Dr Morgentaler Clarifies Misperceptions of Testosterone and Heart Disease Risk

[Nelson Vergel]

I highly recommend watching this lecture.

The video is a recording of a lecture by Dr. Abraham Morgentaler, which took place on March 22, 2015, in Madrid, Spain, at the annual meeting of the European Association of Urology (EAU).

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, the first Men's Health Center in the US, founded in 1999 www.MensHealthBoston.com

Men's Health Boston is dedicated to the special health care needs of men. This includes testosterone deficiency, a common condition that causes sexual and non-sexual symptoms in men, and is associated with a number of general health conditions, such as obesity, diabetes, osteoporosis, and atherosclerosis. Men's Health Boston also offers state-of-the-art treatment to men with problems related to the prostate, as well as sexual and fertility issues.

Dr. Morgentaler pioneered the modern use of testosterone in men, and has over 25 years clinical experience in treating men with hypogonadism. He is actively engaged in medical research, and is the author of the books,TESTOSTERONE FOR LIFE and THE TRUTH ABOUT MEN AND SEX, and more than 150 scientific articles.

Dr. Morgentaler continues to have an active medical practice, sees new patients, and is in high demand as a lecturer. For more information, see www.DrMorgentaler.com

 

[Nelson Vergel]

LECTURE TRANSCRIPTION

Hello everybody, buenas tardes. I'm delighted to be here. I want to thank the organizers for inviting me. In case you haven't noticed, our 2 previous speakers, Professor Khera and Professor Jones have made really important contributions to this field. I hope that some of you appreciate that what you've been hearing at this session today has really been cutting-edge information that you should feel privileged to hear and you can take back to your communities. You may be one of the first in your area or your country to be sharing some of that information.

I want to talk to you now about an issue near and dear to my heart, which is about testosterone and some of the issues that have been going on. These are my disclosures. It's been an amazing year for testosterone.

In November 2013, came an article in the Journal of the American Medical Association that really, for the first time, in a major way, suggested that there might be increased cardiovascular risks with testosterone, mortality, myocardial infarction, and stroke. 2 months later, was an article in a smaller journal, PLoS One, that seemed to confirm the JAMA article. They reported increased risk of non-fatal myocardial infarction in men who receive testosterone. 2 days after that confirmatory or what appear to be a confirmatory paper, the Food and Drug Administration, the FDA in The United States announced that they were going to review the safety of testosterone. The European Medicines Agency followed suit shortly thereafter.

In the United States, the impact of this was enormous. Arguably, the most important newspaper in the United States, The New York Times, published an editorial that combined rising sales with testosterone with this information from the new papers and suggested that testosterone was being oversold and that it was dangerous. The danger was because of the cardiovascular risks.

On television, in newspapers throughout the country, we saw headlines that testosterone is linked to higher heart disease. Maybe an American phenomenon, more than anything else, the lawyers got involved. We had advertised, on prime-time television, every night, advertisements from lawyers saying, "Did you have a heart attack? Did you have a stroke while on testosterone? Call us." We now have class action suits in the United States related to testosterone use.

The impact of these 2 studies has been remarkable. It has absolutely changed medical practice. We have patients who have been on testosterone for years, without any trouble and with significant benefits, who have stopped it because they were afraid they're going to get a heart attack. I've had patients that I've treated for years, where their cardiologist called them and said, "Stop it immediately. You're going to die of a heart attack." Moreover, physicians who prescribe testosterone in their communities were sometimes seen as, "Really? You do that stuff?"

These papers have altered scientific concepts. It is no longer possible to have a testosterone discussion at a scientific meeting without discussing cardiovascular risks. This is completely new, and we have a new area of medical malpractice.

One would hope that studies that have had such a major impact would represent important, solid research, but it's not so. I'm going to show you a little bit about those studies.

