Androgenetic alopecia drugs and male infertility: Evidence from pharmacovigilance and testicular transcriptomics.

چکیده اصلی

OBJECTIVE: To identify disproportionality signals linking androgenetic alopecia (AGA) drugs (finasteride, dutasteride, and minoxidil) with male infertility-related adverse events and to explore infertility-related biological features using testicular transcriptomic datasets. METHODS: A dual-database replication design was employed using FAERS (2004-2025) and EudraVigilance (2002-2025). Disproportionality analysis with multiple signal detection metrics assessed drug-infertility associations. Multi-level bioinformatic analyses-including toxicity prediction, drug-associated target screening, testicular transcriptomic analysis, single-cell RNA sequencing, intercellular communication analysis, gene set enrichment analysis (GSEA), and immune infiltration analysis-were integrated to explore biological features potentially relevant to male infertility. RESULTS: Disproportionality analyses detected signals for all three drugs, with finasteride demonstrating the most prominent reporting signal, followed by dutasteride and minoxidil. Multi-level bioinformatic analysis identified HIF1A as an overlap-derived candidate under the specified datasets and screening criteria, and HIF1A expression was higher in testicular tissue from patients with male infertility. Single-cell analysis showed higher HIF1A expression in late spermatocytes, Leydig cells, and myoid cells from infertility samples, together with group-dependent inferred communication patterns for selected VEGF-, PDGF-, IGF-, and FGF-related signaling axes. GSEA associated higher HIF1A expression with immune-response-, wound-healing-, and cell-adhesion-related processes, whereas lower HIF1A expression was associated with spermatid-development- and cilium/flagellum-dependent motility-related processes. ssGSEA-based analysis showed positive correlations between HIF1A expression and several immune-cell signature scores. CONCLUSION: This study systematically evaluated associations between AGA drugs and male infertility using real-world pharmacovigilance data and integrated bioinformatic analyses. The HIF1A-related transcriptomic findings provide a hypothesis-generating biological context for male infertility but do not establish a shared or drug-specific mechanism linking the three medications to infertility. The pharmacovigilance findings indicate reporting signals rather than incidence or causality.

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