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      Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility

      , 1 , 2 , 2 , 1 , 2 , 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 1 , 11 , 12 , 13 , 14 , 15 , 15 , 16 , 17 , 18 , 19 , 2 , 2 , 20 , 21 , 2 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 64 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 1 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93

      The World Journal of Men's Health

      Korean Society for Sexual Medicine and Andrology

      Infertility, male, MOSI, Oxidation reduction potential, Oxidative stress, Semen

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          Abstract

          Despite advances in the field of male reproductive health, idiopathic male infertility, in which a man has altered semen characteristics without an identifiable cause and there is no female factor infertility, remains a challenging condition to diagnose and manage. Increasing evidence suggests that oxidative stress (OS) plays an independent role in the etiology of male infertility, with 30% to 80% of infertile men having elevated seminal reactive oxygen species levels. OS can negatively affect fertility via a number of pathways, including interference with capacitation and possible damage to sperm membrane and DNA, which may impair the sperm's potential to fertilize an egg and develop into a healthy embryo. Adequate evaluation of male reproductive potential should therefore include an assessment of sperm OS. We propose the term Male Oxidative Stress Infertility, or MOSI, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility. Oxidation-reduction potential (ORP) can be a useful clinical biomarker for the classification of MOSI, as it takes into account the levels of both oxidants and reductants (antioxidants). Current treatment protocols for OS, including the use of antioxidants, are not evidence-based and have the potential for complications and increased healthcare-related expenditures. Utilizing an easy, reproducible, and cost-effective test to measure ORP may provide a more targeted, reliable approach for administering antioxidant therapy while minimizing the risk of antioxidant overdose. With the increasing awareness and understanding of MOSI as a distinct male infertility diagnosis, future research endeavors can facilitate the development of evidence-based treatments that target its underlying cause.

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          Most cited references 98

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          Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989).

          To estimate the prevalence and main causes of infertility, a multicentre survey was conducted over 1 year (July 1988-June 1989) in three regions of France. All the 1686 couples in these regions, who consulted a practitioner for primary or secondary infertility during this period, were included in the investigation. The prevalence rate of infertility was found to be 14.1%, indicating that one woman out of seven in France will consult a doctor for an infertility problem during her reproductive life. The main causes of female infertility were ovulation disorders (32%) and tubal damage (26%), and of male infertility oligo-terato-asthenozoospermia (21%), asthenozoospermia (17%), teratozoospermia (10%) and azoospermia (9%). Infertility was also found to be caused by disorders in both the male and female partners together; thus in 39% of cases both the man and woman presented with disorders. The woman alone was responsible for infertility in one-third of cases and the man alone in one-fifth. Unexplained infertility was found in 8% of the couples surveyed.
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            The genetic causes of male factor infertility: a review.

            To illustrate the necessity for an enhanced understanding of the genetic basis of male factor infertility, to present a comprehensive synopsis of these genetic elements, and to review techniques being utilized to produce new insights in fertility research. Male factor infertility is a complex disorder that affects a large sector of the population; however, many of its etiologies are unknown. By elucidating the underlying genetic basis of infertile phenotypes, it may be possible to discover the causes of infertility and determine effective treatments for patients. The PubMed database was consulted for the most relevant papers published in the last 3 years pertaining to male factor infertility using the keywords "genetics" and "male infertility." Advances have been made in the characterization of the roles of specific genes, but further research is necessary before these results can be used as guidelines for diagnosing and treating male factor infertility. The accurate transmission of epigenetic information also has considerable influence on fertility in males and on the fertility of their offspring. Analysis of the genetic factors that impact male factor infertility will provide valuable insights into the creation of targeted treatments for patients and the determination of the causes of idiopathic infertility. Novel technologies that analyze the influence of genetics from a global perspective may lead to further developments in the understanding of the etiology of male factor infertility through the identification of specific infertile phenotype signatures. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
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              Role of reactive oxygen species in male infertility.

              Human spermatozoa exhibit a capacity to generate ROS and initiate peroxidation of the unsaturated fatty acids in the sperm plasma membrane, which plays a key role in the etiology of male infertility. The short half-life and limited diffusion of these molecules is consistent with their physiologic role in key biological events such as acrosome reaction and hyperactivation. The intrinsic reactivity of these metabolites in peroxidative damage induced by ROS, particularly H2O2 and the superoxide anion, has been proposed as a major cause of defective sperm function in cases of male infertility. The number of antioxidants known to attack different stages of peroxidative damage is growing, and it will be of interest to compare alpha-tocopherol and ascorbic acid with these for their therapeutic potential in vitro and in vivo. Both spermatozoa and leukocytes generate ROS, although leukocytes produce much higher levels. The clinical significance of leukocyte presence in semen is controversial. Seminal plasma confers some protection against ROS damage because it contains enzymes that scavenge ROS, such as catalase and superoxide dismutase. A variety of defense mechanisms comprising a number of anti-oxidants can be employed to reduce or overcome oxidative stress caused by excessive ROS. Determination of male infertility etiology is important, as it will help us develop effective therapies to overcome excessive ROS generation. ROS can have both beneficial and detrimental effects on the spermatozoa and the balancing between the amounts of ROS produced and the amounts scavenged at any moment will determine whether a given sperm function will be promoted or jeopardized. Accurate assessment of ROS levels and, subsequently, OS is vital, as this will help clinicians both elucidate the fertility status and identify the subgroups of patients that respond or do not respond to these therapeutic strategies. The overt commercial claims of antioxidant benefits and supplements for fertility purposes must be cautiously looked into, until proper multicentered clinical trials are studied. From the current data it appears that no single adjuvant will be able to enhance the fertilizing capacity of sperm in infertile men, and a combination of the possible strategies that are not toxic at the dosage used would be a feasible approach.
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                Author and article information

