Sperm DNA integrity and male infertility: a narrative review and guide for the reproductive physicians

Abstract

Background and objective: Conventional semen analysis (SA) remains an essential tool in the initial male fertility evaluation and subsequent follow-up. However, it neither provides information about the functional status of spermatozoa nor addresses disorders such as idiopathic or unexplained infertility (UI). Recently, assessment of sperm DNA fragmentation (SDF) has been proposed as an extended sperm test that may help overcome these inherent limitations of basic SA. In this review, we aim to: (I) discuss the pathophysiological aspects of SDF, including natural repair mechanisms, causes, and impact on reproductive outcomes; (II) explain different assessment tools of SDF, and describe potential therapeutic options to manage infertile men with high SDF; and (III) analyse the strengths, weaknesses, opportunities and threats (SWOT) of current research on the topic.

Methods: This review was constructed from original studies, systematic reviews and meta-analyses that were published over the years up until August 2021, related to the various aspects of SDF.

Key content and findings: Different mechanisms lead to high SDF, including defective chromatin packaging, apoptosis, and seminal oxidative stress. The relevance of sperm DNA integrity to male fertility/infertility has been supported by the frequent observation of high levels of SDF in infertile men, and in association with risk factors for infertility. Additionally, high SDF levels have been inversely correlated with the outcomes of natural pregnancy and assisted reproduction. Terminal deoxynucleotidyl transferase dUTP nick end labelling, sperm chromatin structure assay, sperm chromatin dispersion, and Comet assay are four commonly used assays for measurement of SDF. Addressing lifestyle risks and underlying conditions, antioxidants, hormonal therapy, and advanced sperm selection techniques have all been proposed as potential therapeutic options to lower SDF.

Conclusions: The sum of literature provides evidence of detrimental effects of high SDF on both natural and assisted fertility outcomes. Standardization of the techniques used for assessment of SDF and their incorporation into the work up of infertile couples may have significant implications on the future management of a selected category of infertile men with high SDF.

Keywords: Assisted reproduction; male infertility; natural pregnancy; semen analysis (SA); sperm DNA fragmentation (SDF).

Figure 1

Summary of risk factors, molecular mechanisms of sperm DNA fragmentation, and its clinical implications. Due to exogenous and endogenous factors, SSBs are induced through several molecular mechanisms such as abortive topoisomerase, DNA ligase activity adjacent to lesion, and free radicals, while DSBs are induced by collapsed replication forks, replication in DNA strand with SSBs, and free radicals. Although both SSBs and DSBs could lead to male infertility and impaired reproductive outcomes, DSBs have been clearly linked with significant adverse effects (as demonstrated by the wider arrow). Reprinted with permission, Cleveland Clinic Foundation ^©2022. All Rights Reserved. SSB, single strand DNA break; DSB, double strand DNA break; NC, natural conception; IVF, in vitro fertilization; RPL, recurrent pregnancy loss; IUI, intrauterine insemination; ICSI, intracytoplasmic sperm injection.

Figure 2

Many therapeutic approaches exist to help men with elevated SDF improve their reproductive outcomes. Underlying causes and etiologies, such as varicocele, male genital tract infections, obesity, and lifestyle risk factors should be addressed. Antioxidants can be supplied to counteract the oxidative stress implicated in the pathogenesis of SDF. Reduced ejaculatory abstinence has also been shown to reduce SDF. Hormonal therapy may be given, and finally men can be directed towards assisted methods of reproduction as well as advanced sperm selection techniques. Reprinted with permission, Cleveland Clinic Foundation ^©2022. All Rights Reserved. SDF, sperm DNA fragmentation.

Figure 3

A SWOT analysis into the use of SDF testing in clinical practice. Reprinted with permission, Cleveland Clinic Foundation ^©2022. All Rights Reserved. SWOT, strengths, weaknesses, opportunities and threats; SDF, sperm DNA fragmentation; ART, assisted reproductive technologies.