Effect of varicoceles on spermatogenesis.

Varicoceles are dilated veins within the spermatic cord and a relatively common occurrence in men. Fortunately, the large majority of men are asymptomatic, however, a proportion of men with varicoceles can suffer from infertility and testosterone deficiency. Sperm and testosterone are produced within the testis, and any alteration to the testicular environment can negatively affect the cells responsible for these processes. The negative impact of varicoceles on testicular function occurs mainly due to increased oxidative stress within the testicular parenchyma which is thought to be caused by scrotal hyperthermia, testicular hypoxia, and blood-testis barrier disruption. Management of varicoceles involves ligation or percutaneous embolization of the dilated veins. Repair of varicoceles can improve semen parameters and fertility, along with serum testosterone concentration. In this review, we discuss the pathophysiology of varicoceles, their impact on testicular function, and management.

Targeting COVID-19 and varicocele by blocking inflammasome: Ligand-based virtual screening.

COVID-19 is a new generation of outbreaks that invade not only local emerging region, continental but also the whole globe. Varicocele on the other hand, is a testicular vascular disease that underlies 40 % of male infertility cases. Fortunately, the two diseases can be blocked through targeting one common target, NLRP3 inflammasome. Upon searching for similar drugs that gained FDA-approval in ChEMBL library along with examining their potential blockade of the receptor through docking using CB-DOCK-2, three potential approved drugs can be repurposed, ChEMBL 4297185, ChEMBL 1201749, ChEMBL 1200545 which had binding energy of -9.8 and -9.7 kcal/mol (stronger than the reference inhibitor, -9.3 kcal/mol). Also, ADME profile of the top 3 drugs showed better attributes. Also, the simulated proteins exhibited stable pattern with strong free binding energies. Among the potential inhibitor drugs ChEMBL 4297185 was found to remain inside the binding site of the protein during the 200 ns simulation time. Hence, it is anticipated to have the highest binding and thus inhibition potential against the protein. The suggested drugs, especially ChEMBL 4297185, are potentially repurposable toward treating COVID-19 and varicocele which deserve further experimental validation.

Robotic-assisted versus conventional laparoscopic ICG-fluorescence lymphatic-sparing palomo varicocelectomy: a comparative retrospective study of techniques and outcomes.

PURPOSE: This study aimed to compare techniques and outcomes of robotic-assisted varicocelectomy (RAV) and laparoscopic varicocelectomy (LV). METHODS: The medical records of 40 patients, who received RAV and LV over a 2-year period, were retrospectively analyzed. Palomo lymphatic-sparing varicocelectomy using ICG fluorescence was adopted in all cases. Three 5-mm trocars were placed in LV, whereas four ports, three 8-mm and one 5-mm, were placed in RAV. The spermatic vessels were ligated using clips in LV and ligatures in RAV. The two groups were compared regarding patient baseline and operative outcomes. RESULTS: All patients, with median age of 14 years (range 11-17), had left grade 3 varicocele according to Dubin-Amelar. All were symptomatic and 33/40 (82.5%) presented left testicular hypotrophy. All procedures were completed without conversion. The average operative time was significantly shorter in LV [20 min (range 11-30)] than in RAV [34.5 min (range 30-46)] (p = 0.001). No significant differences regarding analgesic requirement and hospitalization were observed (p = 0.55). At long-term follow-up (30 months), no complications occurred in both groups. The cosmetic outcome was significantly better in LV than RAV at 6-month and 12-month evaluations (p = 0.001). The total cost was significantly lower in LV (1.587,07 €) compared to RAV (5.650,31 €) (p = 0.001). CONCLUSION: RAV can be safely and effectively performed in pediatric patients, with the same excellent outcomes as conventional laparoscopic procedure. Laparoscopy has the advantages of faster surgery, smaller instruments, better cosmesis and lower cost than robotics. To date, laparoscopy remains preferable to robotics to treat pediatric varicocele.

Investigation of sperm hsa-mir-145-5p and MLH1 expressions, seminal oxidative stress and sperm DNA fragmentation in varicocele.

