PURPOSE: The use of antioxidants is common practice in the management of infertile patients. However, there are no established guidelines by professional societies on antioxidant use for male infertility. MATERIALS AND METHODS: Using an online survey, this study aimed to evaluate the practice pattern of reproductive specialists to determine the clinical utility of oxidative stress (OS) testing and antioxidant prescriptions to treat male infertility. RESULTS: Responses from 1,327 participants representing 6 continents, showed the largest participant representation being from Asia (46.8%). The majority of participants were attending physicians (59.6%), with 61.3% having more than 10 years of experience in the field of male infertility. Approximately two-thirds of clinicians (65.7%) participated in this survey did not order any diagnostic tests for OS. Sperm DNA fragmentation was the most common infertility test beyond a semen analysis that was prescribed to study oxidative stress-related dysfunctions (53.4%). OS was mainly tested in the presence of lifestyle risk factors (24.6%) or sperm abnormalities (16.3%). Interestingly, antioxidants were prescribed by 85.6% of clinicians, for a duration of 3 (43.7%) or 3-6 months (38.6%). A large variety of antioxidants and dietary supplements were prescribed, and scientific evidence were mostly considered to be modest to support their clinical use. Results were not influenced by the physician's age, geographic origin, experience or training in male infertility. CONCLUSIONS: This study is the largest online survey performed to date on this topic and demonstrates 1) a worldwide understanding of the importance of this therapeutic option, and 2) a widely prevalent use of antioxidants to treat male infertility. Finally, the necessity of evidence-based clinical practice guidelines from professional societies is highlighted.

Alexandria University Faculty of Medicine Alexandria Egypt

American Center for Reproductive Medicine Cleveland Clinic Ohio USA

American College of Embryology Houston TX USA

ANDROFERT Andrology and Human Reproduction Clinic Campinas Brazil

Andrology and IVF Unit Procrea Institute Lugano Switzerland

Andrology Centre Department of Urology Semmelweis University Budapest Hungary

Andrology Group at Ideia Fertil Institute of Human Reproduction Santo Andre Brazil

Andrology Unit Instituto De Ginecologia y Fertilidad Buenos Aires Argentina

ANDROS Day Surgery Clinic Reproductive Medicine Unit Palermo Italy

Anfa Fertility Center Casablanca Morocco

Austin Fertility and Reproductive Medicine Westlake IVF Austin TX USA

Avant Concierge Urology and University of Central Florida Winter Garden FL USA

Biasa Fertility Clinic Lomè Togo

Cabinet D'Andrologie Victor Hugo American Hospital of Paris Reproductive Center Paris France

Centro ANDROGEN La Coruro Spain

Citmer Reproductive Medicine IVF LAB Mexico City Mexico

Deparment of Andrology Fundacio Puigvert Barcelona Spain

Department of Anatomy and Unit for Multidisciplinary Research in Biomedicine University of Porto Porto Portugal

Department of Andrology and Reproductive Medicine Jindal Hospital Meerut India

Department of Andrology Hammersmith Hospital London UK

Department of Andrology Reproductive Biomedicine Research Center Royan Institute for Reproductive Biomedicine ACECR Tehran Iran

Department of Andrology Sexology and STIs Faculty of Medicine Cairo University Cairo Egypt

Department of Biochemistry College of Medicine University of Garmian Kalar Iraq

Department of Dermatology Venereology and Andrology Faculty of Medicine Sohag University Sohag Egypt

Department of Medical Bioscience University of the Western Cape Bellville South Africa

Department of Metabolism Digestion and Reproduction Imperial College London London UK

Department of Obstetrics and Gynaecology University College Hospital Ibadan Nigeria

Department of Obstetrics and Gynecology Bahcesehir University Istanbul Turkey

Department of Obstetrics and Gynecology Bukovinian State Medical University Chernivtsi Ukraine

Department of Obstetrics and Gynecology University of Nicosia Medical School Nicosia Cyprus

Department of Obstetrics Gynaecology and Reproductive Medicine Flinders University Bedford Park South Australia

Department of Physiology Faculty of Medicine Bioscience and Nursing MAHSA University Kuala Lumpur Malaysia

Department of Surgery McGill University St Mary's Hospital Montreal QC Canada

Department of Urology and Renal Transplantation University of Foggia Policlinico Riuniti of Foggia Foggia Italy

