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Treatment of varicoceles: techniques and outcomes
Treatment of varicoceles: techniques and outcomes Dane Johnson, M.D. and Jay Sandlow, M.D. Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin
Varicoceles, a dilation of veins within the pampiniform plexus, are present in 15% of the general male population. This paper reviews the indications for treatment of varicoceles, post-intervention outcomes following treatment, and the various techniques for treatment of varicoceles. The aim of this review is to describe and compare complications associated with each approach to varicocele treatment. (Fertil SterilÒ 2017;108:378–84. Ó2017 by American Society for Reproductive Medicine.) Key Words: Microsurgery, varicocele, varicocelectomy, subinguinal, hydrocele Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/ 16110-fertility-and-sterility/posts/18600-24605
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aricoceles, a dilation of veins within the pampiniform plexus, are present in 15% of the general male population. It is also one of the most frequent causes of male-factor infertility, with a prevalence of 30%–40% among men presenting for primary infertility evaluation and up to 85% in secondary infertility (1). In certain patients, varicoceles can cause testicular damage resulting in loss of testicular volume, spermatogenic dysfunction, disruption of hormone production, and sperm DNA damage (2–4). The mechanism of testicular dysfunction secondary to varicocele may be related to loss of the countercurrent temperature exchange between the pampiniform plexus and spermatic artery. Under normal physiologic circumstances, the testicle has been demonstrated to be 1–2 C cooler than the core body temperature (5). When varicoceles develop, venous stasis is often encountered, and the pooling of warm venous blood in these varicoceles is thought to lead to a loss of the countercurrent heat exchange (6). Studies using intrascrotal temperature probes
support this hypothesis, finding that patients with varicoceles had intratesticular temperatures that were significantly higher than patients without varicoceles (7). This increased heat has been found to be detrimental to spermatogenesis and to result in germ cell loss and DNA damage (8). Additional studies have found that varicoceles may also induce a state of transient hypoxia, resulting in increased reactive oxygen species that may contribute to testicular dysfunction (9, 10). Fortunately, both mechanisms of injury are typically correctable by means of treatment of the varicocele.
INDICATIONS According to best-practice statements from both the American Urological Association and the American Society for Reproductive Medicine, treatment of clinical varicoceles should be offered to the male partner of a couple attempting to conceive when the following are present: 1) a varicocele is palpable; 2) the couple has documented infertility; 3) the female has normal fertility or potentially
Received July 3, 2017; accepted July 19, 2017. Reprint requests: Jay Sandlow, M.D., Department of Urology, Medical College of Wisconsin, Milwaukee, WI 53226 (E-mail: [email protected]). Fertility and Sterility® Vol. 108, No. 3, September 2017 0015-0282/$36.00 Copyright ©2017 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2017.07.020 378
correctable infertility; and 4) the male partner has one or more abnormal semen parameters or sperm function test results (11). In addition, varicocele treatment is indicated when the goal of treatment is aimed at preventing or reversing testicular atrophy in adolescent males, correcting pain from varicoceles, addressing elevated sperm DNA fragmentation (DNAF), or improving testicular function in hypogonadal men with varicoceles. The incidence of clinical varicocele in adolescence is similar to that of the adult male population (12). Young men or adolescent boys with varicoceles should be evaluated for ipsilateral testicular hypotrophy and, if present, offered treatment. These patients are thought to be at risk for future testicular dysfunction and possible infertility (13). Studies have shown in young men that testicular volume discrepancy between the normal and the affected testis correlated with decreased sperm concentration and motility (14), and a cutoff of >10% size discrepancy has been proposed as a surgical criteria for asymptomatic adolescent varicocele (15). Furthermore, both nonhuman and human studies have shown that varicocele is associated with a progressive duration-dependent decline in testicular function (16) Adolescents with palpable varicoceles and objective
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Fertility and Sterility® evidence of reduced ipsilateral testicular size or abnormal semen parameters should be offered varicocele repair. Pain associated with varicoceles is relatively common and well recognized, with a prevalence of 2%–10% of men with varicoceles (17). This pain is often described as a dull throbbing pain that worsens with strain or physical exertion. When identified, pain from varicoceles is rarely successfully managed with conservative therapy alone, with spontaneous resolution rates of <1% described (18). Patients with pain consistent with symptomatic varicoceles should be offered treatment. Sperm DNA is tightly bound to protamine to protect it from damage during transport through the testis and epididymis (19). However, when sperm is exposed to oxidative stress, DNAF may occur (20). Elevated sperm DNAF has been found to be associated with greater incidence of spontaneous abortion, recurrent pregnancy loss, and lower intrauterine insemination (IUI) and in vitro fertilization (IVF) pregnancy rates (21). Furthermore, varicoceles have been found to have a significant association with elevated DNAF, and treatment of varicoceles has been shown to improve this (22). Pregnancy after varicocelectomy has been associated with decreased sperm DNAF compared with those who do not achieve pregnancy (23). Finally, for couples with male-factor infertility and clinical varicocele, varicocelectomy improves IVF outcomes compared with couples treated with IVF alone (24). Based on these findings, varicocelectomy may be offered to couples with failed IUI, failed IVF, or otherwise unexplained infertility or recurrent pregnancy loss when the male partner has been found to have elevated sperm DNAF with or without abnormal semen parameters. As men age, serum testosterone levels can decrease (25). Unfortunately, men with varicoceles may be at risk for premature androgen insufficiency: Varicoceles are known to impair Leydig cell function, resulting in decreased testosterone production (26), and correction of varicocele can improve serum testosterone levels (27). Hypogonadal men with palpable varicoceles may be offered treatment, although this is still somewhat controversial.
