DNA is the material in all our cells that contain all of our genes. Genes enable cells to make proteins that are the foundation for our bodies to develop and function. In order to produce proteins and other products, DNA in most cells is partially unwound from “histones” and actively transcribed. However, DNA in sperm is packaged differently, in a more condensed manner, much of it around different proteins called “protamines”. This more condensed packaging of DNA is one of several strategies that sperm uses to stabilize and lighten the DNA carries in order to make it all the way on its journey to the egg.
The DNA in sperm has become more of a focus in recent years since the invention and advancement of In Vitro Fertilization (IVF) with Intracytoplasmic Sperm Injection (ICSI). By literally injecting a single sperm into a single egg, many of the barriers to conception are removed. Yet IVF with ICSI is not 100% successful. One mechanism for IVF-ICSI failure that has been explored has to do with Sperm DNA Fragmentation.
DNA fragmentation is a reference to damage to the DNA within sperm. Clinically it is impossible to measure DNA damage within a specific sperm and then use that same sperm for IVF. Rather the incidence of DNA damage for all the sperm in the ejaculate is evaluated. A discriminant value of DNA Fragmentation Index (DFI) appears to be above 30%
DNA fragmentation has been used to predict the chance of natural conception with poor concordance as to whether there is any effect. The place where DNA fragmentation is most often clinically is in the setting of poor embryo development and or early miscarriage, both of which are associated with elevated DFI.
DNA fragmentation Index can be measured by a variety of assays including: Sperm Chromatin Structural Assay (SCSA), Terminal deoxynucleotidyl transferase dUTP neck end labeling (TUNEL), Comet and Sperm Chromatin Dispersion (SCD).
The most commonly accepted theory as to how increased fragmentation occurs is that Increased oxidative stress causes formation of Reactive Oxygen Species (ROS) in the mitochondria that eventually leads to sperm DNA damage.
Correlation between increased DNA fragmentation and an association with decreased initiation of pregnancy is controversial; however data showing an association with poor embryo development in IVF-ICSI and with increased early miscarriage appears more robust. Therefore, application of this test appears most appropriate in these settings.
What are strategies to improve results in the setting of DNA fragmentation?
One approach is to fix any possible underlying problems. A conservative focus on general health including diet, exercise, weight loss if appropriate, smoking cessation has been used with limited success. Decreased abstinence period before ejaculation and use of certain antioxidants may also have some beneficial effect. Agents used include Co enzyme Q 10, carnitine, lycopene beta carotene, vitamins C, E B12, astaxanthin, alphalipoic aci, zinc and seleinium, but there is limited data showing clear evidence of benefit.
A possible anatomic risk factor for increased fragmentation is the presence of a varicocele (abnormally dilated veins in the scrotum next to one or both testes). Several papers have reported a significant majority of men with increased DNA fragmentation and varicoceles will show significant reduction in fragmentation after varicocelectomy.
Another tactic has to due with Sperm selection. One technique known as Physiologic ICSI or PICSI exposes the sperm to hyaluronic acid (HA) and isolates the most mature sperm with the surface HA receptors that can bind to the egg. Results range from improved results to no effect. There is also a technique known as “Microfluidic Sorting” which involves a chip on which sperm samples migrate across chemical micro barriers that mimic the female vaginal environment. Results from this technique may vary as well.
TESE: Testicular sperm extraction or surgical sperm retrieval has also been employed as a method to deal with increased DNA fragmentation. This relies on the assumption that most fragmentation occurs in the epididymis after the sperm has left the testis . In several papers by Esteves et al, TESE was used to successfully improve the chance of live birth in the setting of increase Sperm DNA fragmentation and either recurrent poor embryo development or recurrent early miscarriage.
In my opinion, the issue of DNA fragmentation testing should be limited to patients who have had 2 cycles of poor early embryo development and or recurrent early pregnancy loss. If elevated DFI is detected, I think conservative measures are appropriate, even if frustrating that one must wait 3 months (literature states 3-6 months) to retest and that if levels remain the same, consideration of surgical options: Varicocelectomy and or TESE are appropriate.