Diagnosis and Treatment of Endometriosis 子宮內(nèi)膜異位癥

DiagnosisandTreatmentofEndometriosisCAROLINEWELLBERY,M.D.GeorgetownUniversitySchoolofMedicine,Washington,D.C.Endometriosisisaprogressivediseaseaffecting5to10percentofwomen.Itcancausedyspareunia,dysmenorrhea,lowbackpainandinfertility.Adefinitivediagnosiscanbemadeonlybymeansoflaparoscopy.Medicaltreatmentdesignedtointerferewithovulationgenerallyprovideseffectivepainrelief,buttherecurrenceratefollowingcessationoftherapyishigh,andthistypeoftreatmentwillnotresolveinfertility.Surgicaltreatmentimprovespregnancyratesandisthepreferredinitialtreatmentforinfertilitycausedbyendometriosis.Surgeryalsoappearstoprovidebetterlong-termpainreliefthanmedicaltreatment.Bilateraloophorectomyandhysterectomyaretreatmentoptionsforpatientswithintractablepain,ifchildbearingisnolongerdesired.(AmFamPhysician1999;60:1753-68.)Endometriosisischaracterizedbythepresenceofendometrialtissueontheovaries,fallopiantubesorotherabnormalsites,causingpainorinfertility.Thediseasetendstoprogressundertherepetitiveinfluenceofthemenstrualcycle.Interruptingordecreasingmenstruationisthemainstayofmedicaltherapy.Thegoalofsurgeryistoremoveendometriallesions.Endometriosisislikelytoremainproblematicaslongasmenstruationpersists.Fortunately,symptomscanbemodulatedoralleviatedwithappropriatetreatment.EpidemiologythEndometriosisshouldbeconsideredinwomenwhodevelopdysmenorrheaafteryearsofpain-freecycles.Womenareusually25to29yearsoldattimeofdiagnosis,whichisfrequentlydelayedinthosewhopresentwithinfertilityratherthanpain.1Afamilialtendencyhasbeenidentified.2Endometriosishasbeenfoundin4.1percentofasymptomaticwomenundergoinglaparoscopyforsterilization;however,evidenceofthediseaseispresentin20thEndometriosisshouldbeconsideredinwomenwhodevelopdysmenorrheaafteryearsofpain-freecycles.Approximately24percent(range:4to82percent)ofwomenwhocomplainofpelvicpainaresubsequentlyfoundtohaveendometriosis.3Theoverallprevalence,includingsymptomaticandasymptomaticwomen,isestimatedtobe5to10percent.4Becausesurgicalconfirmationisnecessaryforthediagnosis,thetrueprevalenceofthediseaseisunknown.PathogenesisEndometriosisisnotwellunderstoodandisprobablymultifactorialinorigin.Themostwidelyembracedtheoryinvolvesretrogrademenstruation(Figure1).Althoughrefluxofmenstrualfluidoccursinmany,ifnotall,women,inendometriosistherefluxedcellsimplantinthepelvis,bleedinresponsetocyclichormonalstimulationandincreaseinsizealongwithprogressionofsymptoms.6Immunealterationsmayalsocontributetothepersistenceofimplantsorendometriosis-associatedinfertility.7,8Twoothertheorieshavereceivedsupport.Oneholdsthatperitonealepitheliumcanbe"transformed"intoendometrialtissue,perhapsbecauseofchronicinflammationorchemicalirritationfromrefluxedmenstrualblood.Thistheoryof"coelomicmetaplasia"isbasedontheobservationthatcoelomicepitheliumisthecommonancestorofendometrialandperitonealcells,thusallowingtransformationofonetypeofcellintoanother.Afinaltheoryhypothesizesthatmullerianremnantscandifferentiateintoendometrialtissue.Thecircumstancesinwhichthiswouldoccurarenotclearbut,onceendometriumispresent,itwillcausesymptomsinacyclicfashion.Althoughretrogrademenstruationseemsalmostcertaintobeinvolvedinthepathogenesisofendometriosis,thattheorydoesnotexplainthefullspectrumofthedisease.Forexample,endometrialimplantsareoccasionallyfoundinsuchremotesitesasthelungoreventhenose.Moreover,endometriosisalsooccurs,albeitrarely,inmentakinglargedosesofestrogen.Thetheoriesofcoelomicmetaplasiaandmullerianremnantdifferentiationarebettersuitedthanthetheoryofretrogrademenstruationtoexplainsomeoftheseexceptionalcircumstances.ClinicalFeaturesandDiagnosticEvaluation&1蜀口」ODU「-BE*Endometriosisshouldbeconsideredinanywomanofreproductiveagewhohaspelvicpain(Table1).Themostcommonsymptomsaredysmenorrhea,dyspareuniaandlowbackpainthatworsensduringmensesgDependingonthelocationoftheimplants,rectalpainandpainfuldefecationmayalsooccur.Thediagnosisofendometriosisshouldbeconsideredespeciallyifapatientdevelopsdysmenorrheaafteryearsofpain-freemenstrualcycles.Ofcourse,othercausesofsecondarydysmenorrheaandchronicpelvicpain(e.g.,upperClinicalFeaturesandDiagnosticEvaluation&1蜀口」ODU「-BE*Infertilitymayalsobethepresentingcomplaint.Infertilepatientsoftenhavenopainfulsymptoms,andtheirdiseaseisonlyuncoveredinthecourseofthediagnosticwork-upforinfertility.Thereasonforthisdivergenceinclinicalmanifestationsisunknown.Physicalexaminationshouldbeperformedduringearlymenses,whenimplantsarelikelytobelargestandmosttender.Thephysicianshouldpalpateforafixed,retroverteduterus,adnexalanduterinetenderness,pelvicmassesornodularityalongtheuterosacralligaments.Arectovaginalexaminationisrequiredtoidentifyuterosacral,cul-de-sacorseptalnodules.However,mostwomenwithendometriosishavenormalpelvicfindings,andlaparoscopyisnecessaryfordefinitivediagnosis.Althoughnosinglelaboratorytesthasshownreliableclinicalutility,itispossiblethateventuallyacombinationofbiochemicalmarkersandclinicalassessmentwilldecreasetheneedforsurgicalconfirmation.心Pelvicultrasonography,computedtomographyandmagneticresonanceimagingareoccasionallyusedtoidentifyindividuallesions,butthesemodalitiesarenothelpfulinassessingtheextentofendometriosis.12Evenwithdirectvisualization,diagnosisofendometriosiscanbedifficult.Lesionsappearinmultipleguisesthatareattimesdifficulttointerpret.Thisdiagnosticchallengeiscompoundedbytheunreliablecorrelationbetweenclinicalmanifestationsandsurgicalfindings.13Apatientwhoisasymptomaticorhasverymildsymptomsmayhaveextensivedisease,whereasaninfertilepatientmayhaveveryfewimplants.Abettercorrelationbetweenclinicalandsurgicaldiseasemaybeobservedinmoreseverecases:inatleastonestud^ithasbeenfoundthatwomenwithsevere,chronicpelvicpainhaveamoreadvancedstageofdiseaseatinitialdiagnosis.TheAmericanFertilitySociety'srevisedstaginginstrumentcanhelpstandardizefindingsanddocumentthepatient'sbaselineconditionandsubsequentprogress.15Stagingisbasedonlocation,diameteranddepthoflesions,anddensityofadhesions.Stagesrangefromminimaltoseveredisease.Despitethisstandardization,thecorrelationbetweenstageandextentofdiseaseremainscontroversial.TreatmentInmostpatients,confirmatorylaparoscopyisrequiredbeforetreatmentisinstituted.4Inwomenwithfewsymptoms,anempirictrialoforalcontraceptivesorprogestinsmaybewarrantedtoassesspainrelief.Recently,anempiricthree-monthtrialoftherapywithgonadotropin-releasinghormone(GnRH)analogshasbeenapopularstrategy.16Insevereorunresponsivecases,orintheinvestigationofinfertility,exactdiagnosisisrequiredtodirectmanagementandtojustifypossiblyunpleasantmedicaltreatments.Patientswithinfertilityshouldundergoathoroughbasicevaluationforothercausesofinfertilitybeforediagnosticlaparoscopyisundertaken.Treatmentmaybeexpectant,orapatientmaychooseeithermedicalorsurgicaloptions.Infertilepatientsmayincreasethelikelihoodofsubsequentconceptionbyundergoingsurgery,butmedicaltreatmenthasnotbeenshowntohelpthesepatientsconceive.17,18Furthermore,pregnancyiscontraindicatedinpatientsreceivingmedicaltreatmentandisinfactunlikely,becausethedrugsthatareusedinterferewithovulation.Medicalandsurgicalapproacheshavebeensuccessfulinreducingthepainassociatedwithendometriosis.

