Varicocele-Mediated Male Infertility: From the Perspective of Testicular Immunity and Inflammation.

Background: Varicocele (VC) is present in 35 - 40% of men with infertility. However, current surgical and antioxidant treatments are not completely effective. In addition to oxidative stress, it is likely that other factors such as testicular immune microenvironment disorder contribute to irreversible testicular. Evidence suggests that VC is associated with anti-sperm antibodies (ASAs), spermatogenesis and testosterone secretion abnormalities, and testicular cytokine production. Moreover, inhibition of inflammation can alleviate VC-mediated pathogenesis. The normal function of the testis depends on its immune tolerance mechanism. Testicular immune regulation is complex, and many infectious or non-infectious diseases may damage this precision system. Results: The testicular immune microenvironment is composed of common immune cells and other cells involved in testicular immunity. The former includes testicular macrophages, T cells, dendritic cells (DCs), and mast cells, whereas the latter include Leydig cells and Sertoli cells (SCs). In animal models and in patients with VC, most studies have revealed an abnormal increase in the levels of ASAs and pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha in the seminal plasma, testicular tissue, and even peripheral blood. It is also involved in the activation of potential inflammatory pathways, such as the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing (NLRP)-3 pathway. Finally, the development of VC-mediated infertility (VMI) may be facilitated by abnormal permeability of proteins, such as claudin-11, that constitute the blood-testis barrier (BTB). Conclusions: The testicular immune response, including the production of ASAs and inflammatory factors, activation of inflammatory pathways, and destruction of the BTB may be involved in the pathogenesis of VMI it is necessary to further explore how patient outcomes can be improved through immunotherapy.

Effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation rates in infertile men with clinical varicocele: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation (SDF) rates in infertile men with clinical varicocele. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Infertile men with clinical varicocele subjected to varicocelectomy. INTERVENTION(S): Systematic search using PubMed/Medline, EMBASE, Cochrane's central database, Scielo, and Google Scholar to identify relevant studies published from inception until January 2021. We included studies comparing SDF rates before and after varicocelectomy in infertile men with clinical varicocele. MAIN OUTCOME MEASURE(S): The primary outcome was the difference between the SDF rates before and after varicocelectomy. A meta-analysis of weighted data using random-effects models was performed. Results were reported as weighted mean differences (WMD) with 95% confidence intervals (CIs). Subgroup analyses were performed on the basis of the SDF assay, varicocelectomy technique, preoperative SDF levels, varicocele grade, follow-up time, and study design. RESULT(S): Nineteen studies involving 1,070 patients provided SDF data. Varicocelectomy was associated with reduced postoperative SDF rates (WMD -7.23%; 95% CI: -8.86 to -5.59; I2 = 91%). The treatment effect size was moderate (Cohen's d = 0.68; 95% CI: 0.77 to 0.60). The pooled results were consistent for studies using sperm chromatin structure assay, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, sperm chromatin dispersion test, and microsurgical varicocele repair. Subgroup analyses showed that the treatment effect was more pronounced in men with elevated vs. normal preoperative SDF levels, but the impact of varicocele grade remained equivocal. Meta-regression analysis demonstrated that SDF decreased after varicocelectomy as a function of preoperative SDF levels (coefficient: 0.23; 95% CI: 0.07 to 0.39). CONCLUSION(S): We concluded that pooled results from studies including infertile men with clinical varicocele indicated that varicocelectomy reduced the SDF rates. The treatment effect was greater in men with elevated (vs. normal) preoperative SDF levels. Further research is required to determine the full clinical implications of SDF reduction for these men.

Clinical outcome of pediatric and young adult subclinical varicoceles: a single-institution experience.

