887656 research-article20192019 TAU0010.1177/1756287219887656Therapeutic Advances in UrologyF Palmisano, D Moreno-Mendoza Therapeutic Advances in Urology Original Research Clinical factors affecting semen Ther Adv Urol 2019, Vol. 11: 1–11 improvement after microsurgical DOI: 10.1177/ https://doi.org/10.1177/1756287219887656 https://doi.org/10.1177/1756287219887656 1756287219887656 subinguinal varicocelectomy: which © The Author(s), 2019. Article reuse guidelines: sagepub.com/journals- subfertile patients benefit from surgery? permissions Franco Palmisano , Daniel Moreno-Mendoza, Riccardo Ievoli, Gabriel Veber-Moisés-Da Silva, Carlos Gasanz-Serrano, Juan Fernando Villegas-Osorio, Maria Fernanda Peraza-Godoy, Álvaro Vives, Lluís Bassas, Emanuele Montanari, Eduard Ruiz-Castañé, Joaquim Sarquella-Geli and Josvany Sánchez-Curbelo Abstract Background: The exact mechanism of varicocele-related infertility is still elusive, therefore, the current challenges for its management lie in determining which patients stand to benefit most from surgical correction. The authors aimed to assess the clinical factors affecting semen improvement after left microsurgical subinguinal varicocelectomy (MSV) in relation to patient age, ultrasound varicocele grading (USVG), and presence of a right subclinical varicocele (RSV). Methods: From 2010 to 2017 a total of 228 infertile patients underwent left MSV for clinical Correspondence to: Franco Palmisano varicocele. Descriptive statistics were used to describe the cohort and verify the surgical Department of Urology, Foundation IRCCS Ca’ benefit in terms of semen improvement, in addition, subsets of patients were selected Granda Ospedale Maggiore according to clinical covariates. Logistic regression modeling was applied to evaluate the Policlinico, University of Milan, via della presence of RSV, operative time, age, and USVG as explanatory variables. Commenda, Milan, Italy Results: Sperm concentration (SC), progressive sperm motility (PSM), and normal sperm franco.palmisano@ hotmail.it morphology (NSM) increased significantly after surgery (p = 0.002; p = 0.011; p = 0.024; Daniel Moreno-Mendoza respectively). Mean SC improved after MSV in ⩾35 year-old patients and the grade 3 USVG Carlos Gasanz-Serrano Juan Fernando Villegas- group (p = 0.01; p = 0.02; respectively). Logistic regression modeling showed a that the Osorio Maria Fernanda Peraza- probability of SC improvement was 76% lower in subjects presenting RSV (p = 0.011). In Godoy addition, patients with a grade 3 USVG presented a three-times greater probability of SC Álvaro Vives Lluís Bassas improvement compared with patients with a lower USVG (p = 0.035). In addition, older patients Eduard Ruiz-Castañé Joaquim Sarquella-Geli showed a greater probability of SC improvement after MSV (p = 0.041). Josvany Sánchez-Curbelo Conclusions: MSV is an effective varicocele-related infertility treatment that should also Fundació Puigvert, Department of Andrology, be offered to older patients. In addition, patients with a higher USVG benefit from surgery. Universitat Autonoma de In infertile men with an RSV in association with a left clinical disease, a bilateral varicocele Barcelona, Barcelona, Spain repair should be considered. Riccardo Ievoli Department of Statistics, University of Bologna, Keywords: age, grade, infertility, microsurgery, predictors, semen parameters, subclinical, Bologna, Italy Gabriel Veber-Moisés-Da ultrasound, varicocele, varicocelectomy Silva Hospital de Clínicas de Porto Alegre, Department Received: 6 August 2019; accepted in revised form: 17 October 2019. of Urology, Porto Alegre, Brazil Emanuele Montanari Department of Urology, Introduction drains the testes and may be associated with male Foundation IRCCS Ca’ Granda Ospedale Maggiore Varicocele is defined as a pathological dilation of subfertility, hypogonadism, pain, discomfort, Policlinico, University of the testicular pampiniform venous plexus that and failure of ipsilateral testicular growth and Milan, Milan, Italy journals.sagepub.com/home/tau 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Urology 11 development. This condition is present in 11.7% impaired semen quality according to the World of adult men and in 25.4% of men with abnormal Health Organization (WHO) reference values.10 semen analysis.1 Despite a recent meta-analysis showing semen improvement after surgical cor- The exclusion