A varicocele is a dilatation of the testicular vein and the pampiniform venous plexus within the spermatic cord. Although rare in pediatric populations, the prevalence of varicoceles markedly increases with pubertal development. Varicoceles are progressive lesions that may hinder testicular growth and function over time and are the most common and correctable cause of male infertility. Approximately 40% of men with primary infertility have a varicocele, and more than half of them experience improvements in semen parameters after varicocelectomy. The decision to treat adolescents with varicocele is a controversial one. The task for pediatricians and urologists is to identify those adolescents who are at greatest risk for infertility in adulthood, in an effort to offer early surgical intervention to those most likely to benefit.
A varicocele is a dilatation of the testicular vein and the pampiniform venous plexus within the spermatic cord. Although rare in pediatric populations, the prevalence of varicoceles markedly increases with pubertal development to approximately 15% by the late teenage years, a rate similar to that in adult populations. Varicoceles are progressive lesions that may hinder testicular growth and function over time and are the most common and correctable cause of male infertility. The incidence of varicocele in men with abnormal semen is 25% compared with almost 12% in men with normal semen. Approximately 40% of men with primary infertility have a varicocele, and more than half of them experience improvements in semen parameters after varicocelectomy. However, experts continue to debate the efficacy of surgical intervention in improving fertility as evidenced by a recent Cochrane review, which suggested that “there is no evidence that treatment of varicoceles in men from couples with otherwise unexplained subfertility improves the couple’s chance of conception.” Furthermore, as only 20% of men with a documented varicocele suffer from infertility, care must be taken in the clinical evaluation of a varicocele, and treatment must be tailored to the specific subgroup of individuals most likely to benefit from a surgical intervention.
The decision to treat adolescents with varicocele is a controversial one. Most physicians agree that treating all adolescent boys with varicocele, thus subjecting a large percentage of boys to potentially unnecessary surgery, would be inappropriate, costly, and not without ethical considerations. However, waiting until patients present themselves as adults with possible irreversible infertility would be equally unacceptable. The task for pediatricians and urologists is to identify those adolescents who are at greatest risk for infertility in adulthood, in an effort to offer early surgical intervention to those most likely to benefit.
Anatomy and varicocele formation
The formation of a varicocele has been attributed predominantly to anatomic variance, increased pressure in the left renal vein, and incompetent or congenitally absent valves. Approximately 90% of varicoceles are left sided. Several anatomic differences between the right and left testicular (internal spermatic) veins are thought to contribute to this predominance. Although highly variable, the left system usually consists of 1 or more veins within the spermatic cord that coalesce in the retroperitoneal space to become the testicular vein. The left testicular vein inserts into the left renal vein at a right angle, whereas the right testicular vein joins the inferior vena cava at an oblique angle. The relative greater blood flow in the inferior vena cava is thought to augment drainage on the right. The left testicular vein, however, is 8 to 10 cm longer (more craniad) than the right, with a proportional increase in pressure head.
Increases in left renal vein pressure also have been noted secondary to 2 nutcracker phenomenon mechanisms. The proximal nutcracker phenomenon describes compression of the left renal vein as it passes between the aorta and superior mesenteric arteries. The distal mechanism involves retrograde blood flow through the deferential and external spermatic veins caused by compression of the left common iliac vein as it courses under the left common iliac artery.
Congenitally absent or incompetent valves have classically been thought to be the primary cause of varicocele formation. Subsequent research has shown that there are males without varicocele who have incompetent or absent testicular vein valves and males with varicocele who have competent valves. Even with normal valves, dilation of the testicular vein can cause functional incompetence as a result of loss of coaptation. Valve pathology may not be a sole cause, but it certainly contributes to varicocele formation and severity. Alterations in venous architecture at the microscopic level may also play a role in the pathogenesis of varicocele. However, it remains difficult to differentiate between cause and effect in anatomic analysis, as evidenced by several recent studies, which documented significant histologic changes in the amount of connective tissue present in the vein wall of the pampiniform plexus that appeared to have a linear correlation with varicocele grade.
Although the exact mechanisms have yet to be elucidated, several physical findings have been found to be associated with an increased risk for developing varicocele in adolescence. A low body mass index has been found to be associated with the development of varicocele in adolescence. Increased penile length and circumference as well as rapid pubertal development were also found to be the independent risk factors for the development of varicocele.
