Testosterone Trials

[Michael Scally MD]

Handelsman DJ. Testosterone and Male Aging - Faltering Hope for Rejuvenation. JAMA. 2017;317(7):699-701. Testosterone and Male Aging

Hopes for hormonal rejuvenation appear periodically throughout history—with the most prominent attempt occurring around the turn of the 20th century only to vanish in the 1930s following the discovery of testosterone, which discredited testis extracts and manipulations. In recent decades, there has been a renewed attempt for hormonal rejuvenation with testosterone in men.

Today, 8 decades since the first clinical use of testosterone, the sole unequivocal indication for testosterone treatment is as replacement therapy for men with pathological hypogonadism (ie, organic disorders of the reproductive system).

Yet despite no proven new indications, global testosterone sales increased 100-fold over the last 3 decades, including increases of 40-fold in Canada and 10-fold in the United States from 2000-2011.3 This was achieved by marketing strategies that circumvented the need for efficacy and safety testing of testosterone for male aging by stretching the definition of the term hypogonadism to encompass virtually any condition associated with low circulating testosterone levels.

Promoted under the rubric “low T” (also referred to as andropause or late-onset hypogonadism), this process was facilitated by individual physicians and professional societies that minimized the fundamental distinction between pathological hypogonadism and functional states (including aging) associated with low circulating testosterone levels.4

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[Michael Scally MD]

[OA] Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone

Key Points

Question - Is testosterone treatment of older men with low testosterone associated with a decrease in noncalcified coronary artery plaque volume?

FINDINGS - IN A CONTROLLED CLINICAL TRIAL, 1 YEAR OF TESTOSTERONE TREATMENT OF MEN AGED 65 YEARS OR OLDER WITH A LOW SERUM TESTOSTERONE LEVEL WAS ASSOCIATED WITH A SIGNIFICANT INCREASE IN NONCALCIFIED CORONARY ARTERY PLAQUE VOLUME OF 41 MM3 MORE THAN PLACEBO.

Meaning - Testosterone treatment of older men was associated with an increase in coronary artery plaque volume, but additional studies are needed to determine the clinical significance.

[OA] Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA. 2017;317(7):708-716. - http://jamanetwork.com/journals/jama/fullarticle/2603929 -

Importance - Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk.

Objective - To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume.

Design, Setting, and Participants - Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014.

Intervention - Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.

Main Outcomes and Measures - The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis).

Results - Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, −27 Agatston units; 95% CI, −80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group.

Conclusions and Relevance - Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding.

 

[Michael Scally MD]

[OA] Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment

Key Points

Question - Is treatment with testosterone for 1 year associated with improved memory in older men with low testosterone and age-associated memory impairment?

Findings - In this placebo-controlled study of 788 older men with symptomatic hypogonadism, 493 had age-associated memory impairment, defined by subjective memory complaints and impaired performance on tests of verbal and visual memory. COMPARED WITH PLACEBO, 1 YEAR OF TESTOSTERONE TREATMENT WAS NOT SIGNIFICANTLY ASSOCIATED WITH IMPROVED MEMORY OR OTHER COGNITIVE FUNCTIONS IN THESE MEN.

MEANING - THIS STUDY DOES NOT SUPPORT THE USE OF TESTOSTERONE FOR THE TREATMENT OF AGE-ASSOCIATED MEMORY DECLINE IN OLDER MEN WITH SYMPTOMATIC HYPOGONADISM.

[OA] Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment. JAMA. 2017;317(7):717-727. - http://jamanetwork.com/journals/jama/fullarticle/2603930 -

Importance - Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions.

Objective - To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI).

Design, Setting, and Participants - The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014.

Interventions - Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year.

Main Outcomes and Measures - The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to −26), executive function (Trail-Making Test B minus A; range, −290 to 290), and spatial ability (Card Rotation Test; score range, −80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months.

Results - Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, −0.07 [95% CI, −0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (−0.28 [95% CI, −0.76 to 0.19]; P = .24), executive function (−5.51 [95% CI, −12.91 to 1.88]; P = .14), or spatial ability (−0.12 [95% CI, −1.89 to 1.65]; P = .89).

Conclusions and Relevance - Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions.

 

[Michael Scally MD]

[OA] Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone

Key Points

Question - Will testosterone treatment of older men with low testosterone improve their bone density and strength?

FINDINGS - TESTOSTERONE TREATMENT OF OLDER MEN WITH LOW TESTOSTERONE INCREASED VOLUMETRIC TRABECULAR BONE MINERAL DENSITY OF THE LUMBAR SPINE AND ESTIMATED BONE STRENGTH SIGNIFICANTLY COMPARED WITH PLACEBO.

Meaning - These results suggest that a larger and longer trial to determine whether testosterone treatment decreases fracture risk in this population is warranted.

[OA] Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone - A Controlled Clinical Trial. JAMA Intern Med. Published online February 21, 2017. - http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2604138 -

Importance - As men age, they experience decreased serum testosterone concentrations, decreased bone mineral density (BMD), and increased risk of fracture.

