Here is the transcript of his talk:
PART 1
Neal: ... Is Neal Rouzier and I wish to thank MedQuest Pharmacy for sponsoring this talk this morning. This is going to be 3 lectures crammed into one and I hope to provide for you the most important slide presentation and medical journal articles that you're going to get this entire conference. I will make these slides available to everyone. The last slide will give you that information to contact me and I'll be happy to provide these slides, and the slide presentation to you so that you too may use this slide presentation to your medical staff or anyone else you wish to speak to. This presentation, hopefully, will clear up some doubts as to why we do what we do.
I'm going to talk about a couple of myths this morning, myths that we always see and hear on a daily basis that are not necessarily supported by any good evidence-based literature or science or study, but yet we still do those things because someone once, or I heard somebody say once, "Well, my peers do that, so I must do it too." Nevertheless, what I'm about to present to you is evidence-based medicine to show you why we should what we do, and why we shouldn't do what we commonly do. This topic is going to be primarily for hormones in men, and related to testosterone, estrogen. Are they good, bad or indifferent?
This is the article that set the world on fire, which is the recent article from JAMA of November of last year that demonstrated that testosterone administration, although they didn't really guarantee administration, they guaranteed that they had a prescription for it; resulted in an increased incidence of myocardial infarction and death. This article has turned the anti-aging world on its head because we've got 40 years of others articles and studies showing just the opposite, but nevertheless, since this article appeared, our patients are very concerned about it because they see advertisements on the television at night that if you had a heart attack while you're taking testosterone "contact this attorney firm because we can get you the money you deserve because, what happened is, you had a heart attack and you took testosterone," which couldn't be further from the truth, but that's reality.
The critique of this article, and this is the lecture that I gave to my medical staff, and all my medical staff were concerned also about, "Well, what do we tell our patients?" In the discussion section of this JAMA article, it mentions that this is the only study that showed this adverse outcome, and it was in a select group of individuals. An outcome that we haven't seen in any other study, which is true. However, this was an observational study and all of the randomized controlled trials ... This was not a randomized control trial. All of the randomized controlled trials have shown the opposite outcome. Either no effect or protection against heart attacks.
Even though this article was profound in its statement, 4 years of other past studies, and articles, and randomized controlled trials do not show that. Since all of the studies show the opposite and one study does not negate all prior studies, and there were some definite biases in these studies, I will refer you to the third week ... Excuse me. The first week of March in JAMA, where the editorial comments criticized this article for the use or misuse, shall we say, of their study criteria. This is a perfect example of, if you torture the data long enough, you'll be able to prove anything you want. I will go further into those criticisms, but I suggest that we do not change anything that we have been doing based on one study that has significant flaws and biases.
We'll hear doctor Morgentaler talk about that too. When all of the studies in the past demonstrate protection against heart disease and stroke, and I have included about 20 articles from the literature in this talk that prove that. All of the articles to date, the randomized controlled trials, demonstrate improved longevity in those that are treated with testosterone, but increased morbidity and mortality in those men that were not treated with testosterone. Which group would you like to be in? If you really look at the other side of the coin, despite of the fact that you see advertisements on television for attorneys' firms looking to sue somebody because you had a heart attack with testosterone, I can take the opposite approach and say, "You have a significant increased risk of heart attacks, strokes and death if you did not take testosterone."
That's what the majority of the studies show and prove. A randomized controlled trial would have much more power than this observational study an all of these other studies were randomized trials. Also the problem with an observational study is it does not prove causation. It's an interesting observation but, as I'll get into later on, observation does not prove causation. An interventional study in a blinded fashion is so much more powerful and there are studies that are blinded and randomized controlled trials that prove that testosterone not only does not cause harm, but it protects against heart attacks and death. Therefore observational studies can't really prove causation as RCTs do. What we should take away from this study is what the researchers state in the last paragraph of the article.
That more studies are necessary before definitive conclusions can be made as to the cause and effect of testosterone causing an increased risk of MA. Also treatment decisions should not be based solely on one study that was negative, but rather on a trend of studies. Unfortunately the editorial comment section did not express this clearly. Just because one study shows a negative outcome does not mean that we should jump to conclusions based on that one study and throw about 40 years prior studies that show beneficial protection. Had this study been published years ago, 40 years, and all subsequent studies since then proved protection against cardiovascular disease, then this study probably would have been ignored and forgotten.
