Testosterone and Prostate Cancer: Is There a Link?

[Music] I made Morgentaler I'm not really a prostate cancer guy except I came in through the back door if I can use that they Express and I'm really a sexual medicine guy who's been working with testosterone for many years and it's fantastic at a prostate cancer meeting to have a session in which we talk so much about testosterone not only the age-old way of lowering it but also thinking about the importance of testosterone deficiency or hypogonadism and and possibly with with treating it so the first question here in this first talk and is really is there a link or what is the link between prostate cancer and testosterone and I think some of this is clear we all know that prostates both benign and malignant respond to androgen deprivation that part is not in dispute the part that's really come into question over the last 15 plus years is this higher serum testosterone increased the rate of prostate cancer this higher serum testosterone increased the risk of worrisome prostate cancer higher Gleason score or stage and this higher serum testosterone impact outcomes in the past we just assumed the answer to all these questions was yes but I'm going to show you some of the evidence around this now so I'm 60 years old and I just published the 40-year perspective on testosterone therapy how does that work well when I was an undergraduate at Harvard I really was a lab rat and in a manner of speaking and worked for three years I was going to be a biologist working with the male lizard and almost Carolyn insists which you see here this is the male this is the female these are the little guys but four to five inches you see in Florida and Bahamas we sometimes get your hotel rooms and if you put a male in with the female he's got this bright colored flap the skin called a dewlap and his head goes up and down very quickly we call it a stuttering push up it's as if the going ya-ya-ya-ya-ya and the female if her ovaries are intact we'll do a very stately elegant single pushup the male comes closer the dewlap comes out yeah yeah yeah yeah yeah and then they do it a few times and then they mate if you castrate the male which was my first procedure I ever did bilateral orchiectomy in the male lizard their internal by the way near the kidneys which makes sense embryologically right if you castrate the male that testosterone essentially goes to nil and you put them in a cage with a female after they've recovered and they don't do anything they don't care they have no libido the female will sometimes do her little push up like to say hey buddy I'm over here and the male does nothing so we had known from previous experiments that if you puts elastic pellets of testosterone under the skin you could restore sexual behavior but we were interested in the brain and we had done studies where testosterone was taken up in the brain of these lizards and my project was to actually take tiny amounts of crystal and testosterone put it in the portions of the brain that we knew were related with sexual behavior and that had uptake of the hormone in our studies and that was the medial preoptic area and the anterior hypothalamus and if I had been successful in putting it in there these castrated males in the cage with the female would extend their dewlap yeah yeah yeah yeah and they would meet so when his amazing thing and circulating levels of testosterone were again undetectable so what I got out of this at a very young age was that number one testosterone was a brain hormone and number two at least in the male lizard it was necessary and sufficient for the entire range of sexual behavior so I didn't learn too much more about testosterone through medical school I knew that when I went to medical school I knew that it was involved with viralization of the male fetus I knew was necessary for puberty and the boys I knew was involved with secondary sexual characteristics adam's apple' body hair things like that right but that's pretty much all I knew about it and then I went through six years of residency in urology and learned that if you lower testosterone that's good treatment for men with advanced prostate cancer but the idea of treating men with testosterone was something that was hardly done at all and important to sort of understand the history of this I think it's interesting testosterone was first synthesized in the 1930s the two guys who developed it in 1935 each won the Nobel Prize together but we didn't use much testosterone during my residency in the 1980s because we thought it was going to cause prostate cancer and the only man who received testosterone the 1980s were really three categories of men those who had congenital or genetic issues like Klinefelter's men who had pituitary tumors which interfered with LH release which again is what stimulates testosterone or men who'd lost their testicles to cancer or trauma and the big fear was if we give testosterone to these men their kin they may have cancer it may grow or it may cause cancer and this was the view that I learned and that all of you probably learned the same testosterone was essentially the devil when it came to prostate cancer I learned that prostate cancer was caused by androgens I learned that high testosterone caused rapid prostate cancer growth I learned that low testosterone is protective right that eunuchs were never supposed to get prostate cancer and if you ever hear that of course you have and did if a physician were foolish enough to give testosterone to a man with an existing cancer it was like pouring gasoline on a fire or feeding a hungry tumor anybody have refused those expressions we all have right I mean I did too I taught all my residents and medical students then for years but because of my experience with the lizards and I was doing sexual medicine we didn't have much to treat these guys with right cialis viagra they weren't around and I was just curious and so I started checking testosterone levels in men when I came out of my training in 88 and I was surprised at how often the levels were low and then I started treating these guys with what was then the standard treatment which was an injection of testosterone subpoenaed every four weeks and these guys came back and they said doc this is great my libido is improved my erections are better I'm better in ways you never even told me might happen like what well my wife says I'm nicer to be around I have more patience