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.

High-throughput sperm DNA analysis at the single-cell and population levels

“…Several techniques are available to measure sperm DNA integrity. [22][23][24] Flow cytometry-based techniques, including sperm chromatin structure assay (SCSA) 25,26 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatenick end labelling (TUNEL), [27][28][29] access a few thousand sperm in a short time (∼5 min) 26,30 and provide an accurate assessment DNA quality. However, these methods are not widely applicable to clinics as they require a flow cytometry facility and expert operators.…”

The importance of incorporating sperm DNA fragmentation testing in male infertility diagnostic routine

“…Few fertility clinics currently perform SDF tests routinely, so specialists may have concerns about performing this test and its usefulness. The article by Farkouh and colleagues ( 10 ) discusses the pathophysiological aspects of SDF for assisting physicians in understanding the circumstances in which this parameter could be of clinical value, and proposes different analysis methods to guide physicians in incorporating this parameter into clinical practice, also providing relevant information for its interpretation and subsequent actions.…”

“…DNA breakage can occur throughout the life of the sperm, from spermatogenesis (where enzymatic damage or repair errors predominate), through the epididymis and vaginal tract [where it suffers high oxidative stress (OS)], to fertilization (where the oocyte’s repair mechanisms may be defective) ( 8 , 11 ). As Farkouh et al rightly commented ( 10 ), during spermatogenesis the enzymes responsible for creating and repairing breaks to generate genetic recombination between homologous chromosomes are the main protagonists in the generation of SDF. The roles of the Spo11 protein, which produces double-strand breaks (DSB), and the ataxia-telangiectasia mutated (ATM) protein kinase, which repairs the free ends produced by Spo11, creating chiasms, are notable ( 12 ).…”

“…The main strategy is to reduce OS through the elimination of the risk factors (such as obesity, varicocele, short abstinence or hormone therapy, among others) or the provision of antioxidants, which its effect is still in controversy. Farkouh and collaborators ( 10 ) rightly propose advanced sperm selection as an alternative that, despite being in optimization phases, already produces very significant results in reducing SDF in specific assisted reproductive technologies procedures. Despite the clear implication of the SDF on reproductive success, the limitations in the treatments to reduce it may cause doubts when implementing this assessment in the diagnosis of the disease.…”

Elevated sperm DNA fragmentation levels result in detrimental effects on natural and assisted reproductive outcomes per a review of the medical literature

“…Farkouh et al have written a comprehensive narrative regarding sperm DNA fragmentation (SDF) with systematic reviews and meta-analyses as the basis for their discussion (1). Diagnostic semen testing with enough evidence to support its use has not significantly advanced since spermatozoa were first identified microscopically by Antony van Leeuwenhoek in the mid-17th century until SDF assays (2).…”