Abstract
Varicocele is the most common surgically correctable factor identified in infertile men. The negative impact of varicocele on testicular function, semen parameters and fertility potential have been well recognized for decades. Despite this, the role of varicocele repair in managing infertility remains controversial, especially since the advent of assisted reproductive technologies (ART). This chapter details the current status of varicocele in male infertility. We describe the anatomy, pathophysiology and diagnostics of varicocele and discuss the methods of repair. We then take a critical look at the efficacy and clinical utility of varicocele repair in infertile couples, with an emphasis on clinical benefits for couples undergoing ART.
15.1 Introduction
The management of varicoceles is one of the most controversial areas in urology and reproductive medicine. Varicoceles are the most common correctable cause of male infertility. Although a large body of evidence supports the adverse effects of varicoceles on fertility, the evidence on improved fertility after repair is not consistent. Assisted reproductive technologies (ART) can often overcome poor sperm quality and quantity. Intracytoplasmic sperm injection (ICSI) requires only a single sperm to be injected into an egg. It is not uncommon to encourage the couples with male factor infertility to proceed with ART without giving an opportunity for evaluation and management of potentially correctable causes. While opinions are divided about the role of varicocele repair in management of male infertility, it is even less clear whether varicocele should be addressed within the framework of ART. In this chapter we explore the question whether repair of varicocele benefits couples undergoing ART. We describe the anatomy of varicocele to provide a background for its etiology and overview the putative mechanisms for varicocele-induced infertility. Next, we discuss the diagnostics of varicocele and methods of repair. We then present an unbiased coverage of the literature on the clinical implications of varicocele repair in the context of fertility. Finally, we address the limitations of the current evidence and reflect on ongoing uncertainties.
15.2 Anatomy and Etiology
A varicocele is defined as a pathologic dilatation of the pampiniform venous plexus of the testis. The pampiniform plexus is a network of small veins that drain the testis and epididymis and ascend within a spermatic cord. The surrounding fasciomuscular layer of the spermatic, cremasteric fasciae and the cremasteric muscle assist in perfusion of the cord. The veins of the pampiniform plexus merge into the spermatic (testicular) veins as they pass the inguinal canal. In the abdomen, the left and right spermatic veins travel retroperitoneally alongside the spermatic artery on each side and vary in their drainage pattern. The left spermatic vein ascends vertically, travels posteriorly to the descending colon and drains into the renal vein at a right angle, which raises the hydrostatic pressure of the left spermatic vein. The renal vein then courses between the aorta and superior mesenteric artery to join the inferior vena cava. The right spermatic vein ascends more horizontally, is 8–10 cm shorter and drains directly into the inferior vena cava at an oblique angle. Infrequently, the right spermatic vein drains into the right renal vein, mimicking the left-side pattern. The valves are absent in up to 40% in the left and in 23% in the right spermatic vein, and this further compromises the upward blood flow. While a single spermatic vein drains each testis in most men, an accessory vein is present in 13% of men on the left and in 2% on the right side [1].
The mechanism of varicocele development involves a complex interplay of venous and intra-abdominal pressure, venous valvular function and gravitational force. The factors that favor high drainage pressure and thus predispose to left-sided varicocele, include the failure of the fasciomuscular venous pump of the spermatic cord, the longer length of the left spermatic vein, its right‐angle entry into the left renal vein, the nut‐cracker compression of the left renal vein between superior mesenteric artery and aorta and the absences or incompetence of valves in the testicular veins. Varicoceles are more prevalent in taller men due to the increased length of venous drainage, although there are no clearly defined height cut-offs predisposing to development. In addition, spermatic vein duplication and anastomoses between the spermatic vein and systemic circulation also play a role and may be responsible for varicocele recurrence after spermatic vein ligation or embolization. Less commonly, varicoceles result from external compression by renal or retroperitoneal tumors or from vena cava malformations [1].
The higher occurrence of varicoceles among first-degree relatives suggests the possibility of a genetic component. However, this is an under-researched area and the pattern of inheritance or genes implicated in the condition remains unclear [2].
