The Negative Impact of Testosterone Treatment

Dr. Ryan P. Terlecki presented “The Negative Impact of Testosterone Treatment” at the 26th Annual Perspectives in Urology: Point-Counterpoint, November 10, 2017 in Scottsdale, AZ

How to cite: Terlecki, Ryan P. “The Negative Impact of Testosterone Treatment” November 10, 2017. Accessed. https://dev.grandroundsinurology.com/negative-impact-testosterone-treatment

Summary:

In the second part of the Point-Counterpoint debate on whether or not testosterone treatment is safe and effective, Dr. Ryan P. Terlecki, MD, FACS, argues against the blind use of testosterone treatment as a method to treat prostate cancer and highlights some of the potential dangers and risks of testosterone treatment.

View Dr. E. David Crawford’s Counterargument on Testosterone Therapy

The Negative Impact of Testosterone Treatment

Transcript:

Let me just say that this is supposed to be fun, right?  It’s a debate session and I just want to tell you I have the upmost respect for Dr. Crawford, and also for Dr. Morgentaler and Dr. Khera who the three of them have published collectively.  But if I wasn’t assigned the con side of this argument, I probably would have declined to present the pro.  And I’ve given that pro talk, and maybe he feels Matt’s talk was balanced earlier.  I’ve given that same talk and discounted these articles in cardiovascular risk for the same reasons he tried to present to you because I’ve seen Abe do it, Mo do it, and I was just at the session of medicine society and when I asked questions about recent data, showing a problem, they weren’t addressed.  They were dismissed.  But you’ve got to be careful, a lot of these meetings are funded by companies that supply these products.  Look at the COI, it matters.  Everything I’m going to tell you today I believe, okay?  And I think it’s important for your practice.  I don’t disagree with a lot of what he said.  I think that having an optimal testosterone may improve the reliability of PSA.  It may be beneficial for cancer.  I don’t think testosterone causes cancer.  I don’t.  So I believe he was right on, but the debate is if it’s safe and effective, and you’ve got to think about it for your practice.  And so I’m going to highlight quality data, because a lot of the data that they keep dismissing for its methodology and then they want to site meta-analysis of trash, of garbage studies as being valid, but all they are is a meta-analysis of trash.  So let’s get into it

How many of you have seen Indiana Jones Last Crusade?  A lot of you, right?  Remember the whole quest for the Holy Grail? The Cup of Christ?  Immortality.

So a lot of these guys coming in, they want to feel young again.  I can’t believe some of the advertisements.  Are you feeling older?  Yeah, I am feeling older, I’m getting older.  You know what I mean? So the whole reason Florida was discovered was because Ponce de Leon was looking for the fountain of youth.  You’ve seen these pictures, right?  You remember the BALCO scandal, all these guys getting busted for testosterone doping for performance enhancement.  It’s running ramping.  Guys are coming into your office because Jose Canseco told them they needed it.  Al Sharpton’s on the radio talking about it.

Is it the Holy Grail or is it Pandora’s Box?  Well, it was first used clinically in the 30s, two years after its Nobel Prize winning discovery.  Now it’s nearly a $2 billion market, and the raw drug costs only 1% of the total, and that’s a better return than street drugs.  So in 2003, Institute of Medicine panel concluded there was insufficient evidence of benefit in older men and recommended a coordinated set of clinical trials.  No benefit established, so we need trials.  I’m not even going to go and criticize or even try to tell the benefits of the studies that were criticized.  I can make a case completely apart from them.  

So you heard about those four articles earlier from Matt Rosenberg.  You have two retrospective reviews of poor methodology.  I agree.  One meta-analysis with questionable studies and events.  I agree.  And one prospective trial with few major adverse cardiac events.  Also agree.  No problem.

So we heard about the New York Times editorial.  We heard about the Endocrine Society warned against using in older men for coronary artery disease, we heard that this morning.  And then the FDA announced plans to review safety.  And of course the plaintiff attorneys were looking for cases of heart attack and stroke for class action suits.  

These are all over the Internet.  If you haven’t seen some of these guys in practice, you might, especially if you’re someone that’s prescribing a lot of testosterone.  And remember, a lot of the guys you hear, advocating for this, run practices where that’s all they do.  They don’t operate, all they do is provide testosterone.  Similar to your injection clinics that you may be competing with.

