Materiały źródłowe

• #1 Varicocele – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448113/

  A varicocele is a common medical condition characterized by abnormal dilation and enlargement of the scrotal venous pampiniform plexus, which drains blood from each testicle. Varicoceles are clinically significant because they are the most commonly identified cause of abnormal semen analysis, low sperm count, decreased sperm motility, and abnormal sperm morphology. […] The association between clinically significant varicoceles and male infertility is undeniable. […] There is clear and compelling evidence from multiple studies and meta-analyses that surgical repair of clinically significant varicoceles in infertile males with abnormal semen parameters can significantly improve sperm counts, motility, morphology, and pregnancy rates. […] Varicoceles are thought to develop from a backup of venous blood flow in the internal spermatic vein that causes venous engorgement, which is clinically detectable on scrotal examination.

• #2 Varicocele: Practice Essentials, History of the Procedure, Problem

  https://emedicine.medscape.com/article/438591-overview

  A varicocele is a dilatation of the pampiniform venous plexus and the internal spermatic vein. Varicoceles can have detrimental effects on sperm concentration, motility, and morphology, and can reduce sperm DNA integrity and other aspects of sperm function. […] Several theories have been proposed to explain the harmful effect of varicoceles on sperm quality, including the possible effects of pressure, oxygen deprivation, heat injury, and toxins. […] Despite considerable research, none of the theories has been proved unquestionably, although an elevated heat effect caused by impaired circulation appears to be the most reproducible defect. Supporting this hypothesis is the fact that a varicocele created in an experimental animal led to poor sperm function with elevated intratesticular temperature. Regardless of the mechanism of action, a varicocele is indisputably a significant factor in decreasing testicular function and in reducing semen quality in a large percentage of men who seek infertility treatment. […] An unproven hypothesis holds that a varicocele may represent a progressive lesion that can have detrimental effects on testicular function. An untreated varicocele, especially when large, may cause long-term deterioration in sperm production and even testosterone production.

• #3 Varicocele | UNC Department of Urology

  https://www.med.unc.edu/urology/patientcare/adult-non-cancer/male-fertility/varicocele/

  Male infertility has been found to be the major cause of a couples inability to conceive. […] A varicocele is an abnormal dilation of varicose veins that drain the testicle, and it can be associated with a progressive decline in testicular sperm and testosterone production. Varicoceles are the most common identifiable cause of male infertility worldwide. […] Several theories have been proposed to explain the harmful effect of the varicocele on sperm quality. These include the possible effects of pressure, oxygen deprivation, heat injury, or retrograde flow of toxins. […] Regardless of the mechanism, a varicocele is indisputably a significant factor in decreasing testicular function and worsening semen quality in a large percentage of men seen for infertility. […] In addition, varicoceles may be a cause of progressive damage to the testes, resulting in further atrophy and impairment of seminal parameters.

• #4 :: WJMH :: World Journal of Men’s Health

  https://wjmh.org/DOIx.php?id=10.5534/wjmh.240290

  Varicocele is a common urological disease that can affect male fertility. […] The exact mechanisms by which varicocele can ultimately lead to male infertility are not fully understood; however, the main pathophysiologic mechanisms include increased scrotal temperature, hypoxia, and reflux of toxic metabolites caused by varicocele. Excessive production of reactive oxygen species (ROS) may also be an important pathogenic factor throughout the course of varicocele. […] The main pathophysiologic mechanisms include increased scrotal temperature, hypoxia, reflux of toxic metabolites and excessive ROS production.

• #5 Oxıdatıve Stress, Apoptosıs and Varıcocele-Related Infertılıty

  https://www.gavinpublishers.com/article/view/oxidative-stress-apoptosis-and-varicocele-related-infertility

  Varicocele is the most commonly seen and correctable cause of male factor infertility. The relationship between varicocele and infertility has not been fully elucidated due to the unclear pathophysiology of varicocele. several hypotheses on the impairment of spermatogenesis have been proposed, including endocrine and testicular paracrine disturbances, increased temperature and heat stress, testicular hypoxia, oxidative stress, accumulation of toxic substances, genetic disturbances, and autoimmunity, leading to decreased proliferation of germ cells and apoptosis. […] Although it has been known for many years that varicocele may impair spermatogenesis, this information is not enough to explain the association between varicocele and infertility. […] According to the comprehensive reviews published in the past 10 years regarding the pathophysiology of varicocele, several hypotheses on the impairment of spermatogenesis have been proposed, including endocrine and testicular paracrine disturbances, increased temperature and heat stress, testicular hypoxia, oxidative stress, accumulation of toxic substances, genetic disturbances, and autoimmunity, leading to decreased proliferation of germ cells and apoptosis.

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

  https://www.mdpi.com/2079-7737/13/2/80

  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. […] The next-generation omics advances (proteomics, transcriptomics, epigenomics, etc.) have begun to provide insight into understanding the pathophysiology of infertility associated with varicoceles. […] Regardless of how a varicocele anatomically forms, the mechanisms impairing testicular and cellular function have been thoroughly studied but remain controversial. […] Oxidative stress (OS) has been a well-studied potential mechanism associated with varicocele-induced male-factor infertility.