Taken together, it is evident that the anatomy of testicular venous drainage predisposes to the development of left-sided varicoceles. Isolated varicoceles on the right or rapidly progressing new onset varicoceles warrant the exclusion of an abdominal or retroperitoneal mass with appropriate imaging.
15.3 Epidemiology
Varicoceles are a dynamic progressive condition, exhibiting varying prevalence with age. Varicoceles are rarely seen in pre-pubertal boys but become more prominent after 10–14 years of age due to the increased venous drainage of the developing testes. The prevalence of varicoceles increases from 0.8% in 2–6 years old boys to 11% by the age of 11–19 years, ranging between 4 and 35% in adolescents [3]. In the general adult population, the prevalence of varicoceles ranges from 4.4 to 22.6%, averaging around 15% and reaches up to 42% in elderly men. In men presenting for evaluation of infertility, varicoceles are 2–3 times more common, affecting 19–45% of the evaluated men [1]. In men with secondary infertility, the prevalence of varicoceles has been reported to be raised to 70–80%, but this observation has not been consistently confirmed across the studies. Subclinical varicoceles have been found in 55–70% of infertile men, although these estimates have been reported only by small-sized heterogeneous studies [4].
Whilst varicoceles are considered predominantly a left-sided condition, bilateral clinically apparent varicoceles are reported in 1–30% of the affected men and in up to 59% of adolescents. One study reported that the rate of bilateral subclinical varicoceles in infertile adults may be as high as 80%. Isolated right-sided varicoceles are rare, affecting fewer than 5% of men diagnosed. As stated above, this flags the possibility of sinister pathology causing a mass effect compressing the venous tract [1,4].
15.4 Pathophysiology
Varicoceles impair testicular function by affecting both Sertoli and Leydig cells. This results in negative effect on semen parameters, ultrastructural features of sperm, testicular steroidogenesis and testicular growth. The pathophysiology of varicoceles remains a question and there is no single theory to explain its effect. It is also unclear why fertility is affected in some men but not others, implying the multifactorial nature of the condition. The proposed pathologic mechanisms are largely derived from animal studies and include oxidative stress, heat stress, testicular hypoperfusion, increased apoptosis and impaired steroidogenesis [1,5].
15.4.1 Oxidative Stress
Reactive oxygen species (ROS) are the end products of oxygen metabolism that are deactivated and eliminated by a series of antioxidant defense mechanisms. Disruption to the oxidant-antioxidant balance leads to mitochondrial dysfunction and an accumulation of ROS with subsequent oxidative DNA damage and multiple cellular aberrations. An excess of ROS has been associated with reduced sperm motility, abnormal sperm morphology and compromised sperm DNA integrity, all of which may lead to morphological or functional sperm abnormalities and subsequently to impaired fertilization. The raised levels of ROS in the seminal fluid of men with varicocele have been demonstrated to decline after varicocele repair. Some men with a varicocele presenting with infertility have been shown to have abnormal semen parameters and increased sperm DNA damage. These factors may lead to decreased pregnancy rates both in spontaneous conception and following ART treatments. Varicocelectomy, on the other hand, has been shown to improve sperm parameters and decrease the DNA fragmentation index. It has been proposed that assessment of ROS and DNA fragmentation can be used as a prognostic marker in subfertile men with a varicocele. Clinical utility of these tests is still limited by a lack of standardized laboratory methods and an undetermined decision threshold for most assays [1].
15.4.2 Heat Stress
Spermatogenesis is a temperature-sensitive process, requiring a scrotal temperature of 35–36°C. Varicoceles result in a rise of the scrotal temperature by 2.6°C due to regurgitation of warm blood from the abdomen and dilatation of the engorged scrotal veins. Exposure to scrotal heat may induce testicular heat stress. There is a well-described association between heat and dysfunction within the temperature-sensitive Leydig, Sertoli and germ cells. At a molecular level, heat stress is known to increase oxidative stress markers, accelerate apoptosis and impair function of key enzymes involved in DNA replication, namely topoisomerase I and DNA polymerase [1,5]. The effect of heat stress on testicular function is well recognized in men with cryptorchidism. Febrile illness has also been shown to transiently affect sperm concentration and progressive motility commencing within a few weeks of a febrile episode for a period of several months. Scrotal cooling, on the other hand, has been shown to improve semen parameters in small uncontrolled studies [6].