Pathologic findings related to testicular dysfunction in association with varicocele
The association between varicocele and testicular dysfunction has been observed by scientists and physicians for nearly 2000 years, dating back to the Greek physician, Celsus, who noted a testicular size discrepancy in the face of dilated veins within the scrotum, suggesting that the discrepancy resulted in impaired testicular nutrition. Since the idea resurfaced in medical texts in the late 1800s, varicocele has been documented in association with a variety of conditions including testicular hypotrophy, an abnormal gonadotropin axis, histologic changes within the testicle, abnormal spermatogenesis, and ultimately, infertility. However, despite the existence of a growing body of literature defining these associations, a direct causal relationship has yet to be confirmed conclusively. As such, debate continues on the pathologic effects of varicocele.
Testicular Hypotrophy
The most well-documented abnormality associated with clinical varicocele is testicular hypotrophy. A large multicenter study performed by the World Health Organization found an association between varicocele and ipsilateral testicular volume; Mori and colleagues took it a step further to define a relationship between varicocele grade and incidence of testicular hypotrophy in adolescents. Although testicular size remains an easily observable clinical phenomenon in the presence of varicocele, its relationship to testicular dysfunction, as defined by abnormal semen analysis results, remains more difficult to quantify in adolescents.
Impaired Spermatogenesis
In adults, the most common findings on semen analysis are decreased motility, decreased sperm density, and increased number of pathologic sperm forms. Furthermore, a variety of histologic changes related to testicular dysfunction have been documented in the results of testicular biopsy in males with varicocele, including Leydig cell hyperplasia, decreased number of spermatogonia per tubule, decreased spermatogenesis and maturation arrest, sloughing of germinal epithelium, and interstitial fibrosis. Because the adult testicle is composed mostly of seminiferous and germinal cells, it is not surprising to find a correlation between testicular volume and function as defined by semen analysis in this group. This correlation seems to be consistent when related to dysfunction and postoperative improvement. Although a wealth of research describes abnormal semen analysis results in the presence of varicocele, the heterogeneity of parameters used to define abnormal and the relatively large number of confounding factors related to the desired outcome (successful pregnancy) continue to complicate the debate.
Identifying Pathology in Adolescents
Although the toxic effect of varicocele on semen parameters has been demonstrated in adolescents, the correlation between testicular hypotrophy and abnormal spermatogenesis in this age group has historically been harder to quantify. Haans and colleagues reported that adolescents with pronounced left testicular growth failure had significantly reduced sperm count, but concentration, motility, and morphology were unaffected. This lack of clear association in adolescents could potentially be explained in part by the fact that left testicular growth failure occurs before significant decreases occur in semen parameters. Furthermore, there were relatively few studies to compare semen analysis in adolescents, given the difficulty in obtaining specimens in this age group and ethical questions regarding the psychological impact of their procurement. Researchers have defined a statistically significant correlation between sonographic testicular volume and decreased sperm concentration and total motile sperm counts in adolescents as well as a relation with varicocele grade. Addressing the subject of molecular dysfunction, another study documented an increase in the number of sperm with abnormal DNA and a decrease in the number of sperm with normal DNA in adolescents with high-grade varicocele, even when semen analysis result was normal.
Pathologic findings related to testicular dysfunction in association with varicocele
The association between varicocele and testicular dysfunction has been observed by scientists and physicians for nearly 2000 years, dating back to the Greek physician, Celsus, who noted a testicular size discrepancy in the face of dilated veins within the scrotum, suggesting that the discrepancy resulted in impaired testicular nutrition. Since the idea resurfaced in medical texts in the late 1800s, varicocele has been documented in association with a variety of conditions including testicular hypotrophy, an abnormal gonadotropin axis, histologic changes within the testicle, abnormal spermatogenesis, and ultimately, infertility. However, despite the existence of a growing body of literature defining these associations, a direct causal relationship has yet to be confirmed conclusively. As such, debate continues on the pathologic effects of varicocele.
Testicular Hypotrophy
The most well-documented abnormality associated with clinical varicocele is testicular hypotrophy. A large multicenter study performed by the World Health Organization found an association between varicocele and ipsilateral testicular volume; Mori and colleagues took it a step further to define a relationship between varicocele grade and incidence of testicular hypotrophy in adolescents. Although testicular size remains an easily observable clinical phenomenon in the presence of varicocele, its relationship to testicular dysfunction, as defined by abnormal semen analysis results, remains more difficult to quantify in adolescents.
