We take you through what sperm DNA fragmentation means, what implications it has for fertility, and how it can be tested for and treated.

In about half of all couples experiencing infertility, male factors are found to be important. One contributor to male infertility is sperm DNA fragmentation. But what is this, exactly, and how does it come about? In this article, we’ll take you through what is meant by this term, what implications it has, and how it can be tested for and treated.

What is sperm DNA fragmentation?

When fully mature, human sperm cells (spermatozoa) have the ability to move towards a female egg (ovum), penetrate and fertilise it. When one sperm call (spermatozoon) succeeds, it transfers its genetic material, in the form of 23 chromosomes containing DNA and proteins, to the egg.

A critical component of male fertility is thus healthy sperm: those that can not only move well (known as sperm motility) and that have proper form (morphology), but also those whose DNA is intact, referred to as sperm DNA integrity. In some cases, however, sperm incur damage to their DNA.

On a basic level, sperm DNA damage refers to a variety of chemical changes that can occur within the normal structure of the DNA within sperm. Sperm DNA fragmentation is a specific form of damage, and refers to single or double strand breaks within the DNA, which compromise the integrity of the genetic information. This makes affected sperm less able to contribute to a viable pregnancy.

How does it happen?

Causes of sperm DNA fragmentation can be classified into two main categories. The first is extrinsic, or environmental causes, which include:

  • Exposure to heat
  • Smoking
  • Environmental pollutants
  • Chemotherapy or radiation for treatment of cancer

The second category is intrinsic causes, originating in the body. These include:

  • Abortive apoptosis. During the earliest stages of sperm production (spermiogenesis), a screening mechanism takes place within the Sertoli cells of the testicle; this should detect germ cells (which have the potential to become sperm) containing genetic errors, and eliminate them through the process of apoptosis (cell death). Sometimes, however, this process does not work as it should, such that abnormal sperm survive and continue their journey to become a part of the ejaculate.
  • Abnormal chromatin packaging. As DNA is packed into the head of a sperm cell during spermiogenesis, it is tightly condensed in a process called chromatin remodeling. During this transformative process, breaks in DNA can occur. Often these are subsequently repaired, but when this does not occur, sperm cells with abnormalities are again the result.
  • Oxidative stress. This refers to an excess of molecules known as free radicals or reactive oxygen species (ROS) which can damage cells. ROS are naturally produced by our body during metabolic processes, but when unopposed by antioxidants, they can build up cause damage to DNA. Sperm are vulnerable to this type of damage as they migrate from the seminiferous tubules, where they are formed, through the epididymis.

In some cases, damage incurred through the above processes can be repaired either by the fertilised egg (oocyte) or by the embryo.

What are the risk factors?

Risk factors for sperm DNA fragmentation (SDF) include:

How is it measured?

It should be noted that sperm DNA fragmentation is not tested as a part of standard semen analysis. Usually, such an analysis assesses semen quality by looking at semen parameters such as semen volume, sperm count, sperm concentration, motility and morphology.

In order to evaluate sperm DNA damage, a number of specific tests have been developed. All of these aim to estimate the degree of DNA fragmentation based on a semen sample produced by masturbation. The most commonly-used tests are:

  • The terminal deoxynucleotidyl transferase-mediated deoxyuridine trisphosphate nick end labeling (TUNEL) assay. This type of lab test can be carried out at most fertility clinics, and measures so-called ‘nicks’ or broken sections of DNA by means of flow cytometry or a fluorescence microscope. It can estimate the extent of sperm DNA damage based on a very small sample (200 spermatozoa or fewer).
  • Comet assay. Also known as the single cell gel electrophoresis assay, this method estimates SDF in terms of the number of broken DNA strands in an individual spermatozoon. A specialist looks through a microscope to see how the DNA strands move under the influence of an electric field, in which broken sections become more visible. It requires a relatively small amount of spermatozoa (around 5,000).
  • Sperm chromatin structure assay (SCSA). This test measures how susceptible sperm are to damage from acid or heat, and thereby estimates the amount of abnormal DNA that they contain.
  • Sperm chromatin dispersion (SCD) or 'halo' test. Unlike the other tests, the absence of sperm damage is what is measured in this case. After acid denaturation and removal of nuclear proteins, sperm that are undamaged appear with a halo around the sperm head when viewed under the microscope.

No one of these tests is considered to be the best, although the SCSA tends to be used most often. The choice of test may depend in part on the number of sperm thought to be available for analysis. The TUNEL and Comet assays directly examine DNA fragmentation in sperm, while the SCSA and SCD are indirect, estimating SNA fragmentation by assessing the susceptibility of sperm to damage from acid or heat.

