The male varicocele and its association with infertility have been recognized for many centuries. In De Medicina, written during the first century A.D., Celsus credits the Greeks with the first description of a varicocele and then remarks on veins that “are swollen and twisted over the testicle, which becomes smaller than its fellow, in as much as its nutrition has become defective”. Improvements in semen quality after varicocele repair were first suggested by Barwell in 1885, Bennett in 1889, and Macomber and Sanders in 1929. In spite of these reports, surgical repair of the varicocele was virtually forgotten until 1952, when the Edinburgh surgeon Selby Tulloch demonstrated the restoration of fertility following excision of bilateral varicoceles in an azoospermic patient. Since then, thousands of studies on the diagnosis and surgical correction of varicoceles have appeared in the literature. Unfortunately, this entire body of experimental evidence has been able to neither identify the mechanism of spermatogenesis impairment nor explain why surgical correction improves semen parameters. This post will discuss the diagnosis and consequences of varicoceles, review the etiology and hypothesized mechanisms of gonadal effect, and explore treatment options and complications, with a brief consideration of the adolescent varicocele.

Definition / Prevalence

Defined as an abnormal dilatation of the veins of the pampiniform plexus within the spermatic cord, varicoceles have traditionally been reported predominantly on the left side (77-92%), with isolated right-sided (1%) and bilateral varicoceles (10%, range 7-22%) reported muchless commonly. Varicoceles present almost exclusively after puberty and are often discovered during an infertility evaluation. They are congenital in origin, although acquired lesions have been described in association with renal tumors, retroperitoneal masses, lymphadenopathy, thrombosis or occlusion of the vena cava, and situs inversus. While large varicoceles are typically asymptomatic, they may occasionally present as a persistent, aching discomfort often described by patients as a “heavy” sensation. This feeling of heaviness is almost always relieved on the adoption of a supine position because of varicocele collapse.

The mean incidence of varicocele is between 10% and 15% of the male population. In men presenting with primary infertility, these figures rise to 35%, with one large, recent prospective study suggesting that bilateral varicoceles may be as common as 80% in this population. Men with secondary infertility (i.e., men who were previously fertile) have a varicocele incidence of 69% to 81%. The increased frequency in cases of secondary infertility suggests that varicoceles progressively harm spermatogenesis and that prior fertility in men with varicocele does not confer resistance to its progressive, deleterious effects. Furthermore, since the generally accepted incidence of infertility in males is 5%, it is important to remember that varicoceles are present in many men with normal fertility. In fact, the largest study of varicoceles to date by the World Health Organization found varicoceles in 25.4% of 3626 men with abnormal semen analyses and in 11.7% of 3468 men with normal semen. Interestingly, varicocele incidence is 53% in first-degree relatives of men with varicocele, with no correlations between size or bilaterality.

Anatomy and Pathophysiology

It is particularly important to consider the testicular vascular anatomy in order to understand proposed pathophysiologic mechanisms of varicoceles and the high frequency of their occurrence on the left side.

Anatomic Etiology

The arterial supply to the tesris has three major components: the testicular artery, the cremasteric artery, and the vasal artery. Although most arterial blood in the tesris derives from the testicular artery, rich collateral testicular circulation allows adequate perfusion of the tesris even if the testicular artery is injured or ligated. Venous drainage of the tesris is provided by the pampiniform plexus, which leads into the testicular (internal spermatic), vasal (deferential), and cremasteric (external spermatic) veins. Since spermatic vein varicociries are discovered almost exclusively around the age of puberty, it is likely that the normal physiologic changes that occur during puberty result in increased testicular blood flow, exposing underlying venous anomalies to overperfusion and, eventually, to clinically evident venous ectasia.