BACKGROUND: Mechanisms by which varicocele causes infertility are not clear and few studies have reported that some miRNAs show expression alterations in men with varicocele. Recently, sperm promoter methylation of MLH1 has been shown to be higher in men diagnosed with varicocele. This study aimed to assess the potential effects of miR-145, which was determined to target MLH1 mRNA in silico on sperm quality and function in varicocele. METHODS: Sperm miR-145 and MLH1 expressions of six infertile men with varicocele (Group 1), nine idiopathic infertile men (Group 2), and nine fertile men (control group) were analyzed by quantitative PCR. Sperm DNA fragmentation was evaluated by TUNEL and the levels of seminal oxidative damage and total antioxidant capacity were analyzed by ELISA. RESULTS: Our results have shown that sperm expression of miR-145 was decreased in Group 1 compared to Group 2 (P = 0.029). MLH1 expression was significantly higher in Group 2 than the controls (P = 0.048). Total antioxidant level and sperm DNA fragmentations of Group 1 and Group 2 were decreased (P = 0.001 and P = 0.011, respectively). Total antioxidant capacity was positively correlated with sperm concentration (ρ = 0.475, P = 0.019), total sperm count (ρ = 0.427, P = 0.037), motility (ρ = 0.716, P < 0.0001) and normal morphological forms (ρ = 0.613, P = 0.001) and negatively correlated with the seminal oxidative damage (ρ=-0.829, P = 0.042) in varicocele patients. CONCLUSION: This is the first study investigating the expressions of sperm miR-145 and MLH1 in varicocele patients. Further studies are needed to clarify the potential effect of miR-145 on male fertility.

Impacts of non-coding RNAs in the pathogenesis of varicocele.

Two classes of non-coding RNAs, namely lncRNAs and miRNAs have been reported to be involved in the pathogenesis of varicocele. MIR210HG, MLLT4-AS1, gadd7, and SLC7A11-AS1 are among lncRNAs whose expression has been changed in patients with varicocele in association with the sperm quality. Animal studies have also suggested contribution of NONRATG001060, NONRATG002949, NONRATG013271, NONRATG027523 and NONRATG023747 lncRNAs in this pathology. Meanwhile, expression of some miRNAs, such as miR-210-3p, miR-21, miR-34a, miR-122a, miR-181a, miR-34c and miR-192a has been altered in this condition. Some of these transcripts have the potential to predict the sperm quality. We summarize the impacts of lncRNAs and miRNAs in the pathogenesis of varicocele.

Chlorogenic acid can improve spermatogenic dysfunction in rats with varicocele by regulating mitochondrial homeostasis and inhibiting the activation of NLRP3 inflammasomes by oxidative mitochondrial DNA and cGAS/STING pathway.

In recent years, Varicocele (VC) has been recognized as a common cause of male infertility that can be treated by surgery or drugs. How to reduce the damage of VC to testicular spermatogenic function has attracted extensive attention in recent years. Among them, overexpressed ROS and high levels of inflammation may play a key role in VC-induced testicular damage. As the key mediated innate immune pathways, cGAS-STING shaft under pathological conditions, such as in cell and tissue damage stress can be cytoplasmic DNA activation, induce the activation of NLRP3 inflammatory corpuscle, triggering downstream of the inflammatory cascade reaction. Chlorogenic acid (CGA), as a natural compound from a wide range of sources, has strong anti-inflammatory and antioxidant activities, and is a potential effective drug for the treatment of varicocele infertility. The aim of this study is to investigate the role of CGA in the spermatogenic dysfunction of the rat testis induced by VC and the potential mechanisms. The results of this study have shown that CGA gavage treatment ameliorated the pathological damage of seminiferous tubules, increased the number of sperm in the lumen, and increased the expression levels of Occludin and ZO-1, which indicated the therapeutic effect of CGA on spermatogenic dysfunction in the testis of VC rats. Meanwhile, the damage of mitochondrial structure was alleviated and the expression levels of ROS, NLRP3 and pro-inflammatory cytokines (IL-1ß, IL-6, IL-18) were significantly reduced in the testicular tissues of model rats after CGA treatment. In addition, we demonstrated for the first time the high expression status of cGAS and STING in testicular tissues of VC model rats, and this was ameliorated to varying degrees after CGA treatment. In conclusion, this study suggests that CGA can improve the spermatogenic function of the testis by reducing mitochondrial damage and inhibiting the activation of the cGAS-STING axis, inhibiting the activation of the NLRP3 inflammasome, and improving the inflammatory damage of the testis, highlighting the potential of CGA as a therapeutic agent for varicocele infertility.

Clinical management of nonobstructive azoospermia: An update.

Approximately 1% of the general male population has azoospermia, and nonobstructive azoospermia accounts for the majority of cases. The causes vary widely, including chromosomal and genetic abnormalities, varicocele, drug-induced causes, and gonadotropin deficiency; however, the cause is often unknown. In azoospermia caused by hypogonadotropic hypogonadism, gonadotropin replacement therapy can be expected to produce sperm in the ejaculate. In some cases, upfront varicocelectomy for nonobstructive azoospermia with varicocele may result in the appearance of ejaculated spermatozoa; however, the appropriate indication should be selected. Each guideline recommends microdissection testicular sperm extraction for nonobstructive azoospermia in terms of successful sperm retrieval and avoidance of complications. Sperm retrieval rates generally ranged from 20% to 70% but vary depending on the causative disease. Various attempts have been made to predict sperm retrieval and improve sperm retrieval rates; however, the evidence is insufficient. Further evidence accumulation is needed for salvage treatment in cases of failed sperm retrieval. In Japan, there is inadequate provision on the right to know the origin of children born from artificial insemination of donated sperm and the rights of sperm donors, as well as information on unrelated family members, and the development of these systems is challenging. In the future, it is hoped that the pathogenesis of nonobstructive azoospermia with an unknown cause will be elucidated and that technology for omics technologies, human spermatogenesis using pluripotent cells, and organ culture methods will be developed.

