An emerging case for measuring sperm DNA damage before ART

Published 17 February 2021

While assays for sperm DNA remain controversial in their association with pregnancy, a new opinion paper in Human Reproduction makes the case for screening before ART based not on improving success rates but on minimising adverse health outcomes in the children conceived.

All male patients scheduled for assisted reproduction treatments should be screened for DNA damage to sperm cells, according to a leading andrologist. Professor John Aitken, writing with colleague Hassan Bakos in Human Reproduction, argues that the reason is not so much as a marker of current fertility, but more in consideration of the health and well-being of the offspring.(1) The deterioration in sperm DNA quality, the authors propose, especially when associated with increasing paternal age, has now been clearly linked to an increased mutational load carried by the offspring as well as to a whole catalogue of pathologies sometimes recognised in the offspring of ageing males.

Behind the proposal lies evidence reported in two recent studies. First, a study of sperm samples from more than 25,000 men of all ages attending fertility clinics in the USA and Europe found that advancing paternal age was associated with increased sperm DNA fragmentation (measured as increased percentage of sperm in semen with measurable DNA strand breaks).(2) While the heterogeneity DNA fragmentation values at specific ages precluded ‘the automatic translation of age into an index of DNA fragmentation’, it did reinforce the idea that such evaluation can play a role in detecting potential male infertility.

The second study was a retrospective analysis of almost 17,000 semen samples from men aged up to 55 and over in which DNA fragmentation indices were found to increase significantly with age, with levels of oxidative stress found lowest in patients under 30.(3) The results prompted the authors to propose that DNA and/or oxidative damage in sperm ‘may be just as important to understand as the chromosomal aberrations that are carried in the oocyte’.

The measurement of DNA fragmentation in sperm has been proposed for several years as a marker of fertility in men, based on a principle that during sperm cell maturation the DNA is susceptible to stress factors which may cause the DNA strands to break or fragment. However, the routine acceptance of fragmentation tests has proved controversial. The UK’s HFEA, for example, described the tests as an ‘add-on’ treatment, with ‘currently no traffic light rating for treatments relating to sperm DNA damage’, while the ASRM, in its latest update on male infertility, advises that ‘sperm DNA fragmentation analysis is not recommended in the initial evaluation’. However, the ASRM did add: ‘It is possible that very high levels of sperm DNA fragmentation will have a more substantial adverse impact on pregnancy outcomes with IVF as well as an increased risk of miscarriages.’

But this objective, says this latest opinion, misses the point. Measuring levels of DNA damage should not just be about predicting fertility, but rather, given the chain of associations between sperm DNA damage, mutational load and offspring health, the use of DNA-damaged sperm in ART, particularly in ICSI, ‘will have dire consequences for the health and wellbeing of the progeny’. Hence the proposition that analysis of sperm DNA damage should be undertaken not merely to improve fertility but to prevent oxidative stress in the male germline.

The authors go on to explain that a variety of ‘adverse conditions’, including paternal age, smoking, obesity and toxin exposure, are all capable of inducing a state of oxidative stress in the male germ line. Sperm cells are vulnerable to such stress, resulting in the generation of oxidative DNA damage. However, spermatozoa carrying oxidative DNA damage are still capable of natural or assisted fertilisation but, if DNA repair from the fertilised oocyte is deficient, may influence the viability of pregnancy as well as the health and wellbeing of the offspring. However, despite the hypothesis, the authors acknowledge that ‘there is still much to discover about the links between oxidative DNA damage in spermatozoa, the application of ART and specific forms of morbidity in the offspring’.

Screening for DNA damage in sperm cells, therefore, is justified not because it correlates with the rate of miscarriage or even live birth but because it provides a cue to intervene and reduce levels of DNA damage before assisted conception. And that might be achieved through lifestyle modification, improved sperm selection with cryopreservation and antioxidant treatments.

And then, of course, those interventions have to work. The evidence in favour of weight loss in obesity and quitting smoking seems strong, but the beneficial effects of antioxidant therapies – despite their hype – are inconclusive at best. The latest Cochrane review of antioxidants for male infertility (usually a mixture of vitamin E, vitamin C, carotenoids, selenium and zinc) found some evidence in favour of an improved chance of live birth, but with a ‘low’ overall quality of evidence.(4) Trials are called for, the authors of this latest opinion conclude, not so much with the aim of enhancing pregnancy rates but ‘rather the resolution of oxidative DNA damage in the male gamete’.

1. Aitken RJ, Bakos HW. Should we be measuring DNA damage in human spermatozoa? New light on an old question. Hum Reprod 2021; doi:10.1093/humrep/deab004
2. Evenson DP, Djira G, Kasperson K, Christianson J. Relationships between the age of 25,445 men attending infertility clinics and sperm chromatin structure assay (SCSAVR) defined sperm DNA and chromatin integrity. Fertil Steril 2020; 114: 311–320. doi:10.1016/j.fertnstert.2020.03.028
3. Vaughan DA, Tirado E, Garcia D, et al. DNA fragmentation of sperm: a radical examination of the contribution of oxidative stress and age in 16 945 semen samples. Hum Reprod 2020; 35: 2188-2196.
4. Smits RM, Mackensie-Proctor R, Yazdani A, et al. Amtioxidants for male subfertility. Cochrane Database of Systematic Reviews 2019, Issue 3. CD007411. DOI:10.1002/14651858.CD007411.pub4.

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