criteria were: azoospermia, con- rection, the exact association between reduced comitant right clinical varicocele or bilateral vari- male fertility and varicocele is unknown.2 cocelectomy, male accessory gland infection, anti-sperm antibodies, retrograde ejaculation, Several hypotheses have attempted to explain tumors, undescended testicle(s), and chromo- the correlation between varicoceles and subfer- some defects. tility, with the most commonly acknowledged mechanisms being acceptably attributed to All patients underwent a detailed medical history hypoxia and hemostasis, increased scrotal tem- review, and a general physical and andrological perature, adrenal metabolite reflux, autoimmun- examination. Varicocele was clinically diagnosed ity, and increased oxidative stress.3,4 by physical palpation and classified according to the WHO11 guidelines. In addition, an in-office Because the pathophysiology of varicocele-related testicular ultrasound (US) was performed in both infertility remains elusive, current challenges in the supine and standing position. Grading was its management lie in determining which patients assigned as follows: grade I 3 mm (maximum) stand to benefit most from surgical correction, vein diameter in the pampiniform plexus in asso- and when surgery should be performed. ciation with reflux during the Valsalva maneuver, grade II vein diameter >3 mm accompanied by In this context, sparse data from the literature reflux during the Valsalva maneuver, and grade III has led to unclear and inconsistent evidence that was spontaneous reverse vein flow that increased allows for no reliable recommendations in favor during the Valsalva maneuver. for, or against, varicocelectomy indications in the guidelines of the most important societies world- The MSV procedure was performed by the same wide. In fact, the guidelines sometimes contra- experienced surgical team using an operating dict each other and leave treatment indications microscope that allowed from ×6 to ×25 magni- up to the individual discussions with infertile fication of the operating field (Carl-Zeiss, Jena, couples.5–8 Germany). However, current evidence indicates that the Intraoperative and postoperative adverse events most effective treatment option is microsurgical were recorded. Follow-up was based on a stand- varicocelectomy because it results in fewer com- ard internal protocol that consisted of a sched- plications and lower recurrence rates compared uled re-evaluation 7 days after surgery and an with the other techniques.9 andrological evaluation with semen analysis and scrotal US 3 months postoperatively. With the purpose of identifying the optimal treat- ment strategy for infertile males with left clinical Semen samples were collected by masturbation varicocele, the present study aims to define clini- directly into a sterile plastic container after cal factors affecting semen improvement after 3–5 days of sexual abstinence. The following var- microsurgical subinguinal varicocelectomy (MSV) iables were taken into consideration: sperm con- based on patient age, ultrasound varicocele grad- centration (n × 106/ml SC), progressive sperm ing (USVG), and the concomitant presence of motility (% PSM) and normal sperm morphol- right subclinical varicocele (RSV). ogy (% NSM). Patients and methods Statistical analyses We identified subfertile men with left clinical var- R software was used for statistical analysis (R: icocele within the Department of Andrology, A language and environment for statistical Fundació Puigvert, Barcelona, Spain, who under- computing; R Core Team, 2014; R Foundation went MSV between January 2010 and December for Statistical Computing, Vienna, Austria). 2017. All patients presented with at least 1 year of Statistical significance for the tests was set at infertility with unprotected intercourse and had α < 0.05. 