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

October 17, 2023

Impact of Antioxidant Therapy on Natural Pregnancy Outcomes and Semen Parameters in Infertile Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Authors: Agarwal A, Cannarella R, Saleh R, Harraz AM, Kandil H, Salvio G, Boitrelle F, Kuroda S,
Farkouh Ala’a, Rambhatla A, Zini A, Colpi G, Gül M, Kavoussi P, Hamoda TA, Ko E, Calik G, Toprak
T, Pinggera GM, Park HJ, Ghayda RA, Minhas S, Busetto GM, Bakırcıoğlu ME, Kadioglu A, Chung
E, Russo GI, Calogero AE, Ambar RF, Jayasena CN, Shah R.
World J Men’s Health. 2023 Jan;41(1):14-48. English. Original Article. Open Access
Published online September 7, 2022. https://doi.org/10.5534/wjmh.220067

FULL TEXT LINK
Preamble:
Idiopathic originated male factor infertility plays a significant role in one third of the couples. This systematic review and meta-analysis, conducted by Agarwal et al, consisted of 45 randomized controlled trials with the largest number in the literature, including 4332 infertile men treated with antioxidants (AOX) or no treatment/placebo. The authors found that AOX therapy significantly increased spontaneous pregnancy by 1.97 times higher, and sperm parameters including sperm concentration, motility and normal sperm morphology also increased significantly after AOX therapy, compared to placebo or no treatment. However, this meta-analysis found no significant effect on live birth rate or miscarriage rates post-AOX therapy.

CAPSULE:

This review would be important for clinicians, and for the infertile couples to know that it is sometimes not possible to conceive naturally, and spontaneous pregnancy and sperm parameters might be increased with some kind of medical therapy such as AOX. Therefore, AOX might a) obviate the need for assisted reproductive technology (ART), b) downsize the level of ART needed to bypass idiopathic male factor infertility, and c) increase spontaneous pregnancy rates in couples who want to conceive naturally. 

Previous systematic review and meta-analyses clearly demonstrated that high levels of semen reactive oxygen species are associated with sperm dysfunction, sperm DNA damage and reduced male reproductive potential. The latest Cochrane database review showed statistically significant increases in the spontaneous pregnancy (2.97 times) and live birth rates (1.79 times) among sub-fertile men using AOS treatment. Therefore, this current article reinforces the Cochrane review’s findings by reporting significant increases in pregnancy rates and sperm parameters with the AOX treatment. Furthermore, in addition to previous SRMAs, for the first time, this study showed AOX treatment significantly increased seminal total antioxidant capacity (TAC) and significantly decreased seminal MDA levels, compared to controls.

Of the 45 RCTs, 6 reported outcomes of AOX therapy or no treatment after varicocele repair. Another aspect of this study, which is very important, is to demonstrate significant effect of AOX therapy on spontaneous pregnancy and sperm parameters, regardless of presence of varicocele and/or varicocele repair.

Recommendations:
Based on the findings of this article, clinicians should suggest AOX therapy to improve sperm parameters and spontaneous pregnancy rates. In the future, we need more qualified prospective, randomized, placebo-controlled trials to clarify duration, contents, and dosage of the AOX regimens for defining which AOX would be the best to achieve the highest improvement in sperm parameters, pregnancy, and live birth rates in men with idiopathic infertility.

Contributors Profile:


Selahittin Çayan, MD, FECSM
Professor of Urology
University of Mersin School of Medicine
Department of Urology,
Director of Andrology Unit and Mal Reproductive Laboratory
33343-Mersin, Turkey
selcayan@mersin.edu.tr

An Expert Opinion on the 2023 Antioxidants meta-analysis by Agarwal et al:
Adriano Fregonesi, MD, PhD, Campinas, Brazil


Agarwal et al.'s comprehensive review and meta-analysis provide important insights into the possible benefits of antioxidant therapy for male infertility. My own experience is consistent with the study's findings, indicating improvements in sperm parameters and pregnancy outcomes. The use of rigorous methods and the inclusion of 60 randomized controlled trials lend credibility to the research.


Certain limitations, however, must be acknowledged. The moderate to low evidence quality raises questions regarding the results' reliability. The absence of data on miscarriage and stillbirth, as well as a thorough investigation of potential side effects, generates gaps in our understanding of the treatment's safety and effectiveness. The study's failure to address the variation in antioxidant categories, doses, and durations employed among trials affects the interpretation of results. In addition, the study's insufficient investigation of the root causes of male infertility is a missed chance to fully grasp the issue's multifaceted nature.


Nonetheless, despite these limitations, the study offers valuable insights and paves the way for further research to determine the precise impact, optimal agents, and dosages required for effective treatment in male infertility.


Short biography of Prof. Fregonesi:
Adriano Fregonesi, MD, PhD obtained his medical degree from the University of Campinas, São Paulo, Brazil. He completed residency in urology at the same institution. Additionally, he undertook fellowships at UCLA in 1996 and UCSF in 1999. He currently serves as the Head of the Urology Department at the University of Campinas and holds the position of Associate Professor of Urology at the Faculty of Medicine in Jundiaí, both in Brazil. Dr. Fregonesi is an active member of several professional associations, including the Brazilian Society of Urology, American Urological Association, European Association of Urology, and International Society of Sexual Medicine.

Adriano Fregonesi, MD, PhD
Head Department of Urology
Faculty of Medical Sciences,
Universidade Estadual de Campinas, UNICAMP
Sao Paulo, Brazil
GAF Member
adriano.fregonesi@gmail.com

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