Lessons about testosterone therapy from the testosterone trials
The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and blood sugar control, as well as anemia and heart disease.1 The same health deterioration occur in men who have low testosterone levels due to pituitary or testicular disease, known as classical hypogonadism. In patients with classical hypogonadism, testosterone therapy significantly improves these abnormalities and is mandatory.
With the aging demography and epidemic prevalence of obesity, metabolic syndrome and type diabetes – conditions that are strongly associated with hypogonadism – large scale investigation of the effects of testosterone therapy in men with this kind of hypogonadism, also known as “age-related hypogonadism”2, is warranted. However, even though the term “age-related hypogonadism” is commonly used, it should be pointed out that the majority of older men with hypogonadism are obese and/or have the metabolic syndrome or diabetes. Even though the Testosterone Trials aimed to recruit men with hypogonadism due to no apparent reason other than age, in fact the majority of enrolled men were obese and more than one third had type 2 diabetes. Obesity, metabolic syndrome and/or type 2 diabetes are stronger risk factors for hypogonadism than aging per se. Consequently, the Testosterone Trials provide compelling evidence that testosterone therapy confers significant benefits in the growing population of men with obesity and/or type 2 diabetes. Furthermore, the Testosterone Trials confirm the safety in this patient population; the placebo group experienced more adverse events than the testosterone group.
The Testosterone Trials is a coordinated set of seven trials that investigated if testosterone therapy in elderly men with low testosterone levels, symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be effective in improving the following outcomes:1
- sexual function (Sexual Function Trial)
- mobility (Physical Function Trial)
- fatigue (Vitality Trial)
- cognitive function (Cognitive Function Trial)
- hemoglobin (Anemia Trial)
- bone density (Bone Trial)
- coronary artery plaque volume (Cardiovascular Trial)
Coronary artery plaque is cholesterol-containing deposits in blood vessels supplying the heart.
A “trial” is a specific type of study frequently used in medical research.
Here we summarise the results of the Testosterone Trials and comment on their clinical implications.3
What is known about testosterone therapy and men’s health
Men with hypogonadism, either classical or age-related, commonly suffer from decreased energy, decreased sexual function, decreased muscle mass and increased fat mass, decreased bone density and an increased incidence of fractures, and decreased hemoglobin levels.
Previous randomized controlled trials (RCTs) – the gold standard research methodology in medicine – have shown variable results, in large part due to different therapy protocols, too short treatment duration and under-treatment (i.e. failure to raise testosterone levels sufficiently and long enough to achieve the therapeutic effects of testosterone therapy). To gain more insight into the effects of testosterone therapy in older men with low testosterone, a series of RCTs were conducted, collectively known as the Testosterone Trials.
Lessons from the Testosterone Trials
The Testosterone Trials comprise 7 randomized controlled trials (RCTs). It is the largest series of testosterone RCTs, including 788 men aged 65 years or older with low testosterone levels (275 ng/dL = 9.5 nmol/L), who were treated with either testosterone or placebo for 1 year. The testosterone dose was adjusted to keep testosterone levels in mid-normal range for young men, which was 17.3 - 27.7 nmol/L (500 – 800 ng/dL) for the specific laboratory assay used in the Testosterone Trials.
Sexual Function Trial
Purpose of the Sexual Function Trial
The goal of the Sexual Function Trial was to test the effect of testosterone treatment in older men with low testosterone on sexual activity and libido.5
Lessons from the Sexual Function Trial
Testosterone therapy improved most aspects of sexual function, particularly sexual activity and libido, in older men with low testosterone. This improvement was proportional to the increase in testosterone. The real-life meaningfulness of the effect of testosterone on sexual function can be judged by the responses to the Patient Global Impression of Change question, in which 20% of men treated with testosterone reported that their sexual desire was “much better” than before therapy, compared with less than 10% of men treated with placebo.5
Physical Function Trial
Purpose of the Physical Function Trial
The primary goal of the Physical Function Trial was to test the effect of testosterone therapy on the percentage of men who increased the distance walked in the 6-minute walk test by at least 50 m.5 The secondary goal was to test the effect of testosterone therapy on the percentage of men whose score on the physical-function domain (PF-10) of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) increased by at least 8 points, and changes from baseline in the 6-minute walking distance and PF-10 score.5
Lessons from the Physical Function Trial
Testosterone therapy increased the fraction of men in all Testosterone Trials whose distance walked increased >50 m, as well as the absolute increase in distance walked in 6 minutes.5 It also led to the perception of improved walking ability. Thus, it was concluded that testosterone therapy for older men with low testosterone does improve walking.
