Original Article Male reproductive health and infertility pISSN: 2287-4208 / eISSN: 2287-4690 World J Mens Health 2023 Jan 41(1): 164-197 https://doi.org/10.5534/wjmh.220048 Consensus and Diversity in the Management of Varicocele for Male Infertility: Results of a Global Practice Survey and Comparison with Guidelines and Recommendations Rupin Shah1 , Ashok Agarwal2 , Parviz Kavoussi3 , Amarnath Rambhatla4 , Ramadan Saleh5 , Rossella Cannarella6 , Ahmed M. Harraz7,8,9 , Florence Boitrelle10,11 , Shinnosuke Kuroda2 , Taha Abo-Almagd Abdel-Meguid Hamoda12,13 , Armand Zini14 , Edmund Ko15 , Gokhan Calik16 , Tuncay Toprak17 , Hussein Kandil18 , Murat Gül19 , Mustafa Emre Bakırcıoğlu20 , Neel Parekh21 , Giorgio Ivan Russo22 , Nicholas Tadros23 , Ates Kadioglu24 , Mohamed Arafa2,25,26 , Eric Chung27 , Osvaldo Rajmil28 , Fotios Dimitriadis29 , Vineet Malhotra30 , Gianmaria Salvio31 , Ralf Henkel32,33 , Tan V. Le34,35 , Emrullah Sogutdelen36 , Sarah Vij21 , Abdullah Alarbid8 , Ahmet Gudeloglu37 , Akira Tsujimura38 , Aldo E. Calogero6 , Amr El Meliegy39 , Andrea Crafa6 , Arif Kalkanli40 , Aykut Baser41 , Berk Hazir42 , Carlo Giulioni43 , Chak-Lam Cho44 , Christopher C.K. Ho45 , Ciro Salzano46 , Daniel Suslik Zylbersztejn47 , Dung Mai Ba Tien34 , Edoardo Pescatori48 , Edson Borges49 , Ege Can Serefoglu50 , Emine Saïs-Hamza10,11 , Eric Huyghe51 , Erman Ceyhan52 , Ettore Caroppo53 , Fabrizio Castiglioni54 , Fahmi Bahar55 , Fatih Gokalp56 , Francesco Lombardo57 , Franco Gadda58 , Gede Wirya Kusuma Duarsa59 , Germar-Michael Pinggera60 , Gian Maria Busetto61 , Giancarlo Balercia31 , Gianmartin Cito62 , Gideon Blecher63,64 , Giorgio Franco65 , Giovanni Liguori66 , Haitham Elbardisi25,67 , Hakan Keskin37 , Haocheng Lin68 , Hisanori Taniguchi69 , Hyun Jun Park70,71 , Imad Ziouziou72 , Jean de la Rosette73 , Jim Hotaling74 , Jonathan Ramsay75 , Juan Manuel Corral Molina76 , Ka Lun Lo77 , Kadir Bocu78 , Kareim Khalafalla25,79 , Kasonde Bowa80 , Keisuke Okada81 , Koichi Nagao82 , Koji Chiba81 , Lukman Hakim83 , Konstantinos Makarounis84 , Marah Hehemann85 , Marcelo Rodriguez Peña86 , Marco Falcone87 , Marion Bendayan10,11 , Marlon Martinez88 , Massimiliano Timpano87 , Mesut Altan89 , Mikkel Fode90,91 , Mohamed S. Al-Marhoon92 , Mohammad Ali Sadighi Gilani93 , Mohammad Ayodhia Soebadi94 , Nazim Gherabi95 , Nikolaos Sofikitis96 , Oğuzhan Kahraman52 , Ponco Birowo97 , Priyank Kothari98 , Puneet Sindhwani99 , Qaisar Javed100 , Rafael F. Ambar101,102 , Raghavender Kosgi103 , Ramy Abou Ghayda104 , Ricky Adriansjah105 , Rosita Angela Condorelli6 , Sandro La Vignera6 , Sava Micic106 , Shannon Hee Kyung Kim107,108 , Shinichiro Fukuhara109 , Sun Tae Ahn110 , Taymour Mostafa39 , Teng Aik Ong111 , Teppei Takeshima112 , Toshiyasu Amano113 , Trenton Barrett114 , Umut Arslan17 , Vilvapathy Senguttuvan Karthikeyan115 , Widi Atmoko103 , Yasushi Yumura112 , Yiming Yuan116 , Yuki Kato117 , Davor Jezek118 , Bryan Kwun-Chung Cheng119 , Georgios Hatzichristodoulou120 , Jun Dy121 , Eduard Ruiz Castañé122 , Ahmed I. El-Sakka123 , Received: Mar 8, 2022 Revised: Mar 15, 2022 Accepted: Mar 20, 2022 Published online Jun 13, 2022 Correspondence to: Ashok Agarwal https://orcid.org/0000-0003-0585-1026 Andrology Center and 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, E-mail: agarwaa@ccf.org, Website: www.Clevelandclinic.org/ReproductiveResearchCenter Copyright © 2023 Korean Society for Sexual Medicine and Andrology Rupin Shah, et al: Global Survey on Varicocele Quang Nguyen124,125 , Selcuk Sarikaya126 , Luca Boeri58 , Ronny Tan127,128 , Mohamad A. Moussa129,130 , Ahmed El-Assmy7 , Hamed Alali131 , Naif Alhathal132 , Yasser Osman7 , Dragoljub Perovic133 , Hesamoddin Sajadi98 , Hamed Akhavizadegan134 , Miroslav Vučinić135 , Said Kattan132 , Mohamed S. Kattan132 , Nasser Mogharabian136 , Nguyen Ho Vinh Phuoc34 , Kay Seong Ngoo137 , Mohammad H. Alkandari138 , Shaheed Alsuhaibani139 , Ioannis Sokolakis120 , Mehdi Babaei140 , Mak Siu King77 , Thorsten Diemer141 , Marcelo M. Gava101,102 , Raphael Henrique142 , Rodrigo Spinola e Silva101,102 , Gustavo Marquesine Paul143 , Tiago Cesar Mierzwa144 , Sidney Glina101 , Kashif Siddiqi145 , Han Wu146 , Jana Wurzacher147 , Ala’a Farkouh2 , Hwancheol Son148 , Suks Minhas149 , Joe Lee150 , Nikko Magsanoc151 , Paolo Capogrosso152 , German Jose Albano88 , Sheena E. M. Lewis153 , Channa N. Jayasena154,155 , Juan G. Alvarez156 , Colin Teo157 , Ryan P. Smith158 , Jo Ben M. Chua159 , Christian Fuglesang S. Jensen160 , Sijo Parekattil161 , Renata Finelli2 , Damayanthi Durairajanayagam162 , Keshab Kumar Karna2 , Abdelkareem Ahmed9 , Don Evenson163 , Yukihiro Umemoto164 , Ana Puigvert165 , Gökhan Çeker166,167 , Giovanni M Colpi168 , and on behalf of the Global Andrology Forum* 1 Division of Andrology, Department of Urology, Lilavati Hospital and Research Centre, Mumbai, India, 2American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA, 3Austin Fertility & Reproductive Medicine/Westlake IVF, TX, USA, 4Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA, 5Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag, Egypt, 6Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy, 7Mansoura University Urology and Nephrology Center, Mansoura, Egypt, 8Department of Surgery, Urology Unit, Farwaniya Hospital, Farwaniya, Kuwait, 9Department of Urology, Sabah Al Ahmad Urology Center, Kuwait City, Kuwait, 10Department of Reproductive Biology, Fertility Preservation, Andrology, CECOS, Poissy Hospital, Poissy, France, 11Department of Biology, Reproduction, Epigenetics, Environment and Development, Paris Saclay University, UVSQ, INRAE, BREED, Jouy-en-Josas, France, 12Department of Urology, King Abdulaziz University, Jeddah, Saudi Arabia, 13Department of Urology, Faculty of Medicine, Minia University, Minia, Egypt, 14Division of Urology, Department of Surgery, McGill University, Montreal, QC, Canada, 15Department of Urology, Loma Linda University Health, Loma Linda, CA, USA, 16Department of Urology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey, 17Department of Urology, Fatih Sultan Mehmet Training and Research Hospital, University of Health Sciences, Istanbul, Turkey, 18Fakih IVF Fertility Center, Abu Dhabi, UAE, 19Department of Urology, Selcuk University School of Medicine, Konya, Turkey, 20SENSART Clinic, Istanbul, Turkey, 21Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA, 22Urology Section, University of Catania, Catania, Italy, 23Division of Urology, Southern Illinois University School of Medicine, Springfield, IL, USA, 24Section of Andrology, Department of Urology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey, 25Department of Urology, Hamad Medical Corporation, Doha, Qatar, 26Department of Urology, Weill Cornell Medical-Qatar, Doha, Qatar, 27Department of Urology, Princess Alexandra Hospital, University of Queensland, Brisbane, Australia, 28Department of Andrology, Fundacio Puigvert, Barcelona, Spain, 29 Department of Urology, Aristotle University of Thessaloniki, Thessaloniki, Greece, 30SCM Clinic and Hospital, New Delhi, India, 31 Department of Endocrinology, Polytechnic University of Marche, Ancona, Italy, 32Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK, 33Department of Medical Bioscience, University of the Western Cape, Bellville, South Africa, 34 Department of Andrology, Binh Dan Hospital, Ho Chi Minh City, Vietnam, 35Department of Urology and Andrology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam, 36Department of Urology, Bolu Abant Izzet Baysal University, Bolu, Turkey, 37 Department of Urology, Faculty of Medicine, Hacettepe University, Ankara, Turkey, 38Department of Urology, Juntendo University Urayasu Hospital, Chiba, Japan, 39Department of Andrology, Sexology and STIs, Faculty of Medicine, Cairo University, Cairo, Egypt, 40Department of Urology, Taksim Education and Research Hospital, Istanbul, Turkey, 41Department of Urology, Faculty of Medicine, Bandırma Onyedi Eylül University, Balıkesir, Turkey, 42Reproductive medicine, Clinical Research Centre, Lund University, Malmö, Sweden, 43Department of Urology, Polytechnic University of Marche Region, Ancona, Italy, 44S. H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China, 45Department of Urology, Universiti Teknologi Mara (UiTM) Specialist Centre, Selangor, Malaysia, 46PO San Giovanni Bosco, ASL Napoli 1 Centro, Napoli, Italy, 47Fleury Group and Hospital Israelita Albert Einstein, São Paulo, Brazil, 48Andrology and Reproductive Medicine Unit, Gynepro Medical, Bologna, Italy, 49Fertility Medical Group, São Paulo, Brazil, 50Department of Urology, Biruni University School of Medicine, Istanbul, Turkey, 51Department of Urology and Andrology, University Hospital of Toulouse, France, 52 Department of Urology, School of Medicine, Baskent University, Konya, Turkey, 53Asl Bari, PTA “F Jaia”, Reproductive and IVF unit, Andrology Outpatients Clinic, Asl Bari, Conversano (Ba), Italy, 54Andrology Unit, ART Center - San Carlo Clinic, Paderno Dugnano, Milan, Italy, 55Andrology Section, Siloam Sriwijaya Hospital, Palembang, Indonesia, 56Department of Urology, Hatay Mustafa Kemal University, Antakya, Turkey, 57Laboratory of Seminology—Sperm Bank “Loredana Gandini”, Department of Experimental Medicine, University of Rome “Sapienza”, Rome, Italy, 58Department of Urology, IRCCS Fondazione Ca Granda Ospedale Maggiore Policlinico, Milan, Italy, 59Department of Urology, School of Medicine, Udayana University, Denpasar, Indonesia, 60Department of Urology, Innsbruck Medical University, Innsbruck, Austria, 61Department of Urology and Organ Transplantation, University of Foggia, Ospedali Riuniti of Foggia, Foggia, Italy, 62 Department of Urology, University of Florence, Florence, Italy, 63Department of Surgery, School of Clinical Sciences, Monash University, Melbourne, Australia, 64Department of Urology, The Alfred Hospital, Melbourne, Australia, 65Department of Urology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy, 66Department of Urology, University of Trieste, Trieste, Italy, 67Department of Urology, Weill www.wjmh.org 165 https://doi.org/10.5534/wjmh.220048 Cornell Medicine-Qatar, Doha, Qatar, 68Department of Urology, Peking University Third Hospital, Peking University, Beijing, China, 69 Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan, 70Department of Urology, Pusan National University School of Medicine, Busan, Korea, 71Medical Research Institute of Pusan National University Hospital, Busan, Korea, 72 Department of Urology, College of medicine and pharmacy, Ibn Zohr University, Agadir, Morocco, 73Department of urology, Faculty of Medicine, Istanbul Medipol Mega University Hospital, Istanbul, Turkey, 74Department of Surgery (Urology), University of Utah, Salt Lake City, UT, USA, 75Department of Andrology, Hammersmith Hospital, Imperial, London, UK, 76Servicio de Urología, Hospital Clínico de Barcelona, Barcelona, Spain, 77Division of Urology, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China, 78 Department of Urology, Silopi State Hospital, Sirnak, Turkey, 79Department of Urology, University of Illinois, Chicago, IL, USA, 80 Department of Urology, School of Medicine and Health Sciences, University of Lusaka, Lusaka, Zambia, 81Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan, 82Department of Urology, Toho University Faculty of Medicine, Tokyo, Japan, 83 Department of Urology, Universitas Airlangga/Rumah Sakit Universitas Airlangga Teaching Hospital, Surabaya, Indonesia, 84Department of Urology and Andrology, Locus Medicus, Athens, Greece, 85Department of Urology, University of Washington, Seattle, WA, USA, 86Instituto de Ginecología y Fertilidad (IFER), Universidad de Buenos Aires, Buenos Aires, Argentina, 87Department of Urology, Molinette Hospital, A.O.U. Città della Salute e della Scienza, University of Turin, Torino, Italy, 88Section of Urology, Department of Surgery, University of Santo Tomas Hospital, Manila, Philippines, 89Department of Urology, Haceppete University, Ankara, Turkey, 90Department of Urology, Herlev and Gentofte University Hospital, Copenhagen, Denmark, 91Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark, 92Department of Surgery, Urology Division, Sultan Qaboos University, Muscat, Oman, 93Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran, 94Department of Urology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia, 95Andrology Committee of the Algerian Association of Urology, Algiers, Algeria, 96 Department of Urology, Ioannina University School of Medicine, Ioannina, Greece, 97Department of Urology, Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia, 98B.Y.L Nair Ch Hospital, Mumbai, India, 99Department of Urology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA, 100Department of Urology, Al - Ahlia Hospital Abu Dhabi UAE, Abu Dhabi, UAE, 101Department of Urology, Centro Universitario em Saude do ABC, Santo André, Brazil, 102Andrology Group at Ideia Fertil Institute of Human Reproduction, Santo André, Brazil, 103Department of Urology and Andrology, AIG Hospitals, Hyderabad, Telangana, India, 104Urology Institute, University Hospitals, Case Western Reserve University, Cleveland, OH, USA, 105Department of Urology, Faculty of Medicine Universitas Padjadjaran, Hasan Sadikin General Hospital, Banding, Indonesia, 106Department of Andrology, Uromedica Polyclinic, Belgrade, Serbia, 107IVF Australia, Sydney, New South Wales, Australia, 108Macquarie School of Medicine, Macquaire University, Sydney, New South Wales, Australia, 109Department of Urology, Graduate School of Medicine, Osaka University, Osaka, Japan, 110 Department of Urology, Korea University College of Medicine, Seoul, Korea, 111Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia, 112Department of Urology, Reproduction Center, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan, 113Department of Urology, Nagano Red Cross Hospital, Nagano, Japan, 114Perth Urology Clinic, Perth, WA, Australia, 115 Andrology Unit, Department of Urology, Apollo Hospitals, Greams Road, Chennai, India, 116Andrology Center & Urology Department, Peking University First Hospital, Peking University, Beijing, China, 117Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan, 118Department for Transfusion Medicine and Transplantation Biology, Reproductive Tissue Bank, University of Zagreb, School of Medicine, University Hospital Zagreb, Zagreb, Croatia, 119Department of Surgery, United Christian Hospital, Hong Kong, China, 120Department of Urology, Martha-Maria Hospital Nuremberg, Nuremberg, Germany, 121 Stone and Prostate Treatment Services/Pelvic Floor Center and Anorectal Diseases, St. Luke’s Medical Center, Quezon City, Metro Manila, Philippines, 122Department of Andrology, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain, 123Department of Urology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt, 124Center for Andrology and Sexual Medicine, Viet Duc University Hospital, Hanoi, Vietnam, 125Department of Urology, Andrology and Sexual Medicine, University