Could it be Sperm DNA Fragmentation?

It is now well researched and documented that the Western man’s sperm count has plummeted by 60% in the last 40 years compared to that of men in lesser developed countries. Sperm morphology is also at an all time low and researchers in America are finding that sperm DNA fragmentation is an area that is gathering more interest for embryologists and reproductive health specialists. 

It’s an area that I too am taking more seriously as I’m finding more and more of my fertility patients being diagnosed with “unexplained” infertility or struggling with recurrent miscarriage. Therefore I’ve taken some time to swat up on this growing area of research and have been reading a fascinating book, “A Clinician’s Guide to Sperm DNA and Chromatin Damage”, by Armand Zini and Ashok Agarwal, Professors of Montreal, Canada and Cleveland, USA. It’s a pretty hefty read but I’ve tried to pick out the more salient points for you. 

Sperm DNA fragmentation is caused by oxidative stress, which is an imbalance between free-radicals and antioxidants in the body. “Approximately, one in every six couples suffers from infertility (17%), and male factor contributes to 40-50% of these cases. The cases of almost half of these male factor associated infertilities are unexplained/idiopathic, and within this group, 5-10% of men had a high amount of sperm DNA fragmentation despite having normal semen parameters.” “Today, routine semen analysis is the “gold standard” test used in the evaluation of male infertility; however, it is unable to identify the causes of some of the cases. Therefore, in order to distinguish infertile men from the fertile population and to predict the success of in vitro fertilisation (IVF) cycle outcomes, a new diagnostic test is required. The use of DNA fragmentation tests as a part of the routine analysis in fertility investigation remains controversial, despite the fact that many research groups are greatly in favour of these tests.” 

The difficulty that many couples face is that they are given the standard routine sperm test and then told that their results were slightly below normal, without any real explanation of what this means. Firstly, given that “normal” is 60% worse than that of sperm 40 years ago, a below normal reading is really something that shouldn’t be taken too lightly. That said, I’m not here to worry anyone. More that some men should be taking the health of their sperm more seriously and be putting measures in place to protect and preserve it. 

“Although a few reports have indicated a slight or non-significant association between semen parameters (sperm count, motility, progression and morphology) and sperm DNA damage, many studies show that sperm from abnormal sperm parameters have a higher percentage of DNA damage.” Therefore, if a man has a lower than average morphology, it is possible that they will have DNA fragmentation. 

The thing I struggle with the most is that men with lower than average sperm results are told that there’s nothing they can do to change it, and to just ‘keep trying’! Worse still, women that are able to get pregnant but suffer recurrent miscarriage are told that their partners don’t need a sperm test because they’re able to conceive. I have known in my practice that a missed miscarriage, or an embryo that fails to develop can often be linked to poor sperm quality. Clinicians really do need to adjust the way they address fertility and not offering couples even the basic sperm testing as a matter of course is just nonsensical. 

We know that lifestyle and dietary choices plays a massive role in improving sperm and yet this advice is often not descended down to the patient. Women are switching on to the fact that they must preserve their fertility health but I think it’s time men had a little wake up call too as “unexplained” infertility might be explained, if further testing is made available to men.

“Some studies have shown that sperm DNA fragmentation is correlated with poor reproductive outcomes including miscarriages, chromosomal aberrations, congenital malformations, genetic disorders, neurological defects and cancer in offspring. Understanding the mechanisms after fertilisation in the zygote is therefore important.”

So what is causing these higher levels of sperm DNA damage? 

“Some environmental factors including radiation, smoking and alcohol consumption contribute to male infertility. Untreated cancer patients as well as those who have been exposed to chemotherapy and radiotherapy, environmental pollutants and certain cytotoxic medications may be prone to sperm DNA fragmentation.”

It is also true that Western couples are coming to baby-making much later in life and so age does play a role here too. Up until recently it was considered that only women had a reproductive body clock that starts ticking at age 35. “Some studies have indicated that men with advanced age have an elevated sperm DNA fragmentation, while DNA fragmentation is considerably lower in younger men (<35 years)”. We also know that a younger oocyte [egg] can make do with a lesser quality sperm, which is why we have these preconceived ideas that men can still conceive no matter how old they are. It’s all to do with the quality of the egg and if the sperm is old but the egg young, then the maternal genes are able to repair and make do with much of the damaged DNA strands. However if both partners are in that plus 35 age bracket then it will be harder to conceive. 

“The scrotal temperature is 2-8 °C lower compared to the rest of the body, and this is essential for proper spermatogenesis in mammals. In a mouse model study, a high level of DNA fragmentations was observed in spermatocytes retrieved from testes exposed to 40-42 °C.” Therefore men that are regularly exposed to extreme temperatures may have more sperm damage. 

Varicocele, which is a mass of varicose veins in the spermatic cord, “affects approximately 15-20% of males and is one of the commonest causes of poor sperm quality. Significantly higher DNA fragmentation has been observed in patients with varicocele.”

