A 34-year-old man presents to your clinic for infertility. He has a 4-year-old daughter and has been trying to have a second child with his wife for the last 18 months. He brings with him a semen analysis that shows oligoasthenoteratospermia (OAT). He states that he has noticed a small bulge in his left scrotum for the last few years that does not cause discomfort. His examination is significant for a left grade 2 varicocele, and an ultrasound of his scrotum reveals a left varicocele that enlarges with Valsalva. He is wondering whether there is anything that can be done to help him and his wife conceive. They would like to avoid in vitro fertilization if possible.

Male factor infertility is implicated in 50% of couples being evaluated for infertility. Varicoceles, defined as abnormally dilated scrotal veins, are thought to be the most common attributable cause of infertility in the male [1]. Their pathophysiology is still poorly understood, despite the first varicocele being diagnosed in the first-century CE by Celsus [2]. Most studies are retrospective or case controlled, and there are few well-done randomized studies [3]. With the advances in assisted reproductive techniques (ARTs), some physicians question the need to treat varicoceles at all. Though the debate continues, many studies have shown that treatment of varicoceles in well-selected patients can indeed improve a man’s fertility and chance of pregnancy. We present a review of the evidence for the role and treatment of varicoceles in the infertile male and its effects on the need for assisted reproductive techniques.

While the semen abnormalities caused by varicoceles are likely multifactorial, the development of the varicocele itself is assumed to be more straightforward and is caused by structural abnormalities of the vascular supply of the testis. The arterial supply to the testis is derived from 3 main sources: the testicular artery, which supplies about two-thirds of the blood flow, and the vasal and cremasteric arteries, which supply the rest [8]. This arterial anatomy is important when surgical treatment of a varicocele is planned and will be discussed in further detail later in this chapter.

The venous drainage of the testis is more variable but classically starts in the scrotum as the pampiniform plexus and eventually drains into the testicular (internal spermatic) vein. This vein then drains into the renal vein on the left, or directly into the inferior vena cava (IVC) on the right. The pampiniform plexus is also drained via the vasal vein, which drains into the vesicular veins and the cremasteric veins, which eventually drain into the inferior epigastric vein.

It is theorized that varicoceles result when there is too much back pressure in this drainage system. The left testicular vein is 8–10 cm longer than the right and inserts into the left renal vein at approximately a 90° angle, whereas the right testicular vein inserts more obliquely into the vena cava. These factors are believed to provide the right testicular vein with less turbulent flow and back pressure, which results in a substantially lower incidence of right-sided varicoceles (1–2%) [4, 9]. Large unilateral right-sided varicoceles can suggest the possibility of retroperitoneal or caval pathology, such as retroperitoneal tumors, and most clinicians would order further imaging to rule out an underlying pathology. Another contributing factor to the formation of varicoceles is incompetent (acquired or congenital) or absent (congenital) venous valves in the testicular veins that allow retrograde reflux of blood, which can cause venous dilation [10]. Rarely, varicoceles can result from the nutcracker syndrome as well, where the left renal vein is compressed between the superior mesenteric artery and the aorta, producing high pressure in the left testicular vein [11].

While varicocele formation is usually the result of anatomic or functional inadequacy of the drainage system, there is ongoing debate about the mechanism of spermatogenic impairment in the setting of a varicocele. The leading theory postulates that poor venous drainage disrupts the countercurrent exchange of heat from the spermatic cord causing a relative hyperthermia of the scrotum that affects both testes [12]. The cellular processes of the testis are exquisitely sensitive to increased temperature, and hyperthermia causes reductions in testosterone synthesis by Leydig cells, injury to germinal cell membranes, altered protein metabolism, and reduced Sertoli cell function [13]. While there has been conflicting reports on varicocele’s effect on testosterone production, recent studies have shown that varicocelectomy alone may result in improved testosterone levels in men with low testosterone [14, 15]. When a varicocele is ligated, scrotal temperature is reduced to normal [16].

The impaired venous drainage can also cause hypoxia, poor clearance of gonadotoxins, and elevated levels of oxidative stress. The level of oxidative stress correlates with the varicocele grade [17], and treatment of the varicocele decreases the level of reactive oxygen species, although not to the levels of fertile men [18]. Other theories include decreased perfusion due to an increased level of catecholamines (specifically norepinephrine) in refluxing venous blood. The elevated level of norepinephrine causes constriction of the intratesticular arterioles and decreased arterial perfusion [19]. Prostaglandins have also been found to be elevated in the testicular vein of infertile varicocele patients compared to fertile patients with varicoceles, but the clinical significance of this is not known [20].

