Testosterone Therapy for the Treatment of Age-Related Hypogonadism: Risks with Uncertain Benefits.
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ABSTRACT:
SUBMITTER: Nguyen CP
PROVIDER: S-EPMC8142681 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
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Testosterone Therapy for the Treatment of Age-Related Hypogonadism: Risks with Uncertain Benefits.
Nguyen Christine P CP Hirsch Mark M Kaul Suresh S Woods Corinne C Joffe Hylton V HV
Androgens: clinical research and therapeutics 20210506 1
Testosterone replacement therapy has been approved in the United States since the 1950s for men with "classical" hypogonadism. These men have specific and well-recognized hypothalamic, pituitary, or testicular conditions leading to deficient or absent endogenous testosterone. A more controversial treatment population is aging men, many with comorbidities, who have low serum testosterone concentrations compared with young healthy men and who do not have the well-recognized medical conditions that ...[more]
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Project description:Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different results. In this paper, we analyzed plasma from 20 IS patients with low testosterone (<8 nmol/L) and HOMAi < 2.5. The samples, pre- and post-treatment with testosterone for 60 days, were analyzed by UHPLC and mass spectrometry. Glycolysis was significantly upregulated, suggesting an improved glucose utilization. Conversely, the pentose phosphate pathway was reduced, while the Krebs cycle was not used. Branched amino acids and carnosine metabolism were positively influenced, while β-oxidation of fatty acids (FFA) was not activated. Cholesterol, HDL, and lipid metabolism did not show any improvements at 60 days but did so later in the experimental period. Finally, both malate and glycerol shuttle were reduced. As a result, both NADH and ATP were significantly lower. Interestingly, a significant production of lactate was observed, which induced the activation of the Cori cycle between the liver and muscles, which became the main source of energy for these patients without involving alanine. Thus, the treatment must be integrated with chemicals which are not restored in order to reactivate energy production.
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Project description:We developed a mathematical model to identify the timing of antiretroviral therapy (ART) initiation that optimizes patient outcomes as a function of patient CD4 count, age, cardiac mortality risk, sex, and personal preferences. Our goal was to find the conditions that maximize patient quality-adjusted life expectancy (QALE) in the context of our model. Under the assumption that ART confers disease progression and mortality benefits at any CD4 count, immediate treatment initiation yields the greatest remaining QALE for young patients under most circumstances. The timing of ART initiation depends on the magnitude of benefit from ART at high CD4 counts, the magnitude of increases in cardiac risk, and patients' preferences. If ART reduces HIV progression at high CD4 counts, immediate ART is preferable for most newly infected individuals <35 years even if ART doubles age- and sex-specific cardiac risk.
| S-EPMC3478144 | biostudies-literature
Project description:BackgroundMale hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels.ObjectiveTo evaluate the efficacy and safety of a novel oral testosterone undecanoate therapy for the treatment of hypogonadism.Material and methodsNinety-five (N = 95) hypogonadal men were enrolled in this open-label, single-arm, multicenter study in the United States (NCT03242590). Subjects received 225 mg of oral testosterone undecanoate (TLANDO) twice a day for 24 days without dose adjustment. Primary efficacy was percentages of subjects who achieved mean 24-h testosterone levels within the eugonadal range and secondary efficacies were evaluated based on the upper limit of lab normal range of testosterone concentration.ResultsSubjects enrolled were on average age of 56 years, with about 17% of subjects older than 65 years. The mean body mass index was 32.8 kg/m2 . The baseline mean total testosterone values were below the normal range (202 ± 74 ng/dl). Post-treatment with 450 mg testosterone undecanoate daily dose without dose adjustment, 80% of subjects (95% confidence interval of 72%-88%) achieved a testosterone Cavg in the normal range and restored testosterone levels to mean testosterone Cavg of 476 ± 184 ng/dl at steady state. Testosterone restoration was comparable to other approved testosterone replacement therapy products. TLANDO was well tolerated with no deaths, no drug-related serious adverse events, and no hepatic adverse events.Discussion and conclusionsTLANDO restored testosterone levels to the normal range in the majority of hypogonadal males. This new oral testosterone replacement therapy can provide an option for no-titration oral testosterone replacement therapy. This therapy has the potential to improve patient compliance in testosterone replacement therapy.
