METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005.

FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory).

INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity.

INTRODUCTION: Cross-sectional and longitudinal cohort studies examining the relationship between serum testosterone concentration and depression in men have produced mixed results. There has not, however, been any prior attempt to systematically interrogate the data. Clarification of the relationship has clinical importance because depression may be under-diagnosed in men.

INCLUSION CRITERIA: This review will consider studies involving community-dwelling men who are not receiving testosterone replacement therapy. The exposure of interest reviewed will include endogenous testosterone concentration measured through validated assays. Studies measuring total and testosterone fraction concentration will be included. This review will include studies with depression or incident depression outcomes as defined by either clinical diagnosis of depression or validated self-administered questionnaire assessing depression symptomatology.

METHODS: This review will follow the JBI approach for systematic reviews of etiology and risk. The following sources will be searched: PubMed, PsycINFO, Embase, the Cochrane Central Register of Controlled Trials, Australian New Zealand Clinical Trials Registry and the ISRCTN Registry. Analytical observational studies including prospective and retrospective cohort studies, case control studies and analytical cross-sectional studies published in English or other languages with English translation will be considered. Retrieval of full-text studies, assessment of methodological quality and data extraction will be performed independently by two reviewers. Data will be pooled in statistical meta-analysis, where possible.