Could isotretinoin be a new therapeutic frontier for male infertility? A systematic review and meta-analysis

Retinoic acid is essential for spermatogonial differentiation and meiotic initiation, providing a biologically plausible rationale for exploring retinoid-based therapies in the context of male infertility. Isotretinoin is widely prescribed for acne. However, it has historically raised concerns about potential sexual adverse effects. We aim to synthesize contemporary available clinical evidence on isotretinoin and clarify whether it poses reproductive risks or may hold any potential therapeutic relevance in men across both dermatologic and infertility settings.

Following PRISMA guidelines, we systematically searched MEDLINE/PubMed, Scopus, and Web of Science from inception to November 2025 for original articles investigating the effects of isotretinoin on semen parameters, reproductive hormones, sexual function, or fertility outcomes. A narrative synthesis was conducted in conjunction with a random-effects meta-analysis for semen parameters when means and standard deviations were available.

Six clinical studies involving 225 men were included: three dermatologic cohorts (n = 167) with normal baseline fertility, treated with standard isotretinoin regimens for acne, and three infertility cohorts (n = 58), receiving low-dose isotretinoin for oligoasthenozoospermia, cryptozoospermia, or non-obstructive azoospermia. In dermatologic populations, random-effects meta-analysis showed small but statistically significant increases in sperm concentration (Mean Difference [MD] + 1.77 million/mL, p = 0.028) and vitality (MD + 3.74%, p = 0.009), with non-significant positive trends for progressive motility (MD + 4.12%) and normal morphology (MD + 1.13%). In infertility settings, sperm concentration increased by approximately + 1.3 million/mL, progressive motility improved by + 3%, and normal morphology remained stable in oligoasthenozoospermic men. In comparison, de novo sperm appeared in 37-44% of azoospermic or cryptozoospermic men, enabling pregnancies across three studies (both spontaneous and with assisted reproductive technology). No study reported impaired fertility or treatment-emergent sexual dysfunction. Overall, the certainty of evidence was low to moderate.

Current clinical data do not support reproductive harm from isotretinoin. Instead, isotretinoin may enhance semen quality in healthy men and promote clinically meaningful spermatogenic recovery in selected infertility contexts. Controlled trials are needed to define therapeutic efficacy, identify responders, and clarify its role in male infertility management.