Alessandro, Pizzocaro

Carlo, Bettocchi

Corona, Giovanni

Krausz, Csilla Gabriella

Maggi, Mario

Nikolaos, Sofikitis

Suks, Minhas

Walter, Vena

English

Corona G

Minhas S

Bettocchi C

Krausz C

Pizzocaro A

Vena W

Maggi M

Sofikitis N.

Archivio Istituzionale della Ricerca- Università degli Studi di Foggia

Reply: Sperm retrieval rates by micro-TESE versus conventional TESE in men with non-obstructive azoospermia - The assumption of independence in effects sizes might lead to misleading conclusions

Krausz, Csilla

Florence Research

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.For permissions, please e-mail: journals.permissions@oup.comHuman Reproduction Update, pp. 1–4, 2020doi:10.1093/humupd/dmaa007LETTER TO THE EDITORReply: Sperm retrieval rates bymicro-TESE versus conventionalTESE in men with non-obstructiveazoospermia—the assumption ofindependence in effects sizes mightlead to misleading conclusionsSir,We thank Esteves and co-authors (2020) for their constructive crit-icisms of our meta-analysis. They essentially disagree with our conclu-sions saying that the available evidence did not confirm the superiorityof microdissection testicular sperm extraction (micro-TESE) vs. con-ventional TESE (cTESE) in the achievement of positive sperm retrievalrate (SRR) in patients with non-obstructive azoospermia (NOA). Themain problems that Esteves et al. (2020) emphasized are the high het-erogeneity and the inclusion of all studies with and without direct com-parison. In addition, other methodological problems were identified.First, we want to clarify that observational studies include case-series, case-control, cross-sectional and longitudinal studies wherethe independent variable is not under the control of the researcher(Higgins & Green, 2008; Guyatt et al., 2011). In particular, it is importantto clarify, for the readers of Human Reproduction Update, that a specific......................................................type of observational study deals with the evaluation of possible effectsof a treatment, or of an approach, where the assignment of subjectsinto a specific group versus a control one is outside the control of theinvestigator (Higgins & Green, 2008, Guyatt et al., 2011). As alreadyreported in our meta-analysis (Corona et al., 2019), all available studiescomparing mTESE vs. cTESE belong to the latter category of theobservational trials (Schlegel et al., 1997; Amer et al., 2000; Okadaet al., 2002; Tsujimura et al., 2002; Ramasamy et al., 2005; Ghalayiniet al., 2011; Salehi et al., 2017) except one, which is a randomised-controlled trial (RCT, Colpi et al., 2009). All types of observationaltrials, including comparison trials used by Bernie et al. (2015) in theirmeta-analysis, by Deruyver et al. (2014) in their systematic review andeven in our meta-analysis, present important limitations. The limita-tions include failure to develop and apply appropriate eligibility criteria,flawed measurement of both exposure and outcome, failure to ade-quately control confounding factors and incomplete follow-up (Guyattet al., 2011). For example, due to the lack of blinding assignment, physi-cians might be more likely to use mTESE in healthier individuals withmore favourable clinical characteristics, leading to a higher probabilityof reaching positive SRR. Accordingly, to better clarify the topic and tryto reduce the latter important source of bias, we decided to include inour meta-analysis all observational studies using cTESE or mTESE forSRR as correctly specified in the method section of our study Coronaet al., 2019 and in PROSPERO registration (https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=92017).Figure 1 Sperm retrieval rate (SRR) per testicular sperm extraction (TESE) cycle according to the type of surgical approach indifferent populations. cTESE = conventional TESE; mTESE = microsurgical-TESE. SCOS = Sertoli cell only syndrome; UP = lower limit; UL = upperlimit.Downloaded from https://academic.oup.com/humupd/advance-article-abstract/doi/10.1093/humupd/dmaa007/5841560 by Universita' Degli Studi di Firenze user on 26 May 20202 Letter to the EditorFigure 2 Influence of the number of patients with Sertoli cell only syndrome (SCOS) in the whole sample. (A) and whencomparative studies were excluded (B). Data refer to studies reporting histological evaluation for the whole sample. The size of the circles indicatessample dimension.Regarding the methodological problems emphasized by Esteves et al.