Nelson Vergel
Founder, ExcelMale.com
This video is a presentation given by Dr. Abraham Morgentaler at the European Association of Urology (EAU) Congress, March 2016.
Dr. Morgentaler is a distinguished researcher and clinician who serves as the Associate Clinical Professor of Urology, Harvard Medical School. He is also the Founder of Men's Health Boston - www.MensHealthBoston.com - the first Men's Health Center in the US, founded in 1999.
In this presentation Dr. Morgentaler summarizes his 40 years of clinical experience with testosterone, testosterone deficiency (a.k.a hypogonadism or "Low-T") and testosterone therapy, and its effects on the prostate.
TRANSCRIPT:
Well, thank you very much. It is my great honor to present the AOA lecture today on a topic that is near and dear to my heart, for which, believe it or not I've been involved with for forty years. In 1976 I began researching in a biology lab for three years with the American Chameleon Anolis Carolinensis. You see the male on the right with the dewlap that has come out. This is his sexual display. For three years I worked on figuring out what happens and how hormones influence the brain and the sexual behaviors. Of course testosterone was a critical factor. Through medical school and residency I learned very little about testosterone, other than the fact that we should lower it in men with prostate cancer. |
At the time when I finished my residency in 1988, the use of testosterone was rare. It was limited almost exclusively to men with severe problems, genetic issues, pituitary tumors, men who had lost their testicles to cancer trauma, and the big fear, of course, was prostate cancer. Testosterone was the devil. I learned, as many of you did, that high testosterone caused prostate cancer, or contributed to it. Low testosterone was protective, and raising testosterone in a man with prostate cancer was like feeding a hungry tumor or pouring gasoline on a fire. Every individual in this room knows these expressions, and most of us have used them, including me. When I came out of my training and I started with sexual medicine, we didn't have much to offer. There was no Cialis or Viagra. I was interested in testosterone because of my experience with the lizards. |
I offered testosterone to many of these men and was surprised at how often they responded well. These men did not fit the normal criteria at the time for testosterone therapy. They didn't have pituitary tumors. They had both their testicles, but they had low levels of testosterone. What these men reported back, was that they got better. Erections were better. Libido was better. They were better in ways that I hadn't anticipated, such as extra energy, decreased fatigue, improved mood, cognition. Some of these men would say, "My wife thinks I'm nicer to be around." This use of testosterone in otherwise healthy men in the late 1980s and early 1990s defied standard medical practice. My big concern by doing something that was a little different, were the complications related to prostate cancer. |
Beginning in the early 1990s I began performing prostate biopsies in otherwise normal men, normal PSA less than four, normal digital rectal exam, purely because these men had low levels of testosterone. I thought they were candidates for treatment, and I wanted as best as I could to exclude the presence of prostate cancer. Remember that men with low testosterone were thought to be protected against prostate cancer. They were thought to never get this. Yet right away we found cancers in these men. As a matter of fact, we found eleven cancers in the first seventy-seven men, and published this in JAMA twenty years ago in 1996. That rate of cancer in the era of sextant prostate biopsies, only six cores was as high as men with an elevated PSA of four to ten. |
This paper was the first chink in the armor of the story that high test testosterone is bad, low testosterone is protective. Low testosterone was not protective against prostate cancer. What about high testosterone? Well, for many years I still believed high testosterone was a problem because after all, we lowered testosterone in men with advanced prostate cancer. I believe that [inaudible 00:04:22] from Brazil, we wrote this review in the New England Journal of Medicine in 2004. When we pulled all the papers we could find about testosterone and prostate cancer, the number of papers that we found that showed something worrisome about high levels of testosterone or testosterone therapy and prostate cancer, was exactly zero. This concept was taught to medical students around the world, and yet we could not find any evidence for it. |
Where did this concept come from? It started with Charles Huggins, the patron saint of urology, Nobel Prize winner in 1966, who in 1941, together with his coauthor Clarence Hodges, did the first experiments to show that any cancer, including prostate, could be hormonally sensitive. For this, he rightly deserved the Nobel Prize. I went to the basement of the Harvard Medical School library to find this article because at that time you couldn't get everything online. In the dusty basement I found this 1941 article, and I read it carefully. What Huggins and Hodges wrote, is they took men with prostate cancer metastatic to bone. When they castrated these men or gave them estrogen to lower their testosterone, the serum marker acid phosphatase came down. |
