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Preoperative hormone therapy in single-stage repair of hypospadias: A comprehensive systematic review

Published:January 19, 2023DOI:https://doi.org/10.1016/j.jpurol.2023.01.013

      Summary

      Introduction

      Preoperative hormone therapy (PHT) holds promise for obtaining better surgical conditions for patients undergoing hypospadias correction and increasing the success rate. However, the application and effects of PHT remain uncertain owing to a lack of comprehensive evaluation, thus limiting treatment strategies and development of standardized guidelines. This study aimed to review the following: (ⅰ) the criteria and regimens of PHT; (ⅱ) its impact on penile growth, postoperative complications, and side effects; (ⅲ) and sources of inconsistent clinical outcomes.

      Methods

      This systematic review was registered at PROSPERO (CRD42022346924) and conducted and reported following international recommendations, including the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. We searched the databases over the last two decades to identify eligible studies. This systematic review included literature regarding the use of PHT in the treatment of children with single stage hypospadias repair. Risk of Bias (RoB) was measured using two different tools: randomized controlled trials using a modified version of the RoB Assessment Tool and non-randomized studies of interventions using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I). The R-3.6.3 software was used for the analysis.

      Results

      In total, 25 studies involving 4094 patients were included in the systematic review. The surgeons’ criteria for using PHT varied, with short penile length being the most important. The most frequently reported regimens for intramuscular (IM) testosterone were either 2 mg/kg or empiric 25 mg monthly, and the duration was 2–3 months preoperatively. Androgens were significantly effective in improving penile development, and the changes commonly peaked at 2–3 months. The effects of PHT on complications and side effects are controversial, and the potential causes include hormone sensitivity, degree of hypospadias, surgical techniques, and dosing regimens.

      Conclusions

      This systematic review evaluated PHT in children with hypospadias. Building on previous studies, this review provides a more specific attitude and possible aspects for resolving the controversies. Future studies should identify the applicable subgroups of patients and standardize the dose and mode of delivery for the best clinical results.

