A global view of the pathophysiology of varicocele
TL;DR: The need of application of novel diagnostic techniques that can provide a precise pathophysiological diagnosis to guide potential specific innovative therapies is highlighted to help formulate new treatments and achieve the appropriate selection of patients who can benefit from these treatments.
Abstract: Varicocele is the most common abnormality identified in men being evaluated for subfertility. In this comprehensive review of the pathophysiology of varicocele, we will shed light on novel pathophysiological findings and their clinical implications that may direct future researches; we will shed light on the impact of transient scrotal hyperthermia and the roles of inflammation and differential protein expression and androgen expression in spermatozoa on inducing pathophysiological findings. Furthermore, we will clarify the linked processes contributing to the pathophysiology of varicocele and the impact of genetics on the induction of these processes. Spermatogenesis is a temperature-sensitive process, and heat stress of varicocele is considered the most plausible cause of impaired spermatogenesis. The three processes associated with the presence of varicocele - heat stress, excess reactive oxygen species, and increased apoptosis - appear to be linked; heat stress is associated with increased levels of reactive oxygen species and oxidative stress, which can induce apoptosis. The genetic role should not be overlooked as a contributing factor in the induction of heat stress, excess reactive oxygen species/oxidative stress, and apoptosis; this is evidenced by the association of varicocele with decreased expression of heat-shock proteins, higher polymorphism of glutathione S transferase and nitric oxide synthase genes, and increased BAX and decreased BCL2 genes and proteins. In this article, we will highlight the need of application of novel diagnostic techniques that can provide a precise pathophysiological diagnosis to guide potential specific innovative therapies. Innovative therapies can counteract the varicocele-induced stasis, suppress the degenerative effects of testicular hyperthermia, reduce the varicocele-induced apoptosis, and target the elevated-neutrophil products aiming at abrogating the testicular damage caused by the induced varicocele in rats/mice. In conclusion, on the basis of the novel scientific research, it may be possible to formulate new treatments and achieve the appropriate selection of patients who can benefit from these treatments.
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TL;DR: The environmental and lifestyle factors that promote ROS generation by the spermatozoa are reviewed in this article, as are the techniques that might be used in a diagnostic context to identify patients whose reproductive capacity is under oxidative threat.
Abstract: This article addresses the importance of oxidative processes in both the generation of functional gametes and the aetiology of defective sperm function. Functionally, sperm capacitation is recognized as a redox-regulated process, wherein a low level of reactive oxygen species (ROS) generation is intimately involved in driving such events as the stimulation of tyrosine phosphorylation, the facilitation of cholesterol efflux and the promotion of cAMP generation. However, the continuous generation of ROS ultimately creates problems for spermatozoa because their unique physical architecture and unusual biochemical composition means that they are vulnerable to oxidative stress. As a consequence, they are heavily dependent on the antioxidant protection afforded by the fluids in the male and female reproductive tracts and, during the precarious process of insemination, seminal plasma. If this antioxidant protection should be compromised for any reason, then the spermatozoa experience pathological oxidative damage. In addition, situations may prevail that cause the spermatozoa to become exposed to high levels of ROS emanating either from other cells in the immediate vicinity (particularly neutrophils) or from the spermatozoa themselves. The environmental and lifestyle factors that promote ROS generation by the spermatozoa are reviewed in this article, as are the techniques that might be used in a diagnostic context to identify patients whose reproductive capacity is under oxidative threat. Understanding the strengths and weaknesses of ROS-monitoring methodologies is critical if we are to effectively identify those patients for whom treatment with antioxidants might be considered a rational management strategy.
101 citations
Cites background from "A global view of the pathophysiolog..."
...This condition is also known to be associated with a loss of sperm function and DNA integrity as a consequence of oxidative stress [100,101]....
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TL;DR: In this paper, the authors investigated the internal spermatic veins by venography to understand testicular damage due to varicocele and found that it is a bilateral vascular disease, involving a network of collaterals and small retroperitoneal bypasses.
49 citations
TL;DR: It is reported here that testis and mature sperm show higher signs of autophagy in the varicocele group than in the control and sham groups, probably to try to mitigate the consequences of VCL on thetestis and germ cells.