| S-EPMC9304136 | biostudies-literature
Project description:ImportanceThe effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown.ObjectiveTo compare the effect of TRT vs placebo on the incidences of high-grade prostate cancers (Gleason score ≥4 + 3), any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism.Design, setting, and participantsThis placebo-controlled, double-blind randomized clinical trial enrolled 5246 men (aged 45-80 years) from 316 US trial sites who had 2 testosterone concentrations less than 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. Men with prostate-specific antigen (PSA) concentrations greater than 3.0 ng/mL and International Prostate Symptom Score (IPSS) greater than 19 were excluded. Enrollment took place between May 23, 2018, and February 1, 2022, and end-of-study visits were conducted between May 31, 2022, and January 19, 2023.InterventionParticipants were randomized, with stratification for prior CVD, to topical 1.62% testosterone gel or placebo.Main outcomes and measuresThe primary prostate safety end point was the incidence of adjudicated high-grade prostate cancer. Secondary end points included incidence of any adjudicated prostate cancer, acute urinary retention, invasive prostate surgical procedure, prostate biopsy, and new pharmacologic treatment. Intervention effect was analyzed using a discrete-time proportional hazards model.ResultsA total of 5204 men (mean [SD] age, 63.3 [7.9] years) were analyzed. At baseline, the mean (SD) PSA concentration was 0.92 (0.67) ng/mL, and the mean (SD) IPSS was 7.1 (5.6). The mean (SD) treatment duration as 21.8 (14.2) months in the TRT group and 21.6 (14.0) months in the placebo group. During 14 304 person-years of follow-up, the incidence of high-grade prostate cancer (5 of 2596 [0.19%] in the TRT group vs 3 of 2602 [0.12%] in the placebo group; hazard ratio, 1.62; 95% CI, 0.39-6.77; P = .51) did not differ significantly between groups; the incidences of any prostate cancer, acute urinary retention, invasive surgical procedures, prostate biopsy, and new pharmacologic treatment also did not differ significantly. Change in IPSS did not differ between groups. The PSA concentrations increased more in testosterone-treated than placebo-treated men.Conclusions and relevanceIn a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men. The study's findings may facilitate a more informed appraisal of the potential risks of TRT.Trial registrationClinicalTrials.gov Identifier: NCT03518034.
| S-EPMC10753401 | biostudies-literature
Project description:ImportanceTestosterone therapy is increasingly prescribed in patients without a diagnosis of hypogonadism. This therapy may be associated with increased risk of venous thromboembolism (VTE) through several mechanisms, including elevated hematocrit levels, which increase blood viscosity.ObjectiveTo assess whether short-term testosterone therapy exposure is associated with increased short-term risk of VTE in men with and without evidence of hypogonadism.Design, setting, and participantsThis case-crossover study analyzed data on 39 622 men from the IBM MarketScan Commercial Claims and Encounter Database and the Medicare Supplemental Database from January 1, 2011, to December 31, 2017, with 12 months of follow-up. Men with VTE cases who were free of cancer at baseline and had 12 months of continuous enrollment before the VTE event were identified by International Classification of Diseases codes. Men in the case period were matched with themselves in the control period. Case periods of 6 months, 3 months, and 1 month before the VTE events were defined, with equivalent control periods (6 months, 3 months, and 1 month) in the 6 months before the case period.ExposuresNational drug codes were used to identify billed testosterone therapy prescriptions in the case period (0-6 months before the VTE) and the control period (6-12 months before the VTE).Main outcomes and measuresThe main outcome in this case-only experiment was first VTE event stratified by the presence or absence of hypogonadism.ResultsA total of 39 622 men (mean [SD] age, 57.4 [14.2] years) were enrolled in the study, and 3110 men (7.8%) had evidence of hypogonadism. In age-adjusted models, testosterone therapy use in all case periods was associated with a higher risk of VTE in men with (odds ratio [OR], 2.32; 95% CI, 1.97-2.74) and without (OR, 2.02; 95% CI, 1.47-2.77) hypogonadism. Among men without hypogonadism, the point estimate for testosterone therapy and VTE risk in the 3-month case period was higher for men younger than 65 years (OR, 2.99; 95% CI, 1.91-4.68) than for older men (OR, 1.68; 95% CI, 0.90-3.14), although this interaction was not statistically significant (P = .14).Conclusions and relevanceTestosterone therapy was associated with an increase in short-term risk for VTE among men with and without hypogonadism, with some evidence that the association was more pronounced among younger men. These findings suggest that caution should be used when prescribing testosterone therapy.