Objective - To determine whether testosterone treatment of older men with low testosterone increases volumetric BMD (vBMD) and estimated bone strength.

Design, Setting, and Participants - Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization.

Interventions - Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year.

Main Outcomes and Measures - Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months.

Results - There were 211 participants (mean [SD] age, 72.3 [5.9] years; 86% white; mean [SD] body mass index, 31.2 [3.4]). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, −1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%; P < .001), spine peripheral vBMD, hip trabecular and peripheral vBMD, and mean estimated strength of spine trabecular bone (10.8%; 95% CI, 7.4% to 14.3% vs 2.4%; 95% CI, −1.0% to 5.7%; treatment effect, 8.5%; 95% CI, 6.0%-10.9%; P < .001), spine peripheral bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular than peripheral bone and greater in the spine than hip. Testosterone treatment increased spine areal BMD but less than vBMD.

Conclusions and Relevance - Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk.

 

[Michael Scally MD]

[OA] Association of Testosterone Levels With Anemia in Older Men

Key Points

Question - Will testosterone treatment of older men with low testosterone levels and mild anemia improve their anemia?

FINDINGS - TESTOSTERONE TREATMENT OF OLDER MEN WITH LOW TESTOSTERONE LEVELS AND UNEXPLAINED ANEMIA CORRECTED THE ANEMIA MORE THAN PLACEBO. THIS TREATMENT ALSO CORRECTED ANEMIA MORE THAN PLACEBO IN MEN WHO HAD ANEMIA OF KNOWN CAUSES, SUCH AS IRON DEFICIENCY.

Meaning - Testosterone deficiency in older men results in decreased hemoglobin levels and sometimes in mild anemia. Correcting the testosterone deficiency is associated with increased hemoglobin levels and tends to correct the anemia, even in the presence of a coexisting cause of anemia.


[OA] Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of Testosterone Levels With Anemia in Older Men - A Controlled Clinical Trial. JAMA Intern Med. Published online February 21, 2017. - http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2604139 -

Importance - In one-third of older men with anemia, no recognized cause can be found.

Objective - To determine if testosterone treatment of men 65 years or older with unequivocally low testosterone levels and unexplained anemia would increase their hemoglobin concentration.

Design, Setting, and Participants - A double-blinded, placebo-controlled trial with treatment allocation by minimization using 788 men 65 years or older who have average testosterone levels of less than 275 ng/dL. Of 788 participants, 126 were anemic (hemoglobin ≤12.7 g/dL), 62 of whom had no known cause. The trial was conducted in 12 academic medical centers in the United States from June 2010 to June 2014.

Interventions - Testosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months.

Main Outcomes and Measures - The percent of men with unexplained anemia whose hemoglobin levels increased by 1.0 g/dL or more in response to testosterone compared with placebo. The statistical analysis was intent-to-treat by a logistic mixed effects model adjusted for balancing factors.

Results - The men had a mean age of 74.8 years and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 30.7; 84.9% were white. Testosterone treatment resulted in a greater percentage of men with unexplained anemia whose month 12 hemoglobin levels had increased by 1.0 g/dL or more over baseline (54%) than did placebo (15%) (adjusted OR, 31.5; 95% CI, 3.7-277.8; P = .002) and a greater percentage of men who at month 12 were no longer anemic (58.3%) compared with placebo (22.2%) (adjusted OR, 17.0; 95% CI, 2.8-104.0; P = .002). Testosterone treatment also resulted in a greater percentage of men with anemia of known cause whose month 12 hemoglobin levels had increased by 1.0 g/dL or more (52%) than did placebo (19%) (adjusted OR, 8.2; 95% CI, 2.1-31.9; P = .003). Testosterone treatment resulted in a hemoglobin concentration of more than 17.5 g/dL in 6 men who had not been anemic at baseline.

Conclusions and Relevance - Among older men with low testosterone levels, testosterone treatment significantly increased the hemoglobin levels of those with unexplained anemia as well as those with anemia from known causes. These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men, but the overall health benefits remain to be established. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels.

 

[Michael Scally MD]

[OA] Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency

Key Points

Question - What are the cardiovascular risks of testosterone replacement therapy (TRT) in men with androgen deficiency?

Findings - When use in androgen-deficient men with documented low morning testosterone levels, TRT was not associated with an increased risk of cardiovascular outcomes. DURING LONG-TERM FOLLOW-UP THE RISK OF CARDIOVASCULAR OUTCOMES WAS LOWER IN TESTOSTERONE-TREATED MEN.

Meaning - These findings support the use of TRT in androgen-deficient men.

[OA] Cheetham TC, An J, Jacobsen SJ, Niu F, Sidney S, Quesenberry CP, VanDenEeden SK. Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency. JAMA Intern Med. Published online February 21, 2017. http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2604140

Importance - Controversy exists regarding the safety of testosterone replacement therapy (TRT) following recent reports of an increased risk of adverse cardiovascular events.