What's really interesting and what I'd like you to be thinking about, as I go through this talk, is how is it that we, as physicians or healthcare providers, begin to form our opinions about what is safe and what is dangerous, what is useful and what is not, and what are our influences? I would suggest to you, it may not be what you have always thought it was. In fact, I would suggest that what we have is something that I call hormonophobia. I thank Professor Bruno Lunenfeld for this term. I think it's perfect.

What's a phobia? Definition of a phobia is a persistent, irrational fear of a thing or a situation despite awareness or evidence it is not dangerous. Everybody has phobias or many people do. Fear of spiders-arachnophobia. Fear of heights-acrophobia. What is hormonophobia? I'd like to define it as this. A persistent, irrational fear of sex hormones that includes testosterone and estrogen despite evidence to the contrary.

Let me just tell you a little bit about my perspective. I am what you might call a testosterone lifer. I've been working with testosterone for 39 years, beginning when I was 20, 21, working with these lizards, Anolis carolinensis, looking at the influence of hormones, especially testosterone and estrogen on male sexual behavior. I published my first paper in 1978. Ever since then, testosterone has been really a central area in my thoughts. I've been paying attention to this as a primary interest. What I've seen over these 40 years is something, which is the testosterone is unlike almost any other scientific topic. It creates passions and emotions from individuals who are otherwise rational, cool, calm, and collected.

Our first difficulty was really around prostate cancer. Professor Khera, just a few minutes ago, described some of this. Essentially, all of us, who were trained more than 5 years ago, learned that high testosterone caused prostate cancer or contributed to it. Low testosterone was supposed to be protective. I learned that eunuchs were supposed to never get prostate cancer. Not true. Almost everybody here learned that if you raised testosterone or you gave testosterone to a man with an earlier history of cancer, that it was like pouring gasoline on a fire or feeding a hungry tumor. Professor Khera has gone through the data. There is no evidence for any of this, and yet we have believed it as an axiom of medical oncology.

Dr. Khera showed this slide. The number one concern of physicians in many countries has been prostate cancer. The most amazing thing for me is as the concerns of prostate cancer have diminished, as the evidence has come in that maybe it's not so dangerous ... We even treat some men with prostate cancer with testosterone. Just as the fear has been coming down, all of a sudden, we have a tsunami of worry about the hearts.

I want to talk to you a little bit about what those studies were that have raised these concerns. Because once we understand something in-depth, we know what its strengths are and its weaknesses.

This is the second of the studies. This is by Finkle et al. Its strength that was reported in many media stories was that it looked at a huge population, 55,000 men, but what was it? There was no chart that was examined for these men. This is a beginning of big data studies which you've heard of. They had 2 pieces of information. They have a diagnosis code, which physicians put down in the United States in order to get paid. There's a code that we use for myocardial infarction, and they had prescription data. They were able to match prescription data with codes for myocardial infarction. There is no information of this study about any clinical information at all. Not prior history of MIs. Really? Not smoking, not obesity. There are no lab results. Nobody even knew testosterone values.

What they did is they looked at the rates of non-fatal MIs, 12 months before receiving a testosterone prescription through the period up to 90 days after the prescription. The primary result was that there was a higher rate of MIs after testosterone prescription than before.

I want to show you. This is the design of that study. This is not an experiment. This is what really happen to people. It's looking at the charts afterwards. It's not like there's a time 0, and we follow people with and without testosterone. In fact, whatever happened is that the men who received the testosterone prescription here, they looked at the rate of MIs that followed the receipt of that prescription. They looked at the rates of MIs in the 12 months before the prescription. Instead of a study that starts here, the study here really starts here, and it goes in 2 directions. What I would suggest to you is that this period of time has nothing to do with this period of time.

This is real for rates of MIs after a prescription, but what's happening here? Every one of these men who received the prescription, it only happened because the doctor determined that it was all right to give a prescription. He had access to the information that came before. In fact, if this is a real rate of MIs after a prescription, what does this measure? This measures the willingness of physicians to prescribe testosterone to men who did or did not have an MI in the previous 12 months.

This is not an experimental study. The 2 periods have nothing to do with each other. The comparison, in my opinion, is meaningless.