What they wrote is that they also administer testosterone injections to some of these men. In every case the acid phosphatase went up. What they concluded and all of us essentially learned it decades later, was that cancer of the prostate is activated by testosterone injections. I remember the moment that I read this and I got very nervous. I was treating a considerable number of men with testosterone, and Charles Huggins, hero of urology said it was dangerous. I calmed myself down and I said to myself, "Read it again. How many men received testosterone?" What I discovered is they only gave testosterone to three men. In the results section, they only gave results for two of these men. One of these men had already been castrated, which today we would put in a separate category, which we would call androgen-deprived. |
What this meant was, that the general concept that we all learned, that cancer of the prostate is activated by testosterone injections, was based on a single patient treated for only fourteen days using a marker acid phosphatase that is remarkably erratic. For this reason, we largely abandon it in favor of PSA. What do modern data show? This is the placebo arm of the reduced trial. Over three thousand men. Prostate biopsies years two and four. No association with the development of prostate cancer with serum levels of testosterone or DHT. Specifically, men with the highest levels of these hormones had no greater risk of prostate cancer than men with lower levels. Meta-analysis of twenty-two randomized control trials. Over two thousand men. No difference in prostate cancer rates in men who got testosterone, compared to men who received placebo. |
Think about it for a moment. We know that fifty percent of men fifty and over, have micro [inaudible 00:08:14] prostate cancer in their prostates. If it were really true that higher levels of androgens caused those cancers to grow more rapidly, then we should see more cancers in men with higher testosterone and DHT levels. The data do not support that concept. In 2007 I first proposed the saturation model that tried to make sense of two opposite observations the urologist and the data presented. One is that every urologist LHRH agonists, as testosterone declines PSA will drop. We know that if we take these men out of the castrate range by stopping LHRH agonists, testosterone rises and PSA rises. |
That's fine. That's how we've been thinking about it, but what the data also show, is that throughout most of the range of testosterone, including super physiologic doses, we find no difference in prostate size. No difference in PSA. No difference in outcomes. To resolve this, we have a curve that doesn't go on and on forever up into the sky, more testosterone, more cancer growth, but rather a saturation curve where there's a dramatic increase at very low levels of androgens. Then, it becomes maximal and plateaus. Is there evidence for this in nature? There is. Three lobes of the prostate, one, two, three. We're looking at androgen binding to the androgen receptor. What you see in each of these when we look at specific binding, is that there's a rapid increase, and then a plateau. Rapid increase, and then a plateau. Rapid increase, and then a plateau with maximal binding occurring and very low concentrations. Two to three nano-molars in the rat, four nano-molars per liter in the human. |
If we look at this cartoon, it's actually easy to understand. Here's a prostate cell, or a prostate cancer cell. Testosterone enters is. It's reduced to dihydro testosterone. It binds to the androgen receptor. The complex of the androgen and the androgen receptor trans-locates the nucleus where it binds to DNA, but it's not testosterone alone. It's not DHT alone. It's not the androgen receptor alone. It is the complex of both of them. It's easy to imagine then that once the limited number of copies of androgen receptor are filled with androgen, this mechanism cannot be amplified. Any additional androgen will simply be excess. The old idea that testosterone is like food for a hungry tumor, I'd like to suggest we change it to that it's like water for a thirsty tumor. |
What's the difference? If you drink too much water, you're going to go to the washroom and eliminate it. Imagine this plant, house plant, is prostate cancer and water is testosterone. If we deprive this plant of water, it will shrink. If we give it water at this point, it will grow, but once this plant has enough water, we could run water into twenty-four hours a day and that house plant will never grow to be the size of a tall tree. Once the thirst has been quenched, additional androgen or testosterone has no further effect. Here's a beautiful saturation curve from naturally occurring testosterone levels and PSAs from Mario [inaudible 00:12:18] group in Florence, Italy. You see here a curve here that is just as nice as theoretical curve. |