Impaired Spermatogenesis
In adults, the most common findings on semen analysis are decreased motility, decreased sperm density, and increased number of pathologic sperm forms. Furthermore, a variety of histologic changes related to testicular dysfunction have been documented in the results of testicular biopsy in males with varicocele, including Leydig cell hyperplasia, decreased number of spermatogonia per tubule, decreased spermatogenesis and maturation arrest, sloughing of germinal epithelium, and interstitial fibrosis. Because the adult testicle is composed mostly of seminiferous and germinal cells, it is not surprising to find a correlation between testicular volume and function as defined by semen analysis in this group. This correlation seems to be consistent when related to dysfunction and postoperative improvement. Although a wealth of research describes abnormal semen analysis results in the presence of varicocele, the heterogeneity of parameters used to define abnormal and the relatively large number of confounding factors related to the desired outcome (successful pregnancy) continue to complicate the debate.
Identifying Pathology in Adolescents
Although the toxic effect of varicocele on semen parameters has been demonstrated in adolescents, the correlation between testicular hypotrophy and abnormal spermatogenesis in this age group has historically been harder to quantify. Haans and colleagues reported that adolescents with pronounced left testicular growth failure had significantly reduced sperm count, but concentration, motility, and morphology were unaffected. This lack of clear association in adolescents could potentially be explained in part by the fact that left testicular growth failure occurs before significant decreases occur in semen parameters. Furthermore, there were relatively few studies to compare semen analysis in adolescents, given the difficulty in obtaining specimens in this age group and ethical questions regarding the psychological impact of their procurement. Researchers have defined a statistically significant correlation between sonographic testicular volume and decreased sperm concentration and total motile sperm counts in adolescents as well as a relation with varicocele grade. Addressing the subject of molecular dysfunction, another study documented an increase in the number of sperm with abnormal DNA and a decrease in the number of sperm with normal DNA in adolescents with high-grade varicocele, even when semen analysis result was normal.
Proposed pathologic mechanisms
Although the association of clinically detectable varicocele with testicular hypotrophy, an abnormal gonadotropin axis, histologic changes, abnormal spermatogenesis, and infertility has been clearly documented in the literature, the exact mechanism whereby varicocele induces pathologic change has yet to be elucidated. Many theories have been postulated on the subject, including increased testicular temperature, hypoxia, reflux of adrenal and renal metabolites, and generation of reactive oxygen species (ROS).
Hyperthermia
Elevated scrotal and testicular temperature is the most widely accepted mechanism for testicular dysfunction. Experimentally induced varicocele increases scrotal temperature and is reversible with surgical correction. Hyperthermia has consistently been shown to negatively affect germ cell function, proliferation, and subsequent fertility. Furthermore, scrotal cooling and, consequently, testicular cooling have been documented to improve semen quality. Varicocelectomy in human studies has been shown to normalize temperature, with subsequent increases in sperm count. When comparing infertile men with varicocele to normal controls, as well as to men with varicocele and normal fertility, infertile men with varicocele were shown to have increased intrascrotal temperatures. Several studies have sought to define the molecular basis for infertility in association with elevated testicular temperatures in both adult and adolescent males with varicocele. It would seem that the downregulation of heat shock proteins may be associated with infertility in these groups. Furthermore, an increase in the expression of heat shock proteins after varicocelectomy has been documented.
Hypoxia
Although early studies did not support the proposal that venous stasis and reduced blood flow of the testicular vessels resulted in hypoxia, several recent publications have proposed a direct link between impaired testicular drainage and tissue hypoxia. These studies suggest that tissue damage is the result of impaired testicular microcirculation secondary to increased hydrostatic pressure rather than global hypoxia. This proposal has been supported by studies identifying increased expression of hypoxia-inducible factor-1 alpha in association with varicocele in human and animal models.
Reflux of Renal and Adrenal Metabolites
Reflux of adrenal and renal metabolites has been proposed as a mechanism for testicular damage in men with varicocele. Research has been inconclusive, and experimental studies have shown that toxic effects of varicocele do not require adrenal contribution and that reflux may not occur. Adrenomedullin, a potent vasodilator expressed in adrenal and kidney tissues but not in the testes, has been isolated in blood samples from the testicular veins of men with varicocele. In rat models, varicocele-induced testicular damage was found to be enhanced in subjects with viable adrenal glands when compared with those in whom a unilateral adrenalectomy was performed before varicocele induction. Further research is required to determine if adrenomedullin plays a role in the formation of or toxicity associated with varicocele.