Even if you believe the study by Finkle et al, how big was the magnitude of the risk that they described? They reported 1 extra myocardial infarction per 1,000 person-years of exposure from testosterone. What does this mean?

One of my favorite lines was from one of my teachers, a brilliant man, Alan Retik, chief of pediatric urology, he liked to say, "I'm just a simple country doctor." Well, I'd like to suggest that I'm just a simple country urologist. For me to understand statistical terms, I have to make it meaningful to me.

I created this slide to share with you how I understand person-years of exposure. Imagine, a man in 2014, applies testosterone for 10 years. That's 10 person-years of exposure. 20 years later, if his son decides to use testosterone for 10 years, we now in this family have 20 person-years of exposure. If the grandson, 20 years later, uses testosterone for 10 years, in this family, we now have 30 person-years of exposure and so on.

If this is true in a family, where in every generation, 1 son uses testosterone for 10 years, how long will it take until we see that one event, non-fatal MI, it will be 100 generations, 2,000 years. It will be the year 4014. All of our families and descendants will be living in spaceships. This may be statistically significant, it is clinically meaningless.

The first paper, the one that really caused all the trouble, is this paper by Vigen et al from JAMA. This was a retrospective study that looked at 8,700 individuals in a data set that was consisted of men who had had coronary angiography. They selected out of that population of men. That's where they got the data. They selected men with low levels of testosterone. Some of those men went on to be treated, and some were not treated. Those were our 2 groups, testosterone-treated and untreated, amongst men who had had coronary angiography, looked at retrospectively.

This is a quote from the abstract that gives the results. The key item that was reported in every news and medical journal was this. "The absolute rate of events was 19.9% in the no-testosterone therapy group versus 25.7% in the testosterone therapy group." This was at 3 years after coronary angiography, except this isn't true.

If one takes the numbers here, 7,486 patients who did not receive testosterone, and you look at the events they looked at, this many died, this many had MIs, this many had strokes, and you add them up and divide by the number of men, which is what absolute rate of events is, was 21.2% in the no-testosterone group, 10.1% in the testosterone group. I'm going to say it again because it is not a mistake. Real numbers, real absolute rate of events. The numbers of men who had an adverse cardiovascular event was half as much in the testosterone group as in the no-testosterone group. How is this possible?

The answer is that the authors of this study made a mistake, even though they're statisticians and epidemiologists. It was not an absolute rate of events, which all of you will appreciate, is our sense of what really happened. Real events, real number of people, divide it, get a number. What they used was a statistical methodology that has never been published before for reporting of data of this type called stabilized inverse propensity weighting applied to Kaplan-Meier curves. Within 1 week of publication of this paper, this was pointed out by me to the editor of JAMA. The authors revised their paper. They no longer said, "Absolute rate of events." It became cumulative estimated percentage of events by Kaplan-Meier curve, which sounds very statistical because it's very statistical.

As if that weren't bad enough in response to a challenge about why the authors had excluded 1,132 men, the authors wrote, a few months later, that they had reviewed the 1,132 men and they had made an error. When they looked at the data again, it was no longer 1,132. It was 128 men, which is a difference of over 1,000 individuals. They took 900 of these and they put them in a completely different category, and then oops. They also discovered that they had 100 women in this group, which represented 9% of the total. Imagine, for a second, if you saw a breast cancer study, which mistakenly included nearly 10% men or a prostate cancer study that had nearly 10% women. Would you believe it? The authors stand by their results. The JAMA editors stand by the paper, but it's a little bit like this girl saying, "My room is clean."

In response to these papers and the impact it had on our patients and on science, a group of us formed what we call the Androgen Study Group. The individual members are Andre Guay, who, unfortunately, we lost this past year, Professor Khera, Professor Martin Miner, and Abdulmaged Traish, and we had some assistance from Monica Caliber. Our goal was to try and promote accurate reporting of these studies.

