Anne Z Steiner1, Karl R Hansen2, Kurt T Barnhart3, Marcelle I Cedars4, Richard S Legro5, Michael P Diamond6, Stephen A Krawetz7, Rebecca Usadi8, Valerie L Baker9, R Matthew Coward10, Hao Huang11, Robert Wild2, Puneet Masson12, James F Smith13, Nanette Santoro14, Esther Eisenberg15, Heping Zhang11. 1. Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina. Electronic address: anne.steiner@duke.edu. 2. Department of Obstetrics and Gynecology, Health Sciences Center, University of Oklahoma, Oklahoma City, Oklahoma. 3. Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania. 4. Department of Obstetrics and Gynecology, University of California-San Francisco, San Francisco, California. 5. Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey, Pennsylvania. 6. Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia. 7. Department of Obstetrics and Gynecology & Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan. 8. Department of Reproductive Endocrinology and Infertility, Atrium Health, Charlotte, North Carolina. 9. Department of Obstetrics and Gynecology, Stanford University, Palo Alto, California. 10. Department of Urology, University of North Carolina, Chapel Hill, North Carolina. 11. Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut. 12. Department of Urology, University of Pennsylvania, Philadelphia, Pennsylvania. 13. Department of Urology, University of California- San Francisco, San Francisco, California. 14. Department of Obstetrics and Gynecology, University of Colorado, Denver, Colorado. 15. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Abstract
OBJECTIVE: 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 atrandomization, 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. CLINICAL TRIAL REGISTRATION NUMBER: NCT02421887.
RCT Entities:
OBJECTIVE: 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. CLINICAL TRIAL REGISTRATION NUMBER: NCT02421887.
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