BackTable Urology
Ep. 188 Testosterone Therapy Today: Clinical Advances and Safety with Dr. Abraham Morgentaler
Mon, 09 Sep 2024
What is the role of testosterone therapy in prostate cancer? Urologist Dr. Abraham Morgentaler of Beth Israel Deaconess Medical Center and Harvard Medical School joins host Dr. Jose Silva to discuss the evolution of testosterone therapies, modern testosterone treatments, and how to integrate testosterone replacement therapy into your practice. --- CHECK OUT OUR SPONSOR KYZATREX™ https://www.kyzatrex.com --- SYNPOSIS Dr. Morgenhaler starts by sharing his pioneering journey with testosterone replacement therapy starting in the 1980s, challenging long-held beliefs that it increases prostate cancer risk. He highlights key studies to debunk myths about testosterone’s dangers and emphasizes the ability to improve patients’ quality of life. Further, he discusses modern treatment options and provides practical advice for safely initiating testosterone replacement therapy. Finally, he discusses its use in patients with a history of prostate cancer and emphasizes the importance of individualized treatment plans. --- TIMESTAMPS 00:00 - Introduction 03:04 - Historical Perspectives on Testosterone and Prostate Cancer 21:31 - Evolution of Testosterone Treatments 31:16 - Testosterone and Prostate Cancer: A Controversial History 35:42 - Treating Prostate Cancer Patients with Testosterone 37:12 - A Case Study 43:05 - Shifting Perspectives 57:15 - Final Thoughts --- RESOURCES T4L Education https://t4leducation.com/ Marius Pharmaceuticals https://mariuspharma.com/ Testosterone Replacement in Prostate Cancer Survivors URO98 https://www.backtable.com/shows/urology/podcasts/98/testosterone-replacement-in-prostate-cancer-survivors Men's Health & Testosterone Replacement Therapy URO114 https://www.backtable.com/shows/urology/podcasts/114/mens-health-testosterone-replacement-therapy Testosterone & Hypogonadism: A Clinical Perspective URO124 https://www.backtable.com/shows/urology/podcasts/124/testosterone-hypogonadism-a-clinical-perspective Testosterone: Navigating Options & Implementation in Clinical Practice URO 125 https://www.backtable.com/shows/urology/podcasts/125/testosterone-navigating-options-implementation-in-clinical-practice
One of the things that the orals have transformed is the concept that you have to have a continually high level of testosterone to get the benefits. And clearly that's not true. And the safety seems to be improved, the safety profile, by having levels that fluctuate some during the day, returning close to or even to baseline.
So for example, many of the risks of testosterone that we used to talk about probably aren't accurate anymore. We had the Traverse trial, the biggest randomized control trial ever. that I think disproved the idea that cardiovascular risks were increased with testosterone. They were not paired to placebo.
Hello, everyone, and welcome back to Backtable Urology Podcast, your source for all things urology. You can find all previous episodes of our podcast on iTunes, Spotify, and backtable.com. Now a quick word from our sponsors. This discussion is brought to you by Myros Pharmaceuticals, the makers of Kisatrex, testosterone on the canoid capsule.
Kisatrex is an oral medication indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. In a clinical study of men with low testosterone, nearly 9 out of 10 had normal testosterone levels after 90 days.
As a cash-only oral form of TRT, Kaisertrex simplifies the administration of testosterone therapy while enabling revenue generation for your practice. Discover how Kaisertrex can benefit your patients and your practice. Learn more at kaisertrex.com. Now, back to the show. This is Jose Silva, your host this week. And I'm happy to introduce our guest, the legend, Dr. Abraham Morgenthaler.
Dr. Morgenthaler completed his residency in urology from Harvard Medical School and then joined the faculty of Beth Israel Deaconess Medical Center and Harvard Medical School. He is currently an associate professor of urology at Harvard Medical School, founder and past president of the Androgen Society, and senior editor of Journal of Androgens Clinical Research and Therapeutics.
In 1999, Dr. Morgan Taller founded Men's Health Boston, the first men's health center in the U.S., focusing on sexual, reproductive, and hormonal health for men. Dr. Mogenthaler is a leading international figure in the fields of testosterone therapy, prostate cancer, and male sexuality. He's a physician, an author, and a speaker. Dr. Mogenthaler, welcome to Backtable.
Pleasure to be with you, Jose. So today we're going to be discussing mainly testosterone therapy and prostate cancer. So since you've been working with this, you've been a pioneer in this field, can you tell a little bit of the story in terms of the testosterone evaluation, labs and symptoms? How has it changed the way we treat testosterone in the past 30 years?
You know, Jose, it's actually, it's an amazing story. So I finished my training in 1988 and joined the faculty at one of the Harvard teaching hospitals, Beth Israel Hospital. Now it's called Beth Israel Deaconess Medical Center. And at that time, It's hard to imagine, but people were so scared of testosterone.
They believed testosterone would cause prostate cancer almost in everybody if you raise testosterone. So what that meant was that there was no testosterone therapy being used in the United States except for the rarest of cases. Young men who didn't go through puberty because they had pituitary problems or hypothalamic issues or they'd lost both testicles or some genetic issues like Kleinfelter's.
And it was understood that those men needed testosterone in order to complete puberty and become virilized. And some men who had completed puberty but had some of those other issues I mentioned too, but those were the severe cases. And they only got testosterone until they hit around age 40, 45.
