:46:10

    Genetic analysis of tumors can indicate the aggressiveness of cancer

    1. PAPeter Attia1:43:22

       Yeah, absolutely. So you've got these hundred thousand transcriptomes. They've given you this insane amount of insight.

    2. TSTed Schaeffer1:43:30

       Yes.

    3. PAPeter Attia1:43:30

       How often can you now predict based on a man's genetics?

    4. TSTed Schaeffer1:43:36

       Well, we-

    5. PAPeter Attia1:43:36

       Or do you need a tissue biopsy to map to the transcriptome to say-

    6. TSTed Schaeffer1:43:41

       Yeah

    7. PAPeter Attia1:43:41

       ... "Aha"?

    8. TSTed Schaeffer1:43:41

       Let's talk about the transcriptome of the tumor. So once a patient has a diagnosis, you can get the transcriptome information. It's provided to the providers. It's not commercially available. And the reason that we, it's not provided commercially, because we, you have to be cautious about how you interpret that data and what you pr- you, you advise the patient. Until we have more information from clinical trials about, well, what does a particular molecular phenotype mean for the, A, how you treat their new, new diagnosed localized, or potentially if they have a recurrent disease, how you should better treat it. But those trials are now in process or are just being built based on some of this work. Now, that's the transcriptome

    9. PAPeter Attia1:44:23

       Sorry, just to be clear, Ted, does that mean that someone listening to this who has a biopsy of their prostate, their physician will get this information back, but won't necessarily know how to interpret it?

    10. TSTed Schaeffer1:44:36

        If, if a patient gets a biopsy of their tumor-

    11. PAPeter Attia1:44:39

        Yep

    12. TSTed Schaeffer1:44:39

        ... and they have genomic testing with Decipher Verocite, which I don't have any conflicts with, by the way, they will then get a, a simple readout of how aggressive is their tumor. It's a molecular Gleason score.

    13. PAPeter Attia1:44:52

        Okay.

    14. TSTed Schaeffer1:44:52

        But on the back end, in addition to measuring those 21 different genes that consist of the Decipher score, they capture the whole transcriptome of that tumor.

    15. PAPeter Attia1:45:02

        Yep.

    16. TSTed Schaeffer1:45:02

        And you can get access to what they call the Grid report, which gives you this whole deep dive into what's the biology and nature and phenotype of that particular tumor, which for me, I look at, and I will then look at that and then say, "Okay, this patient on paper perhaps has an X or a Y or Z, but the, the, the molecular phenotype of the tumor is favorable or it's not favorable. I'm gonna alter what I recommend to the patient based on that." So that's how I interpret it. It's kind of experimental use only, so to speak.

    17. PAPeter Attia1:45:36

        Yep.

    18. TSTed Schaeffer1:45:36

        But-

    19. PAPeter Attia1:45:37

        But it is the direction of precision medicine

    20. TSTed Schaeffer1:45:38

        ... it's, it's the future of it, and so based on these papers and many, many others, not just the one I, I did this one, but many, many other papers with really great scientists, they are the platform for, through which all clinical trials in prostate cancer, um, are now reliant on. So the Decipher score as a, as an entry criteria, as a predictor for intensification or de-intensification therapy, um, is part of almost all clinical trials going through the, the National Institute of Health right now, which is exciting.

15. 1:46:10 – 1:54:53

    Genetic risk factors of prostate cancer & the use of PSA to screen for cancer

    1. PAPeter Attia1:46:10

       Yeah. So let's, let's talk a little bit more about the pathogenesis. Um, you talked earlier about the transition zone and the peripheral zone, the orange analogy. Um, I'm assuming that most prostate cancers develop in the peripheral zone.

    2. TSTed Schaeffer1:46:30

       Correct.

    3. PAPeter Attia1:46:31

       And, um, the reason for that is it-- we didn't state this earlier, but you would think or hope, I suppose, that any man who's undergoing, uh, prostate cancer or prostate tissue removal for BPH would have a lower risk of prostate cancer 'cause, hey, you just shed 80% of your prostate.

    4. TSTed Schaeffer1:46:48

       Yeah.

    5. PAPeter Attia1:46:48

       That doesn't seem to be the case, correct?

    6. TSTed Schaeffer1:46:50

       Well, it doesn't necessarily change their risk for developing prostate cancers in the future. However, it changes your ability to monitor them for the development of prostate cancer because remember, the PSA blood test is, you know, it, it's, um, it's been often criticized, but it's a very powerful tool, and it just depends on how you use that blood test to identify people at risk for potentially having prostate cancer.

