Following a Cochrane review in 2022 which found antioxidants of ‘uncertain’ benefit in male fertility, a new analysis of over-the-counter antioxidants reports that only a minority of the 34 eligible had been tested in a published study.
With a steady decline in sperm count found in recent meta-analyses, the market for over-the-counter supplements to improve semen quality and thereby male fertility continues to grow. A just-published ‘scoping’ review, which tracked such supplements via internet shopping sites, ended up with 34 supplements containing 48 different active substances available for qualitative analysis - and these did not include a further 42 supplements containing plant extracts.(1)
The 34 reviewed supplements were all antioxidants, whose benefits, according to the study authors, depend on a reduction of oxidative stress induced by the production of free radicals. Sperm cells, they add, ‘are particularly vulnerable to oxidative stress’. As a result, and according to a recent Cochrane review of antioxidants for male fertility, supplements are ‘widely available and inexpensive when compared to other fertility treatments’ - but evidence of their efficacy is ‘uncertain’.(2) The most evident antioxidants seem to be carnitines, vitamins E and C, N-acetyl cysteine, coenzyme Q10, selenium, zinc, folic acid and lycopene.
The Cochrane review found that use of antioxidants, from ‘low certainty’ evidence, may indeed encourage a slight improvement in pregnancy and live birth rates, but this benefit could not be replicated when studies at high risk of bias were removed from the analysis.
Now, this latest review takes the Cochrane analysis a step further to find, first, that most of the eligible supplements ‘contained excessive doses of vitamins or minerals’, and second, that only a minority (38%) had been tested in a published study. The authors stress that such studies should have ‘relevant outcomes’ (pregnancy and live birth rates), ‘the ultimate goals’ of treatment and recommended as core outcomes for studies on infertility.(3) Well designed clinical trials to boost (and regulate) male fertility are also one clear objective of the Male Reproductive Health Initiative; ‘Current methods for diagnosing cause of male infertility are inadequate and effective treatments are lacking,’ states the MRHI.(4)
As with many meta-analyses, and especially with unregulated substances, strong evidence of benefit in this latest review was hard to find, ‘with often no more than two available studies on one substance’. Moreover, the authors express concern that 80% of the 34 antioxidants analysed were ‘at a dosage exceeding the tolerable upper intake level’. This, they explain, may even be detrimental to semen quality, if ‘reductive’ stress (very low levels of reactive oxygen species, ROS) takes over from oxidative stress.
The analysis also followed the antioxidants to the online market place to find that, in order to follow a recommended minimum three-month course, men must pay an average of at least $159.30, with a maximum cost of $478.92 for a three-month course. These figures they describe as ‘even more remarkable when one considers that only 38% of the supplements were tested in clinical trials which, overall, were poor in quality’.
So where next? The Cochrane review of antioxidants for male fertility concluded that infertile couples should be advised that current evidence of benefit ‘is inconclusive’. But that of course assumes a patient in the care of a professional. Now, this latest review reports adds that many of the claims of over-the-counter supplements are ‘non-transparent’, with an inherent risk of misinformation among a group of patients who may be ‘vulnerable’. As such, the authors urge that the discrepancy between the health claims and supporting evidence ‘should lead to interference by regulatory institutions’, but that, they ruefully add, seems unlikely when there is such inconsistency in regulatory frameworks. In the end, as appears so often the case, the first solution seems to be better and more RCTs, designed with appropriate outcome measures, and of course a more detailed account of the evidence behind the claims of available antioxidants for men.
1. de Ligny WR, Fleischer K, Grens H, et al. The lack of evidence behind over-the-counter antioxidant supplements for male fertility patients: a scoping review. Hum Reprod Open 2023; hoad020, https://doi.org/10.1093/hropen/hoad020
2. de Ligny W, Smits RM, Mackenzie-Proctor R, et al. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews 2022, Issue 5: CD007411.
3. Duffy JMN, Bhattacharya S, Bhattacharya S, et al. Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study. Hum Reprod 2020; 12: 2735–2745. doi.org/10.1093/humrep/deaa243
4. See https://www.eshre.eu/Specialty-groups/Special-Interest-Groups/Andrology/MRH