Unveiling the risk of idiopathic intracranial hypertension associated with testosterone in transgender men: From the FAERS database to molecular mechanisms

Background Exogenous testosterone is a cornerstone of gender-affirming hormone therapy (GAHT) for transgender men, yet its association with idiopathic intracranial hypertension (IIH) requires clarification. This study aimed to evaluate the real-world risk and underlying molecular mechanisms of testosterone-induced IIH in transgender men.Methods Adverse reports (2014–2025) were extracted from the FDA Adverse Event Reporting System. Disproportionality analysis and multivariable logistic regression were performed to quantify IIH risk. Network pharmacology was integrated to elucidate pathogenic pathways.Results Testosterone-related IIH reports overwhelmingly clustered in transgender men. Long-acting testosterone esters show the higher risk factor (adjusted OR = 10.85, p < 0.001), whereas subcutaneous or topical administration reduced risk by 76%. Concomitant tetracyclines acted as significant synergistic triggers. Mechanistically, testosterone drives IIH via a neuroinflammatory axis (TNF/IL-6) intersecting with systemic endocrine-metabolic dysregulation.Conclusion Testosterone is identified as an independent risk factor for IIH in transgender men, which can be optimized through the subcutaneous administration of longer-acting testosterone formulations and the avoidance of tetracycline antibiotics. This work provides an evidence-based framework to safeguard this vulnerable population during GAHT.