2 journals.sagepub.com/home/tau F Palmisano, D Moreno-Mendoza et al. Descriptive and test statistics were used to revealed grade I subclinical right varicocele in describe the cohort and verify the benefits follow- 16.23% of patients (n = 37). Mean operation time ing surgery in terms of semen parameter improve- was 57.5 min (± 19.9), all patients were dis- ments. A one-way Kolmogorov–Smirnov (KS) charged the day of surgery. No cases of hydrocele statistical test was applied to assess the normality were reported, and 19 patients anticipated the of variables. Continuous variables were presented scheduled clinical re-examination, for pain (4.4%, as mean ± standard deviation (SD) and com- 10 patients), scrotal hematoma (2.2%, 5 patients), pared using a Chi-square test, while KS could not or surgical wound discharge (1.8%, 4 patients). reject the null hypothesis, and the Wilcoxon However, hospitalization was never necessary. signed-rank test was applied where normality Figure 1 shows significant semen parameter could not to be assumed (KS test p value <0.05). changes at 3 months after surgery. US persistence Subsequently, subsets of patients were selected of varicocele was observed in 11 patients (3 grade according to clinical covariates and the previous I, 1 grade II, 7 grade III). analyses were repeated. A data driven approach was used to identify variables that could have With regard to patient age, no statistically signifi- potential explanatory significance for semen cant differences were found between groups aA improvement following surgery. The variables and aB preoperatively (Figure 2a). Group aB selected were: patient age, USVG, and the pres- benefited from MSV in terms of mean SC ence of concomitant RSV. Regarding patient age, (23.4 × 106/ml ±31.2; p = 0.01); Figure 2b shows the cohort was divided into two groups: < 35 quantitative semen changes among age groups. year-old (group aA), and ⩾35 years old (group aB), and with respect to USVG, patients were According to USVG, mean age of group USVG1-2 classified as 'low' (I–II, group USVG1-2) or 'high' and group USVG3 were similar, being respectively grade (III, group USVG3). 34.7 (± 6) and 33.3 (± 6.4) years old. Three months after surgery, varicocele repair resulted in a The main aim of the analyses was to assess and significant impact on the NSM of group USVG1-2 quantify the impact of covariates on semen (p = 0.02), while both groups presented SC improvement. Box plots were used to describe improvement (p = 0.05 and 0.02 respectively), as the analysis and to give a visual overview of the observable in Figure 3a. Figure 3b reports quanti- quantitative changes in semen parameters after tative semen improvements after MSV at the surgery. 3-month follow-up for all US grades. Finally, generalized linear model theory12 was Taking into consideration the presence of RSV, a applied to model the probability of semen improve- lack of improvement of semen parameters follow- ment using some determinants. Specifically, logis- ing surgery is highlighted in cases with RSV, while tic regression13 was used to model the probability patients with only left disease significantly of SC improvement, according to some explana- improved after MSV in terms of all considered tory variables, including the presence of RSV, semen parameters (Figure 4). operative time, patient age, and USVG. These variables were chosen using a selection method Table 1 shows the main results of the logistic (stepwise). regression model, the probability of an SC improvement (of 1 × 106/ml of concentration) was lower in patients presenting with a concomi- Results tant RSV (76% lower than others, ceteris paribus; Overall, 228 subfertile patients, with a mean age p = 0.011). This probability varied from 14% to of 34.1 (± 6.1) years, underwent subinguinal 77% in 95% of the samples. In addition, the microscopical varicocele repair. Clinical grade I probability of considerable improvement in terms was reported in 14.7% of patients, grade II and of SC was three-times greater for patients with III were reported respectively in 50% and 35.3% USG3 than for patients with USG1-2, ceteris pari- of patients. The grade of clinical disease was miss- bus (p = 0.035). Moreover, the probability of SC ing for 72 patients. US staging revealed grade I improvement for patients with USG3 was greater for 23 (12.3%) of patients, and grade II and III in for each age group of patients (p = 0.041), with 90 (42.6%) and 92 (45.1%) of patients, respec- the chances varying from 0.03% to 11% in 95% tively, data was missing for 23 patients. US of samples. journals.sagepub.com/home/tau 3 Therapeutic Advances in Urology 11 Table 1. Logistic regression model. Dependent variable: sperm concentration. Estimate Standard error Z value OR CI (95%) p value Age 0.053 0.026 2.048 1.054 (1.003–1.110) 0.041* USVG 2 0.703 0.497 1.412 2.019 (0.769–5.506) 0.158 USVG 3 1.081 0.511 2.114 2.946 (1.095–8.267) 0.035* RSV –1.090 0.431 –2.531 