Testosterone Trials (2016)

In Review

Snyder PJ, et al. "Effects of testosterone treatment in older men". '. 2016. 374(7):611-624.
PubMed • Full text • PDF

Clinical Question

In older male patients with hypogonadism, is testosterone replacement therapy, safe and effective in improving sexual function, physical function, and mood?

Bottom Line

In Caucasian males 65 years of age or older, daily application of testosterone gel moderately improves sexual function and mood, but showed no improvement in vitality or walking distance.

Major Points

Testosterone concentrations decrease while symptoms caused by low testosterone concentrations increase in men with increasing age. Symptoms caused by low testosterone include decrease in sexual function, physical function, and energy. Previous trials have yielded inconsistent results regarding sexual function, physical function, and energy. The Institute of Medicine panel concluded that there was insufficient evidence regarding the benefit of low testosterone treatment in men aged 65 and older with no PMH relating to lowering testosterone concentrations.

The Testosterone Trials include three main trials: the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. 750 male patients with average serum testosterone levels of less than 275 ng per deciliter were randomly assigned to treatment with testosterone AndroGel 1% or treatment with placebo for one year using a minimization technique. Patients were monitored for efficacy and adverse events at 3, 6, 9, and 12 months. Informed consent was provided by all participants. AndroGel 1% Gel and placebo were donated by AbbVie. AbbVie did not participate in the design, analysis, review or reporting of the trials.

The primary outcome of the Sexual Function Trial indicated that sexual activity increased more in men with testosterone treatment when compared to men who received placebo (P<0.001). According to the DISF-M-II, treatment with testosterone was also associated with increased sexual desire (P<0.001). The Physical Function Trial revealed no significant differences between the two groups in the percentage of participants whose 6-minute walking distance increased by at least 50m (P=0.20). Participants in the treatment group were more likely to perceive that their walking ability had improved throughout the course of the trial as compared to the participants who received placebo (P<0.002). The Vitality Function Trial showed no benefit in receiving testosterone over placebo, as interpreted by the FACIT-Fatigue score (P=0.30).

Guidelines

According to the Endocrine Society’s current guidelines, testosterone therapy is recommended for symptomatic men with classical androgen deficiency syndromes aimed at inducing and maintaining secondary sex characteristics and at improving their sexual function, sense of wellbeing, and bone mineral density. Testosterone therapy is not recommended in patients with breast or prostate cancer, and without further urological evaluation in patients with palpable prostate nodule or induration or PSA > 4 ng/ml or PSA > 3 ng/ ml in men at high risk of prostate cancer, such as African Americans or men with first-degree relatives with prostate cancer. It is also not recommended in patients with hematocrit >50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms (AUA/ IPSS score > 19), or uncontrolled or poorly controlled heart failure, or in those desiring fertility.

Design

• Double-blinded, randomized, placebo-controlled trials; coordinated set of 3 separate trials
• n=790
  • Testosterone n=394 (one patient removed due to randomization error)
  • Placebo n=394 (one patient removed due to randomization error)
• Setting: 12 clinical trial sites in the U.S.
• Follow-up: 12 months
• Analysis: Intention-to-treat
• Primary outcomes:
  • Sexual function trial: PDQ-Q4 score
  • Vitality trial: increase of ≥4 in FACIT- Fatigue score
  • Physical function trial: increase of ≥50 m in 6-min walk test

Population

Inclusion Criteria

• 65 and older
• Serum testosterone average less than 275 ng/dL

Exclusion Criteria

• History of prostate cancer
• A risk of all prostate cancer of more than 35% or of high-grade prostate cancer of more than 7% as determined according to the Prostate Cancer Risk Calculator, an International Prostate Symptom Score (IPSS; range, 0 to 35, with higher scores indicating more severe symptoms of benign prostatic hyperplasia) of more than 19
• Conditions known to cause hypogonadism
• Receipt of medications that alter the testosterone concentration
• High cardiovascular risk (myocardial infarction or stroke within the previous 3 months, unstable angina, New York Heart Association class III or IV congestive heart failure, a systolic blood pressure >160 mmHg, or a diastolic blood pressure >100 mmHg)
• Severe depression (defined by a score of ≥20 on the Patient Health Questionnaire 9 [PHQ-9; range, 0 to 27, with higher scores indicating greater severity of depressive symptoms])
• Conditions that would affect the interpretation of the results

