Antioxidant supplements make no difference in infertile men

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Despite many study results suggesting that antioxidants have a positive effect on abnormal sperm parameters associated with male infertility, a large US clinical trial of 174 couples has found that an antioxidant formulation taken daily by the male partner for a minimum of three months made no difference to sperm concentration, motility or morphology, nor to the rate of DNA fragmentation.

Results of the study, which was performed in eight US fertility centres with the support of the National Institutes of Health, was presented at the 34th Annual Meeting of ESHRE by Professor Anne Steiner from the University of North Carolina at Chapel Hill.

All men in the study had been diagnosed with male factor infertility, reflected in sub-normal levels of sperm concentration, motility, or morphology, or higher than normal rates of DNA fragmentation. These sperm parameters were measured at the start of the trial and at three months. In between, the men allocated to the antioxidant intervention were given a daily supplement (in tablet form) containing vitamins C, D3 and E, folic acid, zinc, selenium and L-carnitine; the control group received a placebo.

At three months, results showed only a “slight” overall difference in sperm concentration between the two groups, and no significant differences in morphology, motility, or DNA fragmentation measurements. Sub-group analysis (according to different types of sperm abnormality) found no significant differences in sperm concentration (in oligospermic men), motility (in asthenospermic men), and morphology (in teratospermic men). There was also no change seen after three months in men with high rates of DNA fragmentation (28.9% in the antioxidant group and 28.8 in the placebo group).

A further endpoint of the trial was natural conception during the initial three-month study period, but this too did not differ between the two groups of the entire cohort – a pregnancy rate of 10.5% in the antioxidant group and 9.1% in the placebo. These rates were also comparable at six months (after continued antioxidant or placebo for the male partner and three cycles of clomiphene and intrauterine insemination for the female partner).

As background to the trial, the authors explain that many of the previous studies in which antioxidants have been linked to improvements in sperm quality have been limited by small numbers, heterogeneity in patients, variety of antioxidant, and non-clinical endpoints. This study, therefore, was designed to close these gaps in knowledge and provide a stronger evidence base.

In commenting on this randomised controlled trial, Steiner said it was one of the largest of its kind with a “well characterised” study population. Explaining the three-month study period, she said that spermatogenesis and transport together take approximately 74 days, but that reactive oxygen species have a greater negative effect during the much shorter sperm transport phase rather than during spermatogenesis; thus, antioxidants are thought to have benefit even after a short interval.

As a result and based on findings from this large clinical trial, Steiner and her colleagues now conclude that “the results do not support the empiric use of antioxidant therapy for male factor infertility in couples trying to conceive naturally.”

1. World Health Organisation-defined standard values of semen parameters are as follow: sperm concentration equal to or greater than 15m per millilitre, motility of 32% or higher, and normal morphology equal or more than 4%. In this study men with sperm concentration 15m/ml or less, motility of 40% or less, normal morphology of 4% or less, and DNA fragmentation of 25% or more were eligible. Defects in sperm functions include oligospermia (low sperm count), azoospermia (absence of any sperm cells), teratospermia (high levels of abnormal morphology), as thenospermia (high levels of reduced sperm motility).
2. Natural antioxidants, including vitamins C and E, are found in semen ostensibly as protection against the activity of free radicals and oxidative stress. Several studies have shown that antioxidant levels are lower in the semen of infertile than in fertile men — which thus explains the rationale for antioxidant supplementation. DNA fragmentation is a measure of structural defects of sperm cells. Again, oxidative stress in the form of reactive oxygen species has been implicated in their interaction with DNA to cause strand breaks and fragmentation. Results are usually presented as the percentage of cells having fragmented DNA.
3. A Cochrane review of 48 trials found modest improvements in pregnancy and live birth rates in couples where the men took antioxidant supplements (prior to IVF), but the quality of the evidence was described as “low”.

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European Society of Human Reproduction and Embryology material

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