                Journal
                World J Mens Health
                World J Mens Health
                WJMH
                The World Journal of Men's Health
                Korean Society for Sexual Medicine and Andrology
                2287-4208
                2287-4690
                September 2019
                08 May 2019
                : 37
                : 3
                : 296-312
                Affiliations
                [1 ]American Center for Reproductive Medicine, Cleveland Clinic, OH, USA.
                [2 ]Department of Urology, Cleveland Clinic, Cleveland, OH, USA.
                [3 ]Department of Medical Bioscience, University of the Western Cape, Cape Town, South Africa.
                [4 ]Department of Urology, Lilavati Hospital and Research Centre, Mumbai, India.
                [5 ]School of Biosciences, University of Kent, Canterbury, UK.
                [6 ]Department of Urology, University of Miami, Miami, FL, USA.
                [7 ]Department of Urology, Loma Linda University Health, Loma Linda, CA, USA.
                [8 ]Department of Obstetrics Gynaecology and Reproductive Medicine, Flinders University, Bedford Park, Australia.
                [9 ]Division of Urology, Department of Surgery, University of Campinas (UNICAMP), Campinas, Brazil.
                [10 ]Faculty of Health, Aarhus University, Aarhus, Denmark.
                [11 ]Department of Urology, Hamad Medical Corporation and Weill Cornell Medicine-Qatar, Doha, Qatar.
                [12 ]Centro Androgen, La Coruña, Spain and Harvard Medical School, Boston, MA, USA.
                [13 ]School of BioSciences, University of Melbourne, Parkville, Australia.
                [14 ]Section of Investigative Medicine, Imperial College London, UK.
                [15 ]Department of Andrology, Hammersmith Hospital, London, UK.
                [16 ]Department of Surgery, Union Hospital, Shatin, Hong Kong.
                [17 ]Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag, Egypt.
                [18 ]Boston IVF, Waltham, MA, USA.
                [19 ]Department of Urology, University of Utah, Salt Lake City, UT, USA.
                [20 ]Cooper University Hospital, Camden, NJ, USA.
                [21 ]Departamento de Biología, Universidad Autónoma de Madrid, Madrid, Spain.
                [22 ]Department of Urology, Pusan National University School of Medicine, Busan, Korea.
                [23 ]Medical Research Institute of Pusan National University Hospital, Busan, Korea.
                [24 ]Department of Surgery, McGill University, Montreal, QC, Canada.
                [25 ]Austin Fertility & Reproductive Medicine/Westlake IVF, Austin, TX, USA.
                [26 ]Uromedica Polyclinic, Kneza Milosa, Belgrade, Serbia.
                [27 ]Department of Urology, University of Virginia, Charlottesville, VA, USA.
                [28 ]Sapienza University of Rome, Rome, Italy.
                [29 ]Istanbul Florence Nightingale Hospital, Istanbul, Turkey.
                [30 ]Department of Dermatology, University Hospital Bonn, Bonn, Germany.
                [31 ]Division of Endocrinology, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Umberto I Hospital, Ancona, Italy.
                [32 ]IVI Foundation Edificio Biopolo - Instituto de Investigación Sanitaria la Fe, Valencia, Spain.
                [33 ]University Hospital, School of Médicine and PERITOX Laboratory, Amiens, France.
                [34 ]Division of Urology, Southern Illinois University School of Medicine, Springfield, IL, USA.
                [35 ]Centre for Human Reproductive Science, IMSR, College of Medical & Dental Sciences, The University of Birmingham Edgbaston, UK.
                [36 ]The Birmingham Women's Fertility Centre, Birmingham Women's and Children's NHS Foundation Trust, Mindelsohn Drive, Edgbaston, UK.
                [37 ]Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada.
                [38 ]Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
                [39 ]Fertility Medical Group, São Paulo, Brazil.
                [40 ]Department of Obstetrics & Gynecology, Andrology Unit Faculties of Health Sciences, Tygerberg Hospital, Tygerberg, South Africa.
                [41 ]Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [42 ]IVF Japan Group, Horac Grand Front Osaka Clinic, Osaka, Japan.
                [43 ]Manipal Fertility, Bangalore, India.
                [44 ]Genk Institute for Fertility Technology, Genk, Belgium.
                [45 ]Hasselt University, Biomedical Research Institute, Diepenbeek, Belgium.
                [46 ]Department of Experimental and Clinical Medicine, Center of Excellence DeNothe, University of Florence, Italy.
                [47 ]Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Unit of Sexual Medicine and Andrology, Center of Excellence DeNothe, University of Florence, Florence, Italy.
                [48 ]Department of Urology, Reproduction Center, Yokohama City University Medical Center, Yokohama, Japan.
                [49 ]Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
