Podcast Transcript: Treating Low T: Safe & Effective Testosterone Therapy

[Dr. Amy Pearlman]:
Yes. I think in the very least, when it comes to these technologies, we have to be aware of them because good, bad, indifferent, they're going to impact our patients that see us every day. I love that. Dr. Morgentaler, you've been at the forefront of testosterone for decades. How has your clinical philosophy around testosterone therapy evolved since you began treating men decades ago?

[Dr. Abraham Morgentaler]:
Yes. When I started, I came out of my training in 1988. The belief at that time was that testosterone was dangerous, period, and mainly because of prostate cancer. It was universally believed around the world that if a man got a whiff of testosterone, that his testosterone was increased by small amounts for short periods of time, that man was undoubtedly going to get prostate cancer. It's almost hilarious to think back how naive we were. Because it was believed, nobody did it. Because nobody did it, offering testosterone, it went unchallenged.

The only reason I even was interested in testosterone was it was the beginning of specialization within urology, right around the time I came out of my training. Before that, urologists did everything. We were academic. Urologists were expected to know everything about everything, but there was a lot less information. My chief said to me, "We're going to specialize. I want to do cancer. What do you want to do?" I'd done some research with infertility, so I said, I'll do infertility. Then there were some exciting new operations for erectile dysfunction, penile revascularization, venous ligations, both of which have pretty much died now. I said, I'll do that.

As I started seeing men who had sexual problems, and this was 10 years before Viagra, some of these men were desperate. He said, "My wife's going to leave me," "My girlfriend thinks I'm cheating on her. You've got to help me. I'll do anything." I had done research with lizards as an undergrad where we put testosterone in their brains, in castrated males, and it restored their sexual behavior. I thought, maybe guys are like lizards. I just tried it. I set up three guys for injections. The way I was taught, I didn't know how to treat because I'd never treated during all my residency.

I went to one of the endocrinologists at my hospital, which was Beth Israel then. Now it's called Beth Israel Deaconess Medical Center after one merger after another. The senior endocrinologist said, "Oh, it's easy. You give 100 milligrams of testosterone, cypionate once a month--" I'm sorry, 200 once a month. That's what we did. That's what I did together with my nurse.

I saw these guys back, and they did well. How they did, they did well not only sexually. Sex drive was better. Erections were better. They said things to me that I hadn't anticipated. They said, "My wife likes me again. She says I'm a nicer guy." Another one said, "I wake up in the morning with optimism. I haven't had that in years." Another one said, "I have more patience with my small children than I ever had before." It was like, I didn't really know what that was, but that was pretty remarkable. Another theme is they said, "I felt like myself again."

I decided this was something that was worth pursuing. To me, it was just I was going to try it on three guys and see what happened. It was excellent. I started doing it. We're part of a residency where residents go to several hospitals. You operate with them, and you talk about whatever. There's no secrets because the residents tell the attendings at all the other hospitals what they heard when they were at this hospital or that. Some of the faculty from our program, the Harvard program in urology, I'd see them at meetings or whatever else. They said, "Are you giving testosterone? That's crazy. You're going to regret that."

At the very beginning, I started at some point doing biopsies around 1992 in men before I gave them testosterone because I totally believed that it caused prostate cancer. My patients were willing to go the extra mile and accept the risk in order to feel better. The old belief was that high testosterone caused prostate cancer and low testosterone was supposed to be protective. Part of the lore, folklore around testosterone, was that eunuchs never got prostate cancer. Now, where that came from is a pretty funny story by itself. Needless to say, there weren't a whole lot of eunuchs around when I was learning medicine. That was part of the story.

When I started doing biopsies in men, before I gave them testosterone, it was to exclude the possibility they might have cancer, which would grow like crazy, I believed, if I gave them testosterone. The belief was that if they had low testosterone, none of them should have cancer. Right away, we found cancer. I made my first presentation at the AUA when we had, I believe it was 6 out of the first 33 patients that we biopsied. Normal PSA, normal digital rectal exam. 6 out of 33 had cancer. This was my first moment of glory on the public stage as a young attending.