Because they were entering the prostate years and people were afraid that testosterone would cause cancer. And the belief that that was so was stronger than the idea that smoking would cause lung cancer. Like that would pale in comparison. And today it's, in looking back, it's not that long ago, right? It's like 30 years, 35 years. You know, today it's laughable.
But part of the, because everybody, well, not everybody, there's a lot of millions of men on testosterone. And we now have a lot of data that shows that it doesn't increase the risk of prostate cancer. And part of the reason that that belief persisted so long, testosterone came out in the 1930s.
And in 1941, Charles Huggins, who went on to win the Nobel Prize, figured out the first treatment, first effective treatment for men with metastatic or advanced prostate cancer, which was castration or what we might call today androgen deprivation. And he deserved his Nobel Prize. Because that was the first time anybody had shown that any cancer could be hormone sensitive.
And he went on to work also with ovarian cancer, breast cancer, uterine cancer. But he created the difficulty because he saw this as kind of like an either-or situation. If you remove testosterone, prostate cancers would shrink. And the biomarker they used then, which was called acid phosphatase before PSA, would go down just like we would expect PSA to go down.
And if it was present, he believed, or if you gave testosterone, he believed that it would make the cancer grow rapidly. Today we know, and I'd like to take some credit for it together with my colleague Abdul Tresh, we know that there's a limited amount, limited ability of androgens to stimulate prostate cancer growth or prostate growth. And that limit is achieved at a pretty low concentration.
We call it the saturation point. Prostate tissue needs androgens like testosterone for sure, but it can only use a little bit. And once you have enough, that's it. It's kind of like a plant with water. If you deprive it of water, it shrinks. If you give it back water, it'll grow. But once it has enough water, you can pour water into it all day long.
And let's say a houseplant will never grow to be the size of a tall tree. Because... It's not water that's limiting its growth anymore. So it's just unbelievable how things have changed. Unbelievable. And what's amazing to me is, is that we know that a lot of the original beliefs I guess this is a family show, so I'll be careful what words I use, but it's just not true.
And yet we still have major restrictions on how we're supposed to use or rather avoid testosterone, especially in men with a history of prostate cancer. And I don't think any of those are scientifically based.
And 30 years ago when you started, when you finished residency, how was the landscape at that moment? I mean, how did you say, okay, I'm going to start treating patients or men with testosterone?
How did that happen? It's a good story. So, listen, you know, when I was a young urologist, All I really wanted to do, when you finish your residency, you're not a complete urologist or surgeon yet, right? Like you're hopefully reasonably safe, but you're not skilled. And the challenges then were to do things right, to learn how to do, to become a better surgeon, more efficient.
I wanted to be a good surgeon and I wanted to learn how to treat all these different things. I started off in male infertility and male sexual issues. And part of the reason I picked that was there were some new procedures for sexual dysfunction that required microsurgery or they were just interesting cases. So, you know, arterial bypasses for erectile dysfunction. We hardly do these anymore.
But that was exciting back then. And so I started seeing some men who had ED or decreased libido, and they were desperate, some of them. And this was 10 years before Viagra would show up. And so a couple of these men would say to me, don't you have anything, doctor, that you can help me with? My wife's going to leave me or my girlfriend is really unhappy with me.
And as an undergraduate at Harvard, I had worked in a laboratory for three years with lizards, the kind that you find in Florida and in the Carolinas, the little guys that are everywhere. And the experiments involved testosterone. And my project was to put testosterone into the brains of these males.
If you castrate a male lizard and you put him in a cage with the female, normally if they're not castrated, they have this whole sexual behavior. They've got this bright flap of skin that comes out. The head bobs up and down quickly and they mate. And if you castrate them, you put them in the cage, they don't do anything. They don't care. They have no libido.
and my project we had mapped out where in the brain testosterone was taken up and we knew which of those areas were likely to be the sexual centers and i had a my project was to figure out a way to put little testosterone implants tiny tiny tiny into the sexual centers of their brain and when i was successful and it took a few years to figure this all out even though the male had no circulating testosterone that we could detect
The male would see the female, and the flap of skin would come out, head would bob up and down, and they would mate. It restored all their sexual behavior. It was incredible. And what I learned from that was that testosterone was, amongst other things, a brain hormone. It worked in the brain, and it was enough to regulate the entire sexual repertoire of these lizards.
The deep part of our brain that's also involved with sexual behavior, we still call the reptilian portion of our brain. And we call it that because some of the old parts of the brain are conserved. You know, the processes are identical or almost identical, going back to earlier vertebrates in evolution, like the reptiles.
So having done that research was the only reason I ever conceived of testosterone. All I knew of testosterone was it's dangerous. If somebody has bad prostate cancer, we lower it. Castration was a common procedure I did as a junior resident. And then the LHRH agonist started coming in towards the end of my residency. We started using that. But it occurred to me that maybe men...
were like lizards. And I took a few of these guys who were pretty desperate, and without knowing what the effect would be, I just gave them some testosterone. I told them, you know, there's a risk of prostate cancer, and they were willing to take whatever risk it was. And you know what? It worked for them. And it worked for them sexually, and it worked for them in ways that I hadn't anticipated.
And these men would tell me stories like that they have more patience to play with their small children, that their wife likes them more, that they wake up in the morning with optimism for their day, which they hadn't had in many years. And it was rather remarkable. And so I stuck with it, but I monitored the prostates extremely carefully.
And before too, too long, I actually started doing biopsies of the prostate just to protect myself and my patients to make sure that they didn't have prostate cancer that might grow. And this was prior to the PSA or PSA was already... PSA was relatively new, but it was there. So... You know, in academic centers, we were already using PSA. But as you know, PSA isn't perfect.