• #7 Varicocele and its causes

  https://www.operarme.com/blog/varicocele-and-its-causes/

  The causes of varicocele can be divided into primary and secondary causes. […] It has been found that one of the causes of varicocele is a genetic predisposition to suffer from it, which is one of the primary causes. […] Among the secondary causes of varicocele are diseases or dysfunctions that cause it, such as liver cirrhosis or carcinomas or tumours. […] Varicocele as a venous formation „per se” is caused by a dysfunction of the venous circulatory system in which venous stasis and accumulation occurs, forming a mobile and sometimes palpable and painful mass. […] In the case of varicocele and its causes, the primary root cause of the dysfunction that provokes the venous accumulation that forms the varicocele has not been clearly demonstrated. […] It is considered that it is a conglomerate of alterations (multifactorial origin) that makes it difficult for the venous blood that seeks to leave the testicle and the scrotal sac to do so.

• #8 Contribution to the Pathophysiology and Treatment of Varicoceles | Journal of the Belgian Society of Radiology

  https://jbsr.be/articles/10.5334/jbsr.1453

  The etiology and pathogenesis of varicoceles cannot be explained by one single theory. Valve dysfunction, ontogenetic collateral formation and the nutcracker phenomenon seem to act synergistically. Hyperthermia, elevated hydrostatic pressure and antisperm agents are suggested as possible causes for the pathophysiology how varicoceles induce infertility. However, the combination of patients lifestyle, genetic factors and the consequences of reflux into the pampiniform plexus (PP) are believed to contribute to the infertility. […] The reflux of blood into the ISV is a direct result of the insufficiency of valves, a mechanism we can observe during the phlebography of varicocele patients. By reflux of warm blood, temperature in the testicle rises. Furthermore, in a varicocele patient standing upright, the hydrostatic pressure at the PP and the testicle increases according the height of the fluid column in the ISV. Venous drainage at the PP will then be impaired, and the cooling of the testicle less efficient. This hydrostatic counterpressure might interfere with the arterial and nutritional supply of the testicle and decrease spermatogenesis and testicle growth.

• #9 Varicocele: Treatment indications and repair techniques

  https://www.urologytimes.com/view/varicocele-treatment-indications-and-repair-techniques

  Varicoceles form because of increased hydrostatic pressure in the internal spermatic veins, possibly because of incompetent or absent venous valves. […] Clinical varicoceles can negatively affect sperm concentration, motility, and morphology. The following five mechanisms contribute to the pathogenesis of impaired testicular function: hypoperfusion from retrograde flow leading to hypoxia, heat stress from impaired countercurrent heat exchange, oxidative stress from accumulation of reactive oxygen species, hormonal imbalances from abnormal Leydig cell function and decreased intra testicular testosterone, and accumulation of exogenous toxins. However, no single mechanism accounts for the observed impairment. […] Literature supports that grade of varicocele is associated with degree of spermatogenesis impairment and worse semen parameters.

• #10 Varicocele | Calgary Guide

  https://calgaryguide.ucalgary.ca/varicocele-pathogenesis-and-clinical-findings/varicocele/

  Varicocele: Pathogenesis and clinical findings […] Primary Anatomically: the left spermatic vein drains into the left renal vein Nutcracker Effect: The left renal vein can get pinched by the abdominal aorta and superior mesenteric artery Backup of blood in left renal vein pressure in left spermatic vein […] Obstruction of blood flow spermatic vein pressure Vein valve leaflet failure retrograde bloodflow back towards testicle Dilation of pampiniform plexus and scrotal vein plexus […] Varicocele scrotal blood volume volume in a closed space pressure and distension of scrotal layers scrotal vein plexus pressure Compliant veins distend, becoming visible through scrotum […] Blood heats up the structures it flows through Scrotal hyperthermia Unsuitable environment for spermatogenesis Loss of germ cell mass […] Dull ache/heaviness Decreased fertility Testicular atrophy.

• #11 A rare case of right-sided varicocele in right renal tumor in the absence of venous thrombosis and IVC compression | African Journal of Urology | Full Text

  https://afju.springeropen.com/articles/10.1186/s12301-020-00072-3

  The presence of unilateral right-sided varicocele hints at a serious retroperitoneal disease such as renal cell neoplasm. […] The etiology of a right-sided varicocele includes impairment of the venous drainage of the pampiniform plexus by venous thrombosis, tumor invasion, or extrinsic compression by an intraabdominal tumor. […] The presence of right-sided varicocele should raise a suspicion hidden serious pathological retroperitoneal condition, renal malignancy in particular, and should prompt the treating physician to carry out imaging studies of the retroperitoneum and careful study of the angiographic phase of the CT scan can ascertain the pathogenesis of the varicocele. […] The etiology of varicoceles is multi-factorial. The common causes for left-sided varicocele include absent or incompetent venous valves, perpendicular insertion of internal spermatic vein into the left renal vein and nut-cracker-like compression of the left renal vein between the aorta and superior mesenteric artery. On the other hand, the insertion of the right spermatic vein into the vena cava in an oblique orientation protects it from the high pressures of the vena cava. The right-sided varicoceles result from impairment of drainage of the spermatic vein either by a thrombus or compression.

• #12 Varicocele – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/varicocele/symptoms-causes/syc-20378771

  A varicocele is enlargement of the veins that transport oxygen-depleted blood away from the testicle. […] A varicocele occurs when blood pools in the veins rather than circulating efficiently out of the scrotum. […] The exact cause of a varicocele is unknown. One contributing factor may be the malfunction of valves inside the veins that are intended to keep blood moving in the right direction. Also, the left testicular vein follows a slightly different path than the right vein a path that makes a problem with blood flow more likely on the left. […] When the oxygen-depleted blood gets backed up in the network of veins, they widen (dilate), creating the varicocele.

