Advances in Anatomy Embryology and Cell Biology Vol. 177 Editors F. Beck, Melbourne B. Christ, Freiburg F. Clasc(cid:1), Madrid D.E. Haines, Jackson H.-W. Korf, Frankfurt W. Kummer, Gießen E. Marani, Leiden R. Putz, M(cid:2)nchen Y. Sano, Kyoto T.H. Schiebler, W(cid:2)rzburg K. Zilles, D(cid:2)sseldorf S.C.J. van der Putte The Devlopment of the Perineum in the Human A Comprehensive Histological Study with a Special Reference to the Role of the Stromal Components With46Figures S.C.J.vanderPutte DepartmentofPathology UniversityMedicalCentreUtrecht P.O.Box85500, 3508GAUtrecht, TheNetherlands e-mail:[email protected] LibraryofCongressControlNumber:2004102481 ISSN0301-5556 ISBN3-540-21039-3SpringerBerlinHeidelbergNewYork Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeor partofthematerialisconcerned,specificallytherightsoftranslation,reprinting, reuseofillustrations,recitation,broadcasting,reproductiononmicrofilmorin anyotherway,andstorageindatabanks.Duplicationofthispublicationorparts thereofispermittedonlyundertheprovisionsoftheGermanCopyrightLawof September9,1965,initscurrentversion,andpermissionforusemustalwaysbe obtainedfromSpringer-Verlag.Violationsareliableforprosecutionunderthe GermanCopyrightLaw. 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Editor:Dr.RolfLange,Heidelberg,Germany Deskeditor:AnneClauss,Heidelberg,Germany Productioneditor:AndreasG(cid:2)sling,Heidelberg,Germany Coverdesign:design&productionGmbH,Heidelberg,Germany Typesetting:St(cid:3)rtzAG,W(cid:3)rzburg,Germany Printedonacid-freepaper27/3150/ag –5 4 3 2 1 0 For Marijke Acknowledgements I would like to thank the technicians of the laboratories of histopathology and immunohistochemistry for their technical help and wish to acknowledge in particular the contribution of Mr. H. Sakkers, J.L. Hof, W.J.M. Hermsen, and J.A.S. van Ginkel. IammostgratefultoMr.D.F.vanWichenforhisgreathelpin preparingtheillustrationsandtoMrs.I.L.vanRooijenforher assistanceinthepreparationofthemanuscript. I also wish to express my appreciation to my colleagues Prof. Dr. J. Huber, Drs. G. van Noort (Streeklaboratorium Patholo- gie, Enschede), Dr. P.G.J. Nikkels, and Dr. W.G.M. Spliet for providing the many specimens which were essential for this investigation. I gratefully acknowledge the generosity of the Department of Anatomy and Embryology of the University of Amsterdam (Prof.Dr.W.H.Lamers),DepartmentofAnatomyandEmbry- ology of the Leiden University Medical Centre (Prof. Dr. A.C. Gittenberger-deGroot),DepartmentofFunctionalAnatomyof the University Medical Centre Utrecht (Dr. R.L.A.W. Bleys), and the Hubrecht Institute of Developmental Biology Utrecht (Prof.Dr.R.H.A.Plasterk)forgivingmeaccesstotheircollec- tionsofhumanembryos. Contents 1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . 1 2 MaterialsandMethods. . . . . . . . . . . . . . . . . 2 3 DevelopmentoftheSexuallyIndifferentPerineum 3 3.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . 3 3.2 Observations. . . . . . . . . . . . . . . . . . . . . . . . 4 3.2.1 PrecloacalPerineum(e.3–5mmTotalLength, 24–28DaysFertilizationAge, CarnegieStageXI–XIII) . . . . . . . . . . . . . . . . 4 3.2.2 CloacalPerineum(e.5–15mmCRL,26–45Days FertilizationAge,CarnegieStagesXIV–XVIII). . 5 3.2.2.1 Cloaca:EpithelialStructure . . . . . . . . . . . . . . 5 3.2.2.2 Cloaca:MesenchymalStructure . . . . . . . . . . . 11 3.2.2.3 VascularSystem. . . . . . . . . . . . . . . . . . . . . . 13 3.2.2.4 NervousSystem. . . . . . . . . . . . . . . . . . . . . . 