                [50 ]Androbest Andrology & Urology Center, Hyderabad, India.
                [51 ]Section of Urology, University of Santo Tomas Hospital, Manila, Philippines.
                [52 ]SCSA Diagnostics, Brookings, SD, USA.
                [53 ]Fleury Group and Hospital Israelita Albert Einstein, São Paulo, Brazil.
                [54 ]Origen, Center for Reproductive Medicine, Rio de Janeiro, Brazil.
                [55 ]Department of Urology, University of São Paulo (USP), Brazil.
                [56 ]Division of Urology, Infertility Center ALFA, São Paulo, Brazil.
                [57 ]Head of Male Infertility Division, Andrology Department, Brazilian Society of Urology, Rio de Janeiro, Brazil.
                [58 ]Fertility and IVF Unit, Department of Obstetrics and Gynecology, Hebrew-University Hadassah Medical Center, Jerusalem, Israel.
                [59 ]Infertility and IVF Unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center (Tel Hashomer), Ramat Gan, Israel.
                [60 ]Tarnesby-Tarnowski Chair for Family Planning and Fertility Regulation, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
                [61 ]Soroka University Medical Center, Ben-Gurion University of the Negev Beer-Sheva, Beersheba, Israel.
                [62 ]IVF Unit, Meir Medical Center, Kfar Sava, Israel.
                [63 ]Sackler Medicine School, Tel Aviv University, Tel Aviv, Israel.
                [64 ]Department of Urology, Hamad Medical Corporation, Doha, Qatar.
                [65 ]Department of Andrology and Urology, Diyos Hospital, New Delhi, India.
                [66 ]PUR Clinic, South Lake Hospital, Clermont, FL, USA.
                [67 ]University of Central Florida, Orlando, FL, USA.
                [68 ]Baby Center, Institute for Reproductive Medicine, São Paulo, Brazil.
                [69 ]College Institute of Clinical Research and Teaching Development, São Paulo, Brazil.
                [70 ]Lab for Molecular Reproduction and Genetics, Anatomy, All India Institute of Medical Sciences, New Delhi, India.
                [71 ]Department of Reproductive Biology, Hôpitaux Universitaires Paris Seine Saint-Denis, Bondy, France.
                [72 ]Department of Reproductive Medicine and Embryology, Manipal Hospital, New Delhi, India.
                [73 ]Department of Urology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
                [74 ]Department of Endocrinology/ Andrology, University Hospital Ghent, Ghent, Belgium.
                [75 ]Department of Reproductive Medicine, Hannibal International Clinic, Tunis, Tunisia.
                [76 ]Department of Obstetrics, Gynecology and Reproductive Medicine, Pierre Cherest and Hartman Clinics, Paris, France.
                [77 ]Clinic of Urology, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
                [78 ]Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Jalan Hospital, Selangor, Malaysia.
                [79 ]Department of Embryology, Faculty of Medicine, University of Sousse, Sousse, Tunisia.
                [80 ]Department of Pediatrics, New York University School of Medicine, New York, NY, USA.
                [81 ]Department of Obstetrics and Gynaecology, Lilavati Hospital and Research Centre, Mumbai, India.
                [82 ]Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
                [83 ]School of Natural Medicine, University of the Western Cape, Cape Town, South Africa.
                [84 ]Department of Andrology, Shahid Sadoughi Medical University, Yazd, Iran.
                [85 ]Southend Fertility & IVF, Delhi, India.
                [86 ]Department of Urology, School of Medicine, University of Ankara, Ankara, Turkey.
                [87 ]Redox Biology Laboratory, Department of Zoology and Center of Excellence in Environment and Public Health, Ravenshaw University, Cutrack, India.
                [88 ]Marrakech Fertility Institute, Marrakech, Morocco.
                [89 ]Jindal Hospital, Meerut, India.
                [90 ]Department of Urology, Istinye University Faculty of Medicine, Liv Hospital Ulus, Istanbul, Turkey.
                [91 ]Department of Urology, Ege University School of Medicine, İzmir, Turkey.
                [92 ]Center of Urology, CODRA Hospital, Podgorica, Montenegro.
                [93 ]Fertility and IVF Unit, Soroka University Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel.
                Author notes
                Correspondence to: Ashok Agarwal. American Center for Reproductive Medicine, Cleveland Clinic, Mail Code X-11, 10681 Carnegie Avenue, Cleveland, OH 44195, USA. Tel: +1-216-444-9485, Fax: +1-216-445-6049, Website: CCF.org/ReproductiveResearchCenter agarwaa@ 123456ccf.org
                Article
                10.5534/wjmh.190055
                6704307
                31081299
                Copyright © 2019 Korean Society for Sexual Medicine and Andrology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funding
                Funded by: American Center for Reproductive Medicine;
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                Review Article

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