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Varicocele and male infertility: Part II: Pathophysiology of varicoceles in male infertility
Abstract
Varicoceles are found in 19 to 41% of infertile men, and is one treatable form of male infertility. The mechanism by which varicoceles cause the variable effect on male infertility and spermatogenesis is still unknown. Experimental animal models play a useful (but limited) role due to the sudden and variable iatrogenic nature of the varicoceles and the duration of the studies. Much of the human data are derived by the characterization of associated differences in measurable parameters between men with and without varicoceles. The role of hyperthermia, testicular blood flow and venous pressure changes, reflux of renal/adrenal products, hormonal dysfunction, autoimmunity, defects in acrosome reaction, and oxidative stress, in the pathophysiology of varicocele will be discussed.
Supplementary resource (1)
... 18 The potential reversibility of impaired spermatogenesis due to varicocele pathophysiology may serve as a basis for intervention. 19,20 A previous study has postulated that varicocelectomy may help male patients with infertility with azoospermia by inducing spermatogenesis and improving the rates of spontaneous pregnancy and sperm retrieval. 20 However, the recommendation for varicocelectomy within the current guidelines for patients with azoospermia has not been clearly elucidated, and the supporting evidence is barely consistent. ...
... Understanding the pathophysiology of varicocele-related infertility is fundamental to elucidating the role of varicocelectomy in azoospermia. 19,21 Generally, the major harmful effect of varicoceles is elevated temperatures due to the turbulence of blood flow caused by dilated scrotal veins. 19 A higher scrotal temperature more than 2°C is associated with decrease in sperm count and quality, believed to be caused by DNA and protein damage within the nucleus of spermatic tubule cells and/or Leydig from the thermal injury. ...
... 19,21 Generally, the major harmful effect of varicoceles is elevated temperatures due to the turbulence of blood flow caused by dilated scrotal veins. 19 A higher scrotal temperature more than 2°C is associated with decrease in sperm count and quality, believed to be caused by DNA and protein damage within the nucleus of spermatic tubule cells and/or Leydig from the thermal injury. 21,22 Varicocelectomy plays a major role in correcting scrotal temperature by removing dilated scrotal veins. ...
Patients with azoospermia show a prevalence of varicocele of 10.9% and a 14.8% contribution to male infertility. Patients with azoospermia are thought to produce high-quality semen following varicocele treatment. Advising varicocelectomy prior to sperm retrieval in a reproductive program is still debated. This study reviewed the impact of varicocele repair on male infertility using several factors. A literature search was conducted using Scopus, PubMed, Embase, the Wiley Online Library, and Cochrane databases. Sperm concentration, sperm progression, overall sperm motility, sperm morphology, and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were also compared. Outcomes were compared between those who received treatment for varicocele and those who did not. The data from the pooled analysis were presented as standardized mean difference (SMD) along with a 95% confidence interval (CI). Heterogeneity was evaluated using I ² . Additionally, we conducted analyses for publication bias, sensitivity, and subgroup analysis as appropriate. Nine studies were included after screening relevant literature. Statistical analysis revealed a significant improvement in sperm concentration (SMD: 1.81, 95% CI: 0.84–2.77, P < 0.001), progressive sperm motility (SMD: 4.28, 95% CI: 2.34–6.22, P < 0.001), and sperm morphology (SMD: 3.59, 95% CI: 2.27–4.92, P < 0.001). Total sperm motility showed no significant difference following varicocele repair (SMD: 0.81, 95% CI: −0.61–2.22, P = 0.26). No significant differences were seen in serum FSH (SMD: 0.01, 95% CI: −0.16–0.19, P = 0.87) and LH (SMD: 0.19, 95% CI: −0.01–0.40, P = 0.07) levels as well. This study supports varicocele repair in infertile men with clinical varicocele, as reflected by the improvement in sperm parameters after varicocelectomy compared with no treatment. There were no significant improvements in serum FSH and LH levels.
... However, not all varicoceles affect sperm production. Varicoceles can also cause testicles atrophy [2,3]. Varicocele is a very common finding in young men, The prevalence of varicocele is approximately 15% in general population, 25%-40% among men with primary infertility and 45% to 81% among men with secondary infertility. ...
... [3] Isolated left-sided lesions are seen in 78% to 93% of varicocele patients, unilateral right-sided lesion has a reported incidence of 1% to 7%, bilateral varicocele is found in 2% to 20% of cases [4]. Etiology of varicocele is thought to be multi-factorial, the anatomic differences in venous drainage between the left and right internal spermatic veins varicoceles are much more common in the left testicle than in the right because of several anatomic factors [2], including angle at which the left testicular vein enters the left renal vein, lack of effective antireflux valves at the juncture of the testicular vein and renal vein, increased renal vein pressure due to its compression between the superior mesenteric artery and the aorta (ie, nutcracker effect) and another cause that veins valves that are supposed to prevent backflow fail (venous insufficiency); and Physical exertion during puberty may lead to the development of varicocele whereas physical exertion at a later age can aggravate the condition but does not modify the prevalence of varicocele. Several hypotheses for pathophysiology of how varicocele leads to impaired spermatogenesis and infertility. ...
... This mechanism keeps the temperature in the scrotum 1-2°C lower than the core body temperature. In varicocele patient's dilatation of the pampiniform plexus led to testicular hyperthermia which cause damage to DNA synthesis, gene expression and protein synthesis in the nucleus of the Seminiferous tubules cells and/or Leydig cells [2]; venous stasis and reflux lead to elevate spermatic vein catecholamines; ...
Despite various studies published in the recent years, efficacy of varicocelectomy and its influence on semen parameters, particularly sperm count, motility and morphology has not yet been determined. Conflicting results obtained in different studies, accounts for sparked interest in varicocele management and its effects on seminal parameters. Therefore, present study was designed in an attempt to evaluate the effect of varicocelectomy on the semen parameters by analyzing reports that included men with varicoceles who had both preoperative and postoperative semen examination done. To determine the efficacy of varicocelectomy in improving semen parameters semen parameters (count, motility and morphology) by analyzing reports that included men with varicoceles who had both preoperative and postoperative Spermatogram. The present retrospective study enrolled 50 patients in Tripoli University Hospital medical center, Tripoli /Libya. Varicocele was graded by Dubin grading system by palpation in standing and during Valsalva maneuver under adequate exposure and scrotal Doppler ultrasound Macro and microscopic assessment of semen samples was carried out according to WHO guidelines 2010. The surgical approach used for varicocelectomy was inguinal (low ligation procedure), post operative semen analysis done after 6 months from surgery. Significant improvement in semen parameters (viz sperm counts/ml, sperm counts/ejaculate and sperm motility) were observed after varicocelectomy. We noted no effect of patient’s age on the degree of improvement in semen parameters post operatively. Preoperatively, men with Grade IV varicoceles had lower sperm counts and sperm motility, but significant improvement was observed post-operatively compared to men with Grades II and III varicoceles
... Adding to the complexity of the patient's condition was the finding of a grade III varicocele on the left testicle. Varicocele, an abnormal dilation of the veins in the pampiniform plexus within the scrotum, is a well-established cause of male infertility [6]. It accounts for approximately 40% of all cases of primary infertility and 80% of secondary infertility [6]. ...
... Varicocele, an abnormal dilation of the veins in the pampiniform plexus within the scrotum, is a well-established cause of male infertility [6]. It accounts for approximately 40% of all cases of primary infertility and 80% of secondary infertility [6]. The exact mechanism by which varicoceles contribute to infertility is not entirely understood, but it's generally accepted that they raise the temperature of the testes, impairing spermatogenesis, and causing a decrease in sperm count, motility, and morphology [6]. ...
... It accounts for approximately 40% of all cases of primary infertility and 80% of secondary infertility [6]. The exact mechanism by which varicoceles contribute to infertility is not entirely understood, but it's generally accepted that they raise the temperature of the testes, impairing spermatogenesis, and causing a decrease in sperm count, motility, and morphology [6]. The presence of both a potential genetic factor (AURKC mutation) and a physical factor (varicocele) adds layers of complexity to the patient's condition [7]. ...
This case report focuses on a 33-year-old male patient with a history of infertility, characterized by severe micro-oligo-asthenospermia. Subsequent analysis revealed the presence of multi-headed and multi-flagellated spermatozoa, indicating a potential case of macrocephalic spermatozoa syndrome linked to a mutation in the AURKC gene. Genetic testing confirmed the presence of a pathogenic mutation, c.144delC, in a homozygous state in the AURKC gene. The AURKC gene is known to play a vital role in meiosis during sperm production, and its mutation can lead to abnormalities in sperm morphology and function, resulting in conditions like macrozoospermia and male infertility. Additionally, the patient was diagnosed with a grade III varicocele on the left testicle, which further contributed to his infertility. Varicoceles are associated with decreased sperm production and quality, making them one of the common reversible causes of male infertility. This case highlights the significance of comprehensive diagnostic approaches, including spermogram, ultrasonography, and genetic testing, in managing male infertility cases. It also emphasizes the intricate interplay between genetic mutations and physical conditions in the manifestation of male infertility. Further research is warranted to elucidate the mechanisms underlying AURKC-related sperm abnormalities and to develop effective therapeutic interventions. Moreover, a deeper understanding of such genetic factors may aid in the development of genetic counseling strategies for couples experiencing infertility.
... It is important to learn more about the molecular mechanisms underlying the effect of varicocele on sperm quality and DNA integrity so that we can develop better diagnostics and treat-ments for patients with varicocele. Due to higher heat dissipation, the testes is located on the scrotum, which is outside the body cavity, and the temperature of the testicles is also limited to 35-36 °C [4] . This mechanism of maintaining the temperature of the testicles is necessary for the spermatogenesis process and is regulated by the counter-current of the testicular arteries and veins where heat exchange occurs for the purpose of eliminating high temperatures [5] . ...
... Mechanism of infertility in patients with varicocele is poorly understood and ROS is postulated as a possible mediator [45,46]. Elevated levels of ROS and depressed levels of TAC were associated with varicocele (47)(48)(49). ...
Oxidants are highly unstable molecules that attack every chemical substance they come into contact. Oxidants modify the macromolecules both structurally and functionally. Body has defense mechanisms against oxidants in the form of both enzymatic and non-enzymatic antioxidants. Reactive oxygen species (ROS) are a group of oxidants formed during oxygen metabolism. ROS appears to be involved in the pathogenesis of many human diseases. In reproductive medicine, ROS have both physiological and pathological role in male and female reproduction. Oxidative stress develops when the generation of ROS overwhelms the scavenging capacity of antioxidants. Oxidative stress causes damage to spermatozoa, oocyte and embryos. It appears to play a role in both natural and in vitro fertilization and pregnancy. The patients with oxidative stress may benefit from the strategies to reduce oxidative stress by treatment with potent antioxidant therapy. The present paper reviews the Role of Oxidants & Antioxidants in maintaining optimum Male & Female fertility.
... Experimental research indicates that mobile phone radiation elevates oxygen free radical levels, leading to oxidative stress (67,68). Oxidative stress in testicular tissue impairs Leydig cell function (69) and disrupts the ability of the germinal epithelium to produce normal sperm cells or undergo spermatogenesis (70). The localized thermal effects of EMR may contribute to a decrease in sperm count (71). ...
... Experimental research indicates that mobile phone radiation elevates oxygen free radical levels, leading to oxidative stress (67,68). Oxidative stress in testicular tissue impairs Leydig cell function (69) and disrupts the ability of the germinal epithelium to produce normal sperm cells or undergo spermatogenesis (70). The localized thermal effects of EMR may contribute to a decrease in sperm count (71). ...
Introduction
Male infertility, often attributed to insufficient production of healthy and active sperm, can be exacerbated by electromagnetic radiation emitted from mobile phones, which disrupts normal spermatogenesis and leads to a notable decline in sperm quality. The main targets of mobile phone-induced damage in the testes are Leydig cells, seminiferous tubules, and sperm cells. The aim of this systematic literature review is to identify histopathological changes in the testes due to mobile phone radiation exposure and to examine its effects on sperm parameters in experimental animals.
Methods
In this systematic review, an extensive literature search was conducted across databases such as PubMed, ScienceDirect, Hinari, and Google scholar.
Results
A total of 752 studies were identified for screening, and 18 studies were deemed eligible for data extraction. Studies have identified histopathological alterations in testicular tissue caused by mobile phone radiation, such as reduced seminiferous tubule diameter, tunica albuginea and germinal epithelial thickness, Leydig cell hypoplasia, and increased intertubular space. Consistent exposure to mobile phone radiation has been shown to significantly reduce sperm count, motility, and viability, while also increasing abnormal sperm morphology in male rats, mice, and rabbits.
Conclusion
Animal studies indicate that electromagnetic radiation from mobile phones can negatively impact testicular tissue and sperm parameters, including sperm count, motility, viability, and morphology. As a precaution, preventive measures are recommended to minimize potential risks from mobile phone exposure, and further research is needed to fully understand its effects on human reproductive health.
... It was reported that sperm motility was significantly reduced in varicocele patients compared to healthy individuals [35]. Other studies have reported that varicocele can affect all sperm parameters (number, motility, and morphology) [36]. The increased reactive oxygen species (ROS) level correlates with decreased sperm quality parameters [1]. ...
Varicocele is a leading cause of infertility in couples. It damages sperm and increases oxidative stress (OS) in seminal fluid. Antioxidant treatments like alpha-lipoic acid (ALA) and vitamin C (VC) can improve sperm quality by reducing OS. This study aims to explore the combined effects of these antioxidants in reducing the negative impact of OS caused by varicocele-induced adolescent (ADO) and adult (ADU) rats. This study included 50 male Wistar rats, comprising 25 ADU rats and 25 ADO divided into 10 groups of five. The groups and treatment include Group I (ADO-Control) and VI (ADU-Control): the healthy group, no treatment, Groups II (ADO-Mock) and VII (ADU-Mock): received normal saline for 2 months, Group III (ADO-Varicocele-VC) and VIII (ADU-Varicocele-VC): received VC (100 mg/kg), Group IV (ADO-Varicocele-ALA) and IX (ADU-Varicocele-ALA): received ALA (300 mg/kg), and Group V (ADO-Varicocele-VC + ALA) and X (ADU-Varicocele-VC + ALA): received VC (100 mg/kg) + ALA (300 mg/kg). After 2 months of treatment, the rats were anesthetized. The sperm quality parameters, serum total oxidant and antioxidant properties, and testicular pathology were assessed. There were significant differences (p <0.05) in the varicocele-ALA + VC and varicocele-ALA groups compared to the varicocele-VC and the Mock group (ADO and ADU). Additionally, there was a significant variance (p <0.05) in the OS index between the varicocele-ALA + VC and Varicocele-ALA groups compared to the other groups. The use of ALA has a positive impact on sperm parameters and the structure and function of testicular tissue, leading to a decrease in the OS index. Treatment with VC, along with other antioxidants like ALA, may provide a protective effect, but treatment with VC alone did not show significant effectiveness in varicocele-induced ADO and ADU rats.
... While the pathogenesis of varicocele remains incompletely understood, it is generally accepted that it may be related to a few factors that contribute to increased pressure in the seminiferous plexus or blood reflux [19,20]. Generally, these factors include endothelial dysfunction, absence or insufficiency of the spermatic vein valve, the left spermatic vein flows vertically into the left renal vein, resulting in increased pressure in the spermatic plexus, or the left renal vein being pressed between the abdominal aorta and superior mesenteric artery which called "nutcracker effect" [21][22][23]. In addition, some scholars have found that higher MPV in patients with varicocele is related to graded varicocele increased [13,14,24]; however, there are some scholars who hold a contrary [16]. ...
Objective
To delve into the relationship between mean platelet volume (MPV) and semen quality in patients with varicocele.
Materials and methods
A total of 246 varicocele patients and 120 healthy adult males were enrolled. Physical examinations and the color Doppler ultrasonography were conducted on patients with varicocele to confirm the diagnosis. Venous blood samples and semen samples were collected from all participants for subsequent analysis. A series of statistical analyses were conducted to assess the relationship between their MPV levels and semen quality. A series of statistical analyses were performed to assess the relationship between MPV and semen quality.
Results
No statistically significant differences were found between body mass index (BMI), sexual hormones, semen volume, platelet count, and right testicular volume in all three groups (health subjects, varicocele without symptoms, and varicocele with infertility). When conducting regression analysis on two groups with varicocele, the results indicated that a lower MPV is associated with a reduced risk of varicocele accompanied by infertility (OR = 0.557 95% CI: 0.432–0.719, P < 0.001). Further correlation analysis in varicocele patients revealed that high MPV had a statistically negative impact on the occurrence of poor semen quality, affecting sperm concentration, progressive motility, and morphology (all P < 0.001). More importantly, when predicting varicocele associated with infertility, MPV demonstrated high diagnostic sensitivity (AUC = 0.745, P < 0.001).
Conclusion
Our results indicate that MPV is higher in varicocele with infertility and is closely related to semen quality, which may suggest an accompanying decline in semen quality associated with varicocele. However, these conclusions require further experimental validation.
... (8) The negative impact of varicocele on spermatogenesis can be attributed to several factors, including elevated testicular temperature, increased intratesticular pressure, hypoxia due to reduced blood supply, reflux of toxic compounds from the adrenal glands, and hormonal profile abnormalities. (9,10) Semen analysis involves a set of descriptive measurements of spermatozoa and seminal fluid parameters used to assess semen quality. (11) Determining sperm morphology, however, poses challenges due to subjective factors and inconsistency. ...
Background: Infertility is a complex issue affecting 15% of couples of reproductive age, with men accounting for 40%-50% of infertility cases. Semen analysis comprises various descriptive measures of sperm and seminal fluid to determine semen quality. Transforming qualitative descriptions of sperm deformities and shape changes into quantitative terms can aid in identifying sub-visual abnormalities. This study aimed to evaluate sperm morphometry parameters in both infertile and fertile men. Methods and Results: The study enrolled a total of 101 participants, divided into three groups: Group A included 38 subfertile patients with varicocele, Group B included 33 patients with idiopathic infertility (23 with asthenozoospermia and 10 with oligozoospermia), and Group C (the control group) included 30 healthy fertile men. The mean age of patients was 31.6±5.81, 31.3±6.0, and 29.47±4.27 years in Groups A, B, and C, respectively. Scrotal duplex examinations were performed to identify the presence of varicocele. Semen samples were collected following WHO Manual (2010). Semen dynamic and morphological analyses were conducted using CASA (Computer-Assisted Semen Analysis, MIRALAB, ISO9001, ISO13485). We found that sperm concentration, total sperm count, sperm progressive motility, and sperm progressive+non-progressive motility were significantly lower in Group A and Group B than in Group C (P=0.000 in all cases); however, there were no differences between Group A and Group B regarding these parameters (Table 5). The sperm morphology index was significantly lower in Group A than in Group C (P=0.0024); no differences were found between Group B and Group C and Group B and Group A. The mean value of the sperm deformity index was significantly lower in Group A than in Group C P=0.004). Conclusion: Our study highlights the significant association between sperm morphology and male infertility in varicocele and idiopathic subfertile males.
... The etiology of these defects has yet to be fully elucidated; however, they can have a variety of adverse effects on spermatogenesis due to elevated testicular temperature, heightened pressure within the testes, reduced oxygen levels resulting from decreased blood circulation, the backflow of harmful metabolites from the adrenal glands, and irregularities in hormonal levels [57,58]. Moreover, the toxic accumulation of metabolites due to the chronic reflux of the venous plexus has been shown to disrupt spermatic equilibrium, further contributing to the development of infertility [59]. Although treatments include surgical modalities, there has recently been development in the use of AI for the prevention and treatment of varicoceles. ...
Male infertility has affected an increasingly large population over the past few decades, affecting over 186 million people globally. The advent of assisted reproductive technologies (ARTs) and artificial intelligence (AI) has changed the landscape of diagnosis and treatment of male infertility. Through an extensive literature review encompassing the PubMed, Google Scholar, and Scopus databases, various AI techniques such as machine learning (ML), artificial neural networks (ANNs), deep learning (DL), and natural language processing (NLP) were examined in the context of evaluating seminal quality, predicting fertility potential, and improving semen analysis. Research indicates that AI models can accurately estimate the quality of semen, diagnose problems with sperm, and provide guidance on reproductive health decisions. In addition, developments in smartphone-based semen analyzers and computer-assisted semen analysis (CASA) are indicative of initiatives to improve the price, portability, and accuracy of results. Future directions point to possible uses for AI in ultrasonography assessment, microsurgical testicular sperm extraction (microTESE), and home-based semen analysis. Overall, AI holds significant promise in revolutionizing the diagnosis and treatment of male infertility, offering standardized, objective, and efficient approaches to addressing this global health challenge.
... Potential causes for varicocele-induced infertility include hypoperfusion leading to hypoxia, heat stress, oxidative stress, hormonal imbalances, and exogenous toxicants. In particular, current evidence supports oxidative stress as a crucial arbiter of varicocele-induced infertility [4,22,23]. DNA base modifications, deletions, strand breakage, and chromosomal rearrangements are consequences of oxidative stress. ...
Despite the wide recognition of varicocele as a contributor to infertility, its exact pathophysiologic mechanism is not fully understood. As the field of male infertility continues to see progress in new diagnostic and therapeutic technologies, we sought to obtain a robust understanding of the interplay of varicoceles, oxidative stress, DNA methylation, and male infertility. We performed a comprehensive review of the contemporary literature in PubMed using search terms and keywords associated with varicoceles, DNA methylation, and male infertility. The most important findings from the literature review were included in this report. Articles were selected based on quality and relevance to the topic. Eight studies were included in this review. These studies discuss DNA methylation and varicocele-associated male infertility through evaluation of sperm parameters, DNA methylation, DNA fragmentation, and other relevant factors. Our review of the literature on varicocele-associated sperm DNA methylation indicates that global hypomethylation occurs in association with varicoceles. Some data suggest a dose-dependent effect of varicocele grade on sperm DNA methylation, with the greatest magnitude changes seen in grades II and III varicoceles. While changes in DNA methylation patterns would be expected following varicocelectomy, such changes were not found to be statistically significant in one study reviewed here. However, current human studies are limited by small sample size and short follow-up time. Future clinical and preclinical studies with robust sample sizes and hypothesis-driven investigations are necessary to further understand the relationship between DNA methylation patterns and varicocele-associated male infertility.
... In fact, varicocele is the most common surgically correctable cause of male subfertility, with an estimated prevalence of 15% in the general male population and up to 40% in subfertile men [2]. Varicocele repair can be done by several approaches including the abdominal, inguinal and subinguinal approaches. ...
... Autoimmune infertility is often clinically silent and might be caused by VC and TCT. The higher VC incidence in men with secondary infertility suggests that men with prior fertility may suffer VC-mediated secondary infertility, and the presence of VC may cause a progressive decline in fertility (Naughton et al., 2001). Increased levels of proinflammatory cytokines, leukocytes, and ASAs in seminal plasma indicate that testis/epididymis inflammation occurs in VC and TCT. ...
The main functions of the testis, steroidogenesis and spermatogenesis, depend on the endocrine axis and systemic and local tolerance mechanisms. Infectious or non-infectious diseases may disturb testicular immune regulation causing infertility. Literature has illustrated that bacterial and viral infections lead to autoimmune infertility: either sperm antibodies or autoimmune epidydimo-orchitis. However, little is known about the association between non-infectious testicular pathologic diseases and autoimmunity. Here we review the novel aspect of varicocele and testicular cord torsion pathology linked to inflammation and discuss how immune factors could contribute to or modulate autoimmunity in ipsi- and contralateral testis.
... Varicocele can affect spermatogenesis by different mechanisms [6][7][8]. Varicocele repair in NOA cases aims to alleviate its harmful impact on the testes to recover its spermatogenic activity with subsequent presence of spermatozoa in the semen or to increase the chances for successful TESE for ICSI process [9,10]. ...
Background. Infertile men with nonobstructive azoospermia (NOA) associated with varicocele may benefit from varicocele repair with recovered sperms in semen. Currently, there is no clinically applied method to predict the success of seminal sperm recovery in this subset of azoospermic men. Objective. We aimed to evaluate the predictive role of the seminal testis expressed protein (TEX101) in sperm recovery in the semen of NOA men with palpable bilateral varicocele after microsurgical varicocelectomy. Patients and Methods. This prospective cross-sectional cohort study included 40 patients with NOA and bilateral varicocele. Seminal TEX101 levels were measured followed by subinguinal microsurgical varicocele repair. Two seminal analyses were carried out at 3- and 6-month follow-up periods to evaluate seminal sperm recovery. Results. After varicocele repair, sperms were recovered in the semen of 10/40 patients (25%) along the follow-up periods (seven patients after 3 months and additional three patients after 6 months). The preoperative median seminal TEX101 level was significantly higher in NOA men with seminal sperm recovery compared with NOA patients without seminal sperm recovery (13.5 vs. 9.8 ng/ml, p = 0.014 ). Besides, the serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) median levels were significantly higher in NOA men without seminal sperm recovery compared with NOA men with seminal sperm recovery ( p = 0.001 , p = 0.01 ). There were nonsignificant differences comparing the preoperative testicular volume or serum testosterone levels between the two investigated groups ( p = 0.072 , p = 0.272 ). A cutoff value of 9.9 ng/ml was demonstrated to have preoperative TEX101 prediction of seminal sperm recovery (sensitivity of 90% and specificity of 57%). Conclusion. Preoperative seminal TEX101 could be considered as a biomarker for sperm recovery for seminal sperm recovery in NOA cases associated with varicocele after its surgical repair. Further work at this point with larger number of cases should be carried out to verify its potential importance.
... Varicocele is one of the most frequent causes of male infertility [1,2,3,4,5] with a prevalence in adolescents. ...
... One of the important issues studied is free oxygen radicals and semen parameter disorders, and it is understood that free oxygen radicals (FOR) play an important role in infertility [14]. Oxidative stress resulting from the imbalance between antioxidants and free oxygen radicals in the body causes infertility by damaging sperm [15]. ...
Background/aim: Mechanisms to explain inflammation in male infertility of unknown cause are still being investigated. The inflammasome is a key regulator of innate immunity in the inflammatory response to infections. Our study aims to investigate the effects of varicocele on infertility, its relationship with antioxidant and inflammasome mechanisms, and how it could be guided in azoospermic or nonazoospermic patients. Materials and methods: A cross-sectional cohort study was conducted at the department of urology in our university hospital. Eightyeight randomly selected men aged 20-45 admitted to our hospital because of infertility between September 2019 and July 2020 were included in the study. Patients were divided into four equal groups according to their clinical status, those with/without azoospermia and with/without varicocele. Blood and semen samples were taken from the patients. NOD-like receptor pyrin domain-containing 3 (NLRP3) and interleukin-1 beta (IL1ß) and total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) levels were measured in serum and semen, and the groups were compared statistically. Results: Serum and semen NLRP3, IL1ß, TAS, TOS, and OSI values of the patients with varicocele or azoospermia were significantly higher than those without either varicocele or azoospermia (p < 0.05). The oxidative stress markers TAS, TOS, and OSI values were significantly higher in the other groups than those without azoospermia and varicocele (p < 0.05). Conclusion: Inflammasome mechanisms, such as NLRP3 and IL1-ß molecules, may provide additional benefit in evaluating the need and benefit of surgical or medical treatment in infertility with and without vascular pathology and with and without azoospermia.
Keywords
Infertility, azoospermia, varicocele, NLRP3, inflammasome
... Принято считать, что повышение уровня оксидативного стресса у пациентов с варикоцеле связано с нарушением гемодинамики яичка и повышением внутритестикулярной температуры [34][35][36][37]. В ряде исследований наблюдали повышенное содержание маркеров оксидативного стресса, которое коррелировало со степенью варикоцеле [31,[37][38][39]. ...
Surgical treatment of clinically significant varicocele in infertile men with pathospermia is a common practice. However, the question of the role of this disease in the pathogenesis of such conditions as hypogonadism and orchalgia, as well as the role of varicocelectomy in eliminating pain symptoms in the scrotum and increasing testosterone levels, has remained ambiguous for a long time. The expediency of surgical treatment of varicocele in patients with azoospermia also remains a subject of discussion.
... [2] Varikosel, skrotal ağrıya, testis gelişiminde gerilemeye ve spermatogenezi bozarak infertiliteye neden olabilmektedir. [3] Varikoselin fertilite üzerine etkileri semen analiz parametrelerinde değişiklikler (sperm sayısında azalma, sperm motilitesinde ve morfolojisinde bozulma), testis volümde azalma ve Leydig hücre fonksiyonunda azalmayla ilişkilidir. [4] Varikosel patofizyolojisinde infertilite ve testiküler gelişme geriliğine sebep olan (hipertermi/hipoksi, renal/adrenal metabolitler, oksidatif stres, DNA fragmantasyonu, apoptoz, enflamasyon, hormonal dengesizlik, interstisyel lezyonlar ve otoimmünite) birçok teori vardır. ...
OBJECTIVE: In this study, we aimed to predict the changes in postoperative spermiogram parameters in patients who underwent varicocelectomy by using pre- and post-operative hemogram parameters and inflammatory blood markers. MATRERIAL and METHODS: 25 patients who underwent microscopic varicocelectomy in our clinic and met the study criteria were included in the study. Hemogram parameters were measured just before and twenty (20) days after the surgery, and spermiogram parameters were measured 6 months after the surgery. The patients seperated into two groups. Patients with >50% improvement in postoperative Total Motile Sperm Count (TMS) were included in the recovered patients group, and patients with less than 50% improvement were included in the non-recovered patients group. Neutrophil / lymphocyte ratio (NLR), platelet / lymphocyte ratio (PLR), monocyte / eosinophil ratio (MER), and blood counts such as neutrophil, lymphocyte, platelet, monocyte, eosinophil were compared in groups, also were compared before and after surgery, separate RESULTS: Improvement in TMS was observed in patients with a statistically significant decrease in postoperative NLR (p = 0.009; p <0.01). As a result of the calculations, cut-off point for the NLR change was accepted as 1.06% and above. PLR and MER parameters were not statistically significant in predicting the improvement of TMS. Among the neutrophil, lymphocyte, platelet, monocyte, eosinophil counts, preoperative neutrophil and preoperative monocyte counts were found to be higher in patients with postoperative TMS improvement. Cut-off points for these preoperative neutrophil and monocyte counts were calculated as 3.77 and 0.47, respectively. In our study, we could not reach any statistically significant result for lymphocyte, eosinophil and platelet counts. CONCLUSION: Preoperative and postoperative results of NLR, neutrophil or monocyte counts can be used as a marker to predict improvement in TMS. Keywords: varicocele, NLR, PLR, MER, inflammation
... One of the important issues studied is free oxygen radicals and semen parameter disorders, and it is understood that free oxygen radicals (FOR) play an important role in infertility [14]. Oxidative stress resulting from the imbalance between antioxidants and free oxygen radicals in the body causes infertility by damaging sperm [15]. ...
Background/aim: Mechanisms to explain inflammation in male infertility of unknown cause are still being investigated. The inflammasome is a key regulator of innate immunity in the inflammatory response to infections. Our study aims to investigate the effects of varicocele on infertility, its relationship with antioxidant and inflammasome mechanisms, and how it could be guided in azoospermic or nonazoospermic patients.
Materials and methods: A cross-sectional cohort study was conducted at the department of urology in our university hospital. Eighty- eight randomly selected men aged 20–45 admitted to our hospital because of infertility between September 2019 and July 2020 were included in the study. Patients were divided into four equal groups according to their clinical status, those with/without azoospermia and with/without varicocele. Blood and semen samples were taken from the patients. NOD-like receptor pyrin domain-containing 3 (NLRP3) and interleukin-1 beta (IL1β) and total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) levels were measured in serum and semen, and the groups were compared statistically.
Results: Serum and semen NLRP3, IL1β, TAS, TOS, and OSI values of the patients with varicocele or azoospermia were significantly higher than those without either varicocele or azoospermia (p < 0.05). The oxidative stress markers TAS, TOS, and OSI values were significantly higher in the other groups than those without azoospermia and varicocele (p < 0.05).
Conclusion: Inflammasome mechanisms, such as NLRP3 and IL1-β molecules, may provide additional benefit in evaluating the need and benefit of surgical or medical treatment in infertility with and without vascular pathology and with and without azoospermia.
Key words: Infertility, azoospermia, varicocele, NLRP3, inflammasome
... On the other hand, most men with varicoceles are able to father children and it is unclear how male fertility is affected by the dilated veins [21]. Proposed theories include oxidative stress, scrotal hyperthermia, hypoxia, reflux of renal and adrenal metabolites, hormonal imbalances, and the formation of antisperm antibodies, but none of these theories have been convincingly demonstrated [22]. In our series, neither semen parameters nor reproductive hormones were investigated. ...
Purpose
To present our experience with robot-assisted laparoscopic varicocelectomy in a pediatric population.
Methods
We reviewed 49 consecutive cases performed by the same experienced surgeon. One-to-four veins were ligated at the internal ring of the inguinal canal, while the testicular artery and lymphatics were spared. Information on patient characteristics, surgical time, complications, and recurrences were collected.
Results
Median patient age was 14 (range 10–17) years. Forty-eight had left-sided varicoceles and one had a bilateral varicocele. Forty-five were grade 3. All patients were referred due to discomfort/pain and 20 also had reduced testicular size. The median operating time from skin incision was 48 min (31–89 min) and the median console time was 18 min (7–55 min). Forty-seven patients were discharged the same day. Two patients experienced pain and problems urinating, respectively. These issues had resolved by the first post-operative day. There were no other complications, but at 6 months, eight recurrences were noted (16%). Scrotal complaints had subsided in all patients. Catch-up growth of the affected testicles was seen in 19/20 cases.
Conclusion
Robot-assisted laparoscopic varicocelectomy is feasible and safe in a pediatric population but with a relatively high recurrence rate.
... Renal and adrenal metabolite reflux have also been proposed as an aetiological cause for gonadal varicosities. In male varicoceles, catecholamine reflux from renal/adrenal sources back into the pampiniform plexus and to the testicular artery via the countercurrent exchange system, contributes to chronic testicular vasoconstriction and hypoxia (Naughton et al., 2001). However, other authors have argued that the anatomic arrangement of the LRV junction with the adrenal vein makes it physiologically unlikely for adrenal venous blood to reflux to the internal spermatic vein. ...
Pelvic congestion syndrome (PCS) in females and varicoceles in males may be regarded as closely related conditions since the main pathophysiological cause for both processes is pelvic venous insufficiency. Varicoceles are more prevalent amongst sub-fertile males, with an approximate incidence of 15% in the general male population. PCS is commonly diagnosed amongst premenopausal multiparous women, representing one of the leading causes of chronic pelvic pain. Both conditions appear to be predominantly left-sided and are associated with oxidative stress and pro-inflammatory cascades with subsequent effects on fertility. Clinical examination and pelvic ultrasonography play an essential role in the assessment of varicoceles, PCS and chronic pelvic pain. Venography is generally considered as a gold-standard procedure for both conditions. There is still much debate on how these conditions should be managed. This review article provides a comparative analysis of the underlying pathophysiological mechanisms of both PCS and varicoceles, their impact on fertility, as well as their clinical management.
... Lipid peroxidation is a form of oxidative stress that can cause chain reactions that damage tissue organs (Priyanto, 2007;Gemayangsura, 2015). At the level of the testes, oxidative stress can disrupt Leydig cells capacity to produce steroids and the germinal epithelium's ability to differentiate the spermatozoa (Naughton et al., 2001). This condition can be triggered as a result of consuming a high-fat diet-fed. ...
The impact of free radicals on testicular Leydig cells can result in the disruption of male reproductive health. The present study aimed to evaluate the effects of a high-fat diet on Leydig cells and the potential of kepok banana peel extract as a medication to mitigate these effects. In total of 20 adult male Wistar rats were assigned to five groups and treated with standard feed (P1), high-fat feed (P2), high-fat feed with simvastatin (P3), and high-fat feed with banana peel extract at doses of 100 and 200 mg/kg BW (P4 and P5). After 60 days of treatment, the number of Leydig cells was determined using HE staining methods. Data were analyzed using an One Way ANOVA test. The results showed that the administration of 100 mg/kg BW of kepok banana peel extract (P4) was able to maintain the number of Leydig cells and counteract the negative effects of a high-fat diet. These findings suggest that kepok banana peel extract may have the potential as a herbal medicine for supporting male reproductive health.
... Links between varicocele and testicular dysfunction have remained obscure, with venous reflux and testicular temperature elevation as one of the possible culprits (The Practice Committee of American Society for Reproductive Medicine, 2008). However, increase in seminal levels of proinflammatory cytokines and oxidative stress as well as reduced total antioxidant capacity have been suspected as much [18,19].Besides, in the pathophysiology of varicocele impaired spermatogenesis because of autoimmunity has been proposed [20,21]. Infertility in the male due to immunological causes is mostly associated with antisperm antibodies (ASA), which can develop as a result of testicular damage, infection or inflammation. ...
L-Carnitine (LC) is highly concentrated in the epididymis and plays a crucial role in sperm metabolism and maturation. They are related to sperm motility and have antioxidant properties. The objective of this review is to summarize the multiple roles played by LC in male reproduction, and to highlight their limitations as well as their benefits in the treatment of male infertility. A variety of studies support the conclusion that LC at total daily amounts of at least 500mg per day can significantly improve both sperm concentration and total sperm counts among men with astheno – or oligoasthenozoospermia. Although many clinical trials have demonstrated the beneficial effects of LC in selected cases of male infertility. Additional, a well – designed study is necessary to further validate the use of carnitines in the treatment of patients with male infertility, specifically in men with poor semen quality .
... The venous drainage of the testes comprises a network of small spermatic veins that gradually coalesce to form a pampiniform plexus. This plexus runs alongside the testicular artery, and as it ascends through the inguinal canal, it unites with the testicular vein [13,14]. In addition to this main pathway, the pampiniform plexus also anastomoses with other collateral veins, such as the cremasteric veins, vasal veins, external pudendal veins, and gubernacular veins. ...
Varicocele is a frequently encountered urological disorder, which has a prevalence rate of 8 to 15% among healthy men. However, the incidence is higher in male patients with primary or secondary infertility, with up to 35 to 80% of varicocele cases occurring in this population. The clinical manifestations of varicocele typically include the presence of an asymptomatic mass that feels like a “bag of worms”, chronic scrotal pain, and infertility. Most patients with varicocele only undergo varicocelectomy after conservative treatments have failed. Unfortunately, some patients may still experience persistent scrotal pain due to a recurrence of varicocele, the development of hydrocele, neuralgia, referred pain, ureteral lesions, or nutcracker syndrome. Therefore, clinicians should consider these conditions as potential causes of postoperative scrotal pain, and take measures to address them. Several factors can assist in predicting surgical outcomes for patients with varicocele. Clinicians should consider these factors when deciding whether to perform surgery and what type of surgical intervention to use. By doing so, they can increase the likelihood of a successful surgical outcome and minimize the risk of complications such as postoperative scrotal pain.
... On the other hand, most men with varicoceles are able to father children and it is unclear how male fertility is affected by the dilated veins [19]. Proposed theories include oxidative stress, scrotal hyperthermia, hypoxia, re ux of renal and adrenal metabolites, hormonal imbalances, and the formation of antisperm antibodies but none of these theories have been convincingly demonstrated [20]. In our series, neither semen parameters nor reproductive hormones were investigated because we were dealing with an adolescent population. ...
Purpose: To present our experience with robot-assisted laparoscopic varicocelectomy in a pediatric population.
Methods: We reviewed 49 consecutive cases performed by the same experienced surgeon. One to four veins were ligated at the internal ring of the inguinal canal, while the testicular artery and lymphatics were spared. Information on patient characteristics, surgical time, complications, and recurrences were collected.
Results: Median patient age was 14 (range 10 – 17) years. Forty-eight had left sided varicoceles and one had a bilateral varicocele. Forty-five were grade 3. All patients were referred due to discomfort/pain and 20 also had reduced testicular size. The median operating time from skin incision was 48 minutes (31 – 89 minutes) and the median console time was 18 minutes (7 – 55 minutes). Forty-seven patients were discharged the same day. Two patients experienced pain and problems urinating respectively. These issues had resolved by the first postoperative day. There were no other complications, but at 6 month, eight recurrences were noted (16%). Scrotal complaints had subsided in all patients. Catch-up growth of the affected testicles was seen in 19/20 cases.
Conclusion: Robot-assisted laparoscopic varicocelectomy is feasible and safe in a pediatric population but with a relatively high recurrence rate.
... 23 The main issue is actually infertility, reported in 5 to 20% of the male population and most evident in adult age. 2 Reduced sperm count, motility, morphology, and alternative forms (a "stress pattern" with immature forms, amorphous cells, and tapered forms) are described 24,25 as a result of testicular hypotrophy and altered spermatogenesis. Many mechanisms have been advocated, from increased scrotal temperature (due to stasis and reflux of warm blood) 26 to excessive production of reactive oxygen species (ROS), 27 chronic arteriolar vasoconstriction (due to incremented venous pressure, with subsequent hypoxia), 28 high concentrations of adrenal cortical hormones (with arteriolar vasoconstriction) 29 and FSH or low concentrations of testosterone (due to alterations in the hypothalamic-pituitary-gonadal axis) 30 or inhibin B (correlated with testicular volume and Sertoli cell activity), 31 toxic substances in the refluxing blood (e.g., ROS and cadmium) 28,32 and autoimmunity (antisperm antibodies due to the presence of breaches in the blood-testis barrier). 33 Dilatation of the periprostatic venous plexus (DPVP) seems to reduce sperm motility and increase seminal fluid viscosity. ...
Objectives:
the aim of our study is to compare the incidence of veno-venous shunts in male varicocele and evaluate the possibility to exclude them with manual compression or/and scrotal ligation in order to carry out the procedure of retrograde sclero-embolization.
Methods:
in our retrospective study all patients undergone retrograde sclerotherapy for varicocele in our Interventional Radiology Unit in the last four years were evaluated. Collaterals towards other venous shunts were identified and how many and which patients would be able to complete the procedure safely were considered.