      Keywords

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      References

        • Springer A.
        • van den Heijkant M.
        • Baumann S.
        Worldwide prevalence of hypospadias.
        J Pediatr Urol. 2016; 12: e151-e157https://doi.org/10.1016/j.jpurol.2015.12.002
        • Mole R.J.
        • Nash S.
        • MacKenzie D.N.
        Hypospadias. BMJ. 2020; 369: m2070https://doi.org/10.1136/bmj.m2070
        • Immergut M.
        • Boldus R.
        • Yannone E.
        • Bunge R.
        • Flocks R.
        The local application of testosterone cream to the prepubertal phallus.
        J Urol. 1971; 105: 905-906https://doi.org/10.1016/s0022-5347(17)61657-4
        • Ezomike U.O.
        • Nwangwu E.I.
        • Chukwu I.S.
        • Ekenze S.O.
        Practice patterns of preoperative hormonal stimulation in pediatric penile surgeries-A survey of Nigerian pediatric surgeons.
        J Pediatr Urol. 2020; 16: 440-445https://doi.org/10.1016/j.jpurol.2020.06.001
        • Gorduza D.B.
        • Gay C.L.
        • de Mattos E.S.E.
        • Demède D.
        • Hameury F.
        • Berthiller J.
        • et al.
        Does androgen stimulation prior to hypospadias surgery increase the rate of healing complications? - A preliminary report.
        J Pediatr Urol. 2011; 7: 158-161https://doi.org/10.1016/j.jpurol.2010.05.003
        • de Mattos e Silva E.
        • Gorduza D.B.
        • Catti M.
        • Valmalle A.F.
        • Demède D.
        • Hameury F.
        • et al.
        Outcome of severe hypospadias repair using three different techniques.
        J Pediatr Urol. 2009; 5 (; discussion 212-204): 205-211https://doi.org/10.1016/j.jpurol.2008.12.010
        • Wright I.
        • Cole E.
        • Farrokhyar F.
        • Pemberton J.
        • Lorenzo A.J.
        • Braga L.H.
        Effect of Preoperative Hormonal Stimulation on Postoperative Complication Rates After Proximal Hypospadias Repair: A Systematic Review.
        J Pediatr Urol. 2013; 190: 652-659https://doi.org/10.1016/j.juro.2013.02.3234
        • Chao M.
        • Zhang Y.
        • Liang C.
        Impact of preoperative hormonal stimulation on postoperative complication rates after hypospadias repair: a meta-analysis.
        Minerva Urol Nefrol. 2017; 69: 253-261https://doi.org/10.23736/s0393-2249.16.02634-5
        • Chua M.E.
        • Gnech M.
        • Ming J.M.
        • Silangcruz J.M.
        • Sanger S.
        • Lopes R.I.
        • et al.
        Preoperative hormonal stimulation effect on hypospadias repair complications: Meta-analysis of observational versus randomized controlled studies.
        J Pediatr Urol. 2017; 13: 470-480https://doi.org/10.1016/j.jpurol.2017.06.019
        • Sembiring G.
        • Sigumonrong Y.
        Efficacy of preoperative testosterone therapy in hypospadias: a systematic review and meta-analysis.
        Annals of Pediatric Surgery. 2021; 17https://doi.org/10.1186/s43159-021-00117-4
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        BMJ. 2009; 339: b2535https://doi.org/10.1136/bmj.b2535
        • Cinaz P.
        • Yeşilkaya E.
        • Onganlar Y.H.
        • Boyraz M.
        • Bideci A.
        • Camurdan O.
        • et al.
        Penile anthropometry of normal prepubertal boys in Turkey.
        Acta Paediatr. 2012; 101: e33-e36https://doi.org/10.1111/j.1651-2227.2011.02386.x
        • Higgins J.P.
        • Altman D.G.
        • Gøtzsche P.C.
        • Jüni P.
        • Moher D.
        • Oxman A.D.
        • et al.
        The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928https://doi.org/10.1136/bmj.d5928
        • Sterne J.A.
        • Hernán M.A.
        • Reeves B.C.
        • Savović J.
        • Berkman N.D.
        • Viswanathan M.
        • et al.
        ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
        BMJ. 2016; 355: i4919https://doi.org/10.1136/bmj.i4919
        • Gorduza D.
        • Plotton I.
        • Remontet L.
        • Gay C.L.
        • El Jani M.
        • Cheikhelard A.
        • et al.
        Preoperative Topical Estrogen Treatment vs Placebo in 244 Children With Midshaft and Posterior Hypospadias.
        J Clin Endocrinol Metab. 2020; 105https://doi.org/10.1210/clinem/dgaa231
        • Mohammadipour A.
        • Hiradfar M.
        • Sharifabad P.S.
        • Shojaeian R.
        Pre-operative hormone stimulation in hypospadias repair: A facilitator or a confounder.
        J Pediatr Urol. 2020; 16: 318.e311-318.e317https://doi.org/10.1016/j.jpurol.2020.04.012
        • Casali T.G.
        • Paiva K.C.D.
        • Rodrigues M.N.
        • Silva C.E.S.
        • de Figueiredo A.A.
        • de Bessa J.
        • et al.
        Topical estradiol increases epidermal thickness and dermal collagen of foreskin prior to hypospadia surgery - Randomized double blinded controlled trial.
        J Pediatr Urol. 2019; 15: 346-352https://doi.org/10.1016/j.jpurol.2019.05.014
        • Babu R.
        • Chakravarthi S.