0.336 (0.141–0.771) 0.011* Operation time 0.003 0.008 0.415 1.003 (0.988–1.020) 0.678 Intercept is omitted. *<0.05 CI, confidence interval; OR, odds ratio; RSV: subclinical right varicocele; USVG: ultrasound varicocele grading. Figure 1. (a) comparison of semen parameters before and 3 months after microsurgical subinguinal varicocele repair. (b) box plots indicate quantitative changes in median semen parameters 3 months after surgery. Please note, the red dotted lines indicate WHO reference values (sperm concentration 15 × 106/ml; progressive sperm motility 32%; normal sperm morphology 4%). Discussion evidence used to provide recommendations is, in The aim of our study was to assess clinical factors general, of a low-quality. In this context, guide- affecting semen improvement in a large cohort of lines from the most important societies, including patients who underwent MSV, in a real life set- the American Society for Reproductive Medicine ting. We found a benefit from MSV in terms of (ASRM), American Urological Association mean SC improvement in older patients and in (AUA), European Academy of Andrology (EAA), those with a higher USVG. Of clinical impor- and European Association of Urology (EAU) have tance, we found the presence of concomitant in general, had an undefined impact on the cur- RSV to negatively impact semen improvement rent practice of varicocele treatment and manage- after surgery. ment, giving unclear and sometimes contrasting indications.5–8 The reason for this has been attrib- Our interest was fueled by the fact that there is uted to the lack of well-designed studies and currently insufficient outcome data to support a conflicting data regarding the impact of varico- formal evidence-based guideline, and that the cele formation on infertility, abnormal semen 4 journals.sagepub.com/home/tau F Palmisano, D Moreno-Mendoza et al. Figure 2. (a) Differences between < 35 and ⩾35 year-old patients before surgery. (b) Box plots: quantitative changes in semen parameters 3 months after surgery in different age groups. Please note, the red dotted lines indicate WHO reference values (sperm concentration 15 × 106/ml; progressive sperm motility 32%; normal sperm morphology 4%). parameters, decreased pregnancy rates, and the color Duplex analysis.11 Varicocelectomy should results of varicocele treatment.14 be performed in case of oligozoospermia and evidence of progressive testicular dysfunction, According to the EAU, the diagnosis of varico- while a subclinical varicocele should not be cele must be made by clinical examination and treated.7 However, the AUA does not suggest should be confirmed by US investigation and imaging studies for standard evaluation unless the journals.sagepub.com/home/tau 5 Therapeutic Advances in Urology 11 Figure 3. (a) Comparison of semen parameters changes between US grade I–II and III after microsurgical subinguinal varicocelectomy. (b) Box plots: qualitative changes in median semen values 3 months after surgery in different US grade groups. Please note, the red dotted lines indicate WHO reference values (sperm concentration 15 × 106/ml; progressive motility 32%; normal forms 4%). physical exam is inconclusive.6 Scrotal US, how- spermatic veins that recur or persist after varico- ever, may be indicated for clarification of an cele repair. inconclusive physical examination of the scro- tum. Spermatic venography may be useful to In addition, the EAA underlines contradicting demonstrate the anatomic position of refluxing evidence that allows no reliable recommendation 6 journals.sagepub.com/home/tau F Palmisano, D Moreno-Mendoza et al. Figure 4. (a) Comparison of semen parameter changes after left microsurgical subinguinal varicocele repair in patients with or without right subclinical varicocele. (b) Box plots indicate quantitative changes in median semen parameters 3 months after surgery among all groups. Please note, the red dotted lines indicate WHO reference values (sperm concentration 15 × 106/ml; progressive sperm motility 32%; normal sperm forms 4%). in favor for or against varicocelectomy.8 Varicoce- routine patient investigation.8,15 The Practice lectomy in infertile men with oligo-asthenoterato- Committee of the ASRM is a 21-person commit- zoospermia and palpable varicocele should be tee with male reproductive urologists, androlo- discussed individually with the couple, while gists and reproductive