APPROACHES TO VARICOCELE TREATMENT Microsurgical Subinguinal Varicocelectomy Microsurgical subinguinal varicocelectomy (MSV) uses a 3cm transverse skin incision made over the pubic ramus just below the external ring, then carried down to and through the Scarpa fascia. The cord structures are grasped carefully with an atraumatic Babcock clamp and elevated into the wound. Sharp and blunt dissection are used to free the cord structures from surrounding tissues, allowing mobilization up through the skin incision. The cord is then secured at this level by an army-navy retractor. With the use of a surgical microscope for magnification, the external spermatic fascia is split and then divided. The vas and its perivasal vascular bundle are isolated and preserved. A micro-Doppler probe can then be used to identify the testicular artery. All lymphatic vessels are preserved when possible, as are any additional testicular arteries. All veins within the spermatic cord are ligated with either surgical clips or 4-0 ties. Once the cord has been reduced to the vas deferens, perivasal vessels, artery, VOL. 108 NO. 3 / SEPTEMBER 2017
and lymphatics, the spermatic cord is replaced into the wound. The wound is then closed with interrupted deep dermal suture and a running subcuticular suture (28). Although meta-analyses have shown improved semen parameters and catch-up growth for all techniques of varicocele treatment, microsurgical subinguinal approach is the optimal technique for treating varicoceles, because it is consistently found to have the lowest rates of postoperative complications, including hydrocele formation and varicocele recurrence (29–32). According to a recent meta-analysis by Cayan et al. (33), MSV had significantly lower hydrocele formation rates (0.44%) compared with laparoscopic varicocelectomy (2.84%). They also found recurrence rates to be significantly lower when MSV was performed (1.05%) compared with laparoscopic (4.3%) and radiologic embolization (12.7%). Additional comparative studies evaluating outcomes have supported these findings (34).
Inguinal Varicocelectomy Inguinal varicocelectomy uses a 3–4-cm incision over the lower inguinal canal, starting two to three finger breadths medial and caudal to the anterior iliac spine. The incision is carried down to and through the Scarpa fascia. Superficial inferior epigastric veins are ligated. The aponeurosis of the external oblique muscle is identified and incised parallel to the fascial fibers, with the incision continued inferiorly through the external inguinal ring. The ilioinguinal nerve is identified and freed from the underlying cord structures and then retracted laterally out of harm's way during the remainder of the procedure. The spermatic cord within the canal is isolated and elevated from the wound. The spermatic cord is then divided; vas, perivasal vessels, testicular artery, and lymphatics are all spared; and the veins are ligated. Running absorbable suture is then used to close the oblique fascia and subcutaneous space. The skin is closed with the use of a running subcuticular suture (28). Microscopic inguinal varicocelectomy has also been shown to have a significant positive effect on semen parameters, with success rates similar to the microscopic subinguinal approach and significantly better than retroperitoneal or laparoscopic varicocelectomy (28). With similar outcomes between the two techniques, some have advocated the use of the microsurgical inguinal varicocelectomy as a technically easier procedure (35). Considering that the subinguinal approach encounters more spermatic arteries, inguinal varicocelectomy is thought to involve fewer internal spermatic vessels with larger diameters, resulting in shorter operative time (36). However, comparative studies between the two procedures looking at operative times have found no difference in operative time, suggesting that length of surgery is dependent more on surgeon experience (37). Furthermore, inguinal varicocelectomy does not always address the larger cremasteric veins, which can increase the risk for recurrences. Finally, inguinal varicocelectomy is associated with increased postoperative pain owing to the need to incise the aponeurosis of the external oblique fascia (38). For these reasons, we think that despite similar outcomes between the two approaches, subinguinal varicocelectomy remains the technique of choice. 379
VIEWS AND REVIEWS Microsurgical versus Loupe Magnification In a retrospective review, Cayan et al. (39) compared operative outcomes and complications among patients undergoing microsurgical, loupe-assisted, or macroscopic varicocelectomy. All patients who were treated with the use of a subinguinal or inguinal approach experienced significant improvement in semen parameters. However, the microsurgical technique was associated with the least postoperative complications, including hydrocele (0%) and varicocele recurrence (0%), compared with both loupe-assisted technique (2.9% hydrocele and 2.9% recurrence rates) and unassisted technique (5.9% hydrocele and 8.8% recurrence rates). Additional retrospective studies evaluating outcomes for loupe-assisted varicocelectomy have described both higher hydrocele rates and higher recurrence rates compared with microsurgical varicocelectomy (40, 41).