So I was doing biopsies in prostates of men with normal PSA, normal digital rectal exam, only because their testosterone was low. And my first paper relevant to this to the prostate cancer story was actually the first piece of evidence that the testosterone and prostate cancer story wasn't correct.
Because not only was it believed that high testosterone caused prostate cancer and made it grow quickly, it was also believed that if you had low levels, you would never get prostate cancer. As a resident, we heard, eunuchs never get prostate cancer. It's not exactly true, and one has to wonder, how do people know so much about eunuchs and prostate cancer?
How many doctors were around who had a large population of eunuchs that they would follow for 50 years or so until they were in their 70s or 80s and decided, yep, there's no cancer? Nobody. I mean, it's not real, but that was a story. And so these were men that we were biopsying before testosterone. And the only reason we were biopsying them was because they had low testosterone.
PSA normal, digital rectal exam normal. And we found prostate cancer right away.
And this was still a random biopsy? What were we doing at the time?
This was called, it was a sextant biopsy. We only took six cores back then, and it was totally random. Ultrasound guided, but random. And one out of seven of these men had prostate cancer. Most were Gleason 6, which we were still worried about back then, seriously worried. And some of them were Gleason 7.
And I'll tell you this little story because I think it tells us a little bit about how things work. So I had 50 patients. Now, that's not a ton, but these were probably the first 50 patients that underwent prostate biopsy because they had low testosterone. So I was hoping to treat them if their biopsies came back negative.
and submitted the paper, and I've published my share of papers, and this never happened to me before or since, which is that one of the editors called me on the telephone and said, you know, our editorial board just discussed your manuscript, and it's very interesting. It shows the opposite of what everybody has believed. You have a group of men with low testosterone, high rates,
Of prostate cancer. So we're interested in this. It's very curious. But you know, you only have 50 men. And I tell you what, if you accumulate more men and you do biopsies on them and the numbers hold up, please resubmit your paper and we'll consider it very seriously. So when I had 77 guys, I resubmitted it and it got published in the Journal of the American Medical Association in 1996.
And that was the first time that, and it was clear then, that low testosterone was not protective. And we followed that up a few years later as I started doing more of this with another 345 men and the results were identical. So part of the story was BS. Low testosterone was not protective. These guys had as high rate as prostate cancer as anybody.
But I was still worried about high levels of testosterone. And I'll tell you how, can I tell you how that? Yeah, yeah, go ahead. No, no, I'm enjoying this. This is also amazing. It's sort of funny how these things happen, right? So I had a fellow from Brazil, Hernani Rodin, and he had pulled together a lot of research data for us. We published some.
And the New England Journal of Medicine had published maybe the biggest paper of this century in 2002, which was the Women's Health Initiative, which was about hormone replacement therapy in women. It was the largest placebo-controlled trial at the time. It was something like over 20,000 individuals.
And everybody at that time had thought that hormones in women were great, protective about all these things. And the headline from the 2002 paper in women was that HRT, hormone replacement therapy in women, was actually associated with increased risks, increased. And it really affected that field.
Today, you know, there's lots of follow-up studies from that, and it's clear the scare stories from those initial headlines weren't true. But in 2003, as testosterone was just becoming more popular, We contacted New England Journal and we said, are you interested in a review paper on testosterone? They said, yes, we're interested in a paper on risks.
So we worked with them and we pulled together all the papers we could find on testosterone and prostate cancer. And one day our nanny comes to me and we've divided up the papers and he's a very confident person. Confident man. And now he's a very prominent urologist in Porto Alegre in Brazil. And he looks nervous. I'd never seen him nervous before.
And he says, Chief, do you have the papers that show that high testosterone is dangerous for prostate cancer? And I said, no, Nanny, I thought you must have them. And what we found and published was that we couldn't find one single article that showed any good evidence that high levels of testosterone or testosterone therapy were associated with anything bad with prostate cancer.
Higher prevalence, higher stage, the higher mortality, nothing. And we were shocked. The editors at New England Journal were also shocked. And I was relatively young. This is more than 20 years ago. And they were uncomfortable publishing the paper. So they sent it first to three urologists who gave it high scores. But they didn't believe this thing about the prostate cancer.
It was taught everywhere in the world. So they sent it out for another three reviews, this time to endocrinologists. The endocrinologists didn't mention any papers that we'd missed either. And they gave it high marks. And they still weren't satisfied. And they sent it out for another round of reviews, this time to oncologists, who also couldn't find anything.
And so they published, took about a year to publish it, and it got published in 2004. And that was the first time that any kind of major journal questioned or challenged this idea that high testosterone or testosterone therapy was dangerous for the prostate. So that's 2004. We're now in 2024. It's 20 years later. And I can tell you that there's been a lot of research in the last 20 years.
We have three large randomized controlled trials now, as well as numerous large observational trials. None of them Not one shows anything bad about high levels of testosterone or raising testosterone and prostate cancer. But still, there are many parts of the world where you never, ever, ever give testosterone after the man's had radical prostatectomy or radiation therapy.
The AUA guidelines actually were the first to allow, for 2018, first to allow there to be, to give some cover, to say it's okay, or at least that there's not a contraindication, to give it to men with low-risk cancers where there appears to be what looks like a parent cure.
But, you know, there's still nothing documented anywhere that says maybe we can give it to other men or men on active surveillance or men after radiation. And the argument to not do it, I think, is based on nothing.
And so, Ryan, in 2024, how's that treatment evolve since 2004 in terms of injections, pills, or what were you doing first and then what are you doing now? Just go through the thought process of how you decide where to allocate each patient.
