|Year : 2015 | Volume
| Issue : 4 | Page : 659-667
Varicocele and testicular function
Alexander W Pastuszak1, Run Wang2
1 Center for Reproductive Medicine; Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA
2 Divisionof Urology, University of Texas Medical School at Houston; Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
|Date of Submission||13-Dec-2014|
|Date of Decision||06-Feb-2015|
|Date of Acceptance||28-Feb-2015|
|Date of Web Publication||24-Apr-2015|
Alexander W Pastuszak
Center for Reproductive Medicine; Scott Department of Urology, Baylor College of Medicine, Houston, TX
Source of Support: None, Conflict of Interest: None
Testicular varicocele, a dilation of the veins of the pampiniform plexus thought to increase testicular temperature via venous congestion, is commonly associated with male infertility. Significant study has clarified the negative impact of varicocele on semen parameters and more recent work has shed light on its detrimental effects on the molecular and ultrastructural features of sperm and the testicular microenvironment, as well as more clearly defined the positive impacts of treatment on couples' fertility. The relationship between varicocele and testicular endocrine function, while known for some time based on histologic evaluation, has become more apparent in the clinical setting with a growing link between varicocele and hypogonadism. Finally, in the pediatric setting, while future study will clarify the impact of varicocele on fertility and testicular function, recent work supports a parallel effect of varicocele in adolescents and adults, suggesting a re-evaluation of current treatment approaches in light of the progressive nature of the condition and potential increased risk of future disease.
Keywords: hypogonadism; Leydig cell; male fertility; oxidative stress; Sertoli cell; ultramorphology; varicocele
|How to cite this article:|
Pastuszak AW, Wang R. Varicocele and testicular function. Asian J Androl 2015;17:659-67
| Introduction|| |
Testicular varicocele is a dilation of the veins of the pampiniform plexus draining the testicle. Varicoceles are found in 15% of all men and in 19%-41% of men who present with primary infertility, representing the most common surgically treatable cause of male infertility.  In men with secondary infertility, varicoceles are an underlying cause in 45%-81% of patients, and varicocele remains the most common cause of male infertility worldwide. ,, In men with azoospermia, the incidence of varicocele is 4.3%-13.3%.  Based on a 15% prevalence of infertility in the population, approximately 20% of men with varicocele have evidence of infertility, while 80% do not.  While varicocele can be associated with testicular discomfort and atrophy, the negative effects of varicocele on male fertility and semen parameters, as well as recent evidence identifying varicocele as a risk factor for hypogonadism, are the most relevant ramifications of the condition. ,
In this review, we summarize the most recent literature linking varicocele to male infertility and hypogonadism. Given the progressive nature of the effects of varicocele on sperm production and function, as well as Leydig cell function over time, we also discuss the approach to varicocele in pediatric and adolescent populations, with emphasis on consideration of downstream ramifications of untreated varicocele in these young males.
| Varicocele Pathophysiology|| |
While left-sided varicoceles predominate, a contralateral varicocele is present in 30%-80% of cases.  In contrast, isolated right-sided varicoceles comprise <5% of cases and should raise concern for a retroperitoneal mass effect.  The high incidence of varicocele in humans may be in part explained by our upright posture, resulting in venous congestion.  Several other anatomic explanations for the more common incidence of left-sided varicoceles also exist. First, venous valves are more commonly absent on the left-side, with one study finding valves absent in 40% of left spermatic veins, but absent in only 23% of right spermatic veins.  However, 26% of patients with varicocele have competent valves, making the absence of valves an unlikely unifying cause of varicocele.  Second, right-sided testicular venous drainage is directly into the inferior vena cava, whereas the left spermatic vein drains into the left renal vein, which drains more slowly than the vena cava due to its smaller diameter. Several case studies in men with situs inversus and right-sided varicocele, as well as venographic studies in men with right-sided varicocele and spermatic vein drainage into the right renal vein, support slower spermatic venous drainage on the side draining into a renal vein. ,,, Third, left-sided spermatic vein drainage increases the chances of renal vein compression between the superior mesenteric artery and aorta or obstruction of the left common iliac vein by the left common iliac artery as it crosses above the vein.  However, this type of compression occurs in only 0.5%-0.7% of cases, making this phenomenon a rare cause of varicocele.  Interestingly, predisposition to varicocele likely has a genetic component, with one study demonstrating varicocele in 56.5% of first-degree relatives of patients with varicoceles, in contrast with 6.8% of controls.  However, predisposing genes remain to be identified.
The prevailing theory explaining impairments in testicular function resulting from varicocele posits that poor venous drainage increases testicular temperature, leading to detrimental effects on spermatogenesis and Leydig cell function. Normal scrotal temperature is 1-2°C lower than body temperature, and is maintained by the thin scrotal skin, a lack of subcutaneous fat, and a countercurrent heat exchange system taking advantage of the pampiniform plexus, allowing arterial blood to be cooled as it enters the testis.  Higher intratesticular temperatures have been reported in men with varicocele and fertility difficulties, , and numerous animal and human studies have linked scrotal and testicular hyperthermia to decrements in spermatogenic function, including in the setting of cryptorchidism. ,,,,
Other theories to explain the testicular effects of varicocele include: (1) suboptimal drainage of testicular gonadotoxins due to venous dilatation, (2) reflux of renal and adrenal metabolites contributing to venous dilatation, (3) testicular hypoxia, (4) higher levels of oxidants in the semen, and (5) anti-sperm antibodies. ,,,,,, On a cellular and molecular level, varicocele has been shown to decrease testicular DNA polymerase activity, increase testicular cell apoptosis, increase reactive oxygen species (ROS), alter Sertoli cell function, and decrease Leydig cell testosterone secretion. ,,, While all of the above-mentioned varicocele causes have some evidentiary support, no one cause describes all cases of varicocele, and multiple etiologies may contribute to any single case. In addition, identifying the root causes of varicocele in all patients may not be economically viable and is unlikely to have a significant impact on outcomes if the varicocele is treated using current modalities. Nevertheless, it is helpful to conceptualize the origins of varicoceles in consideration of future treatments that may obviate the need for surgical intervention and specifically address the root cause of the varicocele.
| Testicular Effects of Varicocele|| |
Historically, varicocelectomy did not become part of the armamentarium for managing infertile men until the 1950s, when Tulloch demonstrated improvement in semen parameters in 26 of 30 patients after varicocelectomy, with 10 men having return of normal semen parameters and initiating pregnancy.  In a 1977 study evaluating testicular size in a group of 82 healthy volunteers,61 subfertile men with varicocele, and 27 subfertile men without varicoceles, Lipshultz and Corriere observed testicular atrophy preferentially on the ipsilateral side in men with varicocele, although no differences in semen parameters were observed between groups.  This initial link between testicular atrophy and varicocele was further supported by Johnsen and Agger, who evaluated testicular biopsies before and one year after varicocele repair in 29 men, finding significant improvements in the appearance of seminiferous tubules after surgery and linking varicocele with germ cell content. 
Cellular effects on sperm
The effects of varicocele on semen parameters were first made apparent by MacLeod in 1965, when he noted a decrease in sperm motility and density.  In addition, a "stress pattern" of morphologic changes, not specific to varicocele but including increased numbers of immature forms, amorphous cells, and tapered forms, was also observed. Abnormal sperm morphology in men with varicocele has been repeatedly observed, but to date, no morphologic changes specific to varicocele have been identified. ,, Even with the use of Kruger strict morphologic criteria, only a decrease in the number of normal forms has been observed in men with varicocele, with improvements in morphologic criteria after varicocele repair. , Functionally, sperm from men with varicocele are less able to fuse with female gametes. These sperm bind to hamster and human oocytes, and penetrate hamster oocytes, less well than sperm from normal men. ,
Reactive oxygen species and DNA damage
On a molecular level, men with varicocele have significantly higher levels of ROS, which can be present together with higher levels of DNA fragmentation, corresponding to damage of packaged chromatin and a reflection of poor sperm quality. , While the mechanisms of ROS action have been incompletely elucidated, studies suggest that oxidation and reduction are important in sperm hyperactivation, capacitation, zona pellucida binding, and the acrosome reaction. , Varicocele is associated with increased DNA damage, and exposure to sperm to exogenous ROS can induce DNA damage, particularly in the absence of appropriate antioxidant mechanisms. , ROS are elevated both in the semen as well as systemically in men with varicocele, and varicocelectomy results in a decrease in ROS, improvement in antioxidant levels, and decreases in DNA damage. ,,,, In uncontrolled studies of men with impaired semen parameters with and without varicocele, dietary antioxidant therapy results in improvement in semen parameters, including sperm concentration and motility, even when men with varicocele do not undergo variocelectomy. ,,, Thus, while varicocele predisposes to oxidative damage and compromised DNA integrity, varicocele treatment using medical and surgical approaches can reverse these molecular changes.