Laparoscopic Varicocelectomy Laparoscopic varicocelectomy is typically performed with the use of three transperitoneal ports. A 5-mm laparoscopic port is positioned near the umbilicus and placed in peritoneal space via the Hassan or Veress-needle technique. Two additional 5-mm ports are then placed under visual guidance, one placed between the umbilicus and pubic symphysis, and the other lateral to the left epigastric vessels (42). Approximately 3 cm superior to the internal inguinal ring, the peritoneum overlying the spermatic vessels is incised. With the assistance of a laparoscopic Doppler or micro-Doppler probe, blunt and sharp dissection are then used to divide the spermatic vessels from surrounding tissues. Depending on surgeon preference, the testicular artery may or may not be isolated and spared. The veins are then ligated with clips and divided. The port sites are typically closed with the use of interrupted absorbable suture, and the skin is closed with the use of subcuticular suture (43). The incidence of postoperative hydrocele or recurrence after laparoscopic varicocelectomy is difficult to ascertain, because published studies mainly consist of small cohorts, inadequate follow-up, and a multitude of different techniques. Some authors have suggested that the incidence of postoperative hydrocele after varicocelectomy may be underestimated owing to the significant variation of described techniques (44). The two most commonly described techniques are the non–artery-sparing laparoscopic varicocelectomy, in which the testicular artery and spermatic veins are ligated, and the artery-sparing laparoscopic varicocelectomy, in which the spermatic veins are separated from the artery and only the veins ligated. Studies have shown that the arterysparing approach is associated with higher rates of varicocele recurrence, whereas the nonsparing approach has been found to be associated with increased risk of post-varicocelectomy hydrocele formation (43–45). One study by Esposito et al. demonstrated that the non–artery-sparing technique was associated with 3% recurrence and 17.6% hydrocele rates, whereas the artery-sparing technique was associated with 6% recurrence and 4.3% hydrocele rates (45). Many practitioners advocate for the use of arterysparing technique whenever possible. Studies have shown 380
that ligating the testicular artery has been associated with significant delay in catch up growth (46, 47). This delay has been found whether or not lymphatic sparing is performed at the time of arterial ligation varicocelectomy (43). Patients should be counseled that non–artery-sparing varicocelectomy may increase the risk for developing postvasectomy testicular atrophy, because the testicle depends on the cremasteric artery blood supply after vasectomy. Furthermore, patients should also be counseled on possible complications unique to the transperitoneal approach, including the possibility for injury to viscous, vascular, and other intraperitoneal and retroperitoneal structures. Compared with MSV, the laparoscopic approach is associated with higher recurrence rates and higher hydrocele rates. Studies have reported postoperative recurrence rates ranging from 3% to 6% and hydrocele rates ranging from 7% to 43% of patients undergoing laparoscopic varicocelectomy (46, 47). Recently, the laparoscopic approach has been modified to include lymphatic sparing. A recent study by Rizkala et al. (42) demonstrated that modifying the approach to include lymphatic sparing improves the rates of hydrocele formation to 4.5%. Short-term follow-up is a common limitation in the literature on laparoscopic varicocelectomy. There is a lack of data on outcomes or complications beyond 5 years of follow-up. This leads to an important unanswered question: What are the recurrence rates 10–15 years out from varicocelectomy, when patients are in their 30s and still within the peak reproductive window? One study highlights the significance of this shortcoming: Hassan et al. (48) demonstrated that longer post-varicocelectomy follow-up was associated with a higher rate of hydrocele formation and suggested that the incidence of hydrocele formation may be underreported as a result of insufficient follow-up.
Percutaneous Varicocele Embolization Varicocele embolization is a minimally invasive approach that is associated with decreased postoperative pain and decreased risk of hydrocele compared with the standard surgical approaches. Often before embolization, Doppler ultrasonography is performed to confirm the presence of varicoceles (49, 50). Percutaneous embolization is typically performed under intravenous sedation and local anesthesia, at which time venous access is either obtained via the right common femoral vein for left-sided varicoceles or the internal jugular vein for right-sided or bilateral varicoceles. Once the catheter tip has been advanced to the distal internal spermatic vein and pampiniform plexus, a venogram is performed. Varicoceles are then embolized either with occlusive solid agents, such as coils and vascular plugs, or liquid embolic agents, such as sclerosing tetradecyl sulfate (51). Postoperative ultrasonography is then performed after 3–6 months to confirm successful treatment (49). Multiple studies have demonstrated improvement in semen parameters following embolization, with efficacy similar to surgery (52–54). Prasivoravong et al. (55) demonstrated that among 47 infertile male patients with left varicocele and at least one abnormal semen parameter, VOL. 108 NO. 3 / SEPTEMBER 2017
Fertility and Sterility® percutaneous embolization of the varicocele resulted in improvement in median sperm count from 5.78 million to 38.75 million per ejaculate and significant improvement in progressive motility from 21.8% to 29.32%. Failure to treat is a complication that is unique to embolization. Successful embolization relies on gaining access to the spermatic vein and navigation of the catheter into the vein. Failure to do this occurs in 8%–30% of patients undergoing attempted embolization (49, 56). The meta-analysis by Cayan et al. found an overall technical failure rate of 13.05% among 314 patients, regardless of laterality (33). However, several studies indicate that failure to treat is uncommon when treating left sided varicoceles, while failure rates as high as 49% for right-sided varicoceles have been documented (56, 57). Another characteristic unique to embolization it that there is no risk of hydrocele formation after varicocele embolization, because the lymphatics are completely spared from the intervention. However, the recurrence rate has been found to range from 3% to 11% in the published literature (58–66), rates that are significantly higher than those of microsurgical varicocelectomy. Based on the increased risk of recurrence and risk for failure to gain access to spermatic veins, embolization is not typically recommended as a first-line treatment option for varicoceles in men with infertility (49). However, for patients wishing to avoid surgical incision, or men with recurrence after previous failed varicocele surgery, embolization can be offered.
OUTCOMES When comparing various techniques, previously published studies have not shown any significant differences in outcomes among the various technical approaches to treating varicoceles described in this chapter. The treatment outcomes described below can be generalized for all of the techniques described above.