So in the late 1980s, early 1990s, what we had available was mainly the short-acting injectables, testosterone, cipunate, testosterone, and anthate. There was a pill, methyl testosterone, which wasn't used. It was known to cause some liver damage. It's still available, but doctors are discouraged from using it. Dangerous in most cases. So that was really what we had.
The first real advance in terms of the new technologies branded things was a patch, testosterone patch. It wasn't very successful. You needed to apply it to the scrotum. And so you had to shave your scrotum. And it didn't stick very well because people get sweaty down there.
So, you know, I have a nurse who had been with me for now for 20, 25 years, and it was his job to teach people how to shave their scrotum and how to apply the patch. Not a great part of his day necessarily, but so that didn't work. Then there was a patch you could apply to the chest. And then really the first new popular treatment was the gels. Androgel was the first.
followed by another gel called Testim. They're now all generics. And then later in about 2008 came the pellets. And urologists tend to use a lot of pellets. They're good. Interestingly, pellets were one of the first forms of testosterone, was available after testosterone was synthesized in the 1930s.
And it turned out that there was a pellet called Testopel that was approved by the FDA in the 1970s, but it wasn't marketed. I didn't even know that it existed until a company brought it to the attention of some urologists at the Sexual Medicine Society meeting in, I think it was 2008. It's called Testopel, and it turned out to be very good.
So, you know, subsequently we had long-acting injectables like testosterone and decanoate. Then we have the self-injectors, testosterone and anthate that you inject into the fat of the abdomen, zyasted. And now we have three oral testosterone that are safe, that have been approved over the last several years. And it'll be interesting to see what happens with market share and how doctors use those.
And doctor, you mentioned that the high peaks don't cause prostate cancer. We know that. But in terms of possible side effects, we know that the pills, they say that the peaks are less, the gels, the peaks are less, doing low doses of injectables versus the pellets, which you will get a higher peak. Is that true? Or what are you looking for when you start a treatment for testosterone?
So we're lucky that we have all these different, we have a lot of choices, right? And I was always interested in trying the new treatments. I wanted experience with them. I wanted to see if they would work, how well they worked, who they would work in. And in the end, really, I tried as best as I can to match patient with treatment.
So in urology, there's a lot of kind of macho stuff that, oh, injections are the way to go. We get high levels, the patients are happy, it's inexpensive. But you know, there's a lot of patients that don't want to do injections. It's an amazing statistic, but in a couple of studies, the percentage of men who are still doing injections...
at the end of one year after they started, is only 15%, one out of seven. People stop it. So a lot of urologists I know say, oh no, my patients stay on it. But unless you actually look at your numbers, There's a lot of bias involved with that because we know that we see the patients that come back to us. We don't see the patients that don't come back to us. And we may not remember them.
We see them once, maybe twice, and off they go to learn how to do self-injections. So unless you're keeping statistics on your own, folks, it's hard to know. So injections are fine. It's a good form of therapy. We would give patients the choice of doing self-injection which they could do once a week, usual starting dose is 100 milligrams or half a cc.
Or if they didn't want to do it, we would inject them in the office. They'd come in every two weeks. Once a week is too much for, you know, a lot of people have to take time off from work and fight traffic in a city like Boston and Park and all that. So we'd have them come in every two weeks and we would inject them starting dose 200 milligrams or one cc. And we can adjust the dose after that.
The gels, people say, oh, the gels, the topicals, what a nuisance that is. But there were about, I don't know, 10 plus years where the leading testosterone product in the United States, at least, were the gels. And they have advantages that it's not an injection. There's nothing scary about it. Patient has some control over doing it. They just apply it themselves.
They feel like they have control too. Like, you know, there's nothing really bad that happens with testosterone therapy, but you have the sense if you're applying a cream or a gel every day that you can stop it. You know, if you're worried something's happening, then you just stop doing it, whereas the injection, it's in there.
So, you know, the longer acting treatments, pellets, and the longer acting testosterone injections, testosterone and decanoate, you know, they have advantages, which is that the treatment is less frequent. But there are issues around insurance or cost and, you know, there's a lot that goes into what actually will work for somebody.
And in terms of side effects, I mean, it's mainly the same profile for all of them or, I mean, for example, blood clots. I mean, is that something to be concerned?
No, I think the data are quite clear that it does not cause blood clots. You know, we just had published over the last year or so the TRAVERSE trial. So TRAVERSE was the largest randomized control trial ever with testosterone. It involved more than 5,000 men randomized either to testosterone gel or placebo gel. Mean follow-up was 33 months, so a little bit less than three years.
Mean time on treatment was a little bit less than two years. And that's a big study, 5,000 men. And the original intent of the study was to look at major adverse cardiovascular events, heart attacks, stroke, and death. And it turned out that was fine. There's no difference between testosterone and placebo. They also looked at prostate cancer, and there was no difference there either.
But one of the things they also looked at was venothrombotic events, VTE, which is pretty much pulmonary emboli and DVTs, makes up most of it. And there was no difference there either. And we've had a number of observational studies too. A minority of them showed maybe some increased risk with testosterone. Most showed none. But the best is a large RCT, and there was no difference in that.
So it doesn't cause increased blood clots. I'm pretty comfortable seeing that.
And doctor, let's go back to 2004. You just published the journal that essentially doesn't cause cancer. So how does you evolve into, hey, we have patients with cancer or prostatectomy, low testosterone, how do you start treating them with confidence? Or again, it was more or less same situation as when you were treating them before, like just very cautious. How did that process started?