Department of Urology Cleveland Clinic Cleveland OH USA

Department of Urology Hamad Medical Corporation Doha Qatar

Department of Urology Lilavati Hospital and Research Centre Mumbai India

Department of Urology Loma Linda University Health Loma Linda CA USA

Department of Urology Military Medical Academy Belgrade Serbia

Department of Urology Pusan National University School of Medicine Busan Korea

Department of Urology Tulane University Health Sciences Center New Orleans LA USA

Department of Urology University of Ankara Ankara Turkey

Department of Urology University of Queensland Brisbane Australia

Department of Urology University of Santo Tomas Hospital Manila Philippines

Division of Urology Department of Surgery University of Campinas Campinas Brazil

Division of Urology Southern Illinois University School of Medicine Springfield IL USA

Faculty of Medicine Universiti Teknologi MARA Sungai Buloh Campus Selangor Malaysia

Fertility Medical Group Sapientiae Institute São Paulo Brazil

Fertimed Ltd Olomouc Czech Republic

GAO Bojović Belgrade Serbia

Hamad Medical Corporation Doha Qatar

Honorary Staff of Cooper University Hospital Camden NJ USA

Instituto Ideia Fertil Human Reproduction Centre Faculdade de Medicina do ABC Sao Paulo Brazil

International Centre for Reproductive Medicine Saint Petersburg Russia

IVF Japan Group HORAC Grand Front Osaka Clinic Osaka Japan

IVF Unit Al Boustane Clinic Rabat Morocco

Medical Research Institute of Pusan National University Hospital Busan Korea

Middle East Fertility Society Canadian Foundation for Reproductive Medicine Lebanon

Odyssèe Clinic for Assisted Reproduction Douala Cameroun

Reproductive Medicine Unit New Jahra Hospital Ministry of Health Al Jahra Kuwait

RMU Dr Arab Medical Center Jeddah Saudi Arabia

S H Ho Urology Centre Department of Surgery The Chinese University of Hong Kong Hong Kong

School of Natural Medicine University of the Western Cape South Africa

Section of Andrology Istanbul Faculty of Medicine Istanbul Turkey

Sexual and Reproductive Medicine Department of Urology Faculdade de Medicina do ABC Santo André Brazil

St Barbara Clinic Bad Vigaun Austria

Tiziri IVF Center Algeriers Algeria

Urology VUK Center Belgrade Serbia

Uromedica Polyclinic Andrology Department Belgrade Serbia

Weill Cornell Medicine Qatar Doha Qatar

Yazd Research and Clinical Center for Infertility Yazd Iran

Zobrazit více v PubMed

Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015;13:37. PubMed PMC

Agarwal A, Baskaran S, Parekh N, Cho CL, Henkel R, Vij S, et al. Male infertility. Lancet. 2021;397:319–333. PubMed

Kumar N, Singh AK. Trends of male factor infertility, an important cause of infertility: a review of literature. J Hum Reprod Sci. 2015;8:191–196. PubMed PMC

Fainberg J, Kashanian JA. Recent advances in understanding and managing male infertility. F1000Res. 2019;8:F1000 Faculty Rev-670 PubMed PMC

Leisegang K, Henkel R. Oxidative stress: relevance, evaluation, and management. In: Rizk B, Agarwal A, Sabanegh ES Jr, editors. Male infertility in reproductive medicine: diagnosis and management. Boca Raton (FL): CRC Press; 2019. pp. 119–128.

Agarwal A, Parekh N, Panner Selvam MK, Henkel R, Shah R, Homa ST, et al. Male oxidative stress infertility (MOSI): proposed terminology and clinical practice guidelines for management of idiopathic male infertility. World J Mens Health. 2019;37:296–312. PubMed PMC

Kumar N, Singh AK. Reactive oxygen species in seminal plasma as a cause of male infertility. J Gynecol Obstet Hum Reprod. 2018;47:565–572. PubMed

Agarwal A, Cho CL, Esteves SC, Majzoub A. Reactive oxygen species and sperm DNA fragmentation. Transl Androl Urol. 2017;6(Suppl 4):S695–S696. PubMed PMC