Purpose of the Vitality Trial
The main goal of the Vitality Trial was the percentage of men whose score on the FACIT–Fatigue scale increased by at least 4 points.5 Secondary outcomes were change from baseline in the FACIT–Fatigue, the score on the vitality scale of the SF-36, scores on the Positive and Negative Affect Schedule (PANAS) scales, and depression according to the Patient Health Questionnaire-9.
Lessons from the Vitality Trial
Although testosterone did not improve vitality as assessed by an increase greater than the prespecified threshold value (which was arbitrarily set), it did improve vitality, mood, and depressive symptoms on several scales.5
Cognitive Function Trial
Purpose of the Cognitive Function Trial
The goal of the Cognitive Function Trial was to determine whether testosterone treatment of older men with age-associated memory impairment would improve any aspect of cognitive function.6
Lessons from the Cognitive Function Trial
All men in the Testosterone Trials were given tests to assess a wide range of cognitive functions, but no significant effects were seen in testosterone treated men. Thus, it was concluded that testosterone treatment in older men with low testosterone does not improve cognitive function. The only outcome that improved with testosterone therapy was executive function (mental skills that are needed to get things done).
Purpose of the Anemia Trial
The goal of the Anemia Trial was to determine whether testosterone treatment for older men with low testosterone and unexplained mild anemia (those with a hemoglobin <10 g/dL were excluded) would increase the hemoglobin by ≥1 g/dL and correct the anemia.7
Lessons from the Anemia Trial
Compared to placebo, testosterone therapy for 1 year substantially increased hemoglobin levels and corrected the anemia in a majority of men. This effect occurred regardless of whether the men had, in addition to hypogonadism, another known cause of anemia such as iron deficiency or unexplained anemia.
This effect shows a clear benefit of testosterone treatment for elderly men with low testosterone and low hemoglobin concentrations. The finding that testosterone therapy can “cure” unexplained anemia is notable considering that there is currently no treatment for unexplained anemia, which is present in approximately one-third of all anemia patients.8-11
Purpose of the Bone Trial
The goal of the Bone Trial was to determine whether testosterone therapy in older men with low testosterone would increase volumetric bone mineral density and estimated bone strength.12
Lessons from the Bone Trial
Testosterone therapy for 1 year increased volumetric bone mineral density by 6.8% and estimated bone strength by 8.5%. These striking improvements in volumetric bone mineral density and estimated bone strength are especially impressive for only 1 year of treatment, and are consistent with the effects of testosterone therapy on bone seen in more severely hypogonadal men.
It should be pointed out that these improvements are at least as great in magnitude as the effects of bisphosphonates on volumetric bone mineral density in women with osteoporosis.13,14 Thereby, the Bone Trial provides a strong rationale to conduct a larger and longer trial to determine whether testosterone therapy also reduces fracture risk in older men with low testosterone.
Purpose of the Cardiovascular Trial
The goal of the Cardiovascular Trial was to investigate the effect of testosterone therapy on coronary artery plaque (cholesterol-containing deposits in blood vessels supplying the heart) volume.15 Coronary artery plaque is a major underlying cause of heart disease.
Lessons from the Cardiovascular Trial
Compared to placebo, testosterone treatment resulted in a greater increase in noncalcified coronary artery plaque volume.15 However, no effect was seen on coronary artery calcium, which is another marker of atheosclerosis.15
While the greater increase in noncalcified plaque volume in the testosterone group may be concerning, problems with the study preclude conclusions to be drawn. For example, men in the placebo group had both higher coronary artery calcium scores and higher noncalcified coronary artery plaque volume.