Jose, I got to tell you that I was nervous most of my, almost all my career. And it's very hard to give up concepts that you were taught as a trainee. Very hard. You know, the smartest people that I knew in my training, and some of them were brilliant, taught me that testosterone is dangerous for prostate cancer. It was completely unchallenged. It was just... It was just one of the rules.
And so when I first started treating my guys, I mentioned that I was doing biopsies to make sure they didn't have cancer, but it's still thought that they might develop it. But after a while, what happened is that, so for many years, at least in the Boston area, I was the only doctor. that was offering testosterone therapy to otherwise healthy men. They just had low levels of testosterone.
They didn't have pituitary tumors. They had two testicles. And people were making me nervous, right? Like my urology, my patients would go for a second opinion. And they were told, that guy Morgenthaler is crazy. You're going to get cancer from that. And I had colleagues stop me. I had one colleague, one of my former teachers, stop me at the AUA meeting one year.
I was just out of practice a few years. out of training a few years, and he says, what you're doing is dangerous. You have to stop. And I was brought in. I gave grand rounds in my own hospital to the endocrinologists. And a day or two later, I get a call from the Human Subjects Committee, the IRB, from the chief of the IRB. He says, Abe, we'd like you to come and talk to the IRB.
So they arrange a time. I go in. I don't really know what it's all about. He says, we heard that you're practicing dangerous medicine. And it came, I know it came from one of the endocrinologists that I had spoken to. And you know what's funny is that that was early days.
And the most dangerous thing that I had done then, which was part of my lectures, I mean, I was giving talks on this thing because it was interesting to people. was I gave testosterone to men who on prostate biopsy had been diagnosed with PIN, with high-grade prostatic interpithelial neoplasia. At that time, we thought this was a pre-cancer.
And if a biopsy showed PIN, we automatically scheduled the next biopsy because we were sure there was prostate cancer hiding in there somewhere. Today, we barely care about PIN. Even if somebody has Gleason 6, which was absolute diagnosed cancer, at least that's how we thought of it then. Now we know maybe that doesn't deserve the designation of cancer. And in any case, it's low risk at worst.
But what's funny now is that this dangerous workout I was supposedly doing was because we've given it to 20 guys with PIN. and published it. And one guy eventually was biopsied and had cancer, but that was one out of 20 with, I forget what the follow-up was, but there wasn't much. So that was the dangerous work.
But what happened is that I developed a reputation around testosterone, and it's not just about sex, right? So in the mid to late 1990s, there was a movement that really emphasized health and wellness for people. The idea was that sort of the standard medical training was hospital-based, and that was really for what some people might call sick care.
You know, heart attacks, cancer treatments, things like that. But there were a lot of people who didn't need to be in a hospital, And they weren't feeling that good. And it wasn't just sex. You know, sometimes their mood was down or they felt weaker. They didn't feel like themselves. Energy was down from people who otherwise had led vigorous lives.
And a group of physicians and the public sort of figured out that maybe there's a way to feel better. And they really created the first movement around desire to normalize testosterone levels for quality of life. And they were right. They were right.
And today we know from studies and also just from seeing patients that, you know, what I say to people is that having low levels of testosterone is a reduced state of the human condition. You know, there's a lot of stories that are very colorful of men doing what we were always characterized as foolish things in the past, looking for the fountain of youth. Yeah. Oh, those men are so foolish. Yeah.
There was a guy in the 1800s who was tying off the vas deferens on one side because he thought it would help rejuvenate men by blocking the outflow of sperm, right? They knew that testicles made sperm. And you could think of it as chi or energy or whatever. And so he kept it within. And one of the people who had that procedure done was Sigmund Freud. Another was the famous poet W.B. Yeats.
And people say, how could such intelligent, educated people be fooled in this way? And we ridicule, we mock men for this. But in fact, what I see is that these were people who knew what it was like to be not successful, but sort of to be at the top of their game. They had an A game. And How important, and clearly they weren't feeling that anymore.
And how diminished they must have felt in order to actually try something as dubious as what was being offered. It reflected on how important it was for them. Not that they were stupid or foolish or just looking to be sexual, but there was something that was different to them. And we know that about having low levels, especially very low levels of testosterone. The effects can be profound.
And doctor, right now, I mean, are you treating patients with active prostate cancer, active surveillance? Are you doing them on prostatectomy after radiation therapy?
So as the years went on, I took on what I thought of as riskier and riskier situations. And when you asked if I was nervous, I was always nervous when I did something like that. So first was the guys with PIN, where we thought they had pre-cancers. Then it was guys after radical prostatectomy who appeared cured.
Then it was guys with radical prostatectomies where they had higher great Gleason scores, higher risk, radiation therapy. Then guys on active surveillance. Now, I wasn't, these guys would seek me out. I wasn't saying to anybody, listen, you really should be on testosterone. No, no, no, no. They came to me, they said, will you give me testosterone?
Because they knew about it, or some of them may have been on it before their cancer diagnosis, and they knew how much better they felt. And in the end, I was also giving it to men with metastatic disease and biochemical recurrence. So in 2021, I think it was, we published on 20, 22 guys. who had either biochemical recurrence of their cancer or frank metastatic disease.
And some of those men were on testosterone for years with metastatic disease and not much happened to them. It was just astonishing. So I was nervous with all of them. The first guy that I gave with metastatic disease was an 84-year-old man. And he came to see me. He had widespread METs. His PSA was over 500. And he had done standard treatment with androgen deprivation, and he hated it.