Aitken RJ. DNA damage in human spermatozoa; important contributor to mutagenesis in the offspring. Transl Androl Urol. 2017;6(Suppl 4):S761–S764. PubMed PMC

Ali M, Martinez M, Parekh N. Are antioxidants a viable treatment option for male infertility? Andrologia. 2021;53:e13644. PubMed

Grand View Research. Dietary supplements market size, share & trends analysis report by ingredient (vitamins, minerals), by form, by application, by end user, by distribution channel, by region and segment forecasts, 2020 - 2027 [Internet] San Francisco (CA): Grand View Research; c2020. [cited 2021 Feb 20]. Available from: https://www.globenewswire.com/news-release/2020/03/05/1995948/0/en/Dietary-Supplements-Market-Size-Share-Trends-Analysis-Report-by-Ingredient-By-Form-By-Application-By-End-User-By-Distribution-Channel-By-Region-And-Segment-Forecasts-2020-2027.html.

Negri L, Benaglia R, Monti E, Morenghi E, Pizzocaro A, Levi Setti PE. Effect of superoxide dismutase supplementation on sperm DNA fragmentation. Arch Ital Urol Androl. 2017;89:212–218. PubMed

Arafa M, Agarwal A, Majzoub A, Panner Selvam MK, Baskaran S, Henkel R, et al. Efficacy of antioxidant supplementation on conventional and advanced sperm function tests in patients with idiopathic male infertility. Antioxidants (Basel) 2020;9:219 PubMed PMC

Nazari L, Salehpour S, Hosseini S, Allameh F, Jahanmardi F, Azizi E, et al. Effect of antioxidant supplementation containing L-carnitine on semen parameters: a prospective interventional study. JBRA Assist Reprod. 2021;25:76–80. PubMed PMC

Khani B, Bidgoli SR, Moattar F, Hassani H. Effect of sesame on sperm quality of infertile men. J Res Med Sci. 2013;18:184–187. PubMed PMC

Tartibian B, Maleki BH. Correlation between seminal oxidative stress biomarkers and antioxidants with sperm DNA damage in elite athletes and recreationally active men. Clin J Sport Med. 2012;22:132–139. PubMed

Chattopadhyay R, Yasmin S, Chakravarty BN. Effect of continuous 6 months oral antioxidant combination with universally recommended dosage in idiopathic male infertility. Int J Infertil Fetal Med. 2016;7:1–6.

Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, Hammami S, et al. Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men. Arch Androl. 2003;49:83–94. PubMed

Kessopoulou E, Powers HJ, Sharma KK, Pearson MJ, Russell JM, Cooke ID, et al. A double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat reactive oxygen species associated male infertility. Fertil Steril. 1995;64:825–831. PubMed

Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2019;3:CD007411. PubMed PMC

Imamovic Kumalic S, Pinter B. Review of clinical trials on effects of oral antioxidants on basic semen and other parameters in idiopathic oligoasthenoteratozoospermia. Biomed Res Int. 2014;2014:426951. PubMed PMC

Steiner AZ, Hansen KR, Barnhart KT, Cedars MI, Legro RS, Diamond MP, et al. The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. Fertil Steril. 2020;113:552–560. PubMed PMC

da Silva TM, Maia MCS, Arruda JT, Approbato FC, Mendonça CR, Approbato MS. Folic acid does not improve semen parametrs in subfertile men: a double-blin, randomized, placebo-controlled study. J Bras Reprod Assist. 2013;17:152–157.

Ménézo YJ, Hazout A, Panteix G, Robert F, Rollet J, Cohen-Bacrie P, et al. Antioxidants to reduce sperm DNA fragmentation: an unexpected adverse effect. Reprod Biomed Online. 2007;14:418–421. PubMed

Panner Selvam MK, Agarwal A, Henkel R, Finelli R, Robert KA, Iovine C, et al. The effect of oxidative and reductive stress on semen parameters and functions of physiologically normal human spermatozoa. Free Radic Biol Med. 2020;152:375–385. PubMed

Kuchakulla M, Soni Y, Patel P, Parekh N, Ramasamy R. A systematic review and evidence-based analysis of ingredients in popular male fertility supplements. Urology. 2020;136:133–141. PubMed