    7. PAPeter Attia1:47:17

       Yeah, I, I wanna really talk about this in a minute because there are few things that annoy me more than people who harp on how bad the PSA is, which to me means, no, it's how bad you are at using it. Like, the PSA is a remarkable test.

    8. TSTed Schaeffer1:47:31

       So the issue arises from this overlap in the test because it's not prostate cancer specific. It's prostate specific. So the beauty of having my partner, Amy Krambeck, do a HoLEP and take out 90% of your prostate is that reduces 90% of the PSA-producing cells. The PSA should be below one, but it makes the test way more sensitive for me to follow-

    9. PAPeter Attia1:47:58

       Yep

    10. TSTed Schaeffer1:47:58

        ... for a future potential risk of developing prostate cancer. So in general, I would say that yes, the specificity of the tool changes based on how much prostate tissue you have. So the PSA test is actually exquisitely sensitive in young men to their future risk for developing prostate cancer because they have such limited amounts of transition zone tissue, and the bulk of their prostate is just peripheral zone.

    11. PAPeter Attia1:48:23

        So why is it that the, that the cells in the peripheral zone are susceptible to becoming neoplastic-

    12. TSTed Schaeffer1:48:30

        Yeah, it's a-

    13. PAPeter Attia1:48:31

        ... as opposed to the cells in the transitional zone?

    14. TSTed Schaeffer1:48:32

        It's a great question because under the microscope there, there are some subtle differences as to how they look, but people don't know why that particular zone or that zonal anatomy is such that you have a higher risk of developing it there. It's obviously very unfortunate because-

    15. PAPeter Attia1:48:47

        The real estate problem

    16. TSTed Schaeffer1:48:48

        ... as the name, as the name implies [chuckles] it's in the periphery, and what's just outside of the prostate is the high, high-price real estate of the nerves for erection, the nerves for, for, uh, urinary continence, and the muscles for urinary continence. So that has a big impact on how we manage prostate cancer, and it's been a result-- that's what results in a lot of the potential side effects that occur. But in general, yes, in young men, PSA is a very potent way for us to initially screen someone for their prostate cancer risk. And your PSA, if you're young, good numbers, remember, for the listeners, P- median PSA for a 40-year-old, 0.5, median PSA for a 50-year-old, one. So if your number's over those medians, those age-adjusted medians, then you need to just take action. Do you have to have a prostatectomy? No.

    17. PAPeter Attia1:49:38

        But, but then here's the problem. We talked about it earlier. A lot of those guys are gonna be on 5-alpha reductase inhibitors these days, and now those numbers become very difficult to interpret.

    18. TSTed Schaeffer1:49:46

        Yes, they do. They become difficult to interpret and difficult to follow. So if your numbers are over those, then any-- you should just consider a kind of annual or twice, you know, every other year kind of intensive follow-up. It doesn't mean that you have prostate cancer, but it means if you're over that median, that you have a much higher risk in your future t- next 20 or 30 years of developing it. Again, the issue is in young men who are on 5-alpha reductase inhibitors, their PSAs are gonna be very, very low, and you may miss a early blip. And it-- actually, there's a great, as a somewhat sidebar, there's a great paper published out of the, um, group at UCSD looking at ... finasteride and dutasteride use in veterans, so it's a closed access system, and they asked the question, "Is use of dutasteride and finasteride associated with more prostate cancer lethalities?"

    19. PAPeter Attia1:50:38

        Mm.

    20. TSTed Schaeffer1:50:38

        And it's highly hotly debated about whether or not the drugs actually induce more aggressive cancers and result in, in that. But if you just take that as a side, as a more public health kind of issue, the answer was glaringly yes, there was a huge increased risk of death from prostate cancer in men on finasteride and dutasteride. Why? For the reason we talked about, neglect.

    21. PAPeter Attia1:51:01

        Yep.

    22. TSTed Schaeffer1:51:01

        You don't realize you're on it. You don't know your numbers are rising. Your internist has no idea that your PSA of four isn't really four, it's 10-

    23. PAPeter Attia1:51:08

        Yeah

    24. TSTed Schaeffer1:51:08

        ... 'cause you've been on the meds for 10 years.