Scrotal ultrasound has the advantage of being noninvasive as well as free from ionizing radiation. It can diagnose other scrotal pathology and provide more accurate testicular size measurements. Ultrasound can detect non-palpable varicoceles with a >94% sensitivity and specificity [21]. Because repair of these “subclinical” varicoceles are not thought to improve fertility, routine ultrasound use for varicocele screening is not recommended nor is the treatment of subclinical varicoceles. Its use may be required in special cases such as large body habitus or equivocal physical examination findings. Varicoceles are diagnosed on ultrasound with the demonstration of reversal of venous blood flow with Valsalva or spermatic vein diameter >3 mm [22].

Venography of the testicular veins can be used for both diagnosis and treatment of varicoceles. Venography is the most sensitive imaging modality, with nearly 100% sensitivity (i.e., almost all patients with clinical varicoceles will demonstrate reflux on venography). Unfortunately, its clinical utility is limited since up to 70% of patients without a clinical varicocele are found to have reflux during venography [23, 24]. This modality is also used to access the testicular veins for percutaneous treatments such as sclerotherapy and embolization, which will be discussed later. While not indicated for routine screening or characterization of varicoceles, it can be used to help delineate post-treatment recurrences and then embolize the remaining veins.

Other techniques such as magnetic resonance imaging (MRI), thermography (measuring the temperature of the scrotum), and radionucleotide scans using technetium 99 m pyrophosphate have been used to diagnose varicoceles. These techniques have no better outcomes than the modalities discussed previously and are limited by their cost, inferior diagnostic accuracy, or both. They should not be routinely used.

In the original World Health Organization (WHO) study, the 9034 men with infertility demonstrated lower sperm concentration and motility compared to their fertile peers [4]. Since that time, the WHO reference ranges and evaluation methods for semen analysis have changed 3 times (1992, 1999, 2010). Using the most recent WHO criteria, Agarwal et al. performed a meta-analysis of 10 studies that showed the semen of men with varicoceles has a reduced sperm count, decreased motility, and abnormal morphology. The semen volume remained within normal limits [25].

These findings in addition to an increased number of tapered forms and immature cells make up the originally described “stress pattern” [26]. Unfortunately, this characteristic stress pattern is not a sensitive marker for varicocele as it is seen in other pathology and should not be used to diagnose a varicocele alone.

The American Society for Reproductive Medicine recommends that a varicocele be treated when all or most of the following criteria are met [27]:

In these patients, a successful repair may halt further testicular damage [6, 28], improve spermatogenesis [29, 30], and improve Leydig cell function and testosterone production [14].

Men with pain that is thought to be attributed to a varicocele are also candidates for varicocele repair as up to 80% may experience symptomatic improvement with treatment [31]. Patients with subclinical varicoceles should not be treated due to a lack of efficacy [32].

The decision to treat varicoceles in the adolescent does not follow the same rules set out by the American Society for Reproductive Medicine since most adolescents are not planning on conceiving a child. In this patient population, the goal of therapy is to halt testicular atrophy and preserve function for future conception. Diagnosis in this heterogeneous group is difficult due to the rapidly changing testicular size and hormonal milieu as well as the different stages of development that happen at different ages for different patients. Some authors have recommended treating a palpable varicocele if there is a 2 ml or 20% change in testicular volume compared to the unaffected testis [33]. This is supported by a small study that found recovery of testicular volume or so-called catch-up growth in 80% of adolescents after repair of grade 2 or 3 varicoceles [28]. A second study showed that 43.8% of patients actually have hypertrophy of the left testis following repair of the ipsilateral varicocele. A more recent study has put these results in question though. Kolon et al. reviewed 71 boys being evaluated for varicoceles with ipsilateral testicular hypotrophy who received no surgical repair [34]. They found that 85% had a volume differential of less than 15% after two years. However, there could be a selection bias as a large subset of their original cohort underwent surgical repair of their varicoceles. These results can be difficult to apply to clinical practice due to variations in measurement techniques (orchidometer, calipers, ultrasound) and accuracy [35]. A pretreatment semen analysis can help to determine when to intervene in an adolescent varicocele, though this can be challenging to obtain in this population. Furthermore, there are no established normal ranges for semen analysis in this age-group. Given the controversy surrounding the adolescent varicocele, a shared decision-making approach must be taken with the family to determine whether surgery is right for their child.

In the absence of testicular asymmetry, adolescents with varicoceles should be followed with annual testicular size assessments (preferably ultrasound, given its higher accuracy), as well as semen analysis if possible to assist in determining which patients may benefit from varicocele repair.