Agarwal A, Leisegang K, Majzoub A, Henkel R, Finelli R, Panner Selvam MK, et al. Utility of antioxidants in the treatment of male infertility: clinical guidelines based on a systematic review and analysis of evidence. World J Mens Health. 2021 doi: 10.5534/wjmh.200196. [Epub] PubMed DOI PMC

Majzoub A, Agarwal A. Systematic review of antioxidant types and doses in male infertility: benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate. Arab J Urol. 2018;16:113–124. PubMed PMC

Alahmar AT. Role of oxidative stress in male infertility: an updated review. J Hum Reprod Sci. 2019;12:4–18. PubMed PMC

Sharma R, Roychoudhury S, Singh N, Sarda Y. Methods to measure Reactive Oxygen Species (ROS) and Total Antioxidant Capacity (TAC) in the reproductive system. In: Agarwal A, Sharma R, Gupta S, Harlev A, Ahmad G, du Plessis SS, et al., editors. Oxidative stress in human reproduction: shedding light on a complicated phenomenon. Cham: Springer International Publishing; 2017. pp. 17–46.

Agarwal A, Roychoudhury S, Bjugstad KB, Cho CL. Oxidation-reduction potential of semen: what is its role in the treatment of male infertility? Ther Adv Urol. 2016;8:302–318. PubMed PMC

Castagné V, Lefèvre K, Natero R, Clarke PG, Bedker DA. An optimal redox status for the survival of axotomized ganglion cells in the developing retina? Neuroscience. 1999;93:313–320. PubMed

Henkel R, Sandhu IS, Agarwal A. The excessive use of antioxidant therapy: a possible cause of male infertility. Andrologia. 2019;51:e13162. PubMed

Ko EY, Sabanegh ES, Jr, Agarwal A. Male infertility testing: reactive oxygen species and antioxidant capacity. Fertil Steril. 2014;102:1518–1527. PubMed

Agarwal A, Leisegang K, Sengupta P. Oxidative stress in pathologies of male reproductive disorders. In: Preedy VR, editor. Pathology: oxidative stress and dietary antioxidants. London: Academic Press; 2020. pp. 15–27.

Agarwal A, Majzoub A. Laboratory tests for oxidative stress. Indian J Urol. 2017;33:199–206. PubMed PMC

Henkel R, Leisegang K. Origins of sperm DNA damage. In: Parekattil SJ, Esteves SC, Agarwal A, editors. Male infertility: contemporary clinical approaches, andrology, ART and antioxidants. 2nd ed. Cham: Springer International Publishing; 2020. pp. 361–375.

Agarwal A, Majzoub A, Baskaran S, Panner Selvam MK, Cho CL, Henkel R, et al. Sperm DNA fragmentation: a new guideline for clinicians. World J Mens Health. 2020;38:412–471. PubMed PMC

Dorostghoal M, Kazeminejad SR, Shahbazian N, Pourmehdi M, Jabbari A. Oxidative stress status and sperm DNA fragmentation in fertile and infertile men. Andrologia. 2017;49:e12762 PubMed

Ni K, Steger K, Yang H, Wang H, Hu K, Zhang T, et al. A comprehensive investigation of sperm DNA damage and oxidative stress injury in infertile patients with subclinical, normozoospermic, and astheno/oligozoospermic clinical varicocoele. Andrology. 2016;4:816–824. PubMed

Vaughan DA, Tirado E, Garcia D, Datta V, Sakkas D. DNA fragmentation of sperm: a radical examination of the contribution of oxidative stress and age in 16 945 semen samples. Hum Reprod. 2020;35:2188–2196. PubMed

Homa ST, Vassiliou AM, Stone J, Killeen AP, Dawkins A, Xie J, et al. A comparison between two assays for measuring seminal oxidative stress and their relationship with sperm DNA fragmentation and semen parameters. Genes (Basel) 2019;10:236 PubMed PMC

Dutta S, Henkel R, Agarwal A. Comparative analysis of tests used to assess sperm chromatin integrity and DNA fragmentation. Andrologia. 2021;53:e13718. PubMed

Practice Committee of the American Society for Reproductive Medicine. The clinical utility of sperm DNA integrity testing: a guideline. Fertil Steril. 2013;99:673–677. PubMed