Objective - To investigate the association between TRT and cardiovascular outcomes in men with androgen deficiency.

Design, Setting, and Participants - A retrospective cohort study was conducted within an integrated health care delivery system. Men at least 40 years old with evidence of androgen deficiency either by a coded diagnosis and/or a morning serum total testosterone level of less than 300 ng/dL were included. The eligibility window was January 1, 1999, to December 31, 2010, with follow-up through December 31, 2012.

Exposures - Any prescribed TRT given by injection, orally, or topically.

Main Outcomes and Measures - The primary outcome was a composite of cardiovascular end points that included acute myocardial infarction (AMI), coronary revascularization, unstable angina, stroke, transient ischemic attack (TIA), and sudden cardiac death (SCD). Multivariable Cox proportional hazards models were used to investigate the association between TRT and cardiovascular outcomes. An inverse probability of treatment weight, propensity score methodology, was used to balance baseline characteristics.

Results - The cohorts consisted of 8808 men (19.8%) ever dispensed testosterone (ever-TRT) (mean age, 58.4 years; 1.4% with prior cardiovascular events) and 35 527 men (80.2%) never dispensed testosterone (never-TRT) (mean age, 59.8 years; 2.0% with prior cardiovascular events). Median follow was 3.2 years (interquartile range [IQR], 1.7-6.6 years) in the never-TRT group vs 4.2 (IQR, 2.1-7.8) years in the ever-TRT group. The rates of the composite cardiovascular end point were 23.9 vs 16.9 per 1000 person-years in the never-TRT and ever-TRT groups, respectively. The adjusted hazard ratio (HR) for the composite cardiovascular end point in the ever-TRT group was 0.67 (95% CI, 0.62-0.73. Similar results were seen when the outcome was restricted to combined stroke events (stroke and TIA) (HR, 0.72; 95% CI, 0.62-0.84) and combined cardiac events (AMI, SCD, unstable angina, revascularization procedures) (HR, 0.66; 95% CI, 0.60-0.72).

CONCLUSIONS AND RELEVANCE - AMONG MEN WITH ANDROGEN DEFICIENCY, DISPENSED TESTOSTERONE PRESCRIPTIONS WERE ASSOCIATED WITH A LOWER RISK OF CARDIOVASCULAR OUTCOMES OVER A MEDIAN FOLLOW-UP OF 3.4 YEARS.

 

[Michael Scally MD]

Morgentaler A. The Testosterone Trials: What the Results Mean for Healthcare Providers and for Science. Current Sexual Health Reports. The Testosterone Trials: What the Results Mean for Healthcare Providers and for Science

Purpose of Review - The purpose of this review was to assess the results of the Testosterone (T) Trials with regard to their clinical and scientific implications.

Recent Findings - The T Trials investigated 1 year of T gel versus placebo in 790 men 65 years and older with unequivocally low serum T concentrations (< 275 ng/dl). Safety monitoring was performed for an additional year.

Primary results were improvement over placebo for sexual desire, sexual activity, erection quality, physical activity, and mood. Vitality improved with some instruments, but not all. Improvement was noted in bone density and anemia.

Coronary CT provided mixed results—coronary calcium scores were unchanged whereas volume of non-calcified plaque increased more in the testosterone group. There were no worrisome safety concerns. Major adverse cardiovascular events over 2 years occurred in 9 testosterone-treated men and 16 placebo-treated men.

Summary - The T Trials provide high-level evidence of strong, broad benefits of T therapy, without substantive safety concerns.

 

[Michael Scally MD]

Lessons from the Testosterone Trials

The Testosterone Trials (TTrials) were a coordinated set of seven, placebo-controlled, double blind trials in 788 men of mean age 72 years to determine the efficacy of increasing the testosterone levels of older men with low testosterone.

Testosterone treatment increased the median testosterone level from unequivocally low at baseline to midnormal for young men after three months and maintained that level until month 12.

In the Sexual Function Trial, testosterone increased sexual activity, sexual desire and erectile function.

In the Physical Function Trial, testosterone did not increase the distance walked in 6 minutes in men whose walk speed was slow, but in all TTrials participants, testosterone did increase the distance walked.

In the Vitality Trial, testosterone did not increase energy but slightly improved mood and depressive symptoms.

In the Cognitive Function Trial, testosterone did not improve cognitive function.

In the Anemia Trial, testosterone increased hemoglobin in both men who had anemia of known cause as well as in men with unexplained anemia.

In the Bone Trial, testosterone increased volumetric bone mineral density and estimated strength of the spine and hip.

In the Cardiovascular Trial, testosterone increased coronary artery noncalcified plaque volume by computerized tomographic angiography.

Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial in a much larger number of men for a much longer period would be necessary to determine if testosterone increases cardiovascular or prostate risk.

Snyder PJ, Bhasin S, Cunningham GR, et al. Lessons from the Testosterone Trials. Endocrine reviews 2018. Lessons from the Testosterone Trials | Endocrine Reviews | Oxford Academic