The first percutaneous treatment of a varicocele was described in 1978 when Lima and colleagues used hypertonic glucose and ethanolamine oleate to sclerose the testicular vein [36]. This was followed by the use of detachable balloons [37] and coils [38] to occlude the vein. Complications using this technique include increased radiation exposure, balloon migration [39], and injury to the femoral vein while obtaining access. A variation of the technique, antegrade scrotal sclerotherapy [40], has been described with high success rates, though larger studies with longer follow-up are needed [41].

Due to recurrence rates as high as 11% [42] and lower initial success rates, percutaneous embolization is best used for persistent or recurrent varicocele after surgical repair [13, 43].

Tulloch performed the first-reported varicocele ligations for infertility in 1955 [44]. Since then, it has become the most commonly performed procedure for the correction of male factor infertility [45]. There are many techniques for varicocele repair, each with their pros and cons regarding success rates, recurrence, hydrocele formation, and other postoperative complications. In this chapter, we will discuss the retroperitoneal, laparoscopic, inguinal, and subinguinal approaches. The latter 2 are ideally performed with an operating microscope.

The retroperitoneal approach, also known as the Palomo procedure, is performed by making an incision at the external inguinal ring, splitting the external and internal oblique muscles, and exposing the spermatic cord vessels near the ureter. This technique gives the surgeon the ability to isolate the veins more proximally where there are usually only 1 or 2 large veins that need to be ligated as opposed to the inguinal approaches where there are usually many more veins that must be ligated to have a successful outcome. The biggest disadvantage of this technique, however, is the higher recurrence rate, generally around 15% [46–48], especially when preserving the artery, as failure is usually from preservation of the fine venae comitantes of the artery. Dilated cremasteric veins are also not identified during this approach and may be a source of recurrence [49]. Less commonly, parallel collaterals can exit the testis and bypass the ligated veins [50, 51]. A microscopic retroperitoneal varicocelectomy has been recently described in a small study with similar outcomes to the microscopic subinguinal approach [52].

The laparoscopic varicocelectomy is essentially a retroperitoneal approach performed through the abdomen and with laparoscopic instruments. The magnification provided by the laparoscope allows better visualization of the testicular artery, and with experience, the lymphatics may be visualized and preserved as well to decrease the rate of postoperative hydrocele formation [53]. As this is the only intra-abdominal approach for the treatment of varicoceles, this procedure has increased risk of serious complications such as injury to the great vessels or bowel during insufflation and port placement as well as other laparoscopic complications such as CO₂ air embolus. It also requires a general anesthetic and is usually more expensive. A few centers are using single-port laparoscopic surgery to perform this procedure [54]. Recurrence rates are typically low (2% [55]) but can be as high as 17% [56]. According to a survey of the Pediatric Health Information System, a comparative pediatric database of 45 tertiary care pediatric hospitals, the laparoscopic approach is still the most commonly used in adolescents, likely due to the pediatric urologists familiarity with laparoscopic orchiopexy [57]. While the procedures discussed below have become gold standard for varicocele repair, this technique may be beneficial for the treatment of bilateral varicoceles [58].

The inguinal approach is the same used for a radical orchiectomy or hernia repair and is familiar to most urologic surgeons. An incision is made over the inguinal canal, dissection is carried down to the external oblique aponeurosis, which is opened, and the spermatic cord is encircled and delivered. The cord is then dissected, and all the internal spermatic veins are ligated, while the vas (and its vessels), testicular artery, and lymphatics are preserved. There appears to be a 3–15% risk of hydrocele formation when the operating microscope is not used [59]. Though the subinguinal approach has largely replaced the inguinal approach in most cases, there are some relative indications for the former. Men with solitary testis may benefit from this approach to minimize injury to the testicular artery since the artery should be larger and less branched more proximally. In children and prepubertal adolescents, it is recommended to open the external oblique fascia to facilitate identifying the artery as it is quite small in this age-group and can be difficult to find with the subinguinal technique. Other anatomic considerations that may favor inguinal over subinguinal approaches include a low or tight external ring and a short cord that cannot be brought out of the wound easily.

The subinguinal technique was first described by Marmar and colleagues in 1985 as a way to prevent opening the external oblique fascia and reduce postoperative pain [60]. While it had been used intermittently before 1992, Goldstein popularized the use of the operating microscope [61] when performing varicocele repairs, which greatly increased the ability to see and spare the artery and lymphatics [62]. In this approach, an incision is made below the external ring and the cord is located, grasped, and brought to the surface of the incision. A Penrose drain or a Fuchs platform (sterile tongue depressor slid through a Penrose drain) can be placed below the cord to hold it just above skin level to allow the surgeon to operate with both hands. The cord is dissected, and a micro-Doppler is used to identify arterial pulsations. Clips or suture ligatures are used to divide aberrant veins. This procedure is especially useful in patients with prior inguinal surgery (where the cord is likely scarred to the underside of the external oblique fascia), obese patients, high external rings, and patients with long cords. In both the inguinal and subinguinal approach, the testis can be delivered if necessary to visualize all possible avenues of venous drainage.

As mentioned earlier, hydrocele formation postoperatively from ligation of lymphatics can be a common complication, especially in the inguinal and laparoscopic approaches. This is concerning for infertile men as there is some data that a hydrocele can cause similar hyperthermia of the testis that a varicocele can [63]. With the advent of the microscopic subinguinal technique, hydrocele formation is very rare.

The testicular artery supplies two-thirds of the testicular blood supply [8], and injury to this artery can cause atrophy of the testis. In early renal transplant literature, where the entire cord, with the exception of the vas, was intentionally ligated to facilitate exposure of the iliac fossa, 14% of patients developed testicular atrophy and 70% had hydrocele formation [64]. Unfortunately, the true incidence of artery injury is not known, but has likely improved since the operating microscope began being used for varicocele repair [65]. In prepubertal boys, testicular atrophy is likely less common due to the potential for revascularization of the testis from the vasal and cremasteric arteries, evidenced by similar atrophy rates in both artery sparing and Fowler–Stephens orchidopexies performed for undescended testis [66].

Recurrence rates vary wildly in the literature from 0.6 to 45% [62, 67, 68]. A recent, albeit small, randomized controlled trial demonstrated a recurrence rate of 18% in the laparoscopic group, 13% in the open inguinal group, and 2% in the microscopic subinguinal group [69]. A meta-analysis of 4 randomized controlled trials also showed a statistically significant decrease in hydrocele and recurrent varicocele formation with the microscopic subinguinal technique compared to the laparoscopic and inguinal approaches [70].

The outcomes of varicocele repair are the topic of much debate due to variable diagnostic criteria, follow-up, and outcomes reporting and the retrospective nature of most of the studies performed. A Cochrane review, updated for 2012, looked at 10 randomized controlled studies comparing varicocele repair with no treatment and found an odds ratio for pregnancy of 1.47 with a 95% confidence interval of 1.05–2.05 [3]. Given this confidence interval and what they deemed as low quality of evidence, the authors concluded that the treatment of varicoceles in subfertile men “may improve a couple’s chance of pregnancy,” but the “findings are inconclusive” [3]. This meta-analysis has been criticized for including studies in which the majority of patients had normal semen analysis and subclinical varicoceles; many more studies support varicocele repair improving semen parameters and pregnancy rates [71]. Multiple studies have shown an improvement in semen parameters after varicocelectomy in infertile men with clinical varicoceles. A meta-analysis of 17 studies by Agarwal et al. found post-varicocele repair semen analysis had a mean increase in sperm density of 9.7 million/mL, motility increase of 9.9%, and WHO sperm morphology improvement of 3% [1]. A meta-analysis of adolescents did not show a difference in post-varicocele repair semen analysis, but did show a significant improvement in bilateral testis size (2.9 ml increase on the affected side and 1.5 ml increase on the contralateral side) [72]. Larger varicoceles seem to exert a greater negative effect on semen parameters than smaller ones and also show a more substantial improvement after varicocele repair. Steckel et al. found that the fertility index (sperm count × motility %) of men with grade 3 varicoceles improved to a greater degree (128%) than men with grade 1 (27%) or grade 2 (21%) varicocele [73]. Similarly, repair of bilateral varicoceles also produced an increased benefit compared to the repair of a unilateral varicocele [74]. Other studies have shown improvement in the sperm penetration assay [75] and a decrease in DNA fragmentation [76] and oxidative stress levels [77].

For men with azoospermia, even a modest improvement in semen quality after varicocele ligation can significantly impact a couple’s fertility options. Multiple studies have shown that a number of azoospermic men can have unassisted, natural pregnancies after clinically significant varicocele repair [78, 79]. In the first large series reported, Matthews et al. evaluated 22 men with azoospermia and 56 men with oligoasthenospermia (OAT) [80]. After microscopic varicocelectomy, 55% of the azoospermic men had motile sperm with an average motile sperm count of 2.2 ± 1.1 × 10⁶. Fourteen percent of these men had a pregnancy during follow-up, including 2 patients (9%) who were able to conceive naturally [80]. Gat et al. examined a prospective cohort of 101 men with severe OAT, 32 of whom had true azoospermia [81]. These men were all treated with embolization of their varicoceles. Of the overall group, 82% showed clinically and statistically significant improvement in their semen parameters, while 56.2% of the azoospermic men had improvement. There were 9 pregnancies (26%) in the azoospermic group, 4 (12%) unassisted, and 5 (15%) by intracytoplasmic sperm injection (ICSI) (1 was a twin pregnancy), all resulting in live births [81].