Ultrastructural changes in sperm in men with varicocele
The use of the current semen parameters in the evaluation of male infertility is suboptimal, given that sperm count, morphology determined using light microscopy, forward progression, and motility are largely nonspecific indicators of fertility and incompletely reflect sperm quality and function. In the setting of varicocele, changes in semen parameters after varicocele repair are inconsistent across the literature, with many studies reporting improvements in one or more parameters, but some reporting no changes. ,,, Meta-analyses evaluating the effects of varicocelectomy show improvements in semen parameters overall, but evaluation of sperm and seminiferous tubule histology and ultrastructure in the setting of varicocele before and after treatment may better inform the effects of treatment, particularly in consideration of a growing proportion of infertile couples utilizing assisted reproductive technologies (ART).
A 1978 study evaluating sperm histology in the setting of varicocele observed multinuclear spermatids, suggesting a disturbance in spermiogenesis.  A follow-up study in 1980 evaluated testicular biopsies from 21 men with varicocele using light and electron microscopy, demonstrating spermatid malorientation relative to Sertoli cells More Details and structurally abnormal Sertoli-germ cell junctional complexes, highlighting an adluminal compartment defect in varicocele and suggesting that the Sertoli cell is more sensitive to varicocele pathology than sperm.  Subsequent ultrastructural studies demonstrated increased vacuolization of the endoplasmic reticulum, with possible resultant exfoliation of germ cells and abnormal retention of cytoplasmic droplets. , In a study of quantitative ultramorphological analysis, Reichart et al. examined sperm subcellular organelles in men with treated and untreated varicoceles, finding a significant increase in normal acrosome structure, chromatin condensation, and sperm head appearance, but observing no changes in tail subcellular organelles, in men with treated varicoceles.  In contrast, no changes in semen parameters were observed between groups. This work implicated alterations in sperm head formation and DNA packaging in varicocele pathogenesis and highlighted ultramorphology as a more sensitive tool for assessment of the sperm pathology in the setting of varicocele.
Sperm derived from men with varicocele are also more likely to retain cytoplasmic droplets, which are correlated with ROS production and DNA damage, defective sperm function, impaired spermatogenesis, and worse in vitro fertilization rates, more frequently than sperm from fertile men. ,,, When assessing the relationship between varicocele and sperm function relating to sperm tailpiece mitochondrial activity, Blumer et al. found a higher percentage of men with varicocele to have inactive mitochondria, demonstrating a functional tailpiece defect not previously observed using ultrastructural evaluation.  Importantly, varicocele repair results in improvement in sperm ultrastructure, namely sperm head organelle defects, according to a recent meta-analysis of prospective studies. 
Sertoli and Leydig cell function and hypogonadism
In addition to direct effects on sperm, varicoceles have a detrimental impact on other testicular cell types as well. Clinically, Sertoli cell dysfunction can be observed by a decreased responsiveness to follicle stimulating hormone (FSH), and by alterations in androgen binding protein (ABP), transferrin, and inhibin. In the setting of varicocele, some men present with elevated FSH and decreased testosterone production, and 48%-76% have improvement in one or both of these parameters following varicocelectomy. , Inhibin B levels also often improve after varicocelectomy, suggesting a reversible Sertoli cell defect.  In animal models of varicocele, Sertoli cell dysfunction may also be observed through decreased ABP and transferrin levels, both of which can disrupt spermatogenesis.  In human studies, varicocelectomy results in a rise in transferrin levels, correlating with increased sperm concentration and with improvements in sperm morphology.  Ultrastructurally, seminiferous tubules from men with varicocele demonstrate thickening of the germinal epithelium with increased apoptosis, Sertoli and germ cell cytoplasmic vacuolization, and alterations in spermatids and spermatozoa. 
The impact of varicocele on Leydig cell structure has also been studied. Sirvent et al. observing increased cytoplasmic vacuolization and atrophy in Leydig cells, and a decrease in the number of Leydig cells, even in bilateral testes in men with unilateral varicocele.  Leydig cell malfunction may predispose men to clinical hypogonadism. Studies evaluating serum testosterone levels in men with varicocele have yielded variable results, with some early studies finding decreased levels , and others showing no difference. , A large study by the World Health Organization in 1992 reported on 9034 men presenting for fertility evaluation and observed that men with varicocele over age 30 had significantly lower testosterone levels than men <30 years old with varicocele,  a trend not observed in men without varicocele suggesting an impact on Leydig cell function. Several studies evaluating the effects of varicocele repair have reported normalization of serum testosterone levels after repair, indicating a reversible effect ,,, ([Table 1]).
More recent studies more clearly support a detrimental impact of varicocele on testosterone levels, with a 2007 study by Tanrikut et al. showing a significantly lower serum testosterone level in men with varicocele (412.2 ng dl−1 ) than in men without (462.6 ng dl−1 ).  A follow-up study by the same group in 2011 showed a significant increase (178 ng dl−1 ) in serum testosterone levels after varicocele repair irrespective of varicocele grade, laterality or patient age, more strongly implicating varicocele as a risk factor for androgen deficiency or hypogonadism.  Other recent studies have also echoed these results. ,, Improvement in testosterone levels appears to be age-independent, with one study of 272 men aged 16-65 years old who underwent varicocelectomy demonstrating similar improvements in both semen parameters and testosterone levels independent of age.  To further strengthen the link between varicocele and hypogonadism, a recent query of the Truven Health Analytics MarketScan database, a large outpatient claims database, demonstrated an increased number of hypogonadism claims in young men who had concurrent varicocele claims among more than 224 000 men. 
Several studies have evaluated the relationship between varicocelectomy and hypogonadal symptoms, namely erectile dysfunction (ED), finding improvement in erectile function in men undergoing varicocelectomy. In a 2011 study of 200 hypogonadal infertile men with varicocele treated using varicocelectomy or ART, both significant increase in serum testosterone, with 78% of patients becoming eugonadal, as well as decrease in ED prevalence were observed in the varicocelectomy group.  In contrast, no change in testosterone levels, and a slight increase in ED prevalence were observed in the ART group. In a similar study,141 hypogonadal infertile men with clinical varicocele were treated using varicocelectomy or ART, also with normalization of testosterone levels in 76% of men. International Index of Erectile Function-5 questionnaire scores in men undergoing varicocelectomy also increased in this study, suggesting improvement in sexual function.  While serum testosterone levels are most frequently used to assess Leydig cell function, intratesticular testosterone levels are a key factor in the regulation of spermatogenesis. Although no studies of intratesticular testosterone relating to varicocele in humans exist, a recent rat model demonstrated a significant decrease in intratesticular testosterone levels in the setting of varicocele, suggesting a direct impact on Leydig cell function using a more rigorous and sensitive metric. 
Thus, while definitive data linking varicocele to hypogonadism remain elusive, with large prospective studies, as well as studies evaluating the long-term maintenance of eugonadism in men with a history of varicocele lacking, the link between testicular endocrine function and varicocele is growing stronger and should be considered, particularly in the evaluation and treatment of young men with varicocele.
| Varicocele and Male Fertility|| |
As described above, semen parameters, as well as the seminal and testicular milieu and ultrastructure may be impacted by varicocele, with varicocele being implicated as a causal factor in many infertile males. While treatment of varicocele is not appropriate or necessary in all cases, an improved understanding of ultrastructural changes and improvement following varicocelectomy may argue for varicocele treatment in most men.
| Men with Clinical Varicocele|| |
Numerous studies, including several randomized controlled trials (RCTs) support a benefit to semen parameters in infertile or subfertile men undergoing varicocelectomy, providing high-level evidence in favor of treatment ([Table 2]). In addition to individual studies, meta-analyses evaluating both prospective and randomized studies have also indicated a favorable effect of variocelectomy on semen parameters. , A recent meta-analysis quantified the improvement in several semen parameters, finding an increase in sperm density of 12.32 million sperm per ml and in motility of 10.36%, and found that varicocelectomy improves seminal oxidative stress, sperm DNA damage, and sperm ultramorphology.  These latter factors are of particular significance when discussing treatment in couples considering ART, and will be discussed in more detail below. Varicocele grade also impacts semen parameters, with higher-grade varicoceles having a more significant impact. Correspondingly greater improvements in semen parameters are observed in men with higher-grade (2 or 3) varicoceles after repair.  The effects of varicocele on semen parameters appear to be age-independent, with men ages 14 to >40 years old having similar semen parameters in the setting of varicocele. 
|Table 2: Effects of varicocele repair on semen parameters and pregnancy rates in men with clinical and subclinical varicocele in randomized controlled studies |
Click here to view
While many studies have evaluated the effects of varicocelectomy on semen parameters, fewer have addressed the impact on pregnancy rates. Several RCTs have demonstrated improvement in clinical pregnancy as a result of varicocelectomy ([Table 2]), and a 2007 meta-analysis of five studies found an odds ratio of 2.87 in favor of varicocele with respect to spontaneous pregnancy in men with clinical varicocele and at least one abnormal semen parameter treated with surgical varicocelectomy, with a number needed to treat of 5.7. 