    25. PAPeter Attia1:51:09

        So it's not necessarily... We certainly don't know if 5-alpha reductase inhibition impacts prostate cancer biology, but to our point about detection-

    26. TSTed Schaeffer1:51:19

        Yes

    27. PAPeter Attia1:51:19

        ... it impedes detection.

    28. TSTed Schaeffer1:51:20

        Yes, and, you know, I think, I think that there may be an impact on, on the actual s- subtly on the biology, but that's m- less of a real-

    29. PAPeter Attia1:51:31

        Yep

    30. TSTed Schaeffer1:51:32

        ... you know, kind of general issue. It's really being a lack of awareness of the biomarker that you use to screen for prostate cancer and the effect that dutasteride and finasteride have on that biomarker.
16. 1:54:53 – 2:07:16

    Non-genetic risk factors for prostate cancer

    1. PAPeter Attia1:54:54

       Okay, let's talk a little bit about, uh, non-genetic risk factors, or at least non, um... Or w- we can include sort of polygenic stuff that's im-

    2. TSTed Schaeffer1:55:02

       Yeah

    3. PAPeter Attia1:55:02

       ... embedded. So one of the things I always remember from training, African American men at, at a higher risk.

    4. TSTed Schaeffer1:55:07

       Yeah.

    5. PAPeter Attia1:55:07

       Why?

    6. TSTed Schaeffer1:55:09

       No one knows. Um, I like to think of... There's a great paper published by this, uh, scientist at USC, Chris Haiman, and they looked at, um, genomic risk sc- you know, through SNPs for individuals who did or did not develop prostate cancer. It was like 235,000 guys. Ton, a ton of individuals.

    7. PAPeter Attia1:55:28

       How did they know what SNPs to look at?

    8. TSTed Schaeffer1:55:30

       Well, they did... They, they, there's a, there's been lots of work in, in, in, in single nucleotide polymorphism and risk for prostate cancer, and then this paper was a refreshed look at saying how many SNPs are actually out there associated with risk of developing prostate cancer.

    9. PAPeter Attia1:55:44

       Okay.

    10. TSTed Schaeffer1:55:44

        And it's somewhere around 250 or 260. I don't know the exact number, but there's a certain amount. So what they did was they developed a genomic risk score based on how many SNPs you had and your likelihood or probability of developing prostate cancer, and what they showed was that, that although there's no difference between SNP profiles in men of African ancestry, 'cause they could look genomically where their ancestry was, and Caucasians or non-Black men, um, there was an enrichment for that same group of, uh, of SNPs in Black men and an enrichment in y- men who were diagnosed with prostate cancer at a young age. So why is it that there's an enrichment of these different portfolio of, of SNPs in Black men, and why is there an enrichment in the younger men? We don't know, but we, it doesn't appear as though the tumors are profoundly different from a genomic perspective. And we've looked ourselves. We had a series of grants to look at, again, you know, somatic alterations in prostate tumors between Black and white men with lethal tumors. We found a difference in the, in the cell cycle gene pathway, but again, these are single percentile differences.

    11. PAPeter Attia1:57:04

        Hmm.

    12. TSTed Schaeffer1:57:05

        So what exactly is driving the development of more prostate cancers in Black men than white men is thought to be, at this point, kind of environmental. So, you know, what is their exposure to, um, you know, e- epigenetic changes? What's their exposure to, um, smoking? It's, in general, in urban, you know, uh, populations of, of Black individuals there's more smoking. It has-- it correlates with the, um, food deserts, all these different kinds of epigenetic factors.

    13. PAPeter Attia1:57:37

        I see. So it may not actually be hardwired.

    14. TSTed Schaeffer1:57:41

        It's not hardwired, and most of the kind of-

    15. PAPeter Attia1:57:43

        That's great news.

    16. TSTed Schaeffer1:57:44

        It is good news. And so, yes, I, I think people would bundle that under this kind of umbrella of social determinants of health.

    17. PAPeter Attia1:57:51

        Yep.

    18. TSTed Schaeffer1:57:51

        But you can actually begin to really begin to connect those two ends of what the, are the social determinants, and then what is the impact on the SNPs and the epigenetic changes that occur. So I think a great future project would be to take that and look at exposures in... Think about it, like your exposures in a, in an environment with high smoke, high pollution, poor foods, and the epigenetic changes that occur when you're having a surge in your testosterone in your 20s. That begins to hardwire that person's cells for future development of prostate cancer.

    19. PAPeter Attia1:58:26

        Yeah.

