JAMA published a study today that looked at VA Hospital patients with low testosterone levels. The men were about 62 years old, and were given testosterone replacement therapy for about a year. But what the authors found was surprising: the men who got testosterone did worse than the men who didn’t! Specifically, they had a small increase in heart attacks and strokes. That doesn’t sound good! It’s especially surprising since a very similar trial was published just last year in the Journal of Clinical Endocrinology and Metabolism and got exactly the opposite result! That study also looked at male veterans, about the same age (average age 61), who also had very low testosterone. Those men got the same sort of intervention: testosterone either by injections or gel or patch, and they were tracked for about 43 months. (Today’s JAMA study only followed their patients for 28 months.) Here’s what the authors found in last year’s study: The mortality in testosterone-treated men was 10.3% compared with 20.7% in untreated men (P <0.0001)!
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In an observational cohort of men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment.
The men who got testosterone had half the risk of death! That’s what I would expect to see. So what went wrong in today’s JAMA study??
A Trip Down Memory Lane
First, some history: It has for decades been known that low testosterone levels in men are bad: when your levels drop, you are at increased risk of death from all causes—and particularly from heart disease. Many studies have looked at this: [expandsub1 title=” Click here to see a handful of studies showing that low testosterone levels are associated with heart disease and death.” trigclass=”references”] As part of the European Prospective Investigation into Cancer (EPIC) study, this paper looked at 11,600 men aged 40 to 79 and followed them for about 8 years. They found that low serum testosterone concentrations were related to death due to all causes, cardiovascular disease, and cancer. The authors concluded:
In men, endogenous testosterone levels are inversely related to mortality due to cardiovascular disease and all causes. Low testosterone may be a predictive marker for those at high risk of cardiovascular disease.
Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men: European Prospective Investigation Into Cancer (EPIC) Prospective Population Study. Circulation. 2007; 116:2694-2701 ___ Low Serum Testosterone and Mortality in Older Men This study tracked 800 men for 12 years, and found that low testosterone predicted increased risk of cardiovascular deaths (HR 1.38; CI 1.02–1.85) and respiratory disease deaths (HR 2.29; CI 1.25–4.20), independent of age, body fat, and lifestyle J Clin Endocrinol Metab. 2008; 93:68-75 ___ Low serum testosterone and estradiol predict mortality in elderly men.
Conclusions: Elderly men with low serum testosterone or estradiol have increased risk of mortality, and subjects with low values of both testosterone and estradiol have the highest risk of mortality.
J Clin Endocrinol Metab. 2009 Jul;94(7):2482-8. ___ Relationship Between Low Levels of Anabolic Hormones and 6-Year Mortality in Older Men The Aging in the Chianti Area (InCHIANTI) Study
Conclusions Age-associated decline in anabolic hormone levels is a strong independent predictor of mortality in older men. Having multiple hormonal deficiencies rather than a deficiency in a single anabolic hormone is a robust biomarker of poor health status in older persons.
Arch Intern Med. 2007;167(20):2249-2254. ___ Low serum testosterone and mortality in male veterans. This study evaluated whether low testosterone levels are a risk
factor for mortality in male veterans followed from October 1994 to December 1999. RESULTS:, Mortality in men with normal testosterone levels was 20%, vs 34.9% in men with low testosterone levels. After adjusting for age and other medical problems, low testosterone levels continued to be associated with increased mortality (HR 1.88; CI, 1.34-2.63; P<.001)
CONCLUSIONS: Low testosterone levels were associated with increased mortality in male veterans.
Arch Intern Med. 2006 Aug 14-28;166(15):1660-5. [/expandsub1] In fact, cardiologists have studied testosterone as a treatment for coronary heart disease for over 70 years. The idea appeared in the New England Journal of Medicine way back in May 1942(!!), followed immediately by a series of case reports published in the Journal of Clinical Endocrinology and Metabolism by Dr. L. Hamm, who wrote:
[I] administered testosterone [injections] to 24 patients with angina pectoris in order to determine its influence on the frequency and/or severity of attacks. All patients improved as measured by diminution in frequency, duration, and severity of their anginal attacks and by their ability to increase physical activity without precipitating attacks. This improvement persisted for 2 to 12 months following interruption of therapy. Similar results did not follow injections of sterile sesame oil given as a control measure.
Over the ensuing 70 years, many others have followed in Dr Hamm’s footsteps, with similar results. [expandsub1 title=” Click here to see other studies looking at testosterone injections in men with known coronary artery disease.” trigclass=”references”] This 2004 article published in the journal Heart is representative: Testosterone replacement in men with angina improves ischemic threshold and quality of life:
After a month of testosterone, time to 1 mm ST segment depression assessed by exercise treadmill testing improved by 74 seconds (p = 0.002), and mood scores assessed with validated questionnaires all improved. Compared with placebo, testosterone therapy was also associated with a significant reduction of total cholesterol. Conclusion: Testosterone replacement therapy in hypogonadal men delays time to ischemia, improves mood, and is associated with potentially beneficial reductions of total cholesterol and tumor necrosis factor α.