endocrinology, and monitoring is suggested only for subclinical dis- infertility specialists.5 Their report provides a ease.8 However, scrotal US is considered part of a comprehensive overview of varicocele detection journals.sagepub.com/home/tau 7 Therapeutic Advances in Urology 11 and management recommendations based on lit- children, this may represent a huge bias with no erature reviews and expert opinion.5 They suggest solution. In this context, what is of clinical impor- that the recommendations should be regarded as tance is the effective improvement of the seminal 'appropriate management' but not necessarily 'the parameters of these patients following surgery. only standard of practice'.5 Contrasting findings have been reported by stud- The role of ultrasonography remains controver- ies assessing the role of varicocele grade in a series sial because subclinical varicoceles have a of patients who had undergone surgery for infer- poor concordance with those detected on phys- tility.21–24 Our data demonstrated that patients ical examination.16 The WHO Manual for with USVG3 presented a three-times greater the Standardized Investigation, Diagnosis, and probability of SC improvement compared with Management of the Infertile Male is cited as the patients with a lower USVG (p = 0.041). Our source for varicocele confirmation by color results were similar to Steckel’s findings, where a Duplex US, however, its dogmatic emphasis on greater relative improvement in sperm count in further investigation of grade I and subclinical patients with a grade III varicocele than men with varicoceles by US and thermography is not rep- grade II or I disease was shown.21 However, resentative of the other previously mentioned Wang and colleagues reported that preoperative reports.11 varicocele grade might not predict postoperative semen changes regardless of the possible exist- Previous studies examining clinical factors that ence of anatomic and ultrasonographic associa- possibly minimize semen improvement after vari- tions.22 In addition, Braedel and colleagues23 cocele repair have focused mainly on patient age found less improvement in sperm count in men and clinical grade. In present study, mean SC with grade III varicocele than in men with smaller improved after MSV in ⩾35 year-old patients varicoceles. In addition, in a small cohort of (p = 0.01). Similarly, Yazdani and colleagues patients divided according to the varicocele clini- reported statistically significant SC improvement cal grade, who all underwent a scrotal sonogra- after varicocelectomy in older patients, in this phy with the Valsalva maneuver and showed case, older than 30 years (p < 0.001).17 In addition, pampiniform vein diameters >3 mm, Vahidi Ishikawa and colleagues found improvement of and colleagues highlighted an improved effect of semen characteristics after varicocele repair in microsurgical varicocelectomy on patients with patients aged 20–29 years, and those over 30 years, a higher grade.24 concluding that it is reasonable to perform ligation to improve the semen characteristics A question to be resolved when considering treat- in patients older than 40 years old.18 In addition, ment of varicocele is the gray area of subclinical Cox regression analysis performed by Zhang concern, which relies on the diagnostic criteria and colleagues in a prospective cohort study of employed.25 Obviously, the degree of varicocele 120 males with varicocele who underwent MSV by palpation is subjective, but this dilemma appar- showed no role of age as a predictor of spontane- ently cannot be overcome by ultrasound, whose ous pregnancy rate improvement.19 Of interest, main characteristic is being operator-dependent. Kimura and colleagues revealed that patients In addition, the heterogeneity and nonstandardi- younger than 37 years old experienced greater zation of the various scores and ultrasound classi- early (3 months) and late (⩾6 months) improve- fications complicates the topic. ments in semen parameters after microsurgical varicocele repair, however, they did not exclude Our logistic regression model showed the proba- the possibility of semen parameter improvement bility of SC improvement was 75% lower when in older men, and concluded that microsurgical RSV was present (p = 0.11), which makes a con- varicocele repair could also be beneficial for older tribution to the semen impairment. Although the men.20 