T4DM Trial and its T4Bone Substudy Shed Further Light on Effects of Testosterone Treatment in Middle-Aged and Older Men.
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ABSTRACT:
SUBMITTER: Bhasin S
PROVIDER: S-EPMC8277201 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Age-related changes in testosterone are believed to be a key component of the processes that contribute to cognitive aging in men. The APOE-ε4 allele may interact with testosterone and moderate the hormone's association with cognition. The goals of the present study were to examine the degree to which free testosterone is associated with episodic memory in a community-based sample of middle-aged men, and examine the potential interaction between free testosterone and the APOE-ε4 allele. Data were used from 717 participants in the Vietnam Era Twin Study of Aging. Average age was 55.4 years (standard deviation = 2.5). Significant positive associations were observed between free testosterone level and verbal episodic memory, as well as a significant interaction between free testosterone and APOE-ε4 status. In ε4 carriers free testosterone was positively associated with verbal episodic memory performance (story recall), whereas no association was observed in ε4 noncarriers. Results support the hypothesis that APOE-ε4 status increases susceptibility to other risk factors, such as low testosterone, which may ultimately contribute to cognitive decline or dementia.
| S-EPMC3980008 | biostudies-literature
Project description:BackgroundSerum testosterone deficiency increases with aging. Age is also a major risk factor for prostate cancer (PrCa) and PCa tumors are more frequently diagnosed among men >65 years old. We evaluated the relationship between preoperative serum testosterone and clinical/ pathological features of PrCa in middle-aged and elderly patients.MethodsA total of 605 PrCa patients who underwent robotic-assisted radical prostatectomy between September 2010 and January 2013 at the University of Pennsylvania, and who had serum testosterone levels measured using Elecsys Testosterone II Immunoassay were included in this IRB-approved protocol. Androgen deficiency was determined as serum free testosterone (FT) <47 pg/ml and total testosterone (TT) <193 ng/dl. Demographic, clinical and tumor characteristics of men with low vs. normal TT or FT were compared using t-test or chi-square tests. Logistic regression was used to determine associations of clinical and pathological variables with FT or TT levels.ResultsAmong middle-aged men (45-64 years; n = 367), those with low FT and low TT had, on average, a higher BMI (29.7 vs. 27.4, P < 0.01; and 32.2 vs. 27.6; P < 0.01, respectively) and higher proportion of Gleason 8-10 PrCa (13.3% vs. 4.8%, P = 0.011; and 19.2% vs. 5.1%, P = 0.012) compared to men with normal FT and normal TT values. Patients with low FT had also higher number of positive cores on biopsy (3.9 vs. 3.1 P = 0.019) and greater tumor volume (7.9 ml vs. 6.1 ml, P = 0.045) compared to those with normal FT. Among men ≥65 years (n = 135) there was no difference in prostatectomy specimens of PrCa between patients with low or normal FT or TT.ConclusionAmong men aged 45-64 years low serum pretreatment FT and TT predicted more aggressive features of PrCa in prostatectomy specimens. In middle-aged patients low testosterone levels measured pre-operatively may indicate more aggressive disease parameters.
| S-EPMC5357970 | biostudies-literature
Project description:Aging in men is associated with loss of bone mass, impaired physical function and altered body composition. The objective of this proof-of-concept randomized, double-blind, placebo-controlled, parallel-group, single-center trial was to determine the relative effects of testosterone (T) and estradiol (E(2)) on bone mineral density, body composition, and physical performance in older men. The primary outcome was lumbar spine bone mineral density (BMD), and secondary outcomes were body composition, muscle strength, gait speed, and sex hormone concentrations. Forty three men (age range, 65-82 years; mean age 71 years) with low total T levels <350 ng/dL were randomized to one of three groups: 5 g transdermal testosterone gel (TT) (N = 16), anastrozole (AI) 1 mg (N = 14) or placebo daily (N = 13) for 12 months. Outcomes were assessed at baseline, 3, 6, and 12 months. Both TT and AI increased serum TT levels (>500 ng/dL, p < 0.05) compared to baseline; T values remained stable throughout the duration of the trial. At 12 months, TT improved the primary outcome of lumbar spine BMD (p < 0.01).Both interventions improved knee strength at 12 months compared to baseline (p < 0.05) while lean body mass significantly increased only in the AI group at 6 and 12 months (1.49 ± 0.38 kg, p < 0.01; 1.24 ± 0.39 kg, p < 0.05, respectively) compared to baseline. Interestingly, TT improved fast gait speed at 3 and 12 months (p < 0.01, p < 0.05, respectively). In summary, this proof-of-concept study confirms that aromatization of T is required for maintaining BMD in older men with low-T levels. The trial also uncovered the novel finding that aromatization of T is required for improvement in fast gait speed, an observation that needs to be verified in future studies.
| S-EPMC5836312 | biostudies-literature
Project description:Animal and human research suggests that testosterone is associated with hippocampal structure and function. Studies examining the association between testosterone and either hippocampal structure or hippocampal-mediated cognitive processes have overwhelmingly focused on the effects of testosterone alone, without considering the interaction of other neuroendocrine factors. The aim of the present study was to examine the interactive effects of testosterone and cortisol in relation to hippocampal volume and episodic memory in a sample of late-middle aged men from the Vietnam Era Twin Study of Aging. The average age of participants was 56.3 years (range 51-60). Salivary hormone samples were collected at multiple time-points on two non-consecutive at-home days, and an in-lab assessment. Area under the curve with respect to ground measures for cortisol and testosterone were utilized. Significant testosterone-by-cortisol interactions were observed for hippocampal volume, and episodic memory. When cortisol levels were elevated (1 SD above the mean), testosterone levels were positively associated with hippocampal volume and memory performance. However, when cortisol levels were low (1 SD below the mean), testosterone levels were inversely related to hippocampal volume and memory performance. These findings suggest that in context of high cortisol levels, testosterone may be neuroprotective. In contrast, low testosterone may also be neuroprotective in the context of low cortisol levels. To our knowledge this is the first demonstration of such an interaction in a structural brain measure and an associated cognitive ability. These results argue in favor of broadening neuroendocrine research to consider the simultaneous and interactive effects of multiple hormones on brain structure and function.
