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Testosterone Replacement Therapy: Skating on Thin Ice?

November 11, 2013

A recent VA study published in JAMA indicated that men taking testosterone replacement therapy had a 29% increased risk of stoke, MI and death. The VA study was observational, not a clinical trial, so it’s findings are of limited scope, but as there are now over 5-million prescriptions for testosterone therapy given in the US every year, the study ought to sober up the increasingly rowdy testosterone replacement party. There are naysayers to the study, including the Life Extension Foundation (LEF). I was asked to review the VA/JAMA article and the LEF rebuttal. Below is my analysis.

To ignore the VA study published in JAMA would be a mistake. So too would harboring blind faith that testosterone therapy is harmless. Everything must be put in context as we step forward.

Alternative medicine is inspired by the belief that we can step well ahead of convention (or well behind it) to improve clinical outcomes for our patients. I share that belief, but I also know that this inspiration can also easily become an Achilles heel–especially if our notions are held beyond reproach. Large, long term, double-blind, controlled clinical trials are deservedly the gold standard of demonstrating safety and efficacy. So long as we are practicing methods well ahead of these large clinical trials, we may be, by definition, standing on thin ice. As we move forward in functional medicine, we need to step carefully and listen for the proverbial cracks underneath our feet, lest we lead ourselves and our patients into harm’s way.

Testosterone_functionsThe VA study found that testosterone therapy in low testosterone men (undergoing coronary angiography) was associated with a 29% increased incidence of MI, ischemic stroke, and death. This study was notably limited in that it was observational, not clinical. Another major limitation of the VA study was that they did not track how the testosterone was administered, at what dose, or require that serum testosterone or estrogen levels be measured. The VA/JAMA article was not brazenly anti testosterone. The authors prominently noted that testosterone therapy was associated with improved sexual function and bone mineral density, increasing lean body mass and strength, and improving lipid profiles and insulin resistance.

As seems true in many areas of medicine, functional and conventional alike, there are those who will step forward boldly. Annual prescriptions for testosterone in the United States have increased by more than 5-fold from 2000 to 2011, and there were over five million prescriptions in 2011. This is big business now, and the therapy is being aggressively marketed directly to consumers. I’ve never been one to join a stampede. I’m content to let the first waves of new trends rumble by while I personally weigh the evidence, note pitfalls, watch for signs of zealotry, and see where the pile lands.

The Life Extension Foundation (LEF) and other anti-aging groups share a standing recommendation on testosterone along the lines that people should “restore testosterone levels to youthful ranges for optimal health.” So while I do appreciate the haste in which LEF wanted to cover their significantly exposed posterior here, they could have done better in their rebuttal article. In the first paragraph, they are citing (and probably overstating) the conclusions from single-author review articles from obscure journals to make the key associations of low testosterone with numerous health problems.

testosterone - aromatseI did appreciate that LEF noted an important weak point in testosterone supplementation where the therapy can easily go awry via aromatse conversion of testosterone to estrogens. Here, LEF noted correctly that estrogens need to be monitored in men undergoing testesterone therapy, and that increased estrogen can also promote thrombosis. This seems to underlie the conclusion that giving testosterone therapy without monitoring testosterone and estrogen levels is a bad idea. Here it seems, that LEF and IFM agree whole-heartedly.

I was not impressed that in the second paragraph, LEF tries to sell some academic slight of hand and obscure their exposed weakness by bending the subject to a better supported tangential position: that testosterone improves measures of “cardio-metabolic health”. I don’t doubt that testosterone therapy can make men leaner (and meaner), but I don’t think this tangential argument does anything to address the JAMA finding. My point is that I am not seeing anything in the LEF article that refutes the idea that in addition to some notable benefits, that testosterone therapy may also significantly increase the risk of thrombotic strokes or MI. As the JAMA article’s senior investigator, Dr. Michael Ho, notes “testosterone can increase hematocrit levels, affect platelet aggregation, and worsen sleep apnea.”

The LEF article held especially high a 2011 Swedish osteoporotic fracture study as good evidence that the highest quartile of testosterone levels was shown to be associated with reduced CV events (at least in community-dwelling elderly Swedish men). Here’s the catch though, the Swedish study only measured testosterone levels in men, NOT in men taking extra testosterone. Meaning… this study is not relevant to the interventional question at hand. The other studies LEF noted were similarly not particularly good evidence in that they were not clinical trials, small trials, or short term trials.

