Pathophysiology Of Varicocele Research Articles

Effect of vitamin D in experimental varicocele model in rats

Purpose: Varicocele is a pathological condition that affects approximately 20% of adult men, causing infertility and sperm deterioration. The aim of our study was to investigate the efficacy of vitamin D (Vit. D) in the pathophysiology of varicocele. We performed biochemical, gene expression analyses and histopathological to evaluate the efficacy of vitamin D in the experimental varicocele model.
 Materials and Methods: In the study, 30 adult male Wistar Albino rats were used. The rats were divided into 3 groups equally as control group, experimental group (varicocele), treatment group (varicocele + D vit.). The treatment group received 500 IU/kg D vit. intramuscularly.
 Results: Histopathological, TRPM2-8 gene expression and biochemical analyses were performed on testicular and blood samples collected at the end of the experiment. The experimental group showed a deterioration in tubular structure, a decrease in total antioxidant levels and an increase in total oxidant levels. The treatment group, on the other hand, showed an increase in TAS, a decrease in TOS and a beneficial improvement in tubular structure disorders. Analysis of gene expression levels showed that TRPM2-8 expression levels were significantly increased in the varicocele group and decreased in the treatment group.
 Conclusion: In the varicocele model, the use of vitamin D had a significant effect on TRPM2-8 gene level, pathological seminiferous tubules and biochemical values. Further studies are needed to determine the clinical application of vitamin D in varicocele disease.

The Evolving Landscape of Male Varicocele Pathophysiology in the Era of Multi-Omics: A Narrative Review of the Current Literature.

Male-factor infertility is implicated in over half of the millions of cases of infertility worldwide, and varicoceles are the most common correctable cause of male-factor infertility. The pathophysiologic mechanism for varicoceles is complex and next-generation technologies offer promising insights into the molecular underpinnings of this condition. In this narrative review, we highlight historical and contemporary paradigms associated with varicoceles, with an emphasis on the biological underpinnings of this disease. Specifically, we review the literature describing the underlying causes of varicoceles, discuss the molecular and cellular mechanisms causing pathological changes in some (but not all) men, and highlight key articles regarding the next-generation analyses (e.g., transcriptome, epigenome, proteome, and microbiome) being applied to better understand the condition and its treatment. These data demonstrate an ongoing evolution of the knowledge of varicoceles and the potential for improved personalized care in the future for men with this condition.

Role of varicocele repair in the era of assisted reproductive technologies: Lessons from 2000 cases of microsurgical varicocele repair.

In an era of advanced maternal age, there is less conclusive evidence regarding the treatment outcomes of varicocele repair for assisted reproductive technology (ART). Progress in basic research on varicocele is notable whereas there are many clinically relevant points to discuss. Based on our experience with more than 2000 cases of microsurgical varicocele repair, we focused on the effectiveness of varicocele repair, pathophysiology, surgical approaches, contributions to ART, sperm DNA fragmentation, and varicocele-associated azoospermia in this review with the aim of identifying clearer directions for basic and clinical research on varicocele. Microsurgical low ligation for varicocele repair is expected to remain the gold standard for surgical therapy. Based on the findings from a number of systematic reviews and meta-analyses, negative opinions regarding the efficacy of microsurgical varicocele repair in male infertility treatment have become virtually nonexistent. However, the majority of evidence regarding surgical indications and effectiveness pertains to improvements in semen parameters or non-ART pregnancy rates. Further understandings regarding to pathophysiology of varicocele will likely be gained through comprehensive genetic, transcriptomic, and epigenetic analyses using blood and testicular samples from humans and we hope to develop new diagnostic methods and pharmacotherapy.

Role of Oxidative Stress in Varicocele.

According to the official statistics of the World Health Organization, at least 48 million couples and 186 million people suffer from infertility. Varicocele has been recognized as the leading cause of male infertility and can affect spermatogenesis and cause testicular and epididymal disorders through multiple diverse pathophysiological processes. Reactive oxygen species (ROS) produced by oxidative stress have been reconciled as an important pathogenic factor throughout the course of varicocele. Testis respond to heat stress, hypoxia, and inflammation at the cost of producing excessive ROS. High levels of ROS can lead to infertility not only through lipid peroxidation or DNA damage, but also by inactivating enzymes and proteins in spermatogenesis. This review studies the oxidative stress and its role in the pathophysiology and molecular biology of varicocele in the context of a decline in fertility.

