Varicocele and Oxidative Stress

Seminal oxidative stress (OS) results from an imbalance between ROS production (superoxide anions, hydrogen peroxide, hydroxyl radical, hydroperoxyl radical, and nitric oxide) and ROS scavenging by seminal antioxidants (superoxide dismutase, glutathione peroxidase, catalase, uric acid, vitamins C and E, and albumin). Seminal OS is believed to be one of the main factors in the pathogenesis of sperm dysfunction and sperm DNA damage in male infertility [40-43]. Spermatozoa are particularly susceptible to oxidative injury due to the abundance of plasma membrane polyunsaturated fatty acids [44-47]. These unsaturated fatty acids provide fluidity that is necessary for membrane fusion events (e.g., the acrosome reaction and sperm-egg interaction) and for sperm motility. However, the unsaturated nature of these molecules predisposes them to free radical attack and ongoing lipid peroxidation throughout the sperm plasma membrane. Once this process has been initiated, lipid peroxides accumulate on the sperm surface and this results in loss of sperm motility and viability. ROS can cause damage to the DNA, directly or indirectly via production and subsequent translocation of lipid peroxides [44, 46, 48-51].

Several studies have examined the levels of OS markers (e.g., ROS, lipid peroxidation, oxidative DNA damage) in the semen of infertile and fertile men with and without varicocele. These studies have shown that infertile men with varicocele have higher levels of seminal OS markers than fertile men and infertile men without varicocele [52-62] (Table 18.1). Indeed, seven studies have reported that infertile men with varicocele demonstrate higher semen ROS levels than do fertile men [53-56, 59, 60, 62]. One study reported higher semen ROS levels in men with highgrade compared to low-grade varicocele [57]. In line with these observations, other

Table 18.1 Seminal oxidative stress in men with varicocele

Study

Seminal OS marker Subjects («)

Controls

Findings

Pasqualotto et al. [55] Pasqualotto et al. [56]

Stimulated ROS

Hurtado de Catalfo et al. [58] Pasqualotto et al. [59] Sakamoto et al. [60]

TBARS (seminal and peripheral blood) ROS (by CL) NO

Fertile men with palpable varicocele (7) Infertile (21) and fertile

(15) men with varicocele Infertile men with varicocele (55)

Infertile men with varicocele (77) Infertile normospermic men with varicocele (16) Infertile men with grades 2 and 3

left varicocele Infertile men with varicocele (36)

Fertile men without varicocele (7) Sperm donors without varicocele (17) Sperm donors

Fertile men (19) Healthy donors (19)

Infertile men with grade

1 left varicocele Fertile men (33)

Infertile men with varicocele (21) Fertile men (17)

Oligospermic (15) and normospermic men (15) with varicocele Fertile men with varicocele (33)

Infertile (42) and fertile (45) men with varicocele

Normospermic and oligospermic infertile men (15) without varicocele Fertile men without varicocele (81) Fertile men without varicocele (45)

Higher ROS levels in men with varicocele Higher ROS levels in infertile and fertile men with varicocele Higher ROS levels in men with varicocele Higher ROS levels in varicocele High ROS levels in varicocele group

Higher ROS levels in grade 2-3

varicocele compared to grade 1 Higher ROS in infertile men with varicocele Higher ROS in varicocele group Higher NO levels in varicocele group

No significant difference in ROS levels

High ROS levels in varicocele groups vs. fertile men

CL Chemiluminescence; substances

MDA malondialdehyde; NO nitric oxide; OS oxidative stress; ROS reactive oxygen species; TBARS thiobarbituric acid reactive investigators have detected significantly higher levels of lipid peroxidation (measured as thiobarbituric acid reactive substances, TBARS) and oxidative DNA damage (8-OHdG, 8-hydroxy-2' -deoxyguanosine content) in the semen of infertile men with varicocele compared to that of fertile men [58, 60, 62]. However, it is less clear whether fertile men with varicocele have higher levels of seminal OS markers than fertile men without varicocele, as one of four published studies reported no significant difference in semen OS markers between these groups [52, 53, 61, 62]. Taken together, these studies demonstrate that infertile men with varicocele have elevated semen ROS levels when compared to men without varicocele.

Serum and testicular OS markers have also been examined in men with varico-cele. Studies have shown that testicular tissue from infertile men with varicocele have higher levels of OS markers (e.g., 8-OHdG) than do testicular tissue from men without varicocele and support the premise that infertile men with varicocele have testicular OS [63, 64]. A number of studies have compared the levels of testicular vein and peripheral vein serum OS markers (e.g., NO, H2O2) in infertile men with varicocele and have generally shown higher OS markers in the testicular venous blood compared to the peripheral blood samples [65-68]. In three of these studies, individual patients served as their own controls, and due to the absence of appropriate controls (e.g., infertile men without varicocele, fertile men), the accurate interpretation of the data is not possible. In the one study with appropriate controls (healthy men without varicocele), higher levels of OS markers in the testicular compared to the peripheral blood samples were seen in men with clinical varicocele but not men without varicocele, supporting the premise that varicocele may cause a local (testicular vein), as well as, a milder systemic OS [65].

A number of studies have examined the antioxidant capacity (e.g., catalase, superoxide dismutase, SOD, total antioxidant capacity, TAC) in the semen of infertile and fertile men with and without varicocele. These studies have generally shown that infertile men with varicocele have lower seminal antioxidant levels than do fertile men [53-56, 58-60,62] (Table 18.2). However, one compared infertile men with and without varicocele and reported that infertile men with varicocele have higher seminal antioxidant levels than do infertile men without varicocele [60] . These studies generally support the premise that infertile men with varicocele have lower seminal antioxidant capacity than fertile men, but there is no evidence to show that the seminal antioxidant capacity is lower than in infertile men without varicocele.

To date, there are a number of studies indicating that antioxidants may be beneficial in men with varicocele [69-71]. These studies support the premise that varico-cele may, in part, be caused by oxidative stress.

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