However, since it's a recent study, we tend to believe and reject all the past studies that show the exact opposite outcome. That's the way our mind works, unfortunately. We throw the baby out with the bath water, but we shouldn't do that. Nevertheless, one study does not negate many other studies to show opposite results and beneficial effects, so I will log this study on a negative slide for testosterone results, but it is only one such study on this slide besides the recent PLOS ONE study that was a very similar outcome. This is in contrast to all the other very powerful, much more scientific randomized controlled trials that showed benefits of testosterone administration.
I've put together a list of articles that I present to my medical staff, as well as to patients, as well as to other doctors, that demonstrate the various mechanisms by which testosterone is protecting the heart and brain against heart disease, against stroke, against dementia, and against plaque deposition causing arteriosclerosis that's causing that plaque rupture. If indeed, although we don't see this in 40 years studies, if indeed there was thrombotic mechanism to testosterone, then we could prevent thrombosis, just like in women, if we protected against the plaque buildup in the first place, which means if you administered testosterone to the world, we wouldn't have that plaque buildup that results in that plaque rupture.
The data in the literature is overwhelming in favor of a protective effect of testosterone in men. This recent study, although it's interesting and intriguing, does not change any of the evidence that I present, nor does it change my treatment strategies that I've been using for 20 years now. Until more studies demonstrate the same harm, I'll continue to follow the scientific literature that demonstrates benefit, and not follow one negative study that had significant flaws and biases in that study. As per the suggestion of the authors, they state that more studies needed to evaluate these results, and I agree.
I recommend to patients and physicians that they continue the same identical treatment based on all prior studies that show benefit in spite of the this one negative study. Certain statements deserve comment. The authors do note that other trials and other meta-analyses, studies of multiple studies, do not demonstrate adverse cardiovascular outcomes with testosterone administration. The trend so far in the literature has been a protective effects as the trials demonstrate that testosterone therapy improves a number of intermediate outcomes in cardiac risk factors. In the interventional trials, there's a decrease in heart attacks and also, in the interventional trials, we see all the reasons and beneficial effects of administering testosterone over the last 40 years, that provide protection.
The new JAMA study is the first and only study to demonstrate harm and should therefore be interpreted carefully in light of all the other studies demonstrating opposite results. In addition, the results of this study differ from a retrospective study that was done Shores et al. Same identical patient population group, same identical data set, same identical method of analysis. This showed a 39% reduction in mortality risk amongst patients treated with testosterone, which again suggest that we should use caution in coming to conclusions based on only this present study. An identical study 2 years prior to that came up with completely the opposite results, but that's how our brain works. Of course when our patients see those advertisements on television, they get scared.
Then they go, "I asked my doctor. My doctor scared me. He said I should stop testosterone." Different confounders and biases might account for the discrepancy that we see in this study. There's multiple limitations of this study that are noted by the authors and certainly by the critiques from the March issue of JAMA. All in all it's an intriguing study with unexpected results that are in dis-concordance with all of the prior studies and really, it should not influence our current therapy. It's one that really begs for more study. What about all the past studies, though? Should we ignore those? No. For those patients and physicians that are unfamiliar with the current literature on testosterone therapy, I've included several articles that I'll review for you on testosterone replacement therapy.
First are the studies that review mortality in men treated with testosterone compared to control groups. So far, in every study to date we see protection against myocardial infarction, protection against cerebral vascular disease, protection against all cause death including cancer. There's fewer heart attacks, cancer, and reduced mortality in men treated with testosterone in contrast to the current study. So many patients ... I shouldn't say so many. So many patients have considered stopping the testosterone because their doctor scared them, but the doctors are not aware of, nor are the patients aware of, the fear of heart attack, strokes, and reduction to all cause of mortality, even from cancer, that we seen in all these studies.
