Testing of sperm DNA damage and clinical recommendations

tau.amegroups.com © Translational Andrology and Urology. All rights reserved. Agarwal et al. in their most recent paper (1) propose a clinical guideline on the use of sperm DNA damage testing in infertility treatment. This guideline is extremely relevant for fertility specialists and further insight into the topic is in high demand as the debate regarding the role of DNA damage testing is still ongoing (2,3). We believe that some of the controversies in the field are due to misunderstandings which might be prevented by a more careful communication. In our opinion, the term “fragmentation” is misleading as it implies that the sperm DNA has already been broken into “fragments”—i.e., DNA with double-stranded breaks. Double-stranded DNA breaks represent an irreversible change which is highly unlikely to be repaired by the oocyte. The initial discovery that sperm DNA damage affected the outcome of natural intercourse negatively (4) led to the assumption that there would be a similar impact on the outcome of intrauterine insemination (IUI), in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment. However, several clinical studies subsequently demonstrated that this is not the case and that the outcome of IVF and especially ICSI treatment are less affected than is the case for IUI treatments and natural intercourse. The term “fragmentation” and our perception of the type of sperm DNA damage have led to a number of misunderstandings. As an example, the results of sperm DNA testing have been regarded as “false positive results” in the area of IVF and ICSI treatments. A study by Bungum et al. (5) demonstrated that the impact on treatment outcome depended on the type of fertility treatment. IUI was affected to the same extent as natural intercourse, IVF to a lesser extent, and the smallest impact was seen for ICSI treatments. The work by Bungum et al. (5) and other publications during the past decade have resulted in the “two-step-hypothesis” proposed by Aitken and De Iuliis (6): sperm DNA testing concerns the integrity of the DNA. If DNA integrity is poor, the sperm DNA is fragile and may become damaged after the sperm becomes motile. This is due to increases in the level of reactive oxygen species (ROS) following the oxidative production of energy in the mid-piece. Clearly, the extent of DNA damage depends on the length of the “journey” which the sperm make to the oocyte as well as the demanding process of fertilization. Reducing the length of the journey to the oocyte (IVF) as well as bypassing the process of fertilization (ICSI) will minimize the extent of sperm DNA damage. It is, therefore, not surprising that treatment success rates vary for the different types of fertility treatment. Agarwal et al. (1) provide a comprehensive review of the literature with evidence based recommendations including the role of sperm DNA damage on recurrent miscarriage. A recent review and meta-analysis by Zhao et al. (7) highlighted the importance of sperm DNA damage in relation to miscarriage following IVF and ICSI treatment. In addition, a new review and meta-analysis by Simon et al. (8) also showed that sperm DNA damage negatively affects the outcome of ICSI treatment. The recommendations by Agarwal et al. (1) also include the use of testicular sperm in men with high DNA fragmentation index (DFI) and repeated IVF failure. We agree but would also suggest that factors known to increase the level of sperm DNA damage are identified and recommend that these are treated or corrected prior to fertility treatment. Factors which should be considered Commentary