    20. TSTed Schaeffer1:58:27

        And that's kind of how I think about it now, 'cause we did-- I spent a decade looking for the smoking gun, the heritable germline change. There are some out there, but they're not very big guns.

    21. PAPeter Attia1:58:37

        But they're not big enough.

    22. TSTed Schaeffer1:58:37

        They're not big enough to be f- you know, associated with that change. And so this paper that Chris did and his team of, you know, there's like 150 authors, it's spectacular work, um, really begins to provide more insight, so-

    23. PAPeter Attia1:58:50

        This is the UCSD group that led this?

    24. TSTed Schaeffer1:58:51

        UC- USC, uh-

    25. PAPeter Attia1:58:53

        Oh, USC. Okay.

    26. TSTed Schaeffer1:58:54

        USC. Um, Chris Haiman is the last author, and, um, blanking on the first author's name. Great, great publication.

    27. PAPeter Attia1:59:00

        We'll, we'll, we'll link to that paper.

    28. TSTed Schaeffer1:59:02

        Yeah. Yeah. So it gives you a sense of, you know, so then why are there different subpopulations of individuals that have different risks? It's likely mo- just enrichments for these single nucleotide polymorphism changes, which by the way, if you look at that paper, if you had the highest, let's say, decile or quartile of SNPs, you had about a five-fold increased risk of developing prostate cancer compared to the average man, which is the same fold increase as if you're BRCA2 deficient.

    29. PAPeter Attia1:59:39

        Wow.

    30. TSTed Schaeffer1:59:39

        So having a poor genomic risk score is just as potent as having deficiency in BRCA2, which we know is not good.
17. 2:07:16 – 2:25:59

    PSA as a screening tool: what is PSA, definition of terms, & how to interpret results

    1. PAPeter Attia2:07:16

       So let's talk about the PSA a little bit-

    2. TSTed Schaeffer2:07:18

       Yeah

    3. PAPeter Attia2:07:18

       ... 'cause we've alluded to it a number of times. So let's explain what it is, where it comes from, and, and more importantly, of course, how we use it.

    4. TSTed Schaeffer2:07:25

       Yeah. So PSA is a, is a protein. It exists to aid in the liquefaction of semen. So it's produced by the prostate, and if one were to, um, measure PSA in semen, it would be very, very high. I always tell people, if you looked at PSA in the semen, it would be, I don't know, 100,000 nanograms per milliliter of PSA in semen. It's designed to be there, and it exists there to liquefy the semen to help in the process of fertilization. It is not designed, and it should not exist in the blood, but a certain percentage of PSA made in prostatic epithelial cells leaks into the bloodstream, and when we do a PSA blood test, we're measuring the PSA that has leaked into the bloodstream from a prostatic epithelial cell. Now, most of the PSA that leaks into the bloodstream is bound to other proteins. A certain percentage-

    5. PAPeter Attia2:08:27

       And is that, like, albumin mostly, or sex hormone binding globulin?

    6. TSTed Schaeffer2:08:29

       Alpha, alpha-chymotrypsin.

    7. PAPeter Attia2:08:31

       Oh, so it's its own separate binding protein.

    8. TSTed Schaeffer2:08:34

       It has, that's the most common protein that PSA binds to, but it can bind to a family of three or four, or four or five different-

    9. PAPeter Attia2:08:40

       But these are prostatic proteins?

    10. TSTed Schaeffer2:08:42

        Yeah.

    11. PAPeter Attia2:08:42

        Yep.

    12. TSTed Schaeffer2:08:43

        It's bound. Now, how much it's processed, because as you know, proteins just don't come out finished. They grow into the, their final state, and they grow by shrinking, right? They get things snipped off of them as they're maturing and, and, and going through that process. As PSA is evolving in the normal kind of development of its exocrine function, it gets snipped into smaller and smaller states. Fully, fully processed PSA can float around in the bloodstream freely. That's free PSA. So if you have a benign prostatic epithelial cell, a lot of its PSA will be fully processed and ready to go in the ejaculate, let's just say. And if it leaks into the bloodstream, it can float around freely. You can measure it in an assay, and it's what we call free PSA. A lot of the unprocessed or incompletely processed PSA is bound to protein. Alpha-1 antitrypsin is the most common one, and that is what we would consider to be when we do a measurement of, when we do- looking at total PSA, you're measuring mostly bound PSA-

