Stesura Seveso Archivio Italiano di Urologia e Andrologia 2023; 95(3):11580 1 ORIGINAL PAPER 93% of cases on the left side, while bilateral varicoceles are only found in about 25% of patients (3). Majority of the left sided varicocele is related to the anatomic factors of the left testicular vein (4). In 1952, Tulloch for the first time reported an azoosper- mic case which responded very well to bilateral varicoc- electomy with not only sperm development in the ejacu- late, but also normal pregnancy of the wife (5). Since then, many studies reported significant improvement in the sperm parameters of patients following bilateral varic- ocelectomy (6, 7). One theory that claims varicocele to be a disease of bilaterality is the reflux theory. It depends on the presence of either incompetent or absent gonadal vein valves that allow blood to shunt back into the pampiniform plexus of veins. Obviously, this is an anatomical deficit that should theoretically exist on both sides (8). This explains why left varicocele can also affect spermatogenesis of the right side as well. Previously, the incidence of coexisting right varicocele in the presence of palpable left varicocele was 21-60% as reported by venographic studies. Recently, the incidence of bilateral varicoceles is increasing due to the use of modern diagnostic means besides the physical examina- tion, such as Color Doppler Ultrasound (CDUS) which has a sensitivity of 97% and specificity of 94% (9). As CDUS is operator dependent, its reliability to diagnose and grade varicocele is still controversial (10). Thus, assessment of varicocele bilaterality in infertile men seems to be deficient in the literature. On this basis, this study tried to objectively assess varicocele bilaterality in infertile men aiming to improve treatment outcome in this cohort of patients. PATIENTS AND METHODS This is a case series study that was conducted in Tanta Urology Department in Egypt between January 2019 and January 2022. The study was conducted in accordance with the Declaration of Helsinki and it was approved by Tanta University, Faculty of Medicine review board (IRB number is 35903/10/22). Informed consent was obtained by all subjects when they were enrolled. Objectives: Varicocele is the most common correctable cause of male infertility that always has been a debatable subject as regards how it affects fertility and the best way to treat it. Proper assessment of the disease bilaterality is crucial not to miss one side and not to jeopardize treatment outcome. This study aimed to objectively assess varicocele bilaterality in infertile men aiming to improve treatment outcome in this cohort of patients. Methods: This prospective study was conducted between January 2019 and January 2022 including infertile males with varicoce- les. Assessment of missed concomitant contralateral varicocele done pre-operatively by Color Doppler Ultrasound and intra- operatively by intraoperative Doppler device and measurement of maximal vein diameter of contralateral side. Results: A total of 329 cases completed the study. A hundred cases (30.4%) were initially referred as unilateral varicoceles and 229 (69.6%) as bilateral varicoceles. After reassessment of the study population, bilaterality of varicocele was found to be as high as 98.5% (324/329). Repeat CDUS strongly correlated with the intraoperative measured varicocele diameter (r = 0.9, p < 0.001). Moreover, sperm parameters showed significant improvement 3 and 6 months post varicocelectomy. Normal pregnancy after 1 year of surgery occurred in 118 cases (35.9%). Conclusions: Varicocele bilaterality in infertile men is under- reported. Thorough assessment by expert radiologists and andrologists is of paramount importance not to miss significant pathology or hazard treatment outcome. KEY WORDS: Male infertility; Varicocele bilaterality; Varicocelectomy; Semen parameters. Submitted 9 July 2023; Accepted 28 July 2023 INTRODUCTION Varicocele is the commonest surgical cause of male infer- tility and is found in 40% of patients with primary and 80% of those with secondary infertility (1). The etiopathogenesis of varicocele-induced infertility and the effect of surgical repair on the fertility potentials has always been a matter of debate (2). As reported in the literature, varicocele is found in 78% - Bilaterality of varicocele: The overlooked culprit in male infertility. Case series study Khaled Mohamed Almekaty 1, Ahmed Mostafa Elsharkawy 2, Mohamed Hasan Zahran 3, Maged Mostafa Ragab 1, Ayman Sayed Rashed 4, Mahmoud Mohamed Soliman 5, Khaled Abdelaziz Salem 1, Ahmed Fayez Ghaith 1 1 Urology Department, Tanta University, Tanta, Egypt; 2 Radiology Department, Tanta University, Tanta, Egypt; 3 Mansoura Urology and nephrology centre, Mansoura University, Mansoura, Egypt; 