The Testosterone Trials were a set of seven randomized placebo-controlled trials that evaluated the efficacy of testosterone replacement therapy (TRT) in older men with low testosterone levels [1]. Trials like these are the pinnacle of clinical science. It’s been commonplace to rely on data from small, low-quality trials, or even just ‘expert opinion’ with regard to TRT. This is unreliable for a great variety of reasons. Moreover, while it can give good clues about certain clinical effects, and the direction of it (e.g. improved libido), it usually is quite bad at estimating the effect size. That is: how well something actually works. And, as often is the case, multiple small, low-quality trials, usually demonstrate inconsistent results.
In 2003, a panel of the American Institute of Medicine (IOM) and National Academy of Sciences recommended conducting good-quality trials to evaluate the efficacy of TRT in the elderly. Because, at the time, the data was largely crap. While it took a couple of years, a large group of researchers, including some big names like Shalender Bhasin, Alvin Matsumoto, and Glenn Cunningham, undertook the tremendous effort to set up these trials. Recruitment started in November 2009, and data collection was finally completed in July 2014.
So what were these seven trials? They looked into clinical endpoints as follows:
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Physical function trial – The aim was to see if TRT would improve distance on the 6-minute walk test by at least 50 meter. This might sound silly, but walking isn’t self-evident for the elderly. Moreover, it correlates well with various meaningful clinical outcomes.
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Sexual function trial – Probably doesn’t require much of an introduction. It was to see if TRT improved libido and sexual activity.
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Vitality trial – Formally speaking, it evaluated whether or not TRT improved scores on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (and some other subscales). This scale gives an indication of how well someone with a chronic illness is managing in day to day life, in terms of fatigue, with some questionnaires.
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Cognitive function trial – What’s in the name: participants were bombarded with a bunch of cognitive tests to see how TRT affected it.
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Anemia trial – TRT increases red blood cell production (erythropoiesis). Quite in fact, increased hematocrit (the % of blood volume occupied by red blood cells) is the most frequent adverse effect associated with TRT [2]. This is very useful for people who suffer from anemia, as they have too few red blood cells. Thus this trial evaluated whether TRT could improve unexplained mild to moderate anemia (as measured by hemoglobin status).
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Bone density trial – Osteoporosis is a serious problem in aging. The bones become weak and brittle with a resulting increase in bone fracture risk. This trial evaluated bone mineral density at various sites to see if TRT improved this.
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Cardiovascular trial – One of the major concerns with TRT is that it might increase cardiovascular disease risk. You’d need a huge trial to adequately address this question. You’d need way more participants than this trial had. So, instead, their primary outcome was the progression of noncalcified coronary artery plaque volume. This can already provide some important clues.
A total of 788 men were recruited for these trials. Each man was eligible to participate in any of these trials in parallel, as long as he met the criteria for it. TRT (testosterone gel) was given for 1 year. The dose was titrated up if testosterone levels were below 500 ng/dL (17.4 nmol/L) and titrated down if testosterone levels were above 800 ng/dL (27.8 nmol/L). Median baseline levels were 234 ng/dL (8.1 nmol/L) and increased to a median of about 500 ng/dL (17 nmol/L; apparently dose titration didn’t go that well). Let’s go over each of these trials to see what they demonstrated. (And let’s see if they fit your beliefs about what TRT does and doesn’t do.)