    13. PAPeter Attia2:09:48

        Mm-hmm

    14. TSTed Schaeffer2:09:49

        ... and some free PSA. And that ratio we use, you and I use in our practices, to help discriminate against PSA that's in the bloodstream that may have leaked from a cancer cell or may have leaked from a benign epithelial cell. Now, there are other siblings of PSA that are also produced in prostatic epithelial cells, of course, all in response to androgens. They're produced in those cells, and they can also leak into the bloodstream, and we use those in some advanced PSA-based blood testing as well. But in general, when we are measuring PSA, we are measuring the amount of PSA, this protein, that's leaked from a prostatic epithelial cell into the bloodstream. We can refine that value by saying how much of it is, how much is there and how much is free. If we have high amounts of free PSA, 30%, for example, then we can have good reassurance that most of the PSA in the blood that you're detecting is from benign cells. When most of the PSA that you have in your blood is, um, bound, very limited amounts of free PSA, that's a strong marker that there's something going on, i.e., that cancer cells are leaking the PSA into the bloodstream. Now, as I mentioned, you can also measure other byproducts, um, other, other types of free PSA or other sibling molecules to PSA. PSA's called HK3 or human kallikrein 3. You can measure, for example, how much of human kallikrein 2 is in the blood, and these are part of a more advanced PSA test like the 4K score or, for example, the prostate health index. These are both m- mathematical equations that predict probability of aggressive cancers, but they're built off of looking at not just the PSA itself, but the PSA and how much other types of processed PSA exist as well.

    15. PAPeter Attia2:11:53

        Let's go back and talk a little bit about the free PSA. Um, does the amount of free PSA that we would want to see to be more assured of a benign nature of the PSA vary by age and absolute PSA level?

    16. TSTed Schaeffer2:12:11

        Yes, it does. Um, so we begin to use the kind of free PSAs and the free PSA ratios and all those things when PSAs have crossed over a certain threshold, right? Because-

    17. PAPeter Attia2:12:24

        Yeah, typically a lab, if you, if your PSA is one, uh, we can't even get a lab to check a free PSA.

    18. TSTed Schaeffer2:12:30

        That's right. That's right, because we know if your P- if you're screening someone and your PSA is one, then the chances you, the probability of a prostate cancer that's lethal is incredibly low, right? So that's why they, they just don't, they don't have the assay set up to check it. And oftentimes, or some labs will not do that, you know, secondary default testing unless it's over four, for example-

    19. PAPeter Attia2:12:51

        Yes

    20. TSTed Schaeffer2:12:51

        ... or over 2.5. We, our lab's set up to do everything at low, levels as low as two, so you can get them at lower levels. But in general, the idea is, well, if your PSA is below two, the probability you have a lethal prostate cancer is, you know, less than a one in a million, so we don't have to worry about that individual, and we really wanna use the percent free PSA to discriminate-

    21. PAPeter Attia2:13:12

        Yep

    22. TSTed Schaeffer2:13:13

        ... individuals who have elevated PSAs and having it discriminate between elevated because of BPH and elevated because of a cancer. So yes.

    23. PAPeter Attia2:13:22

        And, and-

    24. TSTed Schaeffer2:13:22

        As you get older, your prostate enlarges. As we talked about, metabolic syndrome causes your prostate, in, in large part, to grow all, you know, just because-

    25. PAPeter Attia2:13:30

        Mm-hmm

    26. TSTed Schaeffer2:13:30

        ... of the T to E ratios.

    27. PAPeter Attia2:13:31

        Mm-hmm.

    28. TSTed Schaeffer2:13:32

        Um, as it gets, as you get older, your prostate gets bigger, so you, we begin to use that, and, and as you get older and your prostate gets bigger, you can have a proportional rise in total PSA in your bloodstream just because your prostate's bigger and it's leakier. But you can easily tease that out by looking at the percent free PSA. So if the percent free PSA is over 18 to 20, then you can be rest- pretty well assured that that's likely not coming from some aggressive bulky tumor.

    29. PAPeter Attia2:14:05

        What about with prostatitis when we see these huge spikes in PSA?

    30. TSTed Schaeffer2:14:08

        Everything goes up in those ca- in those cases, but-
18. 2:25:59 – 2:37:24

    MRI as a screening tool & the prostate biopsy options

    1. PAPeter Attia2:25:59

       let's now talk about that because I think that if you look at people on the other side of this discussion who are saying, "Come on, this PSA test..." I mean, there are a lot of people out there saying, "PSA should never be done. It's an awful test. It leads to a bunch of-"

    2. TSTed Schaeffer2:26:11

       Yeah

    3. PAPeter Attia2:26:11

       ... "unnecessary misery for men 'cause they're getting unnecessary biopsies." Now, let, let's sort of squash that nonsense.

