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Center for Male Reproductive Medicine & Microsurgery

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Dr. Schlegel Responds: The Effect of Antioxidants on Male Factor Infertility

Expert Comment by Dr. Peter N. Schlegel

Sperm have been recognized to be sensitive to the adverse effects of oxidative stress for more than 75 years, leading to the consideration of antioxidants for the treatment of male infertility. A wide variety of different antioxidant products have been used for infertile men, including supplements and vitamins in a variety of different combinations and doses. The potential benefit of antioxidants for male fertility has been difficult to analyze because of the multitude of different treatment approaches used. A meta-analysis of the potential benefits of antioxidants was produced in 2013, suggesting a benefit in fertility rates for men of infertile couples treated with a variety of different antioxidants in four small, randomized, controlled trials of different agents. The Cochrane review was updated in 2019 with seven studies, and had similar findings. The summary was that pregnancy rates would increase from 7% to 12% to 26% if antioxidants were used.1 Antioxidants have also been used as adjuncts for treatment of males during planned, assisted-reproductive treatments (IVF, ICSI) for infertile couples. These treatments have also been suggested to work in small, uncontrolled (or controlled by prior failure of treatment) series without substantive evaluation in randomized, controlled trials. One of the proposed mechanisms of action for antioxidants was to decrease sperm DNA fragmentation; hence, increasing pregnancy rates with an additional decrease in miscarriage rates.

The National Institutes of Health Reproductive Medicine Network performed the MOXI trial, a multicenter randomized controlled trial using a combination of antioxidants for males with infertility and abnormal semen parameters or abnormal sperm DNA fragmentation and normal female evaluation. Essentially, this was a negative study. There were no benefits in semen parameters, sperm DNA fragmentation, or pregnancy rates observed in the trial. These findings raise concern for the benefits of antioxidant treatment of idiopathic male infertility.

As with all studies, there are concerns with the study design and findings. As published, the manuscript does not provide the full study design, as published on the clinical trials website. Subjects were to be enrolled in two different steps, including an internal pilot phase and complete trial enrollment of 790 couples with abnormal semen parameters or abnormal sperm DNA fragmentation. Only the pilot trial results were published. In the pilot component of the trial, only 144 couples were enrolled, including just 44 men with abnormal sperm DNA fragmentation. Given that the primary endpoint of the trial was the pregnancy rate, and the power of the study was calculated based on 790 couples enrolled, there is little surprise that a pilot component of the trial (as published) did not demonstrate benefits of antioxidant treatment. Furthermore, some could argue that agents used as oxidants (eg, alpha tocopherol) do not have antioxidant activity, only mixed or gamma tocopherols. Needless to say, the study was terminated early, without enrollment of all 790 couples intended for the power analysis of this study.

In summary, the MOXI (male antioxidant infertility) trial does not demonstrate benefit of a commercial combination of antioxidants for male infertility. Given the study design and constituents of vitamins/supplements used, this does not provide a definitive statement on use of antioxidants for male infertility. However, this randomized, controlled trial does not show any benefit of their use.

Reference

  1. Smits RM, Mackenzie-Proctor R, Yazdani A, et al. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2019;3:CD007411. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007411.pub4/full

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