Testosterone Replacement in Men with Age-Related Low Testosterone: What Did We Learn From The Testosterone Trials?
Ontology highlight
ABSTRACT:
SUBMITTER: Matsumoto AM
PROVIDER: S-EPMC7009797 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
Publications
Testosterone Replacement in Men with Age-Related Low Testosterone: What Did We Learn From The Testosterone Trials?
Current opinion in endocrine and metabolic research 20190425
The T Trials were a coordinated set of seven double-blind, placebo-controlled trials to assess efficacy and safety of testosterone versus placebo gel treatment for one year in 788 older men 65 years or older with hypogonadism who had self-reported and objective impairment of sexual and physical function and/or vitality and an average of two morning serum testosterone concentrations < 275 ng/dL. Testosterone dose was adjusted to the mid-normal range for young men. Compared to placebo, testosteron ...[more]
Similar Datasets
Project description:ContextTestosterone increases skeletal muscle mass and strength, but the effects of testosterone on aerobic performance in mobility-limited older men have not been evaluated.ObjectiveTo determine the effects of testosterone supplementation on aerobic performance, assessed as peak oxygen uptake (V̇O2peak) and gas exchange lactate threshold (V̇O2θ), during symptom-limited incremental cycle ergometer exercise.DesignSubgroup analysis of the Testosterone in Older Men with Mobility Limitations Trial.SettingExercise physiology laboratory in an academic medical center.ParticipantsSixty-four mobility-limited men 65 years or older with low total (100-350 ng/dL) or free (<50 pg/dL) testosterone.InterventionsParticipants were randomized to receive 100-mg testosterone gel or placebo gel daily for 6 months.Main outcome measuresV̇O2peak and V̇O2θ from a symptom-limited cycle exercise test.ResultsMean (SD) baseline V̇O2peak was 20.5 (4.3) and 19.9 (4.7) mL/kg/min for testosterone and placebo, respectively. V̇O2peak increased by 0.83 (2.4) mL/kg/min in testosterone but decreased by -0.89 (2.5) mL/kg/min in placebo (P = .035); between group difference in change in V̇O2peak was significant (P = .006). This 6-month reduction in placebo was greater than the expected -0.4-mL/kg/min/y rate of decline in the general population. V̇O2θ did not change significantly in testosterone but decreased by 1.1 (1.8) mL/kg/min in placebo, P = .011 for between-group comparisons. Hemoglobin increased by 1.0 ± 3.5 and 0.1 ± 0.8 g/dL in testosterone and placebo groups, respectively.ConclusionTestosterone supplementation in mobility-limited older men increased hemoglobin and attenuated the age-related declines in V̇O2peak and V̇O2θ. Long-term intervention studies are needed to determine the durability of this effect.
| S-EPMC4891791 | biostudies-literature
Project description:Background 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, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this set of trials. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one participant. Conclusion Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.
| S-EPMC4182174 | biostudies-literature
Project description:ImportanceMost cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions.ObjectiveTo 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 participantsThe 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.InterventionsTestosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year.Main outcomes and measuresThe 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.ResultsAmong 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 relevanceAmong 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.Trial registrationclinicaltrials.gov Identifier: NCT00799617.
| S-EPMC5433758 | biostudies-literature
Project description:Growth hormone is the major regulator of growth and body composition. Pulsatile GH secretion declines exponentially with age. Testosterone replacement is being increasingly offered to older men with age-related low testosterone. Testosterone administration has been shown to stimulate GH secretion. However, little is known about the effect of testosterone aromatization to estradiol on GH pulsatility and its impact on IGF-1 in older men. OBJECTIVE:This randomized controlled proof-of-concept trial investigated the relative effects of testosterone and estradiol on GH pulsatility and IGF-1 in older men with low testosterone. DESIGN:Thirty-seven men, ?65years with total testosterone <350ng/dL were randomized to 5g transdermal testosterone gel (TT), 1mg oral aromatase inhibitor (AI) or placebo daily for 12months. Primary outcome was deconvolution and approximate entropy analyses of pulsatile including basal and entropic modes of secretion performed at baseline and 3months. Secondary outcomes included IGF-1 evaluated at baseline, 3 and 6months. RESULTS:At 3months, mean GH and in IGF-1 were similar between the three groups. At 6months, IGF-1 significantly increased by ? 15.3±10.3ng/ml in the TT-group compared to placebo (P=0.03). Both intervention groups significantly increased GH pulse frequency (TT-group, P=0.04; AI-group, P=0.05) compared to placebo. The GH secretory-burst mode (duration) significantly decreased in the TT-group (P=0.0018) compared to placebo while it remained unchanged in the AI-group (P=0.059). CONCLUSIONS:In older men, testosterone increases GH pulse frequency while the aromatization to estradiol is involved in the rise of IGF-1 levels.