Men with isolated sperm defects and clinical varicocele may also benefit from treatment according to a 2008 study by Boman et al. evaluating 118 infertile men with clinical varicocele and isolated asthenospermia.  In this study of 69 men undergoing varicocelectomy and 49 who were observed, varicocelectomy resulted in increases in total motile sperm count and pregnancy rate (65% vs 32% in the observation group). Men with varicocele who are in relationships with recurrent pregnancy loss may also benefit from repair. The results of a 2012 clinical trial comparing varicocelectomy to observation in men whose partners had recurrent first trimester pregnancy loss showed significant improvements in semen parameters, higher spontaneous pregnancy rates (44% vs 19%), and lower miscarriage rates (19% vs 69%).  While the authors did not assess chromatin integrity in their cohort, these results argue that varicocelectomy serves to decrease the risk of transmission of genetic defects that may arise in the setting of increased DNA damage due to varicocele. It is important to mention, however, that men in relationships experiencing recurrent pregnancy loss may carry genetic defects, and that these can be diagnosed in some cases using sperm fluorescence in situ hybridization or another genetic testing.  To better determine the optimal time frames for treatment response, a recent study by Al Bakri et al. established that semen parameters improve significantly up to 3 months after varicocelectomy, with little further improvement thereafter.  This rapid timeline to realizing the benefits of varicocele repair is important and argues for varicocele correction even in couples with advanced maternal age, where timing is critical. Thus, currently available evidence argues for varicocele repair in most men with clinical varicocele and impaired semen parameters, with demonstrated benefits regarding spontaneous pregnancy rates, arguably the most important outcome of male fertility treatment.
| Men with Subclinical Varicocele|| |
While the benefits of varicocelectomy in men with clinical varicocele are clear, the approach to men with subclinical varicocele, defined as a varicocele not palpable on physical exam and identified only using Doppler ultrasonography using a venous diameter of ≥3 mm and reversal of flow, is less obvious. However, up to 50% of infertile men without clinical varicocele may have subclinical varicocele, suggesting that subclinical varicocele contributes to infertility.  In addition, men with unilateral clinical varicocele may also have a subclinical contralateral varicocele 25% of the time.  Several studies, including RCTs, have observed improvement in semen parameters without an impact on pregnancy rates in men with subclinical varicocele ,,,,, ([Table 2]). A 1995 study comparing improvements in semen parameters and pregnancy rates after varicocelectomy in 40 infertile men with clinical varicocele and 46 infertile men with subclinical varicocele showed significant improvements in semen parameters in both groups after treatment, and no difference in clinical pregnancy rates between men with clinical and subclinical varicocele, arguing for repair in all infertile men with any type of varicocele.  A larger recent study evaluating semen parameters and pregnancy rates in 143 men with subclinical left-sided varicocele undergoing microsurgical varicocelectomy, medical treatment with L-carnitine, or observation demonstrated improvement in semen parameters and a higher pregnancy rate in both the L-carnitine and surgically treated groups, with surgery having the highest (60%) pregnancy rate relative to observation (19%).  Similarly, in a study of 42 men with subclinical varicocele randomized to varicocelectomy or clomiphene citrate therapy, more significant improvements in semen parameters were observed in the varicocelectomy group, and while there was no significant difference in pregnancy rates between groups, the varicocelectomy group reported a 12.5% pregnancy rate, whereas the medical therapy group's pregnancy rate was 6.7% (P = 0.59).  Many of the above studies have been underpowered, likely accounting at least in part for the inconsistent effects observed on pregnancy rates. As such, more work is needed to evaluate the efficacy of subclinical varicocele repair on both semen parameters as well as pregnancy rates before conclusions regarding outcomes and treatment recommendations can be made.
| Varicocele and Assisted Reproductive Technologies|| |
In men with spermatogenic failure, the use of ART may be unavoidable. However, men with nonobstructive azoospermia (NOA) and clinical varicocele represent a subset of infertile men with spermatogenic failure in whom varicocelectomy may obviate the need for ART or lessen the degree of ART needed to initiate a pregnancy. In the context of men with NOA, varicocelectomy success is defined as the presence of sperm in the ejaculate and has been variable across studies. The recent, uncontrolled retrospective literature evaluating a total of 262 patients reports the presence of any sperm in the ejaculates of 21%-56% of men postvaricocelectomy, with a maximum sperm concentration of 3.8 million ml−1 . , However, between 5% and 35% of NOA men will occasionally have sperm in the ejaculate without treatment, with relapse of azoospermia in approximately 25%. ,,, Kim et al. evaluated 28 men with a history of azoospermia with uni- or bilateral-varicocele, finding return of sperm in the ejaculate of 43% of men after varicocelectomy.  The likelihood of finding sperm in the ejaculate was directly related to testicular histology, with men with hypospermatogenesis or late maturation arrest having sperm, and men with early maturation arrest or Sertoli cell only histology having none. In this study, all couples eventually required ART to initiate pregnancy. A subsequent meta-analysis by Weedin et al. evaluating 11 studies encompassing 233 patients with NOA found motile sperm in the ejaculates of 91 (39.1%) patients after varicocelectomy with 14 (6%) spontaneous pregnancies being reported.  Again, the likelihood of sperm in the ejaculate was influenced by prerepair testicular histology, with the highest likelihood of sperm in men with hypospermatogenesis (55%) or late maturation arrest (46%), in contrast with men with early maturation arrest (0%) or Sertoli cell only (11.3%). In a 2012 study evaluating factors predicting recovery of spermatogenesis in 31 men with NOA and varicocele, testicular histology impacted the likelihood of sperm in the ejaculate, and while 32% of men had sperm in their ejaculates postvaricocelectomy, persistent recovery was found in only 19%, intermittent recovery in 6.5%, and relapse of azoospermia in 6.5%.  When considering viable sperm obtained after varicocelectomy in NOA men, one study found that of the 22% of NOA men who developed sperm in the ejaculate after varicocelectomy, <10% had viable sperm for intracytoplasmic sperm injection (ICSI), therefore requiring testicular sperm extraction (TESE).  When undergoing microsurgical TESE, however, there was no difference in sperm retrieval rates between men with NOA with and without varicocele. In contrast, others have found that varicocele repair does increase sperm retrieval rates in men with NOA undergoing ICSI. ,
In couples undergoing ART, the decision to repair a varicocele should take into consideration each couple's individual set of circumstances. In the setting of female factor infertility alone, varicocele repair is not recommended.  In couples with both male and female factor contributions, varicocelectomy may facilitate ART, independent of female partner age, with sperm being obtained from the ejaculate rather than requiring a testicular biopsy specimen.  As described above, in some men with azoospermia, varicocele repair may result in sperm in the ejaculate, obviating the need for TESE. However, recent work showed higher pregnancy rates in couples using testicular rather than ejaculated sperm, albeit in cryptozoospermic men, suggesting that a steadfast desire to use ejaculated sperm may be unwarranted.  Nevertheless, initially azoospermic men should be counseled that ART will likely be necessary to produce a pregnancy, as natural conception is relatively rare in these cases.
The molecular milieu of the sperm and egg should be given particular consideration in the setting of ART, which bypasses normal mechanisms for preventing transmission of genetic defects. Elevated levels of sperm DNA damage may impact pregnancy rates, with a recent meta-analysis demonstrating a higher likelihood of pregnancy in couples using ART when the DNA fragmentation index was in the normal range.  Earlier studies had observed variable relationships between sperm DNA integrity testing and pregnancy rates using ART, and some had observed an increased risk of spontaneous abortion when using sperm with higher levels of DNA damage. ,, Importantly, elevated levels of sperm DNA damage correlate with numerical chromosomal abnormalities, which increase the risk of birth defects in couples using ART. , Varicocele repair improves oxidative and DNA damage and sperm ultramorphology, and offers a medication-free path to higher quality sperm.
