Pros and cons of sperm DNA fragmentation testing: weighing the evidence

tau.amegroups.com © Translational Andrology and Urology. All rights reserved. Conventional semen parameters are poor predictors of reproductive outcomes, and do not reliably discriminate between fertile and infertile men (1,2). A growing body of evidence suggests that markers of sperm DNA integrity may help differentiate fertile from infertile men, but the clinical value of sperm DNA fragmentation testing remains a matter of debate (3). Although guidelines and best practice statements published by the American Urological Association (AUA), European Association of Urology (EAU) and the American Society of Reproductive Medicine (ASRM) al l acknowledge the potent ia l contribution of sperm DNA fragmentation to male factor infertility, they do not recommend the routine use of sperm DNA integrity tests in the evaluation and treatment of infertile couples (4-6). Agarwal et al. recently published a summary of the literature describing the clinical utility of sperm DNA fragmentation assays, in the context of commonly encountered clinical scenarios, including varicocele, idiopathic infertility/recurrent pregnancy loss, IVF/ICSI failure, and normal/minimally impaired semen parameters in the setting of environmental risk factors (7). The authors recommended that sperm DNA fragmentation testing be offered to couples in each of these clinical scenarios, albeit for a different clinical goals. Impaired sperm DNA integrity may facilitate decision making—for example, whether or not to pursue varicocelectomy despite minimal impairment in conventional semen parameters, or whether or not to pursue additional fertility treatments after experiencing recurrent pregnancy loss. The authors argue that impaired sperm DNA integrity may also motivate patients to commit to lifestyle changes such as smoking cessation, and weight loss and exercise. These arguments are based on the assumption that sperm DNA integrity is a consistent and reliable predictor of pregnancy rates and reproductive outcomes, following natural conception, IUI, IVF, or ICSI. Based on the available evidence, which is derived primary from uncontrolled cohort studies, infertile men are more likely to have impaired DNA integrity (8). Increased sperm DNA fragmentation is associated with prolonged time to conception (9), lower rates of pregnancy with natural conception (10), IUI (11), IVF (12-14), and ICSI (14,15). One meta-analysis has also demonstrated an association between DNA fragmentation and pregnancy loss (16). However, not all studies have shown consistent results, in terms of association or magnitude of effect (3,5). The recommendations made by Agarwal et al. (7) are, therefore, largely based on expert opinion (grade C), which is reflective of the methodological limitations of the studies on this topic. There are no validated cut points for any of the available sperm DNA fragmentation assays, to allow them to effectively be used as predictors of fertility (5), which limits the ability of these tests to guide management in scenarios such as varicoceles, especially when conventional semen parameters are normal or close to normal. Test sensitivity for predicting pregnancy with IUI has been shown to be less than 25% (3,11), limiting its utility among couples considering IUI. Although a statically significant difference has been found in pregnancy rates after IVF and ICSI among couples with normal and abnormal sperm DNA fragmentation, it is unclear whether this Commentary