Results:
of the 91 patients, as many as 22 (i.e., 24.17%) patients presented anatomical variants, consisting in shunting into left iliac vein (9 [9.89%]), lumbar left veins (3 [3.29%]), right iliac vein (1 [1.09%]), both iliac veins (1 [1.09%]), left femoral vein (1 [1.09%]) or a more proximal portion of the ISV itself without shunting (3 [3.29%]). Patients with duplication could benefit from a more distal injection in order to prevent back-flow; of the 19 left, nine successfully underwent sclerotherapy with manual compression or/and scrotal ligation, whereas in 10 flow through the collaterals could not be interrupted and patients were demanded for surgery.
Conclusions:
many patients with abnormal communications between the internal spermatic vein and the iliac veins (that is, shunts towards the iliac veins) may as well undergo retrograde sclerotherapy safely if compression/ligation is applied.
Advances in knowledge:
no large previous study highlighted the impact of veno-venous shunts in technical feasibility of retrograde sclerotherapy of varicocele.
... Another proposed mechanism for varicocele development is termed the ''nutcracker effect,'' describing compression of the renal vein between the aortic and the superior mesenteric artery, resulting in increased hydrostatic pressure. 5 Varicoceles are graded clinically based on physical examination by the Dubin and Amelar grading system. 6 Grade 0 is assigned to subclinical varicoceles, or those discovered incidentally on imaging that are not palpable on physical exam even with valsalva. ...
... These free radicals then attack the germ cells within the seminiferous tubules leading to extensive apoptosis and spermatogenesis disruption 42 . Oxidative stress in testis is capable of disrupting the steroidogenic capacity of Leydig cells 13 as well as the capacity of the germinal epithelium to differentiate normal spermatozoa 43 . Moreover, it was reported that oxidative stress created in the Leydig cells due to chronic ethanol exposure reduced the steroidogenic enzymes activities of the testes and lowering blood testosterone levels 44 . ...
... In this regard, studies have suggested that the excessive presence of fat around the testicles and epididymides in animal and human models of obesity can alter the temperature of these organs, triggering a process likely developed by an increase in the adipose tissue that covers the pampiniform plexus and affects the testicular cooling system [80]. This increase in scrotal temperature induces a series of alterations at the testicular level that are associated with increased apoptosis and a decrease in the number of spermatogonia in the germinal epithelium [47,81]. ...
Obesity is a condition that has been linked to male infertility. The current hypothesis regarding the cause of infertility is that sperm are highly sensitive to reactive oxygen species (ROS) during spermatogenesis in the testes and transit through the epididymides, so the increase in ROS brought on by obesity could cause oxidative stress. The aim of this study was to evaluate whether the activity of the enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX) is capable of counteracting oxidative stress in sperm. The male Wistar rat was used as an overweight and obesity model, and analysis of fertility in these groups was carried out including the control group. Serum testosterone levels were determined, and the scrotal fat, testes, and epididymides were extracted. The epididymides were separated ini0 3 principal parts (caput, corpus, and cauda) before evaluating sperm viability, sperm morphology, damage to desoxyribonucleic acid of the sperm, and ROS production. The protein content and specific activity of the three enzymes mentioned above were evaluated. Results showed a gain in body weight and scrotal fat in the overweight and obese groups with decreased parameters for serum testosterone levels and sperm viability and morphology. Fertility was not greatly affected and no DNA integrity damage was found, although ROS in the epididymal sperm increased markedly and Raman spectroscopy showed a disulfide bridge collapse associated with DNA. The specific activities of CAT and GPX increased in the overweight and obesity groups, but those of SOD did not change. The amounts of proteins in the testes and epididymides decreased. These findings confirm that overweight and obesity decrease concentrations of free testosterone and seem to decrease protein content, causing poor sperm quality. Implications. An increase in scrotal fat in these conditions fosters an increase of ROS, but the increase of GPX and CAT activity seems to avoid oxidative stress increase in the sperm without damaging your DNA.
... 3 Varicocele is a dilation of the testicular veins within pampiniform plexus of the spermatic cord that holds up a man's testicles. 7 Varicocele may cause infertility if it associated with abnormal semen analysis 3 , but the mechanism is unclear. 8 Sexually transmitted diseases and male accessory gland infection (MAGI) can impair male fertility by increasing the reactive oxygen species, or by causing inflammation lesions of the epididymis, or urithritis, or urethral strictures, or ejaculatory disturbance, or by stimulating anti sperm antibodies (ASA). ...
Background: Infertility is a global health issue affecting approximately 8-10% of couples and has multidimensional problem with social, economic and cultural implications, which can take threatening proportions in countries with strong demographic problems. Reproductive health in Bangladesh focused mainly on women health and ignoring the role of men, in spite of the important role that men are playing in reproduction and fertility which impact his family and environment. Objective: To find out the factors of infertility among the males in selected hospitals of Dhaka city. Methods: A convenience sample of 112 medical records for males diagnosed with infertility in Shaheed Suhrawardi Medical College Hospital, National Institute of Kidney Diseases and Urology, Sher-E-Bangla Nagar, Dhaka, Fertility center Mohammedpur Dhaka, Infertility care and Research Center Mohammedpur Dhaka were retrospectively reviewed for the cause of their infertility. Four months duration of study from May 2016 to August 2016. After completion of data collection, the collected data was checked and verified on regular basis for accuracy, consistency and completeness. Data was edited and coded. The results were presented into the form of tables and figures. Data was processed in computer by using the software SPSS, version 22 and statistical analysis was done. Results: Male factor alone was accounted for 52% of infertility among couples of these 90 had primary infertility and 22 had secondary infertility. The mean duration of infertility was 4.98±3.99 years and the mean age for male cases was 33.5±7.24 years The most common causes among infertile men were, idiopathic infertility 36.6%, varicocele 32.1%, obstruction of the seminal tract 18.8%, and hormonal problems 5.4%. Least common causes found were, medication 1.8%, spinal cord injury 1.8%, cryptorchidism 1.8%, and testicular failure 1.8%. Conclusion: More than half of the infertile couples were from an idiopathic cause. Study results confirm that understanding about male reproductive function and the environmental factors that affect it is insufficient. Provide education to infertile men by doctors in charge about potential risk factors that may affect fertility and not just provide treatment because simple changes in lifestyle can improve fertility. Bangladesh J. Urol. 2021; 24(1): 37-45
... Internal spermatic vein (ISV) reflux, which contains metabolic products, is considered to be toxic for testicular function. 1 The complex structure of the pampiniform plexus causes notable diversity of venous hemodynamics, 2 which might have a different impact on spermatogenesis. Varicocelectomy is a commonly used treatment modality that aims to improve semen quality and pregnancy outcomes in infertile men with varicoceles and affected semen parameters. ...
The hemodynamic characteristics of venous reflux are associated with infertility in patients with varicocele; however, an effective method for quantifying the structural distribution of the reflux is lacking. This study aimed to predict surgical outcomes using a new software for venous reflux quantification. This was a retrospective cohort study of a consecutive series of 105 patients (age range: 22-44 years) between July 2017 and September 2019. Venous reflux of the varicocele was obtained using the Valsalva maneuver during scrotal Doppler ultrasonography before microsurgical varicocelectomy. Using this software, the colored reflux signals were segmented, and the gray scale of the color pixels representing the reflux velocity was comprehensively quantified into the mean reflux velocity of the green layer (MRVG) and the reflux velocity standard deviation of the green layer (RVSDG). Spontaneous pregnancy and changes from baseline in the semen parameters were assessed during a 12-month follow-up period. Data were analyzed using logistic regression analysis. An association of the high MRVG group with impaired progressive motility (odds ratio [OR] = 2.868, 95% confidence interval [CI]: 1.133-7.265) and impaired sperm concentration (OR = 2.943, 95% CI: 1.196-7.239) was found during multivariate analysis. High MRVG (OR = 2.680, 95% CI: 1.086-6.614) and high RVSDG (OR = 2.508, 95% CI: 1.030-6.111) were found to be independent predictors of failure to achieve pregnancy following microsurgical repair. In summary, intense venous reflux is an independent predictor of impaired progressive motility, sperm concentration, and pregnancy outcomes after microsurgical varicocelectomy.
... Varicoceles are common in the general population, and roughly 40% of male patients seeking infertility care present with a varicocele (23). Examination should be performed with and without Valsalva maneuver, as the earliest stages of varicocele can be detected only with the aid of the increased abdominal pressure that this provides (24). ...
Today's reproductive endocrinology and infertility providers have many tools at their disposal when it comes to achieving pregnancy. In the setting of highly efficacious assisted reproductive technology, it is natural to assume that male factor infertility can be overcome by acquiring sperm and then bypassing the male evaluation. In this review, we go through guideline statements and a stepwise male factor infertility evaluation to propose that a thorough male evaluation remains important to optimize pregnancy and live birth. The foundation of this parallel evaluation is referral to a reproductive urologist for the optimization of the male partner, for advanced diagnostics and interventions, and for the detection of other underlying male pathology. We also discuss what future developments might have an impact on the workup of the infertile male.
Spermatogenesis is a complex and highly regulated process involving the proliferation, differentiation, and apoptosis of germ cells. This process is controlled by various hormonal, genetic, and environmental factors, including temperature. In hormonal regulation, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) are essential for correct spermatogenesis development from the early stages and spermatogonia proliferation to germ cell maturation. Other hormones, like inhibin and activin, finely participate tuning the process of spermatogenesis. Genetic regulation involves various transcription factors, such as SOX9, SRY, and DMRT1, which are crucial for the development and maintenance of the testis and germ cells. MicroRNAs (miRNAs) play a significant role by regulating gene expression post-transcriptionally. Epigenetic modifications, including DNA methylation, histone modifications, and chromatin remodelling, are also vital. Temperature regulation is another critical aspect, with the testicular temperature maintained around 2–4 °C below body temperature, essential for efficient spermatogenesis. Heat shock proteins (HSPs) protect germ cells from heat-induced damage by acting as molecular chaperones, ensuring proper protein folding and preventing the aggregation of misfolded proteins during thermal stress. Elevated testicular temperature can impair spermatogenesis, increasing germ cell apoptosis and inducing oxidative stress, DNA damage, and the disruption of the blood–testis barrier, leading to germ cell death and impaired differentiation. The cellular mechanisms of germ cell proliferation, differentiation, and death include the mitotic divisions of spermatogonia to maintain the germ cell pool and produce spermatocytes. Spermatocytes undergo meiosis to produce haploid spermatids, which then differentiate into mature spermatozoa. Apoptosis, or programmed cell death, ensures the removal of defective germ cells and regulates the germ cell population. Hormonal imbalance, genetic defects, and environmental stress can trigger apoptosis during spermatogenesis. Understanding these mechanisms is crucial for addressing male infertility and developing therapeutic interventions. Advances in molecular biology and genetics continue to uncover the intricate details of how spermatogenesis is regulated at multiple levels, providing new insights and potential targets for treatment.
Multiple conditions can cause hypoxia in the testis, including exposure to high altitude, sleep apnoea, testicular torsion and varicocele. Varicocele accounts for up to 44% of instances of primary infertility, but the cumulative contribution of hypoxic conditions to male infertility is undefined. Results of controlled hypobaric hypoxia studies have demonstrated a substantial detrimental effect of short-term and long-term exposures on sperm; however, downstream effects on embryo development and offspring health are less well understood. Hypoxia can have direct and indirect effects on the molecular biology and biochemistry of germ cells, including changes to gene expression, metabolism, oxidative stress and to the endocrine environment. Hypoxia also has often-overlooked effects on the epididymis, such as altered composition and gene expression of epithelial cells, with knock-on effects on sperm maturation, including the capacity to acrosome react. Evidence from model species shows that paternal hypoxia exposure results in disrupted embryo development and transgenerational effects on male fertility and offspring physiology. Overall, hypoxia induces a complex, multifaceted subfertility phenotype that is reversible with resolution of the exposure, in part because of a resilient testis stem cell population that thrives in hypoxia. However, the potential for transgenerational effects deserves further exploration, particularly in considering the purported decline in sperm counts over the past 50 years.
BACKGROUND
Varicocele is an abnormal dilation and torsion of the pampiniform venous plexus in the scrotum due to venous reflux, primarily affecting the left side. It affects 15% of men and is a prevalent contributor to male infertility. Varicocele is a complex disorder influenced by genetic, epigenetic, and environmental factors. Epigenetic modifications, which regulate genome activity independently of DNA or RNA sequences, may contribute to the development and severity of varicocele. These include DNA methylation, histone modifications, and RNA modifications like N6-methyladenosine (m6A). Irregularities in DNA and m6A-RNA methylation during spermatogenesis can cause gene expression abnormalities, DNA damage, and decreased fertility in varicocele patients.
OBJECTIVE AND RATIONALE
The review aims to comprehensively understand the underlying mechanisms of varicocele, a condition that can significantly impact male fertility. By exploring the role of methylation modifications, specifically DNA and m6A-RNA methylation, the review aims to synthesize evidence from basic, preclinical, and clinical research to expand the existing knowledge on this subject. The ultimate goal is to identify potential avenues for developing targeted treatments that can effectively improve varicocele and ultimately increase sperm quality in affected individuals.
SEARCH METHODS
A thorough investigation of the scientific literature was conducted through searches in PubMed, Google Scholar, and Science Direct databases until May 2024. All studies investigating the relationship between DNA and m6A-RNA methylation and male infertility, particularly varicocele were reviewed, and the most pertinent reports were included. Keywords such as varicocele, epigenetics, DNA methylation, m6A-RNA methylation, hypermethylation, hypomethylation, spermatozoa, semen parameters, spermatogenesis, and male infertility were used during the literature search, either individually or in combination.
OUTCOMES
The sperm has a specialized morphology essential for successful fertilization, and its epigenome is unique, potentially playing a key role in embryogenesis. Sperm DNA and RNA methylation, major epigenetic marks, regulate the expression of testicular genes crucial for normal spermatogenesis. This review explores the role of DNA and m6A-RNA methylation, in responding to oxidative stress and how various nutrients influence their function in varicocele condition. Evidence suggests a potential link between varicocele and aberrant DNA/m6A-RNA methylation patterns, especially hypomethylation, but the body of evidence is still limited. Further studies are needed to understand how abnormal expression of DNA/m6A-RNA methylation regulators affects testicular gene expression. Thus, analyzing sperm DNA 5mC/5hmC levels and m6A-RNA methylation regulators may reveal spermatogenesis defects and predict reproductive outcomes.
