Critical Commentary

Zn is a ubiquitous trace element that protects proteins and enzymes from free radical attack. Since Zn does not readily undergo oxidation-reduction reactions, it can function to prevent free radical formation by other highly reactive metals such as copper and iron. The Zn molecule in Zn-containing enzymes shields specific

Table 22.8 Quality assessment of oral zinc supplementation

References Study design Cases Dosage Duration Ages Main outcome

Table 22.8 Quality assessment of oral zinc supplementation

References Study design Cases Dosage Duration Ages Main outcome

Wong et al. [110]

Double-blind randomized controlled

94 (22A;

23B;

24c; 25D)

Folic acid (5 mg/day)A; Zn sulfate (66 mg/day)B; Zn sulfate (66 mg/day) + Folic acid (5 mg/day)c; Placebo13

26-week intervention

t Concentration c(p<0.05) t Morphology A3(p<0.05) f Total normal count c(p< 0.05)

Omu et al. [107]

Case-control

45 (IIa;

12B;

14c; 8D)

Zn sulfate (400 mg/day)A; Zn sulfate (400 mg/day) + vitamin E (20 mg/day)B; Zn sulfate (400 mg/day) + vitamin E (20 mg/day) + vitamin C

3-month intervention

34±9C

t Motility AB C(p< 0.001) f Fertilizing capacity

A-B'c(p< 0.05) f Total antioxidant capacity ABC(p<0.001)

(10 mg/day)c; nontherapy

t Seminal Bcl-2 A-B'c(p< 0.05) I Bax ABC(p<0.01) I MDA ABC(p<0.01) I TNF-a AB C(p< 0.001)

control13

Zn zinc; MDA malone dialdehyde

Zn zinc; MDA malone dialdehyde regions of the enzyme from being oxidized, thereby preserving enzymatic stability and activity.

For such reasons, Zn therapy is thought to be an effective treatment for ROSassociated male infertility. Interestingly enough, fertile and subfertile men have shown significant differences in their seminal plasma Zn concentrations and sperm motility [107,111]. Zn is hypothesized to exert its effects vianumerous pathways to prevent OS formation, apoptosis, and sperm DNA fragmentation by virtue of its stabilizing nature as an antioxidant. Chia et al. noted seminal plasma zinc concentration to be significantly correlated with sperm density, motility, and viability [111]. These findings suggest that Zn may promote male fertility via its positive effect on critical steps in spermatogenesis.

Wong et al. reported an increase in total normal sperm count in both fertile and subfertile men following combination treatment with Zn sulfate (66 mg/day) and folic acid (5 mg/day) [110] . Hence, Zn and folic acid may work in a synergistic manner to protect spermatozoa. There is a need for additional randomized, placebo-controlled trials with larger sample sizes as well as various dosages and intervention periods to confirm the efficacy and safety of Zn and folic acid combination therapy. Establishing the beneficial effects of Zn treatment on fertility may aid in a therapeutic approach for treating iOAT.

22.15 Conclusion

Regulated levels of ROS are essential in physiologically regulating normal sperm function. However, in an environment with uncontrolled, elevated ROS levels, OS ensues and sperm function and viability are endangered. OS resulting from excessive production of ROS, impaired antioxidant defense mechanisms, or both precipitates in a wide range of pathologies that are currently believed to adversely affect sperm quality. Despite the established role of OS in the pathogenesis of male infertility, there is a lack of consensus as to the clinical utility of seminal OS testing in an infertility clinic. A major reason for this disconnect is related to the weakly defined standard protocol for assessing seminal OS.

Nevertheless, antioxidant therapies have illustrated promising results in improving the semen parameters of subfertile men suffering from iOAT. They have become the most widespread utilized and studied novel therapy for treating male factor infertility. However, the proper dosage, type, and duration of antioxidant treatment for clinicians to administer have yet to be confirmed and standardized. Many studies point to improvements in just one or two of the three parameters of iOAT, failing to fully address the disease as a whole. Additionally, safety becomes the primary concern, as high dosages of antioxidant therapy are capable of resulting in adverse effects. It has not been established whether antioxidant therapy is the proper management in cases of elevated ROS production, because intracellular sperm antioxi-dant status, abstinence time, sperm count, as well as other confounding factors must be considered. Since there are no reliable, predictive, and inexpensive methods in determining the extent of ROS exposure and antioxidant capacity in patients, further advances in this area may prove valuable for assigning ROS values to serve as potential indicators of the correct antioxidant therapy to prescribe. Moreover, if ROS exposure values are established, this may help to establish levels in which antioxidant treatment may be administered. Since the liberation of transition-metal ions from metalloproteins during a prooxidative state is thought to serve as catalysts for free radical damage, especially in the reduced state, antioxidant treatment may even enhance oxidation damage. The body faces an "antioxidant paradox" in which the administration of a potent antioxidant to reduce a prooxidative state can worsen conditions. Therefore, establishing "cut-off" values of ROS in which an antioxidant can be used will help to control ROS damage and determine therapeutic values necessary for treating iOAT.

Men with iOAT are often administered a number of various therapies based on experimental studies, yet their supporting evidence in controlled human studies is sparse. Thus, in the absence of approved and effective treatment, medications prescribed are based solely on rationale. Assessment of OS status may also help in selecting the patient population that would most benefit from antioxidant supplementation. Further studies in this area are essential. Antioxidant treatment holds for a promising future as a conservative, inexpensive remedy in treating infertility worldwide.

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