Does this mean that testosterone therapy is bad? No, it means what everyone involved should admit and expect: that the therapy is still on thin ice. It also means that brave doctors practicing testosterone therapy ought to continue to step carefully, follow the IFM hormone motto of “start low and go slow” and monitor testosterone and estrogen levels and coagulation studies whenever the therapy is given.

trmorrisnd headshotDr. T.R. Morris is a licensed naturopathic medical doctor (ND). He is currently serving as faculty and consultant to the Institute for Functional Medicine (IFM). The IFM mission is to revolutionize medicine by teaching the latest genetic, nutritional, hormonal and other biochemically-based integrative medicine techniques to MDs and other practitioners looking for new tools to prevent and treat chronic disease. In the past, T.R. served as the medical director of a large integrative clinic and taught (genetics, physiology, biochemistry, microbiology, cellular & molecular biology) for 10 years for various medical programs in the Puget Sound. He sees patients in person (or long-distance via Skype consultations) from his home office in Seattle.
Contact Dr. Morris

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6 Comments leave one →
  1. Jim permalink
    November 11, 2013 5:54 pm

    Hi, I am a 42 year old man on disability for anxiety/depression. I have also been treated with testosterone for about 10 years. I complained to my doctors that although have my testosterone levels normalized (900ng/dL) I still did not feel much benefit However, I have been depressed for many years prior, so I really don’t know where to go for help. I don’t know if this is the depression causing low testosterone. I am propped up by 120mg Adderall per day, Prozac, Seroquel, and klonopin. If it weren’t for the Adderall I would be bed-ridden. I have had consults from various functional medicine doctors, the latest theory is severe Adult Growth Hormone Deficiency. I have had head trauma in the past, so I don’t know if I have been mis-diagnosed. So now I am washing out the testosterone and arimidex to have a stimulation test in 8 weeks. I am frustrated as to how I can find a reputable physician who will sit down and study my case. Conventional medicine doctors are too concerned with cost/benefit and diagnostic codes and getting patients in and out in 15 minutes. Your point is well made, those who are practicing “cutting edge” medicine should be careful. My case is a prime example of managing your expectations when it comes to any philosophy of medicine. Sometimes you have to accept your situation, that’s why they call it “the practice of medicine”.

    • November 11, 2013 6:03 pm

      Thanks for your post. Like most patients, you need to have someone sit down and fully hear, absorb and digest your entire medical history. You need to be seen as an individual–not just a person-bearing symptom in need of a name and a prescription. That’s what I promise to do for you–as any good functional or naturopathic physician will do. I’m sending you my intake form via email. It’s 12 pages long and if you put the work in to fill it out, then we can hit the ground running on your case. I look forward to helping you to attain and maintain your optimal health.

  2. ray permalink
    November 25, 2013 5:20 pm

    I read the study. There is a glaring error in that the data reported does not agree with the conclusion. If you look at the data those receiving testosterone had half the risk of those who did not.

    Of the 8709 men with a total testosterone level lower than 300 ng/dL, 1223 patients started testosterone therapy after a median of 531 days following coronary angiography. Of the 1710 outcome events, 748 men died, 443 had MIs, and 519 had strokes. Of 7486 patients not receiving testosterone therapy, 681 died, 420 had MIs, and 486 had strokes. Among 1223 patients receiving testosterone therapy, 67 died, 23 had MIs, and 33 had strokes. The absolute rate of events were 19.9% in the no testosterone therapy group vs 25.7% in the testosterone therapy group, with an absolute risk difference of 5.8% (95% CI, -1.4% to 13.1%) at 3 years after coronary angiography. In Cox proportional hazards models adjusting for the presence of coronary artery disease, testosterone therapy use as a time-varying covariate was associated with increased risk of adverse outcomes (hazard ratio, 1.29; 95% CI, 1.04 to 1.58). There was no significant difference in the effect size of testosterone therapy among those with and without coronary artery disease (test for interaction, P?=?.41).

    Testosterone
    Total Yes No
    Total 8709 1223 7486
    Death 748 67 681
    Heart attack 443 23 420
    Strokes 519 33 486
    All Causes 1710 123 1587

    Death 8.6% 5.5% 9.1%
    Heart attack 5.1% 1.9% 5.6%
    Strokes 6.0% 2.7% 6.5%
    All Causes 19.6% 10.1% 21.2%

    • November 25, 2013 5:58 pm

      Thanks for this weighty reply. (It sounds like someone has a background in statistics!) I need you to boil down your response if you can. This study suggested that testosterone therapy increased MI, stroke and all cause mortality in these men (undergoing coronary angiography). Are you suggesting that these conclusions were incorrect by their own data?

      • ray permalink
        November 26, 2013 12:34 pm

        It appears that the conclusion is at odds with the data. It is interesting that the data seems to confirm the previous VA study that showed a benefit of testosterone levels above 550 with respect to cardio health.

        As a VA patient I can attest to the fact that the testosterone replacement is not done in an optimal method. Shots every two weeks leads to increased ESTRADIOL and hemocrit levels and testosterone levels that yo-yo. It is hard to tell how that plays with heart health.

      • November 26, 2013 3:42 pm

        Testosterone therapy must be monitored very carefully because our aromatase enzymes can take this valuable androgen and make it into estrogens–which have many effects that oppose the effects desired by testosterone therapy in the first place. Basically, if you’re giving testosterone or even DHEA, you must be monitoring total estrogens as well as the DHEA and testosterone levels. It’s what I do with all my patients and recommend to my functional medicine students and colleagues.

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