| S-EPMC6865248 | biostudies-literature
Project description:ContextType 2 diabetes mellitus (T2D) is often accompanied by male hypogonadism and both conditions are associated with increased risk for fractures. Testosterone (T) has been shown to improve the bone health of hypogonadal men but has not been tested in patients who also have T2D in addition to low T. To date, there is no treatment that is specifically recommended for bone disease among patients with T2D. This study will evaluate the effect of T therapy on the bone health of male veterans with low T who also have T2D.MethodsThis is a randomized double-blind placebo-controlled trial of 166 male veterans 35-65 years old, with T2D and hypogonadism, randomized to either T gel 1.62% or placebo for 12 months. We will evaluate the effect of T therapy on the following primary outcomes:1) changes in bone strength as measured by microfinite elements analysis (μFEA) using high-resolution peripheral quantitative computer tomography, 2) changes in bone turnover markers, and 3) changes in circulating osteoblast progenitors (COP) and osteoclast precursors cells.DiscussionWe anticipate that T therapy will result in improvement in bone strength owing to improvement in bone remodeling through an increase in osteoblastic differentiation and proliferation in patients with hypogonadism and T2D.
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Project description:BackgroundCurrent guidelines recommend withholding antithrombotic therapy (ATT) for at least 24 h in patients with acute ischemic stroke treated with thrombolytic therapy. Herein, we report a retrospective analysis of a single-centre experience on the safety and efficacy of antithrombotic therapy (ATT) started before or after 24 h of intravenous thrombolysis in a cohort of acute ischemic stroke patients.MethodsA total of 139 patients (Rapid ATT group) received antithrombotic therapy before 24 h of thrombolysis, and 33 patients (Standard ATT group) after 24 h. The brain parenchyma and vessel status were assessed using simple CT scan on admission, multimodal CT scan at the end of thrombolysis, and angio-CT/MRI scan at day 3. Functional outcome was scored using the modified Rankin Scale (mRS) at day 90.ResultsThe two ATT groups had similar demographics, stroke subtypes, baseline NIHSS, thrombolytic strategies, vessel-patency rates at the end of thrombolysis, and incidence of bleeding complications at follow up. At day 3, the Rapid ATT group had a non-significant improved vessel-patency rate than the Standard ATT group. At day 90, a greater proportion of patients in the rapid ATT group had shifted down the mRS, and had improved in the NIHSS score.ConclusionsATT initiated before 24 h of intravenous thrombolytic therapy in acute stroke patients disclosed no safety concerns compared with a conventional antithrombotic therapy delay of 24 h and showed better functional outcome at follow up. The value of early initiation of ATT after thrombolysis deserves further assessment in randomized controlled trials.
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Project description:While US testosterone prescriptions have tripled in the last decade with lower trends in Europe, debate continues over the risks, benefits and appropriate use of testosterone replacement therapy (TRT). Some authors blame advertising and the availability of more convenient formulations whilst other have pointed out that the routine testing of men with erectile dysfunction (a significant marker of cardiovascular risk) and those with diabetes would inevitably increase the diagnosis of hypogonadism and lead to an increase in totally appropriate prescribing. They commented that this was merely an appropriate correction of previous underdiagnosis and undertreatment by adherence to evidence-based guidelines. Urologists and primary care physicians are the most frequent initiators of TRT, usually for erectile dysfunction. Benefits are clearly established for sexual function, increase in lean muscle mass and strength, mood and cognitive function, with possible reduction in frailty and osteoporosis. There remains no evidence that TRT is associated with increased risk of prostate cancer or symptomatic benign prostatic hyperplasia, yet the decision to initiate and continue therapy is often decided by urologists. The cardiovascular issues associated with TRT have been clarified by recent studies showing clearly that therapy associated with clear rise in testosterone levels are associated with reduced mortality. Studies reporting to show increased risk have been subject to flawed designs with inadequate baseline diagnosis and follow-up testing. Effectively they have compared nontreated patients with undertreated or on-compliant subjects involving a range of different therapy regimens. Recent evidence suggests long acting injections may be associated with decreased cardiovascular risk but the transdermal route may be associated with potentially relatively greater risk because of conversion to dihydrotestosterone by the effect of 5? reductase in skin. The multiple effects of TRT may add up to a considerable benefit to the patient that might be underestimated by the physician primarily concerned with his own specialty. This paper will attempt to identify who should be treated, and how they should be treated safely to achieve best outcomes, based on a comprehensive MEDLINE and EMBASE and Cochrane searches on hypogonadism, TRT and cardiovascular safety from May 2005 to May 2015. This revealed 1714 papers with 52 clinical trials and 32 placebo-controlled randomized, controlled trials.
