Lessons about Testosterone Therapy from the Testosterone Trials
STUDY: Snyder PJ, Bhasin S, Cunningham GR, et al. Lessons From the Testosterone Trials. Endocr Rev. 2018;39(3):369−386.
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 glucose tolerance, as well as anemia and coronary artery 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 2 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 or functional 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
Here we summarise the results of the Testosterone Trials and comment on their clinical implications.3
- 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)
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).
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, 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 TTrials 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.
- Testosterone therapy of 1 year in older men with low testosterone increased the coronary artery plaque volume (a 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.
The effects of testosterone therapy on coronary artery plaque volume and cognitive function merits an explanation.
Effect of testosterone therapy on coronary artery plaque
The increase in coronary artery plaque volume3 deserves a comment. While this may seem alarming at first sight, conclusions about the effect of testosterone therapy on atherosclerosis and cardiovascular disease risk cannot be drawn from this study for several reasons. Men in the placebo group had much more plaque at baseline. Non-calcified plaque volume increased from 204 mm3 to 232 mm3 in the testosterone group, and from 317 mm3 to 325 mm3 in the placebo group. Despite a greater increase in plaque volume, men in the testosterone group still had less plaque at study end than men in the placebo group. On the other hand, men in the placebo group had a smaller increase in plaque volume but still more plaque at the end of the study. Similar inconclusive results were seen with total plaque volume.
An analysis of the individual plaque components revealed that the increase was confined to the fibrous component of the plaque, which provides for plaque stability.20 Fatty and necrotic portions, characterized by low attenuation and indicative of a vulnerable plaque20, as well as calcified plaque volume were not affected by testosterone treatment. Thus, testosterone therapy may have resulted in stabilization of coronary plaques. Also, there was no change in coronary artery calcium (CAC, a marker of atherosclerosis). This is consistent with data from the TEAAM trial, which showed that testosterone therapy for 3 years did not affect neither CAC nor CIMT compared to placebo.6 However, other studies show that testosterone therapy decreased CIMT21,22, and retrospective studies have shown a reduction in major adverse cardiovascular events as well as reduced mortality after testosterone therapy.23,24
Effect of testosterone therapy on cognition
The Cognitive Trial reported that 12 months of testosterone treatment in elderly men with age-associated memory impairment (AAMI) did not improve neither the primary (memory) nor secondary (visual memory, executive function, spatial ability) cognitive function outcome measures.9 However, there are several issues with the Cognitive Trial which render this conclusion questionable. As was pointed out in an accompanying Letter to the Editor, the Cognitive Trial included a heterogeneous group of men with memory complaints, mild cognitive impairment, and mild dementia, which makes it unlikely to find meaningful results.25 Furthermore, the definition of subjective memory complaints was arbitrary and important confounders were not controlled for in the data analysis. For example, they did not report on major genetic risk factors, such as Apolipoprotein E (ApoE) ε4allele carriage, or other biomarkers of Alzheimer disease. Apolipoprotein E (ApoE) ε4allele carriage is known to influence the effects of testosterone on cognition.26 Also, some cognitive domains are only associated with testosterone in APOE ε4 carriers.26 Experimental data shows that ApoE4 contributes to cognitive decline by reducing androgen receptor levels in the brain, and that stimulating AR-dependent pathways can reverse ApoE4-induced cognitive deficits.27
The lack of effect of testosterone therapy on cognitive function could possibly be due to insufficient elevations in testosterone levels. In the Cognitive Trial, testosterone therapy increased testosterone levels to approximately 17.3 nmol/L (500 ng/dL).9 In contrast, a study which showed improvement in global cognitive functioning (measured by the Mini Mental State Examination) after testosterone treatment raised testosterone levels into the 25-27 nmol/L (720-780 ng/dL) range.28 A systematic review concluded that despite limitations imposed by inconsistent research methods, promising associations have been found between cognition and testosterone therapy in both eugonadal men and men with low testosterone levels, with and without baseline cognitive dysfunction.29 Therefore, it is premature to conclude that testosterone therapy does not improve cognitive function. Considering that testosterone alters neural activity essential for learning and memory, and plays an important role as a neuroprotective agent in aging30, larger studies and a more standardized approach to cognitive function assessment are needed in order to fully understand and realize potential benefits of testosterone therapy on cognitive outcomes.
Incidence of adverse events in the testosterone group vs placebo group
While the Testosterone Trials were not adequately powered to detect statistically significant differences in adverse events between testosterone and placebo groups, it should be pointed out that numerically more adverse events occurred in the placebo group, as illustrated in figure 1 and figure 2.
Notably, while the number of myocardial infarcts, stroke 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 for health care professionals
The Testosterone Trials give physicians 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 myocardial infarction, stroke 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