The Interplay of Varicoceles, Sperm Epigenetics, and Male Infertility: A Focused, Contemporary Review

Abstract

Despite the wide recognition of varicocele as a contributor to infertility, its exact pathophysiologic mechanism is not fully understood. As the field of male infertility continues to see progress in new diagnostic and therapeutic technologies, we sought to obtain a robust understanding of the interplay of varicoceles, oxidative stress, DNA methylation, and male infertility. We performed a comprehensive review of the contemporary literature in PubMed using search terms and keywords associated with varicoceles, DNA methylation, and male infertility. The most important findings from the literature review were included in this report. Articles were selected based on quality and relevance to the topic. Eight studies were included in this review. These studies discuss DNA methylation and varicocele-associated male infertility through evaluation of sperm parameters, DNA methylation, DNA fragmentation, and other relevant factors. Our review of the literature on varicocele-associated sperm DNA methylation indicates that global hypomethylation occurs in association with varicoceles. Some data suggest a dose-dependent effect of varicocele grade on sperm DNA methylation, with the greatest magnitude changes seen in grades II and III varicoceles. While changes in DNA methylation patterns would be expected following varicocelectomy, such changes were not found to be statistically significant in one study reviewed here. However, current human studies are limited by small sample size and short follow-up time. Future clinical and preclinical studies with robust sample sizes and hypothesis-driven investigations are necessary to further understand the relationship between DNA methylation patterns and varicocele-associated male infertility.