Impact of Varicocele Repair on Semen Parameters in Infertile Men: A Systematic Review and Meta-Analysis

Ashok Agarwal 1, Rossella Cannarella 2 3, Ramadan Saleh 4, Florence Boitrelle 5 6, Murat Gül 7, Tuncay Toprak 8, Gianmaria Salvio 9, Mohamed Arafa 10 11, Giorgio I Russo 12, Ahmed M Harraz 13 14 15, Rajender Singh 16, Nicolas Garrido 17, Taha Abo-Almagd Abdel-Meguid Hamoda 18 19, Amarnath Rambhatla 20, Parviz Kavoussi 21, Shinnosuke Kuroda 3, Gökhan Çalik 22, Pallavi Saini 16, Erman Ceyhan 23, Fotios Dimitriadis 24, Ralf Henkel 25 26 27, Andrea Crafa 2, Ayad Palani 28, Mesut Berkan Duran 29, Evangelos Maziotis 30 31, Émine Saïs 5 6, Marion Bendayan 5 6, Mahsa Darbandi 32 33, Tan V Le 34 35, Sezgin Gunes 36, Petroula Tsioulou 30, Pallav Sengupta 37, Berk Hazir 38, Gökhan Çeker 39 40, Sara Darbandi 32 33, Damayanthi Durairajanayagam 41, Azin Aghamajidi 42, Noora Alkhalidi 43, Emrullah Sogutdelen 44, Kristian Leisegang 45, Abdullah Alarbid 14, Christopher C K Ho 46, Vineet Malhotra 47, Federica Finocchi 9 48, Luís Crisóstomo 49 50 51, Raghavender Kosgi 52, Haitham ElBardisi 10 11, Armand Zini 53, Ponco Birowo 54, Giovanni Colpi 55, Hyun Jun Park 56 57, Ege Can Serefoglu 58, Quang Nguyen 59 60, Edmund Ko 61, Jean de la Rosette 62, Germar M Pinggera 63, Ho Vinh Phuoc Nguyen 34 35, Hussein Kandil 64, Rupin Shah 65

Affiliations

04 January 2023

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doi: 10.5534/wjmh.220142

Abstract

Purpose: Despite the significant role of varicocele in the pathogenesis of male infertility, the impact of varicocele repair (VR) on conventional semen parameters remains controversial. Only a few systematic reviews and meta-analyses (SRMAs) have evaluated the impact of VR on sperm concentration, total motility, and progressive motility, mostly using a before-after analytic approach. No SRMA to date has evaluated the change in conventional semen parameters after VR compared to untreated controls. This study aimed to evaluate the effect of VR on conventional semen parameters in infertile patients with clinical varicocele compared to untreated controls.

Materials and methods: A literature search was performed using Scopus, PubMed, Embase, and Cochrane databases following the Population Intervention Comparison Outcome (PICOS) model (Population: infertile patients with clinical varicocele; Intervention: VR [any technique]; Comparison: infertile patients with clinical varicocele that were untreated; Outcome: sperm concentration, sperm total count, progressive sperm motility, total sperm motility, sperm morphology, and semen volume; Study type: randomized controlled trials and observational studies).

Results: A total of 1,632 abstracts were initially assessed for eligibility. Sixteen studies were finally included with a total of 2,420 infertile men with clinical varicocele (1,424 patients treated with VR vs. 996 untreated controls). The analysis showed significantly improved post-operative semen parameters in patients compared to controls with regards to sperm concentration (standardized mean difference [SMD] 1.739; 95% CI 1.129 to 2.349; p<0.001; I²=97.6%), total sperm count (SMD 1.894; 95% CI 0.566 to 3.222; p<0.05; I²=97.8%), progressive sperm motility (SMD 3.301; 95% CI 2.164 to 4.437; p<0.01; I²=98.5%), total sperm motility (SMD 0.887; 95% CI 0.036 to 1.738; p=0.04; I²=97.3%) and normal sperm morphology (SMD 1.673; 95% CI 0.876 to 2.470; p<0.05; I²=98.5%). All the outcomes showed a high inter-study heterogeneity, but the sensitivity analysis showed that no study was sensitive enough to change these results. Publication bias was present only in the analysis of the sperm concentration and progressive motility. No significant difference was found for the semen volume (SMD 0.313; 95% CI -0.242 to 0.868; I²=89.7%).