As expected, testosterone therapy significantly increased PSA and hemoglobin levels; however, in most men the elevations in PSA and hemoglobin stayed within the normal range.
7 men in each study group had major cardiovascular events (heart attack, stroke, or death from cardiovascular causes) during the 1-year treatment period (figure 1). Surprisingly, the incidence of unstable angina, carotid artery disease, decompensated heart failure and venous thromboembolism (blood clot) was higher in the placebo group. During the subsequent year after treatment, 2 men in the testosterone group and 9 men in the placebo group had major cardiovascular events (figure 2).
Lessons about adverse events
The Testosterone Trials confirmed both the cardiovascular and prostate safety of testosterone therapy. While testosterone therapy increased the risk of erythrocytosis (overproduction of red blood cells), the incidence of erythrocytosis was low compared with that seen in previous trials. This suggests that careful monitoring of hemoglobin levels and appropriate dosing of testosterone effectively minimises this risk.
The main results from all Testosterone Trials are as follows:3
- Testosterone therapy of 1 year for older men with low testosterone improved all aspects of sexual function.
- Testosterone therapy of 1 year for older men with low testosterone improved walking distance.
- Testosterone therapy for 1 year in older men with low testosterone significantly increased some aspects of vitality, and significantly improved mood and depressive symptoms.
- Testosterone therapy of 1 year in older men with low testosterone increased hemoglobin and corrected mild to moderate anemia, including unexplained anemia.
- Testosterone therapy of 1 year in older men with low testosterone markedly increased the volumetric bone mineral density and estimated bone strength.
- Testosterone therapy of 1 year in older men with low testosterone does not improve cognitive function. However, there was an improvement in executive function (mental skills that are needed to get things done).
- Testosterone therapy of 1 year in older men with low testosterone increased the coronary artery plaque volume (a marker of atherosclerosis), but no effect was seen on coronary artery calcium (another marker of atherosclerosis).
- Testosterone therapy of 1 year in older men with low testosterone was not associated with more cardiovascular or prostate adverse events; however, the number of men and the duration of therapy were not enough to draw definitive conclusions about the risks of this therapy.
Incidence of adverse events in the testosterone group vs placebo group
While the Testosterone Trials did not have enough subjects to detect statistically significant differences in adverse events between testosterone and placebo groups, it should be pointed out that more adverse events occurred in the placebo group, as illustrated in figure 1 and figure 2.
Notably, while the number of heart attacks, strokes and cardiovascular deaths during the 1-year treatment period was the same (7 in each group), during the year following the 1-year of testosterone treatment there were 9 cases in the placebo group but only 2 cases in the testosterone group. In addition, the incidence of unstable angina, carotid artery disease, decompensated heart failure and venous thromboembolism was higher in the placebo group during the treatment year. In other words, the adverse events that are commonly believed to be caused by testosterone therapy actually occurred at a higher rate among men treated with placebo, not testosterone.
Take home messages
The Testosterone Trials give five important take home messages:
- Testosterone therapy does not increase risk for cardiovascular disease nor prostate cancer.
- There were fewer deaths in the testosterone group compared to the placebo group, 3 vs. 7 respectively.
- The incidence of heart attacks, strokes and cardiovascular death was lower in the testosterone group compared to the placebo group during the year following testosterone therapy, 2 vs. 9 respectively.
- Testosterone therapy in men 65 years of age or older with moderately low testosterone levels significantly improves all measures of sexual function and some measures of physical function, mood, and depressive symptoms. These improvements were perceived by the testosterone treated men as clinically significant. Testosterone treated men also had marked increases in bone density and bone strength, as well as hemoglobin (resolving anemia, including unexplained anemia).
- Testosterone therapy confers significant and clinically meaningful health benefits in older men with low testosterone levels associated with obesity and/or type 2 diabetes (also known as functional hypogonadism). Thereby, the Testosterone Trials refute FDA’s position that testosterone therapy should only be given to men with classical hypogonadism(caused by pituitary injury/tumor, testicular damage or Klinefelter’s syndrome).4