| S-EPMC5931212 | biostudies-literature
Project description:The hippocampus expresses a large number of androgen receptors; therefore, in men it is potentially vulnerable to the gradual age-related decline of testosterone levels. In the present study we sought to elucidate the nature of the relationship between testosterone and hippocampal volume in a sample of middle-aged male twins (average age 55.8 years). We found no evidence for a correlation between testosterone level and hippocampal volume, as well as no indication of shared genetic influences. However, a significant moderating effect of testosterone on the genetic and environmental determinants of hippocampal volume was observed. Genetic influences on hippocampal volume increased substantially as a function of increasing testosterone level, while environmental influences either decreased or remained stable. These findings provide evidence for an apparent gene-by-hormone interaction on hippocampal volume. To the best of our knowledge, this is the first study to demonstrate that the heritability of a brain structure in adults may be modified by an endogenous biological factor.
| S-EPMC3230702 | biostudies-literature
Project description:BackgroundLow vitality is a common symptom of testosterone deficiency; however, clinical trial results remain inconclusive regarding the responsiveness of this symptom to hormone replacement.AimThe aim of the present study was to determine if the relationship between circulating testosterone levels and vitality would be moderated by the CAG repeat length in the androgen receptor (AR) gene, which influences the receptor's sensitivity to testosterone.MethodsWe examined 676 men in the Vietnam Era Twin Study of Aging when they were, on average, 55.4 years old (SD = 2.5). Salivary testosterone levels were measured by using 3 samples collected at waking on 3 nonconsecutive days. The average testosterone level was classified as low, normal, or high based on 1-SD cutoffs. Analyses were conducted using multilevel, mixed linear models, which accounted for the nonindependence of the twin data, and adjusted for the effects of age, ethnicity, BMI, chronic health conditions, depressive symptoms, and sleep quality.OutcomesVitality was measured using the 36-item Short Form (SF-36) vitality subscale.ResultsWe observed a significant interaction between salivary testosterone and the AR-CAG repeat length. When the repeat length was short, men with low testosterone had significantly lower vitality. As the AR-CAG repeat length increased, the magnitude of the testosterone effect decreased.Clinical translationThe observed interaction between testosterone and variation in the AR gene suggests that men with more sensitive ARs, as indicated by a shorter AR-CAG repeat, are more likely to experience symptoms of age-related testosterone deficiency.Strengths & limitationsStrengths of the present study include our use of a large community-based sample, the use of multiple testosterone measurements, and the availability of a comprehensive set of covariates that may impact the association of interest. Limitations include the homogeneous nature of the sample with respect to ethnicity, the brevity of the 36-item Short Form vitality subscale, and our inability to establish change in testosterone levels because of the cross-sectional nature of data.ConclusionsThe association between testosterone and vitality appears to be clinically meaningful and is in part dependent on variation in the AR gene. Panizzon MS, Bree K, Hsieh T-C, et al. Genetic Variation in the Androgen Receptor Modifies the Association Between Testosterone and Vitality in Middle-Aged Men. J Sex Med 2020;17:2351-2361.
| S-EPMC7718411 | biostudies-literature
Project description:Testosterone regulates numerous physiological processes, and evidence suggests that it plays a critical role in male aging. It has yet to be determined whether the heritability of testosterone varies in accordance with its diurnal rhythm. Similarly, it is unclear whether changes in testosterone level throughout the day are genetically influenced. The aim of the present study was to determine the degree to which genetic and environmental factors contribute to individual differences in testosterone throughout the day in middle-aged men.Saliva-based measures of free testosterone, sampled at multiple time-points both at-home and in-lab, were collected from 783 male twins (193 monozygotic pairs, 196 dizygotic pairs, 5 unpaired twins) as part of the Vietnam Era Twin Study of Aging (VETSA). The average age of participants was 55.9 years (SD=2.6).Testosterone levels declined substantially over the course of the day, with 32-39% of the change occurring in the first 30min after waking. Heritability estimates for specific time-points ranged from .02 to .39. The heritability of the average at-home and in-lab testosterone values were notably higher (.42 and .47 respectively). Daily rates of change showed some evidence of genetic influence, with heritability estimates ranging from .15 to .29, whereas there were no observable genetic influences on coefficients of variation.Genetic influences account for a significant proportion of the variance in average testosterone levels, while environmental factors account for the majority of intra-individual variability. These results highlight the need to explore both genetic and individual-specific environmental factors as determinants of free testosterone levels in aging men.
| S-EPMC3775872 | biostudies-other
Project description:BackgroundSerum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established.MethodsWe assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials--the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants.ResultsTestosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups.ConclusionsIn symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.).
| S-EPMC5209754 | biostudies-literature
Project description:ImportanceIn one-third of older men with anemia, no recognized cause can be found.ObjectiveTo 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 participantsA 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.InterventionsTestosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months.Main outcomes and measuresThe 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.ResultsThe 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 relevanceAmong 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.Trial registrationclinicaltrials.gov Identifier: NCT00799617.
| S-EPMC5433757 | 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