Conclusions: This study provides a high level of evidence in favor of a positive effect of VR to improve conventional semen parameters in infertile men with clinical varicocele. To the best of our knowledge, this is the first SRMA to compare changes in conventional semen parameters after VR with changes in parameters of a control group over the same period. This is in contrast to other SRMAs which have compared semen parameters before and after VR, without reference to a control group. Our findings strengthen the available evidence and have a potential to upgrade professional societies' practice recommendations favoring VR to improve conventional semen parameters in infertile men.

Keywords: Male infertility; Semen; Varicocele.

Conflict of interest statement

The authors have nothing to disclose.

Figures

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow-chart.

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow-chart.

Fig. 2. Forest plot of the semen volume in infertile men with varicocele repair compared to no treatment.

Fig. 2. Forest plot of the semen volume in infertile men with varicocele repair compared to no treatment.

Fig. 3. Forest plot of the semen volume in infertile men with varicocele repair compared to no treatment: sensitivity analysis.

Fig. 3. Forest plot of the semen volume in infertile men with varicocele repair compared to no treatment: sensitivity analysis.

Fig. 4. Funnel plot of the semen volume in infertile men with varicocele repair compared to no treatment.

Fig. 4. Funnel plot of the semen volume in infertile men with varicocele repair compared to no treatment.