Results of an SDF test are often offered in terms of a DNA fragmentation index (DFI), particularly where the TUNEL and SCSA assays are used. The DFI is an estimation of the percentage of a man’s sperm that have DNA abnormalities. Above 30% is often considered to be a high value.

How does sperm DNA fragmentation affect male fertility?

DNA fragmentation in sperm does not automatically spell male infertility, as sperm with this kind of damage are still able to fertilise a female egg. However, sperm DNA damage has also been associated with the following reproductive outcomes:

Sperm DNA fragmentation has been examined in terms of its effect on both unassisted conception and conception via assisted reproductive technologies (ARTs). In terms of the former, one study found that men who conceived with their partners without intervention were significantly more likely to have a DNA fragmentation index (measured by TUNEL assay) below 25%, compared to men who did not.

A 2014 systematic review and meta-analysis examined the overall relationship between sperm DNA damage and live birth rates in ART, and found that couples with high sperm DNA fragmentation in the male partner had significantly lower live birth rates after undergoing in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI). A 2019 study found that a DNA fragmentation index, measured by a TUNEL assay, of above 20% was associated with a significantly lower pregnancy rate among couples undertaking a intracytoplasmic sperm injection (ICSI); it did not seem to have an impact among those who used intrauterine insemination (IUI).

Researchers have attempted to establish SDF cut-off values that would help to predict the likelihood of pregnancy, either with or without the use of assisted reproduction technology (ART). A 2018 meta-analysis found that levels of sperm DNA fragmentation were significantly higher among men experiencing infertility compared to those who were not, and suggested that an SDF cutoff value of 20% might be able to predict which men would be fertile. In other words, men with SDF rates above 20% would be likely to encounter difficulty in contributing to a pregnancy.

Can sperm DNA fragmentation be treated?

There are several lines of treatment for men diagnosed with high sperm DNA fragmentation. They are as follows:

Addressing lifestyle factors. Depending on a man’s risk factors, he might be advised to do some or all of the following:

  • Reach a healthy weight
  • Engage in regular exercise
  • Quit smoking
  • Reduce use of alcohol
  • Wear looser underwear
  • Avoid hot tubs and saunas, in order to avoid exposing the testicles to too much heat
  • Ejaculate more frequently, as this is associated with a reduction in SDF
  • Consume antioxidant-rich foods, such as brightly coloured fruits and vegetables

Antioxidant therapy is another line of treatment that has been shown in meta-analysis to help to reduce oxidative stress and in individual studies to improve sperm DNA integrity. This involves taking supplements including Vitamin C,  Vitamin E, zinc, selenium, and coenzyme Q10.

Varicocele repair may also be indicated, as studies have found that SDF tends to be high among men with varicocele, and also that SDF levels are reduced after varicocele repair.

Treatment of infection is also recommended, as sexually transmitted infections or inflammations of the prostate gland can contribute to sperm DNA fragmentation by increasing oxidative stress.

In addition, although these do not address the underlying cause, there are several strategies to select healthier sperm for assistive reproductive technologies. This includes using a cell sorter, magnetic sorting, or a high-magnification microscope.

It has also been found that testicular sperm—those sourced directly from the testes, as opposed to those that are ejaculated in semen—tend to have better DNA integrity, and lead to better pregnancy outcomes in procedures such as intracytoplasmic sperm injection (ICSI). Thus, certain techniques used for sperm retrieval in cases of azoospermia, such as testicular sperm extraction, may be appropriate for men with high sperm DNA fragmentation.

Commonly asked questions

Can my partner and I still get pregnant if I have sperm DNA fragmentation?

Yes, it is still possible to conceive. While studies show that there are some hurdles—lower pregnancy rates and longer times to conception—there is also good evidence that healthy pregnancies can occur, especially with the use of assisted reproductive technologies.

One set of guidelines suggests that SDF testing could be appropriate for men or couples with:

Takeaway

Healthy sperm are important for initiation and maintenance of pregnancy, but sperm DNA damage can occur due to a number of internal and external factors, and is a cause of male infertility. Furthermore, sperm DNA fragmentation is not routinely investigated in semen tests.

Research shows, however, that this may serve as a useful biomarker when infertility is otherwise unexplained. This is because it can serve as a predictor of fertility potential and is correlated with pregnancy rates and the success of procedures, such as IVF and ICSI. A number of different tests are used to assess sperm DNA fragmentation. Once it is found, steps can be taken to address it.

Cada is committed to helping men and women take charge of their fertility. Are you interested in exploring this issue, or others relating to sperm quality and reproductive health? Get in touch with us so that we can get to know you and your goals. Reserve your spot for a free consultation now.