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1 Original article 65 Impact of varicocele recurrence on semen parameters and pregnancy outcome Emad A Taha a, Emad Eldien Kamal a, Saad R Abdulwahed b and Hossam Elktatny c a Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Assiut University Hospital, Departments of b Radiology and c Obstetric and Gynacology, Faculty of Medicine, Al-Azhar University Hospital, Assiut, Egypt Correspondence to Emad Eldien Kamal, MD, Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Assiut University Hospital, 9th Floor PO Box 71111, Assiut, Egypt Tel: ; fax: ; dremadkamal@hotmail.com Received 22 April 2012 Accepted 22 June 2012 Human Andrology 2012, 2:65 69 Background The role of varicocele in male infertility is a major topic. Objective To determine the effect of varicocele recurrence on pregnancy outcome and semen parameters. Study design Comparative observational study. Patients and methods This study included two groups of patients who had undergone inguinal varicocelectomy: the first group included those with no recurrence of varicocele and the second group included those with recurrent varicocele. The study involved clinical evaluation, conventional semen analysis, sperm vitality assessment, and scrotal color Doppler examination of the two groups. Main outcome measures Comparison between the two groups was carried out in conventional semen parameters, sperm vitality, and percentage of proven pregnancy outcome in a period of at least 1 year after varicocele ligation. In addition, comparison was carried out between semen parameters before and after surgery in both the groups. Results The nonrecurrent group showed a significant increase in the postoperative sperm concentration, total sperm count, normal sperm morphology, progressive sperm motility, and sperm vitality percentages in comparison with the preoperative data, which was not observed in the other group with recurrent varicocele. The nonrecurrent group also had significantly higher postoperative sperm morphology, motility, and vitality percentages in addition to pregnancy rate in comparison with the postoperative data of the recurrent group. Conclusion The recurrence of varicocele was associated with a negative impact on semen parameters and, more importantly, pregnancy rate, which shows the positive role of a properly performed varicocelectomy in selected cases in improving semen parameters and pregnancy outcome. Keywords: color doppler, male infertility, recurrent varicocele, sperm vitality, testicular volume, varicocele Hum Androl 2:65 69 & 2012 Human Andrology Introduction Varicocele is defined as an abnormal dilatation of the testicular veins within the pampiniform plexus [1]. It has an incidence of about % in the general population, which increases to 21 41% of men with primary infertility and 75 81% of those with secondary infertility [2,3]. It is known that varicocele represents the most common identifiable pathology in infertile men [4], and it is considered the most important etiological factor of male infertility [5]. Different theories have reported the negative effect of varicocele on testicular function, human spermatogenesis, and male fertility. Proposed mechanisms include testicular hypoxia and stasis, venous hypertension, autoimmunity, elevated testicular temperature, blood testicular barrier dysfunction, reflux of toxic adrenal catecholamines, increased semen oxidative stress, and sperm DNA damage [5 8]. Although varicocele can be diagnosed clinically, color Doppler ultrasound has been shown to be the best diagnostic tool in the assessment of the diagnosis, especially in case of recurrence [9,10]. Despite the aforementioned data on the negative effects of varicocele on male fertility, the reasons why about two of three men with varicocele retain their fertility after & 2012 Human Andrology DOI: /01.XHA

2 66 Human Andrology varicocelectomy remain unclear [11]. Considering the conflicting reports on the ineffectiveness of varicocele treatment in increasing the chances of conceiving, the role of recurrence should always be considered [10 13]. Despite the presence of numerous methods that have been established to repair varicocele, few comparative studies have been published on the effect of varicocele repair with these techniques on pregnancy outcome [14 16]. Similarly, in the case of recurrent varicocele, most previous studies have reported treatment options and little has been published on its effect on semen parameters and pregnancy outcome [10,17,18]. Considering these points, it is important to determine the effect of recurrence of varicocelectomy on semen and pregnancy outcome to clarify two important points: first, the effect of varicocele on male infertility and, second, the need for reoperation on varicocele. Aim To determine the effect of recurrent varicocele on pregnancy outcome and semen parameters. Patients and methods Patients For this study, data were collected from infertile men attending the outpatient clinic of the Department of Dermatology, Venereology and Andrology, Assiut University Hospital (Assiut, Egypt). The study included 107 men who undergone operations for varicocele. Thirty-five of these men were found to have recurrent varicocele after surgery. Among the 107 men, 60 completed the study, including 30 men without recurrence (group 1) and 30 with recurrence (group 2). Grouping Patients who completed the study (n = 60) were classified into two groups according to the presence or the absence of recurrent varicocele: (1) Group 1: men without recurrent varicocele. (2) Group 2: men with a unilateral