Autoimmunity and Inflammaging in Male Infertility

Abstract

Male factors contribute, alone or in combination with female-related ones, to approximately 40–50% of infertility in couples. Within the spectrum of male infertility, growing evidence indicates that autoimmune mechanisms and chronic inflammation can impair spermatogenesis, sperm function, and reproductive outcomes. The disruption of the testicular immune privilege, blood-testis barrier dysfunction, local inflammatory pathways, and antisperm antibodies represent the best-characterized immune-mediated mechanisms, although their clinical relevance varies and several mechanistic observations remain derived from preclinical models. Systemic autoimmune and chronic inflammatory diseases may also affect male reproductive function through inflammatory cytokines, endocrine dysregulation of the hypothalamic-pituitary-gonadal axis, sexual dysfunction, and treatment-related gonadotoxicity. Emerging data also implicate the gut-testis axis and age-associated low-grade inflammation (inflammaging) as potential contributors to testicular immune remodeling, oxidative stress, and declining reproductive function. This narrative review is intended to encompass disease-specific available reviews and synthesize original research, clinical studies, and systematic reviews published mainly between 2010 and 2026. We distinguish established clinical evidence from experimental or hypothesis-generating data and discuss implications for fertility preservation, assisted reproduction, and individualized management. Integrating reproductive immunology with the clinical evaluation of male infertility may improve risk stratification while avoiding overinterpretation of still-limited immune biomarkers and therapeutic evidence.