Sperm DNA Integrity and Male Infertility

A Narrative Review and Guide for the Reproductive Physicians

Ala'a Farkouh; Gianmaria Salvio; Shinnosuke Kuroda; Ramadan Saleh; Paraskevi Vogiatzi; Ashok Agarwal


Transl Androl Urol. 2022;11(7):1023-1044. 

In This Article

Abstract and Introduction


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.


Infertility is a highly prevalent condition worldwide, but the exact extent of the phenomenon is difficult to assess, since it has various definitions.[1] Current inconsistencies in medical approaches, in addition to individual reproductive choices, allow some cases to go undetected. An epidemiologic study, in which live birth over a 5-year period was measured, reported that the prevalence of couples suffering from infertility was estimated at 48.5 million all over the world.[2] According to the definition by the World Health Organization (WHO) (i.e., absence of conception after 12 months of regular, unprotected intercourse), infertility is a condition in which male factors, female factors, or both may contribute, with males being responsible for 50% of the cases overall. A significant percentage of these cases can be attributed to unexplained infertility (UI), where no currently applied knowledge or tools are able to establish a direct diagnosis.[3]

Semen analysis (SA) is the backbone of male infertility assessment, however it does not provide any insight into the functional status of spermatozoa and cannot justify adverse reproductive outcomes or UI when the baseline evaluation of both partners is unremarkable.[4] The recently published 6th edition of the WHO laboratory manual for the examination and processing of human semen has acknowledged such limitations, and in an attempt to identify and underline the importance of sperm function testing, it has introduced sperm DNA fragmentation (SDF) as an extended examination and recommends this assessment in certain clinical settings, which has been quoted as a major strength of the new manual.[5]

SDF occurs in male germ cells when nuclear DNA damage is induced by different factors and is not properly repaired due to dysfunctional repair systems.[6] Recent evidence has pointed to the relevance of sperm DNA integrity in reproductive outcomes, since high levels of SDF have been found in infertile men[7] and in association with risk factors for infertility (e.g., drugs, pollutants, lifestyle habits and diseases), which can damage male gametes through testicular apoptosis, altered chromatin maturation and, increased reactive oxygen species (ROS) production.[8]

The aim of the present narrative review is to discuss the pathophysiological aspects of SDF including physiological mechanisms that oppose SDF, its causes and significance in terms of reproduction. Additionally, we discuss the different methods of assessment of SDF and provide guidance for potential therapeutic interventions for the management of infertile men with high levels of SDF. Furthermore, we highlight the strengths, weaknesses, opportunities, and threats (SWOT) of current research in SDF and provide insights for future research that may help optimize the diagnostic and predictive potentials of this test in clinical practice. We present the following article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-22-149/rc).