Varicocele and DNA Damage

Spermatozoa of infertile men possess substantially more chromatin defects and DNA damage than spermatozoa of fertile men, suggesting that sperm DNA damage is predictive of male fertility potential [95-97]. The etiology of sperm DNA damage is multifactorial and most investigators have proposed that ultimately, oxi-dative stress, aberrant chromatin remodeling (compaction), and abortive apoptosis can result in sperm DNA damage [98-101],

Table 18.4 Prospective studies on the effect of clinical varicocele repair on mean (±SD) sperm% DNA fragmentation index (DFI)






Smit et al. [84], 2010


35 ± 13

30± 15


Zini et al. [115], 2010


18 ± 11

11 ±6


Several studies have shown that infertile patients with varicocele have high levels of sperm DNA damage [87, 88, 102-104] . The mechanism of varicocele-induced sperm DNA damage is believed to be multifactorial, although most studies have suggested that the sperm DNA damage in these men is, at least in part, due to OS [53]. Smith et al. reported high levels of sperm DNA damage, using two assays of DNA damage (sperm chromatin structure assay, SCSA and Terminal deoxynucle-otidyl transferase-mediated dUTP Nick End-Labeling, TUNEL), in patients with varicocele regardless of semen profile when compared to normozoospermic donors. They also observed that semen ROS levels (as measured by chemiluminescence) were significantly associated with sperm DNA damage [87]. Similarly, Saleh et al. [88] observed that infertile men with varicocele had significantly higher levels of sperm DNA damage (measured by SCSA) and OS (higher semen ROS levels and lower antioxidant capacity) when compared to fertile controls.

Another mechanism by which varicocele may induce sperm DNA damage is by increased apoptosis in the testis. Various endogenous and exogenous factors have been linked to testicular apoptosis in men with varicocele. Factors linked to testicu-lar apoptosis in men with varicocele include alterations in intracellular calcium [104], hypoxia [105,106], androgen deprivation [107], heat stress [108,109], exposure to toxins (e.g., cadmium) [79, 110]. and increased levels of apoptotic factors such as IL-6 and gonadal peptides [111, 112].

Several studies have now evaluated the effect of varicocelectomy on sperm DNA damage [84, 113, 114]. An evaluation of two published prospective studies of vari-cocelectomy on sperm DNA damage demonstrates that varicocele repair is associated with a significant decrease in sperm DNA damage (Table 18.4) [84,115]. These data further support the premise that varicocele reduces testicular OS if we consider that the sperm DNA damage in these men is likely due to OS.

18.9 Summary

Varicocele is a common clinical finding in infertile men seeking fertility treatment. Varicocelectomy remains the most cost-effective and reversible treatment of infertile men with varicocele. Oxidative stress biomarkers (e.g., ROS, malonaldehyde) are significantly higher in the seminal fluid of infertile men with varicocele and this is clinically relevant as oxidative stress has been associated with poor sperm function and sperm DNA damage. Most studies have shown that infertile men with vari-cocele have suppressed levels of seminal antioxidant capacity, although some studies have found high levels of seminal antioxidant enzyme activity in these men. Varicocele repair is associated with improvement in semen parameters, pregnancy rates, and reduced seminal oxidative stress. However, randomized controlled trials are needed to confirm the effects of varicocelectomy on seminal oxidative stress as the available data are derived from uncontrolled studies.

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