(2020), we want to clarify that in order to reduce the risk of problemsrelated to data imputing, all data were blindly reviewed by four of theauthors (G.C., A.P., C.B. and N.S.) already involved in our work and byone (W.V.) not previously involved in the analysis. Some differences,when compared to the Esteves et al. (2020) analysis, were detected(see Supplementary Table S1).In addition, the following points need to be better elucidated.Firstly, Esteves et al. (2020) pointed out the problem related to asubstantial evidence of bias observed in our meta-analysis since up to43% of included mTESE studies involved selected patient populationswith an overall unfavourable prognosis, and by contrast, only 7.5%of the cTESE studies included the so-called ‘unfavourable’ patients,thus possibly over-estimating the SRR. In response to Esteves et al.’s..............................(2020) indication, we performed a sensitivity analysis by comparingSRR in cTESE and mTESE in selected and unselected studies (seeSupplementary Table S1). Similar to what was observed in our overallanalysis, we did not observe any statistical differences between the twotechniques (SRR = 48[44;51]% vs. 49[45;53]%, Q = 0.44, P = 0.51 and46[42;50]% vs.43[38;47]%, Q = 1.14; P = 0.28 for cTESE and mTESE inunselected and selected studies, respectively; see also Fig. 1).Secondly, Esteves et al. (2014), in their original study, found thatmTESE was able to detect higher SRR when compared to cTESEwhen patients with Sertoli only syndrome (SCOS) or tubular atrophywere considered. Hence, they reassessed the SRR in non-comparativestudies, included in our meta-analysis, showing that, when the analysiswas limited to patients with SCOS, mTESE resulted in a significantlyhigher SRR (Esteves et al., 2020). First of all, we wonder how it isDownloaded from https://academic.oup.com/humupd/advance-article-abstract/doi/10.1093/humupd/dmaa007/5841560 by Universita' Degli Studi di Firenze user on 26 May 2020Letter to the Editor 3possible to support one technique for a surgical approach taking intoaccount an outcome obtained only after a histological diagnosis, henceat the end of the procedure. In addition, it is important to recognizethat SCOS is a specific histological diagnosis of testis specimens whichcan result from different pathological conditions either congenital (pureor primitive) or acquired (partial or secondary) (Anniballo et al., 2000;Dohle et al., 2012). In the pure and complete form, the detection ofsperm is theoretically impossible whereas in secondary or partial SCOSit may sometimes be possible. Hence, the correct testis histologicalclassification represents an essential and crucial point. However, severalclassification systems have been described (Anniballo et al., 2000;Dohle et al., 2012). Although Johnsen score represents the most widelyquoted and quantitative histological grading system, the use of differentclassifications has resulted in a wide variation of diagnosis by differentpathologists, limiting the diagnostic and prognostic value of the testicu-lar biopsy (Anniballo et al., 2000; Dohle et al., 2012). This is the reasonwhy we decided not to use the histological classification as a possibleconfounder in our meta-analysis (Corona et al., 2019). In fact, it is ouropinion that it adds only a further source of bias. However, in orderto address Esteves et al.’s (2020) request, we carefully collected all thestudies reporting data on SCOS (Supplementary Table S1). In addition,it is important to emphasize that several studies reported histologicalclassification only for a limited number of patients and not for the wholepopulation studied (see Supplementary Table S1). This represents afurther source of bias. By considering only studies which provided ahistological classification for all patients evaluated and by consideringonly SOCS diagnosis as reported by the original authors (Supple-mentary Table S1), we were unable to detect any prognostic valueof SCOS when a meta-regression analysis was performed (Fig. 2A).Similar findings were observed when only non-comparative studieswere considered (Fig. 2B). The latter result confirms our hypothesisregarding the limitations related to the use of different histological testisclassifications (Anniballo et al., 2000; Dohle et al., 2012). In line withthis finding, by applying the aforementioned criteria, when only non-comparative studies were considered, we were not able to find anydifference when cTESE was compared to mTESE (SRR = 25[20;31] vs.31[26;37], Q = 2.28; P = 0.13, for cTESE and mTESE, respectively; seealso Fig. 1).Thirdly, Esteves et al. (2020) documented that when the analysiswas limited only to non-comparative studies providing confirmatorydiagnostic histopathology details, mTESE resulted in significantly higherSRR when compared to cTESE. Similar to what was reported forSCOS diagnosis, when the analysis was limited to only studies reportinghistological data in the whole sample and only non-comparative studieswere considered, we did not find any difference when cTESE was com-pared to mTESE (SRR = 48[44;52] vs. 47[44;51], Q = 0.12; P = 0.73 forcTESE and mTESE, respectively; see also Fig. 1).As correctly indicated by Esteves et al. (2020) and already recognizedin our study limitations (Corona et al., 2019), high