DNA Fragmentation

Changes in the structure and functionality of sperm can lead to a decrease in the pregnancy rate. The integrity of sperm DNA is one of the fundamental factors for fertility, as it contributes to genetic factors that affect the proper development of embryogenesis.

DNA fragmentation is due to enzymatic defects that lead to a disruption of the normal DNA structure. Similarly, changes in programmed cell death mechanisms, which are essential for eliminating abnormal cells, can lead to the presence of a greater number of sperm with DNA fragmentation.

Furthermore, and no less importantly, oxidative stress is currently being extensively studied due to its more than likely influence on the loss of DNA integrity. Given that the presence of low levels of free oxygen radicals is essential for excellent sperm functionality, we now know that the presence of inflammatory phenomena in the testicle and/or epididymis are highly detrimental to DNA integrity, since they increase the production of these radicals. In addition to inflammatory phenomena, other situations can increase oxidative stress, namely vitamin and growth factor deficiencies, as well as pathologies such as varicocele, obstructive lesions of the seminal duct, and germ cell mutations (as a result of radiotherapy, chemotherapy, etc).

Since sperm analysis is a descriptive assessment that may be able to discriminate between sperm from fertile and infertile men, it is now also evident that sperm DNA damage can occur in men with infertility. DNA fragmentation is a common condition in sperm up to certain levels due to the biology of reproduction itself, but an exaggerated increase in this level of sperm DNA fragmentation has been shown to reduce the possibility of natural conception.

Although no studies have unequivocally and directly tested the impact of sperm DNA fragmentation on the clinical evaluation of infertile couples, sperm DNA fragmentation is more common in infertile men and has been identified as a major contributor to male infertility, in the form of worse outcomes after assisted reproductive procedures, and including changes in embryonic development, more spontaneous abortions, increased recurrent pregnancy loss, and higher frequency of birth defects.

Sperm DNA fragmentation can be increased by several factors. These include hormonal abnormalities, varicocele, chronic infection (particularly of the seminal tract), and lifestyle factors (e.g. smoking).

Several tests have been described to measure sperm DNA fragmentation. It has been suggested that current methods for assessing sperm DNA integrity do not yet validly predict outcomes of assisted reproductive technology and there is controversy as to whether they should be routinely recommended for clinical use.

The most frequently used test, and the one with the greatest current validation, is the sperm chromatin structure test (SCSA), which indirectly assesses DNA fragmentation. This sperm chromatin structure test is still the most widely studied in this area. In SCSA, the number of sperm with DNA fragmentation is indicated by the DNA fragmentation index (DFI). A DFI threshold of 25%, measured with SCSA, is suggested to be associated with reduced pregnancy rates by natural conception or intrauterine insemination (IUI).

Furthermore, DFI values ​​>50% in SCSA are associated with worse in vitro fertilization (IVF) outcomes. More recently, scores for the proportions of sperm with high or low DNA fragmentation have been shown to be valuable in the diagnosis of male infertility and in providing additional discriminatory information for the prediction of live births by IVF and ICSI.

Regardless of the DNA fragmentation rates at the testicular level, which exist even under the best conditions, it is known that extra-testicular factors are highly relevant in the deterioration of these rates. Infections and/or inflammations of the epididymis, seminal vesicles and prostate lead to an increase in free oxygen radicals.

Also, radiotherapy and/or chemotherapy treatments can lead to temporary or permanent damage to the DNA chain, depending on the type of treatment, its duration and intensity.

The presence of varicocele, due to the decrease in oxygen concentrations, the increase in temperature and the venous reflux of catabolites to the testicle, also leads to an increase in oxidative stress levels, suggesting more targeted therapeutic attitudes.

The spermogram, allowing in specific situations and according to very clear indications that vary from man to man, the evaluation of advanced seminal parameters, namely the evaluation of the sperm DNA fragmentation rate, has brought the ability to use this parameter in guiding therapeutic attitudes with greater effectiveness, which means that it is now internationally recognized as a fundamental evaluation for a good interpretation of the sperm’s capacity to fertilize the oocyte.

Testicular sperm have lower levels of DNA fragmentation index (DFI) compared with ejaculated sperm. Couples with high DNA fragmentation may benefit from the combination of testicular sperm extraction and intracytoplasmic sperm injection (ICSI), an approach called TESE-ICSI. However, more evidence is needed to support this practice in the routine clinical setting.

In couples with a history of recurrent miscarriages without a defined cause and long-term idiopathic infertility, measurement of the fragmentation rate is indicated, in order to more carefully define which couples may benefit from sperm collection directly from the testicle. The same applies to men with varicocele who present very high values ​​of the DNA fragmentation rate in their sperm.

Improvement of this parameter after varicocele correction surgery may actually allow natural conception or a substantial increase in the effectiveness of medically assisted reproduction processes.