Sperm DNA Fragmentation: Is It Clinically Relevant?

August 22, 2012 9:30 am

A single spermatozoon is a remarkable achievement of nature.  This is the smallest and most physically active cell in the human body and is highly specialised for one simple function – fertilisation of the egg.  To achieve this, the sperm have adapted to eliminate all unnecessary baggage.  The sperm consists of a tail connected to a biological engine which provides huge energy supplies for the long journey to the egg.  At the head of the sperm is tiny bag-like structure called the acrosome, which detonates on contact, shedding enzymes which cut through the outer layers of the egg allowing the sperm access to the surface, where it binds and then enters initiating fertilisation.  This must surely be one of the most beautiful functions in all biology.

Between the acrosome at the head and the engine at the tail is the all-important payload of the sperm, the male DNA.  The DNA occupies most of the area of the sperm head, there is very little else as the usual cellular cytoplasm or cellular machinery are absent, the embryo derives all these things from the egg.  This is why the egg is the largest cell in the human, full of everything to get the embryo off to a good start.  All the sperm brings to the party is its crucial DNA contribution.  The sperm DNA itself is highly packaged into a very small space, which also protects it against damage.

Classical semen analysis is based mainly on sperm count, the number and ability of the sperm to swim and the shape or morphology of the sperm.  Testing for DNA damage in sperm is not routinely performed in a normal semen analysis, however, scientists are currently turning their attention to this area of fertility research.

 

Can We Accurately Assess DNA Damage in Sperm?

A host of tests designed to measure sperm DNA damage have been developed over the last few years.  Results are generally reported as the percentage of sperm having fragmented DNA, the so called sperm DNA fragmentation index (DFI).  Sperm that have been tested for their DNA integrity cannot then be used for treatment, they are destroyed by the test.  So we may know the percentage of sperm with damaged DNA, but we can never know whether single live sperm has damaged DNA or not.

The various methods are broadly in agreement when assessing any particular sample, though the nature and severity of a specific DNA injury is not revealed.  However, most of the methods require highly specialised equipment and are therefore more expensive than the traditional semen tests in common use.

 

What Things Can Damage the Sperm DNA? 

The dense and compact packaging of DNA in the sperm helps to protect it against the outside world.  However, DNA damage can still occur during the packaging process.  These and other problems can occur during the manufacture of sperm, a process which takes around 3 months from start to finish and is wonderfully named Spermatogenesis.  During this time of testicular spermatogenesis, sperm can be vulnerable to trauma of the testis or extremes of temperature.  Injury to the testes or even an extremely hot bath may show up as a slight transient dip in semen count or motility up to 3 months after the event.  Sperm quality usually recovers as sperm are continually being made in the testes, and sperm manufactured after the trauma are unaffected.  This is one reason why there can be fairly large differences in the standard semen assessment parameters such as motility (ability to swim), morphology (shape) and sperm count in samples obtained from the same man over a period of months.  Repeat semen analyses around 3 – 6 months apart are often recommended, especially where the sample only slightly sub-optimal.

Having been manufactured without defect, the sperm may still undergo DNA damage as they reside in the epididymis waiting for ejaculation.  The main concern here is reactive oxygen species (ROS) which can react with DNA causing breaks and fragmentation.  ROS themselves can be derived from immune cells which may invade the testis during infection or inflammation or from increased scrotal temperature and smoking.  However, it is not always clear whether the DNA damage is entirely due to external factors, in some cases inherent defects in spermatogenesis may leave sperm more susceptible to DNA damage.

 

Can We Do Anything to Minimise Sperm DNA Damage? 

The presence of ROS can be detected in semen samples, but it is not known exactly what threshold level of ROS we should regard as a threat to DNA integrity.  It is possible that increasing antioxidants in the diet, such as vitamins A, C and E may help prevent high ROS levels.  Smoking is a potent source of ROS and stopping has been shown to help semen quality in some smokers.

Overall, the advice to a man concerned about semen quality would be to eat a balanced diet containing sufficient antioxidants and to stop smoking.  Medicinal antioxidant treatments have not been shown to be effective so far, but this is one area of research that is continuing.

 

Does Sperm DNA Damage Really Have an Impact on Fertility? 