Infertility In the past, varicocelectomy for treatment of male-factor infertility had been a controversial topic among reproductive specialists. The literature has been criticized for having few randomized controlled trials (RCTs), with most of the published studies being nonrandomized retrospective reviews. Much of the controversy came to a head after several metaanalyses were unable to identify evidence of linking varicocele treatment with improved pregnancy rates (67). However, many have countered that those meta-analyses were based on poor-quality RCT suffering from biases due to patient selection and questionable semen analysis classification before treatment (68). Furthermore, more recent higher-quality RCTs and non-RCTs have demonstrated that varicocele repair is clearly associated with significant improvement in semen parameters as well as spontaneous pregnancy rates compared with nonintervention (69, 70).
Semen Parameters Treatment of varicoceles is associated with improvements in semen quality. According to a recent randomized control trial VOL. 108 NO. 3 / SEPTEMBER 2017
by Abdel-Meguid et al. (71), treatment of palpable varicoceles in men with at least one abnormal semen parameter resulted in a 15% improvement in sperm count and a 15% improvement in sperm motility compared with the control group. Their findings have been further supported by several high quality meta-analyses of RCTs showing significant improvement in semen parameters after varicocelectomy compared with control groups (72–77). This significant benefit of varicocelectomy even extends to men with nonobstructive azoospermia and varicoceles. In one meta-analyses of azoospermic patients with varicoceles, Esteves et al. found (78) that varicocelectomy led to return of sperm to the ejaculate in 43.9% of patients and was associated with a 13.6% natural spontaneous pregnancy rate. In addition, they found that correction of varicocelectomy in this group was associated with improved sperm retrieval rates (odds ratio [OR] 2.65, 95% confidence interval [CI] 1.69–4.14; P< .001).
Pregnancy Rate Retrospective reviews on varicocele treatment have demonstrated that pregnancy rates are improved with varicocele ligation (72). A more recent prospective RCT found evidence to support this finding: Meguid et al. (71) reported that spontaneous pregnancy was achieved for 32.9% of patients who underwent varicocelectomy whereas only 13.9% of patients in the observation group achieved spontaneous pregnancy (OR 3.04, 95% CI 1.33–6.95). Furthermore, a meta-analysis by Marmar et al. (79) found that compared with nonintervention, patients who underwent varicocelectomy were 2.97 (95% CI 1.60–4.33) times more likely to achieve spontaneous pregnancy.
Testicular Growth Arrest in Adolescence Treatment of adolescent young men with testicular hypotrophy results in catch-up growth in the majority of patients. In an RCT by Paduch et al. (80), 124 patients with grade 2–3 varicocele and testis size discrepancy were assigned to either surgical intervention or observation. At 12 months after treatment, patients who underwent varicocelectomy experienced significant catch-up growth (mean volume discrepancy decreased from 12% to 3%; P< .001) whereas the control group did not (mean volume discrepancy decreased from 10% to 9%; P>.05). Multiple studies, as reported in two meta-analyses, corroborate this finding (15, 81). As with the adult population, adolescents with abnormal semen parameters and varicoceles experience significant improvement with treatment (77).
Pain Pain resolution results after microsurgical repair range from 53% to 93% for complete resolution, 5% to 20% for partial resolution, and 0% to 20% for failed treatment (82). However, selecting patients based on clinical pain characteristics may improve the chances for pain improvement. Specifically, a study by Kim et al. found that patients experiencing dull, aching, or dragging pain were more likely to experience pain resolution with varicocele treatment (83). 381
VIEWS AND REVIEWS Hypogonadism Varicocele repair results in significant improvements in testosterone levels in men with low preoperative testosterone levels (84). On average, varicocelectomy results in a mean increase in testosterone of 105.65 ng/dL (85). Of note, varicocele grade should be considered when deciding whether to treat patients with hypogonadism: Hypogonadal men with lowgrade unilateral varicoceles are not thought to receive significant benefit from varicocele treatment (86). Furthermore, treatment of varicoceles has no effect on testosterone levels in eugonadal men (84–86).
DNA Fragmentation Numerous retrospective and prospective studies have shown that varicocele repair results in a statistically significant improvement in sperm DNAF (22, 23, 87). However, the clinical significance of this is not yet clear. Studies have shown that on average, varicocelectomy results in only a 3.37% improvement in sperm DNAF compared with no treatment (88). Furthermore, a recent prospective study by Nasr-Esfahani et al. examined 162 patients with varicoceles and found no difference in sperm DNAF levels between patients who achieved pregnancy and those that did not achieve pregnancy after varicocelectomy (89). To date, there are no published studies evaluating what levels of improvement in DNAF result in improved pregnancy rates. To fully elucidate the clinical usefulness of DNAF levels in men with varicoceles, these data must be further investigated.
CONCLUSION Though still somewhat controversial, most evidence supports the treatment of clinically palpable varicoceles in the context of male-factor infertility. There is also good evidence for treatment in symptomatic varicoceles, as well as in adolescents with testicular growth retardation and/or abnormal semen parameters. Although most techniques have similar results in terms of outcome, each has its own advantages and disadvantages, and it is up to the provider and the patient to determine what will work best for them. Further studies, including predictive factors for success, more objective ways to diagnose, as well as nontraditional measures of success (e.g., decreased DNAF, improved testicular function) are needed to help us to better understand this condition.