Subclinical varicocele represents an abnormality of veins of the pampiniform plexus on scrotal ultrasound (US) without a clinically palpable varicocele. Its significance remains unclear. While guidelines do not recommend surgical intervention, clinical management is variable. As there is limited information on long-term outcome of subclinical varicoceles due to challenges in diagnosis and management, we performed a single-institution, retrospective review of patients from October 1999 to October 2014 with subclinical varicocele and with available US studies reviewed by a single radiologist. Subclinical varicocele was defined as dilation of the pampiniform venous plexus on US involving ≥2 vessels with diameter >2.5 mm, without clinical varicocele on physical examination or prior inguinal surgery. Thirty-six of 98 patients identified were confirmed as having a subclinical varicocele and analyzed. The mean age at initial visit was 15.5 years, with a mean follow-up of 26.5 months. The majority were right-sided (69.4%, n = 25), usually with a contralateral clinical varicocele. Testicular asymmetry (>20% volume difference of the affected side by testicular atrophy index formula) was assessed in 9 patients with unilateral subclinical varicocele without contralateral clinical or subclinical varicocele and observed in 1 patient. Of 17 patients with follow-up, 3 (17.6%) progressed to clinical varicocele without asymmetric testicular volume, as most remained subclinical or resolved without surgery. In our experience, subclinical varicoceles appeared unlikely to progress to clinical varicoceles, to affect testicular volume, or to lead to surgery. Although our study is limited in numbers and follow-up, this information may aid clinical management strategies and guide future prospective studies.

Semen Biochemical Components in Varicocele, Leukocytospermia, and Idiopathic Infertility.

The evaluation of the seminal plasma plays a relevant role in the definition of male infertility and in assisted reproduction outcomes; for this reason, it would be recommended to find biochemical markers able to characterize sperm pathology. In this study, 53 infertile patients (grouped by the presence leukocytospermia, idiopathic infertility, or varicocele) and 10 fertile men were selected. Spermiogram was performed by light microscopy, and sperm ultrastructure was evaluated by transmission electron microscopy (TEM) mathematically elaborated. Testosterone (TESTO), estradiol (E2), ferritin (FERR), iron (Fe), transferrin (TRSF), triglycerides (TRG), cholesterol (CHOL), and isoprostanes (F2-IsoPs) were detected in seminal plasma. Sperm characteristics and biochemical components were correlated by Spearman's rank correlation coefficient in the whole population and in each group. The levels of TESTO and E2 were positively correlated with sperm quality in particular, and E2 was correlated with fertility index expressing the number of sperm free of ultrastructural defects evaluated by TEM. On the contrary, the indices of iron metabolism (FERR, Fe, and TRSF) were positively associated with low sperm quality and sperm necrosis, particularly in leukocytospermia and varicocele groups, pathologies in which an inflammatory status and oxidative stress condition are present. The study of the seminal plasma composition deserves attention because the levels of the various components seem to be associated with specific reproductive pathologies.

Seminal exosomal miR-210-3p as a potential marker of Sertoli cell damage in Varicocele.

BACKGROUND: Varicocoele-associated stressors, such as hypoxia and heat, can damage cell function and viability, and some exosomal biomarkers released from impaired cells may reflect the cell status in testis. OBJECTIVES: To find if seminal exosomal microRNAs can reflect the Sertoli cell function in varicocoele. MATERIALS AND METHODS: Experimental left varicocoele rat model was established (n = 24), and patients with different grades of varicocoele (n = 104) were enrolled. Primary rat Sertoli cells were isolated with enzymatic hydrolysis. Exosomes were isolated from primary rat Sertoli cells, rat epididymis tissue, and human seminal plasma with polymer-based precipitation method. Exosomal microRNAs were quantified with qPCR. Inhibin-B was detected with enzyme immunoassay. The correlation analysis between microRNA and inhibin-B was evaluated with Spearman's correlation. RESULTS: We screened 12 previously reported hypoxia-responsive microRNAs in the primary rat Sertoli cells and found that 4 exosomal microRNAs increased significantly in response to in vitro hypoxia treatment (P < .05). Of the 4 microRNAs, only miR-210-3p was upregulated in the rats with experimental varicocoele (P < .01). In the patients with varicocoele, we found that seminal exosomal miR-210-3p significantly increased in patients with grade II and III varicocoele (P < .01), and miR-210-3p negatively correlated with sperm count (P < .01) and seminal inhibin-B expression (r = -0.39, P < .01). For the 30 patients with microsurgical varicocelectomy, the operation notably decreased miR-210-3p (P < .01). DISCUSSION AND CONCLUSION: Seminal exosomal miR-210-3p may be a novel, sensitive, and non-invasive biomarker of Sertoli cell damage in varicocoele.