They're almost the same, with a maximal point here, which we call the saturation point at about eight nano-moles per liter, or in nano-grams, per deciliter. About two hundred to forty, two hundred to fifty. Men who have testosterone levels less than this, who get testosterone treatment, will see a rise in their PSA. Men who have testosterone levels above this, who receive testosterone as a group in several studies show no change in their PSA. Based on the saturation model, I want to share with you some rather provocative information we've been putting out for several years. The journal reference is falling off of this slide, but this is journal of urology 2011. Five years ago, together with my colleagues at Baylor, we actually reported on the use of testosterone in men with untreated prostate cancer, specifically they're on active surveillance. |
These men were on testosterone for a median duration of two and a half years. All these men had follow up biopsies. None of these men demonstrated progression of their cancer. Here's their PSA levels at baseline. Over twenty-four months, I think you'd agree with me that PSA did not increase in these men over two years. This is a more recent paper we've just published on an additional twenty-eight men from our center, active surveillance on testosterone, for a median of three and a half years. We compared these with ninety-six men from our sister institution who also had low testosterone, but did not receive treatment. What we found is the progression rates between these two groups with testosterone and without were the same. |
Again, PSA did not rise in these men with untreated prostate cancer receiving testosterone. What does this mean? I'm not here to tell you based on these two studies that testosterone therapy is safe in men who are on active surveillance. The numbers are really small, thirteen men, twenty-eight men, but I want you to appreciate something. This is the first time since Huggins in 1941 gave us our concepts about androgens and prostate cancer, that anyone has bothered to look at what happens in the prostate of a man with prostate cancer if we raise testosterone. The old concept that testosterone treatment must necessarily make these cancers grow and grow rapidly, that I can tell you ladies and gentleman cannot be true as a general statement. |
Here's an example of one of the patients from our early series. This was a man in his mid seventies. He was diagnosed with prostate cancer when his PSA was 6.4. He'd been on testosterone for twenty years and he told he must stop, he has prostate cancer. He felt miserable and his testosterone dropped down to two nano-moles, sixty nano-grams per deciliter. Look what happened to his PSA as he went down below the saturation point. It dropped to 2.3. I treated him with testosterone. Within three months his PSA had doubled. That's right, he had a PSA doubling time of three months. This man should be dead in a year, but his PSA doesn't increase forever and go off the chart. It goes back to approximately where it was when he was androgen replete. |
Look at the data on this, 2009. I've been using this slide a long time. I saw this patient two months ago. He's in his eighties. He's still on testosterone. His PSA is, seven. I'm not worried any longer about high levels of testosterone with prostate cancer. I'm concerned about low testosterone. This is one of our studies as well. Looking at what predicts progression when men are on active surveillance. We found two things. One is a positive family history, highlighted in yellow. The other was a low level of free testosterone with a hazard ratio of more than two. High Gleason score. Gleason eight shown in this column, related, associated with low levels of testosterone. We now have multiple studies. A whole variety of them, showing that low testosterone has worrisome features associated with it. Higher Gleason score, advance stage surgery, increased risk of recurrence after surgery, and decreased survival. Low testosterone, not high testosterone. |
I'd like you, if you would, to imagine with me a thought experiment. Imagine you have two patients, they're brothers, identical twins, age sixty. They both have prostate cancer and you perform radical prostatectomy on both. You do a marvelous job. At once year they come back for their follow up and their PSA is undetectable in both. Brother one walks into your office. He's happy. He's sexually active. You did a great job saving his nerves. His testosterone is robust at twenty nano-moles per liter, or approximately six hundred nano-grams. What do you say to him? "You say you're doing great. Congratulations. I'll see you in a year." Right? Brother two comes in. He's not so happy. He's tired. His libido is absent. He has low testosterone. He's got an undetectable PSA too. |
