E-cigarette aerosol constituents modulate Leydig cell steroidogenic pathways: Evidence from experimental models

The rising prevalence of e-cigarette use has raised concerns regarding potential adverse effects on male reproductive and endocrine health, yet its impact on testosterone regulation remains poorly defined. This narrative review critically synthesizes evidence from preclinical in vivo and in vitro models and from human observational studies to evaluate how e-cigarette exposure may influence testosterone homeostasis and hypothalamic pituitary gonadal axis function. Across experimental models, e-cigarette aerosols and their constituents consistently impair Leydig cell function and testosterone biosynthesis through convergent mechanisms involving oxidative stress, inflammatory signaling, mitochondrial dysfunction, epigenetic modification, and suppression of key steroidogenic enzymes. Several of these mechanisms overlap with those described for combustible cigarette exposure, whereas others, particularly those related to aerosolized solvents, flavoring agents, and device-derived metals, appear more specific to e-cigarettes. In contrast, the available human evidence is limited to cross-sectional studies and yields inconsistent findings, with the largest population-based study reporting no significant differences in circulating testosterone concentrations between e-cigarette users and non-users. Collectively, the evidence supports biological plausibility for e-cigarette-associated disruption of testosterone steroidogenesis but remains insufficient to establish causality in humans. This review therefore identifies critical methodological gaps and highlights priorities for longitudinal, biomarker-anchored human studies required to determine the clinical relevance and reversibility of e-cigarette-associated endocrine disruption.