14 3.2.2.5 ExternalPerineum. . . . . . . . . . . . . . . . . . . . 15 3.2.3 PostcloacalSexuallyIndifferentPerineum (e.15–32mmCRL,44–56Days, CarnegieStageXVIII–XXIII) . . . . . . . . . . . . . 17 3.2.3.1 UrogenitalSinus . . . . . . . . . . . . . . . . . . . . . 17 3.2.3.2 AnalCanal . . . . . . . . . . . . . . . . . . . . . . . . . 25 3.2.3.3 StriatedPerinealMusculature. . . . . . . . . . . . . 28 3.2.3.4 VascularSystem. . . . . . . . . . . . . . . . . . . . . . 28 3.2.3.5 NervousSystem. . . . . . . . . . . . . . . . . . . . . . 30 3.2.3.6 ExternalPerineum. . . . . . . . . . . . . . . . . . . . 30 3.3 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . 31 3.3.1 CloacalEminence . . . . . . . . . . . . . . . . . . . . 32 3.3.2 CloacaandAllantois:PartitionofMesonephric andUretericSystems . . . . . . . . . . . . . . . . . . 32 3.3.3 DivisionoftheCloaca. . . . . . . . . . . . . . . . . . 34 3.3.4 UrogenitalSinus . . . . . . . . . . . . . . . . . . . . . 36 3.3.5 AnalCanal . . . . . . . . . . . . . . . . . . . . . . . . . 40 3.3.6 PerinealStriatedMusculature. . . . . . . . . . . . . 41 3.3.7 VascularSystem. . . . . . . . . . . . . . . . . . . . . . 42 3.3.8 LabioscrotalSwellings. . . . . . . . . . . . . . . . . . 43 X 4 DevelopmentoftheFemalePerineum . . . . . . . 43 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 43 4.2 Observations . . . . . . . . . . . . . . . . . . . . . . . . 44 4.2.1 Vagina . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 4.2.2 TransformationoftheUrogenitalSinusintothe UrethraandVestibulum. . . . . . . . . . . . . . . . . 50 4.2.3 Urethra. . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 4.2.4 Vestibulum . . . . . . . . . . . . . . . . . . . . . . . . . 55 4.2.5 ErectileStructures. . . . . . . . . . . . . . . . . . . . . 57 4.2.6 FascialTissues . . . . . . . . . . . . . . . . . . . . . . . 59 4.2.7 LabiaMajora . . . . . . . . . . . . . . . . . . . . . . . . 64 4.2.8 AnalCanal . . . . . . . . . . . . . . . . . . . . . . . . . 64 4.2.9 PerinealStriatedMusculature . . . . . . . . . . . . . 67 4.2.10 ExternalPerineum . . . . . . . . . . . . . . . . . . . . 67 4.3 Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . 68 4.3.1 Vagina . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 4.3.2 TransformationoftheUrogenitalSinusintothe UrethraandVestibulum. . . . . . . . . . . . . . . . . 73 4.3.3 Urethra. . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 4.3.4 Vestibulum . . . . . . . . . . . . . . . . . . . . . . . . . 75 4.3.5 LabiaMajora . . . . . . . . . . . . . . . . . . . . . . . . 78 4.3.6 AnalCanal . . . . . . . . . . . . . . . . . . . . . . . . . 79 4.3.7 ExternalPerineum . . . . . . . . . . . . . . . . . . . . 80 5 DevelopmentoftheMalePerineum. . . . . . . . . 81 5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 81 5.2 Observations . . . . . . . . . . . . . . . . . . . . . . . . 82 5.2.1 Urethra. . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 5.2.1.1 ProstaticUrethra . . . . . . . . . . . . . . . . . . . . . 83 5.2.1.2 MembranousUrethra . . . . . . . . . . . . . . . . . . 88 5.2.1.3 SpongyUrethra . . . . . . . . . . . . . . . . . . . . . . 89 5.2.1.4 NavicularFossa . . . . . . . . . . . . . . . . . . . . . . 91 5.2.2 ErectileStructures. . . . . . . . . . . . . . . . . . . . . 94 5.2.3 FascialTissues . . . . . . . . . . . . . . . . . . . . . . . 97 5.2.4 PerinealRaphe,Septum,Body,andFasciae . . . . 99 5.2.5 Scrotum . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 5.2.6 Penis,Prepuce,PreputialSacandFrenulum. . . . 