There was the chief of Boston Urology, Bob Crane, who was an enormous figure. He was the chief and really the mentor for Erwin Goldstein and others. He had this booming voice like you always knew when he was in a room. He came to the microphone and he said, "This is garbage. Everyone knows high testosterone causes prostate cancer. Low testosterone is protective. You put your needles places you should have never put them. You found cancers you never should have found. You do another 100 biopsies, you won't find another cancer." Of course, we continued. I said, thank you very much for your comments. It wasn't such a grand first presentation.

The data were real. Eventually, we published that in JAMA in 1996. It was basically a high rate of prostate cancer. One out of seven guys had cancer with low testosterone, normal PSA if one bothered to biopsy them. Those were random biopsies, only six cores at the time. When it started, the evolution of my giving testosterone was that the patients did well enough so that it was almost like I had a secret sauce for these guys. It was quite a number of years before anyone would tell me that they had started doing testosterone too.

During that early time, it was really trial and error. There were no guidelines about how to do this. It turned out that the original recommendation to give 200 milligrams once a month was completely inadequate. The reasons that endocrinologists were doing it back then is that they treated men who only had the most severe cases of testosterone deficiency. Men who had lost both testicles to cancer or trauma, men with Klinefelters or Kallmann syndrome with a central cause with Kallmanns of not having that, people with pituitary tumors resected. Young men were given testosterone.

You want to know something funny? Even though it was known that those young guys needed it in order to behave like men, be sexual with their partners, by the time they reached their 40s and especially the 50s, in what were considered the prostate years, those men had their testosterone discontinued. That's how great the fear was around prostate cancer. The endocrinologists didn't really care much about symptoms. They treated men so that they would complete puberty in the cases where they hadn't gone through it. They would get a beard, secondary sex characteristics. There was some data around osteoporosis and testosterone. That's what they were treated for.

When I told you about my first few patients that I treated, I treated them once a month, once every four weeks like I was instructed. When I saw them, not only did they tell me that things were great with testosterone, but all three of them said, "But you know, Doc, like a week or two before my next injection, I feel like all my symptoms came back. What's up with that?" I didn't know. I didn't know until we checked testosterone levels. It turned out that the 200 milligram injection lasted no more than 14 days. By 14 days, their testosterone levels were back to baseline.

That was part of what taught me that this was real, that the guys could tell when they're testosterone levels were good. They felt well. They had all the great things that they mentioned. When their levels returned to baseline, they felt that too. I learned something. In medicine, we learned the opposite. We learned don't trust the patient. Trust objective data. Really my experience was the opposite. The opposite was, in this particular case, what people were telling me was real and it was supported by the biochemical evidence.

It was weird. I was out there alone and with a lot of trepidation giving testosterone. We had to figure it out. I had a nurse after the first couple years that worked with me. His name's Kevin Flynn. He worked with me for 30-plus years. I gave him some leeway to adjust doses. People think that I'm bold, but I wasn't that bold. He was bolder than I was. We treated guys with, it turned out to be 200 milligrams every two weeks as a starting dose. Nobody was teaching self-injection yet. Later, we went to 100 milligrams once a week. Then we could adjust that upwards.

When we started with 200 milligrams, Kevin would see these guys. I'd see them irregularly for probably every three, six months. Frequently early on, because I was worried about prostate cancer. These guys got a lot of digital rectal exams, a lot of PSAs. Kevin would adjust their dosage. Some of these guys needed 300 milligrams every two weeks and 340. I'd say to Kevin like, "What are you doing?" He'd say, "Oh, it's okay. Look, his blood tests all look fine. The guy's doing well. He wasn't doing well on a lower dose."

What I learned out of that experience, and this was all trial and error, was that some guys needed what I would consider a starting dose, which is 100 milligrams once a week or 200 milligrams every two weeks, and did fine and needed no further adjustment. Some guys needed to be stepped up. The top that I would ever give is about 200 milligrams every week. The number of men who need that is very few, but that still exists as a treatment. I learned that there's a huge amount of variation between individuals. That's really been the theme of treatment of guys throughout my career. There's no single recipe that works for all people.