15.4.3 Toxin Accumulation and Testicular Hypoperfusion
Impaired venous drainage in men with a varicocele results in the stasis of blood, which may initiate activation of trapped white cells and increase the release of ROS. Blood stasis may also lead to low tissue perfusion with subsequent hypoxia, ischemia and impaired function. Stagnation of blood within the testicular microcirculation and ischemic changes within the testes have been confirmed on testicular biopsies in men with a varicocele. High levels of hypoxia-inducible factor 1 (HIF1), known to regulate tissue response to hypoxia, have been observed in the testicular vein in varicoceles. Improvement in testicular blood flow has been demonstrated after varicocelectomy. In animal models with an induced varicocele, administration of vascular endothelial growth factor (VEGF), known to counteract hypoxic changes of tissue hypoperfusion, led to markedly decreased rates of apoptosis and improved testicular function similarly to that observed after varicocelectomy. Likewise, supplementation with Polydeoxyribonucleotide (PDRN), an anti-inflammatory and angiogenic agent, improved spermatogenesis in experimental varicoceles in rats. Little is known about the effect of these agents on testicular function in men, hence their role in treatment is not established [1,5].
15.4.4 Apoptosis
Apoptosis, or programmed cell death, is well described in association with varicoceles and plays an important role in varicocele-induced infertility. Reduced expression of the anti-apoptotic proteins Neuronal Apoptosis Inhibitory Protein (NAIP) and Survivin, as well as decreased spermatogenesis have been observed in animal models of varicocele. Elevated levels of apoptotic markers have been observed in seminal fluid and in testicular tissues of men with varicoceles. Moreover, the expression of molecular mediators of apoptosis is increased in patients with varicoceles with compromised spermatogenesis. Apoptosis can be triggered by a variety of injurious stimuli including but not limited to heat stress, oxidative stress and testis hypoperfusion. Conversely, varicocele repair results in up-regulation of genes encoding anti-apoptotic proteins [5].
15.4.5 Impaired Steroidogenesis
Varicoceles have been linked with testicular fibrosis, featured by collagen deposition in the tubular basement membrane, blood vessels and interstitial tissue. Improvement of testicular histology has been shown after varicocelectomy. In vitro studies clearly demonstrate direct consequences of varicoceles on the viability and function of Leydig cells, which are responsible for testosterone production and maintaining normal intra-testicular testosterone concentrations required for spermatogenesis. There is well-documented association between varicoceles and low testosterone levels. Numerous animal studies show that varicoceles are associated with low intra-testicular testosterone and enzymatic dysfunction at several stages of steroidogenesis. Improvement in testicular histological changes and significant increases in testosterone levels have been observed after varicocele repair. This implies that the hypogonadism in men with varicoceles may be reversible. These observations have been supported in human studies that demonstrate improvement in serum testosterone levels after varicocelectomy [1,5].
15.4.6 Other Factors
Increased levels of inflammatory markers such as epithelial neutrophil activating peptide-78 (ENA-78) and IL-1b have been found in the seminal fluid of men with a varicocele and infertility. ENA-78 is shown to negatively affect sperm motility, while administration of an IL-1b antagonist alleviated damage to germ cells and seminiferous tubules in rats with induced oxidative testicular damage. Animal studies link varicocele with overexpression of proinflammatory cytokines, which can increase the permeability of the blood–testis immunological barrier. Molecular evidence of the disrupted blood–testis barrier and a higher rate of anti-sperm antibodies have been demonstrated in subfertile men with a varicocele, proposing a role of inflammation and altered immune response in varicocele-induced infertility [7]. Furthermore, spermatozoa of men with a varicocele have been shown to have a decreased expression of androgen receptors and display lower rates of capacitation, which leads to decreased fertilization ability. Finally, an influx of adrenal metabolites with retrograde venous flow has been also implicated in the adverse effect of varicoceles on testicular function [5].