| S-EPMC4772354 | biostudies-other
Project description:BackgroundRecent attention has focused on the question of how quickly antiretroviral therapy (ART) should be started once HIV diagnosis is confirmed. We assessed whether rapid ART initiation improves patient outcomes.MethodsWe searched five databases from inception up to August 2017. Rapid ART initiation was defined as initiation within 14 days of HIV diagnosis. Data were pooled using random effects meta-analysis.ResultsAcross the randomized trials, ART start on the same day increased viral suppression at 12 months [three trials: relative risk (RR) 1.17, 95% confidence interval (CI) 1.07-1.27], retention in care at 12 months (RR 1.11, 95% CI 0.99-1.26), and the likelihood of starting ART within 90 days (four trials: RR 1.35, 95% CI 1.13-1.62) and 12 months after eligibility was established (three trials: RR 1.17, 95% CI 1.07-1.27). There was a nonsignificant trend toward reduced mortality (three trials: RR 0.53, 95% CI 0.24-1.08), as well as reduced loss to follow-up at 12 months (2 trials: RR 0.66, 95% CI 0.42-1.04). In the observational studies, offering accelerated ART initiation resulted in a greater likelihood of having started ART within 3 months (two studies: RR 1.53, 95% CI 1.11-2.10). There was a trend toward an increased risk of being lost to follow-up at 6 months (three studies: RR 1.85, 95% CI 0.96-3.55).ConclusionAccelerated ART initiation can lead to improved clinical outcomes and is likely to be of particular benefit in those settings where extensive patient preparation prior to starting ART results in long delays. These findings informed a WHO recommendation supporting accelerated ART initiation, including same day ART start.
| S-EPMC5732637 | biostudies-literature
Project description:ImportanceTestosterone deficiency causes mild anemia. Whether testosterone replacement therapy (TRT) can correct anemia or prevent the development of anemia in men with hypogonadism remains incompletely understood.ObjectiveTo assess the efficacy of TRT in correcting anemia in men with hypogonadism and anemia, and reducing the risk of developing anemia in those without anemia.Design, setting, and participantsThis randomized, placebo-controlled trial included men with hypogonadism at 316 US sites enrolled between May 2018 and February 2022. This study was nested within the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) Study, which evaluated the effect of TRT on major adverse cardiovascular events in middle-aged and older men with hypogonadism. Eligible participants were aged 45 to 80 years, with 2 testosterone concentration results below 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. The last study visit took place in January 2023. Data were analyzed between March and August 2023.InterventionParticipants were randomized with stratification for preexisting CVD to 1.62% testosterone gel or placebo gel daily for the study duration.Main outcomes and measuresProportion of participants with anemia (hemoglobin below 12.7 g/dL) whose anemia remitted (hemoglobin 12.7 g/dL or above) over the study duration. Secondary end points included incidence of anemia among men who were not anemic. Binary end points were analyzed using repeated-measures log-binomial regression.ResultsA total of 5204 men were included, 815 with anemia (mean [SD] age, 64.8 [7.7] years; 247 Black [30.3%], 544 White [66.7%], 24 other [2.9%]) and 4379 without anemia (mean [SD] age, 63.0 [7.9] years; 629 Black [14.4%], 3603 White [82.3%], 147 other [3.4%]). Anemia corrected in a significantly greater proportion of testosterone-treated than placebo-treated men at 6 months (143 of 349 [41.0%] vs 103 of 375 [27.5%]), 12 months (152 of 338 [45.0%] vs 122 of 360 [33.9%]), 24 months (124 of 290 [42.8%] vs 95 of 307 [30.9%]), 36 months (94 of 216 [43.5%] vs 76 of 229 [33.2%]), and 48 months (41 of 92 [44.6%] vs 38 of 97 [39.2%]) (P = .002). Among participants without anemia, a significantly smaller proportion of testosterone-treated men developed anemia than placebo-treated men. Changes in hemoglobin were associated with changes in energy level.Conclusions and relevanceIn middle-aged and older men with hypogonadism and anemia, TRT was more efficacious than placebo in correcting anemia. Among men who were not anemic, a smaller proportion of testosterone-treated men developed anemia than placebo-treated men.Trial registrationClinicalTrials.gov Identifier: NCT03518034.
| S-EPMC10611996 | biostudies-literature