Sperm DNA fragmentation: the evolution of guidelines for patient testing and management

tau.amegroups.com © Translational Andrology and Urology. All rights reserved. Sperm DNA fragmentation (SDF) represents a perplexing biological phenomenon that can, at an elevated level, interfere with either initiating and/or maintaining pregnancy. Although we are in our third decade of studying this problem, few investigators have attempted to assess the value of the various available assays for SDF with the specific aim of amalgamating them into practice guidelines for managing SDF. Agarwal, in collaboration with urological experts from North and South America, has done just that, employing a number of clinical scenarios involving SDF to produce some evidence-based, practical guidelines for patient management (1). But if in our third decade of investigation, why are management guidelines so difficult to come by for patients with elevated SDF? First, it should be emphasized that SDF is an exceedingly complex process involving not one, but a number of causative mechanisms that can generate a variety of insults to the integrity of sperm DNA. Sakkas and Alvarez (2) have described six main mechanisms that can damage both sperm nuclear as well as mitochondrial DNA. Included in this list are testicular apoptotic processes during spermatogenesis, aberrations during the events of chromatin re-modeling, induction by exogenous caspases and nucleases plus damage by chemoand radiotherapy as well as environmental toxicants. Perhaps the most robust events occur in the epididymis in response to insult by reactive oxygen species. That epididymal and ejaculated sperm have higher amounts of DNA fragmentation than testicular sperm is now well documented (3-5). What is not known are the testicular events that render sperm labile to chemical radicals traversing the epididymis. Secondly, the insults can produce single-stranded breaks, double-stranded breaks and/or nucleotide damage. Not all are detected by the same tests, the different types of damage are repaired to different degrees by processes resident in the oocyte and thus, do not have the same prognosis. Likely though, it is the tests used to detect and measure SDF, along with their varying levels of complexity, that introduce the bulk of the conflicting data and conclusions common in the SDF literature. As Agarwal et al. demonstrate in concise tabular form, there are at least eight tests for SDF, each with attendant advantages and disadvantages. The predictive value of these, assuming proper execution and quality control, depends upon the type of DNA damage, the percent of sperm with fragmentation, the extent of damage per sperm, whether there is combined fragmentation and nucleotide damage, whether the lesions affect exons or introns and the effectiveness of the oocytes in repairing DNA damage in zygote genomic DNA contributed by the fertilizing sperm (2). Of interest, SDF fails to affect the fertilizing capacity of sperm (6), so testing is performed to either visualize the state of sperm DNA via differential staining of fragmented versus intact DNA, to reveal the physical restrictions fragmentation places upon DNA dispersion, to measure differential electrophoretic mobility of intact versus fragmented DNA or measure nucleotide incorporation into DNA nicks. A very recent review and meta-analysis by Cissen et al. (7) examined the value of SDF measures in predicting the chance of ongoing pregnancy with in vitro fertilization (IVF) or Commentary