or a bilateral recurrent varicocele. The two groups were followed up for 1 year after surgery. Comparison was carried out between semen parameters obtained preoperatively and postoperatively within each group and between the two groups in addition to the percentage of proven pregnancy within at least 6 months after surgery. Because of ethical considerations, we counseled those with recurrent varicocele for another surgery and we considered only those who preferred expectant management in the study. Inclusion criteria Male patients diagnosed previously with either a unilateral or a bilateral clinical varicocele, confirmed by the presence of at least a single dilated vein of more than 2 mm and a reflux duration of more than 2 s by scrotal color Doppler examination, were included in this study. They had abnormal semen quality documented on multiple analyses according to the WHO [19], criteria before they underwent inguinal varicocele ligation on the affected side. Exclusion criteria Patients with a history of specific genital diseases that may affect testicular size other than clinical varicocele such as orchitis, undescended testis, and idiopathic testicular atrophy were excluded. Patients with hypogonadism and other systemic or endocrine diseases and that may affect reproductive capacity were excluded. Those with female factor were excluded. Finally, we excluded those who dropped out from follow-up during the study period. Clinical procedures For participants, we carried out assessments of clinical history, and obtained data on age, smoking status, duration of infertility, and history of operations or genital tract infections. General and genital examination including assessment of testicular size, consistency, epididymal nodules, and the degree of varicocele. Varicocele was graded as grade I (palpable with Valsalva), grade II (palpable without Valsalva), and grade III (visible through the scrotal skin) [20]. Investigatory procedures Repeated conventional semen analyses according to WHO, guidelines and the sperm hypo-osmotic swelling test for sperm vitality assessment were carried out 6 months and 1 year after surgery [19,21]. The average value of two consecutive semen analyses separated by at least 1 month for each patient in the preoperative period was considered as the net result. For the net postoperative result, we have taken the average of two analyses performed 6 months and 1 year after surgery. The presence or absence of recurrence of varicocele was determined by the presence of definite reflux by a scrotal color Doppler examination, which was performed in the first 3 months after surgery. It was performed using a 7.5 MHz high-resolution linear array transducer (Sonoline Versa plus; Seimens Medical system, Erlangen, Germany) with pulsed and color Doppler capabilities. The patient was first placed in a supine position and examined by gray-scale sonography for assessment of testicular size (ml) and the presence of dilated venous channels. Then, the patient was examined in the standing position. Color mode and spectral analysis were used for the evaluation of testicular veins. The veins were examined before and after Valsalva to detect the occurrence of reflux and its duration. Reflux, whether Valsalva induced or spontaneous, was defined as caudate flow in the internal spermatic vein and considered abnormal if it lasted longer than 2 s [22]. Statistical analysis Data were analyzed and expressed in tables as mean values ± SD using the SPSS version 16 program (SPSS

3 Effect of varicocele recurrence Taha et al. 67 Inc., Chicago, Illinois, USA). A paired t-test was used to compare preoperative and postoperative semen analyses within each group. Unpaired t-test and Mann Whitney U-test were used to compare parametric and nonparametric variables between the two groups. The w 2 -test was used to compare the percentages of pregnancies between two groups. Values were considered significant when P-values were equal to or less than Results The two groups were comparable in age (35.43 ± 7.47 years for group 1 vs ± 8.2 years for group 2), BMI (25.27 ± 4.19 kg/m 2 for group 1 vs ± 3.6 kg/m 2 for group 2), and total testicular size (29.53 ± 4.73 ml in group 1 vs ± 5.23 ml in group 2). Comparison between preoperative semen parameters in the two groups studied showed no significant difference between the two groups (Table 1). However, when we compared postoperative semen parameters in the two groups studied, we found that group 1 had significantly higher normal sperm morphology, progressive sperm motility, and sperm vitality than those in group 2 (Po0.05, 0.01, 0.05) (Table 2; Fig. 1). On comparison of preoperative and postoperative semen parameters in group 1, we found that the postoperative sperm concentration (Po0.01), total sperm count, normal sperm morphology, progressive sperm motility, and sperm vitality percentages (Po0.001 each) were significantly higher than the corresponding preoperative values (Table 3). In group 2, there was no significant improvement in any of postoperative semen parameters compared with the preoperative values (Table 4). Finally, we compared the pregnancy rates in the two groups and we found that the men in group 1 had significantly higher pregnancy rates (Po0.05) in comparison with those in group 2 (Table 5). Table 2 Comparison of postoperative semen parameters in two groups Semen variables Group 1 Group 2 P-value Range NS Mean ± SD 2.36 ± ± 0.49 Range NS Mean ± SD ± ± Range NS Mean ± SD ± ± Range o0.05 Mean ± SD 19.8 ± ± 7.09 Range o0.01 Mean ± SD ± ± 7.5 Range o0.05 Mean ± SD 48.4 ± ± Figure 1 Comparison of postoperative semen parameters and the hypo-osmotic swelling (HOS) test between the two groups. Table 1 Comparison of preoperative semen parameters in two groups Semen variables Group 1 (n = 32) Group 2 P-value Range NS Mean ± SD 2.24 ± ± 0.58 Range NS Mean ± SD 29.1 ± ± Range NS Mean ± SD ± ± Range NS Mean ± SD ± ± 7.32 Range NS Mean ± SD ± ± 6.74 Range NS Mean ± SD ± ± Table 3 Comparison of preoperative and postoperative semen parameters in group 1 Semen variables Preoperative Postoperative P-value Range NS Mean ± SD 2.24 ± ± 0.67 Range o0.01 Mean ± SD 29.1 ± ± Range o0.001 Mean ± SD ± ± Range o0.001 Mean ± SD ± ± 8.91 Range o0.001 Mean ± SD ± ± Range o0.001 Mean ± SD ± ± 17.33

