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
Results of the Sexual Function Trial
Testosterone therapy, compared with placebo, substantially increased sexual activity, recorded in all follow-up visits at 3, 6, 9 and 12 months.5 This effect was seen for most types of sexual activity, from flirting to sexual intercourse.6
Testosterone also substantially increased libido and, to a lesser degree, erectile function.5 The clinical significance of the effect of testosterone on libido 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 Incremental increases in total and free testosterone and estradiol levels were substantially associated with greater improvements in sexual activity and libido, but not erectile function.6 This confirms results from a previous notable RCT showing that estradiol is necessary for optimal sexual function in men and that too low estradiol levels may contribute to sexual dysfunction.7
Lessons from the Sexual Function Trial
Testosterone therapy improved most aspects of sexual function in older men with low testosterone, with the effect proportional to the increase in testosterone. The greater effects on sexual activity and libido than on erectile function are consistent with the postulated effects of testosterone and what has been observed in severely hypogonadal men. These results are consistent with other placebo-controlled studies.8 One study found that testosterone therapy for 12 weeks significantly improves sexual drive in hypogonadal men.8 Improvement was also seen in energy levels on Hypogonadism Energy Diary.8
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
Results of the Physical Function Trial
Testosterone therapy did not significantly increase the number of men whose distance walked in 6 minutes increased >50 m beyond that at baseline, or the absolute increase in the distance walked by the 387 men who qualified for this trial (the primary outcome), although there was a trend toward greater increases in walking distance for the 387 men assigned to testosterone therapy.5
However, when the data from all 788 men in the Testosterone Trials were analyzed, testosterone therapy substantially improved these walking distance parameters. Importantly, all men who were treated with testosterone – including those who had not qualified for the physical function trial - perceived that their walking had improved more than did the men treated with placebo.
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 primary outcome of the Vitality Trial was the percentage of men whose score on the FACIT–Fatigue scale increased by at least 4 points. 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.
Results of the Vitality Trial
While testosterone therapy, compared to placebo, did not significantly increase vitality as determined by an increase of ≥4 points on the FACIT-Fatigue scale for the 474 men in the Vitality Trial (the primary outcome), testosterone therapy did significantly increase vitality when interpreted as a continuous measure from all 788 Testosterone Trials men. Moreover, testosterone therapy significantly increased vitality (determined using the SF-36 vitality subscale), mood (determined using the positive and negative affect scales), and depressive symptoms (determined using the Patient Health Questionnaire-9) which was statistically significant.
Lessons from the Vitality Trial
Although testosterone did not improve vitality as assessed by an increase greater than the prespecified threshold value, it did improve vitality, mood, and depressive symptoms as continuous measures using several instruments.
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 (AAMI) would improve any aspect of cognitive function.9
Results from the Cognitive Function Trial
For the 493 men with AAMI, testosterone treatment, compared with placebo, did not improve delayed paragraph recall, nor did it improve visual memory, spatial ability, executive function, subjective memory complaints, global cognitive function, or immediate paragraph recall. For all 788 men, testosterone improved executive function but did not improve any of the other measures of cognitive function.
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.
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.10
Results of the Anemia Trial
Of the 788 men enrolled in the Testosterone Trials, 126 were anemic (hemoglobin <12.7 g/dL) at baseline.10 Of these, 64 were found to have a known cause of the anemia, such as iron, B12, or folate deficiencies or inflammation. The other 62 were considered to have unexplained anemia of aging.
In the men with unexplained anemia, testosterone treatment compared with placebo substantially increased hemoglobin by >1g/dL (54% vs 15% of men) and corrected the anemia (58% vs 22% of men).
In the men with anemia of known cause, testosterone also substantially increased hemoglobin by >1 g/dL (52% vs 19%) and corrected the anemia (60% vs 15%).
This increase is of clinical significance, because the prevalence of anemia on older men can be as high as 61%11, and the increase was positively and substantially associated with the patient global impression of improvement in general health and vitality in these anemic men. Furthermore, there is currently no treatment for unexplained anemia, which is present in approximately one-third of anemia patients.12-15
Lessons from the Anemia Trial
Considering that testosterone has long been known to stimulate erythropoiesis, it is not surprising that testosterone treatment for older men with low testosterone and mild anemia (mean hemoglobin concentration of 12 g/dL) increases hemoglobin levels and corrected anemia.
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.
Purpose of the Bone Trial
The specific aim of the Bone Trial was to determine whether testosterone therapy in older men with low testosterone would increase volumetric bone mineral density, measured with quantitative computed tomography (qCT).16
Results of the Bone Trial
In the 211 men in the Bone Trial, testosterone therapy for 1 year increased volumetric bone mineral density of trabecular bone in the spine by 6.8% more than did placebo and increased the estimated bone strength of trabecular bone in the spine by 8.5% more than did placebo.16 Testosterone also substantially increased whole bone volumetric bone mineral density, the strength of the spine and trabecular and whole bone volumetric bone mineral density, and the strength of the hip. Increases in areal bone mineral density (measured by DEXA) were smaller.16
Lessons from the Bone Trial
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.17,18 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
To investigate the effect of testosterone therapy on coronary artery plaque progression using serial coronary computed tomographic angiography (CCTA).19
The number of participants in the Testosterone Trials was not sufficient to find out if testosterone therapy increases risk of cardiovascular events. Therefore, the effect of testosterone therapy on the surrogate outcome noncalcified coronary artery plaque volume was tested.
Results of the Cardiovascular Trial
In the 138 men in the Cardiovascular Trial who had undergone CCTA at both baseline and 12 months, testosterone treatment resulted in a statistically significant greater increase in noncalcified coronary artery plaque volume (median change from 204 to 232 mm2) compared with placebo (median change from 317 to 325 mm2).19 However, testosterone therapy compared to placebo did not affect coronary artery calcium.19
The men in both groups at baseline had relatively high rates of obesity, hyperlipidemia, hypertension, diabetes, and atherosclerosis (indicated by coronary artery calcification score >300 Agatston units). Men in the placebo group at baseline had both higher mean calcification scores and higher noncalcified coronary artery plaque volume.
Lessons from the Cardiovascular Trial
While the greater increase in noncalcified plaque volume in the testosterone group may be concerning, methodological issues with this trial preclude conclusions to be drawn. The effect of testosterone therapy on cardiovascular disease risk can be determined only by a larger and longer trial.
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 were adjudicated to have had major cardiovascular events (myocardial infarction, 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 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 were adjudicated to have had major cardiovascular events (figure 2).