4 Urology Department, 6th of October University, Cairo, Egypt; 5 Obstetrics and Gynecology Department, Cairo University, Cairo, Egypt. DOI: 10.4081/aiua.2023.11580 Summary Archivio Italiano di Urologia e Andrologia 2023; 95(3):11580 K. Mohamed Almekaty, A. Mostafa Elsharkawy, M. Hasan Zahran, et al. 2 Infertile men (either primary or secondary infertility) ini- tially assessed or referred as unilateral or bilateral varico- cele patients were enrolled. Patients with history of orchidectomy, cryptorchidism, azoospermia or concomi- tant female partner infertility were excluded. All patients were subjected to physical examination including local scrotal examination to evaluate the degree and laterality of varicocele and semen analysis before the operation. A repeat scrotal Doppler ultrasonography was done for all patients to confirm diagnosis of varicocele and reassess bilaterality of the disease. This repeat CDUS was performed by the same expert uroradiologist who was blinded to the findings of physical examination. All patients underwent microsurgical subinguinal varico- celectomy by expert uroandrologists after taking a written informed consent with explanation of the potential com- plications of the procedure. Patients who were diagnosed with bilateral varicoceles underwent bilateral subinguinal ligation straight away. Those who were referred with unilateral varicocele had a repeat CDUS for reassessment of missed concomitant contralateral varicocele. Their palpable sides were operat- ed on first; then the contralateral side was explored as fol- lows; the spermatic cord was delivered and opened at the level of the external inguinal ring. Then, the maximal dilated internal spermatic vein diameter was measured using a micrometer fixed to the surgical microscope. Also, the veins of the contralateral side were examined for reflux using an intraoperative Doppler device (VTI intra- operative Doppler system 20 MHz). The sound of venous reflux confirmed varicocele diagnosis. Patients were followed up for at least 6 months after surgery to evaluate any complications and assess improvement in semen parameters. The primary outcome meas- ure was to assess disease bilat- erality and the secondary out- come measure was to report on improvement in semen 3 and 6 months post varicoc- electomy and normal preg- nancy rate after 1 year. Female partners were evaluat- ed by full history taking and thorough examination to exclude female factor infertili- ty. Good ovulation was sug- gested if the female showed menstrual regularity, premen- strual syndrome (PMS), mid cyclic pain or discharge, con- firmed by normal Follicle-stim- ulating hormone (FSH), Luteinizing hormone (LH), Thyroid stimulating hormone (TSH), Prolactin, Estradiol (E2), and Anti-mullerian hormone (AMH). Transvaginal ultrasound was done to exclude any uterine pathology or mullerian anomalies that may interfere with the occurrence of preg- nancy. Furthermore, folliculometry was done and the pres- ence of good ovulation was declared and confirmed by mid-luteal phase progesterone. After varicocelectomy, the female partners were followed up for 1 year to assess nor- mal pregnancy rate. Statistical analysis Statistical analysis was performed using SPSS 16.0 for Windows software (SPSS, Inc., Chicago, IL). Chi-Square test is used to determine the significant association between the observed frequencies and the expected frequencies. Wilcoxon sign test and simple Student t-test were used for continuous variables. The difference was considered statis- tically significant at < 0.05. RESULTS In this study 350 patients were initially enrolled and after exclusion, a total of 329 cases completed the study. Figure 1 shows the flowchart of cases. A hundred cases (30.4%) were initially referred as unilateral and 229 (69.6%) as bilateral varicoceles. Table 1 shows the base- line data of the study population. Bilaterality of the disease was reassessed preoperatively by Figure 1. Flowchart of study population. Archivio Italiano di Urologia e Andrologia 2023; 95(3):11580 3 Bilaterality of varicocele: Examining its disease status a repeat CDUS and intraoperatively by measuring the maximal diameter of the largest vein and detecting venous reflux using operative Doppler as mentioned in the methodology section. After reassessment of the study population, bilaterality of varicocele was found to be as high as 98.5% (324/329). This is statistically significantly higher than initial CDUS (p < 0.001). Repeat CDUS showed bilaterality in 95 out of the 100 cases (95%) and all had grade 2 varicoceles with median (range, IQR) diameter of 3.2 (2.5-4.1, 2.8-3.5) mm. The CDUS diameter strongly correlated with the intraop- erative measured diameter 3.4 (1.5-4, 3-3.6) mm, (r = 0.9, p < 0.001). Moreover, seminal