4 68 Human Andrology Table 4 Comparison of preoperative and postoperative semen parameters in group 2 Semen variables Preoperative Postoperative P- value Range NS Mean ± SD 2.17 ± ± 0.49 Range NS Mean ± SD ± ± Range NS Mean ± SD ± ± Range NS Mean ± SD ± ± 7.09 Range NS Mean ± SD 21.2 ± ± 7.5 Range NS Mean ± SD ± ± Table 5 Comparison of pregnancy rates in the two groups Group Group 1 (nonrecurrent varicocele) Group 2 (recurrent varicocele) Pregnancy (number/total) Pregnancy (%) P-value (w 2 ) 12/30 40 o0.05 4/30 13 Discussion Variable figures have been reported for recurrence rates of different treatment methods for varicocele, ranging from 1 to 40% with different maneuvers and surgical interventions for varicocele [23 33]. The highest reported recurrence was with high ligation [28] and the lowest reported recurrence rate was associated with microsurgical repair [29,30]. The cause of recurrence is most frequently shown by retrograde gonadal venography as collateralization of the gonadal vein by retroperitoneal collateral flow, which may communicate with the contralateral gonadal vein, or from lateral retroperitoneal branches, which may communicate with colonic, distal renal, or renal capsular veins [34 38]. Moreover, there is trans-scrotal collateralization of the right and left pampiniform plexus through scrotal veins [39,40]. Clinical studies on varicocelectomy have shown variable effects on postoperative semen parameters and pregnancy rates [41]. This study was carried out to clarify the effect of recurrent varicocele on semen parameters and pregnancy outcome. The study was carried out on 107 patients who underwent operation for varicocele. Only 60 patients completed the study (30 patients without recurrence and 30 patients with recurrence). In this study, we found no significant difference between the two groups in the preoperative semen parameters. However, when we compared postoperative semen parameters in the two groups studied, we found that group 1 had significantly higher normal sperm morphology, progressive sperm motility, and sperm vitality than those in group 2. On comparison of preoperative and postoperative semen parameters in group 1, we found that the postoperative sperm concentration, total sperm count, normal sperm morphology, progressive sperm motility, and sperm vitality percentages were significantly higher than their corresponding preoperative values. In group 2, there was no significant improvement in any of the postoperative semen parameters. Also,thisisinagreementwiththeresultsofJarowet al.[41], who concluded that varicocele repair has been shown to reverse a spectrum of effects contributing to impaired fertility inmen,andtheoperation leads to improvement in the sperm morphology and sperm penetration assays. This result can be explained by the recovery of spermatogenic function from the deleterious effect of varicocele on sperm motility, morphology, and vitality as varicocele is associated with an increase in scrotal temperature because of the failure of the counter-current heat exchange mechanism that can be corrected after varicocelectomy with return of the scrotal temperature to the normal range [42]. However, in patients in group 2 (recurrent varicocele group), there was no significant improvement in the postoperative semen parameters as the pathological changes caused by varicocele were still present, and this confirms the effect of varicocele on semen parameters and male fertility. In terms of the pregnancy rates, we found that the patients in group 1 had significantly higher pregnancy rates in comparison with those in group 2. This is consistent with the WHO multicenter trials [43,44], which reported significant benefits for male fertility after surgical varicocele repair (pregnancy rate 35 and 60%) compared with unoperated controls (pregnancy rate 17 and 10%). In an earlier study, Yamamoto et al. [45] reported a 31% increase in the pregnancy rate achieved by IVF following varicocelectomy among the patients in whom IVF had failed before surgery. Most previous studies on recurrent varicocele have been focused on its treatment options and little has been published on the effect of this recurrence on semen parameters and pregnancy outcome [10,17,18]. It has been concluded that surgical repair of varicocele improved semen parameters [46], decreased sperm DNA fragmentation and miscarriage rates, and increased pregnancy rates [47 49]. Conclusion Recurrence of varicocele was associated with a significantly lower percentage of improvement in semen parameters and sperm vitality and, more importantly, pregnancy rate, which indicates the positive role of a properly performed varicocele repair in selected cases in improving semen parameters and pregnancy outcome. We recommend further studies with a larger number of patients and longer periods of follow-up after varicocelectomy.

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