Abstract: Since autophagy was suspected to occur in the pathological situation of varicocele (VCL), we have attempted to confirm it here using a surgical model of varicocele-induced rats. Thirty Wistar rats were divided into three groups (varicocele/sham/control) and analyzed two months after the induction of varicocele. Testicular tissue sections and epididymal mature sperm were then monitored for classic features of varicocele, including disturbance of spermatogenesis, impaired testicular carbohydrate and lipid homeostasis, decreased sperm count, increased sperm nuclear immaturity and DNA damage, oxidative stress, and lipid peroxidation. At the same time, we evaluated the Atg7 protein content and LC3-II/LC3-1 protein ratio in testis and mature sperm cells, two typical markers of early and late cellular autophagy, respectively. We report here that testis and mature sperm show higher signs of autophagy in the varicocele group than in the control and sham groups, probably to try to mitigate the consequences of VCL on the testis and germ cells.
24 citations
Cites background from "A global view of the pathophysiolog..."
...In addition, testicular hyperthermia associated with VCL also contributes to shift the AO/ROS balance towards oxidative stress [20, 40]....
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...Since oxidative stress, heat stress, and hypoxia are the main factors involved not only in the pathophysiology of varicocele [20] but also in the induction of autophagy [21, 22], we have sought to understand the relationship between autophagy and varicocele....
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TL;DR: Results show that lycopene exerts beneficial effects in testes, and suggest that supplementation with the tomato-derived carotenoid might be considered a novel nutraceutical strategy for the treatment of varicocele and male infertility.
Abstract: Varicocele is one of the main causes of infertility in men. Oxidative stress and consequently apoptosis activation contribute to varicocele pathogenesis, worsening its prognosis. Natural products, such as lycopene, showed antioxidant and anti-inflammatory effects in several experimental models, also in testes. In this study we investigated lycopene effects in an experimental model of varicocele. Male rats (n = 14) underwent sham operations and were administered with vehicle (n = 7) or with lycopene (n = 7; 1 mg/kg i.p., daily). Another group of animals (n = 14) underwent surgical varicocele. After 28 days, the sham and 7 varicocele animals were euthanized, and both operated and contralateral testes were weighted and processed. The remaining rats were treated with lycopene (1 mg/kg i.p., daily) for 30 days. Varicocele rats showed reduced testosterone levels, testes weight, Bcl-2 mRNA expression, changes in testes structure and increased malondialdehyde levels and BAX gene expression. TUNEL (Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling) assay showed an increased number of apoptotic cells. Treatment with lycopene significantly increased testosterone levels, testes weight, and Bcl-2 mRNA expression, improved tubular structure and decreased malondialdehyde levels, BAX mRNA expression and TUNEL-positive cells. The present results show that lycopene exerts beneficial effects in testes, and suggest that supplementation with the tomato-derived carotenoid might be considered a novel nutraceutical strategy for the treatment of varicocele and male infertility.
21 citations
Cites background from "A global view of the pathophysiolog..."
...Nowadays, the exact mechanisms that correlate varicocele and infertility are still unknown; however, scrotal hyperthermia, hypoxia and oxidative stress seem to play important roles [4]....
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TL;DR: Results show that varicocele has a negative effect on spermatogenesis and increased oxidative stress and reduce in antioxidant capacity hand in hand lead to the production of sperm with damaged chromatin which reduces the fertility potential and may jeopardize the future health of the progeny.
Abstract: Purpose: Oxidative stress (OS) plays a central role in the pathophysiology of varicocele (VC), however, comprehensive studies concomitantly assessing semen parameter along with chromatin status, oxidative stress, and enzymatic antioxidants in both testis and sperm are limited. Therefore, this study aims to assess these parameters in varicocelized rats. Materials and Methods: For this study, 30 Wistar rats were randomly divided into three groups: Control group (I); sham-operated group (II) and left varicocele group (III). Left varicocele was induced and two months after surgery, we evaluated sperm parameters, persistent histone, DNA integrity and lipid peroxidation in sperm and also oxidant/antioxidant markers in testis. Results: The results showed that sperm concentration, motility, and normal morphology significantly decreased in varicocele group compared to other groups ( P < 0.001). Also, we observed a significant increase in persistent histone and DNA damage of sperm cells in varicocele rats ( P < 0.05). In addition, oxidant assessment analysis showed that ROS level was higher in testis tissue and sperm cells from the left varicocele rats compared to the control group ( P < 0.05). Conclusion: This results show that varicocele has a negative effect on spermatogenesis and increased oxidative stress and reduce in antioxidant capacity hand in hand lead to the production of sperm with damaged chromatin which reduces the fertility potential and may jeopardize the future health of the progeny.
