Effects of Varicocele Repair on Sperm DNA Fragmentation and Seminal Malondialdehyde Levels in Infertile Men with Clinical Varicocele: A Systematic Review and Meta-Analysis

Rossella Cannarella; Rupin Shah; Ramadan Saleh; Florence Boitrelle; Taha Abo-Almagd Abdel-Meguid Hamoda; Rajender Singh; Gianmaria Salvio; Tuncay Toprak; Marco Falcone; Murat Gul; Fotios Dimitriadis; Amarnath Rambhatla; Giorgio I Russo; Edmund Ko; Armand Zini; Parviz Kavoussi; Nguyen Ho Vinh Phuoc; Hussein Kandil; Ramy Abou Ghayda; Ponco Birowo; Nazim Gherabi; Erman Ceyhan; Jie Dong; Vineet Malhotra; Damayanthi Durairajanayagam; Bircan Kolbasi; Fahmi Bahar; Gokhan Calik; Selahittin Çayan; Germar-Michael Pinggera; Aldo E Calogero; Osvaldo Rajmil; Taymour Mostafa; Widi Atmoko; Ahmed M Harraz; Tan V Le; Jean de la Rosette; Lukman Hakim; Edoardo Pescatori; Oleg Sergeyev; Ayman Rashed; Pallavi Saini; Ashok Agarwal

doi:10.5534/wjmh.230235

Effects of Varicocele Repair on Sperm DNA Fragmentation and Seminal Malondialdehyde Levels in Infertile Men with Clinical Varicocele: A Systematic Review and Meta-Analysis

World J Mens Health. 2024 Apr;42(2):321-337. doi: 10.5534/wjmh.230235. Epub 2024 Jan 2.