Other studies go on to prove that low levels of testosterone increase morbidity and mortality in contrast to men with testosterone levels at the higher quartiles. If you want to increase your risk of mortality, keep your testosterone levels low. If you want to protect against morbidity and mortality that we see as we age, then having higher levels of testosterone in every study have been beneficial and protective. Low levels of testosterone are predictive of an increase in all-cause mortality. That includes cancer. Why? Because of the decrease in visceral fat that see with testosterone administration and the protection against the insulin resistance that we get, so it's not just heart disease that we protect against. It's a multitude of other diseases and illnesses to. Where would you like your testosterone levels to be?
Where the majority of the literature shows better protection against dying or very, very low, where all the literature shows significant increase morbidity and mortality when you keep your levels low? Other articles demonstrate that all the physiologic benefits of testosterone administration were on cholesterol. It lowers the bad ones and it raises the good ones across the board. Lipoproteins. It lows the bad ones and it raises the good ones across the board. It improves insulin sensitivity. It reduces insulin resistance. It protects against diabetes. It lowers inflammatory cytokines. C-reactive protein, interleukin 6, tumor necrosis factor alpha are all lowered with testosterone. There's no drug that does that.
It protects against endothelial dysfunction in every study. It protects against plaque development and it also results in plaque reversal. There's no drug out there does that unless you use very high dose statins, but nevertheless there was quite a few studies in our literature showing that testosterone and estrogen result in plaque reversal. The current NAG study, the elite study giving oral estrogen to women, their in-point is carotid intima-media thickness. It's plaque reversal. What a great drug it is. If we could only come up with a drug that did that. Boy, it would sell like hot cakes, but we've got them, but we ignore them.
It protects against memory loss. It protects against Alzheimer's disease. It helps improve mood, cognition, energy, muscle mass. Fat mass is melted. It protects against osteoporosis and bone loss. It treats erectile dysfunction, sexual dysfunction, and is beneficial in decreasing all-cause mortality. Wow. I told my patients, "If you want to increase the risk of these things, then stop your testosterone, but if you want to protect against all of these things, then you should continue your testosterone." Patients will say, "But my doctor scared me. What I wanted to do is hear from you doctor, because I understand you, and I trust you, and I know you're expert in this. I just needed to hear it from the horse's mouth." Well, you too can help with your patients, cope with this stress that they're having, and if you want to increase the risk of getting all of these things, then stop the testosterone.
That's the risk that you'll take when you stop the testosterone, or if you don't take it in the first place. "But my doctor said." Your doctor doesn't understand. Your doctor doesn't understand this literature. Do you really want to stop the testosterone based on one negative study and risk all of these other things? I'm not and I don't recommend that patients do either. What are the consequences of stopping or not taking testosterone? That's listed in the first paragraph. Extremely important. Multiple studies demonstrate beneficial effects of testosterone replacement therapy on quality of life as well as disease protection. It's amazing the data from testosterone replacement therapy on reduction of body fat, insulin levels, insulin resistance, diabetes, inflammation and vascular disease that we tend to ignore.
It's such a great drug that's pretty much ignored by most of the cardiovascular world, which is really a shame. Testosterone serves to maintain health in every system of the body. Levels of testosterone in the low to mid-normal range are associated with an increase of illness as listed above. "Yeah, but the level is normal. You don't need to treat it because it's normal." Yes, but it's not optimal. There's a difference. I did it with an endocrinologist last night. He says, "It's really interesting that the endocrine world views hormone replacement as replacement." He says, "I don't replace hormones. I optimize them. There's a difference." Normal is not where you want to be. Normal is an average of a population.
If you want to be normal and die like everyone else, then keep your levels normal. If you want to protect against disease and illness, then you need to optimize all of your hormones. It was very refreshing to hear an endocrinologist make these statements. Don't forget, the pun is intended, the protection against Alzheimer's disease and dementia in every study to date. Why does testosterone protect against Alzheimer's disease? We'll get to that in a minute. I'm going to fly through these articles. I don't put these articles up here for you to look at right now, and write down the references and what they say. I'm just showing you all the articles that are available to you in the slide presentation.
All you have to do is contact me and I'll give you this presentation in PowerPoint so you can present to your medical staff, or to your patients, or whomever you want. This is a summary of these articles. I'm going to fly through them, but I'm going to make interesting points out of each one of those studies. This is a study by Shores et al recently done 2 years ago. It's an observational cohort of men with low testosterone levels. They got testosterone treatment and it was associated decreased mortality compared to no testosterone treatment at all. Completely opposite results. Same identical patient group and method of analysis, but completely different results.