The Management of Clinical Varicocele: Robotic Surgery Approach.

Varicocele is a pathologic dilation of the testicular veins within the spermatic cord. Varicocele is considered the most common problem in reproductive medicine practice. It is identified in 15% of healthy men and up to 35% of men with primary infertility. The exact pathophysiology of varicoceles is not very well understood, and several theories have been proposed to explain it. Varicocele can impair sperm quality and fertility via various mechanisms: reflux of adrenal metabolites, increased testicular hypoxia, oxidative stress, and increased testicular temperature have been proposed. Several studies have reported the significant benefits on semen parameters with the surgical treatment of varicocele: reducing oxidatively induced sperm DNA damage and potentially improving fertility. Varicocele repair should be offered as a part of treatment option for male partners of infertile couples presenting with palpable varicoceles. Nowadays, there are several surgical approaches available for the treatment of varicocele, such as the retroperitoneal approach, inguinal approach, and the subinguinal approach. The subinguinal microscopic approach offers the best outcomes, such as shorter hospital stays, preservation of the testicular arteries and lymphatics, least number of postoperative complications, recurrence, and a higher number of pregnancies. Currently robotic-assisted laparoscopic surgery is widely adopted in urology and surgeons began to explore the potential applications of the robotic platform to male infertility microsurgical operations. Robotic approach offers many advantages: elimination of tremor, retraction with third arm, high quality, 3-dimensional visualization and surgeon ergonomics, all contributing to the precision of surgery.

Comparison of spermatic and peripheral blood gases and their correlation with spermogram pattern and varicocele grade in patients with a varicocele

The relationship between infertility and varicocele is still a controversial topic. This study aimed to find the association between the venous blood gas (VBG) pattern of the spermatic veins and peripheral veins with varicocele grade and spermogram variables in infertile patients. A total of 47 patients with a varicocele were enrolled in this study. Blood samples were drawn simultaneously from the spermatic vein and a peripheral vein. The pH, partial pressure of oxygen, the partial pressure of carbon dioxide, oxygen saturation, and bicarbonate values of these samples were analysed. The mean age of participants was 30.48 ± 6.08. The mean volume of semen was 3.92 ± 1.57 mL, and the mean semen pH was 7.88 ± 0.22. The pH was higher (p < 0.01) in the spermatic vein compared with the peripheral vein. However, level of other parameters including pO2 (p = 0.662), pCO2 (p < 0.001), HCO3 concentration of serum (p < 0.01), and base excess (p = 0.172) were lower in the spermatic vein in comparison with the peripheral vein. Correlations between VBGs determinants of the varicocele patients' spermatic vein and sperm morphology and motility were insignificant. In conclusion, although the clinical significance of VBGs is evident, there are limited studies that investigated the VBGs in varicocele patients. We should consider that the deviation in blood gases may be the missing piece in the puzzle to understand the pathophysiology of varicocele. By knowing the pathophysiology more precisely, we can better decide the ideal treatment option for the patients.

COVID-19 and varicocele: The possible overlap factors and the common therapeutic approaches.

Varicocele is recognized as one of the main attributable causes of male infertility which can affect spermatogenesis by various pathophysiological mechanisms. Recent studies have identified oxidative stress and reduction in antioxidant, hyperthermia, hypoxia, hormonal dysfunction, and inflammatory conditions as major factors in the pathophysiology of varicocele, all of which have known direct associations with the coronavirus disease 2019 (COVID-19) and can significantly increase the risk of detrimental COVID-19-related outcomes. Emerging data have shown an association between COVID-19 and inflammation, overproduction of cytokine, and other pathophysiological processes. The present review, summarizes the current understanding of the pathophysiology of varicocele and investigates the potential correlation between the severity of COVID-19 and the varicocele disease. In addition, various possible treatments which can be effective in both diseases were examined. Despite numerous challenges associated with the prevalence of COVID-19 in healthcare systems in infected countries, special attention should be given to maintaining a high level of care for complex patients with a pre-existing disease such as varicocele and providing appropriate practical advice for optimal control of the COVID-19 disease.

Oxidative Stress and Varicocele-Associated Male Infertility.