In couples using ART, the benefit of varicocelectomy on pregnancy rate remains incompletely defined, although appears to overall show a benefit. In a 2012 retrospective review evaluating 248 couples undergoing ICSI, the 169 couples in which men had undergone varicocele repair prior to ICSI did not have higher pregnancy, implantation, or miscarriage rates than the 79 couples in whom varicocele was not repaired.  In contrast, other studies have demonstrated improvement in pregnancy rates in couples using ART after variocele repair. In one study evaluating the impact of varicocelectomy on ICSI outcomes in 242 men with clinical varicocele, an increase in the number of motile sperm and a decrease in the sperm defect score was observed in men after varicocelectomy, with higher pregnancy and live birth rates in the treated group, indicating improved sperm quality in men with treated varicocele.  Similarly, a study evaluating 58 couples undergoing intrauterine insemination with the men having a history of varicocele found higher pregnancy and live birth rates in couples in which the varicoceles had been treated, despite no differences in postwash sperm counts, also supporting improvement in sperm characteristics not evaluated using current semen parameters.  Thus, varicocelectomy is likely to improve molecular features of sperm not routinely considered during contemporary infertility evaluation and treatment, but nonetheless essential for optimal outcomes.
When considering the comprehensive landscape of fertility treatment, varicocele repair may offer a permanent solution to male factor infertility or may shift the level of ART necessary to achieve pregnancy down.  In addition, varicocelectomy is significantly more cost effective than ICSI, with the cost per delivery after varicocelectomy estimated at $26 268, in comparison with $89 091 for ICSI, and with no difference in efficacy rates per pregnancy between the two approaches. 
| Adolescent Males with Varicocele - A Contemporary Perspective|| |
While an abundance of literature exists on the prevalence and effects of varicocele in the adult population, comparatively few data exist on the effects of varicocele in young males. Given the relatively recent findings linking varicocele to androgen deficiency and hypogonadism, as well as the clearly defined relationship between varicocele and male fertility, a discussion of the effects of varicocele and treatment considerations in adolescent males is appropriate. Varicoceles are found in <1% of prepubertal boys but are diagnosed in 15%-20% of postpubertal 12-18 year old males.  The decision to treat varicoceles in the adolescent population is variable and the current best-practice policy on varicocele and infertility from the AUA and American Society for Reproductive Medicine indicates treatment only for adolescents who have varicocele and objective evidence of reduced ipsilateral testicular size.  Other indications for varicocele repair in adolescent males include ipsilateral testicular discomfort and semen abnormalities, although these indications are not universally agreed upon.
In young males with varicocele but without testicular discomfort, the decision to treat is a topic of debate, though many believe testicular asymmetry to be a harbinger of testicular dysfunction.  Similar to findings in adults, varicocele has been shown to progressively decrease sperm motility and vitality in 17-19 years old untreated males followed with serial semen analyses.  A contemporary survey of pediatric urologists found that the majority of pediatric patients with varicoceles are observed, with indications for intervention paralleling those above.  Few pediatric urologists consider hypogonadism or androgen deficiency as an indication for varicocelectomy in this population, highlighting a possible knowledge deficit regarding the link between hypogonadism and varicocele. These findings also highlight the paucity of data evaluating the effects of varicocele in young men.
In the setting of the testicular asymmetry, varicocele repair appears to result in "catch-up" testicular growth and improvement in sperm count.  A large 2012 meta-analysis encompassing 14 studies and 1475 patients evaluating the effect of varicocelectomy on testicular catch-up growth in adolescents with testicular volume discrepancy showed a significant reduction in volume differential after varicocelectomy, albeit in the absence of semen analysis data.  However, when using testicular size discrepancy as a possible indication for varicocele treatment, one must consider that testicular growth in young men is variable between sides, and a causal link between testicular asymmetry and varicocele cannot definitively be established. , Thus, the use of testicular volume as a surrogate for global testicular function is inaccurate, and the ultimate impact of varicocele and its treatment on fertility and pregnancy rates in adolescents remains unknown in the absence of longitudinal studies.
Relatively few studies have evaluated the effects of varicocele on semen parameters in young men, although current data do suggest a detrimental effect. A recent meta-analysis evaluated the natural history of varicocele in terms of the effect of varicocele as well as varicocelectomy on semen parameters in males 15-24 years old, finding that across 10 studies encompassing 357 varicocele and 427 control patients, varicocele correlated with decreases in sperm density, motility, and normal morphology.  In 10 additional studies encompassing 379 treated and 270 untreated men with varicocele, significant improvements in sperm density and motility were observed in treated men. Together, these results suggest that varicoceles have similar repercussions in adults and young men with respect to fertility, with similar benefits from treatment.
Given that there are ethical considerations in obtaining semen analyses in young males not presenting for fertility evaluation, an alternative approach to assessing testicular function is evaluation of gonadotropin levels. Guarino et al. correlated testicular size, gonadotropin levels, and semen parameters in adolescents, finding higher gonadotropin levels in patients with abnormal semen parameters and no correlation with testicular size measurements.  In a more recent study, Deshpande et al. evaluated the reliability of testicular catch-up growth as a marker of normal testicular function in men 18-27 years old who underwent laparoscopic varicocelectomy between 11 and 16 years old.  Using FSH levels, scrotal ultrasonography, and semen analysis, the authors found that an elevated FSH level postoperatively predicts poor testicular function and does not correlate with testicular size. Similar to adults, lower serum inhibin B levels have also been observed in adolescents with varicocele relative to controls in a small study of 16 adolescent males with varicocele and 13 controls.  Unlike with the Guarino study, no differences in testosterone, luteinizing hormone or FSH were observed between groups.
No data from adolescent males are currently available supporting a relationship between varicocele and hypogonadism or androgen deficiency. However, a study examining the effects of varicocele repair in men grouped by age found a significant rise in testosterone in men <30 years old, as well as in all other age groups evaluated, after repair, indicating an age-independent effect.  Available evidence also indicates that varicocele repair results in testicular growth correlating with increased serum testosterone, supporting the relationship between testicular catch-up growth and a rise in serum testosterone. 
While current evidence does not support intervention in cases of adolescent varicocele based on the same criteria used in treating adults, the growing body of evidence supporting an impact of varicocele on adolescent fertility and testicular function in a time-dependent manner should prompt further study and continued discussion of management practices in the pediatric population.
| Conclusion|| |
The impact of varicocele on male fertility continues to grow clearer with additional work, particularly with regards to the positive impact of varicocele repair on semen parameters and pregnancy rates. Integral to this is likely the beneficial molecular effects of varicocele repair on sperm and the testicular microenvironment. As such, our growing understanding of the relationship between varicocele and hypogonadism is likely to benefit from the foundation that studies focused on male infertility have built, and reinforce the molecular effects of varicocele and its treatment in considering patients, particularly younger men, presenting with varicocele. In pediatric populations, relatively little work has linked varicocele to male fertility or semen parameters, but studies suggest that the effects parallel those in adults. With a growing understanding of the pathophysiology and effects of varicocele in both adults and adolescents, treatment guidelines can be adjusted and optimized.
| Acknowledgments|| |
AWP is an NIH Men's Reproductive Health Research K12 scholar (HD073917), and a Urology Care Foundation Russell Scott, Jr., MD, Resident Research Award recipient.
| References|| |
Agarwal A, Deepinder F, Cocuzza M, Agarwal R, Short RA, et al.
Efficacy of varicocelectomy in improving semen parameters: new meta-analytical approach. Urology
2007; 70: 532-8.
Nagler H, Luntz R, FG. Varicocele. In: Lipshultz L, Howards S, editors. Infertility in the Male. St. Louis: Mosby Year Book; 1997. p. 336-59.
Witt MA, Lipshultz LI. Varicocele: a progressive or static lesion? Urology
1993; 42: 541-3.
Czaplicki M, Bablok L, Janczewski Z. Varicocelectomy in patients with azoospermia. Arch Androl
1979; 3: 51-5.
Sigman M. There is more than meets the eye with varicoceles: current and emerging concepts in pathophysiology, management, and study design. Fertil Steril
2011; 96: 1281-2.
Ficarra V, Crestani A, Novara G, Mirone V. Varicocele repair for infertility: what is the evidence? Curr Opin Urol
2012; 22: 489-94.
Tanrikut C, Goldstein M, Rosoff JS, Lee RK, Nelson CJ, et al
. Varicocele as a risk factor for androgen deficiency and effect of repair. BJU Int
2011; 108: 1480-4.
