Systematic review and meta-analysis of risk factors for erectile dysfunction after stroke: a Mendelian randomization...

Erectile dysfunction (ED) is a common yet underrecognized complication in male stroke survivors, severely impairing quality of life and interpersonal relationships. Observational studies on post-stroke ED risk factors are limited by confounding and reverse causation, leaving causal determinants unclear.

This study integrated systematic review, meta-analysis, and two-sample Mendelian randomization (MR) to comprehensively identify and validate causal risk factors for post-stroke ED, addressing critical gaps in causal inference for this clinically relevant complication.

For the systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Library, and Web of Science (inception to March 2025) for observational studies investigating associations between risk factors and post-stroke ED. We pooled effect sizes using random-effects models (R version 4.3.2, metafor package v4.4-0) and assessed heterogeneity via the I² statistic. For MR, we used genome-wide association study summary statistics from public consortia (UK Biobank, FinnGen, MEGASTROKE; European ancestry only) to select genetic instrumental variables for candidate risk factors, applying inverse-variance weighted, MR-Egger, weighted median, MR-PRESSO, and multivariable MR methods to infer causality and assess pleiotropy. All statistical analyses were conducted in R version 4.3.2, with MR analyses implemented via the TwoSampleMR package v0.5.6 and MR-PRESSO package v1.0.

Age, hypertension, and diabetes were significantly associated with post-stroke ED.

A total of 123 studies were initially identified through the database search. After screening the titles and abstracts, 47 studies were selected for full-text review. Finally, 21 studies met the inclusion criteria and were included in the systematic review. Age (pooled OR = 1.05, 95% CI: 1.03-1.07, P < .001; I² = 62%), hypertension (OR = 1.68, 95% CI: 1.42-1.98, P < .001; I² = 45%), and diabetes (OR = 1.82, 95% CI: 1.55-2.14, P < .001; I² = 58%) were significantly associated with post-stroke ED. Funnel plot analysis and Egger's test revealed no significant publication bias for the meta-analyses of age (Egger's P = .22), hypertension (Egger's P = .35), and diabetes (Egger's P = .19). MR analysis (12 valid IVs; 16 initially identified SNPs were excluded due to linkage disequilibrium (r² > 0.01) and confounder associations) confirmed causal relationships: hypertension (IVW beta = 0.32, P = .002), diabetes (IVW beta = 0.41, P < .001), and age (IVW beta = 0.18, P = .04). No significant pleiotropy (MR-Egger intercept P > .05; MR-PRESSO global test P > .05 for all exposures) or heterogeneity (Cochran Q test P > .05) was detected. Multivariable MR analysis confirmed the independent causal effects of hypertension (beta = 0.29, P = .004) and diabetes (beta = 0.38, P < .001) on post-stroke ED after adjusting for age.

This study demonstrates that age, hypertension, and diabetes are causal risk factors for post-stroke ED in individuals of European ancestry.

Expanding the literature search parameters to incorporate studies published in non-English languages may facilitate a more holistic comprehension of the risk landscape associated with post-stroke ED. Second, augmenting the number of genetic variants harnessed as IVs within the MR analytical paradigm can enhance both the statistical power and the reliability of causal inferences. Third, investigating the synergistic effects of multiple risk factors on post-stroke ED may enable more precise stratification of high-risk subgroups, thereby informing targeted prophylactic strategies.

These findings support targeted screening and management of high-risk stroke survivors to reduce ED burden, with hypertension and diabetes representing modifiable intervention targets, and provide actionable guidance for sexual medicine providers in collaborative care and post-ED diagnosis management.