Again, these are observational studies and you cannot extrapolate cause and effect from an observational study. You have to do a randomized trial to study that. Low testosterone levels predict an increase in all-cause mortality during long-term follow-up. Are there any long-term studies? Yeah, there's lots of long-term studies. There's also replacement in this study, improved survivals in men with type 2 diabetes. Endogenous testosterone concentrations at baseline are inversely related to mortality due to all causes. Cardiovascular disease and cancer. Low testosterone predicts mortality from cardiovascular disease.
Prevention of androgen deficiency improves cardiovascular outcomes so far in every study to date, except for the recent JAMA study. Low testosterone levels correlate with increased risk of cardiovascular mortality in every study. A lot of it has to do with the metabolic components associated with that risk. Low levels are associated with increased all-cause death, cancer included. It's not the same study. These are multiple studies basically showing the same effect. Deficiency in testosterone is associated with increased all-cause mortality. There's evidence that testosterone deficiency syndrome is associated with all-cause mortality particularly cardiovascular disease. Why do they do these studies and what should we get out of these studies?
Testosterone is an independent predictor of mortality in men. Where would you like your levels to be? It protects. It also protects against the plaque rupture as well as the plaque deposition. Another study. The lower the testosterone the greater the risk of all-cause mortality and cancer. Different studies. Men in the highest testosterone quartile had a 30% lower risk of death. Men in the lower quartile had the 40% more likely increased risk of dying. Where would you like your levels to be? Based on these studies it's almost malpractice to keep your levels low as opposite to optimal. The evidence overall particular from large recent studies points to testosterone having a pathologic role in cardiovascular disease, and there's no evidence of replacement increases cardiovascular risk. Every study, there's no increased risk of it.
Only protective effects. "Yeah, but that one study ..." One study does not negate 40 years of prior studies. Low levels are associated with all-cause mortality including cancer. If they're a predictive marker, where would you like your levels to be? Testosterone insufficiency is associated risk of dying over 20 years. This is a long-term study published in the Annals of Internal Medicine. In patients with heart failure, when treated with testosterone, there was a significant increase in exercise capacity. In addition to that, there's no significant adverse cardiovascular events in these studies. These are interventional trials. They're not observation.
They're interventional trials to show this. Major cardiovascular events have been studied. Low testosterone levels associated with a significant increased risk of major events. Low levels are independently associated with increased CHF mortality. Where would you like your levels to be? I find very few cardiologists on my staff administering testosterone because they're afraid of their peers. Well, that's out of my specialty. It's out of my realm, but yet that's all out of the cardiovascular literature. Concentration of testosterone is inversely associated with carotid intima-media thickness. Don't you think, doctor Cardiologist, that you would like to decrease that plaque? "Well, he's on a statin." I know that, but he's still developing plaque and all the studies will show you, but yet all these studies show there's a tremendous improvement in plaque deposition with testosterone administration.
"That's beyond my scope of practice." It's beyond your scope of practice to protect against cardiovascular disease? Quite a few studies showing the same thing. A decrease in all-cause mortality. Finally you get bored with this and say, "Wow, there's a tremendous amount of data out there supporting the use of it and a tremendous among of data showing that if you don't treat it, then you're increasing the risk of drying for multiple causes." That's the cardiovascular literature showing that, despite of the fact that some physicians and patients are misled to believe that testosterone is harmful. It's not. Interventional studies show protection. Long-term studies show protection. Low levels in every study to date are associated with an increased risk of morbidity and mortality. It's not harmful. It's protective. That's the first part of this lecture.
The second part of this lecture as to do with estrogen in men. I heard a couple of lectures yesterday allude to the reason that we're starting to see this increased risk of myocardial infarctions based on this one study. If you truly believe that study, which you shouldn't, when you go back and look at the study the criticism is, the raw data actually shows protections against heart attacks, but when they plug it into their statistical analysis formula, it shows an increase, but the raw data by itself shows protection against heart attacks. It's hard to conceptualize that, but that's what they did. Yeah, there's still a lot of people out there saying, "It's the estrogen." You read Life Extension. "It's the estrogen."
