Abnormal Uterine Bleeding in Premenopausal Women - AAFP

The most common causes of abnormal uterine bleeding are described with the acronym PALM-COEIN. · The lifetime prevalence of endometrial polyps ... Advertisement search close Abnormaluterinebleedingisacommoncondition,withaprevalenceof10%to30%amongwomenofreproductiveage.1Itnegativelyaffectsqualityoflifeandisassociatedwithfinancialloss,decreasedproductivity,poorhealth,andincreaseduseofhealthcareresources.2–4In2011theInternationalFederationofGynecologyandObstetricsconvenedaworkinggroupthatproducedstandardizeddefinitionsandclassificationsformenstrualdisorders,whichtheAmericanCollegeofObstetriciansandGynecologistssubsequentlyendorsed.5,6Theupdatedterminologypertainsonlytononpregnantwomenofreproductiveage,whichisthescopeofthisreview. WHATISNEWONTHISTOPIC TheacronymPALM-COEINfacilitatestheclassificationofabnormaluterinebleeding,withPALMreferringtostructuraletiologies(polyp,adenomyosis,leiomyoma,malignancyandhyperplasia),andCOEINreferringtononstructuraletiologies(coagulopathy,ovulatorydysfunction,endometrial,iatrogenic,nototherwiseclassified). Amongmedicaltherapies,the20-mcg-per-dayformulationofthelevonorgestrel-releasingintrauterinesystem(Mirena)ismosteffectivefordecreasingheavymenstrualbleeding(71%to95%reductioninbloodloss)andperformssimilarlytohysterectomywhenquality-adjustedlifeyearsareconsidered. ClinicalrecommendationEvidenceratingReferencesTheInternationalFederationofGynecologyandObstetricsclassificationsystemshouldbeusedtocharacterizeabnormaluterinebleeding.C5,6Allpatientswithabnormaluterinebleedingshouldbetestedforpregnancyandanemia.C6Endometrialbiopsyshouldbeperformedinallpatientswithabnormaluterinebleedingwhoare45yearsorolder,inyoungerpatientswithasignificanthistoryofunopposedestrogenexposure,persistentbleeding,orinwhommedicalmanagementisineffective.C6Transvaginalultrasonographyisthefirst-lineimagingchoiceforevaluatingabnormaluterinebleedinginmostpatients.C6,36The20-mcg-per-dayformulationofthelevonorgestrel-releasingintrauterinesystem(Mirena)ismoreeffectivethanothