Zhiping Wang, The Second Hospital of Lanzhou University – Department of Urology, 80 Cui Ying Meng Street, Lanzhou, GanSu 730000, China. e-mail: firstname.lastname@example.org
Study Type – Therapy (systematic review)
Level of Evidence 1a
What's known on the subject? and What does the study add?
There are several surgical techniques for the treatment of varicocele in infertile men, including open non-microsurgical, laparoscopic and microsurgical varicocelectomy. It is currently unclear, however, which is the most beneficial method for patients.
The present meta-analysis found that microsurgical varicocelectomy is the most effective and least morbid method among the three varicocelectomy techniques for treating varicocele in infertile men.
• To compare various techniques of open non-microsurgical, laparoscopic or microsurgical varicocelectomy procedures to describe the best method for treating varicocele in infertile men.
PATIENTS AND METHODS
• We searched PubMed, Embase, the Cochrane Library, the Institute for Scientific Information (ISI) – Science Citation Index and the Chinese Biomedicine Literature Database up to June 2011. Only randomized controlled trials (RCTs) were included in the present study.
• The outcome measures assessed were pregnancy rate (primary), the incidence of recurrent varicocele, time to return to work, the incidence of postoperative hydrocele and operation duration (secondary).
• Two authors independently assessed the study quality and extracted data. All data were analysed using Review Manager (version 5.0).
• The present study included four randomized controlled trials comprising 1,015 patients in total.
• At the follow-up endpoints, patients who had undergone microsurgery showed a significant advantage over those who had undergone open varicocelectomy in terms of pregnancy rate (odds ratio [OR]= 1.63, 95% confidence interval [CI]: 1.19–2.23].
• There was no significant difference between laparoscopic and open varicocelectomy (OR = 1.11, 95% CI: 0.65–1.88) or between microsurgery and laparoscopic varicocelectomy (OR = 1.37, 95% CI: 0.84–2.24).
• The incidences of recurrent varicocele and postoperative hydrocele were significantly lower after microsurgery than after laparoscopic or open varicocelectomy.
• The time to return to work after microsurgery and laparoscopic varicocelectomy was significantly shorter than that after open varicocelectomy.
• The operation duration of microsurgical varicocelectomy was longer than that of laparoscopic or open varicocelectomy.
• Current evidence indicates that microsurgical varicocelectomy is the most effective and least morbid method among the three varicocelectomy techniques for treating varicocele in infertile men.
• More high-quality, multicentre, long-term RCTs are required to verify the findings.
A varicocele is defined as dilated and tortuous veins within the pampiniform plexus of scrotal veins. They are present in 15% of the normal male population and in up to 40% of patients with male infertility . Varicoceles are now recognized as the most surgically correctable cause of male infertility. Varicoceles are believed to cause male infertility by impaired drainage or pooling of blood around the testis, leading to increased scrotal temperature. Approximately 90% of varicoceles are left-sided. Whereas most studies report an ≈10% prevalence of bilateral varicoceles, a few have reported a higher prevalence of bilaterality . Although a Cochrane database suggested no benefit of varicocele treatment in relation to a couple's chances of conception compared with control subjects, this meta-analysis included patients with subclinical varicoceles or normal semen analyses . Varicoceles are now recognized as the most surgically correctable cause of male infertility. In a meta-analysis, Marmar et al.  reported a 33% pregnancy rate in patients who underwent surgical varicocelectomy and a 15.5% pregnancy rate in the controls receiving no varicocelectomy. A recent randomized controlled trials (RCT) showed that varicocelectomy is superior to observation in infertile patients with palpable varicoceles and impaired semen quality, with increased odds of spontaneous pregnancy and improvements in semen characteristics within1 year of follow-up .
Several surgical approaches have been used for varicocele, including open surgical ligation of the spermatic vein, and microsurgical and laparoscopic varicocelectomy. Each technique has its own advantages and disadvantages, and conflicting results have been achieved in different studies [6–11], but to date there has been no consensus as to which technique should be considered the ‘gold standard’. These conflicting reports from numerous published articles on the efficacy and complications of individual techniques therefore led us to believe there was a need to compare and contrast thoroughly the outcomes of existing techniques to provide better guidance for urologists concerning choice of surgical approach. Cayan et al.  performed a meta-analysis to define the best technique for treating palpable varicocele in infertile patients. The results showed that the microsurgical varicocelectomy technique is associated with higher spontaneous pregnancy rates and lower postoperative recurrence and hydrocele formation than conventional varicocelectomy techniques in infertile patients. However, this meta-analysis included studies with non-randomized prospective (controlled and non-controlled) studies. Therefore, prospective, randomized and comparative studies are needed to compare the efficacy of microsurgical varicocelectomy with that of other treatment modalities in infertile patients with varicocele. In the present study, we carried out a meta-analysis of RCTs to determine the effectiveness of open non-microsurgical, laparoscopic or microsurgical varicocelectomy for male infertility.