Authors

Rossella Cannarella^{1

2

3}, Rupin Shah^{1

3

4}, Ramadan Saleh^{3

5}, Florence Boitrelle^{3

6

7}, Taha Abo-Almagd Abdel-Meguid Hamoda^{3

8

9}, Rajender Singh^{3

10}, Gianmaria Salvio^{3

11}, Tuncay Toprak^{3

12}, Marco Falcone^{3

13}, Murat Gul^{3

14}, Fotios Dimitriadis^{3

15}, Amarnath Rambhatla^{3

16}, Giorgio I Russo^{3

17}, Edmund Ko^{3

18}, Armand Zini^{3

19}, Parviz Kavoussi^{3

20}, Nguyen Ho Vinh Phuoc^{3

21

22}, Hussein Kandil^{3

23}, Ramy Abou Ghayda^{3

24}, Ponco Birowo^{3

25}, Nazim Gherabi^{3

26}, Erman Ceyhan^{3

27}, Jie Dong^{3

28}, Vineet Malhotra^{3

29}, Damayanthi Durairajanayagam^{3

30}, Bircan Kolbasi^{3

31}, Fahmi Bahar^{3

32}, Gokhan Calik^{3

33}, Selahittin Çayan^{3

34}, Germar-Michael Pinggera^{3

35}, Aldo E Calogero^{2

3}, Osvaldo Rajmil^{3

36

37}, Taymour Mostafa^{3

38}, Widi Atmoko^{3

25}, Ahmed M Harraz^{3

39

40

41}, Tan V Le^{3

21

22}, Jean de la Rosette^{3

42}, Lukman Hakim^{3

43}, Edoardo Pescatori^{3

44}, Oleg Sergeyev^{3

45

46}, Ayman Rashed^{3

47}, Pallavi Saini^{3

10}, Ashok Agarwal^{3

48}

Affiliations

¹ Department of Urology, Glickman Urological & Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
² Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
³ Global Andrology Forum, Moreland Hills, OH, USA.
⁴ Department of Urology, Lilavati Hospital and Research Centre, Mumbai, India.
⁵ Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag, Egypt.
⁶ Reproductive Biology, Fertility Preservation, Andrology, CECOS, Poissy Hospital, Poissy, France.
⁷ Department of Biology, Reproduction, Epigenetics, Environment and Development, Paris Saclay University, UVSQ, INRAE, BREED, Jouy-en-Josas, France.
⁸ Department of Urology, King Abdulaziz University, Jeddah, Saudi Arabia.
⁹ Department of Urology, Faculty of Medicine, Minia University, Minia, Egypt.
¹⁰ Division of Endocrinology, Central Drug Research Institute, Lucknow, India.
¹¹ Department of Endocrinology, Polytechnic University of Marche, Ancona, Italy.
¹² Department of Urology, Fatih Sultan Mehmet Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
¹³ Department of Urology, Molinette Hospital, A.O.U. Città della Salute e della Scienza, University of Turin, Torino, Italy.
¹⁴ Department of Urology, Selçuk University School of Medicine, Konya, Turkey.
¹⁵ Department of Urology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
¹⁶ Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA.
¹⁷ Urology Section, University of Catania, Catania, Italy.
¹⁸ Department of Urology, Loma Linda University Health, Loma Linda, CA, USA.
¹⁹ Department of Surgery, McGill University, Montreal, QC, Canada.
²⁰ Department of Reproductive Urology, Austin Fertility & Reproductive Medicine/Westlake IVF, Austin, TX, USA.
²¹ Department of Andrology, Binh Dan Hospital, Ho Chi Minh City, Vietnam.
²² Department of Andrology and Nephro-Urology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
²³ Fakih IVF Fertility Center, Abu Dhabi, UAE.
²⁴ Urology Institute, University Hospitals, Case Western Reserve University, Cleveland, OH, USA.
²⁵ Department of Urology, Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
²⁶ Department of Medicine, Algiers University, Algiers, Algeria.
²⁷ Department of Urology, Faculty of Medicine, Baskent University, Ankara, Turkey.
²⁸ Reproductive Medical Center, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
²⁹ Department of Urology, SCM Clinic and Hospital, New Delhi, India.
³⁰ Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia.
³¹ Department of Histology and Embryology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
³² Andrology Section, Siloam Sriwijaya Hospital, Palembang, Indonesia.
³³ Department of Urology, Istanbul Medipol University, Istanbul, Turkey.
³⁴ Department of Urology, University of Mersin School of Medicine, Mersin, Turkey.
³⁵ Department of Urology, Medical University Innsbruck, Innsbruck, Austria.
³⁶ Andrology Department, Fundació Puigvert, Barcelona, Spain.
³⁷ Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain.
³⁸ Department of Andrology, Sexology and STIs, Faculty of Medicine, Cairo University, Cairo, Egypt.
³⁹ Department of General Surgery, Urology Unit, Farwaniya Hospital, Farwaniya, Kuwait.
⁴⁰ Department of Urology, Sabah Al Ahmad Urology Center, Kuwait City, Kuwait.
⁴¹ Department of Urology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.
⁴² Department of Urology, Istanbul Medipol Mega University Hospital, Istanbul, Turkey.
⁴³ Department of Urology, Universitas Airlangga Teaching Hospital, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
⁴⁴ Andrology and Reproductive Medicine Unit, Next Fertility GynePro, Bologna, Italy.
⁴⁵ Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
⁴⁶ Laboratory of Genetics of Reproductive Disorders, Research Centre for Medical Genetics, Moscow, Russia.
⁴⁷ Department of Urology, 6th October University, Tanta, Egypt.
⁴⁸ Cleveland Clinic, Cleveland, OH, USA. agarwaa32099@outlook.com.

Abstract

Purpose: Varicoceles can be a source of elevated seminal oxidative stress (OS) and sperm DNA fragmentation (SDF). However, it remains unclear whether varicocele repair (VR) could reduce these parameters. This systematic review and meta-analysis (SRMA) aims to investigate the impact of VR on SDF and seminal malondialdehyde (MDA).

Materials and methods: A literature search was performed in Scopus, PubMed, Ovid, Embase, and Cochrane databases. This SRMA included randomized controlled trials and observational studies reporting the pre- and postoperative levels of SDF and seminal OS in infertile men with clinical varicocele that underwent VR. Subgroup analyses included techniques of VR and SDF testing. The effect size was expressed as standardized mean difference (SMD).

Results: Out of 1,632 abstracts assessed for eligibility, 29 studies with 1,491 infertile men were included. The analysis showed a significant reduction in SDF after VR, compared to preoperative values (SMD -1.125, 95% confidence interval [CI] -1.410, -0.840; p<0.0001) with high inter-study heterogeneity (I²=90.965%). Reduction in SDF was evident with microsurgical technique and non-microsurgical inguinal approaches (SMD -1.014, 95% CI -1.263, -0.765; p<0.0001, and SMD -1.495, 95% CI -2.116, -0.873; p<0.0001), respectively. Reduction in SDF was significant irrespective of testing was done by sperm chromatin dispersion (SMD -2.197, 95% CI -3.187, -1.207; p<0.0001), sperm chromatin structure assay (SMD -0.857, 95% CI -1.156, -0.559; p<0.0001) or TUNEL (SMD -1.599, 95% CI -2.478, -0.719; p<0.0001). A significant decrease in seminal MDA levels was observed following VR (SMD -2.450, 95% CI -3.903 to -0.997, p=0.001) with high inter-study heterogeneity (I²=93.7%).

Conclusions: Using pre- and post-intervention data, this SRMA indicates a significant reduction in SDF and seminal MDA levels in infertile men with clinical varicocele treated with VR. These findings may have important implications for the future management of this selected group of infertile patients.

Keywords: DNA fragmentation; Infertility, male; Malondialdehyde; Varicocele.