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Kim HT, Song PH, Moon KH. Microsurgical ligation for painful varicocele: effectiveness and predictors of pain resolution. Yonsei Med J 2012;53:145. Elzanaty S, Johansen C. Microsurgical subinguinal varicocele repair of grade II–III lesions associated with improvements of testosterone levels. Curr Urol 2017;10:45–9. Chen X, Yang D, Lin G, Bao J, Wang J, Tan W. Efficacy of varicocelectomy in the treatment of hypogonadism in subfertile males with clinical varicocele: a metaanalysis. Andrologia 2017, http://dx.doi.org/10.1111/and.12778. [Epub ahead of print]. 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. Smit M, Romijn JC, Wildhagen MF, Veldhoven JL, Weber RF, Dohle GR. Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate. J Urol 2013;189:S146–50. Wang YJ, Zhang RQ, Lin YJ, Zhang RG, Zhang WL. Relationship between varicocele and sperm DNA damage and the effect of varicocele repair: a meta-analysis. Reprod Biomed Online 2012;25:307–14. Nasr-Esfahani MH, Abasi H, Razavi S, Ashrafi S, Tavalaee M. Varicocelectomy: semen parameters and protamine deficiency. Int J Androl 2009;32: 115–22.
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Varicoceles, a dilation of veins within the pampiniform plexus, are present in 15% of the general male population. This paper reviews the indications for treatment of varicoceles, post-intervention outcomes following treatment, and the various techniques for treatment of varicoceles. The aim of this review is to describe and compare complications associated with each approach to varicocele treatment. (Fertil SterilÒ 2017;108:378–84. Ó2017 by American Society for Reproductive Medicine.) Key Words: Microsurgery, varicocele, varicocelectomy, subinguinal, hydrocele Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/ 16110-fertility-and-sterility/posts/18600-24605
V
aricoceles, a dilation of veins within the pampiniform plexus, are present in 15% of the general male population. It is also one of the most frequent causes of male-factor infertility, with a prevalence of 30%–40% among men presenting for primary infertility evaluation and up to 85% in secondary infertility (1). In certain patients, varicoceles can cause testicular damage resulting in loss of testicular volume, spermatogenic dysfunction, disruption of hormone production, and sperm DNA damage (2–4). The mechanism of testicular dysfunction secondary to varicocele may be related to loss of the countercurrent temperature exchange between the pampiniform plexus and spermatic artery. Under normal physiologic circumstances, the testicle has been demonstrated to be 1–2 C cooler than the core body temperature (5). When varicoceles develop, venous stasis is often encountered, and the pooling of warm venous blood in these varicoceles is thought to lead to a loss of the countercurrent heat exchange (6). Studies using intrascrotal temperature probes
support this hypothesis, finding that patients with varicoceles had intratesticular temperatures that were significantly higher than patients without varicoceles (7). This increased heat has been found to be detrimental to spermatogenesis and to result in germ cell loss and DNA damage (8). Additional studies have found that varicoceles may also induce a state of transient hypoxia, resulting in increased reactive oxygen species that may contribute to testicular dysfunction (9, 10). Fortunately, both mechanisms of injury are typically correctable by means of treatment of the varicocele.
INDICATIONS According to best-practice statements from both the American Urological Association and the American Society for Reproductive Medicine, treatment of clinical varicoceles should be offered to the male partner of a couple attempting to conceive when the following are present: 1) a varicocele is palpable; 2) the couple has documented infertility; 3) the female has normal fertility or potentially
Received July 3, 2017; accepted July 19, 2017. Reprint requests: Jay Sandlow, M.D., Department of Urology, Medical College of Wisconsin, Milwaukee, WI 53226 (E-mail: [email protected]). Fertility and Sterility® Vol. 108, No. 3, September 2017 0015-0282/$36.00 Copyright ©2017 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2017.07.020 378
correctable infertility; and 4) the male partner has one or more abnormal semen parameters or sperm function test results (11). In addition, varicocele treatment is indicated when the goal of treatment is aimed at preventing or reversing testicular atrophy in adolescent males, correcting pain from varicoceles, addressing elevated sperm DNA fragmentation (DNAF), or improving testicular function in hypogonadal men with varicoceles. The incidence of clinical varicocele in adolescence is similar to that of the adult male population (12). Young men or adolescent boys with varicoceles should be evaluated for ipsilateral testicular hypotrophy and, if present, offered treatment. These patients are thought to be at risk for future testicular dysfunction and possible infertility (13). Studies have shown in young men that testicular volume discrepancy between the normal and the affected testis correlated with decreased sperm concentration and motility (14), and a cutoff of >10% size discrepancy has been proposed as a surgical criteria for asymptomatic adolescent varicocele (15). Furthermore, both nonhuman and human studies have shown that varicocele is associated with a progressive duration-dependent decline in testicular function (16) Adolescents with palpable varicoceles and objective
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Fertility and Sterility® evidence of reduced ipsilateral testicular size or abnormal semen parameters should be offered varicocele repair. Pain associated with varicoceles is relatively common and well recognized, with a prevalence of 2%–10% of men with varicoceles (17). This pain is often described as a dull throbbing pain that worsens with strain or physical exertion. When identified, pain from varicoceles is rarely successfully managed with conservative therapy alone, with spontaneous resolution rates of <1% described (18). Patients with pain consistent with symptomatic varicoceles should be offered treatment. Sperm DNA is tightly bound to protamine to protect it from damage during transport through the testis and epididymis (19). However, when sperm is exposed to oxidative stress, DNAF may occur (20). Elevated sperm DNAF has been found to be associated with greater incidence of spontaneous abortion, recurrent pregnancy loss, and lower intrauterine insemination (IUI) and in vitro fertilization (IVF) pregnancy rates (21). Furthermore, varicoceles have been found to have a significant association with elevated DNAF, and treatment of varicoceles has been shown to improve this (22). Pregnancy after varicocelectomy has been associated with decreased sperm DNAF compared with those who do not achieve pregnancy (23). Finally, for couples with male-factor infertility and clinical varicocele, varicocelectomy improves IVF outcomes compared with couples treated with IVF alone (24). Based on these findings, varicocelectomy may be offered to couples with failed IUI, failed IVF, or otherwise unexplained infertility or recurrent pregnancy loss when the male partner has been found to have elevated sperm DNAF with or without abnormal semen parameters. As men age, serum testosterone levels can decrease (25). Unfortunately, men with varicoceles may be at risk for premature androgen insufficiency: Varicoceles are known to impair Leydig cell function, resulting in decreased testosterone production (26), and correction of varicocele can improve serum testosterone levels (27). Hypogonadal men with palpable varicoceles may be offered treatment, although this is still somewhat controversial.
