The Role of Genomic Instability in Unexplained Infertility: An Overview

Unexplained infertility (UI) is an ambiguous condition that afflicts a significant number of couples around the world, despite normal findings in routine infertility tests. This review examines the role of DNA damage, especially in spermatozoa, as a potential cause of unexplained infertility. Sperm DNA fragmentation (SDF), often not detected in conventional sperm analysis, has emerged as a key biomarker for assessing male fertility potential. Elevated DNA fragmentation index (DNA) levels, caused primarily by oxidative stress, environmental toxins and incorrect chromatin remodelling, have been associated with poor reproductive performance, including miscarriage and Assisted Reproductive Technologies (ART). In addition, subclinical factors in women, such as early-stage endometriosis or luteal phase defects, may contribute to the diagnosis of uterine fibrosis. Advanced diagnostic techniques such as Terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL), Sperm Chromatin Structure Assay (SCSA) and Comet Assay offer more accurate detection of DNA damage. An understanding of these molecular factors is essential for specific treatment strategies and to improve the success rate of both natural and artificial insemination.