for my kids I wake up in the morning I put my legs over the side of the bed and I have a sense of optimism about my day I thought that was interesting but I thought maybe this is probably a placebo effect so because the guys knew they were getting the male hormone testosterone but what convinced me this was real was that several of these first guy said to me so that's how I feel for the first couple of weeks after the injection but you're giving me an injection every four weeks and for a week or two before my next injection all my symptoms come back what's up with that doc and I didn't know so we checked hormone levels and it turned out that the first two weeks levels are nice and elevated testosterone and with testosterone 15:8 every single guy was back to their baseline low levels of testosterone by 14 days so there was no way the patient's knew that I didn't know it it was a bad version of a double-blind experiment where the patient doesn't know and the doctor doesn't know but what it said to me is that the men could tell when their levels were good and they could tell when they dropped almost to the day so this was real and I started doing more and more of this work and I thought it was interesting it defied standard practice at the time because these men didn't have pituitary tumors they didn't have Klinefelter's they had two testicles and that was all pretty interesting and I was excited and I started doing more and more of this but again the big fear was prostate cancer and we were finding out then late 80s early 1990s that there was a lot of occult prostate cancer around race remember all this stuff guys who were in studies guys died in motor vehicle accidents army studies military ones and so the fear was that if I was giving to these men maybe I was doing a deal with the devil that they may feel better now but their prostate cancers were going to grow some of them must have it and and oh my god maybe something bad was going to happen so I started doing prostate biopsies in men who had low testosterone who I thought were candidates for treatment even though their PSAs were normal less than four and they had normal digital rectal exam I wanted to make sure as best I could that they didn't have a hidden cancer that was going to grow like crazy right gasoline on the fire and remember back then that low testosterone was believed to be protective these guys should have had a vanishingly low rate of prostate cancer these are the days of sextant prostate biases and in JAMA 20 years ago now we published what I think is really the first [ __ ] in the armor of the old story that high testosterone is bad low testosterone is protective because we found a lot of cancer in these men array to 14% it was really similar to men who are at risk because of high PSA so this is a figure from the JAMA article this was the rate of cancer in our men was 14% this is a group of studies from around the same time of biopsies in men who had normal PSA less than four and that rate of cancer was between zero and four and a half percent and then these are rates of cancer and men who either had an abnormal digital rectal exam here's doctor stones here's one from kettle on either abnormal digital rectal exam or abnormal PSA and those rates here were between 13 and 20 percent and I would suggest to you that this number looks more like these studies where there's a risk factor than these studies whether or not and so the concern was actually maybe low testosterone by these are sexton's biopsy results this is why these numbers are lower than what we might see today so that was interesting and so I no longer believed after that that low testosterone was protective and we've gone on and published another series in three hundred and forty five men and that number is it important to keep in mind if you put a needle into the prostates of men who have a PSA less than four but low testosterone the chances are about one in seven that they're going to have cancer you'll find on your biopsy one out of seven now I want to do a little thinking experiment with you the rates of testosterone treatment is gone increased dramatically right it's like tenfold what it was back then and yet we don't have any epidemic of prostate cancer in men who are treated with testosterone if one out of seven men with a normal PSA but lo T has prostate cancer I don't know how many of you treat with testosterone but if you treat any number of men at all more than seven there's a good chance you're treating some men who have prostate cancer with testosterone and their prostate cancers untreated frankly it's undetected right you haven't biopsy them because their PSA is low so I no longer believe that low testosterone was protected but I still believe high testosterone was a problem until 2004 when we wrote this article that that meal was kind enough to show some of the references in his talk this was on the risks of testosterone therapy new england journal together with my fellow in annie Roden now the timing of this is interesting too so the first branded popular testosterone product came out the United States in 2001 that was the gel I hope you don't mind if I use the brand name is just so you guys know what it was was andrew gel and really changed things 2002 was when the Women's Health Initiative came out so there were concerns about hormone therapy and women and so this is 2004 increasing sales of testosterone doctors for the first time are getting information they're getting detailed about this from reps so what are the risks of this therapy we focused a lot on State cancer and earn any yzma it was my fellow he's now a very prominent urologist in Brazil and very confident young men and we reviewed a few hundred articles and we're ready to draft this manuscript and her nanny comes to my office and he says chief he looks nervous do you have the articles that show that testosterone is bad for prostate cancer I said her nanny I thought you had and what we found in published 2004 is that the number of articles in the PSA era that showed something worrisome about testosterone therapy or just higher naturally-occurring testosterone levels and prostate cancer the number of articles we found with zero it's not that there weren't articles they just couldn't find it and it's fascinating to go back now and you read some of these articles a lot of them are sort of by public health people these large population studies and in the conclusions