We did a number of things. When it became clear from the authors of the JAMA paper that their data included nearly 10% women and errors of over 1,000 individuals, we circulated a letter to our colleagues around the world, suggesting that the paper should be retracted, that there had been gross data mismanagement and contamination, and the study was no longer credible. Within a very short period of time, some of you in the audience are included, more than 160 distinguished researchers and clinicians signed this. We had more than 60 full professors, 8 emeritus professors, journal editors from 32 countries, all signing on to suggest that this article should be removed. Not because we disagreed with it, but because the data were no longer anything that could be trusted as being accurate, even if we disagreed with the methods. We got some press over this and put out press results. Within another couple of weeks, we had 29 medical societies that joined with us in this.

I just want to read it just because I think it's fun to see the breadth of this. American Society for Men's Health, Brazilian Society of Endocrinology, Canada, Europe, Germany, Indonesia, several international societies, Italy, Japan, Korea, Malaysia, Mexico, Middle East, Russia, South Asia, Singapore, Latin America. Truly, this was a global repudiation of this article. How many of you know about this if you didn't sign it? You don't have to put up your hands. The answer's probably very few of you.

The original story gets the headlines, and then it carries on and has a life forever. Yet, the data that we saw is completely contradicted by a body of evidence that has been accumulating for 20 to 30 years.

Professor Jones showed you one of his studies in a diabetic population of treated versus untreated men with testosterone. The treated men had a mortality that was half of the untreated men.

This is a second study from the VA system in the United States, by Shores and co-workers, that shows exactly the same. Over 1,000 men over the age of 40, low levels of testosterone, mortality was 10.3% in the treated men, 20.7% in the untreated men. If you look at a meta-analysis of testosterone and cardiovascular risk, 75 randomized controlled trials, we see no increase of cardiovascular risk with testosterone rather there was a protective effect amongst men with metabolic abnormalities with testosterone treatment.

Numerous studies have shown that low testosterone is associated with increased mortality, all-cause mortality and cardiovascular mortality. Low testosterone is bad and yet no one can show that high testosterone is also bad. It's all about low testosterone.

In a submission that we gave to the FDA, as it reviewed these data around cardiovascular risks, and also to the European Medicines Agency, we tabulated some of this information. When we looked at studies, looking at mortality, which we've just reviewed some of this, incident of coronary artery disease, severity of coronary artery disease, carotid plaque/intima-media thickness, these are intervention, these are observation, fat mass and obesity, glycemic control. At that point, the score, if you will, versus beneficial studies compared to harmful studies was 46 to 0. This isn't equivocal. This isn't, "Well, it's a little bit this way and a little bit this way." In fact, the data has been accumulating in a solid, repetitive, uniform way that testosterone therapy improves risk factors, as we know it, and low testosterone is associated with mortality and the presence of risk factors.

We took this work and we put it into a publication, which just came out about a month ago, in Mayo Clinic Proceedings. The conclusion of our extensive investigation of this issue was this. "In summary, we find no scientific basis for the suggestion that testosterone therapy increases cardiovascular risk." We didn't say it wasn't true, but we couldn't find the evidence for it. "In fact, as of this date, we are unaware of any compelling evidence that testosterone therapy is associated with increased cardiovascular risk. On the contrary, the weight of evidence accumulated by researchers around the world over decades clearly indicates that higher levels of testosterone are associated with amelioration or improvement of cardiovascular risk factors and reduced rate of mortality."

We did something that was different than what most doctors are used to. We got really active. I want to talk to you for just a moment about this. We submitted something to the FDA. We submitted our analysis to European Medicines Agency. Our group presented to the FDA. We put out press releases. We did a comprehensive review.

For those of you who are interested, by the way, in our work, and you want to see PDFs of all these documents, you're very welcome to and the website is here, AndrogenStudyGroup.org. Our documents are there and you can see a newsletter.

Why do we do this? I will tell you straight away. It has caused each of us a certain amount of difficulty because we are labeled as being pro-testosterone that we are doing this for the benefit of the drug companies. I can tell you that the Androgen Study Group receives no and has received no payments, whatsoever, or any financial support. Several of us have received payments for research and advisory boards and consulting independently and others have not, but our group does not. We do it because we think that it's important.

