Long-term oral exposure to finasteride and different doses of minoxidil induces testicular and epididymal alterations in adult Balb/c mice

Oral finasteride and topical minoxidil are approved treatments for androgenetic alopecia, while low-dose oral minoxidil has emerged as a promising off-label alternative. Despite its vasodilatory and androgen-modulating properties, the minoxidil effects on male reproductive health remain poorly understood. Given its growing off-label use and potential reproductive impact, this study aimed to evaluate the histopathological, hormonal, and oxidative stress effects of oral minoxidil on the testes and epididymides of adult Balb/c mice. A total of 120 animals were divided into six groups (n = 20) receiving daily oral doses of water, vehicle, finasteride (5 mg/kg), or minoxidil (2.5, 5, or 7.5 mg/kg). Half were euthanized after 42 days and the remainder after 84 days of treatment. On the 42nd day, both minoxidil and finasteride induced testicular structural alterations, including vacuolization of the seminiferous epithelium, reduction in seminiferous epithelium height, and increase in the proportion of Leydig cells. In the minoxidil-treated groups, these alterations were accompanied by decreased serum estradiol levels and oxidative imbalance, suggesting these might be underlying mechanisms of minoxidil-induced reproductive toxicity. After 84 days, although no significant changes were observed in the estradiol levels and oxidative status, testicular structural alterations persisted, characterized by continued vacuolization of the seminiferous epithelium and decreased seminiferous epithelium proportion after finasteride and minoxidil treatments. Although no dose-dependent minoxidil effect was observed, the dose of 5 mg/kg more frequently induced alterations. Histological epididymal changes were identified with both drugs at both time points. However, only finasteride significantly reduced sperm transit time (at 42 and 84 days) and cauda sperm count (at 84 days). These results suggest that while both minoxidil and finasteride induce broader testicular alterations, finasteride significantly affects epididymal function. This study highlights potential reproductive risks associated with long-term oral minoxidil use and emphasizes the importance of clinical studies assessing its safety in male reproductive health, particularly in individuals of reproductive age.