• #13 Varicocele and its causes

  https://www.operarme.com/blog/varicocele-and-its-causes/

  In favour of this type of primary origin that causes varicocele, it has been shown that siblings of patients with varicocele have a 4.5 times higher risk of suffering from the disease than those who do not have direct relatives with the disease. […] This speaks in favour of the association of genetic vascular alterations that may cause this pathological entity. […] Anatomically, the left spermatic vein has no venous valves. […] The absence of these valves could favour the stagnation of part of this venous blood, leading to the appearance of varicocele. […] The left spermatic vein flows directly into the left renal vein, a system with much greater pressure than the inferior vena cava, which means that small changes in the pressures of the venous system can cause alterations and dysfunctions in the circulation, as we will explain below.

• #14 Testis varicocele | PPT

  https://www.slideshare.net/slideshow/testis-varicocele/249304036

  The pathophysiology of the adolescent varicocele is likely to be multifactorial. The primary factors are believed to be increased venous pressure in the left renal vein, collateral venous anastomoses valvular incompetence of the left internal spermatic vein at its junction with the left renal vein […] Nutcracker phenomenon compression of the left renal vein between the aorta and superior mesenteric artery may account for the varicocele in some boys […] Differences in venographic information Adults: reflux induced via collateral pathways, Adolescents: congenital venous abnormalities such as fewer competent valves and more instances of nutcracker phenomenon Genetic factors fourfold to eightfold higher among first-degree relatives of men undergoing vasectomy or male kidney donors, and the incidence was especially high in brothers

• #15 Varicocele and its causes

  https://www.operarme.com/blog/varicocele-and-its-causes/

  Secondary causes of varicocele are defined as any entity, disease or circumstance that can cause the secondary creation of a varicocele by its mere formation. […] The mechanism by which renal carcinoma can cause a varicocele is purely physical. […] The enlarged kidney compresses the left or right renal vein depending on the location of the kidney and this obstruction causes an increase in venous pressure in the inferior vena cava which worsens venous flow. […] As a consequence, an increase in venous stasis in any of its variants causes difficulty in the venous return of the pampiniform plexus, leading to and causing varicocele. […] When a tumour of the peritoneum itself or an increase in its thickness, whatever its cause (peritoneal fibrosis) occurs in the lower or medial part of the peritoneum, it can produce a compression mechanism of the inferior vena cava that can lead to dysfunction or difficulty in the venous return of all the circulatory vascular structures below it, including the pampiniform plexus, resulting in a varicocele, in this case, caused by a tumour or peritoneal fibrosis.

• #16 Varicocele and its causes

  https://www.operarme.com/blog/varicocele-and-its-causes/

  Cirrhosis of the liver as a cause of varicocele has its origin in portal hypertension secondary to cirrhosis of the liver. […] By increasing the hardness of the liver, it causes the structures within the liver to be subjected to more pressure and, in the case of arteries and veins, to increase their internal pressure. […] The definition of portal hypertension is the increased pressure of the venous circulation transiting the vein with consequent dysfunction of the preceding venous circulatory system. […] In this case, an increase in portal hypertension can lead to impaired circulation in the inferior vena cava, as we have explained in previous cases, making it possible to form a venous mass in the pampiniform plexus known as a varicocele.

• #17

  https://step2.medbullets.com/renal/120714/varicocele

  increased venous pressure causing dilated veins in the pampiniform plexus […] primary varicocele […] venous reflux […] secondary varicocele […] renal cell carcinoma causing compression to the veins […] retroperitoneal tumor […] portal hypertension

• #18 SciELO Brazil – From pathophysiology to practice: addressing oxidative stress and sperm DNA fragmentation in Varicocele-affected subfertile men From pathophysiology to practice: addressing oxidative stress and sperm DNA fragmentation in Varicocele-affect

  https://www.scielo.br/j/ibju/a/96DxJvYJBYqQrYHVmG36bFS/

  Despite the link between varicocele and OS, the mechanisms underpinning this association are yet to be fully clarified. The most studied effects of varicocele that could increase ROS production or decrease TAC include scrotal hyperthermia, testicular hypoxia, vein wall shear stress, adrenal/renal metabolites reflux, and epididymal response. […] The optimal temperature for spermatogenesis is 2 to 4C lower than the body’s average temperature. This difference is maintained by several mechanisms, including the contraction of the cremaster and dartos muscles and the countercurrent system in the pampiniform plexus. Incompetent valves of the internal spermatic and cremasteric veins allow venous blood to reflux into the pampiniform plexus, disrupting the countercurrent mechanism and raising the scrotal temperature.

• #19 Endovascular Treatment of Male Varicocele – Endovascular Today

  https://evtoday.com/articles/2011-jan/endovascular-treatment-of-male-varicocele

  Varicocele is defined as the dilatation of the veins of the pampiniform plexus. […] The pathophysiology of varicocele is related to venous insufficiency and reflux involving the veins that drain the testis. […] Varicoceles usually result from venous reflux in the ISV, which may be caused by the congenital absence of valves and/or the presence of variant collateral veins entering the ISV and bypassing competent valves. […] It has been hypothesized that the hyperemia induced by a varicocele produces a persistent increase in testicular temperature, and that this is the reason for impaired fertility and testicular atrophy. […] The decrease in testicular temperature that has been observed in patients after varicocelectomy treatment further suggests that hyperthermia caused by venous reflux into the pampiniform plexus may contribute to the pathology that is associated with varicocele.

