NEAL ROUZIER, M.D.
On the first day the JAMA article was released I received 500 emails from physicians and patients requesting my opinion of the article that demonstrated an increase in heart attacks and strokes in men treated with testosterone. Today is the second day and I’m afraid to turn on the computer. First of all this was an observational study that was retrospective in nature and this type of study is fraught with compounding biases that are difficult to control as expressed in the discussion section of this study. A randomized controlled trial (RCT) would have much more power than this type of study. Also the problem with an observation study is that it does not prove causation as would an interventional study in a blinded fashion. Therefore observational studies can’t prove causation as well as RCTs and what we should take away from the study is that which the researchers state in the last paragraph, that more studies are necessary before definitive conclusions can be made as to cause and effect. Also, treatment decisions should not be based solely on one study but rather on a trend of studies. Unfortunately the editorial comment section did not express this clearly.
The discussion section of this article mentions that this is the only study that showed this adverse outcome and it was in a select group of individuals. All other studies have shown the opposite outcome, either no effect or protection against heart attacks. Since all other studies show the opposite, and one study does not negate all the other studies, and there were some biases in this study, I would suggest that we do not change anything that we do based on one study with flaws and biases when all other studies demonstrate protection against heart disease and stroke (see attached articles). And this was an observational study which has weaker power than a randomized controlled trial. I'm sure that other experts will voice the same opinion once they review the discussion section of this article as there were many biases and flaws in this study. A review of the index lists the studies that demonstrate protection against heart disease and strokes. In the “Longevity Section” that I present in the Part II course, all of the articles demonstrate improved longevity in those treated with testosterone, but increased morbidity and mortality in those men not treated with testosterone. The WHI study showed that Prempro increased heart attacks and strokes in certain individuals. Subsequent studies have proven that estradiol and progesterone, particularly in younger women, don't. Perhaps there is a confounding problem in older Veterans with cardiovascular disease that is different from other studies. However, as presented in the Part II course, every study that I review (and there are many) demonstrated a significant improvement in longevity and decreased morbidity and mortality in addition to improvement in all cardiovascular risk factors in men treated with testosterone as opposed to control groups treated with placebo (see attached studies).
Had this study been published years ago, and all subsequent studies since then showed protection against cardiovascular disease, then this study would have probably been ignored and forgotten. However, since it is recent, then we tend to believe it and reject all the past studies that showed the exact opposite outcome. Nevertheless, one study does not negate many other studies that show opposite results and benefits. So I will log this study on the negative side for testosterone results but it is the only such study on this side. This is in contrast to all the other studies that show benefit of testosterone administration. It is interesting that this study appears now, just after I gave 2 lectures to a medical academy this past weekend in Las Vegas. The two one hour lectures were on all the studies of both estrogen and testosterone protecting against heart attacks and strokes. These reviews of the world's literature demonstrate all the various mechanisms of benefits of hormones in protecting the heart and brain against heart disease, stroke, dementia, and plaque deposition. The data and literature is overwhelming in favor of a protective effect of estrogen in women and testosterone in men. This recent study, although interesting and intriguing, does not change any of the evidence that I presented in these lectures nor does it change my treatment strategies. Until more studies demonstrate the same, I will continue to follow the scientific literature that demonstrates benefit. As per the suggestion from the authors, they state that more study is needed to evaluate these results. I recommend to patients and physicians that they continue the same treatment with both estrogen in women and testosterone in men based on all prior studies that show benefit in spite of this one negative study.
Certain statements in the discussion section of the study deserve comment. The authors do note that other trials and meta-analyses do not demonstrate adverse cardiovascular outcomes. The trend so far in the literature has been a protective effect as trials demonstrated that testosterone therapy improves a number of intermediate outcomes and cardiac risk factors. This 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 similar retrospective VA study by Shores et al that demonstrated a 39% reduction in mortality risk among patients treated with testosterone which again suggests caution in coming to conclusions only based on the present study. Different confounders and biases might account for the discrepancy. Multiple limitations of this study are noted by the authors that certainly can affect outcomes. All in all, it is an interesting study with unexpected results that are in discordance with all other studies and should not influence current therapy, but one that begs for more study.
For those patients and physicians that are unfamiliar with the current literature on testosterone therapy, I have included 3 attachments that review various categories of hormone replacement. First are studies that review mortality in men treated with testosterone compared to control groups. Studies show improved survival in treated men versus untreated men. There are fewer heart attacks, cancer, and reduced mortality in men treated with testosterone (in contrast to the current study). Other studies go on to prove that low levels of testosterone increase morbidity and mortality in contrast to men with testosterone levels in the higher quartiles. Low levels of testosterone are predictive of an increase in all-cause mortality (CAD, CVD, cancer). So where would you like your levels to be? Other studies show that there was no increased risk of cardiac events in men treated with testosterone (in contrast to the current study).
The second attachment lists all the articles that demonstrate all the physiologic benefits of testosterone administration on cholesterol, lipoproteins, insulin sensitivity, diabetes, inflammatory cytokines, endothelial dysfunction, atherosclerosis, blood pressure, memory loss, Alzheimer’s disease, mood, strength, energy, muscle mass, fat mass, osteoporosis, ED, sexual function, and all-cause mortality. Do you really want to stop the testosterone based on only one negative study? I’m not! What are the consequences of stopping or not taking it? Read the foregoing.
The third attachment reviews beneficial effects on quality of life as well as disease protection. It is amazing the data on reduction of body fat, insulin levels, diabetes, inflammation, and vascular disease. “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 in illness as listed above.” And don’t forget (pun intended) the protection against Alzheimer’s disease.
Respectfully submitted, Neal Rouzier
Read Dr. Josh Trutt's response to the JAMA article here.
Read Dr. Mike Clark's response to the JAMA article here.
Find out more about Dr. Rouzier here.