WIDER IMPLICATIONS
Nutri-epigenomics is an emerging field that could enhance the knowledge and management of diseases with unpredictable risks and consequences, even among individuals with similar lifestyles, by elucidating the influence of nutrition on DNA/m6A-RNA methylation through one-carbon metabolism. However, the importance of one-carbon metabolism to varicocele is not well-recognized. Health status and diet influence one-carbon metabolism and its associated DNA/m6A-RNA methylation modification. Future research should identify optimal methylation patterns that promote health and investigate modulating one-carbon metabolism to achieve this. Furthermore, additional studies are necessary to develop personalized dietary strategies through clinical and longitudinal research. However, a research gap exists on dietary interventions utilizing epigenetics as a therapeutic method for treating varicocele.
REGISTRATION NUMBER
Not applicable.
We treated 15 subfertile men with varicocele with combination of subinguinal ligature of spermatic vein or plexus pampiniformis and medicaments. In a five-year period , we registered 5 pregnancies (30%) in female partners of our patients. We consider subinguinal ligature of spermatic vein as minimally invasive and cost-effective initial treatment of "infertile couples".
In recent years, there has been a global decline in the quality of human semen, leading to a gradual increase in the incidence of infertility, which significantly impacts men’s health. Due to the complex etiology of male infertility, clinical treatment is predominantly confined to drugs, surgery, and assisted reproductive technology. However, the efficacy of these approaches often falls short of meeting clinical needs, prompting the exploration of new treatment methods. Acupuncture, a crucial component of traditional Chinese medicine (TCM), has gained increasing prominence in the treatment of male infertility, yielding noteworthy results. This article offers an overview of TCM’s perspective on male infertility, explores the clinical efficacy of acupuncture in treating male infertility and the corresponding mechanisms, and summarizes the existing challenges in the current acupuncture-based treatment of male infertility. It also clarifies the validity of acupuncture and provides references for the future development of acupuncture in the treatment of male infertility.
Varicocele is defined as an abnormal dilation and tortuosity of the veins of the pampiniform plexus with the presence of malfunctioning valves and is the most common correctable cause of male infertility. Varicocele affects nearly 15% of men in the general population and is diagnosed in up to 41% of men with primary infertility and 80% secondary infertility cases. Some fertile and some infertile men with varicoceles may have similar conventional semen parameters, many have diminished parameters which improve with varicocele repair, and there is a significant association between varicocele and male infertility. There are a number of mechanisms of testicular damage, which have been described in men with varicocele. Sperm DNA fragmentation assays and assays measuring seminal oxidative stress have been associated with male infertility and spermatogenic dysfunction. Oxidative stress levels are significantly higher in varicocele patients and significantly reduced following varicocele repair. Elevated sperm DNA fragmentation levels correlate with poor semen quality, impaired preimplantation development, and increased spontaneous pregnancy loss rates and have been shown to improve following varicocele repair.
Introduction. Current evidence suggests that management of any grade of varicocele can improve male fertility. However, diagnosis of grade 1 varicocele in infertile men without the use of scrotal Doppler ultrasound may cause overtreatment.
Objective. To study the comparability and accuracy of the visual palpatory examination method with the scrotal Doppler ultrasound data for the diagnosis of varicocele.
Material & methods. Between November 2005 to January 2022, 2871 patients diagnosed with varicocele and infertility who underwent microsurgical varicocelectomy by inguinal access were examined at RSSPMCU. The average age of the patients was 30.16 ± 0.09 (18 – 60) years. Of the 2871 patients, 2592 (90.3%) were diagnosed by physical examination, and 279 (9.7%) patients underwent additional scrotal Dopper ultrasound.
Results. After Doppler scrotal imaging was introduced into practice, the proportion of patients with bilateral varicocele increased from 32.2% to 61.6% (p < 0.01). The proportion of patients with right-sided varicocele also increased significantly. Experienced physicians during physical examination of infertility patients did not diagnose grade 1 varicocele in 4.3%.
Conclusions. The implementation of scrotal Doppler ultrasound for the diagnosis of male infertility improved the detection of grade 1 varicocele and bilateral varicocele. In turn, this contributed to earlier elimination of the male factor of infertility in this contingent of patients.
Introduction: Varicocele is characterized by abnormal elongation, dilatation and tortuosity of the pampiniform plexus within the spermatic cord and is the most commonly see and correctable cause of male factor infertility. Objectives: Our study aimed to ind hy abnormal elongation, dilatation and tortuosity of the pampiniform and is the most commonly see and correctable cause of male factor infertility. to investigate the correlation between Body Mass Index (BMI) and development of Varicocele among a cohort of infertile patients as compared with the number of subject without Varicocele (control group).Patents and methode: Between January 2016 and December 2017, atotal of 102 patients underwent surgerv underwent history taking careful physical examination and scrotal ultrasound scan Cand severity of Varicoceles. An age-matched controls group consisted of 103 subiects aricoceles according to physical examination only. The age, weight, height, and BMI Addition both grades and side were analyzed in patients group. Results: The mean age was 33.38 ±5.68 in patients group and 38.63 ±7.150 in control group. Of the 102 patients 29(28.43%) were grade I, 70 (68.63%) were grade II, and 3(2.94%)were grade III. All 102 patients had left-side varicoceles and 18 of them had bilateral varicoceles. No cases with only right side involvement.The BMI (mean ±SD)of 102 with varicoceles was (26.55± 4.4)while that of control group was (28.30± 4.3) which is clinically significant (p=0.0001).
OBJECTIVE: This study aims to investigate potential differences in the presence of Transforming Growth Factor-Beta 1 (TGF-β1) between the vein walls of patients with varico-cele and those of healthy individuals. PATIENTS AND METHODS: The study comprised a total of 40 participants, divided into two groups. The control group (Group 1) consisted of 20 patients who underwent coronary bypass surgery, while the varicocele group (Group 2) included 20 patients scheduled for varicocelecto-my. The cytoplasmic and nuclear staining patterns of TGF-β1 immunohistochemistry were assessed in tissue samples under light microsco-py, identifying any differences in TGF-β1 presence between varicocele patient vein walls and normal (saphenous) veins. RESULTS: The varicocele group demonstrated lower nuclear and cytoplasmic TGF-β1 staining rates compared to the control group. After controlling for the independent factor of age, significantly lower nuclear and cytoplas-mic staining was still observed in the varico-cele group. CONCLUSIONS: This study is the first of its kind to compare TGF-β1 staining in the vein walls of varicocele patients and healthy individuals. Previous studies focusing on varicose veins reported elevated TGF-β1 expression. Contrarily, our study observed lower TGF-β1 expression in varicocele patient veins, marking a unique contribution to the field.
Purpose of review:
A male factor is either the primary cause or is contributory in at least half of all couples with infertility. Currently, many male factor problems may be disregarded, as reproductive technology has advanced so much that in-vitro fertilization (IVF)/Intracytoplasmic sperm injection (ICSI) allows the use of even a single sperm to achieve pregnancy.
Recent findings:
Varicocele is the most commonly diagnosed correctable cause. Microsurgical repair is considered the gold standard for repair. Research has shown that varicocele repair can impact the outcome of reproductive management and upgrade male infertility from adoption or donor sperm only to IVF/ICSI and microTESE, or IVF/ICSI with ejaculated sperm, or from IVF/ICSI to intrauterine insemination (IUI) or often naturally conceived.
Summary:
Varicocele diagnosis and repair is an essential part of infertility evaluation. Not only does it potentially impact antiretroviral therapy choices, but it can also increase testosterone levels benefiting long-term male health.
The aim of this systematic review and meta‐analysis was to assess whether oral antioxidant supplementation improves sperm quality in men with infertility and varicocele (VCL) who have not undergone surgical repair. In men with infertility and VCL who had not undergone surgical repair oral antioxidant supplementation significantly increased sperm concentration (WMD +5.86 × 106/ml 95% CI: +1.47 to +10.24, p < 0.01; random effects model, six studies, 213 patients), total motility (WMD + 3.76%, 95% CI: +0.18 to +7.34, p = 0.04; random effects model, three studies, 93 patients), progressive motility (WMD + 6.38%, 95% CI: +3.04 to +9.71, p < 0.01; random effects model, three studies, 84 patients) and seminal volume (WMD +0.55 ml, 95%CI: +0.06 to +1.04, p = 0.03; random effects model, four studies, 120 patients). On the other hand, no significance difference was observed in sperm morphology (WMD +3.89%, 95% CI: −0.14 to +7.92, p = 0.06; random effects model, five studies, 187 patients). In conclusion, limited evidence suggests that the use of oral antioxidants in men with infertility and VCL, who have not undergone surgical repair improves their seminal volume, sperm concentration, total and progressive motility.
Objective To determine the level of malondialdehyde (MDA), an indirect indicator of lipid peroxidation-induced injury by reactive oxygen species, in testicular biopsy specimens from infertile patients with and without varicocele.
Patients and methods Levels of MDA were measured in the testicular biopsy specimens from 25 infertile men (15 with varicocele, mean age 30.0 years, sd 5.7, range 23–45, and 10 without, mean age 28.7 years, sd 4.2, range 21–34). All patients were evaluated by a detailed history, physical examination, semen analysis (at least twice), serum follicle-stimulating hormone and free testosterone levels, testicular biopsy and contact imprint. Scrotal colour Doppler ultrasonography was used to confirm suspected varicocele. The level of MDA in testicular biopsy specimens was measured using the thiobarbituric acid test and the results expressed per unit tissue weight.
Results As a causal factor for infertility, varicocele was identified in 15 men (60%), testicular failure in four (16%), idiopathic infertility in four (16%) and obstruction in two (8%). Of the 15 patients with varicocele, eight had bilateral varicocele and it was subclinical in three; the varicocele was grade I in four, grade II in six and grade III in two. The mean ( sd) MDA level in the men with a subclinical varicocele was 15.7 (3.1) pmol/mg tissue, while in those with grade I–III varicocele it was 32.9 (12.25), 37.1 (12.25) and 86.9 (2.89) pmol/mg tissue, respectively. The levels in patients with grade III varicocele were significantly greater than in the other groups (P < 0.05). The mean MDA level in patients with or without varicocele was 38.3 (22.92) and 33.5 (18.93) pmol/mg tissue, respectively (P > 0.05).
Conclusion These results suggest that increasing levels of MDA are associated with higher grades of varicocele and support a possible rationale for controlled trials in infertile men with varicocele.
Hydrogen peroxide and oxygen radicals are agents commonly produced during inflammatory processes. In this study, we show that micromolar concentrations of H2O2 can induce the expression and replication of HIV-1 in a human T cell line. The effect is mediated by the NF-kappa B transcription factor which is potently and rapidly activated by an H2O2 treatment of cells from its inactive cytoplasmic form. N-acetyl-L-cysteine (NAC), a well characterized antioxidant which counteracts the effects of reactive oxygen intermediates (ROI) in living cells, prevented the activation of NF-kappa B by H2O2. NAC and other thiol compounds also blocked the activation of NF-kappa B by cycloheximide, double-stranded RNA, calcium ionophore, TNF-alpha, active phorbol ester, interleukin-1, lipopolysaccharide and lectin. This suggests that diverse agents thought to activate NF-kappa B by distinct intracellular pathways might all act through a common mechanism involving the synthesis of ROI. ROI appear to serve as messengers mediating directly or indirectly the release of the inhibitory subunit I kappa B from NF-kappa B.
Addition of the divalent cation ionophore, A23187, to washed populations of human spermatozoa resulted in a sudden burst of production of reactive oxygen species which peaked within 3-5 min. This activity was dependent upon the presence of calcium in the external medium and was unaffected by the mitochondrial inhibitors, oligomycin, antimycin and rotenone. Studies with scavengers of reactive oxygen species revealed that, while reagents directed against singlet oxygen and the hydroxyl radical were without effect, cytochrome C reduced the response to A23187 by about 50%, suggesting that the superoxide anion radical is a major product of the activated human spermatozoon. The clinical implications of these studies stem from the considerable variation observed between individuals in the levels of reactive oxygen species produced by the spermatozoa. This variability was shown to be inversely related to the ability of the spermatozoa to exhibit sperm-oocyte fusion on exposure to A23187; defective samples exhibited a basal level of reactive oxygen species production which was 40 times that observed with normal functional cells.
In an attempt to determine whether defective testicular testosterone (T) biosynthesis may be associated with a varicocele, an experimental study was performed in adult rats whereby a unilateral left varicocele was surgically created. At 2, 4, 8, and 12 wk following the creation of the varicocele, intratesticular T as well as the activities of three (17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase) of the five enzymes in the delta 4 pathway of testicular T biosynthesis were measured. Intratesticular T (ng/g testis +/- SEM) in the left testis decreased significantly from 121 +/- 21 in the control group to 59 +/- 8 in the two-wk varicocele group (p less than 0.01), and remained significantly suppressed throughout the experimental period. The T concentrations in the right testis paralleled those in the left in both the control and varicocele animals. At 2 wk following the creation of the varicocele, the activity (nmol/min/testis +/- SEM) of the 17,20-desmolase enzyme decreased significantly, from 115 +/- 8 in the left testis of control rats to 87 +/- 6 in the left testis of the varicocele animals (p less than 0.025), and remained low throughout the 12 weeks of the study. The activity of the 17 alpha-hydroxylase enzyme was significantly decreased at the 8th and 12th weeks of the study, while the 17 beta-hydroxysteroid dehydrogenase activity did not show any significant change during the study period. The enzyme activities in the right testis paralleled those in the left testis.(ABSTRACT TRUNCATED AT 250 WORDS)
Over the past several years, we have worked on human sperm-surface receptor physiology with the intent of characterizing molecules involved in egg recognition and fertilization. We have analyzed the membrane properties of human sperm populations before and after incubations in vitro for the appearance of sperm-surface mannose-ligand receptors, which are correlated with the acquisition of potentially fertilizing in vitro. For mannose-ligand receptors to be expressed on the sperm surface, the cholesterol content of the sperm plasma membrane must be reduced. Cholesterol acts to stabilize the preejaculated sperm plasma membrane and thus is a 'natural contraceptive.' Other membrane-active molecules, such as calcium-ion channel-blocking agents, also prevent mannose-ligand receptor expression in vitro in the same manner as cholesterol. Clinical dosages of these drugs correlate with infertility in men with normospermic semen. We propose to explore these medications as potential male contraceptives.