• #20 VARICOCELE AND ITS TREATMENT | Stony Brook Medicine

  https://www.stonybrookmedicine.edu/patientcare/urology/varicocele_and_its_treatment

  Varicocele is an abnormal dilatation of the veins of the pampiniform plexus. The primary factor in testicular dysfunction secondary to varicocele suggested being abnormal retrograde blood flow within the gonadal veins. The etiology of varicocele is unclear and the most common theories include: […] The exact mechanism of impaired testicular function in patients with varicocele is not known. The most widely accepted concept presently is a varicocele-related increase of testicular temperature. Varicocele can cause an increase in scrotal temperature by 2.60C, neutralizing the required temperature gradient. The varicocele-associated pathology mainly includes changes in testicular size, histology, function of Leydig cells, sperm characteristics and testicular steroidogenesis. Leydig cell dysfunction has been documented in men with varicocele. It was suggested that hyperplasia of the Leydig cells is the poor prognostic factor for fertility.

• #21 Varicoceles — Metrovan Urology

  https://www.metrovanurology.com/varicoceles

  Varicoceles is the name given to varicose veins present in the scrotum. They most commonly result from the failure of valves within veins which are meant to promote one-way flow of blood back to the heart. […] The pampiniform plexus acts as a heat exchange system in which the warm blood coming from the heart is cooled by the blood returning from the testicle back to the heart. This keeps the operating temperature of the testis below that of core body temperature by 1-2 degrees celcius. Sperm production works best when the temperature is a little lower than core temperature. Testicular hyperthermia is thought to be the primary mechanism of varicocele-related infertility. Failure of the valves meant to promote one way flow of blood back the heart is the underlying reason for the development of varicoceles though there are several other less common causes.

• #22 SciELO Brazil – From pathophysiology to practice: addressing oxidative stress and sperm DNA fragmentation in Varicocele-affected subfertile men From pathophysiology to practice: addressing oxidative stress and sperm DNA fragmentation in Varicocele-affect

  https://www.scielo.br/j/ibju/a/96DxJvYJBYqQrYHVmG36bFS/

  Varicocele can reduce male fertility potential through various oxidative stress mechanisms. Excessive production of reactive oxygen species may overwhelm the sperm’s defenses against oxidative stress, damaging the sperm chromatin. Sperm DNA fragmentation, in the form of DNA strand breaks, is recognized as a consequence of the oxidative stress cascade and is commonly found in the ejaculates of men with varicocele and fertility issues. […] However, recent studies have demonstrated that several non-mutually exclusive factors, including excessive oxidative stress (OS), are implicated in the pathophysiology of varicocele. […] Varicocele has been consistently associated with OS and decreased seminal antioxidant capacity. This association is more substantial when comparing infertile men with varicocele to fertile men without varicocele, but even fertile men with varicocele have increased levels of ROS.

• #23 :: WJMH :: World Journal of Men’s Health

  https://wjmh.org/DOIx.php?id=10.5534/wjmh.230260

  Varicocele has been associated with high seminal oxidative stress (OS), impaired semen quality, and reduced male fertility potential. However, the exact mechanism(s) underlying the development of varicocele-mediated infertility and the cause-effect relationship between varicocele and testicular dysfunction are not fully understood. […] The increased levels of OS in men with varicoceles can result in detrimental effects on testicular function, including impairing sperm motility, morphology, and vitality, reducing sperm count, and increasing sperm DNA fragmentation (SDF). […] Factors such as heat stress, alterations in the testicular environment and testicular hypoxia may play a role in the pathogenesis of OS and consequently the development of infertility secondary to varicocele. […] The exact mechanism of pathogenesis of OS in experimental animals with varicocele is not fully understood despite excess heat exposure and hypoxia have been postulated. Varicocele is thought to increase testicular temperature, secondary to the increase in heat shock proteins (HSPs) and their impact on sperm protein denaturation, apoptosis, and male infertility.

• #24 SciELO Brazil – From pathophysiology to practice: addressing oxidative stress and sperm DNA fragmentation in Varicocele-affected subfertile men From pathophysiology to practice: addressing oxidative stress and sperm DNA fragmentation in Varicocele-affect

  https://www.scielo.br/j/ibju/a/96DxJvYJBYqQrYHVmG36bFS/

  Given the vital link between varicocele and sperm DNA fragmentation, the role of varicocele repair in improving sperm DNA has been under scrutiny. […] The first meta-analysis was published in 2012 by Wang and colleagues. The analysis included data from six studies involving 177 men with clinical varicocele. The authors reported a statistically significant reduction in the sperm DNA fragmentation rates after varicocelectomy. […] In the most recent systematic review and meta-analysis, our group compiled data from 19 studies involving 1070 infertile men with palpable varicocele. In our study, varicocelectomy reduced postoperative sperm DNA fragmentation rates with a moderate effect size. […] Overall, current evidence indicates that men with palpable varicocele have increased sperm DNA fragmentation levels than men without varicocele. The effect is more evident in those men with abnormal basic SA parameters. […] The studies summarized above indicate that varicocele repair in infertile men with palpable varicocele reduces sperm DNA fragmentation levels. Furthermore, sperm DNA integrity improvement after the intervention seems to enhance the chance of natural conception.

• #25 SciELO Brazil – From pathophysiology to practice: addressing oxidative stress and sperm DNA fragmentation in Varicocele-affected subfertile men From pathophysiology to practice: addressing oxidative stress and sperm DNA fragmentation in Varicocele-affect

  https://www.scielo.br/j/ibju/a/96DxJvYJBYqQrYHVmG36bFS/

  Venous reflux hampers normal circulation in the testicular microvessels, leading to testicular ischemia in men with varicocele. […] Phlebographic studies have demonstrated retrograde blood flow from renal and adrenal veins to the left testicular vein in men with varicocele. […] Animal models of experimental varicocele have demonstrated structural and functional changes in the epididymis, revealing three critical sources of ROS, namely, metabolically active principal cells, endothelial cells from the capillary network around the epididymis caput, and the luminal fluid from the testis. […] The WHO cut-off levels for basic SA parameters are poor predictors of natural pregnancy and ART success. One reason is that routine SA does not include tests to assess sperm function, making it unable to diagnose alterations that could hamper embryo development and implantation.