PATIENTS AND METHODS
Literature searches were performed to identify RCTs of open non-microsurgical, laparoscopic or microsurgical varicocelectomy procedures for male infertility. The databases PubMed (1966–June 2011), Embase (1974–June 2011), the Cochrane Library (2011 issue 6), the Institute for Scientific Information (ISI) – Science Citation Index (1955–June 2011) and the Chinese Biomedicine Literature database (1978–June 2011) were used with the search terms ‘varicocelectomy’ and ‘infertility’ to identify all relevant RCTs on the subject. We also searched the references of included studies to identify additional, potentially relevant studies. Hand searching of the reference lists of included studies and reviews was undertaken and contact was made with experts in the field; unpublished studies were not sought. The searches were not restricted by publication year or language.
The search strategy described was used to obtain titles and abstracts of RCTs that were relevant to this review. The titles and abstracts were screened independently by two reviewers, who discarded studies that were not applicable, and two reviewers independently assessed the retrieved titles and abstracts of all identified trials to confirm fulfilment of inclusion criteria. Disagreements were resolved in consultation with the third reviewer. Data extraction was carried out independently by the same authors using standard data extraction forms. The quality of the included RCTs was assessed using the Jadad scale for each study, with scores ranging from zero to five points . Additionally, referring to the Cochrane group, allocation concealment was assessed as adequate (A), unclearly concealed (B), inadequate (C) or not reported (D) . Studies were considered to be of high quality if they Jadad score >1 plus allocation concealment A, or Jadad ≥3 plus allocation concealment B, C or D.
Only RCTs testing open non-microsurgical, laparoscopic or microsurgical varicocelectomy procedures in adults with male infertility were included. A patient was considered for varicocelectomy when the history of infertility exceeded 12 months and where there was a clinically palpable varicocele by physical examination and a defect in semen analysis consisting of sperm density <20 million/mL and/or sperm motility <50% – and where the female partner had a normal evaluation. However, patients with subclinical varicocele, defined as scrotal venous reflux without any palpable distension of the pampiniform plexus, were excluded from study.
The outcome measures included incidence of recurrent varicocele, pregnancy rate, time to return to work, the incidence of postoperative hydrocele and operation duration.
The types of intervention were laparoscopic vs open varicocelectomy, microsurgical vs open varicocelectomy and microsurgical vs laparoscopic varicocelectomy.
For the statistical analysis, we analysed the data using Review Manager (version 5.0) and extracted and pooled data for summary estimates. According to the Cochrane guidelines for meta-analysis we combined data on dichotomous outcomes using the Mantel–Haenszel relative risk method (odds ratio [OR]). For continuous outcomes we used the inverse variance mean difference (MD) method and 95% confidence intervals (95%CI). We used the χ2 statistic to assess heterogeneity between trials and the I2 statistic to assess the extent of inconsistency. We used a fixed-effects model for calculations of summary estimates and their 95% CI unless there was significant heterogeneity, in which case results were confirmed using a random effects statistical model.
We identified 655 references to potential studies and subsequently excluded 653 trials for the following reasons: 625 were not randomized and 26 did not meet the previous inclusion criteria. Four RCTs comprising a total of 1015 patients were included [8,10,15,16]. Two trials [10,16] reported all three types of varicocelectomy and patient outcomes, including the incidence of recurrent varicocele, the pregnancy rate, time to return to work, incidence of postoperative hydrocele, operation duration and semen variables. The other two trials [8,15] only reported two types of varicocelectomy, microsurgical and open varicocelectomy, and patient outcomes including the incidence of recurrent varicocele, the pregnancy rate, the incidence of postoperative hydrocele and semen variables.
The quality of the studies included and their characteristics studies are shown in Table 1.