of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam, 126Department of Urology, Gülhane Research and Training Hospital, University of Health Sciences, Ankara, Turkey, 127Advanced Urology Associates, Singapore, 128Mount Elizabeth Hospital, Singapore, 129Department of Urology, Lebanese University, Beirut, Lebanon, 130Department of Urology, Al Zahraa Hospital, UMC, Lebanon, 131King Fahad Specialist Hospital, Dammam, Saudi Arabia, 132King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, 133Urology and Andrology Center, CODRA Hospital, University of Montenegro, Podgorica, Montenegro, 134Department of Urology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran, 135Department of Urology, Užice General Hospital, Zlatibor, Serbia, 136Sexual Health and Fertility Research Center, Shahroud University of Medical Sciences, Shahroud, Iran, 137Urology Unit, Department of Surgery, Hospital Angkatan Tentera Tuanku Mizan, Kuala Lumpur, Malaysia, 138Department of Urology, Mubarak Al-Kabeer Teaching Hospital, Kuwait University, Jabriya, Kuwait, 139 Department of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia, 140Department of Andrology, Shariati Medical Center, Tehran University of Medical Sciences, Tehran, Iran, 141Department of Urology, Pediatric Urology and Andrology, Justus- Liebig-University Giessen (GER), University Hospital Giessen and Marburg GmbH, Campus Giessen, Giessen, Germany, 142Santa Casa de Ribeirão Preto, Ribeirão Preto, Brazil, 143Department of Urology, Hospital de Clínicas of the Federal University of Paraná, Curitiba, Brazil, 144 Androlab, Fertility Clinic, Curitiba, Brazil, 145Department of Urology, Cleveland Clinic, Abu Dhabi, UAE, 146Department of Andrology, PKU 3rd Hospital Reproductive Medicine Center, Beijing, China, 147Department of Urology, University Hospital Innsbruck, Innsbruck, Austria, 148Department of Urology, SMG-SNU Boramae Medical Center, Seoul, Korea, 149Division of Surgery, Department of Surgery and Cancer, Imperial College London, London, UK, 150Department of Urology, National University Hospital, Singapore, 151Department of Surgery, University of the Philippines College of Medicine, Manila, Philippines, 152Department of Urology, University of Insubria, Varese, Italy, 153Examenlab Ltd., Northern Ireland, UK, 154Department of Reproductive Endocrinology and Andrology, Imperial College London, London, UK, 155Department of Andrology, Hammersmith & St. Mary’s Hospitals, London, UK, 156Department of Andrology, Centro ANDROGEN, La Coruña, Spain, 157Department of Urology, Gleneagles Hospital, Singapore, 158Department of Urology, University of Virginia School of Medicine, Virginia, USA, 159Department of Urology, East Avenue Medical Center, Quezon City, Philippines, 166 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele 160 Department of Urology, Copenhagen University Hospital - Herlev and Gentofte Hospital, Herlev, Denmark, 161Avant Concierge Urology & University of Central Florida, Winter Garden, FL, USA, 162Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia, 163SCSA Diagnostics, Brookings, SD, USA, 164Department of Nephro-Urology, Nagoya City West Medical Center, Nagoya, Japan, 165Urological and Human Reproduction Unit, Quiron Hospital, Barcelona, Spain, 166Department of Urology, Başakşehir Çam and Sakura City Hospital, Istanbul, Turkey, 167Department of Embryology and Histology, Zonguldak Bülent Ecevit University Institute of Health Sciences, Zonguldak, Turkey, 168Next Fertility Procrea, Lugano, Switzerland, *Members of the Global Andrology Forum are listed in the Acknowledgements Purpose: Varicocele is a common problem among infertile men. Varicocele repair (VR) is frequently performed to improve semen parameters and the chances of pregnancy. However, there is a lack of consensus about the diagnosis, indications for VR and its outcomes. The aim of this study was to explore global practice patterns on the management of varicocele in the context of male infertility. Materials and Methods: Sixty practicing urologists/andrologists from 23 countries contributed 382 multiple-choice-questions pertaining to varicocele management. These were condensed into an online questionnaire that was forwarded to clinicians involved in male infertility management through direct invitation. The results were analyzed for disagreement and agreement in practice patterns and, compared with the latest guidelines of international professional societies (American Urological As- sociation [AUA], American Society for Reproductive Medicine [ASRM], and European Association of Urology [EAU]), and with evidence emerging from recent systematic reviews and meta-analyses. Additionally, an expert opinion on each topic was provided based on the consensus of 16 experts in the field. Results: The questionnaire was answered by 574 clinicians from 59 countries. The majority of respondents were urologists/ uro-andrologists. A wide diversity of opinion was seen in every aspect of varicocele diagnosis, indications for repair, choice of technique, management of sub-clinical varicocele and the role of VR in azoospermia. A significant proportion of the re- sponses were at odds with the recommendations of AUA, ASRM, and EAU. A large number of clinical situations were identi- fied where no guidelines are available. Conclusions: This study is the largest global survey performed to date on the clinical management of varicocele for male in- fertility. It demonstrates: 1) a wide disagreement in the approach to varicocele management, 2) large gaps in the clinical prac- tice guidelines from professional societies, and 3) the need for further studies on several aspects of varicocele management in infertile men. Keywords: Consensus; Disease management; Male infertility; Survey; Varicocele 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. INTRODUCTION and it was more pronounced in those men with grade III varicoceles. This is keeping with an earlier study Varicocele, defined as an abnormal enlargement from the World Health Organization (WHO) which and tortuosity of veins in the pampiniform plexus, is reported the prevalence of varicocele among infertile the most common correctable cause of male infertility patients with normal and abnormal semen parameters [1]. Varicocele affects nearly 15% of the general male as 11.7% and 25.4%, respectively [4]. population and is diagnosed in 19% to 41% of primary Using bibliometric analytics, Baskaran et al. reported male infertility and 80% of secondary male infertility that the number of publications on male infertility cases [2]. An epidemiological study from six European and varicocele demonstrated an increasing trend from countries, involving 7,035 male subjects from the gen- 1988 to 2018 [5]. A more recent scientometric study on eral population, indicated the presence of clinical vari- human varicocele research showed that between the cocele (grades I–III) in 15.7% of the population, with years 1988 and 2020, there were four times more origi- more than 50% of the men having a variable degree of nal articles published on surgical approaches compared semen quality deterioration [3]. Despite the lack of his- to non-surgical options [6]. However, despite all these tory of infertility in the latter study, impaired semen studies, the practical management of varicocele for fer- quality was present even in low grades of varicocele tility and non-fertility related indications is not clearly www.wjmh.org 167 https://doi.org/10.5534/wjmh.220048 established and many areas of controversy still remain. Questionnaire revisions yielded a final list of 55 Current challenges in the management of subfer- MCQs (Supplement File 1), which covered important tile men with varicocele include determining the true aspects related to varicocele demographics and diag- benefit of varicocele repair (VR) on pregnancy and nosis, indications for VR, technical aspects of VR, and live birth rates [7]. The improvement in sperm param- fertility-related outcomes. Eight of the 55 questions ad- eters and reduction in seminal reactive oxygen species dressed VR for indications other than fertility and are (ROS) or sperm DNA fragmentation (SDF) after VR not discussed in this paper. An additional 8 questions is highly variable and may depend on various factors documented the participants’ demographic data. such as grade of varicocele, age of patient, testes size, This questionnaire was made available online from pre-treatment sperm parameters and hormone levels. July 23, 2021 to August 20, 2021 via a secured tool Moreover, the role of VR in the management of infer- (SelectSurvey) created by the Cleveland Clinic’s Infor- tile men with varicocele and azoospermia or in those mation Technology Department. The initial invitation with subclinical varicocele remains controversial. Ad- to take the survey was sent to 200 urologists/androlo- ditionally, there is no consensus as to the management gists who were part of a global group initiated by the of infertile men with varicocele recurrence. As a result, American Center of Reproductive Medicine with the considerable variation and controversy is expected in purpose of discussing clinical and research topics relat- the worldwide practice patterns of varicocele manage- ed to varicocele. In turn, they forwarded the invitation ment for different clinical situations. to their colleagues involved in the care of infertile men The aim of this study was to use a comprehensive through direct communication. The following societies online survey to determine the attitudes and practice distributed the questionnaire link to their members: patterns of clinicians worldwide in the management of Arab Association of Urology, Asia Pacific Society of varicocele in infertile men, thus identifying divergence Sexual Medicine, Association Francaise d’Urologie, and concurrence in global practice patterns, and to Brazilian Association of Assisted Reproduction, Brazil- compare these with the latest international (American ian Society of Urology, Egyptian Society of Andrology, Urological Association/American Society for Reproduc- European Association of Urology, Indonesian Urologi- tive Medicine [AUA/ASRM], European Association of cal Association, Indonesian Society of Andrological Urology [EAU]) practice guidelines, and with evidence Urology, Iranian Urological Association, Middle East from systematic reviews and recent meta-analyses. Fi- Society for Sexual Medicine, Sociedad Argentina de nally, in order to provide further clarity in each area Andrologia, Société d'Andrologie de Langue Française, of varicocele evaluation and management, an “Expert Société Internationale d’Urologie, Spanish Associa- Opinion” has been provided based on the consensus of tion of Andrology, Sexual and Reproductive Medi- 16 highly-experienced experts from around the globe. cine, Turkish Association of Urology, and Urological Society of Australia and New Zealand. Practitioners MATERIALS AND METHODS were informed about the nature and objective of the survey and requested to volunteer to fill out the online 1. Survey design and participants questionnaire. The questionnaire was provided in the One hundred and eight urologists/andrologists from English language and used standard medical terms. 34 countries were invited to submit multiple-choice Participants were allowed to omit some questions and questions (MCQs) on varicocele-related clinical topics could review their answers at the end of the survey that they considered most important or controversial before final submission. and relevant to their practice. A total of 382 questions were received from 60 practicing urologists/androlo- 2. Statistical analysis gists from 23 countries. A team of 9 experienced urolo- The survey responses were downloaded and saved gists/andrologists* (RS, PK, AR, NP, EK, NT, MEB, as comma-separated (CVS) files from the SelectSurvey HK, TM) made multiple revisions to merge related or tool. Duplicate responses were excluded from the analy- duplicate questions, remove ambiguity, and create a list sis. Summary statistics were calculated using MedCalc of questions that were most representative of clinical Statistical Software (version 19.0.5; MedCalc Software, dilemmas in actual practice. Ostend, Belgium). Since some respondents skipped 168 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele some questions, and some questions allowed multiple 4. Expert opinion answers, each response was reported as a percentage of Since many of the controversial topics were not ad- the number of respondents for that question. Subgroup dressed by the guidelines, sixteen highly-experienced analyses were performed using the chi-square test. A p- clinicians† (GMC, AZ, AK, MG, AR, PK, TH, EK, GR, value of <0.05 was considered statistically significant. HK, MA, TT, EB, OR, GC, AH) from around the world were invited to comment on each section. Their com- 3. International guidelines and other ments were condensed into an “Expert Opinion” that recommendations was representative of the opinion of most experts (75% The latest guidelines from the EAU [8,9] and the consensus) and would provide practical guidance to AUA/ASRM [10-12] were selected as references since clinicians. The alternative opinions are also presented these have been recently updated and are widely re- in addition to the consensus opinion when there was ferred to. The clinical practices of the survey respon- a significant difference of opinion amongst the expert dents were compared to these guidelines. Additionally, panel. recent systematic reviews and meta-analyses, and other relevant studies, were referred to for clarification on the diverse practices and opinions expressed by the survey respondents. SUM (respondents) 1.0 105.0 1. Canada (4) 10. Albania (5) 19. Uganda (1) 28. China (5) 37. Italy (12) 46. Vietnam (12) 55. Korea (36) 2. United States (17) 11. Ukraine (2) 20. Zambia (1) 29. Turkey (59) 38. Saudi Arabia (11) 47. Indonesia (15) 56. Kuwait (4) 3. Mexico (12) 12. Azerbaijan (1) 21.South Africa (1) 30. Egypt (105) 39. Jordan (2) 48. Austria (5) 57. Luxembourg (1) 4. Guatemala (1) 13. Afghanistan (2) 22. Madagascar (1) 31. Greece (38) 40. Iraq (14) 49. Qatar (5) 58. Bahrain (1) 5. Brazil (17) 14. United Arab Emirates (11) 23. Australia (5) 32. Palestine (2) 41. Iran (7) 50. Burkina (8) 59. Singapore (2) 6. Argentina (3) 15. Sudan (4) 24. Malaysia (5) 33. Algeria (8) 42. Pakistan (7) 51. Cuba (1) 7. United Kingdom (5) 16. Tunisia (2) 25. Philippines (34) 34. France (12) 43. Oman (4) 52. Germany (2) 8. Switzerland (1) 17. Morocco (1) 26. Taiwan (2) 35. Serbia (12) 44. India (26) 53. Hong Kong (1) 9. Spain (7) 18. Senegal (1) 27. Japan (8) 36. Bulgaria (1) 45. Cambodia (1) 54. Kenya (1) Fig. 1. Geographical distribution of respondents. The number of respondents is shown in brackets after the name of each country. The violet color indicates the country with the greatest number of respondents (n=105), the blue color are those with a lower number (n=59), the orange color are those with a further reduction in the number of respondents (from 26 to 38), and the yellow color are the countries with the lowest number of respondents (from 1 to 17). www.wjmh.org 169 https://doi.org/10.5534/wjmh.220048 RESULTS AND DISCUSSION 2. Diagnosis of varicocele 1. Demographics of survey participants 1) Method of diagnosis of varicocele The total number of responses received at the end of the survey was 841. After excluding duplicates and (1) Survey results partial responses, a total of 574 responses from 59 Majority of respondents (70.4%; 404/574) based their countries were considered for analysis (Fig. 1, Supple- diagnosis of varicocele on a combination of clinical ment File 2). findings and confirmation by duplex Doppler ultra- Geographical distribution of the respondents includ- sound (US) whereas 18.6% (107/574) based their diag- ed Asia (n=277, 48.3%), Europe (n=103, 17.9%), South nosis on physical examination alone. However, 9.9% America (n=34, 5.9%), Africa (n=134, 23.3%), North (57/574) used imaging alone to diagnose a varicocele, America (n=21, 3.7%), and Australia (n=5, 0.9%). and a few used clinical findings combined with ther- The majority of the respondents’ age were between mography or venography. 