Oxidative Stress in Male Reproductive System and ART Outcomes

The quality of the spermatozoa used for ART is crucial to get successful fertilization and pregnancy [126]. Spermatozoa are vulnerable to oxidative stress because their membranes are rich in unsaturated fatty acids [126] and they have no mechanisms for repairing their damaged DNA [127]. This will result in decrease in membrane fluidity and reduce the activity of membrane and ion channels which will end with impaired spermatozoa fertilization capacity. Hammadeh et al. demonstrated that using DNA-damaged spermatozoa during IVF correlated with high rates of failed fertilization, defective embryo development, implantation failure, and early abortion [128].

Swim-up technique is not suitable for semen preparation of ejaculates that contain large numbers of leukocytes and immature and damaged spermatozoa because they will be a source of ROS which will destroy the functional spermatozoa [129].

The other technique used to prepare spermatozoa for ART is density-gradient centrifugation; this technique employs centrifugation to separate fractions of spermatozoa based on motility, size, and density [130]. This technique is used to isolate mature, leukocyte-free spermatozoa [129], but centrifugation process may activate the leukocytes in the semen samples which will generate high levels of ROS with subsequent adverse effect on the functional spermatozoa [62] . Thus, minimizing centrifugation time reduces the generation of ROS and may ensure the use of high-quality sperm in ART [62]. Therefore, using spermatozoa preparation techniques that reduce the generation of ROS will positively influence the results of IVF and ICSI procedures [128]. Varicocele

Infertile patients with varicocele present with higher levels of ROS and lower levels of seminal antioxidants leading to increased OS. Published data have shown that the varicocele grade has an impact on the levels of seminal ROS, which were proven to decline following the surgical correction of varicocele [131]. The relationship between varicocele and OS is not fully understood; however, some mechanisms have been proposed. Significant amount of nitric oxide (NO) production are released from the dilated pampiniform plexus of veins leading to OS [132]. Additionally, NO may also interact with superoxide anion resulting in the production peroxynitrate, which leads to further sperm damage [133],

Patients diagnosed with infertility and varicocele have significantly higher levels of OS and sperm DNA damage compared to healthy controls. This could indicate a potential pathway for sperm DNA damage resulting from OS in these patients with varicocele [134]. OS and its resulting sperm dysfunction was estimated to cause infertility in 15% of males with varicocele. Another potential cause of sperm DNA damage in varicocele patients is apoptosis. Levels of apoptosis are higher in ejaculated spermatozoa from varicocele patients than in spermatozoa from healthy men [135]. Malignant Conditions

Testicular and systemic malignant conditions have been proven to result in male infertility even before the initiation of cancer treatments. Patients with testicular and systemic malignancies present with higher levels of DNA fragmentation compared to fertile controls [136] . The levels appear to be more significant in patients diagnosed with Hodgkin's and non-Hodgkin's diseases [137]. In addition, management of malignant conditions including chemo and radiotherapy has a negative impact on male fertility. The different therapeutic agents used for cancer treatment result in sperm DNA damage, which may present with mutations, repeated miscarriages, and carcinogenesis in offspring [138].

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