The effects and safety of testosterone replacement therapy for men with hypogonadism: the TestES evidence synthesis and economic evaluation

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\u27s 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\u27s 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.Testosterone is a hormone which is vital for sexual activity, bone growth and muscle development in men. Men with low testosterone levels may experience problems with erections and may suffer from brittle bones (osteoporosis), weakness, feeling down (low mood) and tiredness. The manifestations of low testosterone can be treated with testosterone replacement therapy. However, there is current uncertainty about the positive effects of testosterone replacement therapy and its safety. We brought together results from all available medical studies that looked at the use of testosterone replacement therapy in men with low testosterone and contacted the doctors who led these studies to gather further information on their participants. We found 35 studies (5601 participants) conducted in different countries, 17 of which provided additional information on their participants. We did not find any evidence to show that testosterone replacement therapy increases the risk of heart problems, or any evidence to show that some men who take testosterone replacement therapy benefit more than others. Men with low testosterone reported having low mood, poor concentration and lack of energy; however, medical studies often failed to prove that these manifestations improved with testosterone replacement therapy. Most medical studies were conducted among white men in North America using questionnaires designed specifically for them; therefore, the results may not reflect the experiences of men in other countries and from more diverse ethnic backgrounds. There is too much uncertainty about the benefits of testosterone replacement therapy to accurately estimate its value for money for the NHS. We think our findings offer some reassurance to doctors and patients that testosterone replacement therapy does not increase the risk of heart problems. New studies are needed to find out whether some groups of men (such as older or younger men) are more likely to benefit from testosterone replacement therapy more than others. It is also important to develop tools which better reflect the experience of men from a diverse range of social and ethnic backgrounds. To inform men with low testosterone about our findings, we are creating a website with dedicated YouTube video clips

Unsupervised Cardiac Image Segmentation via Multiswarm Active Contours with a Shape Prior

This paper presents a new unsupervised image segmentation method based on particle swarm optimization and scaled active contours with shape prior. The proposed method uses particle swarm optimization over a polar coordinate system to perform the segmentation task, increasing the searching capability on medical images with respect to different interactive segmentation techniques. This method is used to segment the human heart and ventricular areas from datasets of computed tomography and magnetic resonance images, where the shape prior is acquired by cardiologists, and it is utilized as the initial active contour. Moreover, to assess the performance of the cardiac medical image segmentations obtained by the proposed method and by the interactive techniques regarding the regions delineated by experts, a set of validation metrics has been adopted. The experimental results are promising and suggest that the proposed method is capable of segmenting human heart and ventricular areas accurately, which can significantly help cardiologists in clinical decision support

Multiple Active Contours Guided by Differential Evolution for Medical Image Segmentation

This paper presents a new image segmentation method based on multiple active contours guided by differential evolution, called MACDE. The segmentation method uses differential evolution over a polar coordinate system to increase the exploration and exploitation capabilities regarding the classical active contour model. To evaluate the performance of the proposed method, a set of synthetic images with complex objects, Gaussian noise, and deep concavities is introduced. Subsequently, MACDE is applied on datasets of sequential computed tomography and magnetic resonance images which contain the human heart and the human left ventricle, respectively. Finally, to obtain a quantitative and qualitative evaluation of the medical image segmentations compared to regions outlined by experts, a set of distance and similarity metrics has been adopted. According to the experimental results, MACDE outperforms the classical active contour model and the interactive Tseng method in terms of efficiency and robustness for obtaining the optimal control points and attains a high accuracy segmentation

Low Computational-Cost Footprint Deformities Diagnosis Sensor through Angles, Dimensions Analysis and Image Processing Techniques

Manual measurements of foot anthropometry can lead to errors since this task involves the experience of the specialist who performs them, resulting in different subjective measures from the same footprint. Moreover, some of the diagnoses that are given to classify a footprint deformity are based on a qualitative interpretation by the physician; there is no quantitative interpretation of the footprint. The importance of providing a correct and accurate diagnosis lies in the need to ensure that an appropriate treatment is provided for the improvement of the patient without risking his or her health. Therefore, this article presents a smart sensor that integrates the capture of the footprint, a low computational-cost analysis of the image and the interpretation of the results through a quantitative evaluation. The smart sensor implemented required the use of a camera (Logitech C920) connected to a Raspberry Pi 3, where a graphical interface was made for the capture and processing of the image, and it was adapted to a podoscope conventionally used by specialists such as orthopedist, physiotherapists and podiatrists. The footprint diagnosis smart sensor (FPDSS) has proven to be robust to different types of deformity, precise, sensitive and correlated in 0.99 with the measurements from the digitalized image of the ink mat

Identifying the outcomes important to men with hypogonadism: A qualitative evidence synthesis

OBJECTIVE: Men with male hypogonadism (MH) experience sexual dysfunction, which improves with testosterone replacement therapy (TRT). However, randomised controlled trials provide little consensus on functional and behavioural symptoms in hypogonadal men; these are often better captured by qualitative information from individual patient experience. METHODS: We systematically searched major electronic databases to identify qualitative data from men with hypogonadism, with or without TRT. Two independent authors performed the selection, extraction, and thematic analysis of data. Quality of eligible studies was assessed using the Critical Appraisals Skills Programme and Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative research tools. RESULTS: We analysed data from five studies published in nine reports that assessed a total of 284 participants. Published data were only available within North America, with no ethnic minority or other underserved groups included. In addition to sexual dysfunction, men with MH experienced adverse changes in physical strength, perceptions of masculinity, cognitive function, and quality of life. The experience of MH appeared dependent on the source(s) of educational material. DISCUSSION: We propose a patient-centred approach to clinician interactions rather than focusing on discreet MH symptoms. Current evidence about the experience of MH is limited to North America and predominantly white ethnicity, which may not be broadly applicable to other geographic regions. Broadening our understanding of the MH experience may improve the targeting of information to patients. In addition, a multidisciplinary approach may better address symptoms neither attributable to MH nor alleviated by TRT

Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis

Background Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD.Methods We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005.Findings 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9.5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0.4%] of 1621) than placebo (12 [0.8%] of 1537) without significant differences between groups (odds ratio [OR] 0.46 [ 95% CI 0.17-1.24]; p=0.13). Cardiovascular risk was similar during testosterone treatment (120 [7.5%] of 1601 events) and placebo treatment (110 [7.2%] of 1519 events; OR 1.07 [95% CI 0.81-1.42]; p=0. 62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0.97 [99% CI 0.92- 1.03]; p=0.17), baseline testosterone (interaction 0.97 [0 .82-1.15]; p=0.69), smoking status (interaction 1.68 [0.41-6.88]; p=0.35), or diabetes status (interaction 2.08 [0.89-4.82; p=0.025) were not associated with cardiovascular risk.Interpretation We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.Stress-related psychiatric disorders across the life spa