• #26 :: WJMH :: World Journal of Men’s Health

  https://wjmh.org/DOIx.php?id=10.5534/wjmh.230260

  Varicocele-induced altered intratesticular vascular perfusion and pressure patterns together with local hypoxia are considered important factors of male infertility. […] The presence of hypoxia in the testicular microenvironment triggers changes in the expression of various hypoxia-related factors and genes, subsequently impacting the testicular microenvironment. […] The results of this meta-analysis revealed that varicocele has a detrimental impact on total sperm count, sperm vitality, and total sperm motility. In addition, varicocele in experimental animals is associated with higher SDF levels. These findings support the potential role of OS in the pathogenesis of varicocele-induced testicular damage.

• #27 The role of animal models in the study of varicocele – Katz – Translational Andrology and Urology

  https://tau.amegroups.org/article/view/3517/html

  Varicocele is the most common correctible cause of male infertility and is present in 15% to 20% of the male population. Despite its prevalence, the pathophysiology of varicocele remains under investigation. […] The pathophysiology of varicocele and its effect of spermatogenesis are poorly understood. […] The use of partial occlusion of the left renal vein to create a rat varicocele model has produced variable results in elucidating the pathophysiology of varicocele. […] One possible cause of impaired spermatogenesis is that varicocele causes apoptosis of germ cells. It has been shown that an experimentally induced varicocele in rats causes apoptosis of germ cells at 7-28 days, and that varicocele repair results in a decrease in the number of apoptotic cells. […] Another possible mechanism of impaired spermatogenesis in varicocele is testicular hypoxia. The increased hydrostatic pressure in the venous system is believed to disturb the arterial inflow and cause hypoxia of the testes.

• #28 Oxıdatıve Stress, Apoptosıs and Varıcocele-Related Infertılıty

  https://www.gavinpublishers.com/article/view/oxidative-stress-apoptosis-and-varicocele-related-infertility

  Varicocele is also associated with increased sperm DNA damage, and this sperm pathology may be secondary to varicocele mediated oxidative stress. […] Previous studies of experimental varicocele models in rats documented that increased hypoxia inducible factor-1a and germ cell apoptosis in testes. This means that varicocele can lead to testicular tissue hypoxia and cause germ cell apoptosis. […] It has been theorized that abnormally high levels of germ cell apoptosis may contribute to testicular failure and male infertility. […] Wang et al. showed that there was a positive correlation between the apoptotic index of germ cells and the relative intensity of HIF-1a staining in the bilateral testes of rats in the experimental group. This indicated that, under conditions of testicular hypoxia induced by varicocele, HIF-1a promoted germ cell apoptosis.

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

  https://www.mdpi.com/2079-7737/13/2/80

  Increased levels of renal and adrenal metabolite reflux to the testicle have been proposed to alter the testis microenvironment, resulting in Leydig and Sertoli cell injury. […] Another potential mechanism for varicocele-induced infertility is testicular hypoxia, resulting from venous stasis and decreased flow. […] Temperature regulation within the testes can also be affected by a varicocele. […] Male varicoceles have been shown to negatively affect both Sertoli and Leydig cell functions, causing decreased sperm production. […] Sperm DNA fragmentation (SDF) is a major clinical finding in patients who experience varicocele-associated infertility, and the current AUA and European guidelines recommend evaluation of SDF in couples with recurrent pregnancy loss or other specific circumstances.

• #30 Role of the Toxic Metal Cadmium in the Mechanism Producing Infertility With a Varicocele

  https://ctv.veeva.com/study/role-of-the-toxic-metal-cadmium-in-the-mechanism-producing-infertility-with-a-varicocele

  Varicose veins in the scrotum (varicocele) are responsible for 20% of male infertility in the US. Varicocele are associated with decreased sperm number and markedly reduced sperm fertilizing ability. […] Based on preliminary findings, we will obtain testis biopsies and semen specimens from infertile men with varicocele and prospectively examining the levels of cadmium, a toxic metal, and expression of genes required for normal sperm function. Cadmium and gene expression will be compared with response to varicocele repair (i.e., increased sperm production; pregnancy).

• #31 Oxıdatıve Stress, Apoptosıs and Varıcocele-Related Infertılıty

  https://www.gavinpublishers.com/article/view/oxidative-stress-apoptosis-and-varicocele-related-infertility

  In addition, Reactive Oxygen Species (ROS), which can be created during an intermediate event between hypoxia and the induction of apoptosis, also play an important role in apoptosis induced by hypoxia. […] Elevated temperature of the testis due to various disease, such as varicocele, was reported to be one of the causes of increased programmed cellular death. […] Apoptosis of germ cells is required for normal spermatogenesis through highly conserved events following death of the neighbouring cells. […] It has been shown that in men with abnormal sperm parameters, nuclear DNA damage in mature spermatozoa may be attributed to apoptosis. […] Elevated temperature of the testis due to various disease, such as varicocele, was reported to be one of the causes of increased programmed cellular death.

