Isotretinoin use is associated with persistent alterations in male reproductive function

Background Isotretinoin (ISO) is a systemic retinoid widely used for the treatment of acne vulgaris, yet its potential effects on male reproductive function remain unclear with previous studies reporting inconsistent findings. Methods and finding We conducted a multi-model study combining data from the Danish Young Men Study (DYMS) cohort with ex vivo cultured human testis tissue and an in vitro Retinoic Acid Receptor alpha (RAR) reporter gene assay. In the DYMS cohort semen parameters and reproductive hormone concentrations assessed on a specific examination day were compared between ISO-users (n=322) and non-users (n=4,065). Ex vivo human testis tissue was exposed to ISO and RA for 96 hours to assess changes in hormone secretion and germ cell dynamics, while the in vitro RAR assay evaluated ISO for effects on RA-induced RAR-signaling. In the DYMS cohort, ISO use was associated with reduced FSH concentrations, higher inhibin B/FSH ratio, and elevated estradiol concentrations, along non-significant tendencies of lower sperm counts. These associations persisted even after cessation of ISO use but were not evident in men first initiating ISO use 1 year after their examination date. In the ex vivo testis tissue, ISO exposure altered hormone secretion, including increased testosterone, but did not affect germ cell proliferation or apoptosis. ISO also inhibited RA-induced RAR-signaling in vitro in a competitive manner. Conclusions These findings suggests that ISO-use may influence male reproductive function, potentially with persistent effects. Further randomized clinical trials are needed to validate these effects.