heterogeneity wasdetected. An iterative analysis was performed by excluding outliersin order to reduce the heterogeneity (<50%) of the study (Higgins& Green, 2008). By performing a sensitivity analysis with a study het-erogeneity <50% (I2 = 49.2), we confirmed the absence of differencebetween cTESE and mTESE in SRR (SRR = 46[44;48] vs. 47[45;49],Q = 0.83; P = 0.36 for cTESE and mTESE, respectively).In conclusion, even after the new analysis of the data, accordingto Esteves et al.’s (2020) suggestions, we here confirm that available............................................................................................................................evidence cannot support the superiority of mTESE vs. cTESE in SRR forpatients with NOA. We agree with Esteves et al. (2020) that furtherhigh-quality RCTs are strongly advisable to better clarify this importanttopic.Supplementary dataSupplementary data are available at Human Reproduction Update online.ReferencesAmer M, Ateyah A, Hany R, Zohdy W. 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Reprod Biomed Online 2009;18:315–319.Corona G, Minhas S, Giwercman A, Bettocchi C, Dinkelman-Smit M,Dohle G, Fusco F, Kadioglou A, Kliesch S, Kopa Z et al. Sperm recov-ery and ICSI outcomes in men with non-obstructive azoospermia:a systematic review and meta-analysis. Hum Reprod Update 2019;25:733–757.Deruyver Y, Vanderschueren D, Van der Aa F. Outcome of microdis-section TESE compared with conventional TESE in non-obstructiveazoospermia: a systematic review. Andrology 2014;2:20–24.Dohle GR1, Elzanaty S, van Casteren NJ. Testicular biopsy: clinical prac-tice and interpretation. Asian J Androl 2012;14:88–93 .Esteves SC, Prudencio C, Seol B, Verza S, Knoedler C, AgarwalA. Comparison of sperm retrieval and reproductive outcome inazoospermic men with testicular failure and obstructive azoospermiatreated for infertility. Asian J Androl 2014;16:602–606.Esteves SC, Ramasamy R, Colpi GM, Carvalho JF, Schlegel PN. Spermretrieval rates by micro-TESE versus conventional TESE in men withnon-obstructive azoospermia—the assumption of independence ineffect sizes might lead to misleading conclusions. Hum Reprod Upd2020. doi:10.1093/humupd/dmaa006Ghalayini IF, Al-Ghazo MA, Hani OB, Al-Azab R, Bani-Hani I,Zayed F, Haddad Y. Clinical comparison of conventional testic-ular sperm extraction and microdissection techniques for non-obstructive azoospermia. J Clin Med Res 2011;3:124–131.Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-CoelloP, Montori V, Akl EA, Djulbegovic B, Falck-Ytter Y et al. GRADEguidelines: 4. Rating the quality of evidence–study limitations (risk ofbias). J Clin Epidemiol 2011;64:407–415.Higgins JPT, Green S. Cochrane handbook for systematic reviewsof interventions. Version 5.0.1 [updated September2008]. 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Hum Reprod 2002;17:2924–2929.Giovanni Corona 1,*, Suks Minhas2, Carlo Bettocchi3,Csilla Krausz4, Alessandro Pizzocaro5, Walter Vena5, Mario Maggi7,and Nikolaos Sofikitis6......................................................1Endocrinology Unit, Medical Department, Endocrinology Unit, AziendaUsl Bologna Maggiore-Bellaria Hospital, Bologna, Italy2Department of Urology, Imperial College NHS Healthcare, London, UK3Department of Urology, Andrology and Kidney Transplantation Unit,Department of Emergency and Organ Transplantation, University of Bari,Bari, Italy4Andrology, Women’s Endocrinology and Gender Inconguence Unit,Department of Experimental and Clinical Biomedical Sciences, AziendaOspedaliera Universitaria Careggi, Florence, Italy5Endocrinology Unit, Department of Biomedical Sciences, HumanitasUniversity and Humanitas Research Center IRCCS, Rozzano, Milan, Italy6Department of Urology, Ioannina University School of Medicine,Ioannina, Greece7Endocrinology Unit, Department of Experimental and Clinical BiomedicalSciences, Azienda Ospedaliera Universitaria Careggi, Florence, Italy*Correspondence address. Endocrinology Unit, MedicalDepartment, Azienda Usl Bologna Maggiore-Bellaria Hospital,Bologna, Italy, Largo Nigrisoli, 2, 40133 Bologna, Italy.Tel: +39-51-6478060; Fax: +39-51-6478058;E-mail: jocorona@libero.ithttps://orcid.org/0000-0002-9894-2885doi:10.1093/humupd/dmaa007Downloaded from https://academic.oup.com/humupd/advance-article-abstract/doi/10.1093/humupd/dmaa007/5841560 by Universita' Degli Studi di Firenze user on 26 May 2020

Reply: Sperm Retrieval Rates by micro-TESE Versus Conventional TESE in Men With Non-Obstructive Azoospermia-The Assumption of Independence in Effects Sizes Might Lead to Misleading Conclusions

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Reply: Sperm Retrieval Rates by micro-TESE Versus Conventional TESE in Men With Non-Obstructive Azoospermia-The Assumption of Independence in Effects Sizes Might Lead to Misleading Conclusions

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