He says to you, "Doctor, I'd like some testosterone. Would you prescribe it for me?" What do you say? Well, by and large what we've all said for decades is, "I can't give you testosterone. It's dangerous." "What'll happen?" "It'll make your cancer come back." Then, the patient asks a question because he never went to medical school, that we have failed to ask. He asks, "Why is it all right for my brother to have a testosterone of twenty nano-moles per liter, but not me? And doctor, I love my brother very much. If you think that a normal testosterone is dangerous, I'm going to bring my brother back right now. I want you to lower his testosterone until he feels as lousy as I do, if that's what you think is safe, doctor." |
Do we do this? Of course not. Most of you who do prostate cancer work don't even bother checking the testosterone. You have no idea if your patients before or after have a normal testosterone, a low testosterone, or whatever. We don't do it because it makes no sense, and because it's just irrational. Have we looked at things the right way? No. We've looked at them sideways. The latest issue is cardiovascular risks. This became a big issue over the last two to three years. It made no sense because for twenty years we've been seeing that low testosterone, as with prostate cancer, was bad for cardiovascular disease. Here's a meta-analysis men with low testosterone, increased risk of mortality. |
These are the two studies. They were very weak. They were retrospective. I was surprised at how much press they got. Rather we have considerable data that look more like this, where men with low testosterone who were treated have a lower mortality rate by half, than men who are untreated. My time is short. I won't read this for you, but basically a review article that we published last year showed no evidence to suggest that they were increased cardiovascular risks. On the contrary, we saw something beneficial between a normal testosterone level and cardiovascular health that is yet to be appreciated. The latest article to come out in the New England Journal from just last month, the largest randomized control study so far, placebo versus testosterone, showed something that physicians have recognized for many years, but now we have a large study to confirm it. |
Testosterone provided improvements for libido, erections, physical activity, and mood. What about cardiovascular events? There were seven in the testosterone arm, seven in the placebo arm, the same. The second year, a follow up year, there were nine events in the placebo arm, and only two in the testosterone arm. It is impossible to conclude from this that testosterone is the associated with increased cardiovascular risks. Charles Darwin gave us the reasons, or the explanation why we still fear testosterone. He wrote, "A belief constantly inculcated during the early years of life, while the brain is impressible, appears to acquire almost the nature of an instinct. The very essence of an instinct is that it is followed independently of reason." I want to leave you with my last case. |
The patient was ninety-four years old, a scientist. Completely his brain works perfectly. He had advanced prostate cancer with a positive bone scan, bone metastases, was given androgen deprivation, and he became too weak to walk, and he stopped it. He called me up from another state and he said, "I'm interested in testosterone. Will you give it to me?" His PSA was five hundred. When he came to see me together with his daughter, who was a nurse, I asked, "Why do you want testosterone?" He said, "I used to exercise everyday. It made me feel good. I'm too tired to do it now, and I feel like my brain isn't as sharp." At ninety-four. He'd read my work. He'd read the work of others. |
I consented to give him testosterone. Seven months later, this is a picture of him from just a few weeks ago, the daughter sent it to me, sitting in the dentists office. He looks pretty good for ninety-five, doesn't he? He feels good. He's no exercising daily. His brain is clear. He's working on something like his hundred and tenth patent. His latest PSA is thirteen hundred. He said to me, "Doctor, I feel good. I think you should tell my story." He's given me permission to show is picture and to use his name. Everything that we once learned about testosterone was wrong. High testosterone doesn't cause it. Low testosterone is not protective. Testosterone is not like fuel for a fire. |
This is an evidence based session. I think this is the perfect quote. "We must seek the truth like a lost child seeks it's mother."What about urologists? We are actually the experts with testosterone. We've been manipulating testosterone levels for seventy-five years. We are experts in the most common presentation of low testosterone, mainly sexual symptoms. I believe it is critical for urologists to be aware of testosterone deficiency to diagnose it and to treat it. Why? For the benefit of men everywhere. Thank you very much. |
Okay, thank you. We continue now. It's my pleasure to present Dr. [inaudible 00:24:33] from the Anderson Cancer Center ... Subject of testosterone therapy. Welcome. |