    4. TSTed Schaeffer2:26:17

       Yeah.

    5. PAPeter Attia2:26:17

       That might've been true 50 years ago. But in the year 2023, in the hands of a competent physician, one step above the parking lot attendant, that's categorically untrue, right?

    6. TSTed Schaeffer2:26:28

       Yeah.

    7. PAPeter Attia2:26:28

       So today, let's talk about what we can do with an MRI to check If we have suspicion based on these other blood-based biomarkers, what can we do to increase the probability that if we actually go to the step of a biopsy, the probability is sufficiently high that it was worth it?

    8. TSTed Schaeffer2:26:49

       Yeah, I mean, it's, you just said it. You order an MRI, which, which is, uh, is frankly, like, surprising and appalling to me that I see second opinions in my office weekly that they never had any pre-diagnostic, i.e., pre-biopsy MRI. It's absurd to me. Like, when I leave work, I check on my Google Map if there was an accident on the expressway, and I change my course if there was. It's a test that's approved by all insurances. It should be done before any biopsy, in my opinion. There's really no case. Sure, if the patient's PSA's 1,000 and you just need a tissue diagnosis, okay, that's not, let's not debate that. But for every man who's undergoing routine screening for their prostate cancer, if they have an elevated PSA, they should get a reflex test, which includes for sure percent free PSA, prostate health index or 4K or other tests, depending on the cost. If those are abnormal-

    9. PAPeter Attia2:27:44

       And by the way, typically insurance will approve those if the PSA's over about five, right?

    10. TSTed Schaeffer2:27:49

        PSA over f- PSA-

    11. PAPeter Attia2:27:51

        And or

    12. TSTed Schaeffer2:27:51

        ... PSA over four, uh, for 4K score.

    13. PAPeter Attia2:27:54

        Okay.

    14. TSTed Schaeffer2:27:55

        But we can, we get PHI testing in our lab. They do it for us. It's covered by insurance at any value.

    15. PAPeter Attia2:28:00

        Got it. Okay. Yep.

    16. TSTed Schaeffer2:28:02

        We, it's ver- well-calibrated over two.

    17. PAPeter Attia2:28:05

        Yep.

    18. TSTed Schaeffer2:28:05

        So we do it over two. And by the way, what I'm telling you is based off of a prospective randomized trial published in The New England Journal, where they used advanced PSA testing. They did not use 4K or s- or, or PHI. They used Stockholm3, which is a European-only test. Abnormal advanced PSA testing, do an MRI. If the MRI has a suspicious lesion, we'll talk about that in a second, perform a biopsy, not just of the lesion, but of the whole prostate. Reduce prostate biopsies by 50%, enhance detection of clinically significant disease by 11%. So hello, like, why are you not doing that? I don't know, but frankly, it happens all the time. So what is it? Okay, the blood test we talked about.

    19. PAPeter Attia2:28:55

        Yep.

    20. TSTed Schaeffer2:28:55

        That provides more specificity to someone with an elevated PSA who may have a problem. That's all I tell people. It tells us we need to do the next step. That next step is a high-resolution Google map of their prostate. That is a, typically a 3T MRI.

    21. PAPeter Attia2:29:13

        So three tesla, so-

    22. TSTed Schaeffer2:29:14

        Three tesla

    23. PAPeter Attia2:29:15

        ... moderate power.

    24. TSTed Schaeffer2:29:16

        Yes, and it doesn't need any, like, endorectal coil or any of that. So a 3T magnet doing a prostate MRI, 'cause there's specific sequences, and it's multiparametric. The key, um, you know, parameters that we look at, T2 images. You look at diffusion-weighted imaging and dynamic contrast enhancement. Those are the three components of a multiparametric MRI. However, there are great radiologists, scientists, you're friends with one of them, R- R- uh, Raj, who have, and others have shown that you don't necessarily need the contrast.

    25. PAPeter Attia2:29:52

        You don't even need the contrast, right.