When Data Defied Decades of Belief

[Dr. Amy Pearlman]:
I have so many follow-up questions to ask you, Dr. Morgentaler. The first one I want to ask is, what does it mean to be on the cutting edge? We think about being on the cutting edge of medicine as this really fun and innovative part of our career, but it can also be a very scary place to sit. Can you talk a little bit more about what it was to be on the cutting edge of medicine in your career?

[Dr. Abraham Morgentaler]:
You're sweet to ask that question because the truth is, I don't get asked that very much, but that's what it was. You're right that in academics, people stand out for doing something that's different, but by and large, the thing that's different that they do is incremental. Let's say some treatment is good for, I don't know, diabetics, and then somebody treats the people with kidney failure. Say, "Oh, I didn't know it worked there." That person becomes known for doing that. They get invited to give talks on doing that. If there's a guideline or a recommendation, they get invited, so they talk about that niche area.

What I was doing was contrary to what the conventional wisdom was, universally believed for many, many years. I will tell you that it was uncomfortable. The only thing that kept me going really were my patients. It would have been, when I stood up at that meeting to talk about biopsy results, which were totally opposite of what everybody was being trained to do, and one of the best-known international figures in urology stands up and says that the work is garbage loud enough so that everybody in every room and in the whole convention center could hear it, that's a tough moment.

Also tough was the feeling like, what if I'm wrong, and what if my guys really do get prostate cancer? How is it that my teachers, who I respected tremendously, some of the people who I learned from were absolutely brilliant, and they believed something that my experience was that was incorrect? Maybe it was so easy to think, who am I? I'm just a young pisher, if you will. Maybe I'm wrong. One of the worst moments of my career, when I was finally encouraged to read the work of Huggins.

Charles Huggins is arguably the most important urologist of all time. He was the guy that really created androgen deprivation as a treatment for advanced prostate cancer. He's the only urologist to win a Nobel Prize for urology. There was another guy who won it, Forssmann, I think, who became a urologist, but he was just a surgical intern when he figured out how to get a wire through his veins into the heart, and he walked over to X-ray, and they took a picture, and the wire was in his heart, and that became the basis for cardiac catheterization.

Huggins won the Nobel Prize for coming up with the first treatment for guys with metastatic prostate cancer. It was 1941, and based on experiments in dogs, who also get BPH and prostate cancer, he discovered that if he castrated those dogs, the prostate shrank, and some of them had histological evidence of prostate cancer, and those prostate cancers shrunk, too. In the 1940s, all the way through until PSA became widely prevalent, which is the late '80s, early '90s, most men with prostate cancer presented with metastatic disease.

It was at least a weekly occurrence, a couple of times a week sometimes when I was a junior resident, for guys to walk in, get admitted to urology through the emergency room with terrible bone pain. On plain X-ray, which is all you needed, you had a blastic lesion, which is unusual for metastases. They're usually lytic, and that was the diagnosis of prostate cancer, metastatic cancer. We had a blood test called acid phosphatase that would be abnormally elevated if it was metastatic, but we didn't have PSA. We didn't have anything specific, and we would castrate those men. That was a junior resident case, and the guys would often have improved pain by the same evening as the surgery. Bilateral orchiectomy.

I witnessed with my own eyes that the Huggins regimen, which everybody around the world, was the only treatment really for metastatic prostate cancer, that it worked. Androgen deprivation worked. His paper was written in 1941. In 2004, I wrote a review paper with my fellow for the New England Journal of Medicine, and it was on the risks of testosterone. The WHI Women's Health Initiative had been published in 2002, and although now people understand that the original conclusions from that paper were completely off, what it allegedly showed was all these unexpected risks with HRT in women. That was the basic line from the WHI.

The New England Journal was interested in an article on the risks of testosterone, basically the male equivalent of HRT, and most of that focus was on testosterone. We're working with-- it's sort of an invited article, if you will, so we're working with the editor. I had a fellow who's very-- from Brazil, Ernani Rhoden, who's the first author on that New England Journal article. He's a very confident guy. He's now a well-established middle-to-senior level urologist in Brazil. He was very confident. I'd never seen him nervous. For the first time as we're drafting this article, he comes in to me and he's nervous. I didn't know what to make of it.

