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.

/pdf/the-importance-of-oxidative-stress-in-determining-the-4hnhpgerk3.pdf

The Importance of Oxidative Stress in Determining the Functionality of Mammalian Spermatozoa: A Two-Edged Sword.

Varicocele, Hypoxia and Male Infertility. Fluid Mechanics Analysis of the Impaired Testicular Venous Drainage System

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.

https://downloads.hindawi.com/journals/omcl/2020/5140383.pdf

Signs of ROS-Associated Autophagy in Testis and Sperm in a Rat Model of Varicocele.

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.

https://www.mdpi.com/2072-6643/12/5/1536/pdf

Nutraceutical Effects of Lycopene in Experimental Varicocele: An "In Vivo" Model to Study Male Infertility.

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.

/pdf/evaluation-of-oxidative-stress-in-testis-and-sperm-of-rat-14jb3h9gd7.pdf

Evaluation of Oxidative Stress in Testis and Sperm of Rat Following Induced Varicocele.

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.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/andr.12511

A. N. Kaddah

Papers

A global view of the pathophysiology of varicocele