parameters showed significant improve- ment at 3 and 6 months post varicocelectomy as shown in Table 2. Normal pregnancy after 1 year of surgery occurred in 118 cases (35.9%). DISCUSSION The exact relationship between bilateral varicocele and infertility is not fully understood, but since Tulloch noticed the positive effect of varicocelectomy on improv- ing male fertility, many studies have been conducted to investigate this. Interestingly, the degree of varicocele seems to be unrelated to the degree of testicular function affection or even the improvement after varicocelectomy as even a subclinical varicocele can result in male subfer- tility (11). The only study that tried to clearly address whether or not varicocele in infertile males is a disease of bilaterality is that of Gat et al. (12) They used venography and con- tact thermography to detect “clinically missed” varicoceles. Using these 2 modalities, they detected varicocele in 255 out of 286 infertile males (89.1%); bilaterality was con- firmed in 206 (80.8%). In the current study, reassess- ment of varicocele was done by repeat CDUS by an expert uroradiologist and intraoperatively by measuring the diameter of the largest vein at the level of the external inguinal ring and by detecting venous reflux using intra- operative Doppler device. Out of a total of 329 patients, 229 were referred as bilateral (69.6%) but rate of bilater- ality reached 98.5% (324 cases) after the “second look” evaluation. Most of the studies in the literature reporting the preva- lence of varicocele in infertile men rely on physical exam- ination and scrotal ultrasound. Gonda et al. (13) reported 95% sensitivity with a 2-mm cutoff for vein diameters for diagnosis of varicocele. Both are subjective, operator dependent with significant interpersonal variability. In the current study, 30.4% of patients were referred as unilateral varicocele cases and after reassessment bilaterality was proven in 98.5% (28.9% was misdiagnosed). Reports in the literature looking at the prevalence of varic- ocele bilaterality are scarce. In 1986, McClure and Hricak used CDUS to detect subclinical varicocele and detected bilaterality in 70% of their study population (14). Chatel et al., Gonzalez et al., Cockett et al. and Gat Y et al. detected bilaterality in 60%, 61%, 57% and 89.1% respectively (15-17, 12). The higher prevalence of the disease bilaterality in the Gat et al. and the current study as compared to others can be attributed to the use of Table 1. Patients’ demographics. Total number Referred as bilateral varicocele Referred as unilateral varicocele P-value (No. = 329) (No. = 229) (No. = 100; 4 right and 96 left) Age (years) Mean ± SD 29.1 ± 3.7 29.1 ± 3.6 29.3 ± 4.5 0.8 Age of the partner (years) Mean ± SD 27.1 ± 4.1 26.7 ± 3.6 28.6 ± 5.7 0.7 Duration of infertility (years) Median (IQR) 3.5 (2-5) 3.5 (2-5) 3.5 (2-4) 0.9 Right testicular size (ml) Mean ± SD 14.9 ± 2.1 14.9 ± 1.9 15.1 ± 3.2 0.4 Left testicular size (ml) Mean ± SD 14 ± 1.5 14 ± 1.4 14.3 ± 1.6 0.1 Sperm density (million/ml) Mean ± SD 4.2 ± 1.5 4.2 ± 1.5 4.1 ± 1.2 0.5 Sperm motility (A+B) Mean ± SD 18.2 ± 5.7 18.3 ± 5.8 17.5 ± 4.6 0.3 Grade of varicoceles G1:109 G1: 25 G2:211 G2: 60 G3:138 G3: 15 Table 2. Outcomes of varicocelectomy. Baseline 3 months after surgery 6 months after surgery P1 P2 Sperm density (million/ml) Median (range, IQR) 5 (0.15-13, 4-5) 7.5 (0-80, 7-10) 11 (0-60, 10-13) < 0.001 < 0.001 Sperm motility (A+B) Median (range, IQR) 20 (0-60, 15-20) 25 (0-70, 20-30) 40 (0-60, 35-45) < 0.001 < 0.001 P1: comparison between baseline and 3 months. P2: comparison between baseline and 6 months. Archivio Italiano di Urologia e Andrologia 2023; 95(3):11580 K. Mohamed Almekaty, A. Mostafa Elsharkawy, M. Hasan Zahran, et al. 4 objective methods of assessment; venography in the for- mer and intraoperative Doppler and measurement of the diameter of largest vein in the latter and to the improve- ment in the accuracy of the modern CDUS devices avail- able nowadays. In the current study, both radiologists and surgeons have extensive experience in this field; so repeat CDUS strong- ly correlated to intraoperative assessment of the disease; (r = 0.9, p < 0.001; Pearson correlation coefficient). This means that the experience of the ultrasonographer and the surgeon should play a vital role to avoid misdiag- nosed varicoceles. The exact mechanism by which varicocele might lead to infertility is still unclear. The pathogenesis is thought to be multifactorial and complex, with several factors most- ly acting together. In this complex etiopathogenesis, oxidative stress seems to have a crucial role, among oth- ers. Oxidative stress results from increased hydrostatic pressure in the pampiniform plexus of veins which leads to stagnation of toxic metabolites, hypoxia