35 and 44 years (n=184, 32.1%) and 45–54 years (n=146, 25.4%), followed by 25–34 years (n=108, 18.8%), 55–64 (2) Guidelines years (n=94, 16.4%), and over 65 years (n=42, 7.3%). The AUA/ASRM guidelines (statement-21) state that The respondents were equally divided between gen- “routine use of ultrasonography to investigate pre- eral urologists (n=227, 39.5%) and urologists with a spe- sumed varicocele is to be discouraged” and recommend cial interest in male infertility (n=226, 39.4%). Primary that varicocele should be diagnosed based on physical practice was andrology in 15.9% (n=91) and “other” in examination alone, with sonography being done only if 4.9% (n=28). Approximately half (n=277, 48.3%) of the the physical examination is difficult. respondents had training in clinical andrology. The The EAU guidelines (10.3.6.1.2) also state that the respondents had a wide range of experience: <5 years, “management of varicocele is still mainly based on a 24.6%; 5 to 10 years, 21.9%; 11 to 20 years, 22.8%; and physical examination”, but they also suggest the use of >20 years, 30.7%. US when “palpation is unreliable” or when recurrence The respondents’ frequency of performing VR was or persistence is suspected due to lack of improvement also very varied (Fig. 2) in semen parameters after VR. They also state that The majority of respondents indicated that they “definitive evidence of reflux and venous diameter agreed in varying degrees with the premise of this sur- may be utilised in the decision to treat”. vey that “the results of varicocele treatment for male infertility are controversial” (Fig. 3). (3) Discussion While 18.6% of respondents rely solely on physical examination to establish diagnosis of varicocele, the majority routinely confirm their diagnosis with US Q7. How many varicocele operations (embolization or surgery) Q8. What is your level of agreement with the statement the results do you perform in a year? (Pre-COVID) of varicocele treatment for male infertility are controversial ? 82 (14.3%) Totally agree VR done annually 83 (14.5%) Somewhat agree 99 (17.2%) <5 Somewhat disagree 121 (21.1%) 5 20 Totally disagree 20 50 >50 136 (23.7%) 173 (30.1%) 220 (38.3%) 234 (40.8%) Fig. 2. Number of varicocele repairs (VRs) done annually by the re- Fig. 3. Degree of agreement of the respondents with the premise of spondents. the survey. 170 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele even though this is not indicated by the guidelines. 3 mm vein diameter as the diagnostic cut-off. Possible reasons for this widepread use of US to con- firm a clinically diagnosed varicocele are discussed in (2) Guidelines the section below (2.1.4). The AUA/ASRM guidelines (statement 21) specify Interestingly, 10% of the surveyed clinicians still the presence of multiple veins with a diameter >3 mm establish a diagnosis of varicocele based on US alone. and reversal of blood flow during Valsalva for US di- This is contrary to the guidelines’ recommendations agnosis of varicocele, but do not make any other tech- that state that US is not indicated if there is no pal- nical recommendations. pable clinical varicocele, since subclinical varicocele The EAU (10.4.3.2) has adopted the recommendations should not be corrected. of the European Society of Urogenital Radiology Scro- tal and Penile Imaging Working Group [13]. Varicocele (4) Expert opinion diagnosis is based on a venous diameter of 3 mm or Given the absence of evidence supporting the correc- more of the largest vein measured at any location in tion of subclinical varicoceles, the diagnosis of varico- the upright position during a Valsalva maneuver and cele should be based primarily on physical examination with venous reflux of duration >2 seconds. and not on imaging alone. Routine US imaging to look for a varicocele in every man with subfertility, irre- (3) Discussion spective of physical findings, is not warranted. Since US is widely used to confirm a diagnosis of US is useful when local examination is difficult (e.g., varicocele, it is important to have a consensus of what tight scrotum or thick spermatic cord), and may also venous diameter parameters constitute a US diagnosis be used to confirm clinical recurrence, or to confirm of varicocele. However, the size of the veins required to the diagnosis when clinical findings are equivocal (the diagnose varicoceles differs in the literature. This vari- experts were divided on this: some recommended US ation may be caused by different evaluation positions to confirm a clinical diagnosis of grade I varicocele, (supine or upright position), examination either at rest while others felt the diagnosis should be purely clini- or with Valsalva maneuver, or different measurement cal). Some experts recommended US to assess the grade sites (relative to the testis or the spermatic cord). of reflux in a clinical varicocele and considered this in The 3 mm venous diameter threshold during the their decision to recommend VR. US was also recom- Valsalva maneuver is widely accepted in the scientific mended by some experts for objective documentation literature for the diagnosis of varicocele [14,15]. How- prior to VR, for insurance re-imbursement and in case ever, there is considerable variation in practice with of a legal issue. 40.6% of respondents diagnosing varicocele even when vein diameters are less than 3 mm. They are supported 2) Ultrasound parameters for the diagnosis of by some studies that have validated the diagnostic util- varicocele ity of smaller vein diameters. Karami et al [16] found 2.65 mm as the threshold to differentiate patients (1) Survey results with clinical varicocele from normal subjects with Although the diagnosis of varicocele is based on high sensitivity and specificity. However, there are no clinical examination, many clinicians still use US ex- studies that support 2 mm as the cut-off value, which amination for confirmation. About one-third of the re- was used by 11.2% of the respondents. The presence of spondents do not do US studies themselves. Of the 391 continuous reflux in the spermatic vein has also been who responded, 56.0% (219 respondents) reported using suggested as a useful Doppler finding that predicts im- 3 mm venous diameter for diagnosing varicocele, while provement after VR [17]. 29.4% used 2.5 mm and 11.3% used 2 mm vein diameter as the diagnostic cut-off. A cut-off of >4 mm was used (4) Expert opinion by 3.3%. Sub-group analysis showed that physicians The considerable divergence in the US diagnosis of who received specific training in male infertility, or varicocele needs to be avoided to ensure uniformity of who had more than 10 years experience, were more diagnosis and management. Current evidence favors likely to perform US examinations themselves, and use the adoption of the EAU recommendations for the www.wjmh.org 171 https://doi.org/10.5534/wjmh.220048 Q11. Estimated frequency of presenting complaints in patients with varicocele 400 350 Number of respondents 300 250 200 150 100 50 0 Primary Secondary Palpable/visible Pain or Testosterone Testicular infertility infertility asymptomatic discomfort deficiency atrophy varicocele Percentage of patients with varicocele Fig. 4. Estimated percentage of patients 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% presenting with common symptoms related to varicocele. US diagnosis of varicocele as mentioned above. When varicocele in almost 15% of the normal male popula- US evaluation is indicated to diagnose a varicocele, it tion, in 25% of men with abnormal semen analysis, and should be performed in the upright position, during in 35%–40% of men presenting with infertility. Valsalva, at a fixed location on the cord and with mea- surement of venous reflux. 3) Discussion Improper use of the US and lack of consensus on the The marked variation in estimated prevalence of threshold values used to diagnose clinical varicocele varicocele reported by the survey participants sug- could result in over-diagnosis of early varicoceles and gests a lack of uniformity in the criteria and methods would lead to unnecessary surgeries and/or confusion of establishing a diagnosis of varicocele. This may, in about outcomes after treatment of ‘grade-I’ varicoceles. turn, be the reason for significant outcome differences reported by various studies. 3. Incidence and symptoms of varicocele 4) Expert opinion 1) Survey results There is a need for more studies on the prevalence The estimated frequency of presenting symptoms in of varicocele in fertile and infertile men using well- men (adult and adolescent) with varicocele is presented defined criteria. Clinical examination is the mainstay in Fig. 4. of diagnosis but it is subjective, resulting in varying Primary infertility was reported as the common- estimates of varicocele prevalence. A combination of est presenting symptom of varicocele. In response to a clinical findings and strictly defined US criteria may question on their estimate of what proportion of men help to ensure uniformity in varicocele diagnosis. with oligoasthenoteratozoospermia (OAT) had a clini- cal varicocele, there is a wide divergence in the respon- 4. Indications for varicocele repair dents’ estimates. Thus, while 13.9% of respondents re- The various clinical scenarios in which the respon- ported an estimated incidence of <10%, a slightly larger dents would advise VR are listed in Table 1. percentage (18.8%) reported that >50% of their infertile men had varicoceles. The remaining clinicians were 1) Oligoasthenoteratozoospermia also equally divided between a prevalence of 10%–25% (33.1%) and 25%–50% (34.1%). (1) Survey results Semen analysis was the most common laboratory 2) Guidelines test used to evaluate the impact of a clinical varicocele The EAU guidelines (10.4.3.3.1) quote a prevalence of on fertility (n=559, 97.4%), followed by reproductive 172 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele Table 1. Indications for varicocele repair in men with infertility Q17. “What are your indications for varicocele repair in an infertile couple?” (you can choose multiple options) Answer No. of responses Percentage of respondents Infertility with clinical varicocele, abnormal semen analysis, and normal female partner <35 526 91.6 years old Infertility with clinical varicocele, and abnormal semen analysis or elevated SDF, irrespective 220 38.3 of female partner status Infertility with clinical varicocele, normal semen analysis, normal female partner, but elevated 199 34.7 SDF Clinical varicocele with normal semen analysis, normal SDF, but ipsilateral testicular atrophy 179 31.2 Infertility with clinical varicocele, normal semen analysis, normal SDF, normal female partner, 105 18.3 but failed IUI/IVF Infertility with clinical varicocele, normal semen analysis, normal female partner, but elevated 94 16.4 OS Large asymptomatic, varicocele with normal semen analysis, and normal testicular size 79 13.8 I do not recommend varicocelectomy. I rather prefer to proceed with other treatments (IUI/ 7 1.2 IVF/ICSI) Total number of respondents 574 ICSI: intracytoplasmic sperm injection, IUI: intrauterine insemination, IVF: in vitro fertilization, OS: oxidative stress, SDF: sperm DNA fragmenta- tion. Q18. In a couple with primary infertility, clinical varicocele, moderate OAT, and female partner <35 years old with a normal fertility evaluation, what would be your first choice for treatment? 23 (4.0%) 6 (1.0%) Varicocelectomy, followed by medical treatment if there is no improvement Varicocelectomy followed by ART (IUI, IVF, and/or ICSI) if no improvement Fig. 5. Therapeutic decisions on the Medical treatment, followed by management of a couple with primary 153 (26.7%) varicocelectomy if there is no improvement 251 (43.7%) Medical treatment alone (no varicocelectomy infertility and clinical varicocele. OAT: followed by ART if no improvement oligoasthenoteratozoospermia, ART: Proceed directly to ART (IUI, IVF, and/or ICSI) assisted reproductive technology, IUI: 141 (24.6%) intrauterine insemination, IVF: in vitro fertilization, ICSI: intracytoplasmic sperm injection. hormonal assay (n=303, 52.8%), SDF (n=150, 26.1%), and was detected, 11% of clinicians would advise surgery oxidative stress (OS) testing (n=38, 6.6%). right away, and 50.3% would advise surgery if another When treating a couple with primary infertility, and report within a month showed OAT. However, 28% moderate OAT with a clinical varicocele, 68.3% of the would wait 3 months before doing another semen test respondents stated that they would directly proceed and then advise surgery if OAT persisted, while only with VR as the first line of treatment, and then follow- 10.6% stated that they would consider multiple semen up with medical therapy or assisted reproductive reports before advising surgery. technology (ART) if there was no improvement. 26.7% This trend towards early surgery is also reflected would first attempt medical therapy before proceeding in the time to surgery once the diagnosis and recom- for VR and 1.0% would proceed to ART without VR mendation for VR are made, with 60.5% (328/542) of (Fig. 5). respondents stating that most of their patients under- This variability in the approach to timing of VR was went VR within 3 months of diagnosis. also reflected in the number of semen analyses the When a couple has secondary infertility, 12.0% of re- clinicians requested before proceeding for VR. When spondents stated that their decision would be affected the first semen analysis was abnormal and a varicocele by the female partner’s age, but the majority (58.5%) www.wjmh.org 173 https://doi.org/10.5534/wjmh.220048 Q19. In a couple with secondary infertility, clinical varicocele, moderate OAT, and female partner with a normal fertility evaluation, what would be your first choice for treatment? 