APPROACHES TO VARICOCELE TREATMENT Microsurgical Subinguinal Varicocelectomy Microsurgical subinguinal varicocelectomy (MSV) uses a 3cm transverse skin incision made over the pubic ramus just below the external ring, then carried down to and through the Scarpa fascia. The cord structures are grasped carefully with an atraumatic Babcock clamp and elevated into the wound. Sharp and blunt dissection are used to free the cord structures from surrounding tissues, allowing mobilization up through the skin incision. The cord is then secured at this level by an army-navy retractor. With the use of a surgical microscope for magnification, the external spermatic fascia is split and then divided. The vas and its perivasal vascular bundle are isolated and preserved. A micro-Doppler probe can then be used to identify the testicular artery. All lymphatic vessels are preserved when possible, as are any additional testicular arteries. All veins within the spermatic cord are ligated with either surgical clips or 4-0 ties. Once the cord has been reduced to the vas deferens, perivasal vessels, artery, VOL. 108 NO. 3 / SEPTEMBER 2017
and lymphatics, the spermatic cord is replaced into the wound. The wound is then closed with interrupted deep dermal suture and a running subcuticular suture (28). Although meta-analyses have shown improved semen parameters and catch-up growth for all techniques of varicocele treatment, microsurgical subinguinal approach is the optimal technique for treating varicoceles, because it is consistently found to have the lowest rates of postoperative complications, including hydrocele formation and varicocele recurrence (29–32). According to a recent meta-analysis by Cayan et al. (33), MSV had significantly lower hydrocele formation rates (0.44%) compared with laparoscopic varicocelectomy (2.84%). They also found recurrence rates to be significantly lower when MSV was performed (1.05%) compared with laparoscopic (4.3%) and radiologic embolization (12.7%). Additional comparative studies evaluating outcomes have supported these findings (34).
Inguinal Varicocelectomy Inguinal varicocelectomy uses a 3–4-cm incision over the lower inguinal canal, starting two to three finger breadths medial and caudal to the anterior iliac spine. The incision is carried down to and through the Scarpa fascia. Superficial inferior epigastric veins are ligated. The aponeurosis of the external oblique muscle is identified and incised parallel to the fascial fibers, with the incision continued inferiorly through the external inguinal ring. The ilioinguinal nerve is identified and freed from the underlying cord structures and then retracted laterally out of harm's way during the remainder of the procedure. The spermatic cord within the canal is isolated and elevated from the wound. The spermatic cord is then divided; vas, perivasal vessels, testicular artery, and lymphatics are all spared; and the veins are ligated. Running absorbable suture is then used to close the oblique fascia and subcutaneous space. The skin is closed with the use of a running subcuticular suture (28). Microscopic inguinal varicocelectomy has also been shown to have a significant positive effect on semen parameters, with success rates similar to the microscopic subinguinal approach and significantly better than retroperitoneal or laparoscopic varicocelectomy (28). With similar outcomes between the two techniques, some have advocated the use of the microsurgical inguinal varicocelectomy as a technically easier procedure (35). Considering that the subinguinal approach encounters more spermatic arteries, inguinal varicocelectomy is thought to involve fewer internal spermatic vessels with larger diameters, resulting in shorter operative time (36). However, comparative studies between the two procedures looking at operative times have found no difference in operative time, suggesting that length of surgery is dependent more on surgeon experience (37). Furthermore, inguinal varicocelectomy does not always address the larger cremasteric veins, which can increase the risk for recurrences. Finally, inguinal varicocelectomy is associated with increased postoperative pain owing to the need to incise the aponeurosis of the external oblique fascia (38). For these reasons, we think that despite similar outcomes between the two approaches, subinguinal varicocelectomy remains the technique of choice. 379
VIEWS AND REVIEWS Microsurgical versus Loupe Magnification In a retrospective review, Cayan et al. (39) compared operative outcomes and complications among patients undergoing microsurgical, loupe-assisted, or macroscopic varicocelectomy. All patients who were treated with the use of a subinguinal or inguinal approach experienced significant improvement in semen parameters. However, the microsurgical technique was associated with the least postoperative complications, including hydrocele (0%) and varicocele recurrence (0%), compared with both loupe-assisted technique (2.9% hydrocele and 2.9% recurrence rates) and unassisted technique (5.9% hydrocele and 8.8% recurrence rates). Additional retrospective studies evaluating outcomes for loupe-assisted varicocelectomy have described both higher hydrocele rates and higher recurrence rates compared with microsurgical varicocelectomy (40, 41).