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References

  1.  
    1. Thonneau P, Marchand S, Tallec A, Ferial ML, Ducot B, Lansac J, et al. Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989) Hum Reprod. 1991;6:811–816. - PubMed
  2.  
    1. Odisho AY, Nangia AK, Katz PP, Smith JF. Temporal and geospatial trends in male factor infertility with assisted reproductive technology in the United States from 1999-2010. Fertil Steril. 2014;102:469–475. - PubMed
  3.  
    1. Freeman S, Bertolotto M, Richenberg J, Belfield J, Dogra V, Huang DY, et al. members of the ESUR-SPIWG WG. Ultrasound evaluation of varicoceles: guidelines and recommendations of the European Society of Urogenital Radiology Scrotal and Penile Imaging Working Group (ESUR-SPIWG) for detection, classification, and grading. Eur Radiol. 2020;30:11–25. - PubMed
  4.  
    1. Damsgaard J, Joensen UN, Carlsen E, Erenpreiss J, Blomberg Jensen M, Matulevicius V, et al. Varicocele is associated with impaired semen quality and reproductive hormone levels: a study of 7035 healthy young men from six European countries. Eur Urol. 2016;70:1019–1029. - PubMed
  5.  
    1. Gorelick JI, Goldstein M. Loss of fertility in men with varicocele. Fertil Steril. 1993;59:613–616. - PubMed
  6.  
    1. Jarow JP, Coburn M, Sigman M. Incidence of varicoceles in men with primary and secondary infertility. Urology. 1996;47:73–76. - PubMed
  7.  
    1. World Health Organization. The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril. 1992;57:1289–1293. - PubMed
  8.  
    1. Schlegel PN, Sigman M, Collura B, De Jonge CJ, Eisenberg ML, Lamb DJ, et al. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I. Fertil Steril. 2021;115:54–61. - PubMed
  9.  
    1. Wang J, Xia SJ, Liu ZH, Tao L, Ge JF, Xu CM, et al. Inguinal and subinguinal micro-varicocelectomy, the optimal surgical management of varicocele: a meta-analysis. Asian J Androl. 2015;17:74–80. - PMC - PubMed
  10.  
    1. Minhas S, Bettocchi C, Boeri L, Capogrosso P, Carvalho J, Cilesiz NC, et al. EAU Working Group on Male Sexual and Reproductive Health. European Association of Urology guidelines on male sexual and reproductive health: 2021 update on male infertility. Eur Urol. 2021;80:603–620. - PubMed
  11.  
    1. Baazeem A, Belzile E, Ciampi A, Dohle G, Jarvi K, Salonia A, et al. Varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. Eur Urol. 2011;60:796–808. - PubMed
  12.  
    1. Agarwal A, Deepinder F, Cocuzza M, Agarwal R, Short RA, Sabanegh E, et al. Efficacy of varicocelectomy in improving semen parameters: new meta-analytical approach. Urology. 2007;70:532–538. - PubMed
  13.  
    1. Colpi GM, Francavilla S, Haidl G, Link K, Behre HM, Goulis DG, et al. European Academy of Andrology guideline management of oligo-astheno-teratozoospermia. Andrology. 2018;6:513–524. - PubMed
  14.  
    1. Marmar JL, Agarwal A, Prabakaran S, Agarwal R, Short RA, Benoff S, et al. Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. Fertil Steril. 2007;88:639–648. - PubMed
  15.  
    1. Kroese AC, de Lange NM, Collins J, Evers JL. Surgery or embolization for varicoceles in subfertile men. Cochrane Database Syst Rev. 2012;10:CD000479. - PubMed
  16.  
    1. Shah R, Agarwal A, Kavoussi P, Rambhatla A, Saleh R, Cannarella R, et al. Consensus and diversity in the management of varicocele for male infertility: results of a global practice survey and comparison with guidelines and recommendations. World J Mens Health. 2022 doi: 10.5534/wjmh.220048. [Epub] - DOI - PMC - PubMed
  17.  
    1. Schauer I, Madersbacher S, Jost R, Hübner WA, Imhof M. The impact of varicocelectomy on sperm parameters: a meta-analysis. J Urol. 2012;187:1540–1547. - PubMed
  18.  
    1. Asafu-Adjei D, Judge C, Deibert CM, Li G, Stember D, Stahl PJ. Systematic review of the impact of varicocele grade on response to surgical management. J Urol. 2020;203:48–56. - PubMed
  19.  
    1. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA. 2000;283:2008–2012. - PubMed
  20.  
    1. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647. Erratum in: BMJ 2016;354:i4086. - PubMed
  21.  
    1. Methley AM, Campbell S, Chew-Graham C, McNally R, Cheraghi-Sohi S. PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Serv Res. 2014;14:579. - PMC - PubMed
  22.  
    1. Murray J, Farrington DP, Eisner MP. Drawing conclusions about causes from systematic reviews of risk factors: the Cambridge Quality Checklists. J Exp Criminol. 2009;5:1–23.
  23.  
    1. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. - PubMed
  24.  
    1. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12. - PubMed
  25.  
    1. Schulz KF, Altman DG, Moher D CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332. - PMC - PubMed
  26.  
    1. Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods. 2006;11:193–206. - PubMed
  27.  
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. - PMC - PubMed
  28.  
    1. Andrade C. Mean difference, standardized mean difference (SMD), and their use in meta-analysis: as simple as it gets. J Clin Psychiatry. 2020;81:20f13681 - PubMed
  29.  
    1. Duval S, Tweedie R. A nonparametric “trim and fill” method of accounting for publication bias in meta-analysis. J Am Stat Assoc. 2000;95:89–98.
  30.  