You have to make an informed decision.  So to know that you can choose wisely, think back to the movie.

There were seven T trials that were initiated, and they were to establish benefit rather than risk.  That doesn’t seem to make sense, right?  When you want to know whether it’s safe before you go studying it for benefit.  The answer is no, because it takes a lot more time, a lot more funding to do the studies as it relates to risk.  First you have to know if it’s even with exploring.  So they did a physical function trial; sexual function; vitality, looking for fatigue; cognitive function, the anemia trial looking at hematocrit hemoglobin; bone trial looking at density; and the cardiovascular trial as it relates to plaque volume.

What’s the number one killer of men?  Heart disease. So that’s important.  Probably a lot more important than prostate cancer.  So for these trials to enroll, men had to qualify for at least one of the three main trials, sexual function trial, physical function trial, or the vitality trial.

Looking at their baseline Cunningham published this, and looked at the baseline measures, and this was based in 12 sites in the US.  Free and total testosterone was not associated at baseline with measures of vitality or physical function in symptomatic older men with low T qualifying for these trials.  Now remember, this is level 1 evidence.  The other stuff that was said to you for benefit was not, mostly retrospective, especially when they keep trying the studies by Molly Shores [phonetic] in the VA population.  You’re not going to hear this talk anywhere else, so feel free to stop me at the end or for the panel discussion.

Looking at the vitality trial, physical function.  Testosterone replacement has no significant benefit for vitality based on the main questionnaire that they used.  That was the Tasic [phonetic] questionnaire.  There was no significant improvement in activity from testosterone replacement in the physical function trial.  However, I will acknowledge that if all three trials were pooled, there was an increase in the 6-minute walking distance.  There were four cases of prostate cancer, three in men on testosterone replacement, but it wasn’t powered to assess this.  So we’ll leave that one alone.

What about sexual function?  Nearly 800 men, we’re looking at senior citizens with a level below 275 ng/dL and having symptoms.  They either got a placebo gel or the testosterone gel for a year.  And it was designed to achieve levels consistent with what was felt to be mid to normal for guys between the ages of 19 and 40.  And it was associated with significantly increased sexual activity, sexual desire, and erectile function.  Sounds like a homerun.  It’s not.  The improvement was modest and less than that reported from phosphodiesterase inhibitors,  2.64 points on the full-length IIEF score.  And you remember from an earlier lecture, to keep this in perspective.

Basaria, who had earlier studies too.  We had talked about the TOM trial, and these older guys, bench pressing and all these super high doses of testosterone.  They have something called the TEAMM trial as well which came out.  This is separate from the T trials.  We’re just adding it here for additional information.  Testosterone did not significant improve erectile or ejaculatory fiction, sexual desire, partner intimacy, or health related quality of life.  Consistent with meta-analyses of older testosterone trials.  So we have current data suggest there’s a minor benefit.  You can see a lot of the other data suggest there’s no benefit, so at best, minor in the sexual realm.

What about cognition?  I heard Dr. Morgentaler and a lot of people before these trials came out saying, it might help visual spatial skills and cognition.  Maybe we could use it in patients with Alzheimer dementia, it sounds great.  Again, looking at the same number of guys, same methodology, almost 500 with age-associated memory impairment, no benefit.  

These were the endpoints.  Going back to that TEAMM trial update.  Again, 2016, testosterone replacement for three years to range old levels to young levels, no improvement in cognitive function.  Absence of effect was evident across all domains of cognition tested.  Concluded testosterone to improve cognition in older men with age-related decline, not justified.

What about bone health?  We talk about improving bone density.  Estrogen, think about conversion, we talked a lot about physiology earlier this morning.  So 211 men, again in the T trials, published in JAMA.  Volumetric bone mineral density was assessed in both the spine and hip by CT scan at baseline, and again at one year after therapy.  And they saw a significant increase in both locations.  Okay, so it increases bane density.  Not tied to any clinical benefit.  But let’s say that’s a positive.

