Infertility is defined as the inability of a couple to achieve a clinical pregnancy after one year of regular, unprotected sexual intercourse. Globally, infertility affects more than 15% of couples, with male factors alone or in combination with female factors contributing to 50% of the cases. Despite the prevalence of male infertility, the evaluation of infertile men still relies on conventional semen analysis, which alone does not accurately predict male fertility potential and the success of assisted reproductive technology (ART). Surprisingly, around 15% of infertile patients exhibit a normal semen analysis. While the assessment of sperm concentration, motility, and morphology is standard, it may not fully reflect impaired sperm DNA integrity, which is crucial for normal fertilization, embryo development, and the success of ART.

Fundamental Processes Leading to The Fragmentation of Sperm DNA.

Sperm DNA fragmentation (SDF) primarily occurs due to defective maturation and abortive apoptosis within the testis, as well as oxidative stress (OS) throughout the male reproductive tract. In the course of spermatogenesis, chromatin is compacted through histone exchange with transitional proteins and protamines. Abortive apoptosis during spermatogenesis is another factor inducing SDF. Apoptosis is essential to prevent defective germ cells from differentiating into spermatozoa; however, failure of this process can lead to the accumulation of spermatozoa expressing apoptotic markers in the ejaculated semen. Excessive reactive oxygen species (ROS) can induce DNA damage and activate apoptotic pathways in spermatozoa. OS also activates intrinsic apoptotic pathways in spermatozoa, where externalization of phosphatidylserine serves as an early marker, and SDF acts as a late marker of apoptosis.

Factors in Clinical & Environmental Settings Contributing to Sperm DNA Fragmentation.

Sperm DNA fragmentation (SDF) exhibits an age-related increase, initiating in reproductive years and doubling between the ages of 20 and 60 years. This correlation is attributed to heightened exposure to oxidative stress (OS), defective sperm chromatin packaging, and disrupted apoptosis associated with aging. Clinical conditions linked to elevated SDF include varicocele, which induces testicular damage and SDF through increased intratesticular temperature and retrograde flow of renal and adrenal metabolites, leading to OS and apoptosis. Genitourinary infections and subsequent leukocytospermia contribute to increased reactive oxygen species (ROS) production, amplifying SDF. Men with testicular cancer and other malignancies also exhibit an increase in SDF, possibly due to associated endocrine alterations or OS in these pathologies.

Lifestyle and environmental factors are significant contributors to SDF. Obese men, in particular, display higher levels of OS and SDF compared to those with normal weight or overweight status. Mechanisms linking obesity to altered sperm function and reduced fertility potential include increased scrotal temperature, endocrine imbalance, and chronic systemic inflammation. Weight loss has been shown to lead to a significant improvement in SDF and overall fertility. Men with diabetes often demonstrate higher levels of SDF due to OS, associated with the generation of advanced glycation end products.

Cigarette smoking adversely affects DNA integrity due to tobacco metabolites, including nicotine, cadmium lead and benzopyrene. Alcohol consumption has also been linked to increased SDF and apoptosis

These clinical and environmental risk factors contribute to increased ROS production through various mechanisms, resulting in OS and ultimately leading to SDF

Impact of sperm DNA fragmentation on fertility.

Sperm DNA integrity is crucial for the successful birth of healthy offspring. Growing evidence underscores the independent and significant role of sperm DNA fragmentation (SDF), a marker of damaged chromatin, in male infertility and reproductive success.

High levels of SDF can negatively impact sperm fertilizing potential, affecting aspects such as motility, sperm–zona recognition, acrosomal exocytosis, and sperm–oocyte fusion. While damaged chromatin in spermatozoa may still retain fertilizing ability the diverse nature of DNA damage and the oocyte's repair capacity contribute to mixed results in studies evaluating SDF and fertilization capacity.

The impact of SDF on reproductive success hinges on the balance between DNA damage extent and the oocyte's DNA repair capacity. If sperm DNA damage surpasses the oocyte's repair capacity, it may influence embryo development potential and offspring health, as protaminized sperm chromatin cannot be adequately replaced by histones required for normal DNA replication. For instance, oxidative DNA lesions may lead to mutations, impacting gene expression if not repaired by oocyte base excision repair (BER) enzymes before the zygote S-phase. Consequently, the embryo may fail to develop, implant, or may be naturally aborted later on. Conversely, if existing DNA repair mechanisms within the oocyte restore a biologically stable genome, normal syngamy and subsequent embryonic development can occur.

The impact of SDF on reproductive success is suggested to be more apparent post‐fertilization, depending on the type and extent of sperm DNA damage and the oocyte's DNA repair capacity. SDF might not manifest during fertilization but may cause a late paternal effect related to paternal gene expression in the 4‐ to 8‐cell embryo. Experimental evidence has shown that high levels of induced SDF may allow normal IVF fertilization, corrected by oocytes from younger females, enabling normal embryo development.

The strongest evidence of SDF's adverse effect on fertility comes from animal studies, where confounding variables are minimized compared to clinical studies. Human IVF and ICSI models using proven fertile donor oocytes have also explored the impact of SDF on fertility. An ICSI study with donor oocytes of proven fertility indicated higher SDF rates in nonpregnant couples (34.9%) than pregnant couples (25.3%; p < 0.001; Gosálvez et al., 2013). The authors identified a threshold SDF value of 24.8% for pregnancy prediction, with 75% sensitivity and 69% specificity. Various human studies, despite confounding factors, have investigated the relationship between SDF and fertility in different scenarios, including natural pregnancy, unexplained infertility, recurrent pregnancy loss (RPL), intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI). Confounding factors like female age and comorbidities may influence the magnitude of SDF's effect on reproductive success in these studies.


The significance of sperm DNA fragmentation (SDF) in male infertility and its impact on fertilization, embryo development, and the success of assisted reproductive technology (ART). SDF can be caused by endogenous factors like defective maturation and abortive apoptosis in the testis or by oxidative stress throughout the male reproductive tract. Exogenous sources, including clinical conditions, lifestyle factors, and environmental exposures, also contribute to SDF. Various testing methods are available, with a suggested threshold of 20% for discriminative accuracy. The clinical scenarios where SDF testing is beneficial, such as unexplained infertility, recurrent pregnancy loss, varicocele, and cases opting for ART. Therapeutic interventions, including recurrent ejaculation, antioxidant therapy, lifestyle changes, varicocelectomy, and advanced sperm selection techniques, can be employed in patients with high SDF.

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