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).