Testicular Torsion IR Injury in Testis and Oxidative Stress

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The mechanism of tissue damage due to I/R is common to other organs such as the brain, heart, kidneys, and testis. The primary pathophysiologic event in testicular torsion is ischemia followed by reperfusion; thus, testicular torsion/detorsion is I/R injury to the testis [7]. I/R also induce morphological and biochemical changes by both ischemia and reperfusion of the tissues and induce germ cell-specific apoptosis through cell membrane lipid peroxidation, protein denaturation, and DNA damage. These changes lead to testicular apoptosis, atrophy, necrosis, the loss of spermato-genesis, altered hormone production, and male subfertility or infertility. Testicular infarction begins after 2 h of ischemia, becomes irreversible after 6 h, and complete infarction is established after 24 h [116-118].

Even though the presence of some earlier reports about no injury related to tes-ticular torsion/detorsion, the general acceptance is that of bilateral injuries during testicular I/R process. However, the exact mechanism of the bilateral, especially contralateral injury, is obscure. Torsion of the spermatic cord causes a reduction in the testicular blood flow and leads to testicular ischemia on the affected side. The injury in ipsilateral testis is related to tissue hypoxia due to ischemia and overgeneration of ROS and RNS and necrosis of germinal cells [11]. In terms of the contralateral injury, several theories have been postulated, including blood flow alterations, increased adhesion molecule expression, leukocyte migration and damage to the spermatogenic epithelium, autoimmune response, triggered by blood-testis barrier breakdown, subclinical attacks of contralateral testicular torsion, secondary to isch-emic damage leading to exposition of antigenic material and formation of antibodies against testicular elements, reflex vasoconstriction in contralateral testicular vessels mediated by sympathetic nerves, release of acrosomal enzymes, paired neuroendocrine or vasomotor response during torsion, presence of an underlying defect in spermatogenesis, underlying testicular defect, and presence of an inherent gonadal abnormality [8, 119-121].

Decrease in blood flow to a tissue causes hypoxia, which results in elevated levels of lipid peroxidation products such as lactic acid, hypoxanthine, and thio-barbituric acid reactive products in ischemic tissue. Increase in blood flow after lipid peroxidation leads to the formation of large amounts of oxygen and/or nitrogen-derived free radicals. Indeed, this causes further damage in the ischemic tissue and is known as reperfusion injury. Reperfusion after ischemia causes oxidative stress, which is characterized by imbalance between ROS and antioxidative defense system, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px). Although reinstitute of blood flow and oxygenation are very important to salvage affected testis, reperfusion may cause further damage paradoxically in the ischemic tissue. Thus, reperfusion injury may play an important role in testicular damage related to testicular torsion [108] . It has been postulated that gradual detorsion of torsioned testis has a tendency to decrease the degree of testicular reperfusion injury [108, 113].

Torsion (ischemia) and detorsion (reperfusion) of testis is an important phenomenon that has not been completely defined from the perspective of the signaling pathways. I/R is associated with activation of neutrophils, inflammatory cytokines, and adhesion molecules with increased thrombogenicity, release of massive intrac-ellular calcium, and generation of oxygen-derived free radicals [122]. I/R of testis also results in stimulation of proinflammatory cytokines, secretion of tumor necrosis factor (TNF) alpha (a) and interleukin (IL) 1 beta (P), and activation of nitric oxide synthase (NOS) [123, 124]. Hence, this I/R injury is associated with overgeneration of ROS and RNS [125].

It has been also demonstrated that lipid peroxidation activated mitogen-activated protein kinases (MAPKs), which were of vital importance for signal transduction pathways of germ cell apoptosis [126, 127] and MAPKs family plays an important role in the pathogenesis of testis I/R damage. Active MAPKs are responsible for the phosphorylation of several transcription factors and the production of proinflammatory cytokines. These cytokines has multifunctional effect such as proinflammatory response, immunoregulatory response, apoptosis, and certain testicular pathologies, especially testicular torsion. These findings suggest that a block of MAPKs activation might present a potential therapeutic approach in the treatment of testicular torsion [128].

During the detorsion process, with the resumption of blood flow, a huge amount of molecular oxygen is supplied to the tissues and abundant amounts of free oxygen radicals are produced. Ischemia followed by reperfusion leads to a burst of ROS such as superoxide anions, hydrogen peroxide, hydroxyl radical, nitric oxide (NO), and peroxy nitrite, which cause lipid peroxidation and oxidative stress [18, 108, 111, 117]. High levels of ROS endanger sperm function and viability in reproductive tract. Oxidative stress can arise as a consequence of excessive production of ROS or impaired antioxidant defense systems in semen. Thus, oxidative stress causes a range of pathologies that are thought to affect the male reproductive system. ROS-mediated damage to sperm may account for the defective sperm function observed in a high proportion of infertility patients. Production of high levels of ROS in semen have been correlated with reduced sperm motility and damage to sperm nuclear DNA [129]. Some of the experimental studies to determine oxidative stress in animal models of testicular torsion have measured lipid peroxidation.