15.4.7 Genetic Predisposition
Men with varicoceles have been shown to have a decreased expression of the Heat-Shock Protein gene (HSPs) and Metallothionein-1 M (MT1 M) gene, known to protect against heat stress and oxidative damage. This may result in an increased sensitivity to the insult of testicular hyperthermia and oxidative stress on spermatogenesis in a subgroup of men. Such intrinsic susceptibility provides a possible explanation for genetic predisposition to infertility in men with varicoceles. Genetic polymorphisms have been implicated as a susceptibility factor for infertility and a possible cause for a less favorable response to varicocele repair. The association between genetic aberrations and varicoceles is intriguing; however, the data is scant and the findings are pending further replication [5].
15.5 Classification and Diagnosis
The most widely used classification of varicoceles is the modification of a clinical classification proposed by Dubin and Amelar, endorsed by the World Health Organization (WHO) [8]. According to the WHO classification system, varicoceles are classified as following:
Grade 0 or subclinical: varicocele diagnosed only with imaging techniques and not palpable or visible on physical examination;
Grade 1: varicocele palpable in the upright position with Valsalva maneuver;
Grade 2: varicocele palpable in the upright position without the Valsalva maneuver;
Grade 3: varicocele visible through the scrotal skin in the upright position.
Physical examination represents the cornerstone for detection of a clinically significant varicocele. The majority of men with varicoceles are asymptomatic, but some may present with testicular or groin pain that worsens after prolonged standing or exertion. A common finding on physical examination is painless scrotal swelling. The examination is performed in a warm and relaxed environment, both in the standing and supine positions with and without a Valsalva maneuver. In the context of a varicocele, the examination should include palpation of pampiniform plexus, and assessment of testicular size and consistency. Unfortunately, physical examination is subjective and is limited by intra-observer and inter-observer bias. Factors that limit detection and grading of varicoceles include scrotum tightening due to patient distress or cold temperature, obesity, hydrocele, prior scrotal surgeries and lack of sufficient clinical experience. Physical examination has a diagnostic sensitivity of 71% and a specificity of 69% [9].
Imaging modalities that have been described include ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI), thermography, scintigraphy and venography.
Scrotal ultrasound with Doppler examination is the most widely used modality for detecting varicoceles and testicular pathology. When compared to venography, ultrasound-Doppler has a sensitivity of 97% and a specificity of 94%. Ultrasound of the scrotum is performed in the supine position with a high-frequency linear array transducer 7.5–14 MHz. The study can be then extended with the patient upright and/or with a Valsalva maneuver. The main sonographic criteria of varicocele include multiple anechoic tubular structures in the superior and lateral aspects of the testis with intermittent or continuous flow reversal with or without Valsalva. In general, it has been agreed that varicoceles of more than 2.5–3 mm diameter are clinically significant. However, the standardized diagnostic criteria regarding the extent of venous dilation or magnitude of reflux are lacking and there is limited correlation between the ultrasonographic findings and the clinical assessment of varicocele severity. The prognostic value of ultrasound findings for treatment outcomes is not well established. Ultrasonography remains the primary imaging modality for the evaluation of varicoceles as it is relatively inexpensive, non-invasive and readily available. The important limitations include the operator-dependent nature, limited field of view and poor tissue characterization [9,10]. The American Urological Association (AUA) and the American Society for Reproductive Medicine (ASRM) guidelines recommend scrotal ultrasound only as an adjunct to inconclusive physical examination [11].
CT imaging for the diagnosis of varicoceles is not superior to ultrasound and involves radiation exposure, higher costs and lower availability. Therefore, CT is not routinely used for detecting varicoceles and is mainly reserved for assessment of suspected retroperitoneal lesions [9].
MRI may be more advantageous than ultrasound as it is not operator-dependent and enables detailed visualization of retroperitoneal anatomy. In addition, MRI has the potential to accurately monitor testicular function and to determine the associated testicular damage, such as testicular fibrosis. Its diagnostic and prognostic utility is yet to be established and the exact role in the diagnostic algorithm remains undetermined [9].
Venography is primarily used as an adjunct to therapeutic intervention with embolization and has a value in identifying collateral circulation in patients with failed surgical ligation and is not a primary diagnostic tool. Other methods such as thermography and scintigraphy are not used in routine clinical practice [9].
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