Agarwal A, Sharma R, Roychoudhury S, Du Plessis S, Sabanegh E. MiOXSYS: a novel method of measuring oxidation reduction potential in semen and seminal plasma. Fertil Steril. 2016;106:566–573.e10. PubMed

Elbardisi H, Finelli R, Agarwal A, Majzoub A, Henkel R, Arafa M. Predictive value of oxidative stress testing in semen for sperm DNA fragmentation assessed by sperm chromatin dispersion test. Andrology. 2020;8:610–617. PubMed

Agarwal A, Tvrda E, Sharma R. Relationship amongst teratozoospermia, seminal oxidative stress and male infertility. Reprod Biol Endocrinol. 2014;12:45. PubMed PMC

Mayorga-Torres BJM, Camargo M, Cadavid ÁP, du Plessis SS, Cardona Maya WD. Are oxidative stress markers associated with unexplained male infertility? Andrologia. 2017;49:e12659 PubMed

Wagner H, Cheng JW, Ko EY. Role of reactive oxygen species in male infertility: an updated review of literature. Arab J Urol. 2017;16:35–43. PubMed PMC

Hamada A, Esteves SC, Nizza M, Agarwal A. Unexplained male infertility: diagnosis and management. Int Braz J Urol. 2012;38:576–594. PubMed

Venkatesh S, Shamsi MB, Deka D, Saxena V, Kumar R, Dada R. Clinical implications of oxidative stress & sperm DNA damage in normozoospermic infertile men. Indian J Med Res. 2011;134:396–398. PubMed PMC

Leisegang K, Dutta S. Lifestyle management approaches to male infertility. In: Rizk B, Agarwal A, Sabanegh ES Jr, editors. Male infertility in reproductive medicine: diagnosis and management. Boca Raton (FL): CRC Press; 2019. pp. 141–151.

Sabeti P, Pourmasumi S, Rahiminia T, Akyash F, Talebi AR. Etiologies of sperm oxidative stress. Int J Reprod Biomed. 2016;14:231–240. PubMed PMC

Takeshima T, Kuroda S, Yumura Y. Cancer chemotherapy and chemiluminescence detection of reactive oxygen species in human semen. Antioxidants (Basel) 2019;8:449 PubMed PMC

Masic I, Miokovic M, Muhamedagic B. Evidence based medicine - new approaches and challenges. Acta Inform Med. 2008;16:219–225. PubMed PMC

Showell MG, Mackenzie-Proctor R, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2014;(12):CD007411. PubMed

Showell MG, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2011;(1):CD007411. PubMed

Agarwal A, Panner Selvam MK, Samanta L, Vij SC, Parekh N, Sabanegh E, et al. Effect of antioxidant supplementation on the sperm proteome of idiopathic infertile men. Antioxidants (Basel) 2019;8:488 PubMed PMC

Salonia A, Bettocchi C, Carvalho J, Corona G, Jones TH, Kadioglu A, et al. EAU guidelines on sexual and reproductive health [Internet] Arnhem: European Association of Urology; c2020. [cited 2021 Feb 20]. Available from: https://uroweb.org/guideline/sexual-and-reproductive-health/

Schlegel PN, Sigman M, Collura B, De Jonge CJ, Eisenberg ML, Lamb DJ, et al. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I. J Urol. 2021;205:36–43. PubMed

Turk T, Elhady MT, Rashed S, Abdelkhalek M, Nasef SA, Khallaf AM, et al. Quality of reporting web-based and non-web-based survey studies: what authors, reviewers and consumers should consider. PLoS One. 2018;13:e0194239. PubMed PMC

Silva Junior SH, Santos SM, Coeli CM, Carvalho MS. Assessment of participation bias in cohort studies: systematic review and meta-regression analysis. Cad Saude Publica. 2015;31:2259–2274. PubMed

Bartlett JE, 2nd, Kotrlik JW, Higgins CC. Organizational research: determining appropriate sample size in survey research. Inf Technol Learn Perform J. 2001;19:43

McColl E, Jacoby A, Thomas L, Soutter J, Bamford C, Steen N, et al. Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients. Health Technol Assess. 2001;5:1.:256 PubMed

Bergen N, Labonté R. “Everything is perfect, and we have no problems”: detecting and limiting social desirability bias in qualitative research. Qual Health Res. 2020;30:783–792. PubMed