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      Specialized sperm function tests in varicocele and the future of andrology laboratory

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          Abstract

          Varicocele is a common medical condition entangled with many controversies. Though it is highly prevalent in men with infertility, still it marks its presence in males who do have normal fertility. Determining which patients are negatively affected by varicocele would enable clinicians to better select those men who benefitted the most from surgery. Since conventional semen analysis has been limited in its ability to evaluate the negative effects of varicocele on fertility, a multitude of specialized laboratory tests have emerged. In this review, we examine the role and significance of specialized sperm function tests with regards to varicocele. Among the various tests, analysis of sperm DNA fragmentation and measurements of oxidative stress markers provide an independent measure of fertility in men with varicocele. These diagnostic modalities have both diagnostic and prognostic information complementary to, but distinct from conventional sperm parameters. Test results can guide management and aid in monitoring intervention outcomes. Proteomics, metabolomics, and genomics are areas; though still developing, holding promise to revolutionize our understanding of reproductive physiology, including varicocele.

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          Most cited references 80

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          The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis.

          Is there an association between high levels of sperm DNA damage and miscarriage? Miscarriage rates are positively correlated with sperm DNA damage levels. Most ejaculates contain a subpopulation of sperm with DNA damage, also referred to as DNA fragmentation, in the form of double or single-strand breaks which have been induced in the DNA prior to or following ejaculation. This DNA damage may be particularly elevated in some subfertile men, hence several studies have examined the link between sperm DNA damage levels and conception and miscarriage rates. A systematic review and meta-analysis of studies which examined the effect of sperm DNA damage on miscarriage rates was performed. Searches were conducted on MEDLINE, EMBASE and the Cochrane Library without any language restrictions from database inception to January 2012. We used the terms 'DNA damage' or 'DNA fragmentation' combined with 'miscarriage', 'abortion' or 'pregnancy' to generate a set of relevant citations. Data extraction was performed by two reviewers. Study quality was assessed using the Newcastle-Ottawa Scale. Meta-analysis of relative risks of miscarriage was performed with a random effects model. Subgroup analyses were performed by the type of DNA damage test, whether the sperm examined were prepared or from raw semen and for pregnancies resulting from IVF or ICSI treatment. We identified 16 cohort studies (2969 couples), 14 of which were prospective. Eight studies used acridine orange-based assays, six the TUNEL assay and two the COMET assay. Meta-analysis showed a significant increase in miscarriage in patients with high DNA damage compared with those with low DNA damage [risk ratio (RR) = 2.16 (1.54, 3.03), P < 0.00001)]. A subgroup analysis showed that the miscarriage association is strongest for the TUNEL assay (RR = 3.94 (2.45, 6.32), P < 0.00001). There is some variation in study characteristics, including the use of different assays and different thresholds for DNA damage and the definition of pregnancy loss. The use of methods which select sperm without DNA damage for use in assisted conception treatment may reduce the risk of miscarriage. This finding indicates that assays detecting DNA damage could be considered in those suffering from recurrent pregnancy loss. Further research is necessary to study the mechanisms of DNA damage and the potential therapeutic effects of antioxidant therapy. None.
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            Sperm DNA fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis.

            To review the mechanisms responsible for DNA fragmentation in human sperm, including those occurring during spermatogenesis and transport through the reproductive tract. The mechanisms examined include: apoptosis in the seminiferous tubule epithelium, defects in chromatin remodeling during the process of spermiogenesis, oxygen radical-induced DNA damage during sperm migration from the seminiferous tubules to the epididymis, the activation of sperm caspases and endonucleases, damage induced by chemotherapy and radiotherapy, and the effect of environmental toxicants. The different tests currently used for sperm DNA fragmentation analysis and the factors that determine the predictive value of sperm DNA fragmentation testing and their implications in the diagnosis and treatment of infertility are also discussed. Finally, we also scrutinize how the presence in the embryonic genome of DNA strand breaks or modifications of DNA nucleotides inherited from the paternal genome could impact the embryo and offspring. In particular we discuss how abnormal sperm could be dealt with by the oocyte and how sperm DNA abnormalities, which have not been satisfactorily repaired by the oocyte after fertilization, may interfere with normal embryo and fetal development. Sperm DNA can be modified through various mechanisms. The integrity of the paternal genome is therefore of paramount importance in the initiation and maintenance of a viable pregnancy both in a natural conception and in assisted reproduction. The need to diagnose sperm at a nuclear level is an area that needs further understanding so that we can improve treatment of the infertile couple. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
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              Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis.

              Sperm DNA damage is common amongst infertile men and may adversely impact natural reproduction, IUI-assisted reproduction and to a lesser degree IVF pregnancy. The aim of this study was to examine the influence of sperm DNA damage on the risk of spontaneous pregnancy loss after IVF and ICSI. We conducted a systematic review and meta-analysis of studies on sperm DNA damage and pregnancy loss after an IVF and/or ICSI pregnancy. Two by two tables were constructed and odds ratios (ORs) were derived from 11 estimates of pregnancy loss (five IVF and six ICSI studies from seven reports). These 11 studies involved 1549 cycles of treatment (808 IVF and 741 ICSI cycles) with 640 pregnancies (345 IVF and 295 ICSI) and 122 pregnancy losses. The combined OR of 2.48 (95% CI 1.52, 4.04, P < 0.0001) indicates that sperm DNA damage is predictive of pregnancy loss after IVF and ICSI. In conclusion, sperm DNA damage is associated with a significantly increased risk of pregnancy loss after IVF and ICSI. These data provide a clinical indication for the evaluation of sperm DNA damage prior to IVF or ICSI and a rationale for further investigating the association between sperm DNA damage and pregnancy loss.
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                Author and article information

                Journal
                Asian J Androl
                Asian J. Androl
                AJA
                Asian Journal of Andrology
                Medknow Publications & Media Pvt Ltd (India )
                1008-682X
                1745-7262
                Mar-Apr 2016
                15 January 2016
                : 18
                : 2
                : 205-212
                Affiliations
                [1 ]Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
                [2 ]Androfert, Andrology and Human Reproduction Clinic, Referral Center for Male Reproduction, Av. Dr. Heitor Penteado, 1464, Campinas, SP 13075-460, Brazil
                [3 ]Genetics Unit, Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain
                [4 ]American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA
                Author notes
                Correspondence: Dr. A Majzoub ( majzoua@ 123456ccf.org )
                Article
                AJA-18-205
                10.4103/1008-682X.172642
                4770487
                26780873
                448b7618-a28a-49e1-90f0-7ad48ca937a1
                Copyright: © 2016 Asian Journal of Andrology

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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