        The role of preoperative intra muscular testosterone in improving functional and cosmetic outcomes following hypospadias repair: A prospective randomized study.
        J Pediatr Urol. 2018; 14 (29.e21-29.e26)https://doi.org/10.1016/j.jpurol.2017.07.009
        • Rynja S.P.
        • de Jong T.
        • Bosch J.
        • de Kort L.M.O.
        Testosterone prior to hypospadias repair: Postoperative complication rates and long-term cosmetic results, penile length and body height.
        J Pediatr Urol. 2018; 14 (31.e31-31.e38)https://doi.org/10.1016/j.jpurol.2017.09.020
        • de Andrade E.C.
        • de Castro Paiva K.C.
        • da Silva Guedes S.
        • Souza M.L.C.
        • Pereira M.N.
        • Miana L.P.
        • et al.
        Echocardiographic evaluation of left ventricular mass index in children with hypospadias after hormonal stimulation with topical testosterone: A randomized controlled trial.
        J Pediatr Urol. 2017; 13 (352 e351-352 e357)https://doi.org/10.1016/j.jpurol.2017.03.019
        • Menon P.
        • Rao K.L.N.
        • Handu A.
        • Balan L.
        • Kakkar N.
        Outcome of urethroplasty after parenteral testosterone in children with distal hypospadias.
        J Pediatr Urol. 2017; 13: 292.e291-292.e297https://doi.org/10.1016/j.jpurol.2017.01.001
        • Chen C.
        • Yang T.Q.
        • Dong C.Q.
        • Liu Q.
        • Dong K.
        • Su C.
        • et al.
        Curative effectiveness of human chorionic gonadotropin treatment on hypospadias with micropenis.
        Chinese Journal of Applied Clinical Pediatrics. 2017; 32: 821-824https://doi.org/10.3760/CMA.J.ISSN.2095-428X.2017.11.007
        • Snodgrass W.
        • Bush N.C.
        Re-operative urethroplasty after failed hypospadias repair: how prior surgery impacts risk for additional complications.
        J Pediatr Urol. 2017; 13: 289 e281-e289 e286https://doi.org/10.1016/j.jpurol.2016.11.012
        • Paiva K.C.
        • Bastos A.N.
        • Miana L.P.
        • Barros Ede S.
        • Ramos P.S.
        • Miranda L.M.
        • et al.
        Biometry of the hypospadic penis after hormone therapy (testosterone and estrogen): A randomized, double-blind controlled trial.
        J Pediatr Urol. 2016; 12: 200.e201-200.e206https://doi.org/10.1016/j.jpurol.2016.04.013
        • McNamara E.R.
        • Schaeffer A.J.
        • Logvinenko T.
        • Seager C.
        • Rosoklija I.
        • Nelson C.P.
        • et al.
        Management of Proximal Hypospadias with 2-Stage Repair: 20-Year Experience.
        J Urol. 2015; 194: 1080-1085https://doi.org/10.1016/j.juro.2015.04.105
        • Asgari S.A.
        • Safarinejad M.R.
        • Poorreza F.
        • Asl A.S.
        • Ghanaie M.M.
        • Shahab E.
        The effect of parenteral testosterone administration prior to hypospadias surgery: A prospective, randomized and controlled study.
        J Pediatr Urol. 2015; 11: 143.e141-143.e146https://doi.org/10.1016/j.jpurol.2014.12.014
        • Chen C.
        • Gong C.X.
        • Zhang W.P.
        Effects of oral testosterone undecanoate treatment for severe hypospadias.
        Int Urol Nephrol. 2015; 47: 875-880https://doi.org/10.1007/s11255-015-0972-6
        • Snodgrass W.
        • Cost N.
        • Nakonezny P.A.
        • Bush N.
        Analysis of risk factors for glans dehiscence after tubularized incised plate hypospadias repair.
        J Urol. 2011; 185: 1845-1849https://doi.org/10.1016/j.juro.2010.12.070
        • Snodgrass W.
        • Bush N.
        Tubularized incised plate proximal hypospadias repair: Continued evolution and extended applications.
        J Pediatr Urol. 2011; 7: 2-9https://doi.org/10.1016/j.jpurol.2010.05.011
        • Bastos A.N.
        • Oliveira L.R.
        • Ferrarez C.E.
        • de Figueiredo A.A.
        • Favorito L.A.
        • Bastos Netto J.M.
        Structural study of prepuce in hypospadias--does topical treatment with testosterone produce alterations in prepuce vascularization?.
        J Urol. 2011; 185: 2474-2478https://doi.org/10.1016/j.juro.2011.01.035
        • Ishii T.
        • Hayashi M.
        • Suwanai A.
        • Amano N.
        • Hasegawa T.
        The effect of intramuscular testosterone enanthate treatment on stretched penile length in prepubertal boys with hypospadias.
        Urology. 2010; 76: 97-100https://doi.org/10.1016/j.urology.2009.12.065
        • Catti M.
        • Lottmann H.
        • Babloyan S.
        • Lortat-Jacob S.
        • Mouriquand P.
        Original Koyanagi urethroplasty versus modified Hayashi technique: outcome in 57 patients.
        J Pediatr Urol. 2009; 5: 300-306https://doi.org/10.1016/j.jpurol.2009.03.010
        • Nerli R.B.
        • Koura A.
        • Prabha V.
        • Reddy M.
        Comparison of topical versus parenteral testosterone in children with microphallic hypospadias.
        Pediatr Surg Int. 2009; 25: 57-59https://doi.org/10.1007/s00383-008-2278-6
        • Braga L.H.
        • Lorenzo A.J.
        • El-Hout Y.
        • Farhat W.A.