Increased Venous Pressure

Differences in the configuration of the right and left internal spermatic veins are thought to contribute to marked left-sided internal spermatic vein tortuosity, dilation, and retrograde blood flow. Venous blood from the right testicle drains into the inferior vena cava at an oblique angle (approximately 30°). This angle, coupled with greater inferior vena caval flow (termed the “Venturi effect”), is thought to enhance right-sided drainage. Comparatively, the left testicular vein drains perpendicularly into the left renal vein (approximately 90°). The insertion into the left renal vein occurs 8 to 10 cm more craniad than the insertion of the right internal spermatic vein, resulting in a left-sided 8- to 10-cm higher hydrostatic column with increased pressure and a relatively slower flow of blood in the upright position. The left renal vein may also be compressed proximally between the superior mesenteric artery and the aorta (0.7% of varicocele cases) as well as distally between the left common iliac artery and vein (0.5% of varicocele cases). This “nutcracker phenomenon” may also result in increased pressure in the left testicular venous system.

Collateral Venous Anastomoses

Detailed anatomic studies have demonstrated a superficial and deep anastomotic drainage system, along with left-to-right venous communications at the ureteric (L, spermatic, scrotal, retropubic, saphenous, sacral, and pampiniform plexi. The left spermatic vein branches into medial and lateral divisions at the L4 level in almost all men — findings that must be taken into consideration when choosing a treatment for varicocele. In particular, procedures performed above the level of L4 are at higher risk of failure due to the multiple divisions of the spermatic venous system.

Incompetent Valves

In 1966, Ahlberg proposed that testicular veins contained valves that were protective against varicoceles, and it was their lack or incompetence on the left side that caused varicoceles. In support of his argument, he found an absence of valves in 40% of postmortem left spermatic veins compared with 23% absence on the right. Doubt has been cast on this theory, however, as recent radiographic studies by Braedel et al. found that 26.2% of patients with a competent valve system still had a varicocele present. Some modern anatomists have even proposed that there are no valves in either the right or left spermatic vein system.

Overall, there are multiple theories to explain varicocele formation. For the clinician, it is beneficial to know this background in order to review anatomy with patients and to explain, at least anatomically, why varicoceles exist. Despite these various etiologies, the larger question still looms: “Why do varicoceles cause detrimental effects on testicular function?”

Pathophysiologic Mechanisms of Varicocele Effect

Several mechanisms have been hypothesized to explain the phenomenon of subfertility found in men with unilateral or bilateral varicocele, including increased intrascrotal temperatures causing bilateral gonadal dysfunction, reflux of renal and adrenal metabolites from the renal vein, hypoxia, and accumulation of gonado toxins.

Bilateral Dysfunction

Like many other aspects of varicoceles, the cause of bilateral testicular dysfunction in the presence of a unilateral varicocele is still under investigation. Retrograde right-sided venous flow has been demonstrated in men with left-sided varicoceles and has been proposed as a possible mechanism. Venographic and pressure studies of the right venous plexus have been explored and have all been found to be normal. The most likely mechanistic hypothesis was proposed in the early 1970s by Zorgniotri and MacLeod, in which clinical data on oligospermic men with varicoceles revealed intrascrotal temperatures that were 0.6°C higher than in oligospermic patients without varicoceles. Saypol et al. and Green et al. both described increased bilateral testicular blood flow and temperature in experimental animal models following artificial production of a unilateral varicocele. Additionally, subsequent repair of the varicocele resulted in the normalization of flow and temperature. Since then, researchers have demonstrated that DNA polymerase activity and the enzymes of DNA recombination in germ cells are temperature sensitive, with optimal activity at 33°C. Temperature for protein synthesis in round spermarids has been shown to be optimal at 34°C. Germ-cell proliferation may be affected by the increased temperature from the varicocele due to inhibition of one or more of these important enzymes. Hyperthermic injury is consistent with the reduction in spermatogonal numbers as well as apoptosis observed in testis biopsy samples from patients with a varicocele. Despite these findings, not all investigators have found an association between higher inrratesricular temperatures and varicoceles, leading to the development of alternate mechanistic theories.

Reflux of Vasoactive Metabolites

Because the left adrenal and gonadal veins drain in close proximity to each other at the renal vein, MacLeod proposed that metabolites derived from the kidney or adrenals may reflux into the gonadal vein. If these metabolites were vasoactive (such as prostaglandins), he postulated that they could have deleterious effects on testicular function. Results from animal and human studies have not supported this theory, however. Elevated levels of norepinephrine, prostaglandin E and F, and adrenomedullin (a potent vasodilator) have been identified within the spermatic vein of men with varicocele. Other metabolites such as renin, dehydroepiandrosterone, or corrisol have not been identified. Some authors contend that even in the presence of metabolites, reflux does not alter spermatogenesis.

Hypoxia

In 1980, Shafik and Bedeir theorized that differences in pressure gradients (and subsequent oxygen gradients) between the renal and gonadal vein may cause hypoxia within the gonadal vein. Two other “hypoxia” theories have also been proposed: increased venous pressure with exercise resulting in hypoxia and stasis of blood causing reduced oxygen tension. In support of these, Tanji et al. reported that men with varicoceles were more likely to have “atrophy-pattern” cremasteric fibers on histochemical studies, a denervation-type injury thought to be due to hypoxia. Despite these findings, no significant difference between control and varicocele blood gas oxygen patterns in animal models has been proven.

Gonadotoxins

Several studies have demonstrated that smoking in the presence of a varicocele has a greater adverse effect than either factor alone. Smokers have at least a twofold increase in the incidence of varicoceles, and those with varicoceles have a tenfold increase in the incidence of oligospermia when compared to non-smokers with varicoceles. Nicotine has been implicated as a cofactor in the pathogenesis of varicoceles in animal studies as well as the chemotherapeuric agent cyclophosphamide. Cadmium, a well-recognized gonadotoxin that causes apoptosis, has been found in significantly higher testicular concentrations in men with varicocele and decreased spermatogenesis than in men with varicocele and normal spermatogenesis or obstructive azoospermia. Further work in this area continues to generate interest, and perhaps future efforts will elicit the exact mechanism of action.

Diagnosis and Consequence of Varicocele

Male Varicoceles: Treatment

Adolescent Varicocele

The emerging condition of adolescent varicocele deserves mention. Several studies have revealed an incidence of approximately 15%, which is similar to that of adults. The mechanism of varicoceles in adolescent males is not well understood, but most population studies suggest a causal relationship between puberty and the formation of adolescent varicoceles.

The best clinical indication of significant tesricular dysfunction related to the varicocele in adolescents is tesricular growth arrest. A size discrepancy of 2 mL or greater between the left and right tesris in this population (as determined most accurately by ultrasound) constitutes significant growth arrest in the left testis and should be the main indication for surgery. Reversal of hyporrophy by surgical correction has been reported in 53% to 100% of cases. Other indications for varicocelectomy in adolescents that have been accepted by most pediarric urologists include the following: a decrease in tesricular growth by at least two standard deviations from normal growth curves, symptomatic scrotal pain, large varicoceles (Grade III), bilateral varicoceles, or the presence of a solitary testicle. As GnPvH stimulation studies have yet to be correlated with subsequent infertility and are both expensive and logisrically difficult, its use is not currently advocated in the evaluation of a pediarric varicocele.

Summary

Varicoceles are present in a large percentage of the male population. The majority of these men do not encounter any of the aforementioned sequelae, including scrotal pain, loss of testicular mass, testicular failure, or infertility. Despite the many viable hypotheses, the true etiology of varicocele and the mechanism of its effect remain unclear. Pathologic studies of varicoceles and their association with cigarettes have been shown to be detrimental to testicular spermatogenesis over time. For these reasons, ongoing research is required to fully explain the presence of varicocele and its true impact on the male testicle. Infertile men with oligospermia, large varicoceles (Grade III), and normal serum endocrine measurements are most likely to benefit from varicocelectomy. Treatment of varicocele-related scrotal pain has been demonstrated to resolve orchalgia in over 80% of patients. Testicular atrophy in adolescents has repeatedly been demonstrated to result in catch-up

growth of the affected ipsilateral testicle. Varicocelec-tomy in those presenting for infertility helps to improve conventional semen parameters about two-thirds of the time. Varicocelectomy remains one of the few surgical interventions available for infertility treatment, and couples will likely continue to elect to have this procedure performed if there is any chance that it will improve the possibility of conception. Although difficult to obtain accurately, it is likely that surgical repair improves pregnancy rates by 20% to 30% in the setting of clinical varicocele and subferrility. Ongoing clinic trials, however, continue to identify couples who would have attained pregnancy without intervention. It is for these patients that research on the controversial topic of varicocele is continued.

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