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The Effect of Antioxidants on Male Factor Infertility
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersOBJECTIVE
To determine whether antioxidants improve male fertility, as measured by semen parameters and DNA fragmentation at 3 months and pregnancy resulting in live birth after up to 6 months of treatment, among couples with male factor infertility.
DESIGN
Multicenter, double-blind, randomized, placebo-controlled trial with an internal pilot study.
SETTING
Nine fertility centers in the United States from December 2015 to December 2018.
PATIENT(S)
Men (N = 174) with sperm concentration ≤15 million/mL, motility ≤40%, normal morphology ≤4%, or DNA fragmentation >25%, and female partners who were ovulatory, ≤40 years old, and had documented tubal patency.
INTERVENTION(S)
Males randomly assigned to receive an antioxidant formulation (n = 85) containing 500 mg of vitamin C, 400 mg of vitamin E, 0.20 mg of selenium, 1,000 mg of l-carnitine, 20 mg of zinc, 1,000 μg of folic acid, 10 mg of lycopene daily, or placebo (n = 86). Treatment lasted for a minimum of 3 months and maximum of 6 months, and couples attempted to conceive naturally during the first 3 months and with clomiphene citrate with intrauterine insemination of the female partner in months 4 through 6.
MAIN OUTCOME MEASURE(S)
Primary outcome was live birth; secondary outcomes included pregnancy within 6 months of treatment. For the internal pilot, the primary outcomes were semen parameters and sperm DNA fragmentation index after 3 months of treatment.
RESULT(S)
In the Males, Antioxidants, and Infertility (MOXI) study, after 3 months of treatment, the change in sperm concentration differed between the antioxidant group (median -4.0 [interquartile range-12.0, 5.7] million/mL) and placebo group (+2.4 [-9.0, 15.5] million/mL). However, there were no statistically significant differences between the two groups for changes in sperm morphology, motility, or DNA fragmentation. Among the 66 oligospermic men at randomization, sperm concentration did not differ at 3 months between the antioxidant and control groups: 8.5 (4.8, 15.0) million/mL versus 15.0 (6.0, 24.0) million/mL. Of the 75 asthenospermic men, motility did not differ at 3 months: 34% ± 16.3% versus 36.4% ± 15.8%. Among the 44 men with high DNA fragmentation, DNA fragmentation did not differ at 3 months: 29.5% (21.6%, 36.5%) versus 28.0% (20.6%, 36.4%). In the entire cohort, cumulative live birth did not differ at 6 months between the antioxidant and placebo groups: 15% versus 24%.
CONCLUSION(S)
Antioxidants do not improve semen parameters or DNA integrity among men with male factor infertility. Although limited by sample size, this study suggests that antioxidant treatment of the male partner does not improve in vivo pregnancy or live-birth rates.
Additional Info
Disclosure statements are available on the authors' profiles:
The Effect of Antioxidants on Male Factor Infertility: The Males, Antioxidants, and Infertility (MOXI) Randomized Clinical Trial
Fertil. Steril 2020 Feb 25;[EPub Ahead of Print], AZ Steiner, KR Hansen, KT Barnhart, MI Cedars, RS Legro, MP Diamond, SA Krawetz, R Usadi, VL Baker, RM Coward, H Huang, R Wild, P Masson, JF Smith, N Santoro, E Eisenberg, H ZhangFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
Peter Schlegel is on the medical advisory board of Theralogix, Inc, a producer of nutraceuticals, including the agents used in this trial.