Despite being regarded as one of the most common causes of male subfertility, the pathophysiology of varicocele remains largely unknown. Recently, oxidative stress (OS) is proposed to be the mediator in how varicocele may negatively impact fertility. The imbalance of reactive oxygen species (ROS) and seminal antioxidants results in damage to sperm DNA and lipid membrane. There is evidence demonstrating higher OS level in men with varicocele which is also positively correlated with clinical grading of varicocele. Moreover, a number of studies have revealed the negative correlation between OS and conventional semen parameters. Furthermore, various interventions have shown their potential in alleviating OS in men with varicocele-associated infertility. Although direct evidence on improving pregnancy rate is not available at the moment, varicocelectomy has demonstrated promising results in relieving OS. Oral antioxidants represent another option with a favourable safety profile. The supplement can be used alone or as adjunct to varicocelectomy. However, most of the studies are hampered by heterogenous dose regime and high-level evidence is lacking.

In Silico Sperm Proteome Analysis to Investigate DNA Repair Mechanisms in Varicocele Patients.

Varicocele, a condition associated with increased oxidative stress, negatively affects sperm DNA integrity and reduces pregnancy rates. However, the molecular mechanisms related to DNA integrity, damage, and repair in varicocele patients remain unclear. This study aimed to determine the role of DNA repair molecular mechanisms in varicocele-related infertility by combining an in silico proteomics approach with wet-laboratory techniques. Proteomics results previously generated from varicocele patients (n=50) and fertile controls (n=10) attending our Andrology Center were reanalyzed using bioinformatics tools, including the WEB-based Gene SeT AnaLysis Toolkit, Open Target Platform, and Ingenuity Pathway Analysis (IPA), to identify differentially expressed proteins (DEPs) involved in DNA repair. Subsequently, selected DEPs in spermatozoa were validated using western blotting in varicocele (n = 13) and fertile control (n = 5) samples. We identified 99 DEPs mainly involved in male reproductive system disease (n=66) and male infertility (n=47). IPA analysis identified five proteins [fatty acid synthase (FASN), myeloperoxidase (MPO), mitochondrial aconitate hydratase (ACO2), nucleoporin 93 (NUP93), and 26S proteasome non-ATPase regulatory subunit 14 (PSMD14)] associated with DNA repair deficiency, which showed altered expression in varicocele (P <0.03). We validated ACO2 downregulation (fold change=0.37, change%=-62.7%, P=0.0001) and FASN overexpression (fold change = 4.04, change %= 303.7%, P = 0.014) in men with varicocele compared to controls. This study combined a unique in silico approach with an in vitro validation of the molecular mechanisms that may be responsible for varicocele-associated infertility. We identified ACO2 and FASN as possible proteins involved in DNA repair, whose altered expression may contribute to DNA damage in varicocele pathophysiology.

Characterization of varicocele-induced animal models: Potential role of inflammasome complex in the varicocele pathophysiology

Varicocele mechanisms and its impact in testicular dysfunction has been studied in order to understand the pathophysiology involved in this disease. However, study designs using testicular tissues from varicocele patients are restricted due to ethical limitations. Therefore, the use of animal models, mainly rats, that mimics varicocele and its effects is an option to develop new approaches. The surgical technique, that induces the varicocele in rats, is based on the partial obstruction of the left renal vein, leading to a dilation in the left spermatic vein and consequently to the pampiniform plexus, resulting in varicocele-induced condition. Thus, the study of the cellular and molecular mechanisms involved in varicocele development can be addressed in depth. Besides the animal model goal to uncover the exact varicocele pathophysiology, varicocele induced models are the best options to develop new non-surgical and less invasive therapies. Various animal model studies designed and investigated antioxidant and anti-inflammatory agents to face varicocele conditions. Minding this fact, we tried to discuss a newly uncovered complex in varicocele condition, known as inflammasome complex. Taking into consideration the possible inflammatory state present in varicocele, the inflammasome complex has been proposed to be involved in the pathophysiology of this disease.