MedicalTreatmentMedicaltreatmentshouldbereservedforuseinpatientswithpainordyspareunia,becausenopharmacologicmethodappearstorestorefertility.Becausenopharmacologicmethodappearstorestorefertility,medicaltreatmentforendometriosisshouldbereservedforuseinpatientswithpainordyspareunia.Danazol.Danazol(Danocrine)hasbeenhighlyeffectiveinrelievingthesymptomsofendometriosis,butadverseeffectsmayprecludeitsuse.(Therearenowothertreatmentsthatmaybebettertolerated.)Danazolisasyntheticandrogenthatinhibitsleuteinizinghormone(LH)andfollicle-stimulatinghormone(FSH),resultinginarelativelyhypoestrogenicstate.Endometrialatrophyisthelikelymechanisminthereliefofpainfromendometriosis.AdverseeffectsrelatedtoestrogenBecausenopharmacologicmethodappearstorestorefertility,medicaltreatmentforendometriosisshouldbereservedforuseinpatientswithpainordyspareunia.Danazoltherapyshouldbestartedwhenthepatientismenstruating.Theinitialdosageshouldbe800mgperday,givenintwodividedoraldoses,butthisdosagecanbetitrateddownaslongasamenorrheapersistsandpainsymptomsarecontrolled.Patientswithlessseveresymptomsmaybegiven200to400mgperday,intwodividedoraldoses.Treatmentdurationissixmonthsbutcanbeextendedtoninemonthsinresponsivepatientswithseveredisease.Theoverallresponseratei84to92percent,withbeneficialeffectslastinguptosixmonthsaftertreatmenthasstopped.12TABLE2MedicalTreatmentofEndometriosisDrugDosageAdverseeffectsCost*Danazol(Danocrine)800mgperdayin2Estrogen$410,divideddosesdeficiency,brandandrogenicside367,effectsgenericOralcontraceptives1pillperdayHeadache,29(continuousorcyclic)nausea,brand

hypertension24to27,genericMedroxyprogesterone100mgIMevery2Weightgain,22,suspensionweeksfor2months;depression,brand(Depo-Provera)then200mgIMeveryirregularmenses13,monthfor4monthsororamenorrheageneric150mgIMevery3monthsMedroxyprogesterone5to20mgorallyperdaySameaswith(Provera)otheroralprogestinsNorethindroneacetate5mgperdayorallyfor2Sameaswith113§(Aygestin)weeks;thenincreasebyotheroral2.5mgperdayevery2progestinsweeksupto15mgperdayLeuprolide(Lupron)3.75mgIMeverymonthDecreaseinbone371,for6monthsdensity,estrogenbranddeficiency318,genericGosarelin(Zoladex)3.6mgSC(inupperEstrogen470abdominalwall)every28deficiencydaysNafarelin(Synarel)400mgperday:1sprayin1nostrilina.m.;1sprayinothernostrilinp.m.;starttreatmentonEstrogen431deficiency,bonedensitychanges,nasalirritationday2to4ofmenstrualcycleIM=intramuscularly;SC=subcutaneously.*一Estimatedcosttothepharmacistbasedonaveragewholesaleprices(roundedtothenearestdollar)foronemonthoftreatmentatthelowestdosagelevelinRedbook.Montvale,N.J.:MedicalEconomicsData,1999.Costtopatientwillbegreater,dependingonprescriptionfillingfee.t—CostbasedonpricesofLo-Ovral28andOrtho-Novum.t—CostbasedongenericversionsofLo-Ovral28andOrtho-Novum.