Here’s another: Low-dose testosterone therapy improves angina threshold in men with chronic stable angina: A randomized, double-blind, placebo-controlled study. 22 men with chronic stable angina were treated with Testosterone replacement therapy, and had greater angina-free exercise tolerance compared to controls.
Conclusions—supplemental testosterone treatment in men with chronic stable angina reduces exercise-induced myocardial ischemia.
Circulation (Journal of the American Heart Association) 2000; 102: 1906. ___ And another: Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men
This randomised controlled trial assessed the effect of testosterone therapy [vs placebo on] exercise-induced ischemia, lipid profiles, carotid intima-media thickness (CIMT) and body composition during 12 months treatment in men with low testosterone levels and angina. Testosterone increased time to exercise-induced ischemia, and reduced body mass index and triglycerides. Conclusion: The protective effect of testosterone on myocardial ischemia is maintained throughout treatment. Previously noted potentially beneficial effects of testosterone on body composition were confirmed, and there were no adverse effects.
[/expandsub1] An excellent review of the literature was provided in 2012 by Morris and Channer, which can be seen in its entirety here: Testosterone and Cardiovascular Disease in Men
SO WHAT ABOUT JAMA?
In light of all that, the JAMA results are surprising: Why did the same type of patients (VA Hospital patients around 61 years old) have great results in the testosterone study published last year— half the risk of death! — yet this year another study shows that giving them testosterone increased their risk of heart attacks and strokes?? Which study should we believe?? The answer is, maybe we can believe both studies– because even though both studies looked at men of about the same age and from the same type of treatment center, these two groups of men were very different. The men in today’s JAMA study were in terrible health:
- 20% had had a prior heat attack,
- 18% had Congestive Heart Failure,
- 55% had confirmed obstructive coronary artery disease by angiogram.
By contrast, in last years study, only 20% had heart disease of any kind (angina, heart attacks, or congestive heart failure). To put it another way, its possible that the patients in this year’s study were “too far gone.” Testosterone is perhaps most beneficial as a preventative, and these men were well past the “preventive medicine” stage. As one cardiologist put it: “You need to be careful about the conclusion you draw from this JAMA study,” says Dr. Warren Levy, a cardiologist and director of Virginia Heart, based in Northern Virginia. “The study is of men who had undergone cardiac catheterization – so that already selects out a higher-risk population. The conclusion may be that for men with a higher risk of cardiovascular disease, testosterone therapy may increase risk slightly.” But there is also another issue to be aware of: Dr Anne Coppola, an associate professor of Endocrinology at University of Pennsylvania, wrote an editorial accompanying the JAMA study. This is right on the money:
Frustratingly little information is available in this VA database analysis about whether testosterone was appropriately prescribed according to accepted guidelines. In addition, 36% of the men were using testosterone injections, which have the disadvantage of nonphysiologic peak and trough levels when using either a once a week or once every two weeks dosing strategy.
I could not have said it better myself. This is why we have our testosterone replacement patients at PhysioAge use smaller doses twice a week, to get more physiologic levels. (And my more meticulous patients actually inject tiny doses three
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times a week, to get the smoothest levels possible.) There is another advantage to dosing with small amounts more frequently: You don’t convert as much to estrogen. If you are getting testosterone replacement from a doctor that is advising you to use once-weekly testosterone injections plus an estrogen blocker, you need a new doctor. Blocking estrogen also has significant long term health risks, and with proper dosing, we very rarely need to do so in any of our patients.
CONCLUSION? AN OUNCE OF PREVENTION…
Preventive Medicine is the name of the game. My practice is made up largely of pro-active, healthier patients, but I will certainly discuss this study with my few patients that may have significant health issues prior to walking in the door. With those people, we should proceed more cautiously. And with ALL patients, using physiologic dosing regimens is crucial.
ADDENDUM: February 2014
Perhaps ironically, a month after this article was published in JAMA, another review of testosterone and cardiovascular disease was published… in JAMA ! (December 2013) Not surprisingly, the authors gave a much more positive commentary on testosterone therapy than we have seen in the popular press. They summarized,
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Type 2 Diabetes, myocardial ischemia [angina], exercise capacity, and [improves abnormal QT intervals on EKG].
One month later, there was no mention of this review in the New York Times when they published a story centered on a weak observational study of testosterone therapy. For those of us who have studied and written about the uneven reporting on women’s HRT studies, it feels a bit like deja vu.