Chlamydia and urinary tract infections also cause higher levels of sperm DNA fragmentation. 

So if a man has been diagnosed with high level sperm DNA fragmentation, what are their chances of success? 

One sperm DNA fragmentation test (SCSA) study showed that “If the level of spermatozoa with DNA fragmentation is higher than 30%, the probability of natural conception is almost zero.” 

And what are the chances of success using assisted fertility (IVF or ICSI)?

“Results of several clinical reports have proposed an association between sperm DNA damage/poor sperm quality and embryo development/maturation. The impact of DNA damage on the embryo seem to be related to the development of embryo more than embryo quality.”

Certainly in my clinic I see couples who have gone through the ICSI process who are able to gain Grade A blastocyst embryos but are unable to sustain a pregnancy. Many women blame themselves for being unable to carry the embryo to the next stage, but sperm DNA will affect the embryo much later and so it could be DNA fragmentation that is affecting the development. This is because the “blastocyst development is controlled by maternal genes during the first cell stage (approximately 48-56 hrs after the fertilisation process)”. “Interestingly, a study has demonstrated that the adverse paternal effect on the development of an embryo may occur at a later stage even if there are no morphological anomalies at the zygote stage. Repeated failures of assisted reproduction without any evident defective zygote formation and cleavage [the division of cells in the early embryo] of embryos are frequently correlated with high sperm DNA fragmentation levels.” “DNA fragmentation also has an impact on sperm parameters, embryonic development, chromosomal aneuploidy, implantation, and recurrent miscarriages.” 

So what can be done? 

“The favourable impact of antioxidants including reduction of DNA fragmentation level in ejaculated spermatozoa can be detected following 2 months of oral antioxidant therapy. Additionally, dietary antioxidants are an appropriate therapeutic option to alleviate sperm DNA damage for infertile men.” This is why I am increasingly annoyed when men receive the results of a lower than average sperm assay and are told that there’s nothing that can be done. It’s just not true! Plenty can be achieved with better diet and lifestyle choices, reducing stress, reducing exposure to pollutants and chemicals and lest we forget, regular acupuncture! 

Some studies have suggested that sperm that is stored for a shorter duration in the epididymus (a duct behind the testes) had less DNA fragmentation because their intracellular antioxidants have not been fully consumed. “Hence, recurrent ejaculations can potentially be an approach to reduce sperm DNA damage and improves IVF treatment success rate… Therefore, frequent daily ejaculations can be utilised as an alternative treatment option in male infertility cases with high oxidative stress.” 

Couples who have had unsuccessful rounds of assisted fertility (ICSI) and who have diagnosed sperm DNA fragmentation could go for an, albeit more invasive technique, called TESA. This is where a needle is inserted into the testicle and sperm are aspirated. “The pregnancy rate using testicular and ejaculated spermatozoa was 44% and 6%, respectively. Implantation percentage was found as 22% and 2% using testicular spermatozoa and ejaculated spermatozoa, respectively.” So you can see here the results are vastly better using the TESA technique above the normal ICSI procedure. 

There are other ways of selecting the best sperm for IVF, such as magnetic-activated cell sorting (MACS) or (IMSI) which uses sperm selection under a very high magnification, however most clinics in this country don't possess the technology to carry out these procedures. I advise looking to clinics abroad who are, in general, more technologically advanced than clinics in this country.  

What should you do if you suspect you have sperm DNA fragmentation? 

Well unfortunately, a DNA fragmentation test is not available on the NHS and is unlikely to be any time soon. The test I tend to recommend to patients is the Sperm Comet Test. The patient would need to travel to London to deposit their sample. The test itself is fairly inexpensive (as far as tests go!) at £350. The patient will then receive a user-friendly report giving them the percentage of DNA fragmentation seen in their sample. I really would recommend this test to couples who have: 

1. Received a lower than average sperm test result, be it morphology, motility or count. Even if they have had normal ranges in previous samples. 
2. Have suffered recurrent miscarriage in the 0 - 12 week period, but especially if within the first 8 weeks of conception. 
3. Have “unexplained” infertility. 
4. The man has smoked for a prolonged period. 
5. Has drank heavily for a period of time. 
6. Has been on strong medication/drugs for a prolonged period. 
7. Has undergone chemotherapy or radiotherapy. 
8. Has been exposed to high temperatures, i.e. chefs, welders, builders, underground workers.
9. Is over the age of 35 and has been unable to conceive. 

Details of the Sperm Comet Test can be found here: https://examenlab.com/the-test/

I hope you have found this blog useful. It’s not meant to scare all struggling couples into having a DNA test… I promise I’m not working on commission! But more to help couples who have been trying to conceive but with no medical answers as to why they’re failing. Sperm DNA fragmentation is not a phrase you will ever hear in your IVF consultations but it is something we need to be more aware of and be proactive in arming ourselves with all the facts before we pay for endless ICSI cycles that may never be fruitful because of damaged sperm.