| S-EPMC5950718 | biostudies-literature
Project description:ContextTestosterone increases skeletal muscle mass and strength, but long-term effects of testosterone supplementation on aerobic capacity, or peak oxygen uptake (V̇O2peak), in healthy older men with low testosterone have not been evaluated.ObjectiveTo determine the effects of testosterone supplementation on V̇O2peak during incremental cycle ergometry.DesignA double-blind, randomized, placebo-controlled, parallel-group trial (Testosterone's Effects on Atherosclerosis Progression in Aging Men).SettingExercise physiology laboratory.ParticipantsHealthy men aged ≥ 60 years with total testosterone levels of 100 to 400 ng/dL (3.5 to 13.9 nmol/L) or free testosterone levels < 50 pg/mL (174 pmol/L).InterventionsRandomization to 1% transdermal testosterone gel adjusted to achieve serum levels of 500 to 950 ng/dL or placebo applied daily for 3 years.Main outcome measuresChange in V̇O2peak.ResultsMean (±SD) baseline V̇O2peak was 24.2 ± 5.2 and 23.6 ± 5.6 mL/kg/min for testosterone and placebo, respectively. V̇O2peak did not change in men treated with testosterone but fell significantly in men receiving placebo (average 3-year decrease, 0.88 mL/kg/min; 95% CI, -1.39 to 0.38 mL/kg/min; P = 0.035); the difference in change in V̇O2peak between groups was significant (average 3-year difference, 0.91 mL/kg/min; 95% CI, 0.010 to 0.122 mL/kg/min; P = 0.008). The 1-g/dL mean increase in hemoglobin (P < 0.001) was significantly associated with changes in V̇O2peak in testosterone-treated men.ConclusionThe mean 3-year change in V̇O2peak was significantly smaller in men treated with testosterone than in men receiving placebo and was associated with increases in hemoglobin. The difference in V̇O2peak change between groups may indicate attenuation of its expected age-related decline; the clinical meaningfulness of the modest treatment effect remains to be determined.
| S-EPMC6669813 | biostudies-literature
Project description:ContextThe Testosterone Trials are a coordinated set of seven trials to determine the efficacy of T in symptomatic men ≥65 years old with unequivocally low T levels. Initial results of the Sexual Function Trial showed that T improved sexual activity, sexual desire, and erectile function.ObjectiveTo assess the responsiveness of specific sexual activities to T treatment; to relate hormone changes to changes in sexual function; and to determine predictive baseline characteristics and T threshold for sexual outcomes.DesignA placebo-controlled trial.SettingTwelve academic medical centers in the United States.ParticipantsA total of 470 men ≥65 years of age with low libido, average T <275 ng/dL, and a partner willing to have sexual intercourse at least twice a month.MethodsMen were assigned to take T gel or placebo for 1 year. Sexual function was assessed by three questionnaires every 3 months: the Psychosexual Daily Questionnaire, the Derogatis Interview for Sexual Function, and the International Index of Erectile Function.ResultsCompared with placebo, T administration significantly improved 10 of 12 measures of sexual activity. Incremental increases in total and free T and estradiol levels were associated with improvements in sexual activity and desire, but not erectile function. No threshold T level was observed for any outcome, and none of the 27 baseline characteristics predicted responsiveness to T.ConclusionsIn older men with low libido and low T levels, improvements in sexual desire and activity in response to T treatment were related to the magnitude of increases in T and estradiol levels, but there was no clear evidence of a threshold effect.
| S-EPMC4971331 | biostudies-literature
Project description:OBJECTIVE:The aim of the study was to examine whether receipt of testosterone replacement therapy was associated with reduced 30-day rehospitalization after postacute care among older men with testosterone deficiency. DESIGN, PATIENTS, AND METHODS:We conducted a retrospective cohort study using a 5% national sample of Medicare beneficiaries. We identified 1290 nonsurgical inpatient postacute care discharges between January 1, 2007, and October 31, 2014, for male patients, 66 yrs or older, with a previous diagnosis of testosterone deficiency. Multivariable logistic regression was used to calculate odds ratios and 95% confidence intervals for 30-day postacute care rehospitalization related to receipt of testosterone replacement therapy. RESULTS:In older men with testosterone deficiency, receipt of testosterone replacement therapy was not associated with rehospitalization (odds ratio = 0.87, 95% confidence interval, 0.59-1.29) in the 30 days after postacute care discharge. These findings persisted after adjustment for quintile of propensity scores (odds ratio = 0.90, 95% confidence interval = 0.62-1.30). CONCLUSION:Testosterone replacement therapy was not associated with reduced rehospitalization after postacute care discharge in older men with testosterone deficiency. Further research in this population should examine the effects of testosterone replacement therapy on functional recovery and community independence.
