Stesura Seveso INTRODUCTION Varicocele can affect all parameters of sperm characteris- tics, including sperm count, sperm motility, and mor- phology. Different techniques have been suggested for varicocele treatment, both surgical and non-surgical. The surgical techniques include the open surgical (inguinal, subinguinal, retroperitoneal approach), laparoscopic and microsurgical varicocelectomies. The non-surgical are 143Archivio Italiano di Urologia e Andrologia 2013; 85, 3 ORIGINAL PAPER Varicocele treatment: A 2-centers comparison between non microsurgical open correction, laparoscopic approach and retrograde percutaneous sclerotization on 463 cases Giangiacomo Ollandini 1, Giovanni Liguori 1, Stanislav Ziaran 2, Tomá! Málek 2, Giorgio Mazzon 1, Bernardino de Concilio 1, Stefano Bucci 1, Sara Benvenuto 1, Emanuele Belgrano 1, Carlo Trombetta 1 1 Urologic Unit, Cattinara Hospital, University of Trieste, Trieste, Italy; 2 Urology clinic, University hospital in Bratislava, Comenius University, Bratislava, Slovakia. Objectives: To determine whether there are differences in sperm parameters improve- ment after different varicocele correction techniques. To determine the role of age in sperm parameters improvement. Methods: 2 different European centers collected pre- and postoperative sperm param- eters of patients undergoing varicocele correction. Among 463 evaluated patients, 367 were included. Patients were divided in procedure-related and age-related groups. Ivanissevich inguinal open surgical procedure (OS), lymphatic-sparing laparoscopic approach (LSL) and retrograde percutaneous transfemoral sclerotization (RPS) were performed. As outcome meas- urements sperm count (millions/mL, SC) and percentage of mobile sperms were analyzed. Univariate and multivariate regression between the defined groups; bivariate regression analy- sis between age and sperm count and motility. Results: Number of patients: OS 78; LSL 85; RPS 204. Mean age 30.2 (SD 6.83); postoperative SC increased from 18.2 to 30.1 (CI 95% 27.3-32.9; p < 0,001); motility from 25.6 to 32.56% (30.9-34.2; p < 0.001). OS: SC varied from 16.9 to 18.2 (p < 0.001); sperm motility from 29% to 33% (p < 0.001). LSL: SC from 15.5 to 17.2 (p < 0.001); motility from 27 to 31% (p < 0.001). RPS: SC from 18.9 to 36.2 (p < 0.001); motility from 24% to 32% (p < 0.001). Univariate and multivariate analysis confirmed the significant difference of SC variation in RPS, compared to the other groups (p < 0.001). No significance between LSL and OS (p = 0.826). No significant differences regarding motility (p = 0.8). Conclusions: Varicocele correction is confirmed useful in improving sperm parameters; sclero- tization technique leads to a better sperm improvement compared to other studied procedures; improvement in seminal parameters is not affected by age of the patients treated. KEY WORDS: Andrology; Infertility; Sclerotization; Spermatozoa; Varicocele. Submitted 18 July 2013; Accepted 31 July 2013 No conflict of interest declared Summary represented by the radiological-assisted techniques: embolization or sclerotherapy (1, 2). Several studies related the outcome in terms of invasive- ness and costs between the different techniques used (3, 4); however a comparison of the efficacy on sperm parameters improvement of open ligation, laparoscopic approach and sclerotization is still missing. DOI: 10.4081/aiua.2013.3.143 Archivio Italiano di Urologia e Andrologia 2013; 85, 3 G. Ollandini, G. Liguori, S. Ziaran, T. Málek, G. Mazzon, B. de Concilio, S. Bucci, S. Benvenuto, E. Belgrano, C. Trombetta 144 The goal of our study was to compare the clinical out- comes in terms of sperm quality after varicocele correc- tion using the three cited techniques. We also referred to patients’ age in order to analyze whether there are signif- icant differences of postoperative sperm improvement related to age increment. MATERIAL AND METHODS Two different centers collected data of patients undergo- ing varicocele treatment from 1986 to 2011. Patients were complaining both from infertility or testicular pain. All patients underwent a complete history, physical examination in a warm room, hormonal assessment, semen analysis. Each center treated the patients with a different technique: open ligation of the spermatic vein according to Ivanissevich technique, laparoscopic approach or retrograde sclerotization of the spermatic vein. At least 3 months after surgery, semen analysis and physical examination have been performed: in fact Al Bakri et al. in 2012 demonstrated that there is no signif- icant improvement in sperm parameters after 3 months from correction (6). On a total of 463 patients, 96 have been excluded according to the following criteria: persistence of varico- cele, endocrinological abnormalities, history of