Controversy and Consensus on the Management of Elevated Sperm DNA Fragmentation in Male Infertility: A Global Survey, Current Guidelines, and Expert Recommendations

Abstract

Purpose Sperm DNA fragmentation (SDF) has been associated with male infertility and poor outcomes of assisted reproductive technology (ART). The purpose of this study was to investigate global practices related to the management of elevated SDF in infertile men, summarize the relevant professional society recommendations, and provide expert recommendations for managing this condition. Materials and Methods An online global survey on clinical practices related to SDF was disseminated to reproductive clinicians, according to the CHERRIES checklist criteria. Management protocols for various conditions associated with SDF were captured and compared to the relevant recommendations in professional society guidelines and the appropriate available evidence. Expert recommendations and consensus on the management of infertile men with elevated SDF were then formulated and adapted using the Delphi method. Results A total of 436 experts from 55 different countries submitted responses. As an initial approach, 79.1% of reproductive experts recommend lifestyle modifications for infertile men with elevated SDF, and 76.9% prescribe empiric antioxidants. Regarding antioxidant duration, 39.3% recommend 4–6 months and 38.1% recommend 3 months. For men with unexplained or idiopathic infertility, and couples experiencing recurrent miscarriages associated with elevated SDF, most respondents refer to ART 6 months after failure of conservative and empiric medical management. Infertile men with clinical varicocele, normal conventional semen parameters, and elevated SDF are offered varicocele repair immediately after diagnosis by 31.4%, and after failure of antioxidants and conservative measures by 40.9%. Sperm selection techniques and testicular sperm extraction are also management options for couples undergoing ART. For most questions, heterogenous practices were demonstrated. Conclusions This paper presents the results of a large global survey on the management of infertile men with elevated SDF and reveals a lack of consensus among clinicians. Furthermore, it demonstrates the scarcity of professional society guidelines in this regard and attempts to highlight the relevant evidence. Expert recommendations are proposed to help guide clinicians.

Technical Aspects and Clinical Limitations of Sperm DNA Fragmentation Testing in Male Infertility: A Global Survey, Current Guidelines, and Expert Recommendations

“…Many different treatment strategies also exist for managing infertile men with elevated SDF. These include management of underlying causes such as repair of clinical varicocele and antibiotics for genital tract infections, weight loss, avoidance of risk factors, empiric antioxidants, and reduction in ejaculatory abstinence [ 37 ]. Sperm selection techniques and testicular sperm have also been shown to reduce SDF levels and can be used in ART.…”

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

“…47 Subsequently, DNA analysis has been suggested as an additional standardized test to evaluate the functional competency of sperm. [46][47][48] While DNA integrity results from the SCD assay have been shown to correlate strongly with male fertility potential, 33,38,49 reliance on subjective and manual image analysis methods has resulted in a significant intra-observer and inter-laboratory variations. 37,38 Fig.…”

“…In a recent study, Kuroda et al (2023), validated a software developed for analyzing images from a commercially available halo evaluation system (LensHooke X12PRO®). 42 This software utilizes an artificial intelligence-assisted algorithm to identify sperm and then, it evaluates B/A ratio by fitting an ellipse to the DNA halo.…”

Sperm DNA fragmentation testing in clinical management of reproductive medicine

“…another are currently lacking. 126 The management flowchart for cases with high sperm DNA fragmentation is shown in Figure 3.…”