ROS and Oxidative Stress
Venous blood from varicoceles of infertile men has shown increased production of nitric oxide, its active metabolites, and ROS that are known to play a role in sperm dysfunction. These increased levels have been shown to correlate with the severity of varicocele. Varicocele also reduces antioxidant defenses, potentially adding to the localized oxidative stress (OS). Several studies reported a decrease in markers of ROS-associated damage and an improvement in antioxidant levels after varicocelectomy. Although the relation between varicocele and OS is clear, the exact cause of OS in this case has yet to be clearly defined. Nevertheless, numerous mechanisms have been proposed to identify the origin of OS in patients with varicocele, including the role of cytokines (interleukin 1); increased expression of leptin receptors; increased nitric oxide levels resulting from hypoxia, as an inducer of apoptosis and precursor of oxidants; and downregulation of glial cell line derived–neurotrophic factor receptor (factor involved in spermatogenesis). Whether these complex mechanisms are the final common pathway for varicocele-induced infertility or an effect of testicular injury is still unknown. Although few reports exploring the administration of antioxidants in subfertile men with varicocele have been produced, the use of zinc, glutathione, and Chinese herbal remedies containing a variety of antioxidants have shown some promise.
Diagnosis
Typically, varicoceles are asymptomatic and detected in adolescents during routine physical examination. Occasionally, scrotal mass evaluations referred from primary care physicians are found to be varicoceles. Differential diagnoses for generally painless scrotal masses in adolescence include communicating hydrocele, hydrocele of the spermatic cord, inguinal hernia, epididymal cyst, and spermatocele.
Patients should be examined in a warm room in standing and supine positions and with and without a Valsalva maneuver. Classically, varicoceles are graded according to the following criteria:
Grade 1 (small): palpable only with Valsalva maneuver
Grade 2 (medium): palpable with the patient standing
Grade 3 (large): visible through scrotal skin, palpable with the patient standing.
After examining in an upright position, the patient should be reexamined in the supine position. Idiopathic varicocele is more prominent in the upright position and disappears in the supine position. Secondary varicoceles, especially on the right side, can be caused by retroperitoneal tumors or lymphadenopathy and do not change size as noticeably as in the supine position.
An important part of the physical examination in all boys with varicocele is an accurate assessment of testicular consistency (firmness) and volume. Although the assessment of testicular consistency is subjective, a careful simultaneous comparison of both testes may give the clinician additional qualitative information about the overall condition of the ipsilateral testis. Several methods are available to measure the size of the testis, including visual comparison, calipers, Prader orchidometer (comparative ovoids), Takahira orchidometer (disc elliptical rings), and ultrasonography. Measurement of testis volume has been reported to be assessed accurately and reproducibly by using either a Prader or a disc orchidometer. However, ultrasonography should be considered the standard criterion for assessing testicular volume. Results of ultrasonography have consistently shown high correlation with actual testis volume and have been highly reproducible, with improved detection of bilateral varicoceles and increased sensitivity in the evaluation of volume differentials as compared with orchidometer.
In a clinical study comparing Prader orchidometer and ultrasonography in adolescents with a varicocele, Costabile and colleagues found that 24% of patients with growth arrest would have been missed and 14% would have been identified falsely to have a significant size discrepancy if measured by Prader orchidometer alone. Diamond and colleagues noted similar superiority of ultrasonography for measuring testicular volume; they recommend annual ultrasonography of testis in adolescents with varicocele.
Identifying patients at risk
Left untreated, with time, in a subset of patients, the varicocele will continue to affect testicular growth, with loss of volume and progressive deterioration in semen parameters. In adults, treatment is straightforward and is proposed whenever (1) there is a palpable varicocele, (2) there is documented infertility, (3) it has been confirmed that there is no female infertility problem, and (4) there is at least 1 abnormality found on semen analysis. In the adolescents, significant controversy exists regarding the appropriate methods of evaluation for surgery. The diagnosis of varicocele leads to additional questions about possible infertility and the need to establish clinical criteria for varicocele repair. Currently, a variety of clinical tests are available for identifying adolescents at risk for infertility associated with varicocele. However, a consensus has yet to be reached on the most appropriate combination of tests in evaluation of adolescent varicocele. This topic remains at the forefront of debate and research. Currently, clinical tests proposed in evaluation for surgical intervention in adolescents with varicocele include (1) physical examination and radiologic evaluation, (2) biochemical tests, and (3) semen analysis.