together with increased temperature (18). One of the theories that can explain varicocele bilaterali- ty is that there are venous anastomotic channels between the right and left gonadal veins that were detected in venography studies. Another theory is the reflux theory which supposes that damage or absence of valves in the gonadal veins is the etiology behind varicocele develop- ment which most probably is a bilateral disease (8). This explains why a unilateral palpable varicocele can affect the global testicular function (right and left) and why uni- lateral varicocelectomy may fail to improve sperm param- eters in some cases. The current study supports these the- ories as varicocele bilaterality was found in 98.5% of patients. This finding shows that varicocele bilaterality is clearly underestimated in practice and in the literature. Our technique of artery preservation varicocelectomy using intraoperative Doppler was previously described. Preserving testicular arteries during varicocelectomy pro- vide significantly better sperm improvement especially in patients with severe oligozoospermia (19). Regarding the indication of varicocelectomy, current evi- dence suggests a positive effect of varicocelectomy on sperm parameters and pregnancy rates only in couples with male factor infertility with a clinically palpable varic- ocele and abnormal semen parameters (18). Randomized controlled trials looking at the effect of varicocelectomy on sperm parameters and pregnancy outcomes are lacking. Consequently, available meta- analyses are negatively affected by wide heterogeneity of available studies. However, the randomized controlled trial by Abdel-Meguid et al. supports the findings of meta- analyses which suggest a beneficial effect of varicocelec- tomy on sperm parameters. Abdel-Meguid et al. in 2011 randomized the patients into subinguinal varicocelecto- my (treatment group) and observation (control group). After 1 year of follow up all sperm parameters signifi- cantly improved in the treatment group (32.2 ± 10.6 vs 18.1 ± 5.8× 106 sperm/ml, 41.0 ± 10 vs 25.3 ± 12.8%, and 39.0 ± 4.5 vs 31.2 ± 4.1% for sperm concentration, motility and morphology, respectively); while no signifi- cant difference found in the control group (20). In the current study sperm density and motility signifi- cantly improved after 3 and 6 months and 35.9% of the couples achieved normal pregnancy after 1 year from varicocelectomy (Table 2). The points of strength of this study among others is the good sample size, prospective design and using objective tools for varicocele reassessment, while the limitation is the lack of sperm morphology data. To the best of our knowledge, this is one of a very few reports addressing possible underestimation of varicocele bilaterality which must be taken into account during management of male factor infertility. CONCLUSIONS Varicocele bilaterality in infertile patients seems to be underestimated in the literature and in clinical practice. In our experience, varicocele bilaterality exists in 98.5% of infertile men. Thorough assessment of varicocele bilat- erality in infertile men by expert uroradiologist and andrologists is of utmost importance to avoid disease recurrence and optimize treatment outcomes. REFERENCES 1. Sigman M, Jarow JP. Male infertility. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ (eds.), Campbell’s Urology 8th ed. Philadelphia: Saunders 2002; 1475-1532. 2. Yamaguchi M, Sakatoku J, Takihara H. the application of intrascrotal deep body temperature measurement for the non-inva- sive diagnosis of varicoceles. Fertil Steril. 1989; 52:295-301. 3. Masson P, Brannigan RE. The varicocele. Urol Clin North Am. 2014; 41:129-144. 4. Sabanegh E, Agarwal A. Male infertility, in Campbell-Walsh Urology, A. J. Wein, L. R. Kavoussi, A. C. Novick, and A. W. 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Correspondence Khaled Mohamed Almekaty, MD dr.khaledhafez@med.tanta.edu.eg Maged Mostafa Ragab, MD mmregy@yahoo.com Khaled Abdelaziz Salem, MD khsalemmd@gmail.com Ahmed Fayez Ghaith, MD (Corresponding Author) dr_ahmedfayez@yahoo.com Urology Department, Tanta University, Tanta, Egypt El-Gharbia Govenorate, Tanta. El-Gash st. Medical Campus, The Faculty of Medicine Ahmed Mostafa Elsharkawy, MD ahmed.elsharkawy84@gmail.com Radiology Department, Tanta University, Tanta, Egypt Mohamed Hasan Zahran, MD ahmed.elsharkawy84@gmail.com Mansoura Urology and Nephrology Centre, Mansoura University, Mansoura, Egypt Ayman Sayed Rashed, MD aymanrashed@msn.com Urology Department, 6th of October University, Cairo, Egypt Mahmoud Mohamed Soliman, MD dr_mahmoudsoliman@yahoo.com Obstetrics and Gynecology Department, Cairo University, Cairo, Egypt Conflict of interest: The authors declare no potential conflict of interest.