    1. Gomaa MD, Motawaa MA, Al-Nashar AM, El-Sakka AI. Impact of subinguinal varicocelectomy on serum testosterone to estradiol ratio in male patients with infertility. Urology. 2018;117:70–77. - PubMed
  31.  
    1. McGarry P, Alrabeeah K, Jarvi K, Zini A. Is varicocelectomy beneficial in men previously deemed subfertile but with normal semen parameters based on the new guidelines? A retrospective study. Urology. 2015;85:357–362. - PubMed
  32.  
    1. Seo JT, Kim KT, Moon MH, Kim WT. The significance of microsurgical varicocelectomy in the treatment of subclinical varicocele. Fertil Steril. 2010;93:1907–1910. - PubMed
  33.  
    1. Çakan M, Bakirtas H, Aldemir M, Demirel F, Altug U. Results of varicocelectomy in patients with isolated teratozoospermia. Urol Int. 2008;80:172–176. - PubMed
  34.  
    1. Nilsson S, Edvinsson A, Nilsson B. Improvement of semen and pregnancy rate after ligation and division of the internal spermatic vein: fact or fiction? Br J Urol. 1979;51:591–596. - PubMed
  35.  
    1. Turgut H. The effect of varicocelectomy on the pregnancy rate in patients with severe oligospermia. Niger J Clin Pract. 2020;23:1744–1747. - PubMed
  36.  
    1. Gokce MI, Gülpınar O, Süer E, Mermerkaya M, Aydos K, Yaman O. Effect of performing varicocelectomy before intracytoplasmic sperm injection on clinical outcomes in non-azoospermic males. Int Urol Nephrol. 2013;45:367–372. - PubMed
  37.  
    1. Mansour Ghanaie M, Asgari SA, Dadrass N, Allahkhah A, Iran-Pour E, Safarinejad MR. Effects of varicocele repair on spontaneous first trimester miscarriage: a randomized clinical trial. Urol J. 2012;9:505–513. - PubMed
  38.  
    1. Ghanem MA, Safan MA, Ghanem AA, Dohle GR. The role of varicocele sclerotherapy in men with severe oligo-astheno-teratozoospermia. Asian J Androl. 2011;13:867–871. - PMC - PubMed
  39.  
    1. Abdel-Meguid TA, Al-Sayyad A, Tayib A, Farsi HM. Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial. Eur Urol. 2011;59:455–461. - PubMed
  40.  
    1. Sathya Srini V, Belur Veerachari S. Does varicocelectomy improve gonadal function in men with hypogonadism and infertility? Analysis of a prospective study. Int J Endocrinol. 2011;2011:916380. - PMC - PubMed
  41.  
    1. Di Bisceglie C, Bertagna A, Baldi M, Lanfranco F, Tagliabue M, Gazzera C, et al. Varicocele sclerotherapy improves serum inhibin B levels and seminal parameters. Int J Androl. 2007;30:531–536. - PubMed
  42.  
    1. Di Bisceglie C, Fornengo R, Grosso M, Gazzera C, Mancini A, Andriani B, et al. Follow-up of varicocele treated with percutaneous retrograde sclerotherapy: technical, clinical and seminal aspects. J Endocrinol Invest. 2003;26:1059–1064. - PubMed
  43.  
    1. Grasso M, Lania C, Castelli M, Galli L, Franzoso F, Rigatti P. Low-grade left varicocele in patients over 30 years old: the effect of spermatic vein ligation on fertility. BJU Int. 2000;85:305–307. - PubMed
  44.  
    1. Okuyama A, Fujisue H, Matsui T, Doi Y, Takeyama M, Nakamura N, et al. Surgical repair of varicocele: effective treatment for subfertile men in a controlled study. Eur Urol. 1988;14:298–300. - PubMed
  45.  
    1. Ketabchi AA, Salajegheh S. The effects of acupuncture treatment in infertile patients with clinical varicocele. Nephrourol Mon. 2018;10:e65451
  46.  
    1. Schlegel PN, Sigman M, Collura B, De Jonge CJ, Eisenberg ML, Lamb DJ, et al. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part II. J Urol. 2021;205:44–51. - PubMed
  47.  
    1. Silber SJ. The varicocele dilemma. Hum Reprod Update. 2001;7:70–77. - PubMed
  48.  
    1. Kantartzi PD, Goulis ChD, Goulis GD, Papadimas I. Male infertility and varicocele: myths and reality. Hippokratia. 2007;11:99–104. - PMC - PubMed
  49.  
    1. Silber S. The varicocele argument resurfaces. J Assist Reprod Genet. 2018;35:1079–1082. - PMC - PubMed
  50.  
    1. Agarwal A, Finelli R, Durairajanayagam D, Leisegang K, Henkel R, Salvio G, et al. Comprehensive analysis of global research on human varicocele: a scientometric approach. World J Mens Health. 2022 doi: 10.5534/wjmh.210202. [Epub] - DOI - PMC - PubMed
  51.  
    1. Birowo P, Rahendra Wijaya J, Atmoko W, Rasyid N. The effects of varicocelectomy on the DNA fragmentation index and other sperm parameters: a meta-analysis. Basic Clin Androl. 2020;30:15. - PMC - PubMed
  52.  
    1. Baker HW, Kovacs GT. Spontaneous improvement in semen quality: regression towards the mean. Int J Androl. 1985;8:421–426. - PubMed
  53.  
    1. Persad E, O'Loughlin CA, Kaur S, Wagner G, Matyas N, Hassler-Di Fratta MR, et al. Surgical or radiological treatment for varicoceles in subfertile men. Cochrane Database Syst Rev. 2021;4:CD000479. - PMC - PubMed
  54.  
    1. Kroese ACJ, de Lange NM, Collins J, Evers JLH, Marjoribanks J. Surgery or embolization for varicoceles in subfertile men: summary of a Cochrane review. Fertil Steril. 2014;102:1553–1555.
  55.  
    1. Hinkelmann K, Kempthorne O. Design and analysis of experiments. 2nd ed. Vol. 1, Introduction to experimental design. Hoboken (NJ): Wiley; 2008.
  56.  
    1. Teoli D, Sanvictores T, An J. In: StatPearls. Abai B, Abu-Ghosh A, Acharya AB, Acharya U, Adhia SG, Sedeh PA, editors. Treasure Island (FL): StatPearls Publishing; 2022. SWOT analysis. - PubMed

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