Male Infertility and Neurodegenerative Diseases: A Systematic Review of Associations and Molecular Mechanisms

Abstract

Male infertility has been viewed as a potential biomarker for systemic health and a predictor of future disease. With the global burden of neurodegenerative diseases (NDDs) on the rise, the current systematic review aims to synthesize the reported associations, risks, and shared molecular mechanisms between male infertility and NDDs. Following PRISMA 2020 guidelines, we systematically searched PubMed, Embase, Scopus, and Cochrane CENTRAL in January 2026. Studies examining the relationship between male infertility and NDDs were included. Screening and data extraction were performed by two independent reviewers with a third to resolve conflicts while quality appraisal (ROBINS-E and OHAT) was performed for all included studies. Studies used heterogeneous definitions of male infertility, including clinical diagnosis, semen parameters, and reproductive outcomes. Of the 1566 identified studies, 13 were included in this review including case-control studies, experimental investigations, in vitro studies, bioinformatic analyses, and pedigree studies. The available literature suggests possible mechanistic overlap between male infertility and neurodegenerative disease pathways, particularly in mitochondrial dysfunction, oxidative stress, and proteostasis. However, the evidence remains heterogeneous and preliminary, and large prospective studies are needed before male infertility assessment can be considered a marker of neurodegenerative risk. Registration: The study protocol was registered on PROSPERO (registration code: CRD420261301509).