[Effect of testicular autophagy on spermatogenic cells in varicocele rats].

OBJECTIVE: To study the effect of different levels of autophagy in the testis on the apoptosis of spermatogenic cells in the rat model of varicocele (VC). METHODS: We randomly divided 54 SD male rats into six groups, blank control (n = 6), rapamycin control (n = 6), chloroquine control (n = 6), VC model control (n = 12), VC + rapamycin (n = 12), and VC + chloroquine (n = 12). We observed the histomorphological changes of the testis and epididymis by HE staining, obtained the scores on spermatogenesis in the testis and epididymis, calculated the apoptosis index (AI) of the testicular spermatogenic cells by TUNEL, and determined the expressions of LC3-Ⅱ, LC3-Ⅰ, p62, Bax and Bcl-2 proteins in the testis tissue by Western blot. RESULTS: There were no significant morphological changes in the testis and epididymis of the rats in the blank control, rapamycin control and chloroquine control groups, or significant differences in the scores on testicular and epididymal spermatogenesis and AI of the testicular spermatogenic cells (P>0.05). The animals in the VC model control group exhibited significant pathological damage in the testicular and epididymal tissues, with remarkably decreased scores on spermatogenesis (P<0.01) and increased AI (P<0.01), which were markedly improved in the VC + rapamycin group and slightly aggravated in the VC + chloroquine group compared with the VC model controls. In comparison with the rats in the blank control group, those in the VC model control group showed significantly up-regulated expressions of the autophagy-related protein LC3 (including the LC3-Ⅱ/LC3-Ⅰ ratio) and the pro-apoptotic protein Bax in testicular tissue (P<0.01) but down-regulated expression of the anti-apoptotic protein Bcl-2 (P<0.01). The expressions of LC3 and Bcl-2 in the testis tissue were significantly higher in the VC + rapamycin (P<0.01) but lower in the VC + chloroquine group (P<0.01), while those of p62 and Bax remarkably lower in the VC + rapamycin (P<0.01) but higher in the VC + chloroquine group than in the VC model controls (P<0.01). CONCLUSIONS: Varicocele induces autophagy in the testis and apoptosis of spermatogenic cells in rats. Up-regulating autophagy can inhibit while blocking autophagy can promote the apoptosis of spermatogenic cells.

Paying the price for standing tall: Fluid mechanics of prostate pathology.

BACKGROUND: Age-dependent increase in the incidence of benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are both related to cell proliferation and survival controlled by intraprostatic free testosterone (FT) concentration. Paradoxically, BPH and PCa occur as circulating testosterone levels decrease, so any possible relationship between testosterone levels and development of BPH and PCa remains obscure. RESULTS: In BPH the enlarging prostate is exposed to high testosterone levels arriving directly from the testes at concentrations about hundredfold higher than systemic FT. This occurs because venous blood from the testes is diverted into the prostate due to the elevated hydrostatic pressure of blood in the internal spermatic veins (ISVs). Elevated pressure is caused by the destruction of one-way valves (clinically detected as varicocele), a unique phenomenon related to human erect posture. While standing, human males are ISVs vertically oriented, resulting in high intraluminal hydrostatic pressures-a phenomenon not found in quadrupeds. In this communication, we demonstrate the fluid mechanics' phenomena at the basis of varicocele leading to prostate pathology. CONCLUSIONS: So far, varicocele has been studied mostly for its etiologic role in male infertility and, thus, for its effects on the testes. It is becoming clear that varicocele is a major etiologic factor in BPH and likely also in PCa. Restoring normal testicular venous pressure by treatment of the abnormal ISV's in varicocele has been shown to avert the flow from the prostate with the effect of reducing prostate volume, alleviating symptoms of BPH, and increasing concentrations of circulating FT.