        • Bagli D.J.
        • Khoury A.E.
        • et al.
        Should We Still Use Onlay Island Flap for Penoscrotal Hypospadias Repair?.
        J Urol. 2008; 179: 408-409https://doi.org/10.1016/s0022-5347(08)61196-9
        • Kaya C.
        • Bektic J.
        • Radmayr C.
        • Schwentner C.
        • Bartsch G.
        • Oswald J.
        The efficacy of dihydrotestosterone transdermal gel before primary hypospadias surgery: a prospective, controlled, randomized study.
        J Urol. 2008; 179: 684-688https://doi.org/10.1016/j.juro.2007.09.098
        • Luo C.C.
        • Lin J.N.
        • Chiu C.H.
        • Lo F.S.
        Use of parenteral testosterone prior to hypospadias surgery.
        Pediatr Surg Int. 2003; 19: 82-84https://doi.org/10.1007/s00383-002-0717-3
        • Chalapathi G.
        • Rao K.L.
        • Chowdhary S.K.
        • Narasimhan K.L.
        • Samujh R.
        • Mahajan J.K.
        Testosterone therapy in microphallic hypospadias: topical or parenteral?.
        J Pediatr Surg. 2003; 38: 221-223https://doi.org/10.1053/jpsu.2003.50047
        • Gearhart J.P.
        • Jeffs R.D.
        The use of parenteral testosterone therapy in genital reconstructive surgery.
        J Urol. 1987; 138: 1077-1078https://doi.org/10.1016/s0022-5347(17)43507-5
        • Taghavi K.
        • O'Hagan L.A.
        • Hewitt J.K.
        • Mouriquand P.
        Defining the role of pre-operative hormonal therapy in hypospadias.
        J Paediatr Child Health. 2022; 58: 1508-1519https://doi.org/10.1111/jpc.16087
        • Silver R.I.
        • Russell D.W.
        5alpha-reductase type 2 mutations are present in some boys with isolated hypospadias.
        J Urol. 1999; 162: 1142-1145https://doi.org/10.1097/00005392-199909000-00064
        • Bouty A.
        • Ayers K.L.
        • Pask A.
        • Heloury Y.
        • Sinclair A.H.
        The Genetic and Environmental Factors Underlying Hypospadias.
        Sex Dev. 2015; 9: 239-259https://doi.org/10.1159/000441988
        • Monfort G.
        • Lucas C.
        Dehydrotestosterone penile stimulation in hypospadias surgery.
        Eur Urol. 1982; 8: 201-203https://doi.org/10.1159/000473517
        • Cimador M.
        • Vallasciani S.
        • Manzoni G.
        • Rigamonti W.
        • De Grazia E.
        • Castagnetti M.
        Failed hypospadias in paediatric patients.
        Nat Rev Urol. 2013; 10: 657-666https://doi.org/10.1038/nrurol.2013.164
        • Randall V.A.
        Androgens and hair growth.
        Dermatol Ther. 2008; 21: 314-328https://doi.org/10.1111/j.1529-8019.2008.00214.x
        • Gilliver S.C.
        • Ruckshanthi J.P.
        • Atkinson S.J.
        • Ashcroft G.S.
        Androgens influence expression of matrix proteins and proteolytic factors during cutaneous wound healing.
        Lab Invest. 2007; 87: 871-881https://doi.org/10.1038/labinvest.3700627
        • Gilliver S.C.
        • Wu F.
        • Ashcroft G.S.
        Regulatory roles of androgens in cutaneous wound healing.
        Thromb Haemost. 2003; 90: 978-985https://doi.org/10.1160/th03-05-0302
        • Hofer M.D.
        • Cheng E.Y.
        • Bury M.I.
        • Xu W.
        • Hong S.J.
        • Kaplan W.E.
        • et al.
        Androgen supplementation in rats increases the inflammatory response and prolongs urethral healing.
        Urology. 2015; 85: 691-697https://doi.org/10.1016/j.urology.2014.11.025
        • Hassan J.M.
        • Pope JCt
        • Revelo P.
        • Adams M.C.
        • Brock 3rd, J.W.
        • DeMarco R.T.
        The role of postoperative testosterone in repair of iatrogenic hypospadias in rabbits.
        J J Pediatr Urol. 2006; 2: 329-332https://doi.org/10.1016/j.jpurol.2006.02.008
        • Duckett Jr., J.W.
        Transverse preputial island flap technique for repair of severe hypospadias. 1980.
        J Urol. 2002; 167 (discussion 1183): 1179-1182https://doi.org/10.1016/s0022-5347(02)80375-5
        • Zheng D.C.
        • Wang H.
        • Lu M.J.
        • Chen Q.
        • Chen Y.B.
        • Ren X.M.
        • et al.
        A comparative study of the use of a transverse preputial island flap (the Duckett technique) to treat primary and secondary hypospadias in older Chinese patients with severe chordee.
        World J Urol. 2013; 31: 965-969https://doi.org/10.1007/s00345-012-0990-2
        • van der Horst H.J.
        • de Wall L.L.
        Hypospadias, all there is to know.
        Eur J Pediatr. 2017; 176: 435-441https://doi.org/10.1007/s00431-017-2864-5
        • Manzoni G.
        • Bracka A.
        • Palminteri E.
        • Marrocco G.
        Hypospadias surgery: when, what and by whom?.
        BJU Int. 2004; 94: 1188-1195https://doi.org/10.1046/j.1464-410x.2004.05128.x
        • Netto J.M.B.
        • Ferrarez C.
        • Leal A.A.S.
        • Tucci S.
        • Gomes C.A.
        • Barroso U.
        Hormone therapy in hypospadias surgery: A systematic review.
        J Pediatr Urol. 2013; 9: 971-979https://doi.org/10.1016/j.jpurol.2013.03.009