Baseline Characteristics

From the testosterone group

• Demographics:
  • Age 72 yr (±5.7)
  • Male: 100%
  • Caucasian: 88.4%, African American: 5.3%
  • Non-Hispanic: 95.2%
  • College graduates: 54.2%
  • Married or living with partner: 73.4%
• Concomitant conditions:
  • Average BMI: 31.0 kg/m2
  • Avg 3 alcoholic drinks/week (±4.3)
  • Current smokers (cigarettes or cigars): 7.6%
  • Diabetes: 37.5%
  • Hypertension: 72.4%
  • History of MI: 13.4%
  • History of stroke: 4.1%
  • Sleep apnea: 19.8%
  • Risk(%) of all prostate cancer: 17.3 ± 6.0
  • Risk(%) of high grade prostate cancer: 2.9 ± 1.7
• Medication Use:
  • Alpha blocking agents: 14%
  • 5-alpha reductase inhibitors: 3.8%
  • Phosphodiesterase inhibitors: 7.6%
• Average Sex Hormone levels:
  • Testosterone: 232 ng/dL ± 63
  • Free testosterone: 62.0 pg/mL ± 21.4
  • Dihydrotestosterone: 21.3 ng/dL ± 11.6
  • Estradiol: 20.3 pg/mL ± 6.7
  • Sex hormone binding globulin: 31.4 nM ± 15.2
• Performance:
  • Mini-mental State Examination Score: 28.4 ± 1.7
  • Gait speed: 1.1m/s ± 0.2
  • Derogatis Interview for Sexual Function - Sexual Desire: 13.9 ± 7.7
  • FACIT-Fatigue: 37.0 ± 8.6

Interventions

• Intervention group received:
  • Androgel 1% pump bottle 5 grams applied daily
• Placebo group received:
  • Gel formulated to have similar application and appearance
• Serum testosterone concentration measured at months 1, 2, 3, 6, and 9 in a central laboratory
• Dose of gel was adjusted after each measurement to keep in normal range for young men (19-40)

Outcomes

Comparisons reported as testosterone vs. placebo

Primary Outcomes

Sexual Function

PDQ-Q4 score (range from 0 to 12, with higher scores indicating a greater number of activities): 0.2±1.6 vs -0.1±1.4; Treatment Effect: 0.58 (CI 0.38-0.78), P<0.001

Vitality

increase of ≥4 in FACIT- Fatigue score- no./total no. (%): 147/203 (72.4) vs.120/191 (62.8); treatment effect 1.23 (CI 0.83-1.84), P=0.30

Physical Function

increase of ≥50 m in 6-min walk test - no. /total no. (%)

35/172 (20.3) vs. 20/165 (12.1); treatment effect: 1.42 (CI 0.83-2.45), P=0.20

Secondary Outcomes

Sexual Function

DISF-M-II sexual desire score: 2.6±6.5 vs. 0.0±5.0; Treatment effect: 2.93 (CI 2.13-3.74), P<0.001

IIEF erectile function score: 3.1±6.9 vs. 1.0±6.0; treatment effect: 2.64 (CI 1.68-3.61), P<0.001

Vitality

FACIT-Fatigue Score: 8.0±8.4 vs. 6.7±9.4; treatment effect 1.21 (CI -0.04-2.46), P=0.06

SF-36 vitality score: 8.2±15.3 vs. 6.1±13.8; treatment effect 2.41 (CI 0.31-4.50), P=0.03

PANAS positive affect score: 0.7±3.9 vs. 0.2±3.2; treatment effect 0.47 (CI 0.02-0.92), P=0.04

PANAS negative affect score: -0.6±2.1 vs. -0.1±2.6; treatment effect -0.49 (CI -0.79 to -0.19), P<0.001

PHQ-9 depression score: -1.8±3.7 vs. -1.1±3.8; treatment effect -0.27 (CI -1.20 to -0.23), P=0.004

Physical Function

6-Min walking distance - m: 14.3±45.9 vs. 5.5±46.4; treatment effect: 4.09 (CI 3.00-11.18), P=0.28

Increase of ≥8 in PF-10 score- no./total no. (%): 66/173 (38.2) vs. 58/167 (34.7); treatment effect 1.34 (CI 0.90-2.00), P=0.15

PF-10 Score: 5.8±17.5 vs. 2.4±17.3; treatment effect: 2.75 (CI 0.20-5.29), P=0.03

Adverse Events

PSA increase ≥1.0 ng/mL: 5.84% vs. 2.03% (no p-value reported)

Prostate cancer: 0.25% vs. 0.0% (no p-value reported)

Definite MI: 0.51% vs. 0.0% (no p-value reported)

Hospitalization: 17.3% vs. 20.1% (no p-value reported)

Death from cardiovascular causes: 0% vs. 0.25% (no p-value reported)

Death: 0.76% vs. 1.78% (no p-value reported)

Criticisms

• External:
  • Results only apply to men >65 yrs with testosterone levels <275 ng/dL.
  • The population is homogeneous (i.e. Caucasian males).
  • Patient-oriented outcomes (e.g. more frequent and more satisfactory sex) were not reported

• Internal:
  • Allocation concealment was not described; potential for selection bias.

Funding

Funded by the National Institute on Aging, National Institutes of Health, AbbVie, National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and Stroke, and the National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT00799617.