A single cut-off value of sperm DNA fragmentation testing does not fit all

tau.amegroups.com © Translational Andrology and Urology. All rights reserved. We are delighted to read the insightful commentary by Dr. Evenson (1), a well-known pioneer in the field of SDF testing, in response to the practice recommendations on clinical utility of sperm DNA fragmentation (SDF) testing by Agarwal et al. (2). The process of protamination during spermiogenesis was discovered as early as in the 1940s and 1950s (3,4). It is not until 1970 that the association between sperm DNA damage and reduction in fertility was illustrated (5). In 1980, Dr. Evenson et al. developed sperm chromatin structure assay (SCSA)—a flow cytometric assay for detection of SDF (6). In this test, the semen sample is pretreated by acid and sites of DNA strand breaks are subsequently stained by acridine orange which is a nucleic acid-selective cationic fluorescent dye. The use of flow cytometry allowed evaluation of a large number of cells rapidly by measuring the metachromatic shift of fluorescence (7). Various SDF assays, including terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and sperm chromatin dispersion (SCD), were introduced after SCSA. Following the breakthrough in laboratory assessment of SDF, the etiologies of SDF and its negative impact on reproductive outcomes were studied extensively in the last two decades. The large body of research conducted by Dr. Evenson plays an important role in our understanding of SDF and male infertility. In his commentary, Dr. Evenson shared his perspective on the pivotal role of SDF assay in clinical male fertility assessment (1). He believes that SCSA measures existing DNA strand breaks due to the high penetrating ability of acridine orange dye to the compact nuclear chromatin structure. He discussed the use of flow cytometry in increasing precision and accuracy of SDF assessment, the importance of high correlations of SDF results between laboratories and lastly the evidence supporting the association between SDF result and natural pregnancy/assisted reproduction outcomes were succinctly summarized. Of many points highlighted by Dr. Evenson, we want to expand the discussion on one topic—the threshold value for SDF assays. The lack of a cut-off value for SDF assays is often considered a major handicap as it casts doubts about the wider clinical application of the test. Currently, there seems to be insufficient evidence to support the routine use of SDF in male factor evaluation (8). This is mainly due to heterogeneous test methodologies and lack of rigorous SDF cut-off values in the literature (8). The quest for a clear threshold of a diagnostic test for a specific clinical circumstance would be an ideal situation. However, it is important to note that this approach is not realistic for all situations. A single magic test with a clear cut-off in the context of the complex human reproductive system is probably an oversimplification. The often coexistence of both male and female factors in an infertile couple cannot be accurately assessed by a single laboratory test on either partner. Indeed, a panel of diagnostic tests is usually required clinically for comprehensive assessment of patients nowadays. The incorporation of scoring systems or nomograms into Editorial