Gat Y, Bachar GN, Zukerman Z, Belenky A, Gornish M. Varicocele: a bilateral disease. Fertil Steril
2004; 81: 424-9.
Masson P, Brannigan RE. The varicocele. Urol Clin North Am
Turner TT. Varicocele: still an enigma. J Urol
1983; 129: 695-9.
Ahlberg NE, Bartley O, Chidekel N. Right and left gonadal veins. An anatomical and statistical study. Acta Radiol Diagn (Stockh)
1966; 4: 593-601.
Braedel HU, Steffens J, Ziegler M, Polsky MS, Platt ML. A possible ontogenic etiology for idiopathic left varicocele. J Urol
1994; 151: 62-6.
Comhaire F, Zalata A, Schoonjans F. Varicocele: indications for treatment. Int J Androl
1995; 18 Suppl 2: 67-71.
Dubin L, Amelar RD. Surgical therapy for male infertility. J Reprod Med
1977; 18: 211-7.
Grillo-López AJ. Primary right varicocele. J Urol
1971; 105: 540-1.
Etriby AA, Ibrahim AA, Mahmoud KZ, Elhaggar S. Subfertility and varicocele. I. Venogram demonstration of anastomosis sites in subfertile men. Fertil Steril
1975; 26: 1013-7.
Coolsaet BL. The varicocele syndrome: venography determining the optimal level for surgical management. J Urol
1980; 124: 833-9.
Raman JD, Walmsley K, Goldstein M. Inheritance of varicoceles. Urology
2005; 65: 1186-9.
Dahl EV, Herrick JF. A vascular mechanism for maintaining testicular temperature by counter-current exchange. Surg Gynecol Obstet
1959; 108: 697-705.
Zorgniotti AW, Macleod J. Studies in temperature, human semen quality, and varicocele. Fertil Steril
1973; 24: 854-63.
Goldstein M, Eid JF. Elevation of intratesticular and scrotal skin surface temperature in men with varicocele. J Urol
1989; 142: 743-5.
Lue YH, Hikim AP, Swerdloff RS, Im P, Taing KS, et al.
Single exposure to heat induces stage-specific germ cell apoptosis in rats: role of intratesticular testosterone on stage specificity. Endocrinology
1999; 140: 1709-17.
Yin Y, Hawkins KL, DeWolf WC, Morgentaler A. Heat stress causes testicular germ cell apoptosis in adult mice. J Androl
1997; 18: 159-65.
Shiraishi K, Takihara H, Matsuyama H. Elevated scrotal temperature, but not varicocele grade, reflects testicular oxidative stress-mediated apoptosis. World J Urol
2010; 28: 359-64.
Mieusset R, Bujan L, Mondinat C, Mansat A, Pontonnier F, et al
. Association of scrotal hyperthermia with impaired spermatogenesis in infertile men. Fertil Steril
1987; 48: 1006-11.
Mieusset R, Grandjean H, Mansat A, Pontonnier F. Inhibiting effect of artificial cryptorchidism on spermatogenesis. Fertil Steril
1985; 43: 589-94.
Khera M, Lipshultz LI. Evolving approach to the varicocele. Urol Clin North Am
2008; 35: 183-9, viii.
Allamaneni SS, Naughton CK, Sharma RK, Thomas AJ Jr, Agarwal A. Increased seminal reactive oxygen species levels in patients with varicoceles correlate with varicocele grade but not with testis size. Fertil Steril
2004; 82: 1684-6.
MacLeod J. Seminal cytology in the presence of varicocele. Fertil Steril
1965; 16: 735-57.
Ozbek E, Yurekli M, Soylu A, Davarci M, Balbay MD. The role of adrenomedullin in varicocele and impotence. BJU Int
2000; 86: 694-8.
Fretz PC, Sandlow JI. Varicocele: current concepts in pathophysiology, diagnosis, and treatment. Urol Clin North Am
2002; 29: 921-37.
Hendin BN, Kolettis PN, Sharma RK, Thomas AJ Jr, Agarwal A. Varicocele is associated with elevated spermatozoal reactive oxygen species production and diminished seminal plasma antioxidant capacity. J Urol
1999; 161: 1831-4.
Gilbert BR, Witkin SS, Goldstein M. Correlation of sperm-bound immunoglobulins with impaired semen analysis in infertile men with varicoceles. Fertil Steril
1989; 52: 469-73.
Fujisawa M, Yoshida S, Matsumoto O, Kojima K, Kamidono S. Deoxyribonucleic acid polymerase activity in the testes of infertile men with varicocele. Fertil Steril
1988; 50: 795-800.
Mieusset R, Bujan L. Testicular heating and its possible contributions to male infertility: a review. Int J Androl
1995; 18: 169-84.
Simsek F, Türkeri L, Cevik I, Bircan K, Akdas A. Role of apoptosis in testicular tissue damage caused by varicocele. Arch Esp Urol
1998; 51: 947-50.
Tulloch WS. Varicocele in subfertility: results of treatment 1955. J Urol
2001; 166: 2032-3.
Lipshultz LI, Corriere JN Jr. Progressive testicular atrophy in the varicocele patient. J Urol
1977; 117: 175-6.
Johnsen SG, Agger P. Quantitative evaluation of testicular biopsies before and after operation for varicocele. Fertil Steril
1978; 29: 58-63.
Ayodeji O, Baker HW. Is there a specific abnormality of sperm morphology in men with varicoceles? Fertil Steril
1986; 45: 839-42.
Rodriguez-Rigau LJ, Smith KD, Steinberger E. Varicocele and the morphology of spermatozoa. Fertil Steril
1981; 35: 54-7.
Portuondo JA, Calabozo M, Echanojauregui AD. Morphology of spermatozoa in infertile men with and without varicocele. J Androl
1983; 4: 312-5.
Schatte EC, Hirshberg SJ, Fallick ML, Lipschultz LI, Kim ED. Varicocelectomy improves sperm strict morphology and motility. J Urol
1998; 160: 1338-40.
Vazquez-Levin MH, Friedmann P, Goldberg SI, Medley NE, Nagler HM. Response of routine semen analysis and critical assessment of sperm morphology by Kruger classification to therapeutic varicocelectomy. J Urol
1997; 158: 1804-7.
Vigil P, Wöhler C, Bustos-Obregón E, Comhaire F, Morales P. Assessment of sperm function in fertile and infertile men. Andrologia
1994; 26: 55-60.
Cedenho AP, Spaine DM, Barradas V, Srougi M, Oehninger S. Adolescents with varicocele have an impaired sperm-zona pellucida binding capacity. Fertil Steril
2002; 78: 1339-40.
Moustafa MH, Sharma RK, Thornton J, Mascha E, Abdel-Hafez MA, et al.
Relationship between ROS production, apoptosis and DNA denaturation in spermatozoa from patients examined for infertility. Hum Reprod
2004; 19: 129-38.
de Lamirande E, Gagnon C. Impact of reactive oxygen species on spermatozoa: a balancing act between beneficial and detrimental effects. Hum Reprod
1995; 10 Suppl 1: 15-21.
de Lamirande E, Jiang H, Zini A, Kodama H, Gagnon C. Reactive oxygen species and sperm physiology. Rev Reprod
1997; 2: 48-54.
Kemal Duru N, Morshedi M, Oehninger S. Effects of hydrogen peroxide on DNA and plasma membrane integrity of human spermatozoa. Fertil Steril
2000; 74: 1200-7.
Zini A, Dohle G. Are varicoceles associated with increased deoxyribonucleic acid fragmentation? Fertil Steril
2011; 96: 1283-7.
Mostafa T, Anis TH, El-Nashar A, Imam H, Othman IA. Varicocelectomy reduces reactive oxygen species levels and increases antioxidant activity of seminal plasma from infertile men with varicocele. Int J Androl
2001; 24: 261-5.
Smit M, Romijn JC, Wildhagen MF, Veldhoven JL, Weber RF, et al
. Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate. J Urol
2013; 189: S146-50.
Chen SS, Huang WJ, Chang LS, Wei YH. Attenuation of oxidative stress after varicocelectomy in subfertile patients with varicocele. J Urol
2008; 179: 639-42.
Zini A, Azhar R, Baazeem A, Gabriel MS. Effect of microsurgical varicocelectomy on human sperm chromatin and DNA integrity: a prospective trial. Int J Androl
2011; 34: 14-9.
Kobori Y, Ota S, Sato R, Yagi H, Soh S, et al.