22 (3.8%) 9 (1.6%) Varicocelectomy, followed by medical 69 (12.0%) treatment if there is no improvement Varicocelectomy followed by ART (IUI, IVF, and/or ICSI) if no improvement Medical treatment, followed by 204 (35.5%) varicocelectomy if there is no improvement Fig. 6. Therapeutic decisions on the 138 (24.0%) Choice of treatment will depend on female management of a couple with second- partner s age ary infertility and clinical varicocele. OAT: Medical treatment alone (no varicocelectomy followed by ART if no improvement oligoasthenoteratozoospermia, ART: Proceed directly to ART (IUI, IVF, and/or ICSI) assisted reproductive technology, IUI: 132 (23.0%) intrauterine insemination, IVF: in vitro Total n=574 fertilization, ICSI: intracytoplasmic sperm Total percentage=99.9% injection. still recommended VR as the first step; only 1.6% sug- was no need to rush into VR and that patients may gested proceeding directly to ART (Fig. 6). benefit from an initial trial with medical management The severity of OAT was not a deterrent to advising before considering surgery. This is in concordance with surgery. Responding to a case scenario of severe OAT a recent meta-analysis which suggested that while an- (<1 mill/mL) associated with grade 2 or 3 varicocele, tioxidants (AOX) did not improve pregnancy rates in 73.3% said they would advise VR as the first line of men who had VR, AOX may be of benefit in men with treatment and 17.9% would consider VR if intracyto- unoperated varicoceles [19]. Giving a couple time to plasmic sperm injection (ICSI) had failed. conceive naturally without rushing into VR, especially if they are young, is supported by a study that showed (2) Guidelines similar pregnancy rates between conservative and sur- The AUA/ASRM guidelines (statement 25) recom- gical approaches when the duration of infertility was mend VR if there is infertility and palpable varicocele short, but greater chances of pregnancy after VR if the associated with “abnormal semen parameters, except couple has been infertile for more than 2 years [20]. for azoospermic men.” The older AUA/ASRM guide- Thus, there is no consensus or guidelines on the tim- lines (2012) [18] also recommend VR in men with ab- ing of VR. Some clinicians feel that once a varicocele is normal semen analysis even if they are not currently detected it should be corrected quickly to prevent fur- attempting conception. The EAU guidelines (10.4.3.3.2) ther deterioration. Others adopt a more conservative state that VR results in significant improvement in approach before advising VR [21]. abnormal semen parameters including in some men with non-obstructive azoospermia (NOA), and recom- (4) Expert opinion mend VR in men with OAT, and also suggests that VR is a useful procedure for the treatment of men couples with “otherwise unexplained subfertility” may with OAT and this is reflected in global practice pat- also benefit from VR. terns and the EAU/AUA/ASRM guidelines. Considering the natural variations in semen param- (3) Discussion eters, the possibility of fertility despite the presence The latest Cochrane review [7] states that VR for of an untreated varicocele, and the uncertainty about men with OAT may improve pregnancy rates but it VR outcomes, it is reasonable to not rush into VR if is uncertain whether live birth rates increase. Despite the couple is young and the duration of infertility is this opinion, the majority of respondents favored VR short (1–2 years). However, other than this, VR can be before proceeding to ART, and recommended VR as the recommended as the first step when there is OAT and first step in treatment, in accordance with the guide- a clinical varicocele, after proper counseling about the lines. A different opinion may have been expressed if likelihood of benefit after VR (see section 7.2). the survey population had comprised IVF specialists. The role and duration of conservative management However, one-third of the respondents felt that there in couples with varicocele needs further critical evalu- 174 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele ation as this may help identify couples that can be 3) Isolated teratozoospermia managed medically (avoiding unnecessary VR) from those that are better managed by early VR. (1) Survey results VR for men with isolated teratozoospermia was rou- 2) Isolated asthenozoospermia tinely advised by 41.1% of the respondents, and another 30.3% would do so in selected cases. (1) Survey results VR for men with isolated asthenozoospermia was (2) Guidelines routinely advised by 63% of the respondents, while 22% The EAU and AUA guidelines do not specifically would advise it in selected cases. mention whether VR is indicated in men with isolated teratozoospermia. (2) Guidelines The EAU and AUA/ASRM guidelines do not specifi- (3) Discussion cally mention whether varicocele surgery is indicated Teratozoospermia has become a contentious issue. in men with isolated asthenozoospermia, though the While earlier studies often attributed significant pre- previous AUA/ASRM guidelines [18] stated “one or dictive value to morphology [26], recently there has more parameters” should be abnormal. been criticism that the criteria have become too strict resulting in an excessive diagnosis of teratozoospermia (3) Discussion and loss of clinical predictive value [27,28]. Hence, the “Isolated asthenozoospermia” includes a very diverse willingness of the majority of respondents to offer VR group of patients. A man with normal sperm count but for isolated teratozoospermia is surprising. only 2% motility has a different etiology and prognosis Very few papers address the benefit of VR in men from a man with normal sperm count and 30% motil- with isolated teratozoospermia and these studies report ity. A man with low normal sperm count and astheno- mixed results. While a study by Cakiroglu et al [24] zoospermia may represent a different pathology from demonstrated no improvement in sperm morphology that of a man with high sperm counts and asthenozoo- after VR in men with otherwise normal sperm counts, spermia. other retrospective studies demonstrated an improve- It is clear that varicoceles can have a negative im- ment in sperm morphology [29] as well as pregnancy pact on sperm motility and total motile sperm count rates [30] after VR. This improvement was most likely (TMSC), and that TMSC can improve significantly af- seen with cases of immature spermatozoa and sperma- ter VR [22]. However, there are only a few retrospective tozoa with head abnormalities [31]. studies on the role of VR in isolated asthenozoospermia and they report mixed outcomes [23-25]. They also fail (4) Expert opinion to distinguish between the various sub-groups as dis- There is little evidence to support VR for men with cussed above. Thus, there is limited evidence favoring isolated teratozoospermia. However, since the majority VR in men with isolated asthenozoospermia. However, of respondents have indicated that they would sug- the high endorsement by the survey respondents for gest VR for this indication, there is a need for further VR in men with isolated asthenozoospermia suggests studies so that clear recommendations can be made. that, despite lack of reported evidence, the respondents Monomorphic teratozoospermia (macrozoospermia and may be seeing a benefit in these patients. globozoospermia) has a genetic basis [32] and VR is not indicated for these cases. (4) Expert opinion Further studies are needed to assess the utility of 4) Isolated severe necrozoospermia VR in isolated asthenozoospermia. A distinction should be made between different severity and etiologies of (1) Survey results asthenozoospermia. Until then, based on the survey re- VR for men with isolated severe necrozoospermia spondents’ practices, a guarded recommendation can be was routinely recommended by 42.5% of the respon- made for VR in these cases. dents, while another 27.4% did so in selected cases. www.wjmh.org 175 https://doi.org/10.5534/wjmh.220048 (2) Guidelines and normal SDF if multiple attempts at intrauterine The EAU and AUA guidelines do not specifically insemination/in vitro fertilization (IUI/IVF) had failed. mention whether varicocele surgery is indicated in men with isolated necrozoospermia. (2) Guidelines AUA/ASRM guidelines (statement 19) state that (3) Discussion “there are no well-controlled studies that VR will re- The etiology of necrozoospermia is frequently un- duce risk of recurrent pregnancy loss in men with el- clear but varicocele has been hypothesized as a possible evated SDF”. cause [33]. However, no published studies have evalu- EAU guidelines (10.4.3.3.4) state that there is “in- ated the direct role of VR to improve isolated necrozoo- creasing evidence” that VR may improve SDF and spermia. ART outcomes and recommends VR for men with raised SDF and failed ART (failure of embryogenesis (4) Expert opinion or implantation, or recurrent pregnancy loss) “after ex- There is no evidence to support VR for this indica- tensive counseling”. They make a weak recommenda- tion. Yet, the majority of clinicians have indicated that tion for VR in men with increased SDF and otherwise they would proceed with treatment. Hence, those who unexplained infertility (10.4.3.5), but also state, “the perform VR in men with isolated severe necrozoosper- dilemma is whether varicocele treatment is indicated mia should document and publish their results so that in men with raised DNA fragmentation and normal evidence-based recommendations can be made in the semen parameters”. future. (3) Discussion 5) Isolated increased sperm DNA fragmentation SDF has emerged as an important measure of sperm or oxidative stress function and a predictor of reproductive outcomes [34]. VR is associated with an improvement in SDF, includ- (1) Survey results ing both single-strand and double-strand DNA frag- Among the survey respondents, 34.7% (199/574) indi- mentation, as well as seminal OS [35], and two recent cated of survey respondents indicated that they would meta-analyses calculated a mean reduction in SDF consider VR if SDF was increased even if conven- after VR of 7.23% [36] and 6.14% [37] respectively. tional semen parameters were normal (Table 1), and Men with varicoceles frequently have higher rates 16.4% (94/574) of respondents would advise VR if the of SDF and elevated OS even when a semen analysis OS markers alone were elevated while 18.3% (105/574) shows normal semen parameters [38-41]. In a small, would advise VR even with normal semen parameters controlled trial, Fathi et al [42] reported decreased SDF Table 2. Varicocele repair prior to IVF Q23. “If a man has OAT and clinical varicocele and the couple is willing to undergo IVF, what do you recommend?” (you can choose multiple options) Answer No. of responses Percentage of respondents Recommend varicocele repair before considering IVF 360 62.7 Correct varicocele if IVF fails 131 22.8 Recommend varicocele repair before IVF, only if SDF is high 102 17.8 Proceed directly with IVF 102 17.8 Depends on the female age 230 40.1 Depends on the severity of the varicocele 132 23.0 Depends on the duration of infertility 83 14.5 Depends on the male age 72 12.5 Total number of respondents 574 IVF: in vitro fertilization, OAT: oligoasthenoteratozoospermia, SDF: sperm DNA fragmentation. 176 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele (9% reduction) and higher pregnancy rates in normo- IVF is necessary”. zoospermia men with high SDF (>25% by sperm chro- The EAU guidelines state that VR may improve matin dispersion assay) after VR. ART outcomes in men with OAT (10.4.3.3.2) and also suggest a role for VR before ART when there is el- (4) Expert opinion evated SDF (see discussion above in section 4.5.2). There is evidence to support VR in men with isolated high SDF. VR may be recommended for such men if (3) Discussion other measures to reduce SDF have failed, especially Correcting a varicocele before proceeding for IVF-IC- if there is a history of failed ART. Further research is SI is a controversial topic, and many ART centres take needed to elucidate whether the improvement in SDF no cognizance of a varicocele. However, the majority of and OS after VR in men with a normal semen analysis survey respondents felt that a varicocele should be cor- translates to an increase in natural or ART pregnancy rected before ART. Support for VR before ART comes rates. from a meta-analysis by Esteves et al [43] who reported increased clinical pregnancies and birth rate in 3 of 4 6) Varicocele repair prior to assisted reproductive reviewed studies, and from a meta-analysis by Kirby technology et al [44] who reported that VR improved the ART live birth rate in men with oligospermia (odds ratio [OR], (1) Survey results 1.699). Thus, some couples may benefit from having VR Interestingly, in a couple planning to undergo IVF, before ART. Since VR is a minor procedure compared where the man has OAT and varicocele, 62.7% (360/574) to the time and expense involved in ART, it may be of respondents would recommend VR before proceed- argued that VR should be done for whatever benefit it ing to IVF. Some respondents would decide based on may confer. the age of the female partner or duration of infertility (Table 2). Another 17.8% (102/574) would recommend (4) Expert opinion VR prior to IVF only if SDF was elevated. Recommending VR to all men prior to ART is a deli- cate decision since it will delay the ART procedure by (2) Guidelines 3 to 6 months for an unpredictable benefit. There is a The current AUA/ASRM guidelines do not comment need to identify which subgroups of men with clini- on whether VR prior to IVF will improve pregnancy cal varicoceles will have an improvement in the ART rates, though they do list VR as an option before IVF outcomes after prior VR. Until such evidence is avail- when SDF is raised and there is a history of recurrent able, the decision to perform VR before ART should be pregnancy loss (statement 19). However, older AUA/ individualized based on other variables like varicocele ASRM guidelines [18] state that “VR usually is not grade, SDF levels, history of prior failure, duration of indicated as the primary treatment for couples when infertility, female partner’s age, etc., and after a thor- Table 3. Clinical situations where varicocele repair is not advised Q25. “In a man with a clinical varicocele, OAT and infertility, when are you likely to NOT advise varicocele repair?” (you can choose multiple options) Answer No. of responses Percentage of respondents Grade of varicocele is mild (grade 1) 242 42.2 FSH above normal 161 28.0 Female age >35 years 159 27.7 Small testes (<10 mL) 149 26.0 Will usually advise surgery despite any of the above 145 25.3 Male age >40 years 105 18.3 Severe OAT (<1 mill/mL) 99 17.2 Total number of respondents 574 FSH: follicle stimulating hormone, OAT: oligoasthenoteratozoospermia. www.wjmh.org 177 https://doi.org/10.5534/wjmh.220048 ough discussion with the couple. nificantly increased in all groups after varicocelectomy When ART is being done for an older woman, and (p<0.05) and though pregnancy rate after varicocelec- her male partner has OAT with varicocele, some tomy was higher in group 3 (both partners <35 years experts suggest that the option of performing both old) compared with group 2 (patients ≥35 years old and ART and VR can be considered. ART success rate per their spouses <35 years old) and group 1 (both partners cycle is low in older women [45], and the possibility of ≥35 years old), the differences were not significant achieving a spontaneous pregnancy if the semen qual- (p=0.133). This suggests that even couples with both ity improves after VR can never be excluded a priori. partners over 35 years of age have a reasonable chance of natural pregnancy after VR, and advanced male age 7) When not to recommend varicocele repair is not a contraindication to VR. A similar conclusion was reached in a study by Hsiao et al [47]. (1) Survey results The most common reason (42.2%) for not advis- Participants listed several clinical situations in which ing VR was low grade (grade I) of varicocele. Several they would not recommend VR (Table 3). studies have shown greater improvement and higher pregnancy rates when a higher grade of varicocele (2) Guidelines was operated. A recent meta-analysis of 20 studies by The AUA/ASRM guidelines recommend against VR Asafu-Adjei et al [48], stratified outcomes by varicocele for non-palpable varicoceles (statement 26) and also grade and demonstrated that improvements in sperm when IVF is indicated due to a female factor (2012 concentration and overall motility occurred with all guidelines). The EAU guidelines (10.4.3.3.2) do not rec- grades of varicocele but it was proportional to the ommend VR in men with normal semen analysis and grade of varicocele. Thus, the mean sperm concentra- those with a sub-clinical varicocele. However, no exclu- tion improvement in men with grades I, II, II-III and sions based on any of the other factors are specified. III varicoceles were 5.5, 8.9, 12.7, and 16.0 million sperm/ ml, respectively while the mean improvement in the (3) Discussion percent of overall motility in men with grades I, II, II- Since a significant proportion of men will not benefit III and III varicoceles was 9.6%, 10.6%, 10.8% and 17.7%, from VR, it is important to individualize the recom- respectively [48]. mendation for VR, based on favorable and unfavorable A significant proportion of respondents listed “follicle prognostic factors. stimulating hormone (FSH) above normal” (28% of re- However, there is considerable variation in the clini- spondents) or “testes <10 mL” (26% of respondents) as cal factors that the surveyed physicians take into contraindications to VR. While this correlates with a consideration when deciding that VR is unlikely to common sense approach that these parameters indicate succeed in a given case. Interestingly, one-fourth of re- significant testicular damage and hence improvement spondents indicated that they would take any chance after VR is less likely, there is little evidence in the and would advise surgery despite negative prognostic literature to support such a belief. A study by Birowo factors. et al [49] found improvement in sperm retrieval rates The partner’s age was considered important by 27.7% after VR in men with NOA across all levels of FSH, of the respondents who suggested that if the female while another study showed a reduction in FSH after partner’s age is >35 years, then they would not want VR with a correlation between reduction in FSH and to delay ART and hence would not recommend VR. an increase in semen parameters [50]. Similarly, while The AUA/ASRM guidelines (statement 1) state that studies have shown an increase in testicular volume “maternal age is the strongest predictor of fertility after VR in both adolescents [51] and adults [52,53], outcome”. Therefore, the need for haste is understand- there is no data is supporting the exclusion of VR in able. Similarly, male age >40 years was cited as an ex- men with small testes and OAT. clusion factor by 18.3%. However, a study by Fırat and Only 17.2% of the respondents felt that VR would not Erdemir [46] showed that age need not be an exclusion benefit men with severe OAT (<1 mill/mL) and would factor. The study evaluated outcomes after VR in 293 not recommend VR for this group. While several stud- couples of different ages. TMSC was found to be sig- ies have documented the benefit of VR in men with 178 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele severe OAT (<5 mill/mL) [54,55], few studies address ticular volume, lower FSH, and bilaterality of the vari- the possibility of benefit from VR in case of extreme cocele as key predictors of a higher chance of benefit OAT (<1 mill/mL). In a study of 102 men with severe (Table 4). OAT (<5 mill/mL), Enatsu et al [56] reported that 41.1% of men had significant improvement after surgery, but (2) Guidelines the chances of improvement were greater in men with The AUA/ASRM guidelines state that “maternal age initial counts of 2–5 mill/mL as compared to those with is the strongest predictor of fertility outcome” (state- <2 mill/mL. A study by Dada et al [57] emphasized the ment 1) but do not identify any patient or varicocele- need for genetic testing prior to VR in men with ex- related characteristics that predict a greater chance of treme OAT. benefit from VR. The EAU guidelines do mention that a higher grade of varicocele is associated with greater (4) Expert opinion improvement (10.4.3.3.2) and this should be considered There are no robust contra-indications to VR. How- while counseling a patient. ever, men with very poor baseline sperm parameters (e.g., extreme OAT) and small (grade I) varicoceles are (3) Discussion less likely to experience a clinically significant im- The female partner’s age is the most important pre- provement in sperm parameters after VR. dictor of pregnancy. However, this question focused on Moreover, couples with advanced maternal age or factors that would predict maximum improvement in poor ovarian reserve should be cognizant of the time semen parameters and thus improve pregancy rates. delay associated with a VR and the unfavorable im- In a systematic review of parameters that would pre- pact of maternal age on spontaneous pregnancy rates. dict favorable outcomes after VR, Samplaski and Jarvi These couples should consider opting for ART without [58] reported that the best predictor of improved semen delay but may consider VR as a simultaneous proce- parameters, as well as of natural and ART pregnancy dure to improve semen quality for future attempts. rates, were higher pre-operative semen parameters, and that the greatest improvements were seen in men with 8) Predictors of a successful outcome larger varicoceles. There was some evidence that high- (pregnancy) after varicocele repair er testosterone, larger testes, and younger age were as- sociated with better outcomes. Predictive normograms (1) Survey results have also been described [59]. Kamal et al [60] also When asked to identify which factors could predict a reported that natural pregnancy rates after VR were successful outcome in terms of natural pregnancy after much higher if the initial sperm count was >5 mill/ VR, the majority identified higher grade of varicocele, mL. If US Doppler study has been carried out, then the higher pre-operative motile sperm count, larger tes- presence of continuous reflux predicts a higher chance Table 4. Predictors of pregnancy after varicocele repair Q 36: “In your experience, which of the following pre surgery parameters predict varicocele repair success in terms of pregnancy?” (you can choose multiple options) Answer No. of responses Percentage of respondents Higher grade of varicocele 355 68.1 Higher total motile sperm count 258 49.5 Larger testes volume 232 44.5 Higher total sperm count 214 41.1 Lower serum FSH level 181 34.7 Bilateral varicocele 176 33.8 Higher serum testosterone level 58 11.1 Other 23 4.4 Total number of respondents 521 FSH: follicle stimulating hormone. www.wjmh.org 179 https://doi.org/10.5534/wjmh.220048 of improvement [17]. tion (Table 5). Only 13.4% used an intra-operative Doppler to iden- (4) Expert opinion tify the artery. The majority relied on visual identifica- The greatest improvement in semen parameters and tion using either a microscope (33.1%) or loupes (13.4%); highest chances of natural pregnancy after VR may be 17.4% claimed to identify the artery without the help expected when the female partner is young, initial se- of magnification, while 24.4% did not identify the ar- men analysis shows mild to moderate OAT, varicocele tery and just avoided the area of pulsations. is large (grade III) and bilateral, testicular volume and Only a minority of the survey responders (2.6%) pre- serum FSH are normal, or there is secondary infertility. ferred retrograde embolization or antegrade or retro- grade sclerotherapy as a primary method for VR. 5. Technical aspects of varicocele repair (2) Guidelines 1) Choice of technique, use of magnification, The AUA/ASRM guidelines recommend “surgical identification of artery varicocelectomy” (statement 25) and quote the highest success with subinguinal microsurgical varicocelectomy (1) Survey results as compared to other surgical techniques. The respondents’ choice of technique for VR is shown EAU guidelines state that microsurgical varicocelec- in Fig. 7. tomy “is the most effective among the different varico- Nearly half (43.2%) of the surgeons reported that celectomy techniques” and has the lowest complication they routinely used the operating microscope and and recurrence rates. However, adequate support from 26.0% used magnifying loupes for performing VR. The RCTs is lacking, and “other techniques are also viable rest listed a variety of reasons for not using magnifica- options” (10.4.3.4). Radiological techniques are mini- Q28. Which varicocele repair technique do you prefer? 4 (0.7%) 8 (1.5%) 3 (0.6%) 23 (4.2%) 2 (0.4%) Microsurgical subinguinal varicocele repair 26 (4.8%) Microsurgical inguinal varicocele repair Conventional inguinal varicocele repair Retroperitoneal (Palomo s) varicocele repair Laparoscopic repair Retrograde embolization 119 (22.0%) 296 (54.6%) Antegrade sclerotherapy Robot assisted varicocele repair Retrograde sclerotherapy 61 (11.3%) Fig. 7. Choice of varicocele repair tech- nique. Table 5. Use of operating microscope for varicocele repair Q 29: “Do you perform varicocelectomy using an operating microscope?” (you can choose multiple options) Answer No. of responses Percentage of respondents Yes, I use it routinely 234 43.2 I use magnifying loupes 141 26.0 I don’t have microscope 136 25.1 I feel comfortable with naked eye 79 14.6 I don’t have microsurgical skills 61 11.3 I feel that a microscope doesn’t make much difference in outcomes 38 7.0 Total number of respondents 542 180 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele mally invasive and are widely used but have higher technical challenges in up to 20% of cases [67], and re- recurrence rates. currence rates range from 4% to 27% (EAU guidelines 10.4.3.4). (3) Discussion There are many options for surgical VR, each hav- (4) Expert opinion ing its potential advantages and disadvantages. One Microsurgical subinguinal VR is the standard of care meta-analysis found no specific VR technique to be the because it is associated with lower complication and re- most effective in improving fertility [61], while another currence rates, and possibly higher improvement in se- one reported the highest spontaneous pregnancy rate men parameters. However, it is technically demanding following sub-inguinal microsurgical VR (41%) vs. ret- and needs access to an operating microscope. Not all roperitoneal (37%) vs. inguinal (26%) vs. laparoscopic surgeons are trained in the technique but those who transperitoneal (26%) vs. percutaneous embolization do VR regularly are strongly encouraged to acquire (36%) [62]. microsurgical skills to be able to perform subinguinal Techniques utilizing optical magnification optimize microsurgical VR. Meanwhile, surgeons should utilize the surgeon’s ability to preserve the testicular artery the technique that they are competent in and most and lymphatic channels while ligating all veins to comfortable with. minimize the risk of hydrocele formation or varicocele recurrence. Preservation of the gonadal artery dur- 2) Ligation of additional veins outside the ing VR is considered important, and techniques that spermatic cord facilitate this include optical magnification with an operative microscope or operating loupes, administer- (1) Survey results ing papaverine locally, using a micro-Doppler [63], or a The majority of respondents ligate the external sper- combination of the above. matic or cremasteric veins (always, 33.9%; often, 47.8%). Almost one-fourth (24.4%) of the responders do not In contrast, the majority do not ligate the guber- identify the arteries but just avoid the area of pulsa- nacular veins (never, 25.3%; rarely, 29.3%). Only 15.7% tions. This may lead to an increased possibility of miss- always ligate the gubernacular veins while 16.1% ligate ing surrounding veins and a higher risk of varicocele them when operating for recurrence, and 13.7% ligate recurrence. if there is a grade III varicocele. In this context, microsurgical VR is considered the gold standard procedure having the least postoperative (2) Guidelines complications and lowest recurrence rate [64], and was There are no specific comments on the need to ligate the technique used by more than half of the respon- cremasteric or gubernacular veins. dents. The microsurgical subinguinal approach has the further advantage of a short postoperative recovery (3) Discussion compared to the inguinal approach because no muscle Ligation of the external spermatic or cremasteric or fascia is incised during the procedure. However, the veins has been popular for a long time [68], and most number of veins and arteries encountered in the sub- respondents reported ligating them during VR. On the inguinal approach is more than in the inguinal ap- other hand, the majority of respondents disputed the proach, rendering dissection more challenging [65]. In suggestion that the gubernacular veins should be li- adolescents, use of the microscope makes identification gated. of the tiny testicular arteries easier. The concept of ligating the gubernacular veins was Varicocele treatment by venous embolization or an- proposed by Goldstein in 1992 [69] based on earlier pub- tegrade sclerotherapy [66] was not popular with the lished studies on varicocele recurrence. In a case series respondents, but this may reflect a geographical bias. of 640 men who underwent microsurgical VR with gu- Percutaneous