20 citations
Cites background from "A global view of the pathophysiolog..."
...In view of the fact that oxidative stress is known as the main factor in the pathophysiology of varicocele and in the most cases, increase of ROS level and decrease antioxidant capacity have been observed.((4,13-15)) To the best of our knowledge, this is the first study to evaluate sperm parameters, chromatin status and also ROS level in both testis and sperm of rats with experimentally induced varicocele....
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References
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TL;DR: Results are consistent with a causative role for lipid peroxidation in the etiology of defective sperm function and also suggest a possible physiological role for the reactive oxygen species generated by human spermatozoa in mediating sperm-zona interaction.
Abstract: Recent studies have demonstrated that human spermatozoa are capable of generating reactive oxygen species and that this activity is significantly accelerated in cases of defective sperm function. In view of the pivotal role played by lipid peroxidation in mediating free radical damage to cells, we have examined the relationships between reactive oxygen species production, lipid peroxidation, and the functional competence of human spermatozoa. Using malondialdehyde production in the presence of ferrous ion promoter as an index of lipid peroxidation, we have shown that lipid peroxidation is significantly accelerated in populations of defective spermatozoa exhibiting high levels of reactive oxygen species production or in normal cells stimulated to produce oxygen radicals by the ionophore, A23187. The functional consequences of lipid peroxidation included a dose-dependent reduction in the ability of human spermatozoa to exhibit sperm oocyte-fusion, which could be reversed by the inclusion of a chain-breaking antioxidant, alpha-tocopherol. Low levels of lipid peroxidation also had a slight enhancing effect on the generation of reactive oxygen species in response to ionophore, without influencing the steady-state activity. At higher levels of lipid peroxidation, both the basal level of reactive oxygen species production and the response to A23187 were significantly diminished. In contrast, lipid peroxidation had a highly significant, enhancing effect on the ability of human spermatozoa to bind to both homologous and heterologous zonae pellucidae via mechanisms that could again be reversed by alpha-tocopherol. These results are consistent with a causative role for lipid peroxidation in the etiology of defective sperm function and also suggest a possible physiological role for the reactive oxygen species generated by human spermatozoa in mediating sperm-zona interaction.
1,171 citations
"A global view of the pathophysiolog..." refers background in this paper
...These byproducts are essential to maintain an environment suitable for cellular metabolism, but in excess, they can induce cellular dysfunction (Aitken et al., 1989; Morielli & O’Flaherty, 2015)....
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TL;DR: The testes contain an elaborate array of antioxidant enzymes and free radical scavengers to ensure that the twin spermatogenic and steroidogenic functions of this organ are not impacted by oxidative stress.
Abstract: Spermatogenesis is an extremely active replicative process capable of generating approxi mately 1,000 sperm a second. The high rates of cell division inherent in this process imply correspondingly high rates of mitochondrial oxygen consumption by the germinal epithelium. However, the poor vascularization of the testes means that oxygen tensions in this tissue are low1 and that competition for this vital element within the testes is extremely intense. Since both spermatogenesis2 and Leydig cell steroidogenesis3,4 are vulnerable to oxidative stress, the low oxygen tension that characterizes this tissue may be an important component of the mechanisms by which the testes protects itself from free radical-mediated damage. In addition, the testes contain an elaborate array of antioxidant enzymes and free radical scavengers to ensure that the twin spermatogenic and steroidogenic functions of this organ are not impacted by oxidative stress. These antioxidant defence systems are of major importance because peroxidative damage is currently regarded as the single most important cause of impaired testicular function underpinning the pathological consequences of a wide range of conditions from testicular torsion to diabetes and xenobiotic exposure. This chapter sets out the specific nature of these antioxidant defence systems and also reviews the factors that have been found to impair their activity, precipitating a state of oxidative stress in the testes and impairing the latter’s ability to produce viable spermatozoa capable of initiating and supporting embryonic development.
731 citations
TL;DR: Testicular oxidative stress appears to be a common feature in much of what underlies male infertility, which suggests that there may be benefits to developing better antioxidant therapies for relevant cases of hypospermatogenesis.