We'd reviewed, we'd split up all the articles between him and me, and he nervously said, "Chief, do you have the articles that show that testosterone is bad for prostate cancer?" I said, "No, Ernani, I thought you must have them." It turned out that we couldn't find a single article that provided any compelling evidence that testosterone did anything bad for prostate cancer. There were plenty of studies looking at endogenous hormone levels, like in San Bernardino or Framingham study or things like that, did men with higher testosterone levels compared to lower ones have an increased risk of getting prostate cancer, which would make sense if testosterone was really a problem, right?

There were randomized control trials with testosterone, not as many as we have today and not as large, but not a single one of them showed anything negative about prostate cancer. Aggressive prostate cancer was associated with low testosterone, not high testosterone. Stage of diagnosis was worse with low testosterone, not high testosterone. It was just remarkable, and it took a year for our article that said we don't find any-- We didn't say it wasn't true, we said we didn't find any evidence that it's true.

It took a year for the editors at New England Journal to publish that article because they kept sending it out for more and more reviews because they were certain that there must be some evidence behind this. They weren't ready to publish it based on-- I mean, this is 20 years ago, 2004, I was maybe mid-level, but I was young. None of these reviewers came up with any papers that we had missed, which was a relief for us. I thought maybe we missed them. How can this be so, how can everybody believe this stuff?

Anyway, I was on the lecture circuit, which I was very proud of and having a good time. I'm basically lecturing on how everything we've been taught doesn't look right. We published the New England Journal, there's no evidence that suggests that it provides direct evidence that it's true. There was a very well-known, famous prostate oncologist, a urologist named Paul Lange, really one of the fathers of prostate cancer work in the early days of PSA and radical prostatectomy. He said to me afterwards, "You know, Abe, your stuff is very interesting, very intriguing that you don't find any evidence. It might be different in metastatic prostate cancer because after all, Huggins wrote that that was so. Have you read Huggins?" I said, "Well, I know what it showed, but it was hard to get articles for so long, 1941."

What we had then, it's hard for people today to imagine, but we didn't have phones where you can look up anything. Today, you could find the Huggins article in 15 seconds on your phone. Back then, what people had was that they had bound journals of urology. When I started out as an academic, I had my subscriptions to the Journal of Urology, maybe the Gold Journal of Urology, Fertility and Sterility because I was doing infertility.

At the end of the year, or maybe every two years, you'd send them off to the binder and you'd come up with a thick, leather-bound volume. If you were lucky, your urology group had journals that went back to the beginning of your chief's years when he started doing it and maybe the years before that. For 45, 50 years earlier, who had that? The only place you could find it was in a library, a medical library.

After Paul Lange told me about the Huggins, I really figured I didn't want to because I was afraid I'd read bad news. I figured I had to go read this for myself. I made it to the Countway Medical Library at Harvard. I went to the basement where they have the archives. All these old tomes, they're all dusty. You blow the dust off. I found that article, Cancer Research 1941. There's Huggins' article with Clarence Hodges. Read through it. He talks about castration and how it lowered acid phosphatase, which was their biomarker. He says, in every case that we gave testosterone, the acid phosphatase increased. The very last sentence of that paper is, testosterone injections activate prostate cancer.

I'm reading this and my palms got sweaty. I felt my heart beating. This is Huggins who's saying this. It was this awful feeling that you get sometimes when you're doing surgery and something goes wrong. Oh my God, like in the pit of your stomach. I had visions of the Harvard police coming down to the basement there and then and taking me away in handcuffs and some photographer from the Boston Globe taking my picture and my small children would see me in the newspaper, Harvard doc arrested for unethical treatment of his patients or risky thing.

It was amazing. I forced myself to reread the paper with the basic questions that you would want to know if you were going to give a presentation. How many men exactly did he treat with testosterone? It turned out to be just three. They presented data differently then. It was more like case anecdotes. He only gave data for two of those three men. One of those men had already been castrated, which today we understand is a special case. The body is so hungry for androgen, even if you didn't have cancer, that anything related to the prostate, the synthesis of proteins, chemicals is going to go up.