Antioxidant cosupplementation therapy with vitamin C, vitamin E, and coenzyme Q10 in patients with oligoasthenozoospermia. Arch Ital Urol Androl
2014; 86: 1-4.
Zini A, Al-Hathal N. Antioxidant therapy in male infertility: fact or fiction? Asian J Androl
2011; 13: 374-81.
Oliva A, Dotta A, Multigner L. Pentoxifylline and antioxidants improve sperm quality in male patients with varicocele. Fertil Steril
2009; 91: 1536-9.
Khosravanian N, Razi M, Farokhi F, Khosravanian H. Testosterone and vitamin E administration up-regulated varicocele-reduced Hsp70-2 protein expression and ameliorated biochemical alterations. J Assist Reprod Gene
t 2014; 31: 341-54.
Marsman JW, Brand R, Schats R, Bernardus RE. Clinical and subclinical varicocele: a useful distinction? Eur J Obstet Gynecol Reprod Biol
1995; 60: 165-9.
Parikh FR, Kamat SA, Kodwaney GG, Balaiah D. Computer-assisted semen analysis parameters in men with varicocele: is surgery helpful? Fertil Steril
1996; 66: 440-5.
Schlesinger MH, Wilets IF, Nagler HM. Treatment outcome after varicocelectomy. A critical analysis. Urol Clin North Am
1994; 21: 517-29.
Macleod J. Further observations on the role of varicocele in human male infertility. Fertil Steril
1969; 20: 545-63.
Vydra G. Miltinuclear spermatides observed in varicocele. Morphol Igazsagugyi Orv Sz
1978; 18: 161-5.
Cameron DF, Snydle FE, Ross MH, Drylie DM. Ultrastructural alterations in the adluminal testicular compartment in men with varicocele. Fertil Steril
1980; 33: 526-33.
Zini A, Defreitas G, Freeman M, Hechter S, Jarvi K. Varicocele is associated with abnormal retention of cytoplasmic droplets by human spermatozoa. Fertil Steril
2000; 74: 461-4.
Terquem A, Dadoune JP. Morphological findings in varicocele: an ultrastructural study of 30 bilateral testicular biopsies. Int J Androl
1981; 4: 515-31.
Reichart M, Eltes F, Soffer Y, Zigenreich E, Yogev L, et al
. Sperm ultramorphology as a pathophysiological indicator of spermatogenesis in males suffering from varicocele. Andrologia
2000; 32: 139-45.
Gomez E, Buckingham DW, Brindle J, Lanzafame F, Irvine DS, et al
. Development of an image analysis system to monitor the retention of residual cytoplasm by human spermatozoa: correlation with biochemical markers of the cytoplasmic space, oxidative stress, and sperm function. J Androl
1996; 17: 276-87.
Keating J, Grundy CE, Fivey PS, Elliott M, Robinson J. Investigation of the association between the presence of cytoplasmic residues on the human sperm midpiece and defective sperm function. J Reprod Fertil
1997; 110: 71-7.
Fischer MA, Willis J, Zini A. Human sperm DNA integrity: correlation with sperm cytoplasmic droplets. Urology
2003; 61: 207-11.
Blumer CG, Fariello RM, Restelli AE, Spaine DM, Bertolla RP, et al
. Sperm nuclear DNA fragmentation and mitochondrial activity in men with varicocele. Fertil Steril
2008; 90: 1716-22.
Baazeem A, Belzile E, Ciampi A, Dohle G, Jarvi K, et al.
Varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. Eur Urol
2011; 60: 796-808.
Hudson RW. The endocrinology of varicoceles. Fertil Steril
1988; 49: 199-208.
Cayan S, Kadioglu A, Orhan I, Kandirali E, Tefekli A, et al
. The effect of microsurgical varicocelectomy on serum follicle stimulating hormone, testosterone and free testosterone levels in infertile men with varicocele. BJU Int
1999; 84: 1046-9.
Fujisawa M, Dobashi M, Yamasaki T, Kanzaki M, Okada H, et al.
Significance of serum inhibin B concentration for evaluating improvement in spermatogenesis after varicocelectomy. Hum Reprod
2001; 16: 1945-9.
Li H, Dubocq F, Jiang Y, Tiguert R, Gheiler EL, et al
. Effect of surgically induced varicocele on testicular blood flow and Sertoli cell function. Urology
1999; 53: 1258-62.
Kosar A, Sarica K, Ozdiler E. Effect of varicocelectomy on seminal plasma transferrin values: a comparative clinical trial. Andrologia
2000; 32: 19-22.
El-Kamshoushi AM, Zohdy NI, Abou Khedr NA, Nabhan SA, Mostafa T. Ultrastructure of the seminiferous tubules in oligoasthenoteratozoospermic men associated with varicocele. Andrologia
2013; 45: 319-25.
Sirvent JJ, Bernat R, Navarro MA, Rodriguez Tolra J, Guspi R, et al
. Leydig cell in idiopathic varicocele. Eur Urol
1990; 17: 257-61.
Andó S, Giacchetto C, Beraldi E, Panno ML, Carpino A, et al.
Testosterone and dihydrotestosterone seminal plasma levels in varicocele patients. Andrologia
1983; 15: 374-9.
Younes AK. Low plasma testosterone in varicocele patients with impotence and male infertility. Arch Androl
2000; 45: 187-95.
Hudson RW, Hayes KA, Crawford VA, McKay DE. Seminal plasma testosterone and dihydrotestosterone levels in men with varicoceles. Int J Androl
1983; 6: 135-42.
Swerdloff RS, Walsh PC. Pituitary and gonadal hormones in patients with varicocele. Fertil Steril
1975; 26: 1006-12.
The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. World Health Organization. Fertil Steril
1992; 57: 1289-93.
Su LM, Goldstein M, Schlegel PN. The effect of varicocelectomy on serum testosterone levels in infertile men with varicoceles. J Urol
1995; 154: 1752-5.
Gat Y, Gornish M, Belenky A, Bachar GN. Elevation of serum testosterone and free testosterone after embolization of the internal spermatic vein for the treatment of varicocele in infertile men. Hum Reprod
2004; 19: 2303-6.
Hurtado de Catalfo GE, Ranieri-Casilla A, Marra FA, de Alaniz MJ, Marra CA. Oxidative stress biomarkers and hormonal profile in human patients undergoing varicocelectomy. Int J Androl
2007; 30: 519-30.
Tanrikut C, Choi J, Lee R, Benjamin J, Mulhall J, et al
. Varicocele is a risk factor for androgen deficiency. Fertil Steril
2007; 88: S386.
Hsiao W, Rosoff JS, Pale JR, Powell JL, Goldstein M. Varicocelectomy is associated with increases in serum testosterone independent of clinical grade. Urology
2013; 81: 1213-7.
Di Bisceglie C, Bertagna A, Baldi M, Lanfranco F, Tagliabue M, et al.
Varicocele sclerotherapy improves serum inhibin B levels and seminal parameters. Int J Androl
2007; 30: 531-6.
Abdel-Meguid TA, Farsi HM, Al-Sayyad A, Tayib A, Mosli HA, et al
. Effects of varicocele on serum testosterone and changes of testosterone after varicocelectomy: a prospective controlled study. Urology
2014; 84: 1081-7.
Hsiao W, Rosoff JS, Pale JR, Greenwood EA, Goldstein M. Older age is associated with similar improvements in semen parameters and testosterone after subinguinal microsurgical varicocelectomy. J Urol
2011; 185: 620-5.
Liu JS, Jones M, Casey JT, Fuchs AB, Cashy J, et al
. Diagnosis of varicoceles in men undergoing vasectomy may lead to earlier detection of hypogonadism. Urology
2014; 83: 1322-5.
Sathya Srini V, Belur Veerachari S. Does varicocelectomy improve gonadal function in men with hypogonadism and infertility? Analysis of a prospective study. Int J Endocrinol
2011; 2011: 916380.
Zohdy W, Ghazi S, Arafa M. Impact of varicocelectomy on gonadal and erectile functions in men with hypogonadism and infertility. J Sex Med
2011; 8: 885-93.
Zheng YQ, Zhang XB, Zhou JQ, Cheng F, Rao T, et al
. The effects of artery-ligating and artery-preserving varicocelectomy on the ipsilateral testes in rats. Urology
2008; 72: 1179-84.
Kim KH, Lee JY, Kang DH, Lee H, Seo JT, et al
. Impact of surgical varicocele repair on pregnancy rate in subfertile men with clinical varicocele and impaired semen quality: a meta-analysis of randomized clinical trials. Korean J Urol
2013; 54: 703-9.
