Seminal oxidative stress (OS) is currently identified as a potential contributor to male infertility.4 Imbalanced production of seminal reactive oxygen species (ROS) and antioxidants (AOXs), leading to OS, may occur in several circumstances including smoking, alcohol consumption, other lifestyle factors, environmental factors, varicocele, radiation exposure, and many other conditions.5 OS can impact sperm DNA integrity, cause sperm membrane damage, interfere with capacitation and impair the fertilization process.6,7 Recently, Agarwal et al8 have proposed the term “Male Oxidative Stress Infertility” (MOSI) to include infertile men with abnormal semen analysis and high OS indices, who were previously considered as IMI.
The proposal of AOX therapy is based on the rationale that they may neutralize excessive ROS and thus mitigate their potentially detrimental effects, and preserve sperm DNA integrity and mitochondrial transport.9 This is supported by studies on AOX supplements which demonstrated their beneficial effects on semen parameters, sperm quality, and reproductive outcomes.10-14 A meta-analysis on 576 patients has shown that using AOXs after varicocele repair resulted in significant improvements (p<0.0001, each) in sperm concentration, total sperm motility, progressive sperm motility, and sperm morphology, as compared to placebo.12 AOXs were also reported to significantly improve progressive sperm motility, sperm vitality, and sperm DNA fragmentation (SDF) when administered in patients undergoing sperm freezing and thawing.13 However, despite the reported positive effects, the role of AOXs therapy in male infertility is still debated due to the heterogeneity of data. Thus, the European Association of Urology (EAU)15 and the American Urological Association/American Society for Reproductive Medicine (AUA/ASRM),16 among other major scientific societies, do not recommend the routine use of AOX therapy in infertile men. Recently, Agarwal et al,17 in a large systematic review of 97 clinical trials evaluating the efficacy of AOXs therapies in male infertility, have suggested that a review of the guidelines is needed, as the use of AOXs is supported in cases of (1) abnormal semen quality (grade C recommendation), (2) varicocele (grade C recommendation), and (3) idiopathic and unexplained male infertility (grade B recommendation). Therefore, additional studies are still required to solve the debate on AOXs use in male infertility.
We have conducted a systematic review and meta-analysis of only randomized controlled trials (RCTs),18 aiming to update the evidence on the impact of AOX therapies (using single or combination of AOXs) in male infertility as compared to placebo-treated or untreated controls. Spontaneous clinical pregnancy, live birth, and miscarriage rates were identified as primary outcomes, while conventional sperm parameters, SDF, and seminal OS indices were selected as secondary outcomes. In our study, we finally included 45 RCTs with a large population of a total of 4,332 infertile patients.
We observed, in 16 RCTs including 761 patients treated with AOXs compared to 594 placebo-treated or untreated controls, a significantly higher pregnancy rate (OR 1.97 [95% CI: 1.28, 3.04]; p<0.01), without significant inter-study heterogeneity. However, AOX therapies demonstrated no effect on live-birth or miscarriage rates in four studies. This failure to demonstrate an increase in the live-birth rate, despite an increase in pregnancy rates, is probably due to paucity of RCTs specifically assessing the impact of AOX on live-birth rate. On the other hand, significant improvements of sperm concentration, progressive sperm motility, total sperm motility, and normal sperm morphology were exhibited in AOX treated patients as compared to controls. Regarding AOXs and SDF, there were only three eligible studies with a total of 68 AOX-treated patients and 67 placebo-treated or untreated controls, and these showed no effect of AOX treatment on SDF, with significant inter-study heterogeneity. Further, seminal levels of total antioxidant capacity were significantly higher, while seminal malondialdehyde (MDA) was significantly lower in treated patients than in controls. The previous results are not altered following the exclusion of studies that included men who had undergone varicocele repair.
Our findings upgrade the level of evidence (providing low to moderate evidence) endorsing a recommendation for using AOX therapy in male infertility to improve the spontaneous pregnancy rate and conventional semen parameters. To the best of our knowledge, this is the first meta-analysis of seminal OS indices in infertile men following AOXs treatments, providing a very low to low evidence of the potential positive effect of AOXs therapy. Yet, the scarcity of RCTs examining the impact of AOXs on live-birth rate and SDF prevented us from reaching a firm conclusion about these outcomes. Further RCTs assessing the effects of AOX on live-birth rate, miscarriage rate, as well as SDF are still needed, even though in reality conducting such studies is very difficult.