boundary between clinical and subclinical varico- cele remains elusive and no surgical recommen- The main problem concerning investigations on dation has been given for the treatment of how much age can influence seminal parameters subclinical varicocele,5–8 several studies suggest a and their possible improvement after a treatment role in male infertility that supports our results.26–30 lies in the fact that the patient’s age at the time of In a 2018 retrospective review on 190 infertile varicocele diagnosis is not related to the onset of men who underwent a microsurgical varicocele the disease but is related to the patient’s desire for repair, no differences were found in total motile 8 journals.sagepub.com/home/tau F Palmisano, D Moreno-Mendoza et al. sperm count improvement between men with challenges in clinical practice lie in determining clinical and subclinical varicoceles (p = 0.66).26 when surgery should be performed and for which patients. In our study, we observed the Even if no statistically significant differences clinical outcome using seminal improvements were found for SC, as found in our data, in a as the primary determinant factor in a large well-designed meta-analysis of four randomized cohort. This study helped to reveal the most controlled trials, including 637 cases with left appropriate treatment strategies for infertile clinical and RSV (318 cases in the bilateral var- men with varicocele, indicating a benefit from icocelectomy group and 319 cases in the left surgery also in older patients and for those with varicocelectomy group), the fixed effects model higher grade disease. In addition, our results combined difference in sperm PSM between suggest that bilateral varicocelectomy should be the two groups was 6.42% (CI 95% 5.09–7.75), considered in patients with left clinical and the random effects model combined difference RSV. in NSM between the two groups was 2.04% (CI 95% 0.60–3.48).27 In addition to this, the Several limitations to this study should be odds ratio shown by the fixed effects model in acknowledged, of which the single institution spontaneous pregnancy rate was 1.73 (CI 95% design is probably the most relevant, and has the 1.24–2.43) indicating bilateral varicocelectomy potential to result in a sample of patients that is may be superior to unilateral surgery for infer- not representative of the general population. tile male patients with left clinical and RSV.27 However, given that the reference department is a Despite not increasing pregnancy rates, meta- tertiary referral center for the city of Barcelona analysis performed by Kim and colleagues and for surrounding cities and the region of showed that surgical repair for subclinical vari- Catalonia (Spain), we believe it is safe to assume cocele could improve forward sperm PSM,28 that this limitation was minimal in this study. although no statistically significant benefit Another limitation of the present study lies in the derived from surgery when SC, in contrast to short follow-up period (3 months). However, cur- our results, was considered. Consistent with rent evidence indicates that the degree of improve- our conclusions, and despite the different tech- ment in semen parameters 3 months after nique used, in a prospective study reported by varicocelectomy remains the same, or stable, Cantoro and colleagues percutaneous emboli- 12 months after surgery.20–32 In addition, no com- zation was performed in 218 male patients with parison with other varicocelectomy techniques left subclinical varicocele and abnormal sperm was performed, with microsurgical varicocele parameters, the control group included 119 repair being the gold standard in varicocele treat- cases. After a long follow-up (39.4 ± 6.5 months), ment.7 Another limitation of the current study is the mean SC and total motility in the treatment its retrospective design for which we did not have group were better than those in the control data collection with standardized protocols group, indicating that subclinical varicocele regarding the hormonal profiles of the patients, should be diagnosed and treated.29 In addition, therefore, making any speculation impossible. Cervellion and colleagues revealed that subclin- Similarly, because the quantification of the clini- ical varicocele can progress to clinical varico- cal disease was missing for a large percentage of cele in 28% of male children. Although