§一Foronemonth'stherapyat15mgperday.GnRHAgonists.Theseagents(e.g.,leuprolide[Lupron],gosarelin[Zoladex])inhibitthesecretionofgonadotropinandarecomparabletodanazolinrelievingpain.12-19Likedanazol,GnRHagonistsarecontraindicatedinpregnancyandhavehypoestrogenicsideeffects.Inparticular,theyhavebeenshowntoproduceamilddegreeofboneloss,althoughthisconditionreversesafterthemedicationisdiscontinued.Becauseofconcernsaboutosteopenia,"add-back"therapywithlow-doseestrogenhasbeenrecommendedbutisnotcurrentlyanFDA-labeledindicationforestrogenreplacementtherapy.20,21Thedosageofleuprolideisasinglemonthly3.75-mgdepotinjectiongivenintramuscularly.Gosarelin,inadosageof3.6mg,isadministeredsubcutaneouslyevery28days.Anasalspray(nafarelin[Synarel])isalsoavailableandisusedtwicedaily.Theresponserateissimilartothatwithdanazol;about90percentofpatientsexperiencepainrelief.Thepregnancyrateaftertheuseoftheseagentsisnodifferentfromthatinuntreatedpatients.OralContraceptivePills.Oralcontraceptivepills(OCPs)suppressLHandFSHandpreventovulation.Theyalsohavedirecteffectsonendometrialtissue,renderingitthinandcompact.Thedecidualizationofendometrialimplants,coupledwithreducedrefluxrelatedtolowermenstrualvolume,istheprobablemechanismofpainreliefwithOCPs,makingthemcomparabletoothertreatmentsineffect.9CombinationOCPsalleviatesymptomsinaboutthreequartersofpatients.Nohormonalcombinationappearstobemoreeffectivethananother.Theycanbetakencontinuously(withnoplacebos)orcyclically,withaweekofplacebopillsbetweencycles.TheOCPscanbediscontinuedaftersixto12monthsorcontinuedindefinitely,dependingonsuchfactorsaspatientsatisfactionandthedesirabilityofpregnancy.ProgestationalAgentsProgestinsaresimilartocombinationOCPsintheireffectsonFSH,LHandendometrialtissue.TheymaybeassociatedwithmorebothersomeadverseeffectsthanOCPsand,ifadepotform(i.e.,medroxyprogesteronesuspension[Depo-Provera])isused,returntofertilitymaybedelayed.Nonetheless,progestinsareeffectiveinreducingthesymptomsofendometriosis.Onestudythatpooleddatafrom14investigationsfoundnosignificantdifferencebetweentheefficacyofprogestinsandthatofanyothermedicaltreatment.22Althoughthisconclusionwasbasedonanalysisofthecombinedresultsofahandfulofsmall,heterogeneousstudies,itisimportantbecauseprogestinsaremuchcheaperthaneitherdanazolorGnRHanalogs.Giventhelikelihoodofcomparableefficacy,aswellasthecertaintyofahighrateofrecurrenceregardlessoftheagentused,physiciansmayelecttoprescribeOCPsorprogestinsasfirst-lineagentsonthebasisofcostalone.Ifeffective,theseagentscanbeusedsafelyforlongperiodsoftime.Progestinscanbegivenorallyonadailybasisordeliveredbyinjection.Oralregimensmayincludeonce-dailyadministrationofmedroxyprogesteroneatthelowesteffectivedosage(5to20mg).Depotmedroxyprogesteronehasbeengivenintramuscularlyeverytwoweeksfortwomonthsat100mgperdoseandthenonceamonthforfourmonthsat200mgperdose.MedicaltreatmentsarereviewedinTable2SurgicalTreatmentSurgicaltreatmentisthepreferredapproachtoinfertilepatientswithadvancedendometriosis.12Thebenefitofsurgeryinthesepatientsmaybedueentirelytothemechanicalclearanceofadhesionsandobstructivelesions(Figure2).Someoftheendometriallesionsarecysticornodularandcanbeexcised(Figures3,4and5,whilesomearehemorrhagicorpetechialandamenabletolaserobliteration(Figures6and7.Untilrecently,surgeryininfertilepatientswithlimiteddiseasewasthoughttobenobetterthanexpectantmanagement.However,arecentrandomized,controlledstudyinvolving341infertilewomenwithminimalormildendometriosisdemonstrateda13percentabsoluteincreaseintheprobabilityofpregnancyina36-weekperiod』Infertilepatientswithdocumentedendometriosiscanbenefitfromthesamereproductivetechniques(e.g.,superovulation,invitrofertilization)thatareusedinotherinfertilepatients.24,25TABLE3Surgicalvs.MedicalTreatmentofEndometriosisTreatmentAdvantagesDisadvantagesSurgicalBeneficialforinfertilityExpensivePossiblybetterlong-termresultsInvasiveDefinitivediagnosisOptionfordefinitivetreatmentMedicalDecreasedinitialcostAdverseeffectscommonEmpirictreatmentUnlikelytoimprovefertilityEffectiveforpainreliefendometriallesionsoverlyingtherectum.notebluishnotebluishappearance.FIGURE3.Cysticimplantsadjacenttotherightovary;FIGURE4.Nodularendometriallesionsintheposteriorcul-de-sac.therightureter.therightureter.FIGURE5.Ovarywithendometrioma.Theusefulnessofconservativesurgeryforpainreliefisunclear,butitappearsthatimmediatepostoperativeefficacyisatleastashighaswithmedicaltreatment,andlong-termoutcomesmaybeconsiderablyhigher.26Laparoscopyismuchmoreexpensivethanmedicaltreatment,however,causingsomephysicianstoarguethatoverallcostscanbereducedbyaggressiveuseofempirictreatmentsbeforesurgeryisconsidered.16Table3summarizestheadvantagesanddisadvantagesofmedicalandsurgicaltreatments.Definitivesurgery,whichincludeshysterectomyandoophorectomy,isreservedforuseinwomenwithintractablepainwhonolongerdesirepregnancy.27Inlessseverecases,oneovarymayberetainedtopreserveovarianfunction,althoughimprovementwillbelessdefinitive.Womenwhohaveundergoneoophorectomyshouldbetreatedwithestrogenreplacement,evenattheriskofsomerecurrence.27FIGURE6.Hemorrhagiclesionsoverlying

fossa.Lesionshaveapetechialappearance.FIGURE7.ExtensiveendometriosisintheovarianRecurrenceRatesFIGURE8.AKTPlasermaybeusedtoobliterateendometrialimplants.Arrowsindicateuntreatedimplants.Inpracticalterms,whenthediagnosisofendometriosisismadeatlaparoscopy,surgicalablationoflesionsisfrequentlyperformed.Thus,becauselaparoscopicdiagnosisisusuallyrecommendedbeforeinstitutingtreatment,mostwomenwithendometriosisundergosurgicaltherapyinitially.Itisgenerallyagreedthatfossa.Lesionshaveapetechialappearance.RecurrenceRatesFIGURE8.AKTPlasermaybeusedtoobliterateendometrialimplants.Arrowsindicateuntreatedimplants.Perhapsthestrongestreasonforbeginningwithsurgicaltreatmentistheapparentlylowerrecurrenceratecomparedwithmedicaltreatment.27Earlystudiesofconservativesurgicaltherapyshowedalaparoscopicallydefinedcumulativefive-yearrecurrencerateofabout19percentsThelong-termbenefitofsurgicalinterventionforpainisenhancedbydefinitivesurgery,includingbilateraloophorectomy,witha10percentcumulativerecurrenceafter10years.27Thisrateisconsiderablylowerthanthosefollowingmedicaltherapy.Inonestudyofrecurrenceaftermedicaltreatment,cumulativefive-yearratesofrecurrencewere53.4percent.30Unfortunately,patientswhosepresentingcomplaintwaspainandthoseseekingtreatmentforinfertilityweregroupedtogetherintheanalysis.Otherstudiesshowsimilarrecurrencerates,regardlessofthemedicaltherapyused.26Atleastonestudynotedhigherrecurrenceratesinpatientswithmoreadvancedstagesofdisease.30Combiningorrepeatingtreatmentsmayresultinbetterlong-termoutcomes,butstudiesofcombinedtreatmentsareinconclusivebecauseoflackofrandomization,smallsamplesizeorinsufficientfollow-uptime.Onerandomized,double-blindstudy31showedadditionalpainreliefandobjectiveimprovementwithimmediatepostoperativetreatmentwithdanazolormedroxyprogesterone,butthestudyendedwithasecondlaparoscopyaftersixmonths,toosoontoidentifylonger-termbenefits.Inamorerecentinvestigation,itwasfoundthatthebestandonlystatisticallysignificantlong-termoutcomeswereachievedwithsurgeryfollowedbydanazoltreatment;however,thestudywaslimitedbyasmallsamplesize.32AlthoughfewstudieshavebeenconductedtoevaluateretreatmentwithdanazolorGnRHanalogs,repeatedadministrationsofthesedrugsaretheoreticallyanoptionandareprobablysafeatappropriateintervals.33Figure9depictsanalgorithmicapproachtomanagementofendometriosisbasedonwhetherpainorinfertilityisthepresentingcomplaint.

Figures2,3,4,6and7courtesyofJohnP.A.George,M.D.;Figures5and8courtesyofArthurW.Sagoskin,M.D.TheAuthorCAROLINEWELLBERY,M.D.,isanassistantprofessorintheDepartmentofFamilyMedicineatGeorgetownUniversitySchoolofMedicine,Washington,D.C.Dr.WellberygraduatedfromtheUniversityofCalifornia,SanFrancisco,SchoolofMedicine,andcompletedaresidencyinfamilypracticeattheSantaRosa(Calif.)CommunityHospital.SheservesasassistantdeputyeditorforAmericanFamilyPhysician.AddresscorrespondencetoCarolineWellbery,M.D.,DepartmentofFamilyMedicine,GeorgetownUniversityMedicalCenter,3800ReservoirRd.,Washington,DC20007.Reprintsarenotavailablefromtheauthor.REFERENCESDmowskiWP,LesniewiczR,RanaN,PeppingP,NoursalehiM.Changingtrendsinthediagnosisofendometriosis:acomparativestudyofwomenwithpelvicendometriosispresentingwithchronicpelvicpainorinfertility.FertilSteril1997;67:238-43.MoenMH,MagnusP.Thefamilialriskofendometriosis.ActaObstetGynecolScand1993;72:560-4.EskenaziB,WarnerM.Epidemiologyofendometriosis.ObstetGynecolClinNorthAm1997;24:235-58.LuPY,OrySJ.Endometriosis:currentmanagement.MayoClinProc1995;70:453-63.