104 5.2.7 AnalCanal . . . . . . . . . . . . . . . . . . . . . . . . . 107 5.2.8 PerinealStriatedMusculature . . . . . . . . . . . . . 107 5.2.9 ExternalPerineum . . . . . . . . . . . . . . . . . . . . 108 5.3 Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . 109 5.3.1 Urethra. . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 5.3.2 ErectileStructures. . . . . . . . . . . . . . . . . . . . . 113 5.3.3 PerinealRaphe,Septum,Body,andFasciae . . . . 114 5.3.4 Penis,Prepuce,PreputialSac,andFrenulum . . . 116 5.3.5 Scrotum . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 XI 6 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . 118 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 SubjectIndex. . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 1 Introduction Thedevelopmentalstepswhichleadtotheformationofthehumanperineum seemfirmlyestablished(Arey1965;HamiltonandMossman1972;Mooreand Persaud 1998; Wartenberg 1993; Sadler 1995; Larsen 1997). They form the base for the evaluation of the pathogenesis of a great variety of complicated and often serious malformations which occur in this region. This concept has, however,beenchallengedby the resultsofaninvestigation intothenor- mal and abnormal development of the anorectum in pig (van der Putte and Neeteson 1983, 1984; van der Putte 1986). Observations revealedthat at least in pig, a major element in current ideas about the early development of the perineum, namely the process by which the original simple cloaca is subdi- vided into a urogenital and anal part is incorrect, while additional observa- tions strongly suggested that the same may be true for ideas about female and male sexual transformation. A preliminary investigation in human em- bryos gave similar indications (van derPutte 1986).The data supported ear- lier critical findings (Politzer 1931, 1932; Wijnen 1964; Ludwig 1965) which have apparently been ignored, possibly because they seemed to hinder the understanding of the pathogenesis of congenital malformations such as im- perforate anus and hypospadias. The necessity to provide an embryological basefortheexplanationofthesemalformationshashadaprofoundeffecton prevalent theories about the development of the anogenital region and has evenledtotheoreticalconstructionswhichwereapparentlynotbasedonob- servationsinembryos(Billand Johnson1958;Duhamel etal.1966;Stephens et al. 1988, 1996). The unexpected results from an investigation into heredi- tary congenital anorectal malformations of pig embryos have demonstrated the weakness of such interpretations and constructions (van der Putte and Neeteson 1984) and underlined the need for a new inquiry into the normal developmentof theareainhuman embryos. Theseresultsdemonstratedthat although data from malformations may offer extra information about the normal development of the area, great care has to be taken in using that in- formationforthereconstructionofitsnormaldevelopment,whichshouldbe firmly based on the observation of the evolving microscopic anatomy of the region inthe first place. However, inthis respect original workonthe devel- opment of the perineum gave a confusing picture of fragmentary and often conflicting information. It underlined the necessity that in case a new inves- tigation was undertaken such a study should be comprehensive by address- ing the whole developmental process, including not only the sexually indif- ferentperiod andfemale andmaledifferentiation,butalso ananalysisof the untilnowalmostcompletelyneglectedstromaltissues.