And did I say 84? He was 94. But his brain was sharp. And he came from out of state. He said, I've read all. He was a scientist. I've read all your work. I want to come to Boston. Why don't you give me testosterone? And I said to him over the phone, I'm happy to see you, but I can't promise you anything.
And when I saw him, he was mentally sharp, and he could walk, and he had one nephrostomy tube in the pocket. He wore a jacket. He had one nephrostomy tube bag in one pocket of his jacket, another one in the other pocket. I said, what do you want testosterone for? He says, I used to exercise every day and it made me feel good.
And I've got colleagues in science around the world and I'm just too tired to correspond with them. He says, those were the two main things that gave me pleasure in life and I'd like to be able to do them again. And I said, you know, I've never treated anybody like you. You could die in a week tomorrow if I give you a testosterone. And he said, I've never lived my life in fear.
I don't intend to do it now. He says, and besides, I'm 94 years old. I'm going to die. He says, I've got metastatic prostate cancer. I'm probably going to die from that. But he said, while I'm alive, I'd like to live as well as I can. And he said, I'll sign anything that you want. And so I wrote this very long handwritten note in his chart. And I treated him.
And within a few weeks, he was exercising. He gained weight, which he needed. He was very skinny. His appetite came back. He started corresponding with his colleagues. And he had a bunch of patents. He started to work on a new patent. He had a good year. And we died at the end of the year. But I don't think we shortened his life expectancy by one day. And he died of prostate cancer.
His PSA would rise and rise and rise. So he gave me the courage to do it in younger men. You know, I stopped seeing patients a few years ago. But by the end, it was clear to me, and it's even clearer now from the literature, that I simply do not believe anymore that testosterone makes prostate cancer grow unless the levels are severely low.
below the saturation point, in which case there still is a little room for testosterone, you know, to cause some growth of the cancers. But once you reach the saturation point at around 250 nanograms per deciliter on average, I don't think it does anything negative.
And doctor, in these patients, I mean, you say you are around 20 patients, were they on ADT also or just they weren't getting any treatment for the cancer?
Most, but I don't think all, most had been on ADT and didn't like it. There was one guy who had basically lost his personality. It was just like flat affect. And he'd had a few strokes, and I thought his lack of responsiveness was because of his strokes. And I didn't treat him right away. His wife brought him in and said, this isn't the man I married. I don't recognize him. And I put them off.
I said, maybe stop the ADT. Maybe his testosterone will rise and he'll feel better. And they came back months later and said, we stopped it. He's no different. Please, we want to have him go on testosterone. And they came back a few months later, and he was like a new man. Yeah. He was funny. He spoke fluently. Before, it was just one yes or no. It took a long time for the words to come out.
When I first saw him, he needed help to stand up and to be examined, and now he just stood up on his own. That was an amazing thing. So ADT, people often misunderstand my thoughts about this. So androgen deprivation does work, especially the newer agents that lower testosterone even more. I call them super ADT. And they've shown that progression-free survival is improved.
Overall survival is improved. It's good. There are many men who don't like what happens to them. And there are significant health risks, including mortality, non-prostate cancer mortality, that happens to these men. They become obese. Generally, they put on a lot of weight. They're at risk for more heart attacks and strokes. And they just feel like crap.
And so there's a lot of men that sort of fall outside the system. They just stop their ADT. They're lost to the system. And I'm not saying they should all go on testosterone. So I don't believe that ADT is bad or that it's dangerous. And in the proper circumstances with informed consent, I think it's totally the appropriate thing. But there is a cost.
And sometimes the cost is often decreased quality of life. As a rule, almost everybody that I treated with advanced prostate cancer who came to me and wanted testosterone, they almost all said the same thing, which is that this life that I'm leading now, it doesn't feel like much of a life. And even if it shortens my life, I'd like to live better.
And that was the justification for them wanting to go on testosterone.
And doctor, for urologists out there that are still skeptical about patients that had prostate cancer, what is your recommendation in terms of starting them in any specific gels versus injections or pills, low doses, or do you just treat them as a normal patient?
Yeah. So I treat them as a normal patient because it's a little bit like you can't be a little pregnant. You either are or you're not. The fear, it's taken me 30, 35 years to come to the conclusion that I have around testosterone and prostate cancer. And it took me a long time. And I don't expect people to have a sudden epiphany about it.
So there's no difference in terms of what we were taught about risk, whether you give a little testosterone or normal amounts of testosterone. It was supposed to be dangerous no matter how much you gave. So you may as well just treat them. And what kind of treatment you give matters. It's sort of what the doctor's comfortable with.
I think some people may be more comfortable with gel initially because the levels don't get as high. You can stop it if the PSA goes up and it makes you nervous, then you can stop it. But once you have a little comfort with it, and the easiest patients to start with are the people who had lower risk prostate cancer before definitive treatment, Gleason 6 or Gleason 3 plus 4.
maybe with negative margins, undetectable PSA afterwards, or even radiation therapy, again, with lower risk disease. And I think once you start seeing that lightning does not strike either the doctor down or the patient, that people get more comfortable. Amazing thing happened to me, which is, so at this past year's AUA, I moderated a plenary session.
And the question was about, the debate was on whether or not you could reasonably treat a man with testosterone who was on active surveillance. And it was a case of, I don't remember if it was Gleason 3 plus 4 or 4 plus 3, but it was Gleason 7. And so we had good debaters and they debated it. And then I asked for a show of hands from the audience, you know, and it's one of the plenary sessions.
They've got a couple of thousand people in the room.
I was there. I was there.
Yeah. And about a third of the audience put up their hand saying that they would have treated the case that we had. Now, that's amazing. Amazing. Because just a few years ago, it probably would have just been maybe a couple of hands. So it's shifting.
And part of the reason it's shifting is that so many urologists now and doctors have experience treating men after radical prostatectomy or radiation. They've seen that nothing happens. So then we go on to the next group.
And there's a way of thinking about this that I think is very effective, which is that if you had a patient in that situation, prostate cancer, treated in whatever way, but it's not metastatic, and he had a normal testosterone and felt good, nobody would talk about lowering that person's testosterone.
So if you can imagine as a urologist, as a physician, that there'd be no point in lowering a testosterone in a man with normal testosterone, then what's the danger in raising it to a normal level? It's the same chemical. So the cells that need testosterone cannot tell the difference between testosterone made by the testicles and testosterone that we inject once it hits the bloodstream.
So they all have all these names, right? Like testosterone, cypionate or enanthate, they're esters. But what happens is that when they hit the bloodstream, there are enzymes that cleave off those side groups and what circulates is testosterone. It's the same molecule. So that's one way to think about it.
And, Doctor, going back to that active surveillance patient guy, any special considerations in terms of how to treat that PSA? I mean, would you treat it just the same as somebody that is not on testosterone? Or are you a little more concerned if you see that the PSA is going higher faster?
So the most important thing to understand about PSA is that in order to interpret a PSA level, you actually have to know what the testosterone level is. And the reason I say that is PSA is its production. It's a normal prostate chemical that is androgen dependent. So you can take healthy volunteers, which has been done, and give them an agent that lowers testosterone.
Their PSAs will go down usually to zero. or close to it. When their own testosterone recovers because you've stopped that medication, as the testosterone rises, PSA will rise. until it reaches a maximum. If you give finasteride or dutasteride, we know the PSA drops by about 50%, right? We compensate for it.
So it's a testosterone sensitive chemical that we use to monitor men with prostate cancer or to assess their risk. But if you've got a testosterone less than 250, less than the saturation point, the PSA is going to be suppressed. It's not a real testosterone. It's not its real PSA. If they're less than 250, you don't know exactly what it's going to be if you raise it above 250.
This is true whether men have prostate cancer or not. So if you have a guy with prostate cancer and his testosterone is, let's say, 200, and he goes on testosterone, so there's two versions of this. One is, let's say, they've had radiation. Most guys with radiation have some measurable amount of PSA. The PSA will go up in that circumstance.
If their testosterone is above 250, it probably won't go up much at all or maybe zero. If they've had surgery and their PSA is a very low number, or let's say it's a sensitive assay, right? Let's say it's, I don't know, 0.01, right? Still below the sort of recurrence level if you want.
But there is a chance, especially with a very low testosterone, that the true value of that, which you'll find out when you give testosterone, might be above 0.02. Or 0.2. And so you have to see what that is. And it sometimes changes the status of somebody. But if somebody has a measurable PSA and their T is less than 250, it's almost certainly going to go up.
And it's important for the doctor to know that and also very useful to let the patient know that. Because when it comes back at a month or two months or three months, if you don't tell them, everybody's going to worry that the cancer is growing. So it's expected to go up if the testosterone was less than 250. And the new value at about three months becomes the new baseline.
That's the true baseline. And we only worry if it goes up from there in a consistent way.
So it would be always good to have a baseline of your testosterone prior to treatment in patients with prostate cancer. I don't think it's being done, or at least I'm not necessarily ordering if the patient doesn't have the symptoms. But if at some point they develop the symptoms, it would be good to have that baseline.
Correct. And the funny thing is, is that even though we've been taught, it's been drilled into us, testosterone is dangerous, testosterone is dangerous. Most prostate cancer guys, they don't measure a testosterone. They don't even know what a testosterone is. They don't know whether it's normal or low.
And that's not a criticism of them because the truth is, it doesn't really matter for the outcomes we care about with prostate cancer. It doesn't really matter.
But it matters for the quality of the life of the patient.
Well, it matters if they're symptomatic and you're thinking about giving them testosterone afterwards, for sure. Yeah. And then you have to, if you're using PSA, you have to know whether the testosterone has let the PSA max out to whatever it's going to be, or if it's somewhat inhibited because testosterone is too low.
So, doctor, in terms of treatments, we have now multiple oral medications for testosterone replacement. Can you dive a little bit into pros and cons of these oral medications and a little bit of history in terms of why before they were bad and now why they're better now?
Yeah. So it was one of the great advances in testosterone therapy is the development of these oral medications, pills for testosterone. And, you know, we used to say until they came about, maybe about, what, three, four years ago, that oral testosterone was bad. And the reason we said it is because they were alkylated. They had a side chain.
And when you swallowed them, it had a first pass effect with the liver and it turned out to have some liver toxicity. The new pills are all made out of testosterone undecanoate, which has this long carbon side chain of 11 carbons. And it doesn't get absorbed the usual way through the gastric and through the intestinal vasculature, but rather it gets absorbed through the lymphatics.
And so it bypasses the liver altogether and doesn't have toxicity. The product that I'm most familiar with is called Kisotrex. They're all made out of testosterone and decanoate. And what's nice about the pills are that... You know, the most popular treatment for the last, I don't know, 7 to 10 years with testosterone have been injections. People learn to inject themselves.
