Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
Health Economics Research Unit, University of Aberdeen, Aberdeen, UK.
Health Technol Assess. 2024 Aug;28(43):1-210. doi: 10.3310/JRYT3981.
Low levels of testosterone cause male hypogonadism, which is associated with sexual dysfunction, tiredness and reduced muscle strength and quality of life. Testosterone replacement therapy is commonly used for ameliorating symptoms of male hypogonadism, but there is uncertainty about the magnitude of its effects and its cardiovascular and cerebrovascular safety.
The primary aim was to evaluate the safety of testosterone replacement therapy. We also assessed the clinical and cost-effectiveness of testosterone replacement therapy for men with male hypogonadism, and the existing qualitative evidence on men's experience and acceptability of testosterone replacement therapy.
Evidence synthesis and individual participant data meta-analysis of effectiveness and safety, qualitative evidence synthesis and model-based cost-utility analysis.
Major electronic databases were searched from 1992 to February 2021 and were restricted to English-language publications.
We conducted a systematic review with meta-analysis of individual participant data according to current methodological standards. Evidence was considered from placebo-controlled randomised controlled trials assessing the effects of any formulation of testosterone replacement therapy in men with male hypogonadism. Primary outcomes were mortality and cardiovascular and cerebrovascular events. Data were extracted by one reviewer and cross-checked by a second reviewer. The risk of bias was assessed using the Cochrane Risk of Bias tool. We performed one-stage meta-analyses using the acquired individual participant data and two-stage meta-analyses to integrate the individual participant data with data extracted from eligible studies that did not provide individual participant data. A decision-analytic Markov model was developed to evaluate the cost per quality-adjusted life-years of the use of testosterone replacement therapy in cohorts of patients of different starting ages.
We identified 35 trials (5601 randomised participants). Of these, 17 trials (3431 participants) provided individual participant data. There were too few deaths to assess mortality. There was no difference between the testosterone replacement therapy group (120/1601, 7.5%) and placebo group (110/1519, 7.2%) in the incidence of cardiovascular and/or cerebrovascular events (13 studies, odds ratio 1.07, 95% confidence interval 0.81 to 1.42; = 0.62). Testosterone replacement therapy improved quality of life and sexual function in almost all patient subgroups. In the testosterone replacement therapy group, serum testosterone was higher while serum cholesterol, triglycerides, haemoglobin and haematocrit were all lower. We identified several themes from five qualitative studies showing how symptoms of low testosterone affect men's lives and their experience of treatment. The cost-effectiveness of testosterone replacement therapy was dependent on whether uncertain effects on all-cause mortality were included in the model, and on the approach used to estimate the health state utility increment associated with testosterone replacement therapy, which might have been driven by improvements in symptoms such as sexual dysfunction and low mood.
A meaningful evaluation of mortality was hampered by the limited number of defined events. Definition and reporting of cardiovascular and cerebrovascular events and methods for testosterone measurement varied across trials.
Our findings do not support a relationship between testosterone replacement therapy and cardiovascular/cerebrovascular events in the short-to-medium term. Testosterone replacement therapy improves sexual function and quality of life without adverse effects on blood pressure, serum lipids or glycaemic markers.
Rigorous long-term evidence assessing the safety of testosterone replacement therapy and subgroups most benefiting from treatment is needed.
The study is registered as PROSPERO CRD42018111005.
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/68/01) and is published in full in ; Vol. 28, No. 43. See the NIHR Funding and Awards website for further award information.
低水平的睾酮会导致男性性腺功能减退症，与性功能障碍、疲劳以及肌肉力量和生活质量下降有关。睾酮替代疗法常用于改善男性性腺功能减退症的症状，但对其疗效及其心血管和脑血管安全性的认识尚不确定。
主要目的是评估睾酮替代疗法的安全性。我们还评估了男性性腺功能减退症患者使用睾酮替代疗法的临床和成本效益，以及关于男性对睾酮替代疗法的体验和可接受性的现有定性证据。
根据当前方法学标准，对有效性和安全性进行证据综合和个体参与者数据荟萃分析，对定性证据进行综合，以及基于模型的成本效用分析。
从 1992 年到 2021 年 2 月，主要电子数据库进行了检索，仅限于英语出版物。
我们根据当前的方法学标准进行了个体参与者数据的系统评价和荟萃分析。证据来自评估任何形式的睾酮替代疗法在男性性腺功能减退症患者中的疗效的安慰剂对照随机对照试验。主要结局是死亡率和心血管和脑血管事件。由一名评审员进行数据提取，并由另一名评审员交叉核对。使用 Cochrane 风险偏倚工具评估风险。我们使用获得的个体参与者数据进行单阶段荟萃分析，并使用未提供个体参与者数据的合格研究中提取的数据进行两阶段荟萃分析，以整合个体参与者数据。开发了一个决策分析马尔可夫模型，以评估不同起始年龄患者群体使用睾酮替代疗法的成本效益。
我们确定了 35 项试验（5601 名随机参与者）。其中，17 项试验（3431 名参与者）提供了个体参与者数据。由于死亡人数太少，无法评估死亡率。睾酮替代疗法组（120/1601，7.5%）和安慰剂组（110/1519，7.2%）心血管和/或脑血管事件的发生率无差异（13 项研究，优势比 1.07，95%置信区间 0.81 至 1.42；=0.62）。睾酮替代疗法几乎在所有患者亚组中都改善了生活质量和性功能。在睾酮替代疗法组中，血清睾酮水平升高，而血清胆固醇、甘油三酯、血红蛋白和血细胞比容均降低。我们从五项定性研究中确定了几个主题，这些主题显示了低睾酮水平如何影响男性的生活及其对治疗的体验。睾酮替代疗法的成本效益取决于是否将对全因死亡率的不确定影响纳入模型，以及用于估计与睾酮替代疗法相关的健康状态效用增量的方法，这可能是由于性功能障碍和情绪低落等症状的改善所致。
由于定义事件的数量有限，对死亡率进行有意义的评估受到阻碍。心血管和脑血管事件的定义和报告以及睾酮测量方法在试验之间存在差异。
我们的研究结果表明，在短期至中期，睾酮替代疗法与心血管/脑血管事件之间没有关系。睾酮替代疗法可改善性功能和生活质量，而不会对血压、血清脂质或血糖标志物产生不良影响。
需要严格的长期证据来评估睾酮替代疗法的安全性和最受益于治疗的亚组。
该研究在 PROSPERO CRD42018111005 中注册。
该奖项由英国国家健康与保健卓越研究所（NIHR）卫生技术评估计划（NIHR 奖项参考：17/68/01）资助，并在 ; 第 28 卷，第 43 期。有关进一步的奖励信息，请访问 NIHR 资助和奖励网站。