Background and aims. There is a high incidence of varicocele or dilatation of the spermatic vessels associated with reflux in the male population varying, according to statistics, from 4.5 to 30.7%. Among the numerous hypotheses put forward to explain infertility in approximately 50% of patients with varicocele, it has recently been shown that there is an increased concentration of noradrenalin in the spermatic vessel which might be responsible for chronic arterial vasoconstriction affecting the gonads, leading to endothelial hyperplasia and consequent infertility Materials and methods. In this study the authors have evaluated the bilateral flow of spermatic arteries at the level of the scrotum in patients with varicocele and in the healthy (varicocele-free) population with normal and hypospermatogenesis. Results. In all groups and in the absence of other major pathologies (including arterial hypertension), no significant differences were found in systolic peak velocity (SPV) in relation to the presence or otherwise of varicocele and the degree of reflux. Mean SPV ranged between 3-5 and 4 cm/sec in patients with hypo- and/or normal zoospermia both in the varicocele and healthy population Conclusions. In line with other authors, we feel that despite the lack of substantial differences in arterial flow in the patients examined, it is not possible at present to explore the testicular microcirculation and possible hypoperfusion using eco color-Doppler, in spite of the fact that the method shows a high level of diagnostic accuracy in the diagnosis of phlogistic pathologies and/or twisting of the spermatic cord. New approaches might be provided through the improved study of the microcirculation using power Doppler which appears to be more sensitive than eco color-Doppler in visualizing small intraparenchymal vessels.
It has been previously shown that 30-day experimental left varicocele (ELV) in adult rats produces a bilateral increase in testicular blood flow and temperature, as well as a concomitant decrease in epididymal sperm count and motility. In the present study, adult male rats with induced ELV were subjected to a variety of studies to determine the mechanism by which unilateral ELV causes a bilateral testicular response. The results demonstrate that ELV does not alter the blood-testis barrier (BTB) to 3H-inulin (MW 5000), it being largely excluded from entry into the tubule lumen in both control and ELV animals. Neither left nor right cauda epididymidal temperature was altered by ELV. Intraepididymal Na+ and K+ concentrations in the left caput epididymidis were 81.3 +/- 3.8 mEq/l and 26.3 +/- 1.5 mEq/l, respectively. From the cauda epididymidis, these values were 25.0 +/- 2.2 mEq/l and 46.8 +/- 1.0 mEq/l, respectively. These values were similar on the right side and in the left and right epididymis of ELV animals. Left testis arterial pH was 7.3 +/- 0.1, and PO2 and PCO2 were 116.0 +/- 6.4 mm of mercury and 44.3 +/- 3.2 mm of mercury, respectively. Left testicular venous values were 7.3 +/- 0.1 (pH), and 52.6 +/- 2.2 mm of mercury and 49.9 +/- 2.0 mm of mercury. These values were similar for right control testicles and left and right testicles of ELV animals. These results indicate that the mechanism by which unilateral ELV produces a bilateral change in testicular or epididymal function is not by altering the BTB, epididymal temperature or electrolyte concentrations, or testicular blood gas concentrations.
The imbalance between reactive oxygen species (ROS) production and total antioxidant capacity (TAC) in seminal fluid indicates oxidative stress and is correlated with male infertility. A composite ROS–TAC score may be more strongly correlated with infertility than ROS or TAC alone. We measured ROS, TAC, and ROS–TAC scores in semen from 127 patients and 24 healthy controls. Of the patients, 56 had varicocele, eight had varicocele with prostatitis, 35 had vasectomy reversals, and 28 had idiopathic infertility. ROS levels were higher among infertile men, especially those with varicocele with prostatitis (mean ± SE, 3.25 ± 0.89) and vasectomy reversals (2.65 ± 1.01). All infertile groups had significantly lower ROS–TAC scores than control. ROS–TAC score identified 80% of patients and was significantly better than ROS at identifying varicocele and idiopathic infertility. The 13 patients whose partners later achieved pregnancies had a mean ROS–TAC score of 47.7 ± 13.2, similar to controls but significantly higher than the 39 patients who remained infertile (35.8 ± 15.0; P < 0.01). ROS–TAC score is a novel measure of oxidative stress and is superior to ROS or TAC alone in discriminating between fertile and infertile men. Infertile men with male factor or idiopathic diagnoses had significantly lower ROS–TAC scores than controls, and men with male factor diagnoses that eventually were able to initiate a successful pregnancy had significantly higher ROS–TAC scores than those who failed.
Plasma testosterone concentration was decreased in 10 patients combining varicocele with sexual inadequacy (mean 346.2 ng/100 ml) against normal concentration observed in 23 men with varicocele without sexual disturbances (mean 567.8 ng/100 ml) and in 31 patients with pure psychogenic impotence (mean 581.6 ng/100 ml). There was a significant inverse linear correlation between age and plasma testosterone concentration in the varicocele patients (r= minus 0.56, P smaller than 0.01) in contrast to the absence of such correlation in normal men or in patients with psychogenic impotence of the same age range. The secretion products of the secondary sex glands were more often in the lower range in the ejaculates of men combining varicocele with sexual disturbance (P smaller than 0.02), proving the decreased testosterone level to induce a deficient function of these glands. Plasma testosterone levels normalized after surgical correction in varicocele patients with a low preoperative concentration. Since adequate surgical or hormonal treatment resulted in complete recovery of sexual potency in the majority of patients with varicocele and sexual inadequacy, it is suggested that the decreased testosterone production might have contributed to the impairment of sexual function.
Sera from 591 men attending Fertility Clinics have been tested for agglutinating, immobilising and immunofluorescent antisperm antibodies. There was good correlation between the presence of high titres (more than 1/32) of agglutinating and immobilising antibodies which were found in 50 patients (8.5%). 27 of these men had normal sperm counts, but crossed hostility testing showed that in 21 of 22 couples the sperms were unable to penetrate the cervical mucus, apparently because of the antibodies. 17 patients were treated with prednisone for an average of 6 months and 1 pregnancy was produced. 17 patients were treated with methylprednisolone for 7 days and 1 pregnancy resulted. No correlation was found between the present of immunofluorescent antibodies and the other antibodies of impaired sperm penetration of cervical mucus.
PIP
Between September 1975-March 1977, sera from 591 men attending the Fertility Clinic at Chelsea Hospital in London were tested for agglutinating, immobilizing, and immunofluorescent antisperm antibodies. The 3 techniques used to test are described. Results of the testing were correlated with the patients' clinical state and findings on seminal analysis. When antisperm antibodies were found, the behavior of the husband's sperm was studied in the cervical mucus of his wife. This result was compared with behavior of donor sperm with no antisperm antibodies and with donor cervical mucus. Test data indicate that high titers of immobilizing and agglutinating antibodies did prevent the sperm from effectively penetrating cervical mucus. This was not true with antibodies detected by immunofluorescent techniques. The crossed hostility testing is necessary in cases of marital infertility to identify which partner in the marriage has the antibodies. Treatment for infertility resulting from antisperm antibodies is steroid therapy combined with sperm washing and insemination.
Intraoperative internal spermatic vein phlebography was performed in 20 subfertile patients with a varicocele; 10 patients with varicoceles and left-sided indirect inguinal hernias without fertility problems served as controls. Phlebography was carried out during surgery with the patient supine and in a 45 degree anti-Trendelenburg position to stimulate an "erect" posture. In all 25 patients with a varicocele, valvular insufficiency was demonstrated at the renal-spermatic vein junction. When visualized, the position of the left adrenal vein in all instances was medial to or opposite the renal-internal spermatic vein confluence. This observation, reinforced by simultaneous determinations of cortisol levels in the internal spermatic and antecubital veins, practically excluded the validity of the theory of adrenal hormonal suppression of testicular tissues. In 40% of subfertile patients with a varicocele, double internal spermatic veins and reflux to the distended external spermatic (cremasteric) venous plexus were demonstrated. In no instance were such phenomena observed in the control groups. The not-infrequent failure of operative correction of varicocele seems to relate directly to such overlooked pathology. Broad clinical application of operative phlebography, especially in recurrent, persistent, or clinically advanced cases, will detect such anomalies and should reduce significantly the operative failures in the surgical correction of varicocele.
Complicated interdigitation-like junctions between the immature Sertoli cells were frequently observed in prepubertal testis (3--8-year-old). Tight or gap junctions could not be found. Subsurface cisternae appear in the testes of 7 and 8-year-old boys. In pubertal testis (11 to 13 years old), junctional specializations between Sertoli cells are composed of membrane fusions, bundles of microfilaments and associated cisternae. These tight junctions block the deep penetration of lanthanum into the seminiferous tubules. The lanthanum-filled Sertoli junctions show characteristic features of membrane fusions. In the seminiferous tubules spermatocytes were not present at 11 years of age but complete spermatogenesis was noted at 12-13 years of age. It is suggested that the human blood-testis barrier is estabilished shortly before or after the spermatogonia proliferate to give rise to primary spermatocytes.
Eighty males with varicocele underwent internal spermatic vein ligation as therapy for infertility. Semen quality improved in 78 per cent following ligation, and 51 per cent of wives became pregnant. The results in this series compare favorably with previous studies. We believe that spermatic vein ligation is a very successful adjunct in the treatment of the infertile male with varicocele.
Over a twelve-year period, surgical correction of varicocele was performed on 986 selected subfertile men. They were followed up for at least two years after surgery. Semen quality was improved in 70 per cent, and 53 per cent of the wives became pregnant. Statistically, the results were better in terms of semen quality improvement and pregnancy for patients who had preoperative sperm counts over 10 million per milliliter (85 per cent improved, 70 per cent pregnancy rate) than for patients who had preoperative sperm counts of less than 10 million per milliliter (35 per cent improved, 27 per cent pregnancy rate). The empirical use of postoperative human chorionic gonadotropin therapy in this latter group improved results significantly (55 per cent improved, 45 per cent pregnancy rate).
Selektive retrograde Venographie der Vena spermatica interna: Ein überzeugendes Vorgehen zur Sicherung der Diagnose einer Varikocele
Bei 25 Patienten mit Verdacht auf eine Varikocele wurde eine selektive retrograde Katherisierung der linken Vena spermatica interna vorgenommen; hierzu wurde parcutan eine Punktion der rechten Vena femoralis nach der Methode Seldinger durchgeführt und der Katheter unter dem Monitor in die linke Vena renalis vorgeschoben. Dann wurde in stehender Lage des jeweiligen Probanden das Kontrastmedium injiziert, das bei Vorhandensein einer Varikocele eine retrograde Füllung der varikösen Vena spermatica ergab, während dieser Effekt bei normalen Männern, d.h. ohne Varikocele, nicht eintritt. Nach Ansicht der Autoren ist die Venographie indiziert für diagnostische und therapeutische Zwecke. Sie ist die einzig brauchbare nicht chirurgische Technik zum Nachweis eines gestörten Venenflusses der Hodenregion.
Venografia retrógrada selectiva de la vena espermática interna un método definitivo para el diagnóstico de varicocele
En 25 pacientes sospechosos de varicocele se efectuó la cateterización retrógrada selectiva de la vena espermática interna izquierda a nivel de su desembocadura en la vena renal. Quando se inyecta el contraste, el paciente con varicocele, estando en posición de pie, muestra un llenado retrógrado de la vena espermática varicosa, en contraste con la ausencia de tal reflujo en el hombre normal.
La venografía está indicada con fines diagnósticos y terapeúticos y es la única técnica útil no quirúrgica para probar la existencia de alteración del flujo venoso en la región testicular.
Adrenocortical hormones were measured in the peripheral and spermatic venous blood samples, taken simultaneously at the time of a high vasoligation for left varicocele in 95 patients.
Our results do not confirm the hypothesis of MacLeod that the deleterious effects of a varicocele on male fertility are caused by an higher local concentration of adrenocortical hormones, due to venous reflux through incompetent valves. If this is the case it occurs only in a minority of patients.
Blutproben aus der Cubitalvene und aus der V. spermatica wurden hinsichtlich ihres Gehaltes an NNR-Steroiden (Cortisol, DHEA und Androsteron) untersucht und zwar bei 95 Patienten anläßlich der hohen Ligatur der V. spermatica links wegen Varikocele. Die Autoren können mit ihren Resultaten die Hypothese von John MacLeod nicht bestätigen, der schädliche Einflüsse einer Varikocele auf die Fruchtbarkeit des Mannes durch eine höhere lokale Konzentration von NNR-Hormonen im Zusammenhang mit einem venösen Reflux bei insuffizienten Klappen annahm. Wenn das tatsächlich der Fall sein sollte, dann könnte das nur für eine Minorität der Patienten zutreffen.
Se midieron hormonas adrenocorticales en muestras de sangre periférica y de vena espermática, obtenida simultáneamente en el momento de la ligadura alta por varicocele izquierdo, en 95 pacientes.
Nuestros resultados no confirman la hipótesis de MacLeod de que los efectos deletéreos del varicocele sobre la fertilidad masculina son producidos por una alte concentratión local de hormonas adrenocorticales, debida al reflujo venoso por insuficiencia valvular.
Si esta es la causa, sucede sólo en una minoria de pacientes.
Five infertile males, ages 25 to 35, with oligospermia and varicocele had following gonadotropin-releasing hormone (LRF) infusion a rise of serum follicle-stimulating hormone, luteinizing hormone, and testosterone levels which was not different from that of normal fertile males. The response of these hormones to LRF infusion was unaltered by spermatic vein ligation, but a significant elevation of the sperm count occurred. Thus, improvement in sperm count following spermatic vein ligation is not mediated via changes in peripheral gonadotropin or testosterone concentrations.
