Sperm DNA Fragmentation: A New Guideline for Clinicians

Abstract

Sperm DNA integrity is crucial for fertilization and development of healthy offspring. The spermatozoon undergoes extensive molecular remodeling of its nucleus during later phases of spermatogenesis, which imparts compaction and protects the genetic content. Testicular (defective maturation and abortive apoptosis) and post-testicular (oxidative stress) mechanisms are implicated in the etiology of sperm DNA fragmentation (SDF), which affects both natural and assisted reproduction. Several clinical and environmental factors are known to negatively impact sperm DNA integrity. An increasing number of reports emphasizes the direct relationship between sperm DNA damage and male infertility. Currently, several assays are available to assess sperm DNA damage, however, routine assessment of SDF in clinical practice is not recommended by professional organizations. This article provides an overview of SDF types, origin and comparative analysis of various SDF assays while primarily focusing on the clinical indications of SDF testing. Importantly, we report four clinical cases where SDF testing had played a significant role in improving fertility outcome. In light of these clinical case reports and recent scientific evidence, this review provides expert recommendations on SDF testing and examines the advantages and drawbacks of the clinical utility of SDF testing using Strength-Weaknesses-Opportunities-Threats (SWOT) analysis.

Keywords: Assisted reproductive techniques outcome; Clinical guidelines; Infertility, male; Oxidative stress; Sperm DNA fragmentation.

Fig. 1. Different types of DNA damage that can occur at DNA level: mismatched bases, abasic sites, base modifications (oxidation, alkylation, deamination), adducts and intrastrand crosslinks, pyrimidine dimers, and single and double strand fragmentation. ROS: reactive oxygen species, UV: ultraviolet.

Fig. 2. Overview of the origins of sperm DNA fragmentation (SDF). SDF result from underlying mechanisms such as defective maturation, abortive apoptosis, and oxidative stress. Moreover, clinical (age, infection, cancer, hormonal imbalances, obesity, diabetes) and environmental (heat exposure, environmental toxins, radiation, smoking, drug abuse, diet) risk factors lead to SDF. MAPK: mitogen-activated protein kinase, ERK: extracellular signal-regulated kinase, JNK: c-JUN N-terminal kinase, ROS: reactive oxygen species, ART: assisted reproductive techniques.

Fig. 3. (A) Main insults that result in DNA single strand breaks are abortive topoisomerase, free radicals, and DNA ligase activity adjacent to lesion. (B) Main insults that result in DNA double strand breaks are free radicals, collapsed replication forks, replication in DNA strand with single-stranded breaks, ionizing radiation, genotoxic chemicals, and radiomimetic drugs.

Fig. 4. Clinical algorithm to elucidate the applications of sperm DNA fragmentation (SDF) testing in clinical practice. ICSI: intracytoplasmic sperm injection.

Fig. 5. Strengths-Weaknesses-Opportunities-Threats (SWOT) analysis on the clinical utility of sperm DNA fragmentation (SDF) testing in specific male infertility scenario. ART: assisted reproductive techniques.