Idiopathic Oligoasthenoteratozoospermia

iOAT is a complex medical condition that affects approximately 30% of all infertile men and is the most common cause of male infertility [16, 17]. As a three-part disorder, low sperm concentration and motility and morphologically abnormal sperm characterize iOAT. Three classifications have been put into place to evaluate the severity of the disease: (1) isolated astheno ± teratozoospermia (no alteration in sperm concentration); (2) moderate (sperm concentrations between <20 x 106/mL and >5 x 106/mL); and (3) severe (sperm concentrations <5 x 106/mL) [18].

Although iOAT is often thought to be related to defects in spermatogenesis, its actual cause remains unknown and cannot be diagnosed using common laboratory techniques. In addition, a majority of the infertile patients suffering from iOAT have normal physical examinations, normal hormonal profiles, and no discernable cause for their subfertile status. The age of patients may have an adverse effect on sperm motility and volume, which have been reported to continuously decrease from the age of 22-80 [19] : The lower metabolic rate frequently observed in older age is thought to contribute to this decrease in sperm motility.

Additional etiologies for iOAT have been suggested. An increase of ROS in the tubules and seminal plasma may cause apoptosis, consequently affecting sperm concentration, motility, and morphology [16]. ROS are also able to penetrate through the sperm membrane, thereby disrupting sperm motility. Leukocytospermia has been reported to have similar adverse effects; however, much controversy remains behind the exact mechanistic pathways and reasoning of the noted positive correlation [20],

Infection and the subsequent release of cytokines, including IL-6, IL-8, and tumor necrosis factor-alpha, have been associated with decreased sperm quality. Inflammation-mediated cytokines have been shown to induce ROS production, causing lipid peroxidation (LPO) of the sperm cell membrane [20] . A recent study conducted by Fraczek et al. revealed that cytokines released during the oxidative burst from inflammation intensify the degree of OS associated with leukocytes [21]. Furthermore, it has been reported ROS levels in whole ejaculates to be negatively correlated with sperm concentration (r = -0.52, p = 0.0003), motility (r=-0.41, p = 0.006), and morphology (r = -0.34, p = 0.02), while also correlating positively to seminal leukocyte concentration (r = 0.65, p < 0.0001) [22]. Another study that compared 167 infertile patients with 19 controls found that sperm concentration, motility, and morphology were significantly reduced, while the mean ROS levels were significantly higher in infertile subjects than controls [23] . The positive correlation between ROS levels in whole ejaculates and seminal leukocyte concentrations provides a rationale for treatment of OS-positive infertile patients with antioxidant supplementation and other strategies to control excessive leukocyte infiltration.

Cytoplasmic droplets have also been implicated in the pathogenesis of iOAT. These residues have been found to develop from defects in spermatogenesis. They contain large amounts of glucose-6-phosphate dehydrogenase (GiPD), which is known to generate NADPH. NADPH activation generates ROS production in spermatozoa via the action of NADPH oxidase, thereby promoting OS in the sperm membrane [24] . Interestingly, male infertility seems to have a familial relation among brothers and maternal uncles [25]. A genetic etiology is currently considered the most accepted theory for iOAT. Bujan et al. suggests an autosomal recessive mode of inheritance [26]. Thus, it is essential for future genomic and proteomic studies to focus on identifying possible genetic defects or mutations that could give rise to male infertility.

Oligozoospermia. Multiple mutations in mitochondrial DNA (mtDNA) have been correlated with oligozoospermic patient [27]. An in vitro study using a mouse model revealed that different proportions of mutated mtDNA had respiratory chain defects from meiotic arrest during spermatogenesis [28]. This indicated that respiration-deficient spermatocytes were incapable of completing meiosis and eliminated by apoptosis. The study confirmed that the mutated mtDNA that affected mitochondrial respiration function also resulted in not only oligozoospermia, but also asthenozoo-spermia and teratozoospermia. Moreover, since mtDNA is more susceptible than the nuclear genome, any impairment of the electron transport chain consequently enhances ROS generation in mitochondria from incomplete reduction of oxygen [29], Other reports indicate that mitochondrial dysfunction is associated with decreased membrane potential and increased production of superoxide anions, hydroxide radicals, and hydrogen peroxide [30, 31] . An experimental study suggests that genetic alterations found in sperm mtDNA may have occurred during cell differentiation, spermatogenesis, or from random segregation of mtDNA during cell division [32],

Asthenozoospermia. Impairment in sperm motility has been attributed to increased ROS generation [33]. Impaired motility is thought to result from a cascade of events, involving lowered axonemal protein phosphorylation and sperm immobilization, both of which are associated with reduced membrane fluidity that is essential for sperm-oocyte fusion [34] . It has also been hypothesized that membrane-soluble hydrogen peroxide may potentially diffuse across membranes into cells and become oxidized even further, thereby inhibiting the activity of enzymes, particularly G6PD. This cyto-solic enzyme controls the rate of glucose flux through the hexose monophosphate shunt, regulating the intracellular availability of NADPH. Spermatozoa use this as a source of electrons to stimulate the generation of ROS by NADPH oxidase [35]. Any impairment or inhibition of G6PD leads to a decrease in the availability of NADPH and a concomitant accumulation of oxidized glutathione (GSH). Subsequently, this can lower antioxidant defense of spermatozoa and result in LPO [36]. Since energy production is critical in order to facilitate movement of sperm, any impairment in the process of ATP production may have a detrimental effect on sperm motility.

Teratozoospermia. Morphologically abnormal spermatozoa have been established as a predominant source of high ROS generation in human ejaculate [37]. The irregular structure is thought to result from impairments during spermatogenesis, whereby cytoplasmic extrusion pathways become impaired. As a result, spermatozoa released from the germinal epithelium during spermiation carry excess residual cytoplasm, and under such conditions, are believed to be immature and functionally defective [38]. Studies have shown that levels of ROS production in semen were negatively correlated with the percentage of normal sperm forms [39, 40].

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