• #32 Immunological Aspects of Varicocele – MedCrave online

  https://medcraveonline.com/MOJI/immunological-aspects-of-varicocele.html

  Varicocele is the most common cause of infertility in men. The mechanism by which varicocele cause the variable effect on male infertility and is still unknown. […] The exact mechanism by which varicocele affects male fertility and spermatogenesis is unknown Clearly, the factors contributing to abnormal sperm function caused by varicocele that lead to infertility are ambiguous. Several hypotheses have been raised to explain the mechanisms by which scrotal varicocele may exert a deleterious effect on spermatogenesis and male fertility. They include renal and adrenal reflux, hypoxia, hormonal dysfunction, hyperthermia, and apoptosis of germ cells. […] It is suggested that the spermatogenic dysfunction in varicocele testis may be related partly to an abnormal control of apoptosis. Apoptosis, or signal-induced cell death, is a process in which a genetic mechanism, responsible for a series of events related to morphologic and biochemical changes, initiates by certain stimuli and culminates in the death of a cell.

• #33 Immunological Aspects of Varicocele – MedCrave online

  https://medcraveonline.com/MOJI/immunological-aspects-of-varicocele.html

  The Fas Protein (APO-1 or CD95) and its ligand (Fas-ligand or Fas-L) are members of the tumor necrosis factor (TNF) family. When Fas binds to Fas-L, a molecular complex is formed, signaling initiation of apoptosis, which involves caspase 8 activation and a subsequent cascade of events leading to DNA fragmentation and cell death. […] The Fas system in the testis has been identified as a paracrine signaling system by which Sertoli cells, expressing Fas-L, can initiate. […] In the past 10 years, oxidative stress (OS) has been the most investigated factor involved in the pathophysiology of varicocele. Oxidative stress is essential to maintain cellular homeostasis, but excess killing of Fas expressing germ cells. […] Sakkas et al. first described the presence of Fas on ejaculated sperm and proposed the abortive apoptosis theory states that an apoptotic process begins in germ cells but fails to be completed and deleted, can end up as Fas positive sperm in the semen.

• #34 Oxıdatıve Stress, Apoptosıs and Varıcocele-Related Infertılıty

  https://www.gavinpublishers.com/article/view/oxidative-stress-apoptosis-and-varicocele-related-infertility

  Apoptosis has been observed in testicular germ cells as a factor in regulating sperm production suggesting that spermatogenic dysfunction may be related to abnormal control of apoptosis. […] Apoptotic signaling during oxygen deprivation occur through the release of cytochrome c and Apaf-1 mediated caspase-9 activation leading to cell apoptosis. […] Increased apoptosis is found in all of the following conditions: hormonal insufficiency, cryptorchidism, and increase in blood flow to the testis, local temperature increase in testis, and hypoxia due to venous stasis. […] High apoptotic activity has been found in testicular dysfunction, and it has been reported that deterioration of spermatogenesis and hypospermatogenesis may be related to uncontrolled apoptosis. […] In a study done by Simek and coworkers, testicular biopsies were obtained from patients undergoing varicocelectomy and from healthy males. They proposed that apoptosis should also be expected in patients with varicocele, and determined the mean number of apoptotic cells in varicocele patients to be seven times higher than in a control group.

• #35 Oxıdatıve Stress, Apoptosıs and Varıcocele-Related Infertılıty

  https://www.gavinpublishers.com/article/view/oxidative-stress-apoptosis-and-varicocele-related-infertility

  The presence of these enzymes stimulates caspase-9 activation, leading to caspase-3 execution of cell apoptosis. […] The oncogenic properties of Bcl-2 have been attributed mainly to its ability to inhibit apoptosis by interfering with the activation of the cytochrome c/Apaf-1 (apoptotic protease activating factor-1; apoptosome) pathway, through stabilization of the mitochondrial outer membrane. […] The high incidence of varicocele among infertile men is usually associated with testicular hypotrophy and impairment in semen parameters. These histological changes are associated with varicocele-induced hypoxia, increased ROS and apoptosis.

• #36 Varicocele and its effect on testosterone: implications for the adolescent – Alkaram – Translational Andrology and Urology

  https://tau.amegroups.org/article/view/5322/html

  The treatment of varicoceles in adolescents is highly controversial. Recent evidence in adults suggests that varicocele may be a cause of hypogonadism. […] Varicoceles have been linked to hypogonadism in the adult male. […] Venous backflow with elevation of testicular temperature, increased spermatic vein pressure, accumulation of adrenal waste products and autoimmunity have been hypothesized to create a toxic environment to both Sertoli and Leydig cells. […] In an elegant investigation on the effect of experimentally induced varicoceles in adult Sprague Dawley rats, Rajfer et al. demonstrated the detrimental effect of a unilaterally induced varicocele on intratesticular T and the inhibition of two of the enzymes responsible for the production of T, 17,20-desmolase and 17 -hydroxylase.

• #37 Varicocele and its effect on testosterone: implications for the adolescent – Alkaram – Translational Andrology and Urology

  https://tau.amegroups.org/article/view/5322/html

  Human studies have shown that increased testicular temperature is closely associated with increased Leydig cell apoptosis, increased cytoplasmic vacuolization and Leydig cell atrophy. […] Hypogonadism may very well impact the adolescent, both during and well beyond his procreative years. […] Although no data are available on T levels before and after varicocele repair in adolescents, there are studies of this in adults. […] The recent adult literature suggests that hypogonadism may also be an indication for repair in adults and it seems that this should be studied in adolescents.

