Utility of Antioxidants in the Treatment of Male Infertility: Clinical Guidelines Based on a Systematic Review and Analysis of Evidence – Beyond the Abstract

Infertility impacts 15% of couples attempting to conceive, and a malefactor is involved in up to 50% of the time.  Male infertility incidence varies across geographical locations and can range anywhere from 20 – 70%.1  Although there are many identifiable causes for male infertility, such as infection, hormonal abnormalities, varicocele, and malignancy to name a few, a large proportion of cases remain unexplained (UMI) or idiopathic (IMI).


Oxidative stress (OS) has been established to be an etiology for many identifiable as well as unexplained causes of male infertility.2  Because of this, the use of oral antioxidant (AOX) supplements to mitigate the negative impact of OS on sperm quality and function has become an important part of the treatment regimen to address OS-mediated male infertility.  AOX therapy is an attractive treatment for many men due to its availability, low cost in comparison to assisted reproduction, and excellent safety profiles and tolerability of many of the supplements.2

AOX use for infertility has been studied for many decades but the studies thus far have been difficult to decipher with mixed outcomes due to the sheer number of antioxidants, varying formulations and dosing regimens, the difference in treatment duration, and inconsistently studied outcome measures.  A Cochrane meta-analysis performed first in 2011 and most recently updated in 2019 summarized the literature on AOX and infertility and concluded that there is low-level evidence supporting AOX therapy in improving pregnancy and live birth rates.3  Even with these findings, as clinicians and scientists, we sought to evaluate the current literature to further expand our understanding of AOX impact on male infertility. We, therefore, performed an extensive literature review based on PRISMA guidelines and evaluated the Cambridge Quality Checklist, Cochrane Risk of Bias, JADAD score, and CONSORT guidelines to achieve the following objectives:

  • To systematically analyze the current evidence of AOX use for treating male infertility.
  • To use the evidence to propose evidence-based clinical guidelines on the use of AOX for treating male infertility (based on Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence).

There were 1978 articles identified and systematically through a SCOPUS database search.  Of these, 97 articles were eligible for inclusion based on our criteria and systematically evaluated. This resulted in 99 studies investigating the impact of antioxidant treatment on reproductive outcomes and 21 articles published between 1/2019 to 7/2020 investigating the impact of antioxidant treatment on reproductive outcomes.

Overall, there were 20 high-quality studies identified in the review with 65% and 58% of the studies reporting an improvement in semen parameters and sperm function after AOX treatment.  The studies were stratified into high versus low-quality studies and further separated for specific clinical conditions including varicocele, abnormal semen quality, idiopathic male infertility, and unexplained male infertility.  For varicocele, 75% and 83% of low-quality studies demonstrated improved semen parameters and sperm function with AOX therapy, respectively, but not found to be statistically significant.  For abnormal semen quality, 94% and 90% of low-quality studies demonstrated improved semen parameters and sperm function, respectively (p < 0.0001). 50% and 60% of high-quality studies also demonstrated improved findings, respectively, but were not statistically significant. Interestingly, for UMI and IMI, all of the high-quality studies reviewed demonstrated improved semen parameters and sperm function (p < 0.0001). When the most recent publications since January 2019 were analyzed, 90.5% (19/21) demonstrated improved semen parameters. Very few of the studies investigating reproductive outcomes were very limited with only 3 of 5 studies reporting improved pregnancy rates with AOX therapy, with no improvement in birth rates in the 2 studies reporting this variable.

This systematic analysis on the impact of AOX therapy on male infertility demonstrates the weaknesses inherent in many of these studies that make it very difficult to provide concise recommendations to couples seeking fertility and confirm many of the findings in Majzoub and Agarwal’s 2018 study4 and the 2019 Cochrane meta-analysis. The analysis highlights the following issues found in many published studies:

  • Lack of placebo-controlled randomized studies
  • Lack of standardized test for evaluation of OS in semen pre and post treatment
  • Lack of standardized treatment regimen/supplement
  • Lack of standardized dose of treatment
  • Lack of standardized treatment duration
  • Lack of standardized outcome measures (semen parameters, sperm function, pregnancy rates, live birth rates, etc.)
  • Inability to control for dietary intake
  • Inability to control for confounding female partner variables

We, therefore, formulated clinical guidelines and recommendations utilizing these current high- and low-quality studies in hopes of setting the foundation upon which future studies can be based upon and adopted by our fertility societies and global specialists treating infertile males.

Recommendations:

  • Antioxidants can improve conventional semen parameters and measures of sperm function (grade C)
  • Antioxidants in addition to varicocele ligation result in further improvement in semen parameters (grade C)
  • Antioxidants significantly increase sperm quality in men with IMI and UMI (grade B)

There are several factors that should be the primary focus of any future high-quality AOX treatment study:  standardized testing for OS, improvement of OS levels, improvement in semen parameters, and pregnancy outcomes – including pregnancy rates as well as birth rates.  These studies will be difficult to undertake given the multifactorial causes for infertility and the difficulties in controlling for many of the factors as outlined above.

Despite the shortcomings of the currently published papers, there is evidence that AOX therapy for infertile men has an overall positive impact on semen parameters and sperm function when combining the high- and low-quality studies together.  We look forward to future multi-institutional collaborative studies in hopes of achieving these lofty goals. 

Written by: Edmund Y. Ko, MD, Department of Urology, Loma Linda University, Loma Linda, CA, USA and Ashok Agarwal, PhD, American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA

References:

  1. Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endo- crinol 2015;13:37.
  2. Leisegang K, Henkel R. Oxidative stress: relevance, evalua- tion, and management. In: Rizk B, Agarwal A, Sabanegh ES, editors. Male infertility in reproductive medicine: diagnosis and management. Boca Raton: CRC Press; 2019;119-28.
  3. Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Co- chrane Database Syst Rev 2019;3:CD007411.
  4. Majzoub A, Agarwal A. Systematic review of antioxidant types and doses in male infertility: benefits on semen param- eters, advanced sperm function, assisted reproduction and live-birth rate. Arab J Urol 2018;16:113-24.

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