Varicocele and male infertility: Historical, anatomical and urological perspectives – a mini review

Varicocele is defined as an abnormal dilatation of the pampiniform plexus of the spermatic cord. This is seen in 10 to 20% of general population and is one of the most common correctable causes of male infertility. The history of varicocele dates back to the era of Ancient Greeks to about 600 BC, who had sculptured varicocele in their statues as a tortuous bag of wormsin the scrotum. It was Ambrose Pare who gave a poetic description to the pooling of blood in the spermatic cords and subsequently Curling coined the term Varicocele The intricacy of the venous drainage of the scrotum and its contents and the criss crossing of the veins makes the thermo-regulatory mechanism regulating spermatogenesis, even more complex. The Cremaster and Dartos greatly aid in facilitating the thermo-regulatory mechanism of scrotal wall, which forms the anatomical basis of oligospermia in patients with varicocele. Apart from a visible change in seminal parameters, the benefits of varicocelectomy have extended on to an improvement in serum testosterone and enhancement of erectile and ejaculatory functions. With a greater knowledge of the pathophysiology of varicocele and with better understanding of the roles of gene polymorphisms and reactive oxygen species, the indications for varicocelectomy gain more support and evidence. A sound anatomical knowledge and an in-depth understanding of the events that take place at molecular level might shift the treatment focus in future from varicocelectomy to molecular targeted therapies.

The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele.

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors’ roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.

Oxidative Stress: A Comprehensive Review of Biochemical, Molecular, and Genetic Aspects in the Pathogenesis and Management of Varicocele.

Oxidative stress is a condition due to an imbalance between the concentrations of oxidants and antioxidants, and it is a well-recognized contributor in several male infertility conditions. Varicocele, a common vascular condition, may cause male infertility due to hyperthermia, hypoxia and/or exposure to toxic adrenal and renal metabolites. In this review, the mechanisms by which oxidative stress can affect cellular integrity and functions are described, along with molecular markers of cellular oxidative damage, and the most commonly performed techniques for their detection in seminal fluid. Moreover, we focus on the role of oxidative stress in the pathophysiology of varicocele based on recently published evidence from omics based studies, such as proteomics and genomics. Finally, we discuss strategies for the management of oxidative stress and the clinical guidelines for testing oxidative stress-related sperm DNA fragmentation in this group of patients.

Varicoceles

A varicocele is an abnormal venous dilatation and/or tortuosity of the pampiniform plexus in the scrotum. The exact pathophysiology of varicoceles is not very well understood, including whether there is any effect on male infertility. They can, however, be uncomfortable or painful and may result in testicular growth arrest during and prior to puberty. Varicocoeles can cause significant anxiety in patients about infertility, testicular cancer, or appearance. This article will not only discuss how to diagnose, when to investigate, and how to treat varicoceles, but also when to leave them alone.

Relation of nitric oxide synthase gene (NOS3) polymorphisms to varicocele risk and post-varicocelectomy seminal oxidative stress reduction.

The pathophysiology of varicocele remains to be unknown. Several genetic factors have been implicated in varicocele etiopathogenesis. We studied the relationship between NOS3 c.894G>T, c.786T>C and 4b/a polymorphisms to varicocele risk and their prognostic value as regards improvement of the post-operative seminal parameters &/or seminal malonaldehyde levels. The three NOS3 polymorphisms were evaluated in 100 patients with varicocele and 100 healthy subjects by RT-PCR. Seminal plasma MDA level was measured pre-operatively and 3months after varicocelectomy by the thiobarbituric acid method. The GT, TT, TC and bb genotypes of NOS3 polymorphism were more commonly observed in varicocele patients (30%, 9%, 28% and 70% respectively) compared to normal controls (12%, 0%, 10% and 50% respectively). The mean percentage of post-varicocelectomy seminal MDA reduction was highest with the GT genotype (p<.001). Genotypes GT+TT, TC and bb were associated with varicocele occurrence in our patients. The T (c.894G>T), C (c.786T>C) and b (NOS3 intron 4 VNTR) alleles were significantly associated with varicocele occurrence in our cohort of patients. We also report a better response regarding the reduction of seminal MDA after varicocelectomy with the GT and ba genotypes.

The association between high-grade varicocele and endothelial dysfunction.