There are several strategies for decreasing the effect of ROS after I/R. The first strategy involves prevention of ROS formation. Another strategy for reducing ROS

effects involves eliminating ROS once they have formed. Free radical scavengers such as SOD and catalase convert toxic ROS to water and oxygen [117]. The ROS are difficult to quantify directly in tissue because of their high reactivity and short half-life. MDA, a stable end-product of lipid peroxidation generated by ROS, is usually used as a good indicator of the degree of lipid peroxidation. MDA levels in testicular tissue increase after testicular injury [130]. GSH is a key component in cell growth, differentiation, and protection. MPO is stored in the primary granules of neutrophils and the enzyme activity is a common measure of neutrophil accumulation.

Testicular torsion has been used in the laboratory animals to reproduce the clinical situation and to study the biological effects of ischemia on both testes and fertility. The end-points include testicular size, weight, histopathology, testicular biopsy score index (Johnsen score), biochemical enzyme parameters, semen characteristics, apoptosis, and general endocrine changes [131-134].

Testicular size correlates primarily with germinal epithelial mass. It has been known that the ratio of ischemia determines testicular salvage. Endocrine function (testosterone production from the Leydig cells) appears to be unaffected if the testis remains viable. Nevertheless, exocrine function (spermatogenesis) is unusually abnormal because ipsilateral ischemia has affected the contralateral testis. Spermatogenesis is significantly impaired in most patients after testicular torsion. Antisperm antibodies have been implicated as a result of the exposure of testicular tissue to the bloodstream after ischemic event. Detection of antisperm antibodies after torsion is variable. Many reports have confirmed abnormal semen analysis after acute testicu-lar torsion [29] .

To avoid testicular loss and eventual impaired fertility, prompt diagnosis and immediate surgery are the most important factors in patients for the treatment of testicular torsion. It has been postulated that unilateral testicular torsion causes damage to the ipsi- and contralateral testis and reduces future fertility. There are lots of experimental studies in animals about the short- and long-term (for example 60 days) [5] impacts of testicular torsion on fertility potentials in terms of semen analysis and fertility rate [135]. Moreover, animal models usually show histologic lesions and biochemical changes and, abnormal levels of antisperm antibodies after experimental testicular torsion. However, in human studies such an effect has not been fully proven in terms of long-term impacts by histopathologic examination or other conventional assays of spermatogenesis. Abnormal semen results have been noted in 40 to >60% of patients after unilateral testicular torsion [136]. Clinical problems, medicolegal issues for surgeon, ethical approach, and biopsy are limited to long-term and prospective clinical studies. Testicular ipsi- and/or contralateral biopsies are traumatic management and can reduce the future fertility of humans. Thus, there are case reports and retrospective analysis studies on testicular torsion in humans. Surprisingly few follow-up studies have been reported on semen analysis and fertility issues in humans after testicular torsion. In the light of these findings, it can be said that testicular torsion is an I/R injury and lead to oxidative stress. Thus, it affects semen quality and lead to infertility.

It has been demonstrated that testicular venous serum testosterone concentrations have not been affected after experimental torsion repair in rats. The resting testicular vein testosterone concentrations or those in response to in vivo ED50 or ED100 luteinizing hormone administration were little changed after repair of 1 h, 720° torsion in the rat, whether at acute (1 day) or chronic (30 day) periods [137]. However, another reports showed that reperfusion-induced oxidative stress in testicular torsion might play a role in Leydig cell dysfunction, as well as by acting directly in germ cell apoptosis [10].

Recently, Yang et al. [138] reported a 20-year retrospective study (between 1990 and 2010) in a single institution. They advocated immediate surgical exploration with suspected testicular torsion. Long-term hormonal levels are within the normal range regardless of the fate of the testis. They suggest that further follow-up studies are needed to confirm fertility after testicular torsion.

Numerous studies have used testicular torsion in rats as a model to study the effects of I/R on testicular tissue. Administration of many antioxidant agents and ROS scavengers provides significant rescue in experimental model of testicular torsion; however, none of these agents have been used as adjunctive therapy to torsion repair in humans [139].

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