The effects and safety of testosterone replacement therapy for men with hypogonadism: the TestES evidence synthesis and economic evaluation
Authors: Cruickshank Moira , Hudson Jemma , Hernández Rodolfo , Aceves-Martins Magaly , Quinton Richard , Gillies Katie , Aucott Lorna S , Kennedy Charlotte , Manson Paul , Oliver Nicholas , Wu Frederick , Bhattacharya Siladitya , Dhillo Waljit S , Jayasena Channa N , Brazzelli Miriam 
Published: September 2024

Background
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.

Aims of the research
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.

Design
Evidence synthesis and individual participant data meta-analysis of effectiveness and safety, qualitative evidence synthesis and model-based cost-utility analysis.

Data sources
Major electronic databases were searched from 1992 to February 2021 and were restricted to English-language publications.

Methods
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.

Results
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; p = 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.

Limitations
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.

Conclusions
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.

Future work
Rigorous long-term evidence assessing the safety of testosterone replacement therapy and subgroups most benefiting from treatment is needed.

Study registration
The study is registered as PROSPERO CRD42018111005.

Funding
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 Health Technology Assessment; Vol. 28, No. 43. See the NIHR Funding and Awards website for further award information.