Peripheral vein luteinizing hormone, follicle stimulating hormone, testosterone, and estradiol, and spermatic vein testosterone and estradiol levels were determined in 13 subfertile men with clinically diagnosed varicoceles, 5 patients with idiopathic infertility, and 13 control patients. Testis biopsies and semen analyses were also performed on most of the infertile patients and some of the controls. Secretion of both gonadal steroids and pituitary gonadotropins was normal in the subfertile men with varicoceles. It appears likely that mechanisms other than abnormal reproductive hormonal factors are responsible for the altered spermiograms and decreased fertility of such patients.
The role of antisperm antibodies in human infertility remains controversial. Indications for antisperm antibody testing of male partners of infertile marriages have been based upon anecdotal reports and studies using outdated assays. In an effort to define the indications for antisperm antibody testing of the male partner, the immunobead assay for antisperm antibodies was performed upon 100 consecutive men referred for evaluation of male factor infertility. The prevalence of antisperm antibodies in this patient population was 18% and only 9% when patients with a history of vasectomy were excluded. Of all the factors analyzed, only a history of vasectomy and sperm agglutination on semen analysis were predictive of antisperm antibody status (p < 0.001). Use of the aforementioned parameters as an indication for antisperm antibody testing would have resulted in a sensitivity of 94%, specificity 73% and negative predictive value 98% in this patient population. The only way to identify all patients with significant levels of antisperm antibody activity (sensitivity 100%) would have been to test every patient.
To evaluate the effectiveness of surgical correction of varicocele in restoring the function of the varicocelized testicle, experimental varicoceles were created in 16 male rabbits by partly ligating the left lumbotesticular trunk. Five control rabbits received a sham operation (group A). Two months later, eight of the varicocelized rabbits underwent surgical repair by ligation and cutting of the dilated left testicular vein (group B). The remaining eight varicocelized animals did not receive any additional treatment (group C). Five months after the initial operation, group C animals had a significantly lower sperm concentration, sperm motility, bilateral testicular androgen-binding protein activity, bilateral testicular vein testosterone concentration, bilateral testicular versus intraabdominal temperature difference, and fertility when compared with groups A and B. These findings suggested that the surgical repair of an experimental varicocele in the rabbit can significantly improve the parameters indicating the harmful effects of the varicocele on the testicles.
To determine the incidence of reactive oxygen species formation in semen of a population of patients consulting for infertility.
The incidence of reactive oxygen species formation in whole semen and in washed spermatozoa was studied. The values obtained were correlated with semen parameters. The effect of the type of sperm washing on reactive oxygen species formation was also investigated.
Semen samples from patients consulting for infertility and control subjects were obtained by masturbation after 3 days of sexual abstinence. Reactive oxygen species formation was measured in whole semen, sperm suspension washed by Percoll gradients, or repeated centrifugations. Sperm motility parameters were measured by computer-aided sperm analysis.
Fertile control men and an unselected population of patients consulting for infertility.
None.
Reactive oxygen species formation by fresh semen specimen or washed spermatozoa was measured in a computer-driven LKB 1251 Luminometer (LKB-Wallac, Turku, Finland).
Reactive oxygen species formation was detected in 40% of the semen with spermatozoa from infertile patients, whereas none was found in 6 azoospermic men and 10 control men. The level of reactive oxygen species formation was inversely correlated to the semen volume, the percentage of motile spermatozoa, and sperm linearity both in semen and in Percoll-washed spermatozoa. Washing by repeated centrifugation-resuspension increased 20- to 50-fold sperm reactive oxygen species formation. This enhancement was caused by the centrifugation itself and by the removal of seminal plasma. Both morphologically normal and abnormal spermatozoa produced reactive oxygen species.
The data suggest that reactive oxygen species formation by spermatozoa may be a significant cause for male infertility.
Convective transport is a critical element in the regulation of steroidogenesis and spermatogenesis in the testis. Steroid hormones are distributed to their target cells within seminiferous tubules via interstitial fluid. The movement of interstitial fluid and lymph, which transports protein hormones and many of the substrates required for spermatogenesis and steroidogenesis, is driven by capillary filtration. Despite the importance of convective transport in testicular function, however, the mechanisms regulating transvascular exchange in the testis are unknown. As a first step in understanding this process, we measured directly the microvascular hydrostatic pressure distribution in the hamster testis (pentobarbital sodium, 70 mg/kg ip). Using a servo-null transducer, intravascular pressure was measured in all vessel types accessible beneath the surface of the testis of 19 animals. Systemic arterial pressure averaged 89 +/- 2 (SE) mmHg. The most significant observations were that mean capillary pressure was extremely low (10.1 +/- 0.8 mmHg) and remarkably constant (range 8.2-13.3 mmHg), despite a 45 mmHg range in systemic mean arterial pressure among the animals observed. The maintenance of a low hydrostatic pressure in testicular capillaries may serve to sustain fluid filtration at a rate that prevents washout of essential solutes while preserving convective transport. Unfortunately, the anatomical and functional characteristics that determine this unique microvascular environment may also expose the testis to significant pathological risks. For example, the large pre- to postcapillary resistance ratio observed suggests that testicular capillaries must be highly susceptible to increases in venous pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Simultaneous measurements of left and right scrotal, and axillary skin temperatures were recorded in 58 consecutive adolescents (mean age 14.4 years) with a grade II-III left sided varicocele, and nine control adolescents without genital pathology (mean age 15.7 years). Left and right testicular volumes were determined in both groups. The adolescents with a varicocele had a significant bilateral elevation of the scrotal temperatures compared to the control subjects. This relative hyperthermia was present in both supine and standing positions. The mean left scrotal temperature of varicocele patients was significantly higher in the standing position than in the supine position, which may reflect the dependent venous filling of the varicocele. Those varicocele patients who maintained a left scrotal temperature at least 1.4 degrees C cooler than axillary did not have significant left testicular volume loss, whereas those whose left temperature was approximately equal to axillary did have significant growth retardation of the left testis. Following successful varicocele surgery, left scrotal temperatures were significantly cooler, and statistically indistinguishable from controls. The left testicular volumes were also significantly improved with respect to corresponding right testicular volumes. These observations suggest that adolescents with a moderate to large left varicocele have a significant bilateral loss of testicular thermoregulation. In those individuals with a significantly warmer left hemiscrotum, there is a definite increased potential for left testicular volume loss. Varicocele surgery can reverse this process.
Previous experiments have found that experimental left-sided varicocele (ELV) in rats is associated with significant bilateral reductions in intratesticular testosterone concentrations. The current experiments were performed to determine the source of this endocrinopathy. Sensitivity and responsivity of Leydig cells and gonadotrophs were determined in control male rats and in those with ELV. Initially, dose-response relationships were determined for luteinizing hormone (LH) stimulation of testosterone secretion by Leydig cells and for luteinizing hormone releasing hormone (LHRH) stimulation of LH secretion by gonadotrophs. Maximally (ED100) and half-maximally (ED50) stimulating doses of LH and LHRH were selected from these studies and administered to sham-operated and ELV rats 30 days after the operation to induce ELV. Leydig cell and gonadotroph sensitivity (response to ED50) and responsivity (response to ED100) to LH and LHRH, respectively, were determined. Responsivity of Leydig cells in control and ELV rats was similar. Responsivity of gonadotrophs to LHRH was significantly suppressed in ELV animals, but the physiologic relevance of this singular finding is unclear. It is possible that the previously determined ELV-associated decrease in intratesticular testosterone concentrations is subsequent to a wash-out phenomenon that follows the increased testicular blood flow that also is known to be associated with ELV.
In a group of 31 patients with idiopathic varicocele (IV), testicular biopsy showed a decreased tubular diameter, hyperplasia in the number of Leydig's cells (LC; many with cytoplasmic vacuolization and atrophy) and a decrease in the number of positive LC in testicular tissue sections stained with the testosterone peroxidase-antiperoxidase method. Similar values were seen for the testis with IV and for the contralateral testis. All of this, in addition to the lack of significant differences in the volume of cytoplasmic organelles in the LC, leads us to think that both testes are equally involved. Estradiol levels were significantly increased and testosterone, FSH and LH were normal in peripheral blood (compensated LC dysfunction).
The application of a new, miniaturized portable digital data recorder "Thermoport" (Institute for Reproductive Medicine, Münster, West Germany) for continuous determination of scrotal temperatures revealed great variations of scrotal temperature during 24 hours in normal men. Maximum temperatures approached body core temperatures. Mean scrotal temperatures of 10 normal men rose during sauna from 32.72 +/- 0.23 degrees C to 37.53 +/- 0.38 degrees C. During treadmill running, scrotal temperatures increased by more than 2.5 degrees C. Minimal scrotal temperatures were increased in some men with varicocele compared with normal fertile men indicating impaired cooling mechanisms. The continuous temperature measurements facilitate assessment of temperature dynamics. The miniaturized design of the Thermoport makes it suitable for routine use in outpatients of infertility clinics, in occupational medicine for evaluation of heat hazards, and for investigations of body temperatures under various experimental conditions.
Testicular and reference organ blood flows and testicular temperatures were determined in peripubertal and mature rats with and without experimental left varicocele (ELV). Testicular blood flow and temperature were significantly increased bilaterally 30 days after surgery to induce unilateral varicocele, and this was the case in both the younger and older animals. It has not previously been known that the pathophysiological effects of ELV extended to the peripubertal testis. Previous experiments have demonstrated that the left testis is not necessary for the right testicular response to varicocele. In the present paper, animals were subjected to left orchiectomy simultaneously with the surgery to induce ELV. Thirty days later, the animals were divided into those with and those without the left spermatic vein varicosity. Testicular blood flow was determined in all these animals as well as in a separate group of control and experimental varicocele animals. The group of ELV animals with left spermatic varicosity demonstrated a significant increase in contralateral testicular blood flow while the ELV group without left spermatic varicosity did not. We speculate that left venous distention is involved in the mechanism for the contralateral response to unilateral varicocele.
The ability of human spermatozoa to exhibit sperm-oocyte fusion in response to the ionophore, A23187, was examined in relation to the capacity of these cells to generate reactive oxygen species. In 70 fertile control donors, there was an overwhelming pattern of high levels of sperm-oocyte fusion associated with low levels of reactive oxygen species production. By contrast, 88% of the 74 oligozoospermic patients exhibited less than 25% oocyte penetration in response to A23187 and 58% exhibited no penetration whatsoever. Of the 40 oligozoospermic patients who failed to respond to A23187, nine had low levels of reactive oxygen species production in association with impaired liquefaction of seminal plasma. Of the remainder, 17 (55%) exhibited defective sperm function together with elevated production of reactive oxygen species. These observations, which are the first to describe a biochemical defect in the spermatozoa of oligozoospermic patients, may carry significant implications for the etiology and treatment of this condition.
The purpose of this investigation was to create a varicocele model in animals and to study the subsequent alterations in testicular physiology. The study comprised 22 dogs divided into 2 groups: test and control. In the test group (17 dogs), excision of a longitudinal strip of the fasciomuscular tube of the spermatic cord was done on one side only. In the control group (5 dogs), the spermatic cord was exposed without interference with the tube. Testicular temperature was measured, and biopsies from the 2 testicles and semen specimens were examined. Re-examination for variceal changes was performed in 3 dogs at the 4th postoperative week; in 3 dogs at the 6th, and in 16 dogs (11 test and 5 control) at the 8th postoperative week. Sections from spermatic cord and testicle were examined microscopically. Serum levels of testosterone follicle-stimulating hormone, luteinizing hormone and prolactin were assayed preoperatively and at the time of re-examination. Manifest varicocele was detected in 16 of 17 detubated dogs. It was huge in all dogs re-examined after 8 weeks. Semen showed decreased sperm count in all test animals except 1. The animals with induced varicocele had higher testicular temperature than the controls. Microscopically, the detubated spermatic cords have shown variceal changes and the testicle degenerative changes in all the test animals. Similar changes were encountered in the contralateral testicle in the animals re-examined at 8th week. Radioimmunoassay showed a significant decrease of serum testosterone and increase of prolactin postoperatively. Follicle-stimulating hormone and luteinizing hormone showed no significant change from the preoperative level.(ABSTRACT TRUNCATED AT 250 WORDS)
Sperm-bound immunoglobulins were found in 27 (32%) of 84 infertile men with palpable varicoceles. These men were divided into two groups based on the presence (group I; 32%) or absence (group II; 68%) of sperm-bound immunoglobulins, as measured by an enzyme-linked immunosorbent assay. Circulating antisperm antibodies were identified in 52% of patients with sperm-bound immunoglobulins and 14% of group II patients. The presence of sperm-bound immunoglobulins was associated with a small but significant decrease in both sperm concentration and motility. Sperm-bound immunoglobulins are present in a greater percentage of infertile men with varicoceles than infertile men without varicoceles. Their presence may be a marker for damage to the seminiferous epithelia in men with varicoceles and may also contribute to varicocele-associated infertility.
The precise mechanism of the hypospermatogenesis associated with varicocele has remained uncertain, although there have been a number of speculations on the etiology of the associated infertility. The altered spermatogenesis has been attributed to the reflux of toxic metabolites from either adrenal or renal origin, disturbed hormone status, spermatic venous hypertension, testicular hypoxia secondary to stasis, and abnormal temperature regulation. However, the biochemical changes of the testicular tissue with varicocele have been only partially explored. This overview includes the available information on the biochemical change in the testes associated with varicocele as well as the introduction of basic biochemical aspects on the testes, which may give new insights into the possible pathophysiological mechanism of male infertility.
A possible mechanism of varicocele-induced infertility is believed to be elevation of testicular temperature. Sensitive needle thermistors were used to measure directly intratesticular and bilateral scrotal surface temperatures simultaneously in anesthetized infertile men with varicocele and control subjects. We found that intratesticular temperature is elevated significantly in humans with varicocele. In addition, we have shown that scrotal skin surface temperature is elevated in men with varicocele. Furthermore, we demonstrate that unilateral varicocele is associated with bilateral elevation of scrotal surface temperature. These findings confirm the results of animal studies revealing elevation of intratesticular temperature associated with varicocele and suggest bilateral elevation in unilateral varicocele.