embolization of varicoceles will result in bernacular vein ligation, he reported a low recurrence less post-procedural pain than surgical repairs. Howev- rate of 0.6%. However, there was no control group and er, interventional access to the internal spermatic veins the low recurrence rate may have been due to the mi- (especially the right side) may not be possible due to crosurgical cord dissection. A subsequent paper, from www.wjmh.org 181 https://doi.org/10.5534/wjmh.220048 the same institution, which included a control group unilateral VR when there are bilateral clinical varico- of men whose testes were not delivered showed similar celes [73]. However, the choice of procedure becomes less recurrence rates and improvement in semen param- clear when the varicocele on the right side is equivocal eters in both groups [70]. Similarly, a controlled ran- or subclinical. domized study by Huo et al [71] found no difference in A large meta-analysis of 4 randomized controlled tri- either recurrence or improvement rates, but observed als (RCTs) with 637 cases compared outcomes following that gubernacular vein ligation increased the operat- unilateral or bilateral VR in men with left-clinical and ing time by a mean of 6 minutes and increased the right-subclinical varicoceles [74]. The authors reported incidence of scrotal edema and testicular engorgement no significant difference in the increase in sperm con- (raising the suspicion that ligation of gubernacular centration and sperm motility in the two groups but veins resulted in occlusion of normal drainage chan- the odds ratio for spontaneous pregnancy rate was 1.73 nels). favoring bilateral ligation. The authors concluded that On the other hand, a randomised, controlled study bilateral ligation may be superior but more RCTs were by Allameh et al [72] found lower recurrence, greater needed. improvement in sperm motility, and no increase in the A prospective, randomized controlled study by Sun complications, in the group that underwent gubernacu- et al [75] compared the outcomes at one year following lar vein ligation. unilateral VR (179 men) versus bilateral VR (179 men) in infertile men with left clinical and right subclinical (4) Expert opinion varicoceles. Both groups showed improvement but the Ligation of the external spermatic veins is easy, adds increase in sperm concentration, progressive motility, minimal operating time, may reduce recurrence, and and morphology were significantly greater, and preg- can be done routinely. Gubernacular vein ligation re- nancy rates were higher in the bilateral group (42.5% quires additional steps and a larger incision to deliver vs. 26%). the testis. Since the benefit of this extra step is contro- On the other hand, an earlier, smaller study on 104 versial, it should be deemed optional, and as suggested men found equal improvement in semen parameters by the survey respondents may be omitted entirely or and pregnancy rates following unilateral or bilateral limited to selected cases of grade III or recurrent vari- VR in this group of men [76]. cocele. (4) Expert opinion 3) Unilateral versus bilateral repair When there is a bilateral clinical varicocele then VR should be performed bilaterally. (1) Survey results However, there is controversy in the medical litera- In the presence of a left clinical varicocele, 63.8% ture regarding concomitant repair of a subclinical right of respondents would operate the right side only if a varicocele at the time of left clinical VR, and a defini- clinical varicocele was present on the right side, while tive recommendation cannot be made. Taking into 18.8% would correct the right side even if it was sub- consideration the general injunction against VR for a clinical. Besides, 17.4% stated that they did not perform subclinical varicocele, the consensus of expert opinion simultaneous bilateral repair. recommends against VR of the right subclinical varico- cele in this situation. (2) Guidelines If the clinician is considering bilateral ligation for While both EAU and AUA guidelines are clear that such a case then it should be a shared decision between subclinical varicoceles should not be operated upon, the surgeon and patient with the understanding that there is no specific recommendation regarding a right- the benefit of a bilateral procedure is uncertain, and side subclinical varicocele when there is a left-sided involves extra operative time and an additional inci- clinical varicocele. sion. (3) Discussion A recent systematic review favored bilateral VR over 182 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele 4) Sperm cryopreservation prior to (4) Expert opinion varicocelectomy Sperm cryopreservation prior to VR is not recom- mended as a routine procedure since the additional (1) Survey results costs are not warranted. However, in keeping with the Opinion was divided on the need for prior sperm survey findings, it should be considered when there is cryopreservation. Overall, 32.5% of the clinicians never a solitary testis or extreme OAT (<100,000/mL). Sperm recommend it, while 32.5% recommend it when there is cryopreservation may also be considered in men with severe OAT, and 25.5% consider cryopreservation pru- varicocele who have severe OAT and progressively de- dent when operating on a solitary testis. clining semen parameters but are delaying VR. (2) Guidelines 5) Testicular biopsy at the time of varicocele There are no recommendations on when sperm repair for oligoasthenoteratozoospermia should be cryopreserved before VR. (1) Survey results (3) Discussion The vast majority (94.1%) of respondents do not per- The spermatic artery can be damaged during VR, form a testicular biopsy when VR is being done for especially when utilizing non-magnified surgical tech- OAT. niques, and this may further jeopardize an already im- paired spermatogenesis with significant consequences (2) Guidelines if the original sperm count was already very low [75]. The guidelines do not make any recommendation for Further, men with severe OAT may progress naturally testicular biopsy when VR is done for OAT. to azoospermia [77], and if that happens after VR, then the VR procedure may be blamed. Not all men under- (3) Discussion going VR will have an improvement in their semen While it was a practice in the past to do a testicular parameters, and sometimes there may be deterioration biopsy at the time of VR for “prognostic purposes”, it which may even result in azoospermia in men who is not recommended currently as there is no evidence had extreme OAT pre-operatively [78]. Hence, it seems that the biopsy results influence further management prudent to advise sperm cryopreservation before VR in [80], and it may lead to the formation of antisperm an- men with extreme oligozoospermia. tibodies which may affect sperm parameters later on. Further, testicular atrophy can occur rarely after VR [79], and while this may not have much of an impact (4) Expert opinion if there is a normal contralateral testicle, it would be Testicular biopsy is not indicated at the time of VR disastrous in a man with a solitary testicle. Therefore, for management of OAT. it would be safer to cryopreserve sperm before VR on a Men who are undergoing VR for infertility, and also solitary testis. have bilateral testicular microlithiasis, may be offered a simultaneous testicular biopsy to look for germ cell neoplasia in situ (GCNIS) and future risk of testicular Table 6. Doppler ultrasound evaluation for follow-up after varicocele repair Q 42: “Do you perform Doppler or ultrasound evaluation after varicocele repair?” (you can choose multiple options) Answer No. of responses Percentage of respondents If physical examination suggests residual varicocele 216 41.5 If semen parameters have not improved 157 30.1 If patient is not relieved of pain 121 23.2 Never 113 21.7 In every case 77 14.8 Total number of respondents 521 www.wjmh.org 183 https://doi.org/10.5534/wjmh.220048 germ cell tumor (TGCT) (EAU guidelines 10.4.2.2). small study on adolescents post-VR, there was marked variation between clinical and US findings, with US 6. Follow-up and recurrence after varicocele reporting residual/recurrent varicocele in 12/15 cases repair [81]. When US detects a residual “subclinical” varicocele following VR, it could lead to unjustified patient disap- 1) Post varicocele repair follow-up with pointment and anxiety, and may cause a management ultrasound or Doppler ultrasound dilemma. Post VR Doppler US has been recommended in the (1) Survey EAU guidelines when there is no improvement in se- There was considerable divergence of opinion on men parameters and a recurrence is suspected. How- follow-up, with 14.8% (77/521) advising post-VR US rou- ever, as discussed above, it is not clear whether the tinely for all patients, and 21.7% (113/521) never asking US detected recurrence is of significance if the clinical for post-op US. Others advised it conditionally for rea- examination is normal. A small-study [82] reported a sons listed in Table 6. 60% recurrence 5 years after VR when the men were examined with Doppler US, supporting the suggestion (2) Guidelines that Doppler US may over-estimate post VR recur- The AUA/ASRM guidelines (statement 21) recom- rence. On the other hand, often there is thickening of mend against routine scrotal US to look for varicocele; the spermatic cord due to thrombosed veins after VR there is no specific recommendation about the use of and a Doppler US study can confirm whether there is US to monitor follow-up or look for recurrence. significant reflux in the thickened cord. The EAU guidelines (10.4.3.2) recommend scrotal Doppler US to look for residual/recurrent varicoceles (4) Expert opinion if there is no improvement in semen parameters after Routine scrotal Doppler US after VR is not recom- VR. mended, though some surgeons may choose to do it to monitor the technical success of their VR procedure. (3) Discussion Repeat US may be considered if there is no improve- Routine Doppler US follow-up after VR can act as a ment in semen parameters, or non-resolution of pain, quality control measure, helping the clinician to con- and there are findings on physical examination sug- firm that there is no residual varicocele (failed VR) gestive of residual or recurrent varicocele. and that the artery is intact. However, this has sev- eral disadvantages apart from the additional cost and 2) Post-operative complications time spent. Often a post-VR Doppler US may detect a varicocele that is not clinically significant, and this (1) Survey results could lead to a false diagnosis of failed surgery. In a A number of complications of varicocele surgery Q44. Complications after varicocele repair 0% 1 2% 3 5% 6 10% >10% Wound infection 51 39.6 3.8 4.7 0.9 Testicular atrophy 65.1 31.1 2.8 1 0.0 Scrotal hematoma 46.2 37.7 11.3 3.8 1 Residual varicosities 5.6 38.7 34.0 13.2 8.5 Hydrocele 30.2 40.6 15.1 9.4 4.7 Decrease in semen parameters 22.6 42.5 23.6 10.4 0.9 Absent arterial flow without atrophy 72.6 18.9 5.7 0.9 1.9 0 20 40 60 80 100 Percentage of respondents Fig. 8. Frequency of complications after varicocele repair. 184 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele were reported by the respondents but the overall inci- tween the first and second year (41%). dence was less than 10% (Fig. 8). The main factors listed as the cause of recurrence were surgeon’s experience (61%) and/or surgical ap- (2) Guidelines proach (51.7%), indicating missed tributaries of the The recent AUA/ASRM guidelines do not comment spermatic vein as the main cause. However, 29.8% list- on post-VR complications, but the 2011 guidelines warn ed cremasteric veins, and 23.2% named gubernacular that laparoscopic VR does have some risk of major veins as possible causes of recurrence. intraperitoneal complications. The EAU guidelines Opinion on the management of recurrence was wide- (10.4.3.4) state that microsurgical varicocelectomy is the ly divided. While 14.6% recommended repeating VR for most effective with the least complications. all recurrences, 17.1% said that they do not usually sug- gest treatment of a recurrent varicocele. (3) Discussion The remaining respondents made their decision The most common reported complications were hy- based on the outcome of the first surgery but expressed drocele and residual varicocele, both of which are mini- contrasting viewpoints. While 27% would suggest a re- mized by the use of magnification to preserve lymphat- peat procedure if there had been no improvement after ics while ligating all tributaries of the spermatic vein. the first procedure, 28.5% would suggest repeat proce- A fall in sperm count after treatment was also re- dure only if there had been significant improvement ported by a fair number of surgeons. This may be due after the first procedure followed by a gradual decline, to spontaneous variation in semen parameters or may and an additional 12.7% agreed that they would not be due to an undetected damage to the testicular ar- operate if there had been no benefit after the first sur- tery which did not result in atrophy but compromised gery. the testicular function. This would be avoided by the The choice of procedure also varied widely. For re- use of magnification and other intra-operative mea- currence after a subinguinal microsurgical varicoce- sures to preserve the testicular artery during surgery. lectomy, one-third (34.9%) of the surgeons opted for a Spermatic vein embolization would be free of surgi- repeat procedure at the subinguinal level while 28.4% cal complications and risk of damage to the testicular opted to go higher (inguinal, 14.5%; Palomo, 8.7%; lapa- artery. However, the technique demands interventional roscopic, 5.2%). Besides, 15% recommended venographic radiologic expertise, is associated with a higher failure occlusion while 21.8% opted not to treat the recurrence. rate, and has potential serious complications including vascular perforation, coil migration leading to renal (2) Guidelines vein thrombosis, and thrombosis of pampiniform plex- The EAU guidelines (10.4.3.4 – Table 41) state that us [81]. inguinal/subinguinal microsurgical VR has the lowest recurrence rate compared to other surgical techniques, (4) Expert opinion and that radiological occlusion procedures have sig- Subinguinal microsurgical varicocelectomy is associ- nificantly higher rates of recurrence. The guidelines ated with the lowest complication rate and is the gold (10.4.3.2) recommend Doppler US to look for recurrent standard for VR. However, surgeons should adhere to varicocele if there is no improvement after VR but do the technique that they are comfortable with since a not comment on the likelihood of benefit from VR for poorly done microsurgical procedure will do more harm recurrent varicoceles. than good. Nevertheless, to minimize the complications rate, obtaining formal microsurgical training is highly (3) Discussion advisable for surgeons who do VR