| S-EPMC6522284 | biostudies-literature
Project description:ImportanceRecent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk.ObjectiveTo test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume.Design, setting, and participantsDouble-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.InterventionTestosterone 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 measuresThe 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).ResultsOf 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 relevanceAmong 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.Trial registrationclinicaltrials.gov Identifier: NCT00799617.
| S-EPMC5465430 | biostudies-literature
Project description:Background:Serum testosterone levels and insulin sensitivity both decrease with age. Severe testosterone deficiency is associated with the development of insulin resistance. However, the effects of long-term testosterone administration on insulin sensitivity in older men with low or low-normal testosterone levels remain unknown. Methods:The Testosterone Effects on Atherosclerosis in Aging Men Trial was a placebo-controlled, randomized, double-blind trial. The participants were 308 community-dwelling men, ?60 years old, with total testosterone 100 to 400 ng/dL or free testosterone <50 pg/mL. A subset of 134 nondiabetic men (mean age, 66.7 ± 5.1 years) underwent an octreotide insulin suppression test at baseline and at 3 and 36 months after randomization to measure insulin sensitivity. Insulin sensitivity was estimated as the steady-state plasma glucose (SSPG) concentration at equilibrium during octreotide and insulin administration. Secondary outcomes included total lean mass (TLM) and total fat mass (TFM) by dual energy x-ray absorptiometry. Results:There was a significant (P = 0.003) increase in SSPG in the placebo group, whereas no change was seen in testosterone-treated subjects from baseline to 36 months; however, the between-group differences in change in SSPG over 3 years were not statistically significant (+15.3 ± 6.9 mg/dL in the placebo group vs +6.2 ± 6.4 mg/dL in the testosterone group; mixed-model effect, P = 0.17). Changes in SSPG with testosterone treatment were not associated with changes in serum total or free testosterone concentrations. Changes in TFM but not TLM were associated with increases in SSPG. Stratification by age or baseline total testosterone level did not show significant intervention effects. Conclusion:Testosterone administration for 36 months in older men with low or low-normal testosterone levels did not improve insulin sensitivity.
| S-EPMC6276701 | biostudies-literature
Project description:Testosterone (T) replacement is being increasingly offered to older men with age-related decline in testosterone levels. The effects of long-term testosterone replacement and aromatase inhibition (AI) on glucose homeostasis and cardiometabolic markers were determine in older non-diabetic men with low testosterone levels. Men ?65 years, mean age 71 ± 3 years with serum total T < 350 ng/dL were randomized in a double-blind, placebo-controlled, parallel-group, proof-of-concept trial evaluating the effects of 5 g transdermal testosterone gel (TT) (n = 10), 1 mg anastrozole (n = 10) or placebo (n = 9) daily for 12 months. Homeostatic Model Assessment of insulin resistance (HOMAIR ) was the primary outcome. Secondary outcomes included OGIS in response to OGTT, fasting lipids, C-reactive protein (CRP), adipokines, and abdominal and mid-thigh fat by computed tomography. All outcomes were assessed at baseline and 12 months. After 12 months, absolute changes in HOMAIR in both treatment arms (TT group: -0.05 ± 0.21); (AI group: 0.15 ± 0.10) were similar to placebo (-0.11 ± 0.26), as were CRP and fasting lipid levels. Adiponectin levels significantly decreased in the TT group (-1.8 ± 0.9 mg/L, p = 0.02) and abdominal subcutaneous fat (-60.34 ± 3.19 cm2 , p = 0.003) and leptin levels (-1.5 ± 1.2 ng/mL, p = 0.04) were significantly lower with AI. Mid-thigh subcutaneous fat was reduced in both treatment arms (TT group: -4.88 ± 1.24 cm2 , p = 0.008); (AI group: -6.05 ± 0.87 cm2 , p = 0.0002). In summary, in this proof-of-concept trial, changes in HOMAIR AI were similar in all three groups while the effects of intervention on subcutaneous fat distribution and adipokines were variable. Larger efficacy and safety trials are needed before AI pharmacotherapy can be considered as a treatment option for low T levels in older men.
| S-EPMC5794008 | biostudies-literature