But the truth is a lot of people don't want to inject, right? Nobody looks forward to it. It may be worth it to them, but nobody looks forward to it. And people are used to pills. We take pills for all sorts of things, Tylenol for headaches and whatever else. And so the pills are taken twice daily. They all have different dosages.
For Kisotrex, the usual starting dose that most urologists are using now is 400 BID. So it's two of the 200 pills taken twice a day. The testosterone levels go up and then they drop. And then you take it again and it goes up and it goes down. And the symptomatic response is excellent.
And one of the interesting things is because the body goes back to, because there's not the sustained high testosterone level, some of the side effects or the things that we worried about with testosterone don't happen as much. So there's less suppression of the gonadotropins LH and FSH, which are the hormones that act on the testicle to make sperm.
So I don't know this has been shown yet, but anecdotally, testicular size doesn't shrink the way it does with some other products. And I think we're waiting on some fertility studies. But the early indications are is that this, we used to say testosterone always is, you can't do it if you're trying to make babies.
So it's going to drop your sperm counts to zero or close to it if you're on injections or pellets. Should recover, but not always. But with the oral, I think that's going to turn out to be not as common a problem. So that may be very, very helpful.
And doctor, just a parenthesis regarding, you mentioned the short-acting testosterone and the possible side effects, going back to a baseline. So going back to where we talk about the prostate cancer, I mean, so will that also transcribe? I mean, can you have a patient, let's say, castrated levels with ADT, and can you give them pulses, just short pulses of testosterone at least to get a boost?
And in theory, it should keep that low baseline castrated levels.
Is that more or less accurate? What an interesting idea. So the question I think you're asking about is what about trying to give them a little daily boost without really changing much? I think that's a very interesting idea. I'm not aware that anybody is trying that yet or has reported any data on it, but it's a very interesting idea.
Because if it's work for fertility, I mean, it might in theory work also for, I mean, it won't change your, I would say, your constant, that high level, that constant level of testosterone shouldn't affect it that much in theory.
Yeah. You know, so one of the things that the orals have transformed is the concept that you have to have a continually high level of testosterone to get the benefits. And clearly that's not true. And the safety seems to be improved, the safety profile, by having levels that fluctuate some during the day, returning close to or even to baseline. So for example...
You know, many of the risks of testosterone that we used to talk about probably aren't accurate anymore. You know, we had the Traverse trial, the biggest randomized control trial ever that I think disproved the idea that cardiovascular risks were increased with testosterone. They were not compared to placebo. And the same is true for prostate cancer.
I think the data is now becoming overwhelming that testosterone does not increase the risk of prostate cancer. But one of the things we've always worried about is polycythemia, the risk of getting a high hematocrit, which can happen in up to 20% of men who do injections. And the rate with the orals appears to be more in the 2% to 3% range.
It doesn't happen as much, almost certainly because the levels of testosterone aren't sustained at the high level, and yet people still get the benefits.
So to be able to have levels of testosterone that provide men with whatever it is they need, like the testosterone level they need for sex drive, for vitality, for mood, and at the same time to have fewer of the adverse effects or potentially fewer, that's a pretty good trade-off.
So that's great, doctor. So, I mean, I think we have covered a lot today. Any thoughts, any words to those young Uralis out there?
Yeah, so the words of wisdom is don't be afraid. Realize that the goalposts have shifted a lot over the last 30 years. It used to be you can't do this ever, give testosterone to anybody. Then it became you can't do it to anybody who were worried about prostate cancers, had prostate cancer. And now that's clearly not true, right?
Because there's so many people who give it to men after radical prostatectomies with the parent cure. And it's just, it's an old story that just needs a little bit more time to die maybe. But I'm very hopeful.
You know, I gave, I was at Tulane and I spoke to the residents there and Wayne Hellstrom is at Tulane and he's been, you know, very highly involved with the testosterone and prostate cancer story. He runs a course at the AUA on testosterone. And the residents have learned from him.
And I was just chatting with them before I started my presentation and said, you guys treat guys in the clinic that you see with testosterone? They say, yes. I say, you treat after radical prostatectomy? They said, yeah. I say, what about guys on active surveillance? You don't do that, do you? They say, oh, yeah. I say, what if it's like Gleason four plus three?
Like they're looking at each other like what's the problem? And the reason is that they now have the experience of treating these men and nothing happens to them. There's a baseline level, of course, of recurrence and progression, but they're not seeing some terrible thing happen. One of the reasons that testosterone was not used for about 50 years after Huggins published his paper
was because everybody was so scared that there were no doctors that had a large group of patients on testosterone that they could say, now hold on a second, I have experience with this. I've got all these patients and they're not getting prostate cancer. Nobody had that experience and so it lived on without a challenge.
Once doctors have clinical experience with this, it becomes impossible to tell them something that isn't quite true. Like the idea that just a little sniff of testosterone is going to create some trouble makes no sense to somebody if they're already treating and they haven't seen that problem.
So I think that urologists are already well on their way with the younger generation to recognizing that testosterone really appears to be quite safe in most, maybe not all circumstances, but in most circumstances of men after prostate cancer.
So, doctor, thank you for your time. Definitely thank you for all the, how you have done in the past. I certainly have helped the patients in our community. I see patients five, 10 years ago had parietal prostatectomy. Nobody has touched them with testosterone. They come just happy. And it's not, like you mentioned, it's not about sex.
It's about just feeling better, enjoying what they used to do and just the little things.
Right. It's the little things. Those are the little things that give us pleasure in life and make us feel like this is a life worth living.
Well, thanks for being a guest here, and hopefully I'll talk to you next time. Great. It's been my pleasure.
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