unde- scended testis, bilateral varicocele, and abnormal right testis. Mean age of patients was 30.2 yr (SD 6.83); medi- an clinical grade was 2 (IQR 1); mean sperm concentra- tion was 18.0 millions/mL (SD 14.7) and mean sperm motility was 25.6% (SD 17.51). Surgical procedures: the operative procedures are widely described in the literature. In Ivanissevich open surgery inguinal approach (under general anesthesia) the exposure of the internal spermat- ic vessels within the inguinal canal takes place through an incision of the external oblique aponeurosis (7). In laparoscopic ligation of spermatic veins (under gener- al anesthesia) the patients underwent varicocelectomy by the lymphatic sparing technique. In this procedure the internal spermatic veins alone were divided. Using a microsurgical technique both the artery and the lym- phatics were preserved (8). Patients underwent retrograde percutaneous sclerotiza- tion of their left spermatic vein, using the right trans- femoral retrograde percutaneous approach. The femoral vein is entered below the inguinal ligament using the standard Seldinger technique. Renal phlebography is carried out by injection of contrast medium under Valsalva maneuver. After superselective catheterization of the spermatic vein, a guidewire is introduced and act as a guide for a very distal catheterization, through contin- uous fluoroscopy. Superselective angiography shows every possible collateral circle and the possible presence of multiple spermatic veins. Sclerotization technique is performed by injecting a 2-4 mL of sodium tetradecyl sulfate 3% mousse. Patients are required to perform a Valsalva maneuver at least 10 seconds long during the injection. Venography is then performed again: should there be bulky veins, the operation is repeated at a high- er lumbar level. After this procedure, a control venogra- phy is performed to confirm the absence of renosper- matic reflow (9, 10). It is known from the literature that up to 20% of patients have anatomical abnormalities of their veins, that could eventually make not possible the retrograde technique. When this happened, we per- formed anterograde sclerotization according to Tauber technique during the same session (11). Semen analysis Specimens were obtained by masturbation after 3 to 5 days of abstinence. The specimens were valuated within 1 hour from collection for the following parameters: sperm concentration (millions/mL), percentage of sperms with A + B motility (A, speed linear motility; B, slow linear motil- ity; C, motility in situ; D, no motility at all), percentage of morphologically typical sperms. The laboratories evaluat- ed the parameters according to WHO criteria. Statistical analysis Statistical analyses were performed with SPSS 17.0 soft- ware package. Description of population and parameters have been reported as mean values with standard devia- tion (SD) for continuous variables, and with median val- ues with interquartile range (IQR) for non-continuous ones. The significances of differences between preopera- tive and postoperative values within groups have been valued with the paired Student t-test, if appropriate, or with the Wilcoxon signed rank test. Means variations between two groups has been valuated with Mann- Whitney U test. ANOVA univariate analysis of variance with LSD post-hoc evaluation has been carried out in order to compare mean values of more than two groups. MANOVA Multivariate analysis has been then performed between our data. The linear regression coefficients have been calculated in order to test the correlation between age and parameters. Probability values < .05 were considered significant. RESULTS Patients included in the study were a total of 367. Among these, 78 underwent open surgical approach; 85 were treated by laparoscopy and 204 by sclerotization technique. Persistence and minor complication rates are shown in Table 1. No major complications occurred. Complications in surgical ligation of spermatic vein were hydrocele, difficult wound healing and hematomas. Complications among sclerotization techniques were mostly represented by persistent (more than 3 days) pain at the spermatic chord. Due to the injection of sclerosing substance, though, self-recovery pain and an acceptable increase of volume and consistence of the chord was not considered as a complication. Sperm concentration increased postoperatively in 73% of global cases; motility from 25.6 to 32.56% (p < 0.001). Average postoperative sperm concentration increased to 30.1 millions/mL (SD 29.9; CI 95% 27.3- 32.9; p < 0.001) and motility to 32.56% (SD 17.3; CI 95% 30.9-34.2; p < 0.001). Patients have been divided into three groups, according to the procedure performed, and into 4 groups, accord- ing to their age. Every difference within the groups obtained a