Along the same lines, Rodriguez Peña et al. [271] failed to observed changes in nitric oxide concentrations after varicocele repair . Their study, however, included varicocele patients with no history of infertility that might have biased their results. Lacerda et al. [272] showed that varicocele repair was associated with no demonstrable beneficial effect of varicocelectomy in reducing seminal levels of malondialdehyde in adolescents with varicocele, despite a positive effect on sperm DNA integrity and mitochondrial activity. The aforesaid authors speculated that varicocele repair was unable to alter the levels of seminal plasma oxidative stress because these levels were not elevated pre-operatively in their group of adolescents, and suggested that varicocele itself does not alter seminal plasma lipid peroxidation in this particular subset of patients. However, it is still unknown whether a time-dependent effect of varicocele on markers of OS will occur in adolescents at later age.

Some studies have also examined blood levels of thiobarbituric acid reactive substances (TBARS) and plasma peroxidation susceptibility lag time (a marker of antioxidant levels) in spermatic veins and peripheral veins before and after varicocele repair. A marked reduction in peripheral vein plasma TBARS levels, indicating a decrease in ROS, and a significant increase in plasma peroxidation susceptibility lag time, indicating an increase in the antioxidant levels, have been observed several months to 1 year after repair, as shown in Table 8.1 [65, 156].

By contrast, the clinical interpretation of studies assessing seminal antioxidant response to varicocele repair poses a more complex problem. For non-enzymatic antioxidants, such as vitamin C, retinol, zinc, selenium, protein thiols and albumin, most studies have shown pre-operative reduced levels and significant postoperative increases to normal levels [64, 74, 149, 156, 270]. With regards to vitamin E, although one study showed that low pre-operative levels can be normalized post-operatively, [156] a contrary report demonstrated a significant reduction in vitamin E levels 3–6 months after varicocelectomy [64]. However, since vitamin E is an essential vitamin and its levels in body fluids are influenced by dietary intake, no definite predictive value for its measurement in semen can be anticipated to reflect the balance between oxidants and antioxidants without controlling for the diet. As far as the activities of enzymatic antioxidants are concerned, two studies demonstrated that seminal superoxide dismutase (SOD), and intracellular superoxide dismutase, catalase (CAT) and glutathione peroxidase (GPx) activities were elevated in men with varicocele, all of which were reduced after surgery [149, 156]. In contrast, Mostafa et al. [64] observed a significant increase in post-operative seminal plasma levels of SOD, CAT, GPx.

Although some observations suggest that seminal enzymatic antioxidants exhibit lower activities in infertile men with varicocele than fertile men, which might be attributed to auto-oxidation as well as protein unfolding and degradation. Additional studies are needed to resolve the discrepancy in the results as shown by different researchers.

Notably, the time required to observe any improvement in oxidative stress markers after varicocele repair is variable. In one report, Dada et al. [74] showed that decline in ROS levels after varicocelectomy was proportional to the length of the postoperative period. In their study, damage to sperm DNA, which usually takes extended periods to revert to normal status, improved only after 6 months. Mostafa et al. [64] observed that markers of seminal oxidative stress (NO, H₂O₂ and malondialdehyde) were significantly reduced whereas antioxidant levels of superoxide dismutase, catalase, glutathione peroxidase and vitamin C were elevated 3 and 6 months after varicocele repair. In another report, Hurtado de Catalfo et al. [156] showed that levels of non-enzymatic antioxidants (zinc and selenium) and the proportion of sperm exhibiting DNA fragmentation were still abnormal 1 month after varicocele repair, while levels of reduced and oxidized seminal glutathione and antioxidant enzymes were normalized as compared with age-matched fertile controls. Additionally, Chen et al. [270] demonstrated that sperm mitochondrial DNA deletions and 8-OHdG were reduced whereas seminal plasma protein thiols and ascorbic acid levels were elevated 6 months after varicocele repair compared with their preoperative levels. Lastly, Sakamoto et al. [149] found that a time lag of approximately 6 months is required to achieve a marked improvement in seminal ROS markers, such as NO, 8-OHdG and hexanoyl-lysine, after varicocele repair.