Physical Examination and Radiologic Evaluation
Physical examination includes identification of varicocele grade and the measurement of testicular volume, as well as some novel approaches to ultrasound imaging to measure retrograde flow in the spermatic venous plexus. There remain conflicting opinions about the correlation between the grade of varicocele and its ultimate effect on the testis. Some investigators have found no correlation between varicocele grade and testicular size or semen parameters, whereas others have noticed that boys with severe varicoceles have smaller ipsilateral testis and increasingly abnormal findings in semen analysis in comparison with those adolescents with lower-grade varicoceles. In an early study involving adolescent boys and young men aged 12 to 25 years, 34% of subjects with a grade-2 varicocele had testicular changes, compared with 81% of those with grade-3 varicocele. Within the grade-3 group, the percentage of subjects aged 18 to 25 years with testicular change reached almost 98%, illustrating the progressive nature of varicocele-induced testicular damage and indicating that testicular hypotrophy is almost inevitable in males with grade-3 varicocele. Although the higher-grade varicoceles seem more concerning, varicocele grade should not be a sole determinant in recommending treatment.
There is abundant literature confirming that varicocele is associated with testicular growth arrest in adolescents and that varicocele repair results in testicular catch-up growth. The risk for testicular growth arrest also has been shown to be time dependent and to correlate with varicocele and reflux grade. However, according to a study by Zampieri and associates, involving 465 patients, only 32% of patients had complete catch-up growth. Also, Preston and colleagues determined that a statistically significant number of adolescents with varicocele and testicular-size discrepancy experience testicular catch-up growth as a normal function of development. Nevertheless, the relationship between testicular hypotrophy and infertility remains clear, and a recent study confirmed that size differentials greater than 10% between normal and hypotrophic testicles correlated with a decreased sperm concentration and total motile-sperm count. Furthermore, this difference was found to increase dramatically when the size differential reached 20%. These data would suggest that patients with a persistent size differential of greater than 20% should be offered surgical intervention without further investigation. Although a waiting period is recommended for adolescents to assess for resolution of size discrepancy, a recent study proposed that peak retrograde flow velocities of greater than 38 cm/s (found to be a predictor of persistent asymmetry), when combined with a size differential of 20% or greater, negated the need for such a waiting period.
Biochemical Tests
Biochemical tests are based on the integrity of the testis and any effect of the varicocele on the hypothalamic-pituitary axis. At the testis level, serum inhibin levels reflect the integrity of the seminiferous tubules and the function of Sertoli cells. A recent study suggests that in adolescents, inhibin B levels are elevated in untreated varicocele and directly correlate with testicular volume. Because inhibin levels have been shown to improve in men whose semen analysis improved after varicocelectomy, inhibin may have a role postoperatively as well. However, contradictions exist among the studies, and there are not enough data to support the use of serum inhibin levels in stratifying adolescents with varicoceles.
The gonadotropin-releasing hormone (GnRH) stimulation test is based on the theory that damage to germinal epithelium results in compensatory stimulation of the pituitary gland and subsequent increase in the production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by gonadotrophs. Several studies demonstrate an abnormal gonadotropin axis in men with varicocele as evidenced by increased FSH or LH response to administration of GnRH. Although some would recommend the GnRH stimulation test for adolescents as part of a standardized evaluation for surgery, the GnRH stimulation test has not been conclusively shown to be a good predictor of postsurgical improvement in adolescents.
Semen Analysis
Semen analysis in men with varicoceles reveals decreased motility, decreased sperm density, and more pathologic forms. By applying strict morphologic criteria to semen analysis, varicocele repair improves the seminal parameters in approximately 70% of patients, with the improvement in motility being the most common.
Over the last several years, researchers have increasingly come to use semen analysis in the evaluation of testicular dysfunction associated with adolescent varicoceles. Studies suggest that the effect of varicocele on semen quality is similar in adults and adolescents. In a study of 88 boys, Laven and colleagues found a statistically significant increase in sperm concentration values 1 year after varicocele repair. No differences in total sperm count, sperm motility, or morphology were observed among postoperative varicocele patients, normal healthy boys, and in controls with untreated varicoceles. However, difficulties remain because established norms for adolescent semen analysis have yet to be defined. Semen analysis cannot adequately be performed until the subjects have progressed to the point in pubertal development necessary for adequate ejaculation, and sample procurement continues to raise several ethical questions. Nevertheless, it would seem from current trends in the literature that recommendations for the role of semen analysis in evaluation of adolescent varicocele are forthcoming.
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