they say we don't know why we didn't find this obvious relationship but we didn't and we suggest the future studies look at ABC and then the next paper comes out says we looked at ABC we don't know why we couldn't find her relationship we suggest future studies look at XYZ it wasn't there so where did this idea come from because every medical student around the world was being taught that prostate cancer was related to testosterone levels high testosterone was dangerous low testosterone was protective so Paul Anka many of you know I was at a conference like this with him and I gave a talk after we've done that paper and I said you know we just can't find the evidence and he said you know a bit your stuff is interesting but you better be careful because maybe metastatic disease is different Huggins wrote that it was the testosterone was really bad so in the days before you could just pull up any article on PubMed he actually had to go to this strange institution called the library and which is where I went to find the original article by Charles Huggins 1941 Huggins of course wanted the Nobel Prize is the patron saint to be relevant she and and I found his article down there in the stacks and can'twe library and I read this article which great title its landmark article the effect of castration of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate this paper number one established acid phosphatase as the marker for metastatic disease and number two gave us the idea about androgens and and Caston number two castration or its equivalent medical was effective for metastatic disease and then the third is sort of an add-on in a way which is the testosterone added to these men was dangerous so I read through this paper and Huggins writes with Hodges that every individual who they gave testosterone to had rise in their acid phosphatase and that and by this time I'm treating a lot of men and I remember that moment my palms were sweaty oh my god some of my patients are going to come back with terrible prostate cancer Huggins said so and one of these moments where I forced my heart's racing I forced myself to reread this article I say how many men did he actually give testosterone to and it turned out they had only given it to three of these men with metastatic prostate cancer in the results section they only gave results for two men one of these men had already been castrated before I got testosterone and today we would call that a special case we would say that man was androgen deprived so in the end the general rule that we all learned and this is their quote that cancer of the prostate is activated by testosterone injections was based on only a single hormonal intact man who received testosterone for only 14 days and his acid phosphatase curves goes up and down it is uninterpretable this is their basis for medical students around the world learning the testosterone injections or testosterone therapy was dangerous for prostate cancer so what do modern what does modern evidence show this is a pooled data from a teen longitudinal studies over 3,000 men with cancer 6000 H matched controls you see quintiles therefore testosterone free testosterone DHT there's no relationship between androgen concentrations and the development of prostate cancer specifically men with the highest levels of testosterone or DHT or free testosterone all right no greater risk of developing cancer prostate cancer than men with the lowest levels it's not there the placebo arm of the reduced remember the reduced trial with doot asteroid but this is the placebo arm they received nothing these guys had testosterone and DHT levels measured at baseline and then as part of the study they had biopsies mandatory year two and year four what did it show prostate cancer risk was not associated with either serum clear DHT and men with high testosterone again had no greater prostate cancer risk than men with low levels meta-analysis of 22 randomized controlled trials over 2000 men no difference in prostate cancer rates for men who did or did not receive testosterone so the old idea that higher testosterone contributes to the development of prostate cancer is not supported by the current evidence and if you look back historically where you got this from it was actually based on the weakest of evidence and possibly misinterpretation of the author's own data and and so the question is like how does this all work then we know that if we deprive men of androgens there's important things that happen right so we we do androgen deprivation all the time with men with advanced disease but their studies of even giving LHRH agonist and men who are healthy and what happens to their PSAs and their prostate volumes they go down substantially right PSAs can become undetectable in healthy individuals no cancer makes sense really right finasteride DEET a stride drop the block to D H keep part not the tea part and PSAs go down by about half there's clearly a relationship but higher levels don't seem to be doing much of anything so I think part of the answer comes from data like this this is from a study in men really looking at muscle stuff but what they're looking at here for safety is testosterone these men were given an LHRH agonist so they make none of their own testosterone and then different groups were given different weekly doses of testosterone injections 125 is really kind of replacement dose we use a hundred but consider this sort of normal these are two lower doses and these give you super physiologic testosterone levels and if you look at the blue which is testosterone you can see that the higher levels here a thousand is top level for normal these guys here are more than twice the upper limit of normal okay for testosterone at twenty weeks four and a half months what's happened to PSA it's flat it's as if the prostate doesn't care how much high testosterone it's seeing and actually this makes sense because testosterone and many hormones work through their actions via receptors so these are three lobes of the rat prostate and what we're looking at here is the binding of trittye ated this is an androgen here that's used in studies doesn't bind to SHBG so it's useful for these studies and here's the free concentration if you look at the specific binding okay what you see is that as the concentration of this androgen increases the bound part to sex hormone binding globulin goes up I'm sorry to the androgen receptor not