Steckel J, Dicker AP, Goldstein M. Relationship between varicocele size and response to varicocelectomy. J Urol
1993; 149: 769-71.
Andrade-Rocha FT. Significance of sperm characteristics in the evaluation of adolescents, adults and older men with varicocele. J Postgrad Med
2007; 53: 8-13.
Marmar JL, Agarwal A, Prabakaran S, Agarwal R, Short RA, et al.
Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. Fertil Steril
2007; 88: 639-48.
Boman JM, Libman J, Zini A. Microsurgical varicocelectomy for isolated asthenospermia. J Urol
2008; 180: 2129-32.
Mansour Ghanaie M, Asgari SA, Dadrass N, Allahkhah A, Iran-Pour E, et al
. Effects of varicocele repair on spontaneous first trimester miscarriage: a randomized clinical trial. Urol J
2012; 9: 505-13.
Hwang K, Weedin JW, Lamb DJ. The use of fluorescent in situ
hybridization in male infertility. Ther Adv Urol
2010; 2: 157-69.
Al Bakri A, Lo K, Grober E, Cassidy D, Cardoso JP, et al
. Time for improvement in semen parameters after varicocelectomy. J Urol
2012; 187: 227-31.
Yarborough MA, Burns JR, Keller FS. Incidence and clinical significance of subclinical scrotal varicoceles. J Urol
1989; 141: 1372-4.
McClure RD, Hricak H. Scrotal ultrasound in the infertile man: detection of subclinical unilateral and bilateral varicoceles. J Urol
1986; 135: 711-5.
Jarow JP, Ogle SR, Eskew LA. Seminal improvement following repair of ultrasound detected subclinical varicoceles. J Urol
1996; 155: 1287-90.
McClure RD, Khoo D, Jarvi K, Hricak H. Subclinical varicocele: the effectiveness of varicocelectomy. J Urol
1991; 145: 789-91.
Yamamoto M, Hibi H, Hirata Y, Miyake K, Ishigaki T. Effect of varicocelectomy on sperm parameters and pregnancy rate in patients with subclinical varicocele: a randomized prospective controlled study. J Urol
1996; 155: 1636-8.
Grasso M, Lania C, Castelli M, Galli L, Franzoso F, et al
. Low-grade left varicocele in patients over 30 years old: the effect of spermatic vein ligation on fertility. BJU Int
2000; 85: 305-7.
Unal D, Yeni E, Verit A, Karatas OF. Clomiphene citrate versus varicocelectomy in treatment of subclinical varicocele: a prospective randomized study. Int J Urol
2001; 8: 227-30.
Seo JT, Kim KT, Moon MH, Kim WT. The significance of microsurgical varicocelectomy in the treatment of subclinical varicocele. Fertil Steril
2010; 93: 1907-10.
Berookhim BM, Schlegel PN. Azoospermia due to spermatogenic failure. Urol Clin North Am
2014; 41: 97-113.
Mehta A, Goldstein M. Varicocele repair for nonobstructive azoospermia. Curr Opin Urol
2012; 22: 507-12.
Ron-El R, Strassburger D, Friedler S, Komarovski D, Bern O, et al.
Extended sperm preparation: an alternative to testicular sperm extraction in non-obstructive azoospermia. Hum Reprod
1997; 12: 1222-6.
Schlegel PN, Kaufmann J. Role of varicocelectomy in men with nonobstructive azoospermia. Fertil Steril
2004; 81: 1585-8.
Pasqualotto FF, Sobreiro BP, Hallak J, Pasqualotto EB, Lucon AM. Induction of spermatogenesis in azoospermic men after varicocelectomy repair: an update. Fertil Steril
2006; 85: 635-9.
Gat Y, Bachar GN, Everaert K, Levinger U, Gornish M. Induction of spermatogenesis in azoospermic men after internal spermatic vein embolization for the treatment of varicocele. Hum Reprod
2005; 20: 1013-7.
Kim ED, Leibman BB, Grinblat DM, Lipshultz LI. Varicocele repair improves semen parameters in azoospermic men with spermatogenic failure. J Urol
1999; 162: 737-40.
Weedin JW, Khera M, Lipshultz LI. Varicocele repair in patients with nonobstructive azoospermia: a meta-analysis. J Urol
2010; 183: 2309-15.
Abdel-Meguid TA. Predictors of sperm recovery and azoospermia relapse in men with nonobstructive azoospermia after varicocele repair. J Urol
2012; 187: 222-6.
Haydardedeoglu B, Turunc T, Kilicdag EB, Gul U, Bagis T. The effect of prior varicocelectomy in patients with nonobstructive azoospermia on intracytoplasmic sperm injection outcomes: a retrospective pilot study. Urology
2010; 75: 83-6.
Inci K, Hascicek M, Kara O, Dikmen AV, Gürgan T, et al
. Sperm retrieval and intracytoplasmic sperm injection in men with nonobstructive azoospermia, and treated and untreated varicocele. J Urol
2009; 182: 1500-5.
O'Brien JH, Bowles B, Kamal KM, Jarvi K, Zini A. Microsurgical varicocelectomy for infertile couples with advanced female age: natural history in the era of ART. J Androl
2004; 25: 939-43.
Ben-Ami I, Raziel A, Strassburger D, Komarovsky D, Ron-El R, et al
. Intracytoplasmic sperm injection outcome of ejaculated versus extracted testicular spermatozoa in cryptozoospermic men. Fertil Steril
2013; 99: 1867-71.
Zhang Z, Zhu L, Jiang H, Chen H, Chen Y, et al
. Sperm DNA fragmentation index and pregnancy outcome after IVF or ICSI: a meta-analysis. J Assist Reprod Genet
2015; 32: 17-26.
Collins JA, Barnhart KT, Schlegel PN. Do sperm DNA integrity tests predict pregnancy with in vitro
fertilization? Fertil Steril
2008; 89: 823-31.
Zini A, Boman JM, Belzile E, Ciampi A. Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis. Hum Reprod
2008; 23: 2663-8.
Lin MH, Kuo-Kuang Lee R, Li SH, Lu CH, Sun FJ, et al
. Sperm chromatin structure assay parameters are not related to fertilization rates, embryo quality, and pregnancy rates in in vitro
fertilization and intracytoplasmic sperm injection, but might be related to spontaneous abortion rates. Fertil Steril
2008; 90: 352-9.
Enciso M, Alfarawati S, Wells D. Increased numbers of DNA-damaged spermatozoa in samples presenting an elevated rate of numerical chromosome abnormalities. Hum Reprod
2013; 28: 1707-15.
Simpson JL, Lamb DJ. Genetic effects of intracytoplasmic sperm injection. Semin Reprod Med
2001; 19: 239-49.
Pasqualotto FF, Braga DP, Figueira RC, Setti AS, Iaconelli A Jr, et al
. Varicocelectomy does not impact pregnancy outcomes following intracytoplasmic sperm injection procedures. J Androl
2012; 33: 239-43.
Esteves SC, Oliveira FV, Bertolla RP. Clinical outcome of intracytoplasmic sperm injection in infertile men with treated and untreated clinical varicocele. J Urol
2010; 184: 1442-6.
Daitch JA, Bedaiwy MA, Pasqualotto EB, Hendin BN, Hallak J, et al.
Varicocelectomy improves intrauterine insemination success rates in men with varicocele. J Urol
2001; 165: 1510-3.
Cayan S, Erdemir F, Ozbey I, Turek PJ, Kadioglu A, et al
. Can varicocelectomy significantly change the way couples use assisted reproductive technologies? J Urol
2002; 167: 1749-52.
Schlegel PN. Is assisted reproduction the optimal treatment for varicocele-associated male infertility? A cost-effectiveness analysis. Urology
1997; 49: 83-90.
Meacham RB, Townsend RR, Rademacher D, Drose JA. The incidence of varicoceles in the general population when evaluated by physical examination, gray scale sonography and color Doppler sonography. J Urol
1994; 151: 1535-8.
Practice Committee of American Society for Reproductive Medicine. Report on varicocele and infertility. Fertil Steril
2008; 90: S247-9.
Fine RG, Poppas DP. Varicocele: standard and alternative indications for repair. Curr Opin Urol
2012; 22: 513-6.
Paduch DA, Niedzielski J. Semen analysis in young men with varicocele: preliminary study. J Urol
1996; 156: 788-90.
Pastuszak AW, Kumar V, Shah A, Roth DR. Diagnostic and management approaches to pediatric and adolescent varicocele: a survey of pediatric urologists. Urology
2014; 84: 450-5.