They didn't control the estrogen and we know that, since estrogen causes heart attacks in women, it must also cause it in men, so that's why you want to keep your levels low. How do we make that jump and that extrapolation? You cannot extrapolate. You should not extrapolate. Don't extrapolate. You have to study it. You have to study it to then prove it. You cannot extrapolate, but yet I hear everyone extrapolating, "You got to keep the estrogen low because it causes heart attacks and that's what we see in women." Okay. We've got 40 years of studies giving testosterone to men that raises estrogen levels. Please show me one study, I'm waiting, where raising estrogen in men is harmful. "That one study that showed that there's a high level of estrogen associated with heart disease." That's not what I asked.
I asked, give me a study where we raise testosterone. What you're quoting is an observational study. Give me one study where we raise estrogen in men, by either giving testosterone or giving estrogen, that results in harm. Okay, give me a study where we lower estrogen in men and has shown to be protective and beneficial. I'm waiting. You mean there aren't any? Then why do you lower estrogen? "Well, because someone said and this study here shows that in men, when the level is high, there's an increased risk of heart disease." Okay- Let me go through a couple of slides and explain to you the difference between observation, association and causation.
In order for you to understand the second lecture, you have to understand the difference between observation, association and causation. There's also this study. Show that premenopausal women with elevated testosterone levels are at increased risk of breast cancer. Do you give testosterone to women? Yeah, of course you do. It says right here that you're going to increase the risk of cancer in those women. Why would you do that? Why do you continue to give testosterone to women if this study shows that the high levels are associated with a breast cancer risk? The reasons associated with an increased risk of breast cancer is because that's what you see on premenopausal women with PCOS that have high testosterone levels. Yeah, that's what's caused them the breast cancer. No, it's not.
It's the insulin resistance, inflammatory cytokines in the visceral fat that are increasing the risk of breast cancer and uterine cancer. "Yeah, but there's an association." Does not prove causation. How do you prove causation? You study it. In part two, the course that I teach on cancer, every study to date, when we administer testosterone to women, in interventional trials, it protects against breast cancer. Testosterone is apoptotic to cancer cells. I'll give you that lecture tomorrow. "Yeah, but it says here ..." That's an association. Don't extrapolate association to causation. In order to prove causation you have to do an interventional study intervene, give them testosterone and see what happens.
In every study when we give testosterone to women, its apoptotic cancer cells, it protects against it. Some of you may be old enough like me. If remember what we gave patients with metastatic breast cancer. IM injections of testosterone. Guess what happened? It significantly decreased the metastasis from breast cancer. Another study shows that postmenopausal women that have high baseline estrogen are at risk for breast cancer. Another study showing that estrogen is harmful and causes breast cancer. It says it right there. What is it that you don't understand about that? Do you give estrogen to women? Yeah, you do. Well, you're causing breast cancer according to this study.
According to the Women's Health Initiative study and the [Dennis 00:28:07] trial, [Annie Lee 00:28:10] trial, and the CORA study, and the West trial, giving estrogen to women not only did not increase the risk of cancer, but it decreases the risk of cancer in the breast. "Yeah, but this one right here says that high ..." That's an association. Women with increased visceral fat produce more estrone, produce higher levels of estrogen. "Yeah, that's that estrogen that's causing the breast cancer." No, that's an association. It's not causation. How do you prove causation? You administer estrogen to women. Any study out there showing that? No. Then why do you? "Because the study says." That's an association, but if you'll notice it says, "Increased BMI," the first letters up here. Body mass index increases, associated with increased risk of breast cancer and it raises estrogen.
That's an association. It does not prove causation. To prove causation you administer. We don't see that in these studies. Levels of endogenous hormones estrogen are strongly associated with breast cancer risk in postmenopausal women. Then why do you give estrogen to women if it's associated with an increased risk of breast cancer? Do you give estrogen to women? Yes. What is it you don't understand about this study? This is a re-analysis of 9 prospective studies. What you don't understand is this is an association and the association is, the higher the estrogen baseline, the greater the risk, but there's also a greater risk of heart disease, and a greater risk of stroke, and a greater risk of diabetes.