    26. TSTed Schaeffer2:29:54

        And that a, on average, a T2, uh, and the dyna- the diffusion-weighted imaging are nearly as good, not identical, but nearly as good at evaluating the prostate for any risky lesions. Now, is an MRI perfect? No. It misses prostate cancers. It will miss small, low-grade prostate cancers. But, like we'll talk about in a sec, that's not necessarily a bad thing. But that's how the test works. It's done, and it's a screening tool to help us identify bulky, higher grade, higher risk tumors. Now, when you look at your, um, MRI report, because as part of the 21st Century Cures Act, every patient can look at their entire medical record, you'll see that they'll give y- they'll give you a good, well-done MRI. The report should contain the size of the prostate.

    27. PAPeter Attia2:30:46

        Yep.

    28. TSTed Schaeffer2:30:46

        And I, it's baked into our reports, 'cause when I c- came to Chicago, I said, "We're gonna do PSA density," so you get the density. And then it tells you if there's a suspicious lesion, and there's this degree of suspicion. It's called the RADS score, the PI-RADS for prostate imaging RADS score, and it goes between one and five. One and two are considered to be BPH lesions. They're not cancer. So really we worry about RADS 3s, RADS 4s, and RADS 5s. And in general, most recommendations would be if you have a RADS 3, 4, or 5 lesion in your prostate that, and you've never had a biopsy before, that you should consider a biopsy that samples the spot and systematically, that would be what we call target, and systematically samples the areas around the target, i.e., the peripheral zone in the area kind of mapped around that lesion.

    29. PAPeter Attia2:31:40

        How easy is it for you to see this and make this determination? For example, when you look at the MRI and you see the lesion in presumably the peripheral zone-

    30. TSTed Schaeffer2:31:51

        Yes
19. 2:37:24 – 2:40:45

    Ted’s randomized trial comparing different methods of prostate biopsy

    1. PAPeter Attia2:37:24

       So what percentage-

    2. TSTed Schaeffer2:37:24

       Now, with that approach-

    3. PAPeter Attia2:37:25

       ... of your biopsies are done with the trocar versus transrectally?

    4. TSTed Schaeffer2:37:28

       I like the transperineal approach, but, um, in a, in a nod to just not adopting things without, with closed eyes and saying it's better, we are in the midst of completing a 16 institution randomized trial that explores whether or not transperineal prostate biopsy is actually, quote, unquote, "better" than transrectal prostate biopsy, and the primary endpoint is infection. So as I mentioned, modern contemporary infections with transrectal, between one and 4%. We think our approach to preventing infections transrectally is very good, and we're probably more on the 1% range. When we do a transperineal approach, and Matt Allaway's published a lot on this, you can do that without any antibiotics, and the infection rate is less than one in 1,000.

    5. PAPeter Attia2:38:15

       Wow.

    6. TSTed Schaeffer2:38:16

       So really, we're trying to say, you know-

    7. PAPeter Attia2:38:18

       So you'll obviously, I mean, you're presumably powered to show a difference in that direction.

    8. TSTed Schaeffer2:38:24

       It's a lot. The power is hard. So we, we, we had a power calculation. The NCI reviewed our power calculations, and they gave, they said this is the appropriate power to detect a difference. Um, so I think what will end up happening, and we're looking at the data right now, so I'm not gonna, I'm not gonna say, but it, my sense is we're gonna have 0% infections in TP, transperineal prostate biopsy, but will we have done enough transrectals to d- to really-

    9. PAPeter Attia2:38:49

       To, to-

    10. TSTed Schaeffer2:38:49

        ... statistically show a difference? However, in my mind-

    11. PAPeter Attia2:38:51

        Will there be secondary outcomes-

    12. TSTed Schaeffer2:38:53

        Yes

    13. PAPeter Attia2:38:53

        ... that look at detection?

    14. TSTed Schaeffer2:38:54

        Yes. So in my mind, if you have an approach that is 0% infections, I don't care if it's 1% or, you know, point, you know, 2%-

    15. PAPeter Attia2:39:02

        Yeah

    16. TSTed Schaeffer2:39:02

        ... it's still a difference.

    17. PAPeter Attia2:39:03

        Unless, unless you're losing detection.

    18. TSTed Schaeffer2:39:05

        Yes. So the other endpoints for the study are pain-

    19. PAPeter Attia2:39:08

        Mm-hmm

    20. TSTed Schaeffer2:39:08

        ... and side effects. As I mentioned, transperineal biopsy with the old grid approach was 15% retention, meaning a catheter.

    21. PAPeter Attia2:39:15

        The old grid approach, yeah.