there is the patients, we only used US grading in the anal- no related study in adults men, bilateral varico- ysis. Because of this, physical examination is often celectomy might stop the progress of subclini- ambiguous due to its subjective nature and cal varicocele in infertile men.30 In light of this, dependence on the experience of the examiner. It a recent study suggested that subclinical varico- is of limited value in very obese patients, patients cele might be a less severe form of clinical vari- with high-located testes, patients with a history of cocele and the pathogenic mechanism was the surgery in the scrotal or groin region, patients same, justifying its treatment.31 with a coexistent hydrocele, and in patients with a postoperative recurrence of varicocele. Under Because varicocele-related subfertility is a con- these conditions, US assessment may be very dition with a ill-defined pathophysiology, and helpful or even necessary in these patients. because is has not yet been clarified how clinical factors such as patient age, varicocele Despite this, our results promote MSV as an effec- grade, and the presence of a concomitant RSV tive technique for the treatment of varicocele-related may influence semen parameters, the current infertility, even in older patients and those with a journals.sagepub.com/home/tau 9 Therapeutic Advances in Urology 11 higher US grade. In addition, it highlights the role ORCID iD that RSV plays in semen improvement after MSV. Franco Palmisano https://orcid.org/0000-0002 -0197-9033 Conclusion When surgical treatment in considered in infertile men with varicocele, MSV should be offered for References older patients. Patients with higher USVG benefit 1. World Health Organization. The influence of from surgery in terms of postoperative semen varicocele on parameters of fertility in a large changes. In infertile men with both RSV and a left group of men presenting to infertility clinics. clinical disease, a bilateral varicocele repair should Fertil Steril 1992; 57: 1289. be considered. 2. Agarwal A, Deepinder F, Cocuzza M, et al. Efficacy of varicocelectomy in improving semen Authors’ note parameters: new meta-analytical approach. Riccardo Ievoli is now affiliated to Department Urology 2007; 70: 532–538. of Economics and Management, University of 3. Will MA, Swain J, Fode M, et al. The great Ferrara, Ferrara, Italy. debate: varicocele treatment and impact on fertility. Fertil Steril 2011; 95: 841–852. Acknowledgements 4. Pallotti F, Paoli D, Carlini T, et al. Varicocele This retrospective study was conducted accord- and semen quality: a retrospective case-control ing to the guidelines and principles of the study of 4230 patients from a singlecentre. J Declaration of Helsinki and standard ethical Endocrinol Invest 2018; 41: 185–192. conduct for research involving humans; after 5. American Society for Reproductive Medicine. approval of the our Ethical Committee for Clinical Report on varicocele and infertility: a committee Research, all patients signed an informed con- opinion. Fertil Steril 2014; 102: 1556–1560. sent agreeing to supply their own anonymous 6. American Urological Association. The optimal data for this and future studies. The study also evaluation of the infertile male: AUA best guaranteed compliance at all times with Law practice statement. Linthicum, MD: American 15/1999 on Protection of Personal Data (Spanish Urological Association Education and Research Government). Inc; 2010. The authors thank Dana Kuefner PhD for review- 7. Jungwirth A, Diemer T, Kopa Z, et al. European ing the language in this manuscript. association of urology guidelines on male infertility. In: Presented at the EAU Annual F.P. and D.M.M. contributed equally to this work. Congress Copenhagen 2018. Arnhem, The Conceptualization: F.P., D.M.M., J.S.G., J.S.C. Netherlands: EAU Guidelines Office. Data curation: F.P., D.M.M., J.S.C. Formal anal- ysis: F.P., R.I. Investigation: F.P., D.M.M., R.I., 8. Colpi GM, Francavilla S, Haidl G, et al. G.V.M.d.S., C.G.S., J.F.V.O., M.F.P.G., A.V.S., European Academy of Andrology guideline Management of oligo-astheno-teratozoospermia. J.S.G., J.S.C. Methodology: F.P., R.I., C.G.S., Andrology 2018; 6: 513–524. J.F.V.O., J.S.C. Supervision: L.B.A., E.M., E.R.C., J.S.C. Validation: D.M.M., M.F.P.G., 9. Ding H, Tian J, Du W, et al. Open non- A.V.S., J.S.G., J.S.C. Writing – original draft: microsurgical, laparoscopic or open microsurgical F.P., G.V.M.d.S. Writing – review & editing: F.P., varicocelectomy for male infertility: a meta- G.V.M.d.S., J.S.C. analysis of randomized controlled trials. BJU Int 2012; 110: 1536–1542. 