Experimental left varicocele (ELV) is known to induce bilateral changes in the rat testis that, where comparisons are possible, are similar to the changes induced by unilateral varicocele in the human. In the present study, we have determined whether or not left adrenal products are important to the changes induced by ELV and whether or not reflux of left renal vein content occurs in the ELV rat. In the first study, testicular blood flow and temperature were studied in control animals and those with ELV, left adrenalectomy (LAX), or ELV + LAX. Control left and right testicular blood flow (33.6 +/- 0.8 and 33.6 +/- 1.5 ml./min./100 gm. tissue respectively) was significantly elevated by ELV (to 39.9 +/- 0.9 and 41.2 +/- 2.7 ml./min./100 gm. tissue, respectively) and the difference between abdominal and testicular temperatures (delta T) was significantly reduced. Control delta T's for right and left testes were 3.2 +/- 0.2C and 3.2 +/- 0.2C, respectively, and right and left delta T's for ELV animals were 2.0 +/- 0.3 degrees C and 2.0 +/- 0.3C, respectively. These blood flow and temperature changes also occurred when ELV animals were subjected to simultaneous LAX. Additionally, when 85Sr-labelled microspheres were infused into the left renal vein, they did not appear in either left or right testes of ELV animals. We conclude that there is no evidence for reflux down the spermatic vein in ELV in rats and adrenal products do not reach the testis via this route after being secreted into the renal vein. We raise the suggestion that the same may be true in the human.
Spontaneous lipid peroxidation in washed human spermatozoa was induced by aerobic incubation at 32 C and measured by malonaldehyde production; loss of motility during the incubation was determined simultaneously. Malonaldehyde production at the point of complete loss of motility, defined as the lipoperoxidative lethal endpoint (LLE), was 0.10 +/- 0.03 nmol/10(8) cells (mean +/- SD, n = 40), and was independent of the time to complete loss of motility. Human spermatozoa produced both H2O2 and O2-. during aerobic incubation. Inhibition of superoxide dismutase in these cells with KCN showed that all the H2O2 production is due to action of the dismutase. The superoxide dismutase activity of individual human sperm samples varied between 1 and 10 U/10(8) cells, variations between samples from a single donor being nearly as great as those between different donors. The time to complete motility loss (tL) showed equal variation of 1 to 10 hours among samples. The rate of spontaneous lipid peroxidation, calculated as LLE/tL, for a given sperm sample and the superoxide dismutase activity of the same sample, determined prior to aerobic incubation, gave a good linear correlation (r = 0.97). Glutathione reductase, glutathione peroxidase, and glutathione were found to be present in human spermatozoa, but showed little variation among samples. These results suggest that superoxide dismutase plays the major role in protecting human spermatozoa against lipid peroxidation. In addition, the superoxide dismutase activity of a fresh sperm sample appears to be a good predictor of the lifetime (up to the complete loss of motility) of that particular sample, and so may prove useful in semen analysis.
The results of surgical treatment of 50 subfertile patients with left varicocele are presented. Improvement of the spermiogram was noted as follows: 70% of patients had improvement of semen count, 48% of semen motility and 69.4% in the morphological pattern of spermatozoa. Pregnancy occurred in 50% of patients' wives. Eighty-four percent of the pregnancies took place during the first 12 months after the operation. A direct correlation was observed between the size of the varicocele and the number of pregnancies. Severely oligozoospermic patients with sperm count less than 10 million per milliliter semen constituted 72% of the men whose wives became pregnant. There was no statistically significant change after the operation in levels in the semen of luteinizing hormone, follicle stimulating hormone, testosterone and prolactin.
A total of 130 men presenting with oligospermia and clinically identifiable scrotal varicoceles was evaluated, treated surgically and followed for 1 year for pregnancy rate. The treatment outcome was compared to an age-matched cohort of 83 oligospermic men who had received empirical medical therapy with clomiphene citrate (25 mg. per day) for the same 1-year interval. This study was done to contrast treatment modalities in infertility and not as a strict control. Only eugonadotropic patients in both groups were used for comparison. In the varicocele group the over-all pregnancy rate was 38.5 per cent. Four variables (a lack of testicular atrophy, sperm density greater than 50 million per ejaculate, sperm motility 60 per cent or more and serum follicle-stimulating hormone values less than 300 ng. per ml.) proved to be accurate preoperative predictors of postoperative pregnancy success. Four other variables (varicocele size and laterality, sperm forward progression greater than 2 and normal sperm morphology 60 per cent or more) did not yield statistically significant rates of improvement in pregnancy postoperatively. The pregnancy rate of the eugonadotropic patients undergoing varicocele repair was 45.8 per cent. Despite statistical similarity in patient age, sperm density and mean gonadotropin levels the medically treated patients had a pregnancy rate of only 25.5 per cent, significantly lower than the surgically treated patients. In summary, patients with an identifiable varicocele had a greater chance of achieving a pregnancy following surgical correction than did those treated with empirical drug therapy. In addition, certain preoperative variables in the physical and laboratory analyses appeared to portend a greater surgical response.
The presence of a varicocele in adult men has been correlated with infertility. This study documents the effect of an experimentally induced unilateral varicocele in 21-day-old juvenile prepubertal and 51-day-old adult rats (n = 10 per group) on subsequent adult testicular function. Varicoceles were induced by partial occlusion of the spermatic vein. There were ten sham-operated and five nonoperated control rats in each age group. The rats were sacrificed 1 month after surgery. Intrascrotal temperatures were elevated in both groups with varicoceles. Histologically, the ipsilateral testes of rats in both age groups demonstrated a decrease in the numbers of functioning seminiferous tubules and germ cells, but the decrease was significantly greater in the juveniles than in the adult rats. No changes were seen in the contralateral testes. Significant titers of cytotoxic sperm antibodies were present in all animals with varicoceles, which is in contrast to controls. The juveniles had significantly lower antibody titers (mean log2 +/- SEM; 3.2 +/- 0.09 vs. 8.5 +/- 1.1, P less than 0.001) than the adults. The induction of a unilateral varicocele damaged spermatogenesis and testicular function to a greater extent in juveniles than in adult rats. This damage may be immune complex-mediated.
To study the effect of temperature on human spermatogenesis, both the number and DNA synthesis of germ cells were investigated in tissue fragments of human testes cultured for 22 h at 31 degrees C and 37 degrees C. The number of differentiated germ cells such as spermatids and spermatozoa cultured at 37 degrees C was significantly smaller than that cultured at 31 degrees C. The number of spermatogonia and resting primary spermatocytes was not significantly different between these two temperatures, but the functional ability of DNA synthesis in these cells was significantly lower at 37 degrees C than at 31 degrees C. It seems that in normal body temperature (37 degrees C) differentiated germ cells such as spermatids and spermatozoa are fragile and the DNA synthesis of spermatogonia and resting primary spermatocytes is retarded.
To assess the existence of a possible immunologic factor in varicocele-associated infertility, we searched for antispermatozoal antibodies in serum, seminal plasma, and bound to spermatozoa in 32 infertile men with varicocele and 22 infertile patients without palpable varicocele, with the use of an enzyme-linked immunosorbent assay. In addition, we performed morphologic and microbiologic analyses of the semen and urethral smears for isolation of Chlamydia trachomatis. Twenty-nine men from the varicocele group (90.6%) demonstrated antispermatozoal antibodies, compared with only 9 men (40.9%) in the control group. The antibodies in both groups, when present, were mainly serum and seminal plasma immunoglobulins IgA and IgM. A significant quantitative difference between the varicocele and control groups was also observed for serum IgA, seminal plasma IgA and IgM, and sperm-bound IgG, IgA, and IgM. Oligozoospermia and asthenozoospermia were significantly more prevalent in the varicocele men. An asymptomatic genital tract infection with C. trachomatis, Ureaplasma urealyticum, and Escherichia coli was traced in 40.6% of the varicocele men and in 45.5% of the control group. No interaction could be demonstrated between the infection and antispermatozoal antibody formation. These data suggest that an immunologic factor may play a role in varicocele-associated infertility; however, its impact on reproduction has yet to be assessed.
The influence of temperature on Leydig and Sertoli cell functions was investigated in two experiments. One experiment was performed with testes of men with or without varicocele, because the temperature differs between right and left testes of men with left varicocele and right testes of men without varicocele. There were no significant differences in follicle-stimulating hormone (FSH), human chorionic gonadotropin (hCG) receptors, and testosterone (T) concentrations among the testes. The other experiment was performed with the use of testicular organ culture. Specific binding sites for FSH, hCG, and T production were similar in cultured testes maintained at 33 degrees and 37 degrees C for 7 days. It is concluded that high temperature may not disturb Leydig and Sertoli cell functions in the short term.
It has been previously shown that 30-day experimental left varicocele (ELV) in adult rats produces a bilateral increase in testicular blood flow and temperature, as well as a concomitant decrease in epididymal sperm count and motility. In the present study, adult male rats with induced ELV were subjected to a variety of studies to determine the mechanism by which unilateral ELV causes a bilateral testicular response. The results demonstrate that ELV does not alter the blood-testis barrier (BTB) to 3H-inulin (MW 5000), it being largely excluded from entry into the tubule lumen in both control and ELV animals. Neither left nor right cauda epididymidal temperature was altered by ELV. Intraepididymal Na+ and K+ concentrations in the left caput epididymidis were 81.3 +/- 3.8 mEq/l and 26.3 +/- 1.5 mEq/l, respectively. From the cauda epididymidis, these values were 25.0 +/- 2.2 mEq/l and 46.8 +/- 1.0 mEq/l, respectively. These values were similar on the right side and in the left and right epididymis of ELV animals. Left testis arterial pH was 7.3 +/- 0.1, and PO2 and PCO2 were 116.0 +/- 6.4 mm of mercury and 44.3 +/- 3.2 mm of mercury, respectively. Left testicular venous values were 7.3 +/- 0.1 (pH), and 52.6 +/- 2.2 mm of mercury and 49.9 +/- 2.0 mm of mercury. These values were similar for right control testicles and left and right testicles of ELV animals. These results indicate that the mechanism by which unilateral ELV produces a bilateral change in testicular or epididymal function is not by altering the BTB, epididymal temperature or electrolyte concentrations, or testicular blood gas concentrations.
Scrotal temperatures, testicular volumes, and sperm characteristics were studied in 150 infertile, nonazoospermic men and in 37 fertile men, used as a control group. The mean scrotal temperature values of the infertile men were significantly greater than those observed in the fertile men (+0.4 degrees C for the right; +0.5 degrees C for the left). In the infertile men, it was found that the higher the scrotal temperature, the more alterated the sperm characteristics. The only clinical element that seemed to be linked to the existence of scrotal hyperthermia in the infertile men was testicular hypotrophy. Although the scrotal temperatures of the infertile men with varicocele were significantly higher than those of the fertile men, they did not significantly differ from those of the infertile men without varicocele. No other specific pathologic factor, infectious or surgical urogenital history was found to be responsible for the scrotal hyperthermia observed in the infertile men.
Varicocele was surgically induced in monkeys to study the long-term effects of the condition on seminal and testicular parameters. Sperm motility was depressed but improved after varicocelectomy. Sperm concentration was less affected, but sperm morphology showed long-term degenerative changes, i.e., for more than 2 years. Testicular blood flow was depressed acutely but returned to normal after 2 years. Electron microscopy showed changes in the basal lamina and spermatogonia that persisted throughout the study. Left adrenalectomy, at the time of varicocele induction, did not alter the development of varicocele-related changes. The sequence of changes suggests that the effects of this experimental varicocele may be reversed in the monkey model through changes in collateral and ancillary revascularization.
The effects of varicocele and varicocele repair on testicular blood flow, temperature, sperm counts, and sperm motility were assessed in adult male rats. The duration of the experimental varicocele and the varicocele repair were three and two times as long, respectively, as that studied previously. Varicoceles were created by partial ligation of the left renal vein and repairs were accomplished by high ligation of the left spermatic vein. Testicular blood flow was determined by using the radiolabeled microsphere technique. Testicular temperature was taken via needle probe thermometer. Sperm samples were obtained by micropuncture of the cauda epididymidis, and were counted on a hemacytometer and observed for motility under the light microscope. Varicoceles were studied 100 days after their creation. Repairs were performed on varicoceles that had lasted 100 days and the animals were studied 60 days after repair. Mean testicular blood flow (ml/100 g tissue/min) was significantly increased (P less than 0.05) in animals with varicocele (left testis (LT) = 42.2 +/- 1.1, right testis (RT) = 39.1 +/- 1.2) when compared with normal controls (LT = 29.3 +/- 1.6, RT = 29.6 +/- 1.7), animals with varicocele repair (LT = 30.7 +/- 1.3, RT = 30.0 +/- 1.6), or sham-operated animals (LT = 29.7 +/- 1.4, RT = 31.1 +/- 1.4).(ABSTRACT TRUNCATED AT 250 WORDS)
Although varicocele remains the most frequently diagnosed cause of male infertility, and improvement in semen quality is associated with repair of varicocele, improvement in spermatozoal fertilizing capacity has not been conclusively demonstrated. The sperm penetration assay was employed to monitor prospectively surgical (n = 59) and nonsurgical (n = 40) groups of men with varicocele. There were no significant increases in the average count, motility, morphologic features, or sperm penetration assay results for either group. Varicocele surgery enhanced assayable egg penetration rates in 14 of the 59 patients (23.7%), whereas the nonsurgical group had 10% spontaneous improvement. Of those in the surgery group who showed assayable fertility enhancement and were attempting conception, pregnancies were achieved in 70% (7 of 10 patients). Of patients in the nonsurgical group who improved in the assay, no pregnancies were obtained.
The gonadotropin responses to a 4-hour infusion of gonadotropin-releasing hormone (GnRH) and seminal plasma dihydrotestosterone (DHT) and testosterone levels were assessed before and 6 to 12 months after varicocelectomy in 22 men with varicoceles. Twelve men were severely oligozoospermic (sperm densities less than 10 X 10(6)/ml), whereas 10 men had sperm densities between 11 and 30 X 10(6)/ml. Each man had excessive gonadotropin responses to GnRH and lower than normal seminal plasma DHT levels preoperatively. Eight of the 12 severely oligozoospermic men and 6 of the other 10 men had postoperative improvements in sperm density. These men (responders) had normalization of gonadotropin response and seminal plasma DHT levels. The nonresponders had identical hormonal parameters before and after surgery. These results indicate that the pantesticular defect in hormonal synthesis and spermatogenesis, seen in some men with varicoceles, can be reversible.