Table 1. Characteristics and quality assessment of the studies included in the meta-analysis
At the follow-up endpoints, patients who had undergone microsurgery showed a significant advantage over those who had undergone open varicocelectomy in terms of pregnancy rate (OR = 1.63, 95% CI: 1.19–2.23). However, there was no significant difference between laparoscopic and open varicocelectomy (OR = 1.11, 95% CI: 0.65–1.88). The pregnancy rate was higher after microsurgery than after laparoscopic varicocelectomy (39.1% vs 31.8%), although there was no statistical difference (OR = 1.37, 95% CI: 0.84–2.24). The pregnancy rate results are shown in Fig. 1.
The incidence of recurrent varicocele (Fig. 2A) was significantly lower after microsurgery than after laparoscopic or open varicocelectomy (OR = 0.12, 95% CI: 0.05–0.32 and OR = 0.13, 95% CI: 0.07–0.25, respectively), while there was no significant difference between laparoscopic and open varicocelectomy (OR = 1.55, 95% CI: 0.88–2.75).
The incidence of postoperative hydrocele (Fig. 2B) was significantly lower after microsurgery than after laparoscopic or open varicocelectomy (OR = 0.05, 95% CI: 0.01–0.36 and OR = 0.09, 95% CI: 0.03–0.29, respectively), while there was no significant difference between laparoscopic and open varicocelectomy (OR = 1.71, 95% CI: 0.77–3.80).
We used a random effects model for operation duration because of statistical heterogeneity, explored by χ2 tests and I2 statistics. Regardless of whether it was a left or bilateral varicocele, the duration of microsurgical varicocelectomy was longer than that of laparoscopic or open varicocelectomy, while the duration of laparoscopic varicocelectomy was only longer than open varicocelectomy for a single left varicocelectomy. The results are shown in Fig. 3A.
The time to return to work (Fig. 3B) was significantly shorter after microsurgery or laparoscopic varicocelectomy than after open varicocelectomy (OR =−1.11, 95% CI: −1.69 to −0.53 and OR =−0.97, 95% CI: −1.60 to −0.34, respectively). However, there was no significant difference between microsurgery and laparoscopic varicocelectomy (OR =−0.32, 95% CI: −1.13 to −0.50).
Varicocele repair by occlusion of the affected spermatic vein(s) is the treatment of choice for most physicians, and can result in improvements in scrotal discomfort, serum testosterone, semen variables and spontaneous pregnancy . Baazeem et al.'s  study showed that the natural pregnancy rate is higher in patients after varicocelectomy than in those not undergoing surgery at all (all patients presenting with ≥1 year of infertility, a clinically palpable varicocele and abnormally reduced semen variables on two or more semen samples were deemed to be candidates for varicocele repair). A new meta-analysis showed that, although there is no conclusive evidence that a varicocele repair improves spontaneous pregnancy rates compared with no treatment, varicocelectomy improves sperm variables (count and total and progressive motility), reduces sperm DNA damage and seminal oxidative stress, and improves sperm ultramorphology . These studies indicate that varicocele repair is an effective therapy for varicocele in infertile men. To date, no systematic review or meta-analysis of RCTs comparing different varicocele repair in patients with infertility has been published.
Open surgical approaches are high retroperitoneal (Palomo), modified Palomo, inguinal and subinguinal approaches done macroscopically or microscopically. The retroperitoneal approach involves ligation of the internal spermatic vein as it exits the inguinal canal and preservation of the internal spermatic artery. The retroperitoneal approach was one of the first techniques developed and, although still a reasonable technique, it has been associated with higher rates of recurrence and postoperative hydrocele. A common complication of the retroperitoneal approach is varicocele recurrence or persistence, estimated to be between 11% and 15% [20–22]. A possible explanation for varicocele recurrence is that this approach does not allow ligation of the external gonadal (cremasteric) vessels, which have been thought to cause recurrent or persistent varicoceles. The advantage of this technique is ligation of a reduced number of veins at this higher level, which might minimize the potential for recurrence of varicocele. However, a disadvantage of this technique is that it does not allow identification and ligation of the external spermatic vein as the second cause of recurrent and persistent varicoceles after varicocelectomy [23,24]. Two modifications of this technique include the inguinal (Ivanissevich) and subinguinal approaches. Both approaches involve an incision at (subinguinal) or above (inguinal) the external inguinal ring. The subinguinal technique has the benefit of preserving muscle layers and the inguinal canal; however, it is also more technically challenging due to the greater number of internal spermatic veins and arteries below the external ring . The non-microsurgical versions of these procedures also have relatively low rates of other complications (e.g. hydrocele). The laparoscopic approach is very similar to the retroperitoneal approach as far as identifying anatomical landmarks. Advantages include higher magnification than other non-microsurgical open procedures . However, this technique is still considered fairly invasive and can be challenging when attempting to delineate spermatic veins and arteries. Surgical repairs by most urological reproductive surgeons involve microsurgical techniques to preserve the internal spermatic arteries and lymphatics. The inguinal and subinguinal approaches are the preferred ones. For the microsurgical technique, the microscope is now brought into the operating field. The internal and external spermatic fasciae are incised, and the dilated veins are identified .