Evaluation of the role of reflux pattern in Color Doppler Ultrasound on spermogram improvement after varicocelectomy.

PURPOSE: Many attempts are being made to find an association between varicocele characteristics and sperm parameters. In this study, we investigated the association between a newly introduced varicocele reflux grading pattern and sperm parameters, as well as its effect on spermogram improvement after varicocelectomy. METHODS: In a prospective study, 73 patients with a clinical single-sided varicocele who underwent corrective varicocelectomy were included. Reflux pattern was determined on Color Doppler Ultrasound (CDUS) and categorized into four grades: grade 1 (retrograde), grade 2 (augmentation), grade 3 (enhancement), and grade 4 (stasis). The association of pre- and postoperative spermogram with the patients' reflux pattern was evaluated. RESULTS: A significant positive association was found between the venous diameter and reflux pattern. Higher grades of the reflux pattern were associated with the more severe hemodynamic pattern of the reflux (shunt type). A significant association was found between the reflux pattern and preoperative semen characteristics, and this association was more prominent in constant venous diameter. In this respect, the enhancing reflux type was associated with the most impaired preoperative sperm count, motility, and morphology. The enhancing type also revealed the most improvement in spermogram after varicocelectomy. CONCLUSION: Patients with a higher reflex grade, particularly enhancing pattern, will most benefit from the surgical correction of varicocele. These findings suggest reflux pattern as a promising prognostic factor for a favorable outcome after varicocelectomy.

Differential DNA methylation pattern and sperm quality in men with varicocele.

OBJECTIVE: To study the global DNA methylation pattern in spermatozoa of patients with varicocele as well as investigate their semen quality. DESIGN: Prospective observational case-control study. SETTING: University-affiliated hospital. PATIENT(S): A total of 26 men with varicocele and 26 fertile men without the disorder. INTERVENTIONS: Analysis of semen quality and sperm DNA methylation patterns. MAIN OUTCOME MEASURE(S): Semen quality evaluated by semen analysis, and sperm DNA methylation patterns investigated using the Infinium MethylationEPIC BeadChip platform. RESULT(S): Men with varicocele displayed decreased semen quality. The sperm DNA methylation analysis showed that men with varicocele exhibit global hypomethylation in comparison with the control group. A total of 59 differentially methylated CpG sites were identified, most of them hypomethylated in the varicocele group. In regional analyses, 1,695 DNA regions were differentially methylated in men with varicocele. These regions show associations with gamete generation, meiotic and meiosis cell cycle, and semen quality based on gene ontology analysis. CONCLUSION(S): Gene ontology results suggest that changes in methylation may be associated with the low semen quality phenotype observed in some varicocele patients because the observed differentially methylated regions in varicocele patients are related to male reproductive pathways. Additionally, the varicocele grade may influence the magnitude of global sperm DNA methylation change. To our knowledge, this is the first report analyzing changes at a regional or CpG-specific level in men with varicocele.

Ecchymosis and Coldness in Peripheral Varicose Vein Patients: Observations From VEIN-TURKEY Study.

The purpose of this subgroup analysis is to investigate and analyze the venous leg symptoms including sense of coldness and sign of ecchymosis in patients with or without peripheral varicose veins (PVVs) from VEIN-TURKEY study population. A total of 600 patients, who were enrolled to VEIN-TURKEY study recently, were included in this subgroup analysis. Patients were examined clinically for the presence and severity of PVV and varicocele. Patients were asked to answer the VEINES-Sym questionnaire consisting of 10 parts and questions about ecchymosis and coldness in their legs. Frequency of symptoms present in the VEINES-Sym instrument, coldness (16.6%, 6.5%, P = .002, respectively), and ecchymosis (16.6%, 2.7%, P < .001, respectively) were significantly higher in patients with PVV compared to patients without PVV. Mean score of each symptom was significantly lower in PVV (+) patients including scores of ecchymosis and coldness. Total VEINES-Sym score was also correlated with the scores of ecchymosis (r = 0.18, P < .001) and coldness (r = 0.35, P < .001). Logistic regression analysis revealed that heavy legs, aching legs, night cramps, and ecchymosis are significantly and independently associated with PVV. In conclusion, sign of ecchymosis and coldness are significantly higher in patients with PVV compared to patients without PVV in a population recruited from the urology clinics. In clinical evaluation, presence or sign of ecchymosis and coldness in legs should be considered to be compatible with PVV in the absence of trauma, hematologic pathologies including antiplatelet treatment, and arterial stenosis or obstruction.