Abstract: Oxidative stress results from the production of oxygen radicals in excess of the antioxidant capacity of the stressed tissue. Many conditions or events associated with male infertility are inducers of oxidative stress. X-irradiation, for example, or exposure to environmental toxicants and the physical conditions of varicocele and cryptorchidism have been demonstrated to increase testicular oxidative stress, which leads to an increase in germ cell apoptosis and subsequent hypospermatogenesis. Such stress conditions can cause changes in the dynamics of testicular microvascular blood flow, endocrine signaling, and germ cell apoptosis. Testicular oxidative stress appears to be a common feature in much of what underlies male infertility, which suggests that there may be benefits to developing better antioxidant therapies for relevant cases of hypospermatogenesis.
476 citations
TL;DR: There are many unresolved questions concerning the exact role of ROS during infections of the male genital tract because of the difficulty of specifically assessing the site of generation and the short-lived effects of ROS.
Abstract: In the male genital tract, reactive oxygen species (ROS) are generated by spermatozoa and leukocytes including neutrophils and macrophages. ROS are involved in the regulation of sperm functions such as capacitation and the acrosome reaction. Infections lead to an excessive ROS production, resulting in an 'oxidative burst' from neutrophils/macrophages as a first-line defence mechanism. This is modulated by several cytokines and the pro-oxidant mechanisms of bacteria and viruses. At the site of an infection, the degree of activation of leukocytes, i.e. the amount of ROS produced, and the available antioxidative systems determine whether spermatozoa are damaged or not. During an infection, an imbalance of pro- and antioxidants favouring the former results in oxidative stress which impairs the sperm functions mentioned, as well as motility and fertilization. ROS produced during infections of the testis and epididymis are especially harmful to spermatozoa due to the longer contact time and the lack of antioxidant protection. In the final ejaculate, only very high numbers of ROS-producing leukocytes are detrimental to sperm functions. An infectious injury involving ROS in the prostate gland, seminal vesicles or epididymis could impair sperm functions indirectly. Pro- and antioxidative properties of therapeutics are currently receiving more attention as part of anti-infectious therapies. At present, there are many unresolved questions concerning the exact role of ROS during infections of the male genital tract because of the difficulty of specifically assessing the site of generation and the short-lived effects of ROS. New techniques may enable specific studies to fill this gap in the near future.
351 citations
"A global view of the pathophysiolog..." refers background in this paper
...Activated leukocytes (Ochsendorf, 1999) and abnormal spermatozoa (Gil-Guzman et al., 2001) can produce excess ROS, which can negatively impact nearby normal spermatozoa....
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TL;DR: There is significant cell-to-cell variation in ROS production in subsets of spermatozoa at different stages of maturation and that oxidative damage of mature spermatozosa by ROS-producing immature spermatoza during sperm migration from the seminiferous tubules to the epididymis may be an important cause of male infertility.
Abstract: BACKGROUND: Reactive oxygen species (ROS)-mediated damage to human spermatozoa has been implicated in the pathogenesis of male infertility. Although ROS production by human spermatozoa has been extensively studied, the cell-to-cell variation in ROS production by spermatozoa at different stages of maturation has never been investigated. METHODS: In this study, we determined ROS production by subsets of human spermatozoa at different stages of maturation isolated by density gradient centrifugation of ejaculated spermatozoa obtained from healthy donors and from patients attending a clinic for infertility screening. RESULTS: Four different fractions were obtained. ROS production was highest in immature spermatozoa with abnormal head morphology and cytoplasmic retention and lowest in mature spermatozoa and immature germ cells (P < 0.01). ROS production was highest in immature spermatozoa from males with abnormal semen parameters compared with donors (P < 0.0001) or patients with normal semen parameters (P 0.015). ROS production by immature spermatozoa was inversely correlated with the recovery of motile, mature spermatozoa in the high density fraction 4 (P 0.01). CONCLUSIONS: The results of this study indicate that there is significant cell-to-cell variation in ROS production in subsets of spermatozoa at different stages of maturation and that oxidative damage of mature spermatozoa by ROS-producing immature spermatozoa during sperm migration from the seminiferous tubules to the epididymis may be an important cause of male infertility.
326 citations
"A global view of the pathophysiolog..." refers background in this paper
...Activated leukocytes (Ochsendorf, 1999) and abnormal spermatozoa (Gil-Guzman et al., 2001) can produce excess ROS, which can negatively impact nearby normal spermatozoa....
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