10. Cooper TG, Noonan E, von Eckardstein S, et al. Funding World Health Organization reference values for The author(s) received no financial support for human semen characteristics. Hum Reprod Update the research, authorship, and/or publication of 2010; 16: 231–245. this article. 11. Rowe PJ, Comhaire FH, Hargreave TB, et al.; World Health Organization. WHO manual Conflict of interest statement for the standardized investigation, diagnosis, and The authors declare that there is no conflict of management of the infertile male. New York: interest. Cambridge; 2000. 10 journals.sagepub.com/home/tau F Palmisano, D Moreno-Mendoza et al. 12. Nelder JA and Wedderburn RWM. Generalized 23. Braedel HU, Steffens J, Ziegler M, et al. A linear models. J R Stat Soc A 1972; 135: 370– possible ontogenetic etiology for idiopathic left 384. varicocele. J Urol 1994; 151: 62–66. 13. Hosmer Jr DW, Lemeshow S and Sturdivant RX. 24. Vahidi S, Moein M, Nabi A, et al. Effects of Applied logistic regression. Vol. 398. John Wiley & microsurgical varicocelectomy on semen analysis Sons, 2013. and sperm function tests in patients with different grades of varicocele: role of sperm functional tests 14. Shridharani A, Owen RC, Elkelany OO, et al. in evaluation of treatments outcome. Andrologia The significance of clinical practice guidelines 2018; 50: e13069. on adult varicocele detection and management. Asian J Androl 2016; 18: 269–275. 25. Howards SS. Subclinical varicocele. Fertil Steril 1992; 57: 725–726. 15. Lotti F and Maggi M. Ultrasound of the male genital tract in relation to male reproductive 26. Thirumavalavan N, Scovell JM, Balasubramanian health. Hum Reprod Update 2015; 21: 56–83. A, et al. The impact of microsurgical repair of subclinical and clinical varicoceles on total motile 16. Petros JA, Andriole GL, Middleton WD, sperm count: is there a difference? Urology 2018; et al. Correlation of testicular color Doppler 120: 109–113. ultrasonography, physical examination and venography in the detection of left varicoceles in 27. Niu Y, Wang D, Chen Y, et al. Comparison men with infertility. J Urol 1991; 145: 785–788. of clinical outcome of bilateral and unilateral varicocelectomy in infertile males with left clinical 17. Yazdani M, Hadi M, Abbasi H, et al. Efficacy of and right subclinical varicocele: A meta-analysis varicocele repair in different age groups. Urology of randomised controlled trials. Andrologia 2018; 2015; 86: 273–275. 50: e13078. 18. Ishikawa T and Fujisawa M. Effect of age and 28. Kim HJ, Seo JT, Kim KJ, et al. Clinical grade on surgery for patients with varicocele. significance of subclinical varicocelectomy in Urology 2005; 65: 768–772. male infertility: systematic review and meta- 19. Zhang JW, Xu QQ, Kuang YL, et al. Predictors analysis. Andrologia 2016; 48: 654–661. for spontaneous pregnancy after microsurgical subinguinal varicocelectomy: a prospective cohort 29. Cantoro U, Polito M and Muzzonigro G. study. Int Urol Nephrol 2017; 49: 955–960. Reassessing the role of subclinical varicocele in infertile men with impaired semen quality: a 20. Kimura M, Nagao K, Tai T, et al. Age is a prospective study. Urology 2015; 85: 826–830. significant predictor of early and late improvement in semen parameters after microsurgical varicocele 30. Cervellione RM, Corroppolo M and Bianchi A. repair. Andrologia 2017; 49. Subclinical varicocele in the pediatric age group. J Urol 2008; 179: 717–719; discussion 719. 21. Steckel J, Dicker AP and Goldstein M. Relationship between varicoceles size and 31. Chen SS. Significant predictive factors for response to varicocelectomy. J Urol 1993; 149: subfertility in patients with subclinical varicocele. 769–771. Andrologia 2017; 49. 22. Wang H, Wang X, Fu D, et al. Does varicocele 32. Fukuda T, Miyake H, Enatsu N, et al. Visit SAGE journals online grade predict the postoperative changes of Assessment of time-dependent changes in semen journals.sagepub.com/ home/tau semen parameters following left inguinal micro- parameters in infertile men after microsurgical varicocelectomy? Asian J Urol 2015; 2: 163–166. varicocelectomy. Urology 2015; 86: 48–51. SAGE journals journals.sagepub.com/home/tau 11