Because pregnancy is the ultimate goal for patients who are infertile, we adopted spontaneous pregnancy rate as the primary outcome measure, and varicocele recurrences, hydrocele rates and time to return to work as secondary outcome measures. However, in the present meta-analysis, we did not include comparison of postoperative improvement in semen variables between the techniques because of the lack of data from studies. In the present study, the meta-analysis results showed that microscopic varicocelectomy is more successful than open varicocelectomy and laparoscopic varicocelectomy in terms of spontaneous pregnancy rates (40.2% vs 29.3% and 39.0% vs 31.8%, respectively), and less than laparoscopic and open varicocelectomy in relation to varicocele recurrences (2.5% vs 17.2% and 2% vs 14%, respectively) and hydrocele rates (0% vs 0.1% and 0.005% vs 0.08%, respectively), results that are consistent with previous studies.
Cayan et al.  examined 36 studies, and concluded that microscopic varicocelectomy techniques led to higher spontaneous pregnancy rates (41.97%), fewer varicocele recurrences (1.05%) and lower hydrocele rates (0.44%) than other methods of varicocele repair, including laparoscopic and open varicocelectomy. The time to return to work after microscopic and laparoscopic varicocelectomies was shorter than that after open varicocelectomy. Only the operation duration of microsurgical varicocelectomy was longer than that of laparoscopic or open varicocelectomy, indicating that surgeons require microsurgical training. Watanabe et al.  performed 144 varicocelectomies on infertile patients with left clinical varicocele, and the results showed that subinguinal microscopic varicocelectomy could be a minimally invasive procedure compared with the other two techniques (open and laparoscopic varicocelectomy) and a worthy method for treating male infertility due to clinical varicocele.
The pooled results indicated that the main advantage of the microsurgical over the non-microsurgical technique is the significant reduction in postoperative complications, such as hydrocele formation and varicocele recurrence. These improved results of hydrocele formation are thought to be due to a greater ability to identify and preserve individual lymphatics, and the fact that all internal and external spermatic veins can be ligated to prevent varicocele recurrence.
Goldberg et al.  proposed that embolization should be considered as the initial treatment of varicocele because of its reduced invasiveness and similar pregnancy outcome to retroperitoneal high ligation. Sautter et al.  reported that antegrade sclerotherapy is less invasive than laparoscopic varicocelectomy in treating male varicocele with lower costs and better outcomes, should therefore be the preferred treatment for this condition. However, Yavetz et al.  reported that high ligation of the internal spermatic vein yields better results than embolization as far as semen quality and subsequent pregnancy rates are concerned. Depending on the skill level of the team performing the procedure, the failure rate can vary from 4% to 27% . However, because of a lack of studies comparing surgical approaches with embolization, we did not carry out a meta-analysis to evaluate the differences between surgical approaches and embolization in the present study.
Four trials scored less than 3 on the Jadad scale. Two RCTs failed to describe sequence generation sufficiently [8,10]. None of the four trials described allocation concealment or blinding procedures. However, because of the ethical limitations and characteristics of surgical studies, we deemed that the quality of the included studies was higher than that of other studies, such as case–control and cohort studies.
The number of the included studies is relatively small, Only two trials reported all three types of varicocelectomy and outcomes. The small number of participants and included studies might not allow a reliable conclusion to be drawn. Because of the special nature of surgical intervention involved in the four included studies, none of them mentioned blinding and intention-to-treat analysis, which could produce high performance bias, measuring bias and selective bias. There might also be publication bias. Future research should clearly spell out how to implement blinding and allocation concealment.
In conclusion, the current evidence indicates that microsurgical varicocelectomy is the most effective and least morbid method among the three varicocelectomy techniques for treating varicocele in infertile men. However, in the future, we still need more high-quality, multicentre, long-term RCTs to verify the findings.