Effects of androgen replacement therapy on cognitive function in patients with hypogonadism: A systematic review and meta-analysis

Hypogonadism, characterized by low testosterone levels, is linked to cognitive decline, particularly in memory and executive function. Androgen replacement therapy (ART) aims to counter these deficits by restoring testosterone levels. In the present systematic review and meta-analysis, it was hypothesized that ART improves cognitive function in hypogonadal men, with domain-specific effects. A comprehensive literature search was conducted across databases up to October 2024, identifying 14 studies that met inclusion criteria. Cognitive outcomes were categorized into memory, attention, executive function and visuospatial abilities, and a meta-analysis was performed using a random-effects model. Study heterogeneity was evaluated using prediction interval statistics, and sensitivity analyses were conducted. Publication bias was assessed using Begg's and Egger's tests, with adjustments using the trim-and-fill method. The meta-analysis demonstrated statistically significant but domain-specific cognitive effects of ART. The pooled standardized mean difference (SMD) for overall cognition was 0.454 (95% CI: 0.341-0.566; P<0.001). Domain-specific analyses revealed that ART led to improvements in executive function (SMD=0.488; 95% CI: 0.372-0.604; P<0.001) and memory (SMD=0.457; 95% CI: 0.338-0.577; P<0.001), but smaller effects were observed in attention (SMD=0.217; 95% CI: 0.084-0.351; P=0.001) and visuospatial abilities (SMD=0.226; 95% CI: 0.146-0.306; P<0.001). Sensitivity analyses confirmed the stability of the findings. Despite the detection of publication bias (Kendall's tau = 0.265, P<0.001; Egger's intercept = 1.92, P<0.001), the adjusted effect size remained consistent after applying the trim-and-fill method. Study heterogeneity was moderate, likely reflecting variations in cognitive assessment tools and intervention protocols. ART significantly improves executive function and memory in hypogonadal men, while the impact on attention and visuospatial abilities is less pronounced. These findings underscore the domain-specific nature of ART's cognitive benefits and highlight the importance of considering study heterogeneity when interpreting results. Clinically, this suggests that ART may be more effective in targeting memory and executive function deficits. However, the modest effect sizes and presence of publication bias indicate a need for further research to refine protocols, including standardized cognitive assessments and exploration of long-term effects.