Laparoscopic Varicocelectomy Laparoscopic varicocelectomy is typically performed with the use of three transperitoneal ports. A 5-mm laparoscopic port is positioned near the umbilicus and placed in peritoneal space via the Hassan or Veress-needle technique. Two additional 5-mm ports are then placed under visual guidance, one placed between the umbilicus and pubic symphysis, and the other lateral to the left epigastric vessels (42). Approximately 3 cm superior to the internal inguinal ring, the peritoneum overlying the spermatic vessels is incised. With the assistance of a laparoscopic Doppler or micro-Doppler probe, blunt and sharp dissection are then used to divide the spermatic vessels from surrounding tissues. Depending on surgeon preference, the testicular artery may or may not be isolated and spared. The veins are then ligated with clips and divided. The port sites are typically closed with the use of interrupted absorbable suture, and the skin is closed with the use of subcuticular suture (43). The incidence of postoperative hydrocele or recurrence after laparoscopic varicocelectomy is difficult to ascertain, because published studies mainly consist of small cohorts, inadequate follow-up, and a multitude of different techniques. Some authors have suggested that the incidence of postoperative hydrocele after varicocelectomy may be underestimated owing to the significant variation of described techniques (44). The two most commonly described techniques are the non–artery-sparing laparoscopic varicocelectomy, in which the testicular artery and spermatic veins are ligated, and the artery-sparing laparoscopic varicocelectomy, in which the spermatic veins are separated from the artery and only the veins ligated. Studies have shown that the arterysparing approach is associated with higher rates of varicocele recurrence, whereas the nonsparing approach has been found to be associated with increased risk of post-varicocelectomy hydrocele formation (43–45). One study by Esposito et al. demonstrated that the non–artery-sparing technique was associated with 3% recurrence and 17.6% hydrocele rates, whereas the artery-sparing technique was associated with 6% recurrence and 4.3% hydrocele rates (45). Many practitioners advocate for the use of arterysparing technique whenever possible. Studies have shown 380
that ligating the testicular artery has been associated with significant delay in catch up growth (46, 47). This delay has been found whether or not lymphatic sparing is performed at the time of arterial ligation varicocelectomy (43). Patients should be counseled that non–artery-sparing varicocelectomy may increase the risk for developing postvasectomy testicular atrophy, because the testicle depends on the cremasteric artery blood supply after vasectomy. Furthermore, patients should also be counseled on possible complications unique to the transperitoneal approach, including the possibility for injury to viscous, vascular, and other intraperitoneal and retroperitoneal structures. Compared with MSV, the laparoscopic approach is associated with higher recurrence rates and higher hydrocele rates. Studies have reported postoperative recurrence rates ranging from 3% to 6% and hydrocele rates ranging from 7% to 43% of patients undergoing laparoscopic varicocelectomy (46, 47). Recently, the laparoscopic approach has been modified to include lymphatic sparing. A recent study by Rizkala et al. (42) demonstrated that modifying the approach to include lymphatic sparing improves the rates of hydrocele formation to 4.5%. Short-term follow-up is a common limitation in the literature on laparoscopic varicocelectomy. There is a lack of data on outcomes or complications beyond 5 years of follow-up. This leads to an important unanswered question: What are the recurrence rates 10–15 years out from varicocelectomy, when patients are in their 30s and still within the peak reproductive window? One study highlights the significance of this shortcoming: Hassan et al. (48) demonstrated that longer post-varicocelectomy follow-up was associated with a higher rate of hydrocele formation and suggested that the incidence of hydrocele formation may be underreported as a result of insufficient follow-up.
Percutaneous Varicocele Embolization Varicocele embolization is a minimally invasive approach that is associated with decreased postoperative pain and decreased risk of hydrocele compared with the standard surgical approaches. Often before embolization, Doppler ultrasonography is performed to confirm the presence of varicoceles (49, 50). Percutaneous embolization is typically performed under intravenous sedation and local anesthesia, at which time venous access is either obtained via the right common femoral vein for left-sided varicoceles or the internal jugular vein for right-sided or bilateral varicoceles. Once the catheter tip has been advanced to the distal internal spermatic vein and pampiniform plexus, a venogram is performed. Varicoceles are then embolized either with occlusive solid agents, such as coils and vascular plugs, or liquid embolic agents, such as sclerosing tetradecyl sulfate (51). Postoperative ultrasonography is then performed after 3–6 months to confirm successful treatment (49). Multiple studies have demonstrated improvement in semen parameters following embolization, with efficacy similar to surgery (52–54). Prasivoravong et al. (55) demonstrated that among 47 infertile male patients with left varicocele and at least one abnormal semen parameter, VOL. 108 NO. 3 / SEPTEMBER 2017
Fertility and Sterility® percutaneous embolization of the varicocele resulted in improvement in median sperm count from 5.78 million to 38.75 million per ejaculate and significant improvement in progressive motility from 21.8% to 29.32%. Failure to treat is a complication that is unique to embolization. Successful embolization relies on gaining access to the spermatic vein and navigation of the catheter into the vein. Failure to do this occurs in 8%–30% of patients undergoing attempted embolization (49, 56). The meta-analysis by Cayan et al. found an overall technical failure rate of 13.05% among 314 patients, regardless of laterality (33). However, several studies indicate that failure to treat is uncommon when treating left sided varicoceles, while failure rates as high as 49% for right-sided varicoceles have been documented (56, 57). Another characteristic unique to embolization it that there is no risk of hydrocele formation after varicocele embolization, because the lymphatics are completely spared from the intervention. However, the recurrence rate has been found to range from 3% to 11% in the published literature (58–66), rates that are significantly higher than those of microsurgical varicocelectomy. Based on the increased risk of recurrence and risk for failure to gain access to spermatic veins, embolization is not typically recommended as a first-line treatment option for varicoceles in men with infertility (49). However, for patients wishing to avoid surgical incision, or men with recurrence after previous failed varicocele surgery, embolization can be offered.