ThomasEJ.Endometriosis,1995—confusionorsense?IntJGynecolObstet1995;48:149-55.BrosensIA.Endometriosis—adiseasebecauseitischaracterizedbybleeding.AmJObstetGynecol1997;176:263-7.GleicherN.Immunedysfunction—apotentialtargetfortreatmentinendometriosis.BrJObstetGynaecol1993;102(12suppl):4-7.Martinez-RomanS,BalaschJ,CreusM,FabreguesF,CarmonaF,VilellaR,etal.Immunologicalfactorsinendometriosis-associatedreproductivefailure:studiesinfertileandinfertilewomenwithandwithoutendometriosis.HumReprod1997;12:1794-9.AmericanCollegeofObstetriciansandGynecologists.Endometriosis.ACOGtechnicalbulletinno.184.Washington,D.C.:ACOG,1993.MedlM,OgrisE,Peters-EnglC,MierauM,BuxbamP,LeodolterS.Serumlevelsofthetumour-associatedtrypsininhibitorinpatientswithendometriosis.BrJObstetGynaecol1997;104:78-81.BrintonDA,Quatrociocchi-LongeTM,KiechleFL.Endometriosis:identificationbycarbonicanhydraseautoantibodiesandclinicalfeatures.AnnClinLabSci1996;26:409-20.12.OliveD,SchwartzLB.Endometriosis.NEnglJMed1993;328:1759-69.13.RippsBA,MartinDC.Correlationoffocalpelvictendernesswithimplantdimensionandstageofendometriosis.JReprodMed1992:37:620-4.14.StovallDW,BowserLM,ArcherDF,GuzickDS.Endometriosis-associatedpelvicpain:evidenceforanassociationbetweenthestageofdiseaseandahistoryofchronicpelvicpain.FertilSteril1997;68:13-8[PublishederratuminFertilSteril1998;69:979].RevisedAmericanFertilitySocietyclassificationofendometriosis.FertilSteril1985;43:351-2.HeinrichsWL,HenzlMR.Humanissuesandmedicaleconomicsofendometriosis.JReprodMed1998;43(3suppl):299-308.HullME,MoghissiKS,MagyarDF,HayesMF.Comparisonofdifferenttreatmentmodalitiesofendometriosisininfertilewomen.FertilSteril1987;47:40-4.18-TelimaaS,PuolakkaJ,RonnbergL,KauppilaA.Placebo-controlledcomparisonofdanazolandhigh-dosemedroxyprogesteroneacetateinthetreatmentofendometriosis.GynecolEndocrinol1987;1:13-23.BromhamDR,BookerMW,RoseGL,WardlePG,NewtonJR.Updatingtheclinicalexperienceinendometriosis—theEuropeanperspective.BrJObstetGynaecol1995;102(12suppl):12-6.KieselL,SchweppeKW,SillemM,SiebzehnrublE.Shouldadd-backtherapyforendometriosisbedeferredforoptimalresults?BrJObstetGynaecol1996;103(14suppl):15-7.MoghissiKS.Add-backtherapyinthetreatmentofendometriosis:theNorthAmericanexperience.BrJObstetGynaecol1996;103(14suppl):14.VercelliniP,CortesiI,CrisgnaniPG.Progestinsforsymptomaticendometriosis:acriticalanalysisoftheevidence.FertilSteril1997;68:393-401.MarcouxS,MaheuxR,BerubeS.Laparoscopicsurgeryininfertilewomenwithminimalormildendometriosis.NEnglJMed1997;337:217-22.TummonIS,AsherLJ,MartinJS,TulandiT.Randomizedcontrolledtrialofsuperovulationandinseminationforinfertilityassociatedwithminimalormildendometriosis.FertilSteril1997;68:8-12.KodamaH,FukudaJ,KarubeH,MatsuiT,ShimizuY,TanakaT.Benefitofinvitrofertilizationtreatmentforendometriosis-associatedinfertility.FertilSteril199