information about sperm DNA fragmentation for patients

Almost 50% of all cases of infertility may be associated with a male factor. A semen analysis that measures sperm concentration, motility and morphology has classically been used as the gold standard test for determining a man’s fertility. However, this test does not provide any information about the integrity of the genetic material (DNA) that the sperm delivers to the egg, which is essential for normal embryo development. Thus, a high level of DNA damage in sperm cells may represent a cause of male infertility that conventional examinations cannot detect. It is currently known that sperm DNA fragmentation is significantly higher in infertile men and while men with poor semen parameters are more likely to have high sperm DNA fragmentation, high sperm DNA fragmentation is also found in men with normal semen parameters who may be diagnosed with unexplained infertility.

Sperm DNA and embryo development

Sperm with high DNA damage may result in poor embryo development and failed implantation. High sperm DNA fragmentation is more likely to affect embryos from day two of development but can impact the embryo at any point after that. There is even some evidence to suggest that DNA damage in the embryo could result in health issues for the children.

Sperm DNA and pregnancy, miscarriage and recurrent pregnancy loss

There is considerable evidence to show that the chances of an ongoing pregnancy are significantly reduced in couples where the male partner has a high percentage of sperm with fragmented DNA. Several large studies have revealed that high sperm DNA fragmentation is associated with reduced pregnancy rates and live birth rates following natural or assisted conception as well as an increased risk of miscarriage. There is even more convincing evidence for high sperm DNA damage in partners of women experiencing recurrent pregnancy loss. Because of this, The European Society for Human Reproduction and Embryology (ESHRE 2022) guidelines recommend sperm DNA fragmentation testing for men whose partners experience recurrent miscarriage. Overall, the results of these studies lend support for the value of testing for sperm DNA fragmentation to identify possible causes for unexplained infertility, failed IVF treatment cycles or recurrent miscarriage.

Causes of sperm DNA fragmentation

A major cause for sperm DNA damage is oxidative stress due to an imbalance in oxidants and antioxidants in the reproductive tract. Other factors include defects in sperm DNA packaging and DNA repair mechanisms during sperm development as well as abnormalities in the regulation of programmed cell death which is vital for regulating sperm production. Increased sperm DNA fragmentation is also associated with a variety of lifestyle and environmental factors listed below.

Factors influencing sperm DNA fragmentation

Indications for male patients who may benefit from a sperm DNA fragmentation test

  • unexplained infertility
  • arrested embryo development
  • poor blastocyst development
  • multiple failed IVF/ICSI treatment
  • recurrent miscarriage in partner
  • advanced age
  • varicocoele/varicocoelectomy
  • diabetes
  • poor semen parameters
  • exposure to harmful substances

How does the DNA fragmentation test work?

Sperm are stained with a fluorescent probe that interacts with the DNA molecule. The fluorescence signal changes when the DNA is fragmented, and this is monitored using a flow cytometer. The style of test used has been developed using human and animal models over the last 40 years and is one of the most statistically robust tests available for sperm DNA fragmentation. It is a standardised, validated test with high reproducibility and low variability.

The test report

The test report provides two indicators of DNA damage:

1. DNA Fragmentation Index (%DFI: % sperm cells containing damaged DNA)

Results are reported showing 4 statistical categories of fertility potential:

  • < 15% DFI = excellent to good sperm DNA integrity
  • 15 to 25% DFI = good to fair sperm DNA integrity
  • 25% to 50% DFI = fair to poor sperm DNA integrity
  • > 50% DFI = very poor sperm DNA integrity

The statistically significant DFI threshold for subfertility has been established at > 25 %.

However, normal full-term pregnancies are possible with an elevated DFI, but the higher the level of fragmentation, the greater the incidence of reduced term pregnancies and miscarriage.

2. High DNA stainability (HDS)

This shows the percentage of sperm with immature, abnormal DNA structure. Levels of more than 25% HDS may result in early embryo death with IVF or ICSI and reduce the chances of pregnancy.

Treatment for sperm DNA fragmentation

One of the simplest ways to reduce sperm DNA damage is to encourage frequent ejaculation as this has been shown to significantly reduce sperm DNA damage and improve pregnancy outocmes. Sperm DNA damage is associated with clinical varicocoele (a clump of varicose veins in the testes), which is the leading known cause of male infertility. There is now growing evidence to show that clinical varicocoele repair may improve sperm DNA integrity. Treatment of infection with antibiotics may also be beneficial in reducing sperm DNA damage. DNA fragmentation may be caused by oxidative stress resulting from varicocele or infection. Alternatively, oxidative stress may arise from insufficient levels of antioxidants in the semen. A change in lifestyle and a diet designed to protect against oxidative stress may help reduce the levels of DNA fragmentation in some of these cases. Furthermore, studies using antioxidant supplementation to reduce DNA damage are promising. Men with low sperm counts and elevated DNA damage may also benefit from treatment with FSH. Initiatives to reduce the levels of DNA fragmentation can be assessed by undertaking a second test three months after the first.

Circumvention of Sperm DNA Damage

It is not always possible to repair sperm DNA damage particularly if the damage is due to abnormal DNA packaging or abnormal programmed cell death. It has been proposed that DNA damage can occur after the sperm leave the testis so that testicular sperm may have healthier DNA integrity than ejaculated sperm. Several studies show that use of testicular sperm rather than ejaculated sperm

significantly increases pregnancy rates in cases where men have low sperm counts and high sperm DNA fragmentation or in men who have normal sperm counts with high DNA fragmentation and unexplained infertility. Several studies show that ICSI may be a more effective treatment than IVF for sperm with high DNA fragmentation since fertilisation and pregnancy rates are better than IVF

alone. The use of sperm selection methods such as microfluidic chambers or chemically coated dishes (PICSI) to improve the yield of sperm with low DNA damage can be used in conjunction with ICSI to optimise outcomes for men with high sperm DNA fragmentation. IUI is not advised when Sperm DNA fragmentation levels are high as pregnancy outcomes are very poor.

Advantages of a sperm DNA fragmentation test

The test provides a reliable analysis of sperm DNA integrity that may help to identify men who are at risk of failing to initiate a healthy ongoing pregnancy. Information about sperm DNA integrity may help in the clinical diagnosis, management and treatment of male infertility and may be of value in assessing outcome of your assisted conception treatment. Identification of high levels of DNA

fragmentation in the sperm may guide your doctor as to whether sperm donation may be appropriate. Sperm DNA fragmentation testing may help you make an informed choice regarding your subsequent course of treatment.


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Prepared by: S Homa Date: 30 October 2023

Authorised by: P J Ford