regularly. There is a wide range in the incidence of recurrence reported based on surgical approach, technique, dura- 3) Recurrence after varicocele repair tion and method of follow-up [83]. The recurrence of a varicocele is disturbing to both the surgeon and the pa- (1) Survey results tient. An early recurrence is a residual varicocele that The majority of respondents reported that varicocele has enlarged again. recurrence occurred within the first year (35.1%) or be- Missed tributaries of the spermatic vein are the pri- www.wjmh.org 185 https://doi.org/10.5534/wjmh.220048 mary cause of recurrence and therefore microsurgical small percentage stated that increased pregnancy rates VR has the lowest recurrence rate since small tribu- (16.3%) or an increase in live birth rate (9.8%) should be taries can be identified and ligated [84]. The role of the the primary outcome measure. cremasteric and gubernacular veins is still debated. About 58.7% stated that a significant improvement Franco et al [85] performed left iliac vein venographic in semen parameters, even if it did not reach normal studies of 73 men with primary or recurrent varico- reference values, would be considered a successful out- celes and failed to demonstrate reflux from the extra- come, while 15.2% would consider the VR a success only funicular veins into the pampiniform plexus. They if the semen parameters improved to normal. observed that the cremasteric vein was always con- The majority (73.9%) asked for the first post-opera- tinent even when grossly dilated, and concluded that tive semen report at 3 months, and 19% chose to wait the cremasteric vein has a limited, if any, role in the till 6 months, while a few asked for it earlier or later pathogenesis of varicocele or its recurrence. However, than 3–6 months. the majority of survey respondents reported ligating the cremasteric veins (see section 5.2.1). (2) Guidelines The diverse practices of the survey respondents Both AUA/ASRM and the EAU guidelines comment would suggest that the benefit from re-operating a on VR outcomes in terms of both semen parameters recurrent varicocele is unclear. However, a systematic and pregnancy rates. The EAU guidelines also state review [83] of men undergoing VR of recurrent varico- that VR reduces SDF and improves OS. cele by surgery, retrograde embolization, or antegrade sclerotherapy reported high rates of success in treating (3) Discussion the recurrence and highly significant improvement in While Cochrane reviews and systematic reviews on semen parameters. the efficacy of VR emphasize spontaneous pregnancy rates and live birth rates [7] as the important outcome (4) Expert opinion measures, the majority of clinicians responding to this Care should be taken to ligate all tributaries of the survey considered VR successful if semen parameters spermatic vein to prevent a recurrence. When cremas- increased significantly. This may reflect the fact that teric veins are easily accessible (as in low approaches) pregnancy depends on many factors, both male and they should also be ligated. Routine delivery of the tes- female, and that the role of VR is to improve one of tes to ligate gubernacular veins is not recommended (see these factors. Also, VR may help to improve ART out- section 5.2.3). comes. The counter-argument is that if the live birth Surgery for recurrent varicocele may be advised but rate is not changed, then the improvement brought with a cautionary note about chances of improvement about by VR is not of significance. in semen quality. When the previous VR was by a high approach, then the repeat surgery should be at the sub- (4) Expert opinion inguinal or inguinal level. When the primary surgery Patients who undergo VR benefit in terms of im- was sub-inguinal, then repeat surgery at a lower level provement in semen parameters and sperm function. can be done but would be significantly more difficult, However, the impact of this on pregnancy and live and hence venographic occlusion, or an inguinal ap- birth rates may be limited as they depend on many proach, could be considered. other factors. Thus, although the improvement in se- men parameters after VR may not result in a propor- 7. Outcomes tionate increase in live birth rates, improvement in the semen parameters is valid as a primary outcome 1) Parameters of a successful outcome measure of VR. When sufficient data is available from RCTs, then live birth rates can be considered as the (1) Survey results primary outcome measure. In response to a question as to what the respon- Also, improvement in semen parameters may allow dents considered the main parameter for determin- couples to succeed with lower levels of treatment, such ing whether the VR had a successful outcome, only a as ovulation induction cycles or IUI rather than IVF. 186 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele Q38. When you counsel patients on the chances of clinically Q39. When you counsel patients on the chances of spontaneous significant improvement in semen parameters following pregnancy following varicocele repair, what percentage do you varicocele repair, what percentage do you usually quote? usually quote? 38 (7.3%) 14 (2.7%) 67 (12.9%) <30% <30% 30 50% 30 50% 50 70% 84 (16.1%) 111 (21.3%) 50 70% >70% >70% 192 (36.8%) 224 (43.0%) 312 (59.9%) Fig. 9. Chances of clinically significant improvement in semen param- Fig. 10. Chances of spontaneous pregnancy after varicocele repair. eters after varicocele repair. Thus, improved semen parameters after VR will be a (4) Expert recommendation useful outcome for these patients. Patients can be counseled that there is a 50%–70% chance of significant improvement in their semen pa- 2) Chances of benefit after varicocele repair rameters after VR, and a 30% to 50% chance of a natu- ral pregnancy. However, there is also a need to better (1) Survey results define the expected outcomes of VR and provide a When asked about how they counsel their patients more precise, individualized prognosis based on clinical about the chances of benefit from VR, the majority of findings, semen parameters, hormonal levels, prognos- clinicians quoted moderately optimistic figures with tic biomarkers, duration of infertility, and the couple’s 43.0% of respondents offering a 50% to 70% chance of age. A validated prognostic model would be helpful. significant improvement in semen parameters (Fig. 9), and 59.9% clinicians advising a 30% to 50% chance of 3) Time to maximum improvement after spontaneous pregnancy (Fig. 10). varicocele repair (2) Guidelines (1) Survey results The AUA/ASRM guidelines (statement 25) quote There exists considerable variation in the expected an estimated pregnancy rate of 52% (95% confidence time to maximum improvement. About 34% of clini- interval [CI], 24%–83%) after subinguinal microsur- cians opted for 3–6 months, 29.2% for 6 to 9 months, gical VR. The EAU guidelines (10.4.3.3.2) quote two and 26.7% for 9 to 12 months. Lastly, 8.6% suggested meta-analyses to suggest that VR improves chances of waiting for more than 12 months. pregnancy with a combined OR of 2.39 (95% CI, 1.56– 3.66)–4.15 (95% CI, 2.31–7.45), with time to improvement (2) Guidelines up to two spermatogenic cycles and time to spontane- Both AUA/ASRM and EAU guidelines suggest that ous pregnancy of 6 to 12 months. improvement should be expected within 1-2 spermato- genic cycles, that is within 3 to 6 months, and recom- (3) Discussion mend semen testing every 3 months up to one year. Several meta-analyses have been published evalu- ating the benefit of VR on semen parameters and (3) Discussion pregnancy rates, and report an improvement in semen The expected time to maximum improvement is parameters and pregnancy rates that are in agreement clinically important since lack of improvement by that with the chances that are counseled by the survey re- time period would be an indication of failure of benefit spondents [86,87]. from the procedure, and the need to proceed with ART. Waiting too long would result in unnecessary delay in www.wjmh.org 187 https://doi.org/10.5534/wjmh.220048 the next step. clinical varicocele, 26.5% answered “always”, 23.9% an- A few studies have examined the time to maximum swered “usually”, and 32.5% asked for it “occasionally”. improvement after VR. The majority of these studies Thus, only 17.1% abided by the guidelines recommen- suggest that improvement in semen parameters occurs dation that US is not indicated to look for a subclinical by the first 3 months after varicocelectomy with no varicocele. further significant improvement seen afterward [88-90]. Along similar lines, when asked when they would re- Machen et al [91] stratified the improvement in sperm pair a subclinical varicocele, only 44.7% replied “never”. count by time after VR and reported that 78.8% had The remaining majority of clinicians were willing to improvement at 3 months, 16.9% at 6 months, and 4.2% recommend VR, even for subclinical varicoceles, for a beyond 6 months. When specifically evaluating men variety of clinical indications (Table 7). with severe oligospermia pre-operatively, with TMSC The frequency of performing VR in patients with of <5 million/mL, the largest improvement may be seen subclinical varicocele tended to be higher among re- between 3–6 months post-operatively [92]. sponders with up to 10 years of clinical experience as compared to those with more than 10 years of experi- (4) Expert opinion ence (212/267 [79.4%] vs. 214/307 [69.7%]; p=0.048). How- Most of the evidence suggests that if improvement ever, the difference in the proportion of responders occurs it will happen in the first 3 months after sur- with and without sub-specialty training in infertility gery which corresponds with the spermatogenesis that performed VR in patients with subclinical vari- cycle. However, men with severe OAT may take up to 6 cocele was not significant (220/297 [74.1%] vs. 206/277 months for maximal improvement. If improvement in [74.4%]). semen parameters has not occurred by 12 months post- On the other hand, the approach to the management operatively, then it is not likely that there will be any of a grade I varicocele was different. When asked about improvement. On the other hand, examining the semen the management of bilateral clinical grade I varicocele earlier than 3 months after VR may lead to an errone- in a man with moderate OAT, half of the respondents ous assessment of the outcomes. stated that they would not recommend surgery (22.5%, never; 22.1%, rarely) and 20% would recommend sur- 8. Subclinical varicocele gery only occasionally (in 10%–25% cases). Only one- fourth of clinicians would routinely advise surgery in 1) Survey results this situation (usually, 16.4%; always, 19%). The survey reveals a contradiction in the clinicians’ approach to subclinical varicoceles. Earlier (section 2) Guidelines 2.1.1), most respondents have stated that they relied on The AUA/ASRM (statement 26) and EAU (10.4.3.3.2) physical examination to diagnose a varicocele. How- guidelines are unequivocal in recommending against ever, when asked how often they did US to look for a the treatment of a subclinical varicocele. varicocele in a man with OAT, even when there was no Table 7. Varicocele repair for subclinical varicocele Q 50: “When do you repair a bilateral subclinical varicocele?” (you can choose multiple options) Answer No. of responses Percentage of respondents Never 230 44.7 If OAT has not improved with medical therapy 180 35.0 In all infertile men with a subclinical varicocele 106 20.6 Chronic orchalgia 80 15.6 If semen parameters are normal but SDF is elevated 73 14.2 Total number of respondents 514 OAT: oligoasthenoteratozoospermia, SDF: sperm DNA fragmentation. 188 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele 3) Discussion after surgery for grade-I varicoceles was small in mag- There appears to be considerable confusion and di- nitude, and clinically significant improvement was versity of opinion and practice when it comes to sub- more likely when the varicocele was large (grade II-III clinical and grade-I clinical varicoceles. or III) [48]. Thus, half of the clinicians do not believe that cor- recting a grade-I varicocele is of benefit and usually 4) Expert opinion do not recommend its repair. However, paradoxically, Based on current evidence, VR for subclinical vari- when faced with the frustration of having nothing to coceles is not recommended, and VR for grade I vari- offer a man with idiopathic OAT, the majority of clini- coceles may be considered after discussing the lower cians succumb to “clutching at straws” and ask for an likelihood of significant benefit. US even though there is no suspicion of varicocele on However, the practice patterns revealed by this sur- examination, and would offer VR if a varicocele is de- vey suggest a need for a reassessment of the evidence tected on US. on the utility, or otherwise, and of correcting subclini- Though there are studies claiming benefit from re- cal and grade-I clinical varicoceles (since the boundary pair of subclinical varicoceles [93,94] the consensus, as between the two is often blurred) so that clinicians reflected in the AUA and EAU guidelines, is that sub- are empowered to take an informed and firm stand on clinical varicoceles should not be repaired, and there- whether or not to treat these cases. fore US should not be performed to look for a varico- cele when there is no clinical suspicion of a varicocele. 9. Varicocele and non-obstructive Correlating benefit from surgery with grade of vari- azoospermia cocele, a recent meta-analysis of 20 studies involving 2001 patients, showed that while there was a statisti- 1) Survey results cally significant improvement in semen parameters Half of the respondents do not favour VR in men after VR for all grades of varicocele, the improvement with NOA (never, 15.5%; in <10% of cases, 34.9%), and 16.3% recommend it only in 10%–25% of their azoosper- Q52. How often do you perform varicocelectomy in a man mic men. However, one-third of respondents believe that VR has a useful role in men with NOA with 7.5% with a clinical varicocele and non-obstructivie azoospermia? Never recommending VR in 25%–50% of their patients, and <10% of cases 79 (15.5%) 10 25% of cases 25.9% performing VR in >50% of their azoospermic 132 (25.9%) 20 50% of cases men (Fig. 11) . >50% of cases However, there is some discrepancy in responses to 38 (7.5%) 178 (34.9%) a related question in which 58.6% of respondents said they would offer VR prior to microdissection testicular 83 (16.3%) sperm extraction (microTESE) (Fig. 12). This is prob- ably a reflection of the confusion that surrounds the Fig. 11. Frequency of varicocele repair in a man with NOA. NOA: non- role of VR in NOA. obstructive azoospermia. The respondents were equally divided on the role of Q51. What is your approach in patients with clinical varicocele and non-obstructive azoospermia? 