• #38 Varicocele – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448113/

  Researchers theorize that the sperm may be damaged due to excess heat caused by increased oxidative stress on the sperm from blood pooling, causing reduced oxygenation, direct hydrostatic pressure injury effects on the testis, toxin formation, hypoxia, autoimmunity, or an increase in adrenal steroids concentration being delivered to the testicle since the adrenal veins empty into the left renal vein almost directly opposite the entry of the internal spermatic vein. […] Varicoceles may also reduce spermatic DNA integrity (fragmentation), increase oxidative stress, and negatively affect other aspects of spermatic function. […] The most accepted theory is that increased blood flow leads to higher intratesticular temperature, the main cause of impaired sperm in varicoceles. […] It is thought that large varicoceles may eventually cause testicular failure, ultimately resulting in lower hormonal production, oligospermia, and testicular atrophy. […] Varicoceles can also decrease sperm nuclear DNA integrity, which has been linked to reduced sperm motility, viability, counts, and abnormal morphology. […] Varicocelectomy improves the serum testosterone level in 80% of patients, with a mean increase between 100 ng/mL and 140 ng/mL.

• #39

  https://www.alliedacademies.org/articles/a-histoarchitectural-study-of-varicocele.html

  In the present study, there was an increase in intimal thickness in varicocele compared to normal as described by some workers. […] This study demonstrated that tunica adventitia and tunica media thicknesses seem to be increased in patients with varicocele compared with normal subjects. […] Therefore, the pathological abnormalities in varicocele were not due to deficiency of smooth muscles, but could be referred to the inability of muscle cells to provide the necessary tone in the vessel wall leading to vein wall dilatation. […] Another postulation reported by others was that after disruption of intimal endothelium lead to the smooth muscle cells exposure to blood flow and thus their function might be modulated by changes in the local hemodynamic environment. […] Thus contractile function becomes disturbed due to morphological changes of the venous wall that may lead to impairment of blood return of the veins, promoting the development of varicocele.

• #40

  https://www.alliedacademies.org/articles/a-histoarchitectural-study-of-varicocele.html

  Varicocele is an abnormal enlargement of vein of pampiniform plexus vein draining the testis. […] Defective valves or compression of the veins by adjacent structures can cause dilatation of the veins of pampiniform plexus leading to formation of varicocele. […] The mechanism of varicocele development still remains enigmatic. […] The increase in the pressure within the spermatic veins would cause the mechanical distension of the venous wall and the release of endothelial mediators, which might cause the increase in the number of smooth muscle cells and the deposition of extracellular matrix, which could ultimately cause an alteration of blood flow and reflux. […] Our results show marked reduction in varicocele vein vascularization and innervations, in addition to degradation of the outer longitudinal smooth muscle coat.

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

  https://www.mdpi.com/2079-7737/13/2/80

  Numerous studies have demonstrated an association between male infertility and genomic abnormalities. […] The blood–testis barrier (BTB) is one of the tightest blood–tissue barriers in the human body and divides the seminiferous tubule into distinct basal and apical compartments. […] The epigenome refers to the combined post-translational genetic modifications that do not alter the underlying genetic code, but rather its degree of utilization and accessibility. […] In addition to the epigenome and transcriptome, the male proteome has been of interest in the varicocele literature. […] The microbiome is a term describing the sum of bacteria, viruses, and fungi living within a niche in the human body. […] Varicocele pathophysiology and its ensuing male-factor infertility remains a complex disease process with an evolving knowledge base.

• #42 Varicocele, Functional Foods and Nutraceuticals: From Mechanisms of Action in Animal Models to Therapeutic Application

  https://www.mdpi.com/1422-0067/23/24/16118

  The increased production of TNF-α, together with augmented Transforming Growth Factor (TGF)-β, a pleiotropic cytokine with strong regulatory and inflammatory activity, impairs the normal organization of the blood-testis barrier (BTB). […] In varicoceles, the activation of inflammatory pathways can induce the destruction of the BTB, thus producing male infertility. […] During inflammation, an activation of inflammasomes was also observed. […] The consequent increase of these pro-inflammatory cytokines in the testis could cause damages in testicular function, spermatogenesis and androgen production. […] Varicocele-induced inflammation can be explained by the concomitant down-regulation of pErk 1/2 and TGF-β3, thus improving the functional and structural features. […] The increase of inflammatory cytokines is able to downregulate the expression of StAR in testicular tissue, thus reducing testosterone production. […] Recent experimental animal studies and current clinical trials suggest the positive effects of dietary habits on fertility-associated problems in varicoceles.

• #43 Varicocele, Functional Foods and Nutraceuticals: From Mechanisms of Action in Animal Models to Therapeutic Application

  https://www.mdpi.com/1422-0067/23/24/16118

  Varicocele is one of the main causes of infertility in men, thus representing an important clinical problem worldwide. Inflammation contributes mainly to its pathogenesis, even if the exact pathophysiological mechanisms that correlate varicocele and infertility are still unknown. […] The damage of testicular function is linked to physio-pathological events, including testicular hypoxia and hyperthermia, inflammation, oxidative stress, hormonal imbalance and cellular death. […] A correct diagnosis of varicocele is particularly important to avoid a worsening of the pathology and to be able to combine traditional surgery with treatment with natural substances capable of modulating the pathogenetic mechanisms involved in the disease, with particular regard to the inflammatory cascade. […] Varicocele triggers inflammation through infiltration and activation of macrophages and lymphocytes, which leads to higher quantities of inflammatory cytokines.