Varicocele is determined as dilatation of veins in the pampiniform plexus of the spermatic cord. Although various factors have been implicated in the pathophysiology of varicocele, the underlying aetiological cause is not fully understood. Endothelial dysfunction is a precursor of vascular pathologies that may develop gradually and a substantial inducer in atherosclerosis aetiology. Brachial artery flow-mediated dilatation (FMD) measurement with sensitive brachial artery ultrasonography for assessing endothelial function is the most common noninvasive method. Similarly, carotid intima-media thickness (CIMT), measured using noninvasive ultrasonographic methods, is a tool for evaluating subclinical atherosclerosis and gives information on early changes in the vessel wall structure. Totally, 128 patients met the criteria were evaluated in this study. FMD was significantly lower in the varicocele group compared with the control group (9.16±3.34 vs.7.96±1.88, p=.013). CIMT measurements were similar between the groups (p=.091). Multivariate logistic regression revealed that FMD was independently associated with varicocele [odds ratio (OR): 0.814; 95% confidence interval (CI): 0.697-0.950; p=.009]. We suggest that endothelial dysfunction may have a role in the varicocele. Therefore, we recommend that every patient with symptomatic varicocele should be evaluated and followed up regularly for cardiovascular pathologies.

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

Oxidative stress (OS) plays a central role in the pathophysiology of varicocele (VC), however, com-prehensive 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. 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. 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). 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.

Pattern of varicocele vein blood gases in patients undergoing microsurgical Varicocelectomy

BackgroundVaricocele is known to be associated with infertility and sperm disorders. The exact cause of this ailment is not fully understood. There are limited numbers of studies where venous blood gases (VBGs) of varicocele veins were determined with conflicting results. Therefore, we have investigated the pattern of VBGs in both internal spermatic and external spermatic varicocele veins and correlation with semen quality parameters in infertile individuals who underwent left microsurgical varicocelectomy.MethodsPatients (n = 27) undergoing left microsurgical varicocelectomy at a tertiary care hospital, were included in the study. Before surgery, semen parameters and scrotal color Doppler ultrasonography was performed. During surgery, blood sample was drawn from varicocele veins (internal spermatic and external spermatic veins) and a peripheral arm vein of the same patient as a control. The VBGs of all veins under study were estimated and compared with each other. The VBGs were also correlated with various semen quality parameters. Data, expressed as Mean ± SD, regarding VBGs in three veins were analyzed using one-way ANOVA. The correlation between VBGs and semen quality parameters was determined using Pearson’s correlation. Differences were considered significant at p < 0.05.ResultsThe pH was found to be higher (p < 0.01) in the internal spermatic vein compared with the external spermatic and the peripheral veins. Partial pressure of oxygen (pO2) and oxygen saturation (sO2) were higher (p < 0.01) in the internal spermatic vein compared with the peripheral vein. However, concentration of bicarbonate (HCO3) was lower (p < 0.01) in both veins compared with the peripheral vein. Partial pressure of carbon dioxide (pCO2) was also lower (p < 0.01) in the varicocele veins compared with the control vein.ConclusionThe internal spermatic veins had higher pH and oxygen tension, but lower HCO3 and pCO2 levels compared with the control peripheral veins. External spermatic veins had lower pCO2 and HCO3 but other VBGs were similar to the peripheral veins. The shift of VBGs of internal spermatic vein toward arterial blood pattern may be a missing link to understand the pathophysiology of varicocele.

Treating varicocele in 2018: current knowledge and treatment options.

Varicocele is defined as a state of varicosity and tortuosity of the pampiniform plexus around the testis caused by retrograde blood flow through the internal spermatic vein. The prevalence of clinically relevant varicocele ranges from 5 to 20% in the male population and is often associated with infertility and reduction of sperm quality. In this review, the pathophysiology and clinical aspects of varicocele are reviewed along with therapeutic options and treatment effects on sperm parameters and fertility both in adult and in pediatric/adolescent subjects. We conducted a Medline and a PubMed search from 1965 to 2018 to identify publications related to varicocele clinical aspects, treatment procedures and treatment outcomes. Keywords used for the search were: "varicocele", "varicocelectomy", "sclerotherapy", "male infertility", "subfertility", and "semen abnormalities". Data from a large number of studies in adolescent and adult males indicate that varicocele correction improves semen parameters in the majority of patients, reducing oxidative stress and improving sperm nuclear DNA integrity either with surgical or percutaneous approach. Varicocele repair seems to represent a cost-effective therapeutic option for all males (both adolescent and adults) with a clinical varicocele in the presence of testicular hypotrophy, worsening sperm alterations or infertility. On the other hand, some investigators questioned the role of varicocelectomy in the era of assisted reproduction. Thus, a better understanding of the pathophysiology of varicocele-associated male subfertility is of paramount importance to elucidating the deleterious effects of varicocele on spermatogenesis and possibly formulating new treatment strategies.

A global view of the pathophysiology of 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.