OUTCOMES When comparing various techniques, previously published studies have not shown any significant differences in outcomes among the various technical approaches to treating varicoceles described in this chapter. The treatment outcomes described below can be generalized for all of the techniques described above.
Infertility In the past, varicocelectomy for treatment of male-factor infertility had been a controversial topic among reproductive specialists. The literature has been criticized for having few randomized controlled trials (RCTs), with most of the published studies being nonrandomized retrospective reviews. Much of the controversy came to a head after several metaanalyses were unable to identify evidence of linking varicocele treatment with improved pregnancy rates (67). However, many have countered that those meta-analyses were based on poor-quality RCT suffering from biases due to patient selection and questionable semen analysis classification before treatment (68). Furthermore, more recent higher-quality RCTs and non-RCTs have demonstrated that varicocele repair is clearly associated with significant improvement in semen parameters as well as spontaneous pregnancy rates compared with nonintervention (69, 70).
Semen Parameters Treatment of varicoceles is associated with improvements in semen quality. According to a recent randomized control trial VOL. 108 NO. 3 / SEPTEMBER 2017
by Abdel-Meguid et al. (71), treatment of palpable varicoceles in men with at least one abnormal semen parameter resulted in a 15% improvement in sperm count and a 15% improvement in sperm motility compared with the control group. Their findings have been further supported by several high quality meta-analyses of RCTs showing significant improvement in semen parameters after varicocelectomy compared with control groups (72–77). This significant benefit of varicocelectomy even extends to men with nonobstructive azoospermia and varicoceles. In one meta-analyses of azoospermic patients with varicoceles, Esteves et al. found (78) that varicocelectomy led to return of sperm to the ejaculate in 43.9% of patients and was associated with a 13.6% natural spontaneous pregnancy rate. In addition, they found that correction of varicocelectomy in this group was associated with improved sperm retrieval rates (odds ratio [OR] 2.65, 95% confidence interval [CI] 1.69–4.14; P< .001).
Pregnancy Rate Retrospective reviews on varicocele treatment have demonstrated that pregnancy rates are improved with varicocele ligation (72). A more recent prospective RCT found evidence to support this finding: Meguid et al. (71) reported that spontaneous pregnancy was achieved for 32.9% of patients who underwent varicocelectomy whereas only 13.9% of patients in the observation group achieved spontaneous pregnancy (OR 3.04, 95% CI 1.33–6.95). Furthermore, a meta-analysis by Marmar et al. (79) found that compared with nonintervention, patients who underwent varicocelectomy were 2.97 (95% CI 1.60–4.33) times more likely to achieve spontaneous pregnancy.
Testicular Growth Arrest in Adolescence Treatment of adolescent young men with testicular hypotrophy results in catch-up growth in the majority of patients. In an RCT by Paduch et al. (80), 124 patients with grade 2–3 varicocele and testis size discrepancy were assigned to either surgical intervention or observation. At 12 months after treatment, patients who underwent varicocelectomy experienced significant catch-up growth (mean volume discrepancy decreased from 12% to 3%; P< .001) whereas the control group did not (mean volume discrepancy decreased from 10% to 9%; P>.05). Multiple studies, as reported in two meta-analyses, corroborate this finding (15, 81). As with the adult population, adolescents with abnormal semen parameters and varicoceles experience significant improvement with treatment (77).
Pain Pain resolution results after microsurgical repair range from 53% to 93% for complete resolution, 5% to 20% for partial resolution, and 0% to 20% for failed treatment (82). However, selecting patients based on clinical pain characteristics may improve the chances for pain improvement. Specifically, a study by Kim et al. found that patients experiencing dull, aching, or dragging pain were more likely to experience pain resolution with varicocele treatment (83). 381
VIEWS AND REVIEWS Hypogonadism Varicocele repair results in significant improvements in testosterone levels in men with low preoperative testosterone levels (84). On average, varicocelectomy results in a mean increase in testosterone of 105.65 ng/dL (85). Of note, varicocele grade should be considered when deciding whether to treat patients with hypogonadism: Hypogonadal men with lowgrade unilateral varicoceles are not thought to receive significant benefit from varicocele treatment (86). Furthermore, treatment of varicoceles has no effect on testosterone levels in eugonadal men (84–86).
DNA Fragmentation Numerous retrospective and prospective studies have shown that varicocele repair results in a statistically significant improvement in sperm DNAF (22, 23, 87). However, the clinical significance of this is not yet clear. Studies have shown that on average, varicocelectomy results in only a 3.37% improvement in sperm DNAF compared with no treatment (88). Furthermore, a recent prospective study by Nasr-Esfahani et al. examined 162 patients with varicoceles and found no difference in sperm DNAF levels between patients who achieved pregnancy and those that did not achieve pregnancy after varicocelectomy (89). To date, there are no published studies evaluating what levels of improvement in DNAF result in improved pregnancy rates. To fully elucidate the clinical usefulness of DNAF levels in men with varicoceles, these data must be further investigated.
CONCLUSION Though still somewhat controversial, most evidence supports the treatment of clinically palpable varicoceles in the context of male-factor infertility. There is also good evidence for treatment in symptomatic varicoceles, as well as in adolescents with testicular growth retardation and/or abnormal semen parameters. Although most techniques have similar results in terms of outcome, each has its own advantages and disadvantages, and it is up to the provider and the patient to determine what will work best for them. Further studies, including predictive factors for success, more objective ways to diagnose, as well as nontraditional measures of success (e.g., decreased DNAF, improved testicular function) are needed to help us to better understand this condition.
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