significance p-value < 0.001. Differences between the groups Univariate ANOVA regression analysis and multivariate MANOVA have been performed in order to evaluate the differences between the groups and set their significance (Table 2). Post hoc evaluation of variances between proce- dure-related groups have been reported for sperm count. Variation of sperm count has been demonstrated to be related to the procedure (Figure 1), being significantly higher for patients treated by sclerotization procedure. Age decades showed no significant differences in mean values of sperm count and sperm motility improvement (Table 2). Mean variation of sperm concentration showed also no significant differences between age-relat- ed groups (Figure 2). The linear regression standardized coefficient between age and sperm motility for preoperative values is -0.09 (p = 0.048) and for postoperative values is -0.10 (p = 0.021). Therefore there is no significant difference between the calculated coefficients (Figure 3). DISCUSSION In our study we found: • As already known from the literature, varicocele cor- rection is confirmed as useful in improving sperm parameters 145Archivio Italiano di Urologia e Andrologia 2013; 85, 3 Varicocele treatment: A 2-centers comparison between non microsurgical open correction, laparoscopic approach and retrograde percutaneous sclerotization Figure 1. Mean variation of sperm concentration and motility between the three procedure-related groups. Technique N Excluded Included Complications Other reasons Recurrency (%) Total Open Surgery 77 2 7 (9,1%) 9 68 7% Laparoscopic 80 4 1 (1,3%) 5 75 0% Sclerotization 366 57 25 (9,3%) 82 284 5% Total 523 63 33 96 427 Table 1. Total number of treated and excluded and rate of overall post-operative complications. Age (SD) Sperm Concentration (95% CI) Motility (95% CI) Pre Post* Pre Post* Procedure Open Surgery 32,1 (6,85) 16,9 (13,4-20) 18,2 (15,0-21,5) 29 (25,8-32) 33,1 (30,9-35,4) Laparoscopy 26 (5,6) 15,5 (13,7-17,1) 17,2 (15,5-18,9) 27 (23,5-29,6) 31,2 (28,7-33,8) Sclerotization 25,9 (5,2) 18,9 (17-20,1) 36,2 (32,8-40,7) 24 (21,3-29,9) 32,9 (30,3-35,6) p-value Univariate 0,2 < 0,0001 0,25 0,21 Multivariate 0.18 < 0,0001 0.18 0.15 Age decades Group 1 0-20 18,8 (13,7-23,9) 27,3 (25,7-38,8) 30,6 (26,1-35,2) 38,5 (33,9-43,0) Group 2 21-30 17,8 (15,7-19,9) 29,5 (25,4-33,6) 26,3 (24,0-28,5) 33,8 (31,5-36,2) Group 3 31-40 17,2 (15-19,4) 30,9 (26,2-35,5) 24,1 (21,2-27,0) 30,9 (28,1-33,7) Group 4 > 41 22,5 (17,1-27,9) 36,4 (28,2-44,6) 23,2 (16,0-30,3) 30,2 (24,7-35,7) p-value Univariate 0,85 0,32 0,08 0,004 Multivariate 0.97 0.30 0.13 0.003 Table 2. Univariate ANOVA and Multivariate MANOVA analysis of variance. *p-value < 0,001 for each of the parameters withing the groups. Archivio Italiano di Urologia e Andrologia 2013; 85, 3 G. Ollandini, G. Liguori, S. Ziaran, T. Málek, G. Mazzon, B. de Concilio, S. Bucci, S. Benvenuto, E. Belgrano, C. Trombetta 146 • Sclerotization technique leads to a better sperm improvement compared to other studied procedures • Improvement in seminal parameters is not affected by age of the patients treated. The usefulness of varicocele repair remains a highly debated topic. The 2009 updated Cochrane review by Evers and Collins discussed the indication to varicocele treatment in infertile men, and according to their meta- analysis there was no clear evidence of indication in varicocele correction to improve fertility (12). This review, though, have been debated by a contrary opinion: the Authors (Ficarra et al.) analyzed the methodology of the study and concluded that it was weak and poorly significant, as they included patients with subclinical varicoceles and normal semen parame- ters (13). More recently a randomized, controlled trial by Abdel-eguid et al. (14) concluded that there is a statisti- cally significant improvement in semen quality after microsurgical correction of varicocele and a higher preg- nancy rate, comparing the results with the control arm. Therefore the main focus of our study was not to demon- strate the outcome in terms of fertility and pregnancy rate, but to compare the efficacy in sperm improvement between the different used techniques. In 1998 Barbalias et al. carried out a randomized clinical trial comparing a total of 88 patients who underwent varicocele correction either by retroperitoneal, inguinal, subinguinal or percutaneous approach. They analyzed pre and postoperative sperm parameters concluding that microsurgical subinguinal technique had a greater performance (15). A newer study in 2010 confirmed that microsurgical approach obtains better results compared to the standard inguinal approach (16). However microsurgical treatment of varicocele needs a greater amount of time and instruments than the other techniques. Several studies compared the