35 (6.9%) Varicocelectomy, then wait for 3 6 months with possible medical treatment; if no sperm, then microTESE/ICSI Varicocelectomy, then wait for 6 12 months with possible 68 (13.3%) medical treatment; if no sperm, then microTESE/ICSI 153 (30.0%) I usually do not advise varicocelectomy for an azoospermic man Varicocelectomy, combined with TESE/microTESE and 108 (21.2%) sperm freezing Fig. 12. Management of patients with Proceed directly for microTESE/ICSI and, if negative, then clinical varicocele and NOA. NOA: non- 146 (28.6%) may consider varicocelectomy obstructive azoospermia, TESE: testicular sperm extraction, ICSI: intracytoplasmic sperm injection. www.wjmh.org 189 https://doi.org/10.5534/wjmh.220048 Table 8. Testicular biopsy during varicocele repair for a man with non-obstructive azoospermia Q 54: “Do you perform testicular biopsy at the time of varicocele repair for a man with non-obstructive azoospermia?” (you can choose multiple options) Answer No. of responses Percentage of respondents Never 152 29.8 Rarely 70 13.7 In select patients 131 25.7 In most cases 108 21.2 For cryopreservation if sperm are found 104 20.4 For prognosis 46 9.0 To rule out ITGCN 32 6.3 Total number of respondents 510 ITGCN: intratubular germ cell neoplasia. a diagnostic testicular biopsy before VR in men with survey reveals a reluctance on part of the majority of NOA to determine whether VR would be of benefit. respondents to consider VR in men with NOA. There For example, 16.9% recommend a prior biopsy in most could be several reasons for this. Firstly, in almost all of their cases, and 28.4% recommended it in selected cases the sperm count achieved is very low, and ICSI cases. However, the other physicians recommended it is still needed [98], and sometimes the appearance only rarely (19.6%) or never (35.1%). of sperm is only transitory [99,100]. Further, a major More than half the respondents perform a testicular criticism of these studies is that none of them are con- biopsy at the time of VR in most, or selected patients, trolled and the appearance of sperm in these men may with the goal of cryopreserving sperm, establishing be due to spontaneous variation and not be due to the prognosis, and ruling out ITGCN (intratubular germ VR (AUA/ASRM guideline statement 27). A recent cell neoplasia) (Table 8). study showed that 23.9% of men diagnosed as azoosper- mia were found to have rare sperm in the ejaculate 2) Guidelines when tested with additional centrifugation and stain- AUA/ASRM guidelines (statement 27) states, “the ing with nuclear fast picroindigocarmine [101]. couple should be informed of the absence of definitive Men with NOA are a very heterogeneous group with evidence supporting VR prior to ART”. varying testes size, hormone levels, grades of varico- The EAU (10.4.3.3.3) guidelines state that VR in men cele, and presence of other etiological factors; since few with NOA may result in the appearance of sperm in the studies have addressed these variables prospectively ejaculate (20.8% to 55%) and is associated with improved the selection of NOA patients for VR remains a matter surgical sperm retrieval rates (OR, 2.65; 95% CI, 1.69– of personal belief and choice. Also, an increasing num- 4.14). However, it cautions that the evidence is based on ber of genetic mutations are being identified as causes observational studies and advises that “the risks and of maturation arrest [102] and VR would be unproduc- benefits of VR must be discussed fully with the patient tive in these cases. with NOA and a clinically significant varicocele”. Some support for correcting a varicocele in this group comes from studies that have shown higher sperm re- 3) Discussion trieval during microdissection TESE if the varicocele The controversy over the role of VR in men with has been corrected earlier [103,104] and a meta-analysis NOA is reflected in the wide divergence in practices showed a strong trend towards improved live birth reported by the survey respondents. rates following VR (OR, 2.208; p=0.052) [44]. Despite several meta-analyses [95-97] showing that Studies have shown that testicular histopathology a percentage of men with NOA ranging from 34% to has a predictive value in NOA with men who have late 43.9% will have appearance of a few sperms in the maturation arrest or hypospermatogenesis being the ejaculate after correction of a clinical varicocele, the most likely to have sperm in the ejaculate after VR [99], 190 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele However, this survey shows that clinicians are divided Since the total number of invitations to participate in in their opinion on doing a biopsy either prior to or the survey is not known, we are unable to calculate during VR in these cases. the denominator to the response rate. However, 574 re- sponses received from 59 countries provide a valid and 4) Expert opinion comprehensive perspective of global practices. Though There is limited and controversial evidence sup- the questionnaire used is not a validated one, it was porting VR in men with NOA. Hence, the decision to developed from 382 questions submitted by 60 uro-an- recommend or not recommend VR for NOA is left to drologists from 23 countries and thus is representative the discretion of the clinician. When it is being offered of global clinical concerns. (in men with large varicoceles, non-atrophied testes, Despite these limitations, the authors feel that the no genetic or known cause for testicular failure) there survey findings address many of the important issues should be a detailed discussion of the prognosis. If about the diagnosis, treatment, and expected outcomes sperm appear in the ejaculate after VR, sperm cryo- of infertile men with varicoceles. It also raises impor- preservation should be considered since relapse of azo- tant questions for future clinical trials to improve and ospermia has been reported [99]. standardize guidelines for the management of these At centers performing needle testis biopsy, one ap- patients. proach could be to take a couple of percutaneous biop- sies before considering VR: one biopsy can be sent for CONCLUSIONS histopathology and another to the IVF laboratory. If the histology is favorable (late arrest or hypospermato- The questionnaire used for this survey has been cre- genesis), then VR can be recommended since chances ated from questions raised by a large, international of benefit are higher; if sperm are found in the IVF group of clinicians, and thus reflects the real-life, prac- laboratory then these can be cryopreserved and the tical concerns of physicians dealing with male infertil- couple can proceed for ICSI. ity and varicocele. If VR is opted for without doing prior testicular bi- The survey responses represent the opinions and opsy, the biopsy may be done as an optional procedure practices of 574 clinicians from 59 countries and reveal at the time of VR to establish prognosis, rule out pre- a marked diversity in all aspects of varicocele manage- malignant state, and to check for sperm. If sperm are ment. The survey highlights several areas where there found they can be cryopreserved and the couple may is inconclusive data and the need for more research, proceed for ICSI without delay. and also identifies numerous lacunae in the manage- There is a need for controlled studies that assess out- ment guidelines issued by professional bodies (EAU, comes after VR in well-defined subgroups of men with AUA, ASRM), which need to be addressed in future NOA. guidelines. Besides, this survey serves the useful purpose of al- LIMITATIONS OF THIS STUDY lowing clinicians to compare their practices with those of their peers, and against recommended guidelines While this is the first global survey of this nature, and the latest research findings, and thus rethink it has several limitations. The survey was conducted some of their own practices and clinical protocols. This in English and this may have restricted participation survey invites clinicians to ponder over what they by clinicians from predominately non-English speak- know, what they do, where they go wrong, and what ing regions and countries. The survey was distributed they should do. through a global group of experts experienced in vari- Finally, professional societies can survey their mem- cocele management rather than to all male infertility bership using such questionnaires to assess the extent specialists, which could have a created a bias in selec- to which their guidelines are being followed and to tion or exclusion of those answering the survey. There identify areas of dispute or confusion where further is a preponderance of responses from some countries clarifications are needed. (Turkey, Egypt), while there is marked under-repre- sentation from some large countries (Russia, China). www.wjmh.org 191 https://doi.org/10.5534/wjmh.220048 Conflict of Interest Seong Ngoo, Keisuke Okada, Keshab Karna, Koichi Nagao, Koji Chiba, Konstantinos Makarounis, Landon Trost, Lawrence The authors have nothing to disclose. Jenkins, Lucia Rocco, Lukman Hakim, Mahsa Darbandi, Mara Simopoulou, Marah Hehemann, Marcelo Rodriguez Peña, Marco Funding Alves, Marco Falcone, Marion Bendayan, Marjan Sabbaghian, Marlon Martinez, Marziyeh Tavalaee, Massimiliano Timpano, This research was supported by the American Center for Mazdak Razi, Mesut Altan, Mesut Berkan Duran, Mikkel Fode, Reproductive Medicine, Cleveland Clinic (Project Number: Miroslav Vučinić, Mitsuru Nago, Mohamad Moussa, Mohamed IF100066). Arafa, Mohamed Elkhouly, Mohamed Khalili, Mohamed S. Al- Marhoon, Mohammad Ali Sadighi Gilani, Mohammad Ayodhia Acknowledgements Soebadi, Mohammad Hossein Nasr-Esfahani, Mohan S Kamath, Muhammet Rasit Ugur, Murat Gül, Mustafa Emre Bakırcıoğlu, Authors are thankful to the artist Sarah Rolitsky, from the Nam Cheol Park, Natalio Cruz, Nazim Gherabi, Neel Parekh, Cleveland Clinic’s Center for Medical Art & Photography for Nguyen Ho Vinh Phuoc, Nicholas Tadros, Nicolas Garrido, her help with the illustrations. We would like to acknowledge Nikolaos Sofikitis, Niloofar Sodeifi, Noora Al Khalidi, Oğuzhan all the members of Global Andrology Forum: Abderrazak Bou- Kahraman, Ohad Shoshany, Osvaldo Rajmil, Paksi Satyagraha, zouita, Abdullah Alarbid, Ahmed El-Sakka, Ahmed M. Harraz, Panagiotos Drakopoulos, Paraskevi Vogiatzi, Parisa Dolati, Ahmed Shokeir, Ahmet Asci, Ahmet Gudeloglu, Akira Tsu- Partha Das, Parviz Kavoussi, Peter Ka-Fung Chiu, Petroula A. jimura, Ala'a Farkouh, Aldo E. Calogero, Amarnath Rambhatla, Tsioulou, Ponco Birowo, Premal Patel, Priyank Kothari, Puneet Amin Bouker, Amr El Meliegy, Ana Puigvert, Andrea Crafa, Sindhwani, Qaisar Javed, Quang Nguyen, Rafael F. Ambar, Aram Adamyan, Arif Kalkanli, Armand Zini, Armen E. Avoy- Raghavender Kosgi, Rajender Singh, Ralf Henkel, Ramadan an, Ashok Agarwal, Ates Kadioglu, Ayad Palani, Aykut Baser, Saleh, Ramy Abou Ghayda, Raneen Sawaid Kaiyal, Raphael Azin Aghamajidi, Balantine Eze, Bambang Sasongko Noegroho, Henrique Ferreira Santos, Ricky Adriansjah, Rima Dada, Rosita Basuki Purnomo, Berk Hazir, Bircan Kolbaşı Erkan, Birute Angela Condorelli, Rossella Cannarella, Rupin Shah, Sakti Brod- Zilaitiene, Carlo Giuloni, Chak-Lam Cho, Christopher C.K. Ho, jonegoro, Saleem Ali Banihani, Samantha Schon, Sami AlSaid, Ciro Salzano, Colin Teo, Damayanthi Durairajanayagam, Dan- Sandro La Vignera, Sara Darbandi, Sava Micic, Selcuk Sari- iel Suslik Zylbersztejn, Davor Jezek, Deniz Kulaksiz, Dimitrios kaya, Sezgin Gunes, Shannon Hee Kyung Kim, Sheena E Lewis, Kafetzis, Dong Sup Lee, Doron Stember, Dung Mai Ba Tien, Sheryl Homa, Shingai Mutambirwa, Shinichiro Fukuhara, Edmund Ko, Edoardo Pescatori, Edson Borges, Ege Can Serefo- Shinnosuke Kuroda, Shubhadeep Roychoudhury, Sijo Parekat- glu, Emine Saïs-Hamza, Emrullah Sogutdelen, Eric Chung, Eric til, Siu King Mak, Sofia Ines Leonardi Diaz, SreelathaGopal- Huyghe, Erman Ceyhan, Ettore Caroppo, Evangelini Evgeni, akrishnan, Stephen Krawetz, Suks Minhas, Sun Tae Ahn, Sunil Fabrizio Castiglioni, Fahmi Bahar, Faisal Alhajeri, Fatih Go- Jindal, Taha Abo-Almagd Abdel-Meguid, Tan V Le, Taymour kalp, Federica Finocchi, Florence Boitrelle, Fotios Dimitriadis, Mostafa, Teng Aik Ong, Teppei Takeshima, Thorsten Diemer, Francesco Lombardo, Franco Gadda, Fulvio Colombo, Gede Tiago Cesar Mierzwa, Tomer Avidor-Reiss, Toshiyasu Amano, Wirya Kusuma Duarsa, George Tsangaris, Germar-Michael Trenton Barrett, Tsung Yen Lin, Tuncay Toprak, Umut Arslan, Pinggera, Gian Maria Busetto, Giancarlo Balercia, Gianmaria Vijay Kumar, Vilvapathy Senguttuvan Karthikeyan, Vineet Salvio, Gianmartin Cito, Gideon Blecher, Giorgio Franco, Giorgio Malhotra, Wael Ibrahim, Walid Kerkeni, Widi Atmoko, Wongi Ivan Russo, Giovanni Liguori, Giovanni M. Colpi, Gokhan Calik, Woo, Yasushi Yumura, Yiming Yuan, Yoshiharu Morimoto, Gökhan Çeker, Gustavo Marquesine Paul, Haitham Elbardisi, Yuki Kato, Yukihiro Umemoto, Yu-Sheng Cheng. Hakan Keskin, Hamed Akhavizadegan, Haocheng Lin, Hassan The authors are thankful to the following societies and jour- N Sallam, Herik Acosta, Hisanori Taniguchi, Hussein Kandil, nals for promoting this online survey through the efforts of Hyun Jun Park, Imad Ziouziou, Ioannis Sokolakis, Israel Mal- their members, as listed below: donado Rosas, Jackson Kirkman-Brown, Jae Il Shin, Jean de la 1) Arab Association of Urology (Hussein Kandil, MD, UAE) Rosette, Jens Sonksen, Jie Dong, Jim Hotaling, Jo Ben Chua, 2) Asia Pacific Society of Sexual Medicine (Hyun Jun Park, Joe Lee, Joel Marmar, Jonathan Ramsay, Jose Moreno- Sepul- MD, South Korea) veda, Ju Tae Seo, Juan Alvarez, Juan Manuel Corral Molina, 3) Association Francaise d’Urologie (Eric Huyghe, MD, Ka Lun Lo, Kaan Aydos, Kadir Bocu, Kareim Khalafalla, France) Kashif Siddiqi, Kasonde Bowa, Kavindra Kumar Kesari, Kay- 4) Brazilian  Association of Assisted Reproduction (Edson 192 www.wjmh.org Rupin Shah, et al: Global Survey on Varicocele Borges Jr, MD) Kavoussi, TH: Taha Abo-Almagd Abdel-Meguid Hamoda, EK: 5) B  razilian Society of Urology (Rafael F. Ambar, MD, Brazil) Edmund Ko, GR: Giorgio Ivan Russo, HK: Hussein Kandil, MA: 6) E  gyptian Society of Andrology (Mohamed Arafa, MD, Qa- Mohamed Arafa, TT: Tuncay Toprak, MEB: Mustafa Emre tar) Bakırcıoğlu, OR: Osvaldo Rajmil, GC: Gokhan Calik, AH: Ahmed 7) E  uropean Association of Urology (Fotios Dimitriadis, MD, M. Harraz. Greece; Nikolaos Sofikitis, MD, PhD, Greece) 8) I ndonesian Urological Association (Ponco Birowo, MD, Supplementary Materials PhD; Gede Wirya Kusuma Duarsa, MD, PhD; Widi At- moko, MD) Supplementary materials can be found via https://doi. 9) Indonesian Society of Andrological Urology (Ricky Adri- org/10.5534/wjmh.220048. ansjah, MD) 10) Iranian Urological Association (Mohammad Ali Sadighi REFERENCES Gilani, MD, Iran) 11) Middle  East Society for Sexual Medicine (Amr El Meliegy, 1. Su JS, Farber NJ, Vij SC. Pathophysiology and treatment op- MD, FECSM, Egypt) tions of varicocele: an overview. 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