A summary of suggestions on the use of antioxidant therapy is presented in table 1.
| Patient | Target Outcome | Level of Evidence |
|
Spontaneous pregnancy rates |
Moderate |
|
Conventional semen parameters |
Moderate |
|
Seminal OS indices |
Low |
Written by:
- Taha Abo-Almagd Abdel-Meguid Hamoda, Department of Urology, King Abdulaziz University, Jeddah, Saudi Arabia, Department of Urology, Faculty of Medicine, Minia University, Minia, Egypt.
- Rupin Shah, Department of Urology, Lilavati Hospital & Research Centre, Mumbai, India.
- Ashok Agarwal, Global Andrology Forum, Moreland Hills, Ohio, USA
- Agarwal A, Baskaran S, Parekh N, Cho CL, Henkel R, Vij S, et al. Male infertility. Lancet 2021;397:319-33.
- Irvine DS. Epidemiology and aetiology of male infertility. Hum Reprod 1998;13 Suppl 1:33-44.
- Salonia A, Bettocchi C, Boeri L, Capogrosso P, Carvalho J, Cilesiz NC, et al.; EAU Working Group on Male Sexual and reproductive health. European Association of Urology guidelines on sexual and reproductive health-2021 update: male sexual dysfunction. Eur Urol 2021;80:333-57.
- Sharma RK, Agarwal A. Role of reactive oxygen species in male infertility. Urology 1996;48:835-50.
- Takeshima T, Usui K, Mori K, Asai T, Yasuda K, Kuroda S, et al. Oxidative stress and male infertility. Reprod Med Biol 2020;20:41-52.
- Agarwal A, Cho CL, Esteves SC, Majzoub A. Reactive oxygen species and sperm DNA fragmentation. Transl Androl Urol 2017;6(Suppl 4):S695-6.
- Aitken RJ. Reactive oxygen species as mediators of sperm capacitation and pathological damage. Mol Reprod Dev 2017;84:1039-52.
- Agarwal A, Parekh N, Panner Selvam MK, Henkel R, Shah R, Homa ST, et al. Male oxidative stress infertility (MOSI): proposed terminology and clinical practice guidelines for management of idiopathic male infertility. World J Mens Health 2019;37:296-312.
- 9. Ali M, Martinez M, Parekh N. Are antioxidants a viable treatment option for male infertility? Andrologia 2021;53:e13644.
- Wei G, Zhou Z, Cui Y, Huang Y, Wan Z, Che X, et al. A Meta-Analysis of the Efficacy of L-Carnitine/L-Acetyl-Carnitine or N-Acetyl-Cysteine in Men With Idiopathic Asthenozoospermia. Am J Mens Health. 2021;15:15579883211011371.
- Zhang X, Cui Y, Dong L, Sun M, Zhang Y. The efficacy of combined l-carnitine and l-acetyl carnitine in men with idiopathic oligoasthenoteratozoospermia: a systematic review and meta-analysis. Andrologia 2020;52:e13470.
- Wang J, Wang T, Ding W, Wu J, Wu G, Wang Y, et al. Efficacy of antioxidant therapy on sperm quality measurements after varicocelectomy: a systematic review and meta-analysis. Andrologia 2019;51:e13396.
- Bahmyari R, Zare M, Sharma R, Agarwal A, Halvaei I. The efficacy of antioxidants in sperm parameters and production of reactive oxygen species levels during the freeze-thaw process: a systematic review and meta-analysis. Andrologia 2020;52:e13514.
- Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Cochrane Database Syst Rev 2019;3:CD007411.
- Salonia A, Bettocchi C, Carvalho J, Corona G, Jones TH, Kadioǧlu A, et al. Sexual and reproductive health. Arnhem: European Association of Urology; 2022;282.
- Schlegel PN, Sigman M, Collura B, De Jonge CJ, Eisenberg ML, Lamb DJ, et al. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I. J Urol 2021;205:36-43.
- Agarwal A, Leisegang K, Majzoub A, Henkel R, Finelli R, Panner Selvam MK, et al. Utility of Antioxidants in the Treatment of Male Infertility: Clinical Guidelines Based on a Systematic Review and Analysis of Evidence. World J Mens Health. 2021;39:233-290.
- Agarwal A, Cannarella R, Saleh R, Harraz AM, Kandil H, Salvio G, Boitrelle F, Kuroda S, FarkouhAla’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. 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.