    22. TSTed Schaeffer2:39:16

        You know, it was terrible. So we're looking at side effects. I think it's, done properly, they're minimal, and then we use a lot of medication to do our blocks. So I'll te- I'll tell you a little anecdote about-

    23. PAPeter Attia2:39:27

        Like a pudendal nerve block or something?

    24. TSTed Schaeffer2:39:29

        Yeah, we do a pudendal nerve block, and we use lidocaine, and we don't just use any lidocaine. We use buffered lidocaine because, uh, lidocaine, when it comes out of the vial, is a pH of about 5.

    25. PAPeter Attia2:39:40

        Yep.

    26. TSTed Schaeffer2:39:40

        So, you know, when you went to-

    27. PAPeter Attia2:39:41

        Put a little bicarb in?

    28. TSTed Schaeffer2:39:42

        Yeah.

    29. PAPeter Attia2:39:42

        Yeah.

    30. TSTed Schaeffer2:39:42

        You know how you go to the doctor, they go, "Pinch and a burn?"
20. 2:40:45 – 3:03:01

    When a biopsy is necessary, interpreting results, explaining Gleason score, & more

    1. PAPeter Attia2:40:45

       Okay, so let's talk about the different types of results that one gets from the biopsy.

    2. TSTed Schaeffer2:40:50

       Yeah.

    3. PAPeter Attia2:40:50

       You've already mentioned the word Gleason. Let's talk about what that means and what the scores, uh, how, how the scores are determined and, and what the implications are.

    4. TSTed Schaeffer2:40:58

       Yeah. So you, when you do a biopsy, you systematically, you first sample the targeted part... Let's, let's just do one thing before we talk about this. So who needs a prostate biopsy? As-

    5. PAPeter Attia2:41:14

       Uh, yeah. That, that's-

    6. TSTed Schaeffer2:41:14

       Who needs a prostate biopsy? Somebody who has abnormal blood testing, they go on to get an MRI. Now, that's our regular pathway. Who do we say you don't need an MRI? Men who have bilateral hip replacements, an MRI is effectively useless, so we don't do an MRI for those individuals. We can calculate PSA density with an ultrasound, and it's fast, it's cheap, it's effective. Otherwise, people are go- we, we have everyone go to an MRI. It's worth it that much.

    7. PAPeter Attia2:41:45

       Even with a single hip replacement?

    8. TSTed Schaeffer2:41:46

       Single hip, our radiologists are really good, and a good radiologist can read an MRI effectively with a single hip. If somebody has profound anxiety and they need general anesthesia for something, we'll be nuanced about whether or not we think an MRI makes sense. But for the average person, 99.5% of people, you know, you get an MRI. Now, MRI shows a suspicious lesion.

    9. PAPeter Attia2:42:09

       3, 4, or 5 on the PI-RADS.

    10. TSTed Schaeffer2:42:10

        A PI-RADS 3, 4, or 5, you need a biopsy. MRI shows-

    11. PAPeter Attia2:42:14

        Sorry. Independent of PSA density?

    12. TSTed Schaeffer2:42:17

        Independent of PSA density.

    13. PAPeter Attia2:42:19

        Okay.

    14. TSTed Schaeffer2:42:20

        If your MRI shows, um, no lesion but a high PSA density, so a young man, let's say, under 60, that's a PSA density of more than .1 or .12.

    15. PAPeter Attia2:42:33

        Yep.

    16. TSTed Schaeffer2:42:34

        If you're older, I'll give you a little bit more of a le- longer leash, and we'll, we'll say .15 over 65 or 70. If you have a PSA density that's below that threshold and you have a high PSA, low percent free, et cetera, you need a biopsy in my opinion, okay?

    17. PAPeter Attia2:42:51

        We're gonna include, Ted, the slide that you shared with me couple months ago that I still have. I still look at it all the time now.

    18. TSTed Schaeffer2:43:00

        Yeah.

    19. PAPeter Attia2:43:00

        Which shows by PI-RADS, by PSA density-

    20. TSTed Schaeffer2:43:04

        Yes

    21. PAPeter Attia2:43:05

        ... the outcome of biopsies.

    22. TSTed Schaeffer2:43:07

        That's right.

    23. PAPeter Attia2:43:07

        And it's mind-boggling.

    24. TSTed Schaeffer2:43:08

        Yes. So PSA density is a huge variable in terms of impacting probability of having cancer when you sample a suspicious lesion-

Episode duration: 3:46:39