Effect of venous reflux time on testosterone and semen parameters of infertile males after microscopic varicocelectomy.

This study aimed to search whether there is a link between reflux flow and hormonal profile. Data of 250 patients were retrospectively investigated. Pre-operative and 6th month semen analyses of these patients' results were compared with pre-operative and post-operative 6th month serum levels of testosterone. Based on the venous flow on pre-operative Doppler ultrasonography, patients were divided into two groups. Patients with a venous flow ≤4 s were assigned to Group 1 and those with a venous flow >4 s to Group 2. Venous reflux time cut-off was calculated as 4 s using ROC curve according to the increase in testosterone level. When venous reflux time was selected as approximately 4.0 s, ROC had 79.8% sensitivity and 72.8 specificity. The probability of a post-operative increase in testosterone is high in patients with a venous reflux time longer than 4 s.

Effect of Varicocele and Its Treatment on Testosterone in Hypogonadal Men with Varicocele: Review of the Literature

Varicocele might cause deterioration in Leydig cell functions, and it is a significant risk factor for hypogonadism. Some controversial issues have been raised in the treatment of hypogonadal men with varicoceles. Symptomatic hypogonadal men with varicoceles have two options: testosterone replacement therapy or varicocele treatment. Both approaches have some advantages and disadvantages. This review summarizes the effect of varicoceles on total plasma testosterone level and addresses whether varicocele repair is effective to improve testosterone levels in hypogonadal men with varicoceles. Experience from large clinical studies in the literature suggests that varicocele repair may increase serum testosterone level in men with varicoceles and testosterone deficiency. Varicocele repair could be offered to men with clinically palpable varicocele and hypogonadism. As the treatment method, microsurgical varicocele repair could be preferred to provide the best improvement. Another advantage of varicocele repair for hypogonadism, instead of exogenous testosterone treatment, is its ability to preserve the fertility status in men who may desire a child in the future. However, further studies are required to clarify varicocel-related Leydig cell dysfunction and to advise hypogonadal patients about the sufficient effectiveness of varicocele repair.

Seminal plasma miR-210-3p induces spermatogenic cell apoptosis by activating caspase-3 in patients with varicocele.

The aim of this study was to investigate the role of seminal plasma miR-210-3p in the impairment of semen quality caused by varicocele. This study included 102 patients whose semen quality was normal when they were diagnosed with varicocele. A 2-year follow-up for included patients was performed, and they were divided into Group A (semen quality became abnormal) and Group B (semen quality remained normal) according to the results of semen analysis during the follow-up. Semen parameters and seminal plasma miR-210-3p expression were investigated by semen analysis and quantitative real-time polymerase chain reaction, respectively. In vitro experiments with GC-2 cells were performed to explore the role of miR-210-3p in spermatogenic cells. The results of quantitative real-time polymerase chain reaction showed that the level of seminal plasma miR-210-3p in Group A was higher than that in Group B both after 2-year follow-up and when they were diagnosed with varicocele (both P < 0.01). Apoptosis and proliferation assays showed that miR-210-3p induces apoptosis of spermatogenic cells by promoting caspase-3 activation. In conclusion, our study indicated that seminal plasma miR-210-3p induces spermatogenic cell apoptosis by activating caspase-3 in patients with varicocele. Seminal plasma miR-210-3p may be a potential biomarker for predicting impaired semen quality caused by varicocele.

