Cited by 213Sperm and Testicular FunctionReproductive Health and TechnologiesMale Reproductive Health Studies

The DOI matches its Crossref record; 26 of the 28 references it cites were found in a registry or an index; 10 of the 12 sources its claims cite were checked for support.

The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial

Open access

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 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.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In the MOXI randomized trial, a daily combination antioxidant formulation did not improve semen parameters or sperm DNA fragmentation in men with male factor infertility, and it did not increase pregnancy or live birth rates. The trial was stopped early after the internal pilot failed to show benefit.

Key findings

  • After 3 months, change in sperm concentration differed between antioxidant and placebo groups [−4.0 (−12.0, 5.7) M/ml vs +2.4 (−9.0, 15.5) M/ml; p=0.03], but there were no significant differences in change in sperm morphology, motility, or DNA fragmentation.
  • In subgroups, no significant differences were seen at 3 months: oligospermic men (n=66) sperm concentration 8.5 (4.8, 15.0) vs 15.0 (6.0, 24.0) M/ml, p=0.08; asthenospermic men (n=75) motility 34±16.3% vs 36.4±15.8%, p=0.53; men with high DNA fragmentation (n=44) 29.5 (21.6, 36.5)% vs 28.0 (20.6, 36.4)%, p=0.58.
  • Cumulative live birth at 6 months did not differ: 15% (13/85) with antioxidants vs 24% (21/86) with placebo, p=0.14. Pregnancy rates did not differ in phase 1 (9% vs 9%, p=0.98) or phase 2 (12% vs 21%, p=0.11).
  • Adherence was 88% in the antioxidant group and 82% in placebo (p=0.26); adverse events occurred in 41% vs 40% (p=0.83). Enrollment was stopped after the internal pilot failed to reject the null hypothesis for motility and DNA fragmentation.

Methods

  • Multicenter, double-blind, randomized, placebo-controlled trial with a pre-specified internal pilot, conducted at 9 U.S. fertility centers from December 2015 to December 2018.
  • Eligible couples had male factor infertility: men ≥18 years with at least one abnormal semen parameter (sperm concentration ≤15 M/ml, motility ≤40%, normal morphology ≤4%, or DNA fragmentation ≥25%); female partners were 18–40 years, ovulatory, and had documented tubal patency.
  • Men were randomized 1:1 to a daily antioxidant formulation (500 mg vitamin C, 400 mg vitamin E, 0.20 mg selenium, 1000 mg L-carnitine, 20 mg zinc, 1000 mcg folic acid, 10 mg lycopene, and 2000 IU vitamin D) or placebo for 3–6 months. Couples attempted natural conception in months 1–3 and received clomiphene citrate with intrauterine insemination in months 4–6 if not pregnant. Primary outcome was live birth; pilot outcomes were semen parameters and SCSA-measured DNA fragmentation at 3 months. Intention-to-treat analyses used chi-square/Fisher exact, Wilcoxon rank-sum, and t-tests, with p<0.05.

Limitations

  • Stated: the trial was limited by sample size for pregnancy/live birth outcomes and was not powered to determine group differences in live birth; larger trials are needed.
  • Stated: the design could not differentiate effects of individual nutrients and assumed no interactions among antioxidants in the combination formulation.
  • Stated: patients may have been selected who were unlikely to benefit, such as men without elevated reactive oxygen species; future studies could target subpopulations such as men with low vitamin levels or high seminal ROS.
  • Evident from the text: baseline imbalances existed (placebo-group men were more likely to have fathered a pregnancy previously; antioxidant-group men had a lower percentage of morphologically normal sperm), and dropout was numerically higher in the antioxidant group (21% vs 11%, p=0.055).

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Integrity signals

Registry

Crossref · 10.1016/j.fertnstert.2019.11.008

Cites

26 of 26 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

10 of 12 cited sources checked · 6 supported · 1 flagged · accuracy not yet measured

Show all 26 claims

  • It may state two separate claims as one. 16
  • Probably not a substantial claim. 16
29 of 29
  • The authors state this as an assumption.

    There are no interacting effects between the different antioxidants in the formulation.

    “inherently assumes namely that there are no interacting effects between the different antioxidants in the formulation.”
  • The authors state this as an assumption.

    The effect of the intervention on live births is at least partially mediated through improvements in sperm motility and a reduction in sperm DNA fragmentation.

    “The trial stopping rule had the strong underlying hypothesis that the effect of the intervention on live births is (at least partially) mediated through improvements in sperm motility and a reduction in sperm DNA fragmentation.”
  • The paper relies on this without support.

    Conventional semen quality parameters and even sperm DNA fragmentation are, at best, modest predictors of a couple’s fertility when trying with or without medical assistance.

    “However, conventional semen quality parameters and even sperm DNA fragmentation are, at best, modest predictors of a couple’s fertility when trying with or without medical assistance.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Completion claim conflicts with reported dropouts

    Minor

    The paper says all enrolled couples completed the study protocol, but earlier reports that only 144 of 171 randomized couples completed the study.

1 of 1

Citations

Cites

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Show all 28 references

2 of the 28 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Peivandi, 2010, Effects of l-carnitine on infertile men’s spermogram; a randomised clinical trial, J Reprod Infertil, 10, 245

Cited by

Sorted by citations

Items 201–213 of 213

Metadata

Authors
Steiner, A. Z., Hansen, K. R., Barnhart, K. T., Cedars, M. I., Legro, R. S., Diamond, M. P., Krawetz, S. A., Usadi, R., Baker, V. L., Coward, R. M., Huang, H., Wild, R., Masson, P., Smith, J. F., Santoro, N., Eisenberg, E., & Zhang, H.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • University of Oklahoma Health Sciences Center (US)
  • University of Pennsylvania (US)
  • University of California, San Francisco (US)
  • Pennsylvania State University (US)
  • Augusta University (US)
  • Wayne State University (US)
  • Stanford University (US)
  • Yale University (US)
  • University of Colorado Denver (US)
  • National Institutes of Health (US)
Corresponding author
Steiner, Anne Z.
Venue
Fertility and Sterility
Publisher
Elsevier BV
Published
2020-03
Volume
113
Issue
3
Pages
552-560.e3
ISSN
0015-0282 (ISSN-L)
OpenAlex
W3006771562
Cited by
213
References
28
Citations by year
2026: 33 · 2025: 29 · 2024: 25 · 2023: 31 · 2022: 42 · 2021: 32 · 2020: 21
FWCI
22.74
Type
journal article
Language
en
Open access
Locations
  • Fertility and Sterility (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Health Sciences › Medicine › Reproductive Medicine › Reproductive Health and Technologies
  • Health Sciences › Medicine › Urology › Male Reproductive Health Studies
Keywords
male factor infertility, antioxidants, male fertility, sperm DNA fragmentation, semen parameters, sperm concentration, live birth, vitamin C, vitamin E, selenium, L-carnitine, zinc, folic acid, lycopene, intrauterine insemination, clomiphene citrate, oligozoospermia, internal pilot study
MeSH terms
Adult, Antioxidants, Double-Blind Method, Female, Humans, Infant, Newborn, Infertility, Male, Insemination, Artificial, Homologous, Male, Ovulation Induction, Pilot Projects, Pregnancy, United States, Pregnancy Rate

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