Significant reduction in left testicular volume shown by ultrasonography in infertile patients with left-side grade 2-3 varicocele as compared to less than grade 2: An evidence for indication of varicocelectomy.

PURPOSE: Testicular volume (TV) is known to be one of the main parameters for testicular function (TF). This study was conducted to re-evaluate the indications of a varicocelectomy based on a survey of preoperative TV results in left-side varicocele patients considered to reflect the detrimental effects of a varicocele on TF. METHODS: TV results of infertile patients determined using ultrasonography by a single expert physician were retrospectively evaluated. RESULTS: Of 590 examined patients, 424 had no varicocele findings (Group A), while 148 had a left-side varicocele (Group B). Group B was subdivided based on varicocele grade into Group B0 (subclinical), B1 (grade 1), B2 (grade 2), and B3 (grade 3). Comparisons of left-side TV showed no significant differences for grade among Group A, B0, and B1, whereas that for Group B2 and B3 was significantly lower as compared with Group A (p < 0.01, 0.02, respectively). The median TV of Group B I (composed of Groups B0 and B1) was 9.8 cm3, while that of Group B II (Groups B2 and B3) was significantly lower at 8.4 cm3 (p < 0.05). In contrast, a comparison of right TV values identified no significant differences among the groups (p = 0.918). CONCLUSION: A varicocelectomy should be performed for patients with a grade 2 and 3 varicocele for ameliorating testicular function.

Association between left-sided varicocele and epididymo-orchitis with sonographic findings.

OBJECTIVE: The aim of this study was to investigate the relationship between left-sided varicocele and epididymitis or epididymo-orchitis. MATERIALS AND METHODS: The study included 72 patients with left side epididymitis (EP) or epididymo-orchitis (EPO) (Group 1) and a control group of 72 patients without EP or EPO (Group 2). Those with right EP-EPO were excluded due to possible other underlying retroperitoneal pathologies causing varicocele. Groups were evaluated for presence of left side varicocele, varicocele grade and pampiniform plexus vein diameter. RESULTS: The average age was 38 ± 8.4 years (range, 18-50 years) in Group 1, and 36 ± 9.1 years (range, 16-47 years) in Group 2. Varicocele was significantly more common in patients with EP or EPO (p < 0.001). The rate of varicocele was 66.7% (48/72) in Group 1, and 22.3% (16/72) in Group 2. The median grade of varicocele was 2 in Group 1, and 0 in Group 2. Pampiniform plexus vein diameters were found to be significantly larger in patients with EP or EPO compare to patients without EP and EPO. The median vein diameter was 3.3 mm with the 25th and 75th percentiles at 2.7 and 3.8 mm, and was 1.9 mm with the 25th and 75th percentiles at 1.7 and 2.3 mm, respectively (p < 0.001). CONCLUSIONS: Left-sided varicocele was significantly more common in patients with EP or EPO and it is an important cause for the development of EP/EPO because of chronic venous stasis.

Video-Assisted Telescope Operating Monitor 3D System in Microsurgical Varicocelectomy: A Preliminary Report.

INTRODUCTION: Video-assisted telescope operating monitor (VITOM®) with 3D Visualization technology was developed and has been used with favorable results by several surgical specialties. Our study aims to be a preliminary report for initial experience using the VITOM® 3D system for microsurgical varicocelectomy on varicocele patients. METHODS: We performed 35 microsurgical varicocelectomy procedures using the VITOM® 3D system on varying types and grades of varicoceles. The surgeon had the option of using either a 2.5 or 3.5 magnifying loupe in addition to the exoscope for each operation evaluated. The exoscope is a standalone camera head with an integrated 3D telescope and remote control with zoom and focus functions. It is connected to the 3D monitor via a mechanical holding arm. During the procedure, surgeons, assistants, and observers were able to view the 3D high-definition stream displayed on a 26-inch 3D monitor at a convenient viewing angle and distance. The varicocele ligation was performed using a Carl Zeiss Meditec AG microscope. RESULTS: There were 35 patients with varicocele aged 31.51 years old on average, which were included in this report. Most patients had grade 3 bilateral varicocele (n = 13, 37.1%). All procedures were performed without any intraoperative complications. After the procedures, only a few patients suffered from postoperative complications. Three patients suffered scrotal edema (8.6%), while another had hydrocele (2.9%). The postoperative pain results were also very minimal from .89 1 day after the operation to .26 3 days after the operation. CONCLUSION: The VITOM® 3D system showed promise in microsurgical varicocelectomy.