Sperm DNA Fragmentation: A New Guideline for Clinicians

CAPSULE

Contributors: Ahmad Motawi, MD, PhD, FECSM (Egypt), and

Charalampos Thomas, MD, MSc, PhD, FECSM (Greece)

Commentary:

Despite the technological advances, conventional semen analysis is still the corner stone of infertile men evaluation, but it has limitations in predicting male fertility potential and the outcome of assisted reproductive technology. A normal semen analysis does not rule out infertility in some patients. About 15% of them have normal results.

Sperm DNA Integrity is crucial for fertilization, embryo development and ART outcomes. Many studies have reported a link between SDF and male infertility. So far not only we do not have a routine assessment of Sperm DNA Fragmentation (SDF) but also it isn’t recommended by professional organizations as standard practice.

This article provides a thorough overview on SDF types and methods of assessment, emphasizing on the impact they have in diagnosis and treatment of male infertility. By using clinical scenarios, the authors provide helpful paradigms of implementation of all the current knowledge, and they concluded by performing a SWOT analysis of SDF testing evaluating 4 parameters: Strength-Weakness-Opportunities and finally Threats in order to understand the advantages and drawbacks for the clinical utility of SDF in specific clinical scenarios regarding male infertility.

SDF could originate from either endogenous or primary mechanisms such as defective maturation and abortive apoptosis occurring within the testis, or by oxidative stress throughout the male reproductive tract, or exogenous clinical and environmental risk factors as obesity, smoking, varicocele via increased intratesticular temperature, environmental pollution, exposure to heavy metals or even electromagnetic waves. Any type of DNA damage can be observed, including loss of base, bases mismatch or modifications, single strand (SSB) or double strand breaks (DSB), which induces SDF thus compromising natural conception or ART outcomes.

Numerous techniques have been described, in order to assess SDF, such as tests that label the broken ends of the DNA strands, as TUNEL, SCSA and SCD. However, these tests cannot tell the difference between single-strand breaks (SSBs) and double-strand breaks (DSBs) in the DNA. The two-tailed Comet assay is the only test that can do that. Another test that is recently developed is the γH2AX test, which specifically detects DSBs in sperm DNA.

So, what test should someone order when male infertility is under investigation? The authors have provided detailed tables, comparing the techniques in terms of pregnancy outcome, clinical cut-offs, sensitivity, and specificity among other parameters. Alongside they offer a list of men/couples who will benefit the most from an SDF testing, including men with varicocele, couples with recurrent pregnancy loss, idiopathic and unexplained male infertility, or high-risk patients among others. They also provide suggestions in management of men with high SDF, including oral antioxidants, infections treatment, varicocelectomy, life-style changes, short ejaculatory abstinence, methods of sperm processing and preparation and even the use of testicular sperm for ICSI in some cases.

The authors gave an example of 4 clinical cases that visualize the whole concept, where they provide clinical paradigms of diagnostic workflow and treatment methods.

Finally, the study provided expert recommendations on SDF assessment with SWOT analysis on the clinical utility of sperm SDF testing in specific male infertility scenarios.

1. Strengths:

• SDF testing can be a valuable additive in specific clinical scenarios, such as inability of natural conception, idiopathic infertility, varicocele, RPL, ART failure and exposition to lifestyle/environmental risk factors.
• Interventions such as recurrent ejaculation, oral antioxidants, varicocelectomy in clinical varicocele, treatment of GU infections, advanced sperm selection techniques for ICSI or using testicular sperm have been proved efficient in alleviating high SDF in clinical practice in terms of improving fertility.

2. Weaknesses:

• By far, the greatest limitation is the lack of a definitive cut-off value above which a sample is considered anomalous.
• Lack of strong recommendation upon the use of SDF in everyday practice.

3. Opportunities:

• The authors have highlighted the need for further, well designed studies to enhance our understanding of the clinical use of SDF.

4. Threats:

• International societies such as EAU and AUA do not recommend SDF testing as a routine for the evaluation of male infertility due to lack of sufficient high-quality evidence supporting data.
• However, emerging data from upcoming research will probably provide sufficient data for the justification of performing SDF testing as routine.
• SDF cost has to be considered, since it may not be reimbursed by health systems around the globe. However, what may the cost be, please take into consideration how useful it may be in terms of improving the outcome of treatment and the impact on the overall treatment cost.



Take Home Message: (contributor: Ashok Agarwal)

1. Sperm DNA integrity is critical for successful fertilization and the development of healthy offspring. Damage to sperm DNA can significantly impact both natural and assisted reproductive outcomes.
2. Various clinical and environmental factors can negatively affect sperm DNA integrity, including lifestyle choices and exposure to toxins, underscoring the importance of a comprehensive evaluation of male fertility beyond traditional semen analysis.
3. The article underscores the utility of SDF testing in certain clinical scenarios, such as unexplained infertility, recurrent pregnancy loss, and prior to assisted reproductive techniques, to better inform treatment strategies and improve outcomes.
4. Despite the availability of several assays for assessing sperm DNA damage, there is a lack of consensus on standard cut-off values for predicting reproductive outcomes, highlighting the need for further research and standardized guidelines.
5. The article emphasizes a multidisciplinary approach to the management of male infertility, incorporating SDF testing alongside other diagnostic tools to tailor interventions more effectively and improve the chances of achieving pregnancy.