I want to show you what the regulatory agencies have done. Before the FDA came out with its final report, it actually published the analysis. It said about the Finkle study, "It is difficult to attribute the increased risk for non-fatal MI to testosterone alone." About the Vigen study, the FDA writes, "Given the described limitations of the study, it is difficult to attribute the reported findings to testosterone treatment." EMA, "Taking all the data into account, the signal for an increased cardiovascular risk associated with the use of testosterone remains weak and inconclusive."

Nonetheless, just this month, the FDA announced it would require the addition of a warning to testosterone labels that treatment may increase the risk of heart attack and stroke. Some people have said, "Well, it must be true then." I want to suggest to you that the role of regulatory agencies is not to govern physicians or to insert or replace clinical decision-making. Regulatory agencies are created to protect public health. They regulate the pharmaceutical industry. It is never intended to regulate MDs. The FDA says so itself, as does the European Medicines Agencies. We see warnings to labels all the time without the need for definitive evidence.

Here's one question I want to ask you. Why do we believe these things? I show you a score of 46 to nothing, and yet 2 papers very flawed come up, and all of a sudden, everyone believes that testosterone is dangerous for cardiovascular risk. I'd suggest to you that once we have a dominant idea in the media or even in medical media or medical thinking, it is almost impossible to change it for many, many years. Huggins and Hodges wrote, in 1941, "Testosterone activates prostate cancer." Dr. Khera has shown you all the reasons why that's not true.

The title of this talk includes the term "hormonophobia," which I would include estrogens. In 2002, the Women's Health Initiative came out. Everybody learned that estrogen increases breast cancer risk as well as other risks, and yet the WHI, Women's Health Initiative, published a follow-up in 2013. It reported in the estrogen-alone versus placebo, breast cancers were reduced by 21%, statistically significant. The estrogen and progesterone-alone had a little bit more, so maybe progesterone is an issue. Estrogen is not, and yet nobody seems to be aware of this fact. It is repeated over and over and over again, as if it's true, that estrogen increases breast cancer. Not true, at least, not by this study.

We think and we talk a lot about evidence-based medicine. I suggest we often practice media-based medicine. Why? Because we don't have time to read all the articles. We defer to trusted sources. We believe, if something is published in a journal like New England Journal or JAMA, it must be true. The methods are so complex. A few of us can understand it anymore such as stabilized inverse propensity weighting. The media works hand in hand with the journals to make the most controversial stories a sensation. It increases impact factor for the journals, and the media likes it as well.

I know my time is late. I just want to leave you with a thought. There's something different between belief or opinion, if you will, and what I call considered judgment. Belief is an opinion. It's often superficial. It often comes from our own preassumptions of what may or may not be true. Whereas considered judgment comes from an in-depth knowledge of a field, including strengths and weaknesses of the evidence.

I think the testosterone story has been a mess because it is full of belief, and many of those beliefs have been mixed up with issues that are non-scientific. We have feelings about anti-aging medicine in the way testosterone has been promoted. We have anger at the pharmaceutical industries or some do about their profits. We have anger at direct consumer marketing. All of this seems wrong. This has nothing to do with the scientific question of whether testosterone may be beneficial for men who are deficient or whether it increases cardiovascular risks.

These are my first principles that impel me to do whatever it is that I want to do. Number one, what is scientifically true. Number two is what is best for my patients.

How do we confront hormonophobia? I think the answer is we present the facts and the evidence as calmly as possible. We separate out scientific issues from non-scientific. When we hear misinformation, we correct it with the facts. Here's the scary part. Sometimes, it may be worthwhile to speak out when the science has been hijacked by non-scientists and when the health of our patients has been compromised.

I can't say it any better than this. I'll leave you with this quote by Galileo Galilei. "In questions of science, the authority of a thousand is not worth the humble reasoning of a single individual." Thank you very much.