[Pediatric and adolescent varicocele - When, why and how to treat?] / Varikozele im Kindes- und Jugendalter.

The treatment of a varicocele in childhood and adolescence is considered very controversial. In the past varicocele was often diagnosed during the medical examination for military purposes, but today varicocele is common in the J1 exam and is found rather frequently. However, we are still lacking evidence-based recommendations. This means that urologists and paediatric urologists are increasingly confronted with the question of whether intervention is necessary or not.The literature on this is very contradictory. Systematic reviews and meta-analyses have recently shown that there are only modest benefits of intervention in terms of testicular size and spermiogram quality. Solid data on the impact on paternity rates are still lacking. However, it has been shown that if an intervention is to be made, the lymphatic sparing techniques have a distinct advantage.Possible indications for intervention may be the persistent difference in size of the testes (> 20 % for at least 6 months), a symptomatic varicocele (very subjective criterion), a pathological spermiogram (better 2), and possibly the presence of additional fertility-limiting factors.

[Paediatric and adolescent varicocele: when, why and how to treat it]. / Varikozele im Jugendalter, wenn ja, wann und wie? Kontra OP.

Available indicators to justify varicocele treatment in adolescents are insufficient: testis volume is a variable parameter, and testicular asymmetry may be physiological. Testis volume and semen parameters are subject to pubertal development. For evaluation of possible testicular impairment, both parameters should be measured prospectively and at consecutive points in time. Endocrine parameters, which might contribute to a better understanding of possible impairment of testicular function, are neglected in studies. No evidence exists to confirm that varicocele treatment during adolescence leads to the prevention of fertility impairment in adulthood. In summary, risks and benefits of varicocele treatment have to be considered. There is no clear evidence-based recommendation to treat adolescents with varicocele.

Prokineticin 2 overexpression induces spermatocyte apoptosis in varicocele in rats.

Varicocele is one of the most important causes of male infertility, as this condition leads to a decline in sperm quality. It is generally believed that the presence of varicocele induces an increase in reactive oxygen species levels, leading to oxidative stress and sperm apoptosis; however, the specific pathogenic mechanisms affecting spermatogenesis remain elusive. Prokineticin 2 (PK2), a secretory protein, is associated with multiple biological processes, including cell migration, proliferation, and apoptosis. In the testis, PK2 is expressed in spermatocytes under normal physiological conditions. To investigate the role of PK2 in varicocele, a rat varicocele model was established to locate and quantify the expression of PK2 and its receptor, prokineticin receptor 1 (PKR1), by immunohistochemistry and quantitative real-time PCR assays (qPCR). Moreover, H2O2 was applied to mimic the oxidative stress state of varicocele through coculturing with a spermatocyte-derived cell line (GC-2) in vitro, and the apoptosis rate was detected by flow cytometry. Here, we illustrated that the expression levels of PK2 and PKR1 were upregulated in the spermatocytes of the rat model. Administration of H2O2 stimulated the overexpression of PK2 in GC-2. Transfection of recombinant pCMV-HA-PK2 into GC-2 cells promoted apoptosis by upregulating cleaved-caspase-3, caspase-8, and B cell lymphoma 2-associated X; downregulating B cell lymphoma 2; and promoting the accumulation of intracellular calcium. Overall, we revealed that the varicocele-induced oxidative stress stimulated the overexpression of PK2, leading to apoptosis of spermatocytes. Our study provides new insight into the mechanisms underlying oxidative stress-associated male infertility and suggests a novel therapeutic target for male infertility.

The Effect of Schisandra chinensis Baillon on Cross-Talk between Oxidative Stress, Endoplasmic Reticulum Stress, and Mitochondrial Signaling Pathway in Testes of Varicocele-Induced SD Rat.

