Impact of Antioxidant Therapy on Natural Pregnancy Outcomes and Semen Parameters in Infertile Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Ashok Agarwal; Rossella Cannarella; Ramadan Saleh; Ahmed M Harraz; Hussein Kandil; Gianmaria Salvio; Florence Boitrelle; Shinnosuke Kuroda; Ala'a Farkouh; Amarnath Rambhatla; Armand Zini; Giovanni Colpi; Murat Gül; Parviz Kavoussi; Taha Abo-Almagd Abdel-Meguid Hamoda; Edmund Ko; Gokhan Calik; Tuncay Toprak; Germar-Michael Pinggera; Hyun Jun Park; Ramy Abou Ghayda; Suks Minhas; Gian Maria Busetto; Mustafa Emre Bakırcıoğlu; Ates Kadioglu; Eric Chung; Giorgio Ivan Russo; Aldo E Calogero; Rafael F Ambar; Channa N Jayasena; Rupin Shah

doi:10.5534/wjmh.220067

Impact of Antioxidant Therapy on Natural Pregnancy Outcomes and Semen Parameters in Infertile Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

World J Mens Health. 2023 Jan;41(1):14-48. doi: 10.5534/wjmh.220067. Epub 2022 Sep 7.

Authors

Ashok Agarwal¹, Rossella Cannarella^{2

3}, Ramadan Saleh^{4

5}, Ahmed M Harraz^{6

7

8}, Hussein Kandil⁹, Gianmaria Salvio¹⁰, Florence Boitrelle^{11

12}, Shinnosuke Kuroda³, Ala'a Farkouh¹³, Amarnath Rambhatla¹⁴, Armand Zini¹⁵, Giovanni Colpi¹⁶, Murat Gül¹⁷, Parviz Kavoussi¹⁸, Taha Abo-Almagd Abdel-Meguid Hamoda^{19

20}, Edmund Ko²¹, Gokhan Calik²², Tuncay Toprak²³, Germar-Michael Pinggera²⁴, Hyun Jun Park^{25

26}, Ramy Abou Ghayda²⁷, Suks Minhas²⁸, Gian Maria Busetto²⁹, Mustafa Emre Bakırcıoğlu³⁰, Ates Kadioglu³¹, Eric Chung³², Giorgio Ivan Russo³³, Aldo E Calogero², Rafael F Ambar^{34

35}, Channa N Jayasena^{36

37}, Rupin Shah³⁸

Affiliations

¹ American Center for Reproductive Medicine, Global Andrology Forum, Moreland Hills, OH, USA. [email protected].
² Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
³ Glickman Urological & Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
⁴ Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag, Egypt.
⁵ Ajyal IVF Center, Ajyal Hospital, Sohag, Egypt.
⁶ Department of Urology, Mansoura University Urology and Nephrology Center, Mansoura, Egypt.
⁷ Department of Surgery, Urology Unit, Farwaniya Hospital, Farwaniya, Kuwait.
⁸ Department of Urology, Sabah Al Ahmad Urology Center, Kuwait City, Kuwait.
⁹ Fakih IVF Fertility Center, Abu Dhabi, UAE.
¹⁰ Department of Endocrinology, Polytechnic University of Marche, Ancona, Italy.
¹¹ Reproductive Biology, Fertility Preservation, Andrology, CECOS, Poissy Hospital, Poissy, France.
¹² Department of Biology, Reproduction, Epigenetics, Environment and Development, Pari. Saclay University, UVSQ, INRAE, BREED, Jouy-en-Josas, France.
¹³ American Center for Reproductive Medicine, Global Andrology Forum, Moreland Hills, OH, USA.
¹⁴ Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA.
¹⁵ Division of Urology, Department of Surgery, McGill University, Montreal, QC, Canada.
¹⁶ Next Fertility Procrea, Lugano, Switzerland.
¹⁷ Department of Urology, Selcuk University School of Medicine, Konya, Turkey.
¹⁸ Austin Fertility & Reproductive Medicine/Westlake IVF, Austin, TX, USA.
¹⁹ Department of Urology, King Abdulaziz University, Jeddah, Saudi Arabia.
²⁰ Department of Urology, Faculty of Medicine, Minia University, Minia, Egypt.
²¹ Department of Urology, Loma Linda University Health, Loma Linda, CA, USA.
²² Department of Urology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey.
²³ Department of Urology, Fatih Sultan Mehmet Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
²⁴ Department of Urology, Medical University Innsbruck, Innsbruck, Austria.
²⁵ Department of Urology, Pusan National University School of Medicine, Busan, Korea.
²⁶ Medical Research Institute of Pusan National University Hospital, Busan, Korea.
²⁷ Urology Institute, University Hospitals, Case Western Reserve University, Cleveland, OH, USA.
²⁸ Division of Surgery, Department of Surgery and Cancer, Imperial College, London, UK.
²⁹ Department of Urology and Organ Transplantation, University of Foggia, Ospedali Riuniti of Foggia, Foggia, Italy.
³⁰ SENSART Clinic, Istanbul, Turkey.
³¹ Section of Andrology, Department of Urology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
³² Department of Urology, Princess Alexandra Hospital, University of Queensland, Brisbane, Australia.
³³ Urology Section, University of Catania, Catania, Italy.
³⁴ Department of Urology, Centro Universitario em Saude do ABC, Santo André, Brazil.
³⁵ Andrology Group at Ideia Fertil Institute of Human Reproduction, Santo André, Brazil.
³⁶ Department of Reproductive Endocrinology and Andrology, Imperial College London, London, UK.
³⁷ Department of Andrology, Hammersmith & St. Mary's Hospitals, London, UK.
³⁸ Division of Andrology, Department of Urology, Lilavati Hospital and Research Centre, Mumbai, India.

Abstract

Purpose: Seminal oxidative stress (OS) is a recognized factor potentially associated with male infertility, but the efficacy of antioxidant (AOX) therapy is controversial and there is no consensus on its utility. Primary outcomes of this study were to investigate the effect of AOX on spontaneous clinical pregnancy, live birth and miscarriage rates in male infertile patients. Secondary outcomes were conventional semen parameters, sperm DNA fragmentation (SDF) and seminal OS.

Materials and methods: Literature search was performed using Scopus, PubMed, Ovid, Embase, and Cochrane databases. Only randomized controlled trials (RCTs) were included and the meta-analysis was conducted according to PRISMA guidelines.

Results: We assessed for eligibility 1,307 abstracts, and 45 RCTs were finally included, for a total of 4,332 infertile patients. We found a significantly higher pregnancy rate in patients treated with AOX compared to placebo-treated or untreated controls, without significant inter-study heterogeneity. No effects on live-birth or miscarriage rates were observed in four studies. A significantly higher sperm concentration, sperm progressive motility, sperm total motility, and normal sperm morphology was found in patients compared to controls. We found no effect on SDF in analysis of three eligible studies. Seminal levels of total antioxidant capacity were significantly higher, while seminal malondialdehyde acid was significantly lower in patients than controls. These results did not change after exclusion of studies performed following varicocele repair.

Conclusions: The present analysis upgrades the level of evidence favoring a recommendation for using AOX in male infertility to improve the spontaneous pregnancy rate and the conventional sperm parameters. The failure to demonstrate an increase in live-birth rate, despite an increase in pregnancy rates, is due to the very few RCTs specifically assessing the impact of AOX on live-birth rate. Therefore, further RCTs assessing the impact of AOX on live-birth rate and miscarriage rate, and SDF will be helpful.

Keywords: Antioxidants; Male infertility; Meta-analysis; Pregnancy; Semen parameters; Sperm DNA fragmentation.