In the end, it was all based on one guy who only received testosterone for 18 days and his acid phosphatase during and after testosterone goes up and down and up and down. It's uninterpretable. Of course, that was the problem with acid phosphatase. It was an erratic test, gave erratic results, and why it was almost completely abandoned once PSA came in. The end of that story is that everybody listened to Huggins.

Huggins became the preeminent authority on prostate cancer for the next 25 years. He was young when he made this original observation. He won the Nobel Prize in 1966, 25 years later. In his Nobel speech, he continues to say that testosterone activates prostate cancer as if it's an accelerant, a promoter of cancer growth, even in hormonally intact men. I've read everything by Huggins. The only patients that he ever reported treating are those three initial guys. There's a couple of lessons from that.

First of all, not everything you read is real. The most preeminent authorities can have incorrect ideas. The most amazing thing was to realize that everybody was following what Huggins said. By this time, I knew that none of the evidence supported what he was saying. You ask about what it was like being out in front. In ways, it was exhilarating and felt like I knew something that nobody else knew. At other times, it was terrifying because there was always the possibility that I was wrong. It's funny now, and in my career with prostate cancer, I know I've taken you a little far afield from where you wanted to take me, but at every step along the way, I was nervous.

When I just started treating normal guys without any evidence of prostate cancer, I was worried they would get prostate cancer. Eventually, I had guys who had been treated for prostate cancer successfully with radical prostatectomies. There'd been a couple of case reports of those guys being treated by other doctors without their PSA ever coming back. I said, that makes complete sense to me now. I started doing that.

Then guys with radiation, which was a little trickier because the prostate cancer is still in situ. We knew at that time, I don't know if the data are still the same, but at that time, it was believed that there was evidence that if you re-biopsied men with known prostate cancer, treated with radiation, about 20% of the time they still had prostate cancer. That felt riskier, but I started doing that. Nobody was getting recurrences of cancer. It seemed good. The most important thing is that this wasn't an agenda of mine. The patients were asking for it. They were told the risks and they were happy. They were happy. They were getting benefits.

Then I started doing it with men on active surveillance. Then eventually, even in men with metastatic disease, which I've published on. In none of those cases did I ever see rapid progression of prostate cancer. You trained with Baylor. Larry Lipshultz and I were-- Larry had invited me at some point to co-chair what used to be called the Endocrine Forum at the AUA. We're just chatting before the thing gets started and catching up. I don't remember who said it first, but one of us said, "So I treated a guy on active surveillance with testosterone. Listen to this story." The other one of us said, "Me too."

It turned out we put our cases together and we ended up with, I don't remember, 11 or 13 cases of active surveillance. All these men back then, we used to do active surveillance by doing a biopsy every freaking year. The active surveillance now is everybody does it. It's not a big deal. It was a big deal back then because we thought Gleason 6 was as dangerous as anything. If they had low-risk disease and people didn't want to be treated, we said, okay, but we were worried that we would miss a window where they could be cured. We didn't have MRI then. It wasn't considered a useful test. The only way to figure out what was going on was PSA and biopsy.

These men had cancer and we biopsied them in a year regardless of what their PSA was, and usually the year after, and usually the year after. Later, it got stretched out. Now we've got MRIs, so they don't need as many biopsies. Back then, it was multiple biopsies. Not one of those, I should know, but 11 or 13 guys, I forget which, had progression of their cancer. People would say to me, "Well, you only have 11 guys or 13 guys. What does that show?"

What I would say to them was that this is the first evidence since the time of Huggins, who introduced the idea that testosterone activates prostate cancer, that we have evidence of what happens to a prostate with cancer in situ. We raise testosterone and get pathologic evidence of what happened, and nothing happened. It was possible that the 14th patient or the 21st might have progression of their cancer. The idea that everybody gets progression of their cancer with a rise in testosterone could not be true. It was, in fact, the only evidence pre and post Huggins of what actually happens to these cancers up until that time.

Reframing Testosterone’s Role in Prostate Cancer