Schisandra chinensis Baillon (SC) has been utilized for its antioxidants and anti-inflammatory activities in a broad variety of medical applications. However; SC uses for improving fertility in males and related disorders with proper scientific validation remain obscure. The present study aimed to investigate the effects of SC on varicocele (VC)-induced testicular dysfunction and the potential molecular mechanism associated with VC-induced germ cell apoptosis. The male Sprague-Dawley rats were equally divided into four groups consisting of 10 rats in a normal control group (CTR), a control group administered SC 200 mg/kg (SC 200), a varicocele-induced control group (VC), and a varicocele-induced group administered SC 200 mg/kg (VC + SC 200). Rats were administrated 200 mg/kg SC once daily for 28 days after induction of varicocele rats and sham controls. At the end of the treatment period, body and reproductive organ weight, sperm parameters, histopathological damages, proinflammatory cytokines, apoptosis markers, biomarkers of oxidative stress, endoplasmic reticulum (ER) stress, and steroidogenic acute regulatory protein (StAR) were evaluated. The effects of SC extract on human sperm motility were also analyzed. SC treatment reduces VC-induced testicular dysfunction by significantly increasing testicular weight, sperm count and sperm motility, serum testosterone level, Johnsen score, spermatogenic cell density, testicular superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase level, and steroidogenic acute regulatory protein (StAR) level. Furthermore, the effects of SC on malondialdehyde (MDA) level, reactive oxygen species (ROS)/reactive nitrogen species (RNS) level, apoptotic index, serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, Glucose-regulated protein-78 (Grp 78), phosphorylated c-Jun-N-terminal kinase (p-JNK), phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1α (p-IRE1α), cleaved caspase 3, and Bax:Bcl2 in VC-induced rats were significantly decreased. Treatment with SC extracts also increased sperm motility in human sperm. Our findings suggest that the SC ameliorate testicular dysfunction in VC-induced rats via crosstalk between oxidative stress, ER stress, and mitochondrial-mediated testicular germ cell apoptosis signaling pathways. SC promotes spermatogenesis by upregulating abnormal sex hormones and decreasing proinflammatory cytokines (interleukin-6; TNF-α).

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.

Semen and reproductive hormone parameters in fertile men with and without varicocele.

Although varicoceles are a widely accepted identifiable male factor in infertile couples, the benefit of varicocele repair in improving pregnancy and live birth rates remains uncertain. The Study for Future Families obtained semen and reproductive hormone samples from US men whose partners were currently pregnant. In our analysis cohort of 709 men, a varicocele was detected by clinical examination in 56 (8%) of men. Men with varicocele had smaller left testis, and lower total and total motile sperm counts than men without varicocele. Gonadotropin levels were higher as well in men with varicocele. Interestingly, testosterone levels were also slightly higher in men with varicocele. Despite these differences, there was no difference between the groups in the time to achieve the study pregnancy or percentage of men with a previous pregnancy. We conclude that even in fertile men, varicoceles are associated with some degree of testicular hypofunction. This would support current recommendations to consider varicocele repair in male partners in infertile couples who demonstrate both a varicocele and abnormal semen parameters and after evaluation for treatable female factors.

Impact of varicocelectomy on urine dopamine value in patients with premature ejaculation and varicocele.

Dopamine is an important regulator of male sexual function and behaviour. Decreased levels of this substance have been observed in blood and seminal plasma of infertile men. Hence, this study was carried out to determine the impact of varicocelectomy on 24-hr urine dopamine values in patients with both premature ejaculation (PE) and varicocele. In this prospective study, 55 consecutive patients with premature ejaculation and grade 2 or 3 varicocele were enrolled. The urine dopamine level was measured in a 24-hr sample by HPLC method in a single laboratory centre. Two samples were gathered from each patient, one before and the other 1 month after varicocelectomy. The mean initial and final 24-hr urine dopamine levels were 259.6 ± 86.3 and 602.9 ± 88.4 micrograms, respectively, showing statistically significant increase (p = .0001), while there was no statistically significant difference between urine volume and creatinine. However, the change in intravaginal ejaculation latency time value was not statistically significant at this short time visit. According to our findings, varicocelectomy results in a significant increase in 24-hr urine dopamine levels in patients with premature ejaculation and varicocele. However, the effect of this change on premature ejaculation in the long term has yet to be determined.