open surgery technique to sclerotization procedure, with contradicto- ry results (12, 13, 17, 18); though one of the main out- comes of those studies was the pregnancy rate, this parameter seems to be affected by too many confounding factors to be eligible as a main outcome. Many other studies, moreover, focused on the costs of the treatments, and the time to recovery: operative costs are shown to be similar for all the studied procedures, but the time to recovery is significantly less for patients treated by scle- rotization technique. Therefore Bechara et al. concluded that the radiological- assisted procedure has a cost-benefit compared to surgi- cal treatment (19). The rate of technical failure of sclerotization procedure is described to vary from 5% to 20%, due to the anatomi- cal abnormalities, venospasm or technical difficulties (13, 17, 19). In our experience the intervention is converted during the same session to an anterograde sclerotization, according to Tauber technique. This possibility permits to obtain a 100% rate of technical success. Our data clearly show that the sclerotization technique leads to a better improvement of sperm concentration compared to laparoscopic and Ivanissevich techniques. Moreover, these appear to obtain a similar outcome both regarding sperm density improvement and sperm motil- ity improvement. The hypothesis regarding the better results of sclerotiza- tion techniques are probably related to: • Better anatomical view and complete repair of varico- cele • Complete manteinance of lymphatic vascularization • No arterial injuries. Figure 2. Variation of sperm concentration is not significantly different among patients from different age decades. Figure 3. Pre and postoperative percentage of motility among age groups: the negative trend remains constant. Sclerotization differs from the surgical approaches because of the venography that is repeated during the whole procedure, in order to guide step by step the intervention. This allows to obtain a clear imaging of the venous vascularization, and to close selectively every single vessel that is implicated in varicocele for- mation. In fact it is commonly known, that 19% of patients with varicocele have an aberrant anatomical situation (20). This situation cannot be completely discovered by laparoscopic and surgical approach, and will be proba- bly not treated completely, even if post operatively there is no sign of clinically detectable persistence. The pathogenetic factors involving poor sperm quality on varicocele patients, if not completely corrected, could in fact continue their damage of the testis, that have been showed in several studies (21, 22). Moreover, the risk of injuries to the testicular arteries is significantly higher in patients undergoing surgical pro- cedures than in patients undergoing sclerotization, due to the procedure itself (23), even if the role of artery injury in sperm parameter’s outcome is not certainly sig- nificant (23, 24). Finally, the preservation of lymphatic vessels is assured with sclerotization technique, while in patients undergo- ing surgical procedures the lymphatic damage is most likely avoided (laparoscopy) or most probably occurs (Ivanissevich). Lymphatic vessels ligation is thought to induce a significant worsening of testicular function, due to testicular edema (8). We may assume these factors cooperate in obtaining a better result in sperm concentration improvement in patients undergoing sclerotization of their varicocele instead of the other procedures. Though there is an evidence of correlation between patients’ age and sperm parameters worsening in some studies in the literature (26, 27), according to other recent studies the role of age in sperm quality improve- ment after varicocele correction is believed to be not sig- nificant (9, 25). In our study the only significant trend, at linear regression estimation, is the decrease of sperm motility in relation to patients’ age. This trend is not affected by the intervention, as it remains constant after correction of varicocele, and rep- resents the normal decrement of motility due to patient’s age. CONCLUSIONS Varicocele treatment leads to improvement in seminal parameter examined in 73% of the cases. 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Correspondence Giangiacomo Ollandini, MD (Corresponding Author) g.ollandini@gmail.com viale Gabriele d’Annunzio 63, 34138 Trieste (Italy) Giovanni Liguori, MD Giorgio Mazzon, MD Bernardino de Concilio, MD Stefano Bucci, MD Sara Benvenuto, MD Emanuele Belgrano, MD Carlo Trombetta, MD Urologic Unit, Cattinara Hospital, University of Trieste Via di Fiume 447 - 34149 Trieste, Italy Stanislav Ziaran, MD Tomá! Málek, MD Urology Clinic, University Hospital in Bratislava, Comenius University, Bratislava, Slovakia