The question of how much impact DNA damage has on human fertility has generally been directed towards assisted reproductive techniques (ART), principally intracytoplasmic sperm injection (ICSI) in which a single sperm is manually selected and injected into the egg.  Remember that only a single sperm out of maybe 300 million in a typical ejaculate actually completes the journey to and fertilises the egg.  This is the reason nature favours the generation of huge sperm numbers and then allows them to race to the egg.  We believe that this is a natural selection mechanism and that damaged or incomplete sperm fall by the wayside, only the fittest completing the journey.

The selection mechanism is absent when ICSI is performed and this is why research scientists have identified this as the most likely situation in which to look for any adverse effects of sperm DNA fragmentation.  The main concern is whether there could be a risk of birth defects where a sperm with a high DFI is selected for ICSI.  Research has also been directed to the question of whether patients with high levels of sperm DNA fragmentation are less successful in when having other forms of fertility treatment.

 

Risk of Birth Defects

There has been a suggestion that the risk of birth defects could be elevated when intracytoplasmic sperm injection (ICSI) is performed with sperm samples having high DNA fragmentation.  The evidence for this is inconsistent and it is thought that some other male infertility related factors could also play a role.  This area of research deals with risks that are already extremely small, so it is difficult to quantify the various factors that may or may not contribute to the normal background risk.

Typically, we see scientific reports describing a risk of 0.2% for a given problem, instead of the 0.1% background risk, often followed by articles in the press claiming a particular treatment doubles the risk, when in fact the risk is still proportionally extremely small!  Quite often, this type of reporting does not inform the reader about the size or nature of the real issues involved.  More importantly, if any increased risk genuinely exists, we would expect to see these results corroborated in other independent studies before being accepted, and this has not happened to date.   Overall, there is no human study showing a direct association between birth defects and sperm DNA fragmentation.

 

IVF Success

If we cannot say that sperm DNA damage is responsible for an increased risk of birth defects can we say anything about whether it affects the chances of success in IVF?  Well, there is some evidence that sperm DNA fragmentation is associated with reduced implantation rates in mice.  The situation in the human is certainly different to the mouse, and the studies that have been conducted provide conflicting evidence.   In some cases authors have suggested better outcomes when sperm DNA fragmentation is low whilst other studies have actually reported slightly better outcomes when the sperm DNA is more fragmented!

One of the major problems with this kind of investigation is that there are so many other confounding factors present, such as the types of patients included in any given study, the variation in semen quality in the individual, and other varied underlying causes of the couple’s fertility problems.   Added to this is a lack of consensus about which of half a dozen different tests for sperm DNA fragmentation should be used and what level of sperm DNA fragmentation should be regarded as a threshold value to indicate poorer outcome.

Similar studies focussing on fertilisation rates have been conducted, and it is fair to say that the majority so far have shown little or no effect.  None of this categorically rules out a role for sperm DNA damage, it is just that sometimes the only scientifically rational position to take is to say we do not have sufficient evidence at present.

 

Summary

Despite suggestions that sperm DNA fragmentation could be a marker of sperm quality and predictor of fertility treatment outcome, this has not generally been supported by the evidence so far.  In some cases sperm DNA testing may be of value and recommended by your physician, but this will depend on individual circumstances.  As analysis techniques improve and more refined studies are undertaken we may see a much larger role for sperm DNA fragmentation testing in the future, but it cannot be regarded as part of the routine semen assessment at the current time.

  • Sperm DNA fragmentation may vary considerably over time in a single individual.
  • The best way to reduce sperm DNA fragmentation is to eat fresh foods, particularly those containing antioxidants or vitamin C and E, and to stop smoking.
  • The tests for sperm DNA fragmentation are still being refined and tested but no consensus regarding the maximum tolerable level of DNA damage currently exists.
  • There is no compelling evidence that sperm DNA fragmentation reduces IVF success rates or significantly increases the risk of inherited birth defects, though research continues.
  • Routine testing for sperm DNA fragmentation is not currently recommended, though it may have a role in the assessment or monitoring of some patients at the discretion of their physician.
  • This is currently an active area of scientific research and we are likely see improvements in the testing, risk assessment and treatment of sperm DNA fragmentation.

 

 

Science Director
Concept Fertility Clinic
www.conceptfertility.com

 

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