While tests for sperm DNA damage are controversial because of their uncertain association with pregnancy, andrologist Jackson Kirkman-Brown in an invited presentation proposed that there’s much more to assessing the effect of sperm on the health of offspring.
Sperm DNA damage should be considered more widely as a diagnostic and therapeutic target, with miscarriage identified as an example, according to data presented on the opening day of this year’s annual meeting. Using evidence from his own meta-analysis, Jackson Kirkman-Brown emphasised how miscarriage is a model of severe problems in offspring health, noting that paternal sperm damage almost doubles the chance of spontaneous pregnancy loss in the first 23 weeks, with older women especially at risk.
The former co-ordinator of ESHRE’s SIG Andrology, from Birmingham University in the UK, said male factor and sperm damage have huge potential for impact on future generations – and diagnosis is ‘just the start’ for couples and clinicians. Not all sperm start equal and routine semen analyses generally provide accurate results. But these tests only give ‘extremes’ such as zero sperm or motility, he explained, and clinicians need to look elsewhere for the causes of male factor infertility.
Outlining how sperm DNA is highly condensed and organised in very specific patterns, Kirkman-Brown suggested that oxidative stress is just one factor in DNA sperm damage and that the full picture of which genes are more exposed to damage is far more complex. Indeed, the jury is still out on the benefits of tests to determine sperm abnormalities. Two systematic reviews carried out to date came to different conclusions: one found there was sufficient data to recommend testing, the other insufficient. Only two assays (TUNEL and COMET) of the four main tests available are supported by strong evidence - with the challenge being that each uses different mechanisms so results cannot be compared; a study by Kirkman-Brown and colleagues which suggested little/no correlation. On this basis, he said, future obligations for sperm DNA testing should include using the test most relevant to outcome and which goes beyond sperm DNA damage alone.
Can practitioners specifically select undamaged sperm to boost the chances of a healthy baby? Physiological hyaluronan-selected ICSI (PICSI) is one strategy being currently investigated to improve the success rates of standard ICSI. Sperm are introduced to a surface coated with hyaluronic acid and those that stick – the ones with reduced levels of DNA damage and aneuploidy – are used for fertilisation. A randomised trial of 2772 couples published in 2019 concluded then that PICSI does not improve LBRs overall and should not be recommended at present.(1) However, a secondary outcome of the same trial found a lower chance of miscarriage with PICSI (14% PICSI vs 22% ICSI). Furthermore, unpublished data from another UK trial suggests that the age of the female partner increases the probability of miscarriage in ICSI but not in PICSI.
The data on PICSI are backed up by studies which show that female ageing reduces the DNA repair capacity of oocytes, and other evidence that mosaicism in IVF blastocysts seems related to paternal age and oligozoospermia. What appears to be happening, according to Kirman-Brown, is that DNA sperm damage accentuates the role of female ageing in miscarriage and the choice of healthy sperm through PICSI may alleviate these effects.
All possible steps must also be taken in advance of treatment, said Kirkman-Brown, to optimise a man’s conception chances – for example, increasing ejaculatory frequency and using supplements. Based on current evidence, he cautioned against using low sperm DNA quality as a reason to move to sperm donation, instead advising in favour of tailored treatment.
A recent opinion piece in Human Reproduction has argued that all male ART patients should be screened for sperm DNA damage. Describing this as a ‘discussion for another day’, Kirkman-Brown ended his presentation by urging clinics not to focus solely on DNA damage at the point of ejaculation but also later, when sperm has left its ‘blissful life of oxidated balanced control’ for real-life conditions.
1 Miller D, Pavitt S, Sharma V, et al. Physiological, hyaluronan-selected intracytoplasmic sperm injection for infertility treatment (HABSelect): a parallel, two-group, randomised trial. Lancet 2019; 393: 416-422. doi.org/10.1016/S0140-6736(18)32989-1
2 Aitken RJ, Bakos HW. Should we be measuring DNA damage in human spermatozoa? New light on an old question. Hum Reprod 2021; 36: 1175-1185.