• #44 lncRNA and mRNA sequencing of the left testis in experimental varicocele rats treated with Morinda officinalis polysaccharide

  https://www.spandidos-publications.com/10.3892/etm.2021.10570

  Varicocele is a common disease of the male reproductive system. […] the underlying molecular mechanisms of this effect are poorly understood. […] Following validation by reverse transcription-quantitative PCR, the Yip1 domain family member 7 (YIPF7) gene was identified as a key mediator of varicocele pathogenesis and repair effect of MOP. […] We hypothesize that TMEM255B could be a potential novel diagnostic biomarker for varicocele; WNT9B and P2RX4 likely play notable roles in the pathophysiology of the disease through the Wnt signaling pathway and regulation of transmembrane ion channels, respectively. […] the present study delineated the molecular mechanisms underlying varicocele pathogenesis and the therapeutic effect of MOP, identified a potential novel diagnostic marker and therapeutic target for varicocele, and provided feasible directions for further studies in the future.

• #45 lncRNA and mRNA sequencing of the left testis in experimental varicocele rats treated with Morinda officinalis polysaccharide

  https://www.spandidos-publications.com/10.3892/etm.2021.10570

  Researchers have shown that the following mechanisms contribute to the pathogenesis of varicocele: i) Neuroendocrine system dysfunction; ii) hypoxia; iii) accumulation of metabolites and toxicants; iv) oxidative stress; v) disruption of the blood-testis barrier (BTB); and vi) cell damage resulting from increased testicular temperature. […] However, the molecular mechanisms underlying the pathophysiology of varicocele and the physiological functions and therapeutic effects of MOP in varicocele are yet to be explored in detail. […] The results of the present study provide compelling evidence for the involvement of Wnt/-catenin signaling in varicocele progression and the therapeutic effect of MOP in varicocele; this evidence is worthy of further research. […] The results of GO and KEGG pathway enrichment analyses showed that ligand-gated calcium channel activity, cytokine-cytokine receptor interaction and the Wnt signaling pathway may all be implicated to underlie this effect.

• #46 lncRNA and mRNA sequencing of the left testis in experimental varicocele rats treated with Morinda officinalis polysaccharide

  https://www.spandidos-publications.com/10.3892/etm.2021.10570

  Based on its diverse biological activities and intimate connection to TNF-, YIPF7 is considered a key mediator of varicocele pathogenesis and therapeutic effects of MOP. […] TMEM255B may be a potential novel diagnostic marker for varicocele; the role of WNT9B and P2RX4 in varicocele is possibly mediated by the activation of Wnt signaling and the regulation of transmembrane ion channels and the inflammatory response, respectively.

• #47 Varicocele Male Infertility: Protein Candidate Biomarkers

  https://www.thermofisher.com/blog/proteomics/varicocele-linked-male-infertility-differentially-expressed-protein-candidate-biomarkers/

  Varicoceles are enlarged veins in the scrotum, similar to varicose veins; they are present in 35% to 50% of men with primary infertility and 80% of men with secondary infertility. […] Although several known factors influence the pathogenicity of varicoceles, the precise mechanisms linking them to infertility remain unclear. […] The findings in this study also augment the current understanding of varicocele pathogenesis and may shed light on the detrimental outcomes associated with bilateral presentation.

• #48 VARICOCELE AND ITS TREATMENT | Stony Brook Medicine

  https://www.stonybrookmedicine.edu/patientcare/urology/varicocele_and_its_treatment

  The detrimental effect of varicocele on spermatogenesis in the subfertile male is manifested by low sperm count, decreased sperm motility and low percentage of normal sperm morphology together or in different combinations. […] The goal of treatment of the varicocele is to obstruct the refluxing venous drainage to the testis while maintaining arterial inflow and lymphatic drainage. The relationship between varicocele, altered spermatogenesis, and infertility is now widely accepted and varicocelectomy is the most common surgical procedure for infertility in males. Varicocelectomy was found to improve the biopsy score independent of the duration or size of the varicocele. […] The grade of varicocele may have significant effect upon the outcome of varicocelectomy. Patients with large varicocele experience greater seminal improvement postoperatively than patients with small varicocele. […] Microsurgical varicocelectomy provides a safe and effective approach to varicocele with preservation of testicular function, improvements in semen quality, and improvements in pregnancy rates in a significant number of men.

• #49 Varicocele Treatment in Atlanta | Georgia Urology

  https://www.gaurology.com/condition/varicocele/

  Varicoceles may cause progressive injury to the production and the maturation process of sperm, with worsening sperm count over time. […] The mechanism by which varicocele impairs fertility in a matter of ongoing debate. The most likely explanation is the abnormal elevation of scrotal temperature. Normal scrotal temperature is a few degrees lower than the core body temperature, as required for normal sperm production and maturation to proceed. […] Varicoceles affect seminal parameters in many ways. These include reduced sperm count, motility, morphology, sperm penetration scores, and possibly the production of anti-sperm antibodies.

• #50 Varicocele | UNC Department of Urology

  https://www.med.unc.edu/urology/patientcare/adult-non-cancer/male-fertility/varicocele/

  Although the mechanisms whereby varicoceles cause impairment in sperm production and semen quality remain theoretical, the statistical association between varicocele and male infertility is unquestionable. Furthermore, improvement in semen quality after varicocele correction has been repeatedly demonstrated. […] The resultant improvement in semen quality occurs in close to 70% of patients, and the pregnancy rate is as high as 40%. Correction of varicoceles has been shown to improve sperm motility, density, and shape (morphology), but also specific functional sperm defects including oxidative damage (ROS) and breaks in DNA. […] The scrotal varicocele remains the most correctable factor when treating poor semen quality. Therefore, when present in the infertile male who demonstrates abnormalities of semen quality, surgical correction should be strongly considered.

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