Laven JS, Haans LC, Mali WP, te Velde ER, Wensing CJ, et al
. Effects of varicocele treatment in adolescents: a randomized study. Fertil Steril
1992; 58: 756-62.
Li F, Chiba K, Yamaguchi K, Okada K, Matsushita K, et al.
Effect of varicocelectomy on testicular volume in children and adolescents: a meta-analysis. Urology
2012; 79: 1340-5.
Korets R, Woldu SL, Nees SN, Spencer BA, Glassberg KI. Testicular symmetry and adolescent varicocele - does it need followup? J Urol
2011; 186: 1614-8.
Poon SA, Gjertson CK, Mercado MA, Raimondi PM, Kozakowski KA, et al
. Testicular asymmetry and adolescent varicoceles managed expectantly. J Urol
2010; 183: 731-4.
Nork JJ, Berger JH, Crain DS, Christman MS. Youth varicocele and varicocele treatment: a meta-analysis of semen outcomes. Fertil Steril
2014; 102: 381-387.e6.
Guarino N, Tadini B, Bianchi M. The adolescent varicocele: the crucial role of hormonal tests in selecting patients with testicular dysfunction. J Pediatr Surg
2003; 38: 120-3.
Deshpande A, Cohen R, Tsang I, Ambler G, Fleming S. The validity of testicular catch-up growth and serum FSH levels in the long-term postoperative assessment of laparoscopic varicocele correction in adolescents. Urol Ann
2011; 3: 29-32.
Romeo C, Arrigo T, Impellizzeri P, Manganaro A, Antonuccio P, et al.
Altered serum inhibin b levels in adolescents with varicocele. J Pediatr Surg
2007; 42: 390-4.
Lee RK, Li PS, Goldstein M. Simultaneous vasectomy and varicocelectomy: indications and technique. Urology
2007; 70: 362-5.
Rodriguez Peña M, Alescio L, Russell A, Lourenco da Cunha J, Alzu G, et al
. Predictors of improved seminal parameters and fertility after varicocele repair in young adults. Andrologia
2009; 41: 277-81.
Nilsson S, Edvinsson A, Nilsson B. Improvement of semen and pregnancy rate after ligation and division of the internal spermatic vein: fact or fiction? Br J Urol
1979; 51: 591-6.
Madgar I, Weissenberg R, Lunenfeld B, Karasik A, Goldwasser B. Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil Steril
1995; 63: 120-4.
Nieschlag E, Hertle L, Fischedick A, Abshagen K, Behre HM. Update on treatment of varicocele: counselling as effective as occlusion of the vena spermatica. Hum Reprod
1998; 13: 2147-50.
Krause W, Müller HH, Schäfer H, Weidner W. Does treatment of varicocele improve male fertility? results of the 'Deutsche Varikozelenstudie', a multicentre study of 14 collaborating centres. Andrologia
2002; 34: 164-71.
Al-Kandari AM, Shabaan H, Ibrahim HM, Elshebiny YH, Shokeir AA. Comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial. Urology
2007; 69: 417-20.
Abdel-Meguid TA, Al-Sayyad A, Tayib A, Farsi HM. Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial. Eur Urol
2011; 59: 455-61.
[Table 1], [Table 2]
|This article has been cited by|
||Seminal plasma miR-210-3p is a biomarker for screening dyszoospermia caused by varicocele
| ||Yawei Xu,Yuanyuan Zhang,Yongjiao Yang,Xiaoqiang Liu,Yegang Chen |
| ||Andrologia. 2019; : e13244 |
|[Pubmed] | [DOI]|
||Effect of royal jelly on testicular antioxidant enzymes activity, MDA level and spermatogenesis in rat experimental Varicocele model
| ||Nematollah Asadi,Arash Kheradmand,Mohammadreza Gholami,Seyed Hojatolah Saidi,Seyed Ahmad Mirhadi |
| ||Tissue and Cell. 2019; 57: 70 |
|[Pubmed] | [DOI]|
||Alpha-Lipoic Acid improves the testicular dysfunction in rats induced by varicocele
| ||Erfaneh Shaygannia,Marziyeh Tavalaee,Gholam R. Akhavanfarid,Mahshid Rahimi,Maurizio Dattilo,Mohammad H. Nasr-Esfahani |
| ||Andrologia. 2018; : e13085 |
|[Pubmed] | [DOI]|
||Role of varicocele treatment in assisted reproductive technologies
| ||Mehmet G. Sönmez,Ahmet H. Haliloglu |
| ||Arab Journal of Urology. 2018; |
|[Pubmed] | [DOI]|
||The use of diffusion-weighted MR imaging in the functional assessment of the testes of patients with clinical varicocele
| ||Sally Emad-Eldin,Abdullah M. A. Salim,Manal Halim Wahba,Amr Tharwat Elahwany,Omar Abdelaziz |
| ||Andrologia. 2018; : e13197 |
|[Pubmed] | [DOI]|
||The clinical usefulness of a novel grading system for varicocoeles using duplex Doppler ultrasound examination based on postsurgical modifications of seminal parameters
| ||G. Cavallini,F. I. Scroppo,G. M. Colpi |
| ||Andrology. 2018; |
|[Pubmed] | [DOI]|
||Comparison of the clinical characteristics of patients with varicocele according to the presence or absence of scrotal pain
| ||Seung Ryong Baek,Hyun Jun Park,Nam Cheol Park |
| ||Andrologia. 2018; : e13187 |
|[Pubmed] | [DOI]|
||Spermiological Profile of Patients with Varicocele in Cotonou
| ||Dodji Magloire I. Yevi,Hamid Fagbemi,Jean Sossa,Michel Michaël Agounkpe,Gilles Natchagande,Josué D. G. Avakoudjo,Prince Pascal Hounnasso |
| ||Open Journal of Urology. 2017; 07(02): 40 |
|[Pubmed] | [DOI]|
||Varicocele and male infertility
| ||Christian Fuglesang S. Jensen,Peter Østergren,James M. Dupree,Dana A. Ohl,Jens Sønksen,Mikkel Fode |
| ||Nature Reviews Urology. 2017; |
|[Pubmed] | [DOI]|
||Varicocele and semen quality: a retrospective case–control study of 4230 patients from a single centre
| ||F. Pallotti,D. Paoli,T. Carlini,A. R. Vestri,G. Martino,A. Lenzi,F. Lombardo |
| ||Journal of Endocrinological Investigation. 2017; |
|[Pubmed] | [DOI]|
||Unilateral right-sided varicocele associated with pancreatic cancer: A cadaveric case report
| ||Kelly E. Davis,Charles T. Simpkin,Cindy K. Funk |
| ||Translational Research in Anatomy. 2017; 7: 1 |
|[Pubmed] | [DOI]|
||Nationwide survey of urological specialists regarding male infertility: results from a 2015 questionnaire in Japan
| ||Yasushi Yumura,Akira Tsujimura,Takashi Imamoto,Yukihiro Umemoto,Hideyuki Kobayashi,Koji Shiraishi,Takeshi Shin,Hisanori Taniguchi,Koji Chiba,Yasushi Miyagawa,Teruaki Iwamoto |
| ||Reproductive Medicine and Biology. 2017; |
|[Pubmed] | [DOI]|
||Treatment effect of TUSPLV on recurrent varicocele
| ||Tian-Zhong Yan,Xiao-Qiang Wu,Zhi-Wei Wang |
| ||Experimental and Therapeutic Medicine. 2017; 13(1): 45 |
|[Pubmed] | [DOI]|
||Does the number of veins ligated during varicococele surgery influence post-operative semen and hormone results?
| ||A. Majzoub,H. Elbardisi,M. Arafa,A. Agarwal,S. Al Said,K. Al Rumaihi |
| ||Andrology. 2016; |
|[Pubmed] | [DOI]|
||Association between clinical and ultrasonic characteristics of varicocele and lower extremity varicose vein in men
| ||Peng Qiu,binshan Zha,Huagang Zhu,wentao Xie,Xiaomao Si,Dongdong Tang,Chao Zhang |
| ||Annals of Vascular Surgery. 2016; |
|[Pubmed] | [DOI]|
||An association between sperm PLC? levels and varicocele?
| ||Elham Janghorban-Laricheh,Nasim Ghazavi-Khorasgani,Marziyeh Tavalaee,Dina Zohrabi,Homayon Abbasi,Mohammad H. Nasr- Esfahani |
| ||Journal of Assisted Reproduction and Genetics. 2016; 33(12): 1649 |
|[Pubmed] | [DOI]|