a CPG it goes up very quickly at the beginning and then plateaus goes up very quickly at the beginning and then plateaus goes up very quickly in plateaus once you get to a very low number here in the rat which is about two to three nano moles which is equivalent about sixty to ninety nanograms per deciliter in men pretty low we're done there's no more binding in humans the number is closer to about 250 and so from this we came to the idea of the saturation model in the past we thought if this is prostate cancer growth and this is CMT we thought that the higher testosterone went the more there was growth and it went on upwards and upwards to infinity but in fact it looks like it really plateaus in here and so it's true that prostate tissue cancer and benign needs androgens for maximal growth but it satisfied its ability to use those that nutrient if you will at a pretty low concentration and so at some point here this is within this range here we have variable dependent growth more testosterone more growth this is prostate cancer PSA but at some point here it stops mattering and this is a nice cartoon that's stolen from Tindall and rip master so imagine this is a prostate cell or a prostate cancer cell testosterone enters the cell is reduced to DHT DHT binds to the androgen receptor and then the complex gets translocated to the nucleus where it binds to androgen response elements and tells the cell to do whatever it needs to do that's androgen sensitive but notice that it's not testosterone alone coming in it's not DHT alone coming in it's not even the androgen receptor alone coming in it's the complex that's doing it and we only have so many copies of androgen receptor per cell and once these are all bound adding in more testosterone can't influence this mechanism anymore so in some ways you could say this is the molecular the molecular basis for the idea of saturation and here's a nice naturally-occurring model from Miriam Aggies lab 3,000 men seen for sexual dysfunction and all he did here is plot total testosterone against PSA and he's got this beautiful saturation curve right here which again it comes in around 8 animals per liter which is around 242 150 nanograms per deciliter I like to think of this as a flower as a plant in water imagine that testosterone is the water and the plant is the prostate cancer if you deprive the plant of water it will shrivel it will lose mass it will lose volume if it's still alive at this point and you water it it'll grow but once it has enough water you could have a garden hose running into this house plant 24 hours a day and that house plant will never grow to be the size of a sequoia tree because it's used whatever it can use from its growth from that nutrient if you will so saturation model is that at very low testosterone levels there's exquisite sensitivity of prostate cancer to changes in testosterone that's why you guys are trying to get in the guys who need androgen deprivation lower and lower testosterone levels but we have minimal or no sensitivity to changes at higher testosterone the androgen receptor becomes maximally bound with androgens at a pretty low androgen concentration and we when we do large increases of serum T it even turns out based on work by Lenny marks at UCLA that even the rise in serum T is not correspondent with Rises and intra prostatic androgens it appears there's some local homeostatic mechanism as well I just want to show you actually I'm going to skip this one so I think we're running late on time I'm going to skip this one as well I higher tea concentrations associated with increased risk of bad actors in prostate cancer and the answer is no as a matter of fact higher Gleason scores are associated with low testosterone levels here's one study and there's several like this this is low-grade prostate cancers Gleason 5 or less we don't see this much anymore but this is 2001 at least a 6 7 & 8 and above these are tips that mean testosterone levels and you can see that the Gleason aids and hires have low levels of testosterone compared to better behaved tumors what do we find in terms of pathology stage prognostic factors this is from andreas ellonija who works with my horsey in Italy in Milan 673 men underwent radical prostatectomy they had their blood obtained the day of prior to surgery for testosterone and low levels of testosterone defined as less than 300 were associated with a greater than 50% increase in high-grade Gleason score and a 91% almost a doubling increase in seminal vesicle invasion in men who had extremely low testosterone had a three-fold increase in seminal vesicle invasion so it's not high testosterone that's associated with bad prognostic features it appears to be low testosterone in fact we have a number of items that are associated with low testosterone and prostate cancer risk we have higher Gleason scores associated with low testosterone advanced stage at surgery there's data increased risk of recurrence after surgery and decreased survival all reviewed in this paper here sort of a master's review in European urology interesting for those of you who I have patients on active surveillance we put these data together from our group just looking at what factors would predict a progression 154 men and the two things highlighted is prostate cancer family history that makes sense right hazard ratio of 2.3 but a very low free testosterone was also predictive of progression low testosterone may be the issue not high testosterone so the paradigm has shifted we know there's really no evidence that high testosterone causes prostate cancer low testosterone is not protective and the current evidence is really consistent with a saturation model where very low concentrations there's clearly an impact on prostate cancer but the higher levels appear not to be and we're now worried I'm worried about low testosterone in men and so one of the things just to go back to it Neal was talking about with this hypogonadism screener is that I think it's men with low testosterone who need to really be watched and looked out four in terms of their prostate cancer if they have it the chances of them having a worse Gleason score and worse outcomes I think is real I think [Music] you

Channel: Grand Rounds in Urology

Views: 25,400

Keywords: Abraham Morgentaler, Scottsdale Prostate Cancer Symposium, SPCS, Grand Rounds in Urology

Id: _4Hd8JExDpI

Length: 29min 26sec (1766 seconds)

Published: Fri Jun 02 2017