What about anemia?  Those of you that are giving BL, now you should follow up on the CBC.  Check the hematocrit.  If it gets hemoglobin above 18 a lot of times, which is multiplied time 3, 53 in hematocrit.  If it’s too high, maybe you have your patients giving blood.  Maybe you give them a holiday.  Maybe you’re doing something else.  The main outcome measure in this study was the percentage of men with unexplained anemia, with a hemoglobin rise of a gram or more at one year.  Okay, so testosterone did better than placebo.  No surprise.  Was there a clinical benefit toed to this race?  No.  But again, the argument of performance enhancement by raising testosterone go back to the Lance Armstrong pictures and so forth.

What do we know about raising the hematocrit?  What about in the guys that come in with normal levels, and you’re putting them on it.  Well, there’s a TAMRISK study, it’s was a Finnish study looming at 670 men, over the age of 55 followed for 28 years.  And they looked at those with hematocrit below 50 to those with or higher than 50.  Those with higher hematocrit were 2.4 times more likely to die from coronary artery disease, and that was significant.  After adjusting for the established risk factors, it remained significantly high, 1.8.

So this is the bug one.  And this is the one that Matt touched on briefly and then started to criticize.  This is the best designed study out there for this.  And these were the studies that were designed to answer these questions, and decide if it’s even worth doing a men’s health initiative like they did for women.  The hypothesis was that testosterone would slow progression of non-calcified coronary plaque volume.  And that’s the bad type.  And so they had a CT angiogram at baseline given at a year and there was actually significant increase in those men receiving Androgel relative to placebo.  No major events but it weren’t long enough and it wasn’t designed to follow them for that.  But this degree of coronary luminal narrowing in 12 months is unprecedented.  It’s been called an unprecedented drug effect and it appears ominous.  Can you imagine getting a drug to market right now if you showed a significant increase in coronary plaque volume in only one year?  

But these are some of the things they say.  Those were older men and the testosterone group was worth at baseline.  I heard this at this year’s SMS.  Remember the levels of evidence when you’re comparing data.  Let me take you back to my childhood.  I was born in the 70s, and I grew up largely in the 80s.  

You know what I liked?  I like pro wrestling. Macho Man Randy Savage snapped into a Slim Jim.  I love this guy.  Died at age 58, had a heart attack while he was driving.  He was a long-term steroid user.  I may hear you say okay, he was a little older anyway.  

The Ultimate Warrior, love this guy too.  Great moves, every Saturday morning, and he admitted to testosterone use and claimed he was rampant in the field.  Died at age 54, Mi due to atherosclerosis based on autopsy.  Still he made it to 54.

Chris Benoit. One of the four horsemen when they reinvented it.  It was awesome.  Died at age 40, killed his wife and his seven year old son before hanging himself and was found to have 10 times the normal testosterone level.

His best friend, Eddie Guerrero.  Died at age 38, atherosclerotic cardiovascular disease, and was outed in a Sports Illustrated report as a testosterone user.

The British Bulldog, Davey Boy Smith died May 2002 at the age of 39.  MI, autopsy report stated that anabolic steroids were causative.

Flying Brian Pilman, also one of the Four Horsemen, dead from MI at age 35, atherosclerosis.

Don’t be like these guys sticking your head in the sand.  These so called experts continue to support this.  But what if testosterone is one of the differences why our life expectancy isn’t the same as women.  You see these associations that he showed you as far as testosterone coming down and cancer going up.  But again, it’s guns and butter if you know anything about economics, and you’ve taken those lectures early in life.  Think about the women’s health initiative and the potential parallels as estrogen did increase the risk for stroke, and pulmonary embolism.  

Another wrestler, Rowdy Roddy Piper died a cardiac death with a massive PE.  Bret ‘the Hitman’ Hart you might have heard because he had prostate cancer.  He was picked up on that, suffered a stroke and was also diagnosed with his cancer subsequent to that.  So in the words of my kids, ‘just sayin.’

John Brinkley.  How many have read this book, Charlatan by Pope Brock?  Do yourself a favor, get a copy, it’s awesome.  

He was born in the 1880s in impoverished North Carolina.  He was called a ‘quack; and a “Snake-oil sales” and put ads in the paper saying, “Are you a manly man full of vigor.”  He injected colored distilled water, faked his medical degree, he got bailed out of jail, and took a job as a house medic at a meat-packing firm where he saw the mating habits of goats.

George Lydston and Sergey Voronoff were famous for implanting human testicular tissue or monkey gonads in elderly men to improve virility.  Brinkley took goat testicles and put it into a farmer who claimed a sex drive of full speed afterwards.  He goes to LA in the 20s, on Wilshire Boulevard to advertise, which was also name for a charlatan by the way.  

He built a radio station, it could be heard all over the world.  And was eventually exposed to, retreated to Mexico and created the most powerful radio station.  And by the end of the 30s, he had $12 million.  He was like the inventor of concierge care, but he had all these people believing that they could feel younger because he was going to out goat testicles into them.  

This is number three of my four kids.  Shay, he awesome, I love this kid, right?  But you know what he wants all the time?  

Candy.  Why?  Make him feel good, seems to have more energy.  But when it wears off, he crashes and then he craves more.  Sound familiar?  Long-term, presumably a risk of weight, presumably a risk of other problems.

But patients want it and you have Press Ganey score and online satisfaction to think about.  And giving them a prescription makes them feel you did something for them, so what’s the harm?  Does this sound like anything else?

Remember the Z-pack?  How many patients wanted this for their viral upper respiratory tract infection?  Sales were crazy, through the roof.  And then the following year the FDA warned ahead there was an associated risk of cardiovascular death, and now we have a lot of resistant bacteria.  

Well, they’re well informed, right?  So it’s okay if they have informed consent.  Well maybe their lawyer might not think so after their cardiac stent.  When they get those injections in your office that come out of the bottle, are they seeing that the FDA is requiring a labeling message, like they would if they got Androgel at home?  Probably not.

I see these guys all the time, clinic full of guys 45 to 50 years old, missing the glory days, needing the prior auth forms filled out.  Come in their Jesse Centura workout pants, huge I arms covered n acne.  Hairline running for the hills and their testicles look like raisins.  Touting their witch-doctor provided regimen of testosterone, hcg, arimidex, DHEA, and a garbage bag full of products from GNC, asking you to hurry so that they can get to their chiropractor.

So it’s the new normal.  They’re hoping for a less stigmatic solution to ED in most cases.  You might think that they’re there to treat hypogonadism.  A lot of these guys want better erections is really what they want.  So oftentimes, these may see minimal clinical benefit, but there’s potentially a placebo effect, but it doesn’t mean that they won’t suffer in withdrawal.  You get their levels up and then they don’t stick with these therapies very long.  And then what happens?  It bottoms out so it’s lower than where they started, and they go oh yeah, it was helping me.  But no, because I just made you worse.  

Like Janet Jackson said, “What have you done for lately?”  And for the GNR song, “I used to do a little, but a little wasn’t doin, so a little got more and more.”  That was in reference to cocaine, but you can see the relevance here.

So what are you chasing?  A symptom?  A questionnaire score?  Some arbitrary magic number on a blood test so you can convince a patient that they’re better and it’s worth getting the metal trocar in their rear every few months to slide in some pellets that, in case you’ve never looked closely, have glass shards attached to them, which is why risk management pulled it from my hospital.

There’s AUA resources on this, there’s a position statement that says, “Only FDA approved medication should be used.”  For the patients you’re probably treating, it’s off label.

In conclusion, no benefit for physical function; no benefit for vitality; no benefit for improved cognition; modest increase in sexual function early on; improved bone density and anemia but a potential risk for raising their hemotocrit; a potentially dangerous increase in coronary plaque volume which is never a good thing; and given limited efficacy from the T trials, public funding does not appear warranted to support long-term powered randomized trials for cardiovascular risk.

Remember how to be a good doctor lie we heard about earlier?  Give sound advice.  Weight loss; moderate to high intensity exercise which can drastically change testosterone one day to the other, that’s why you need two values early morning before you start therapy; sleep hygiene, I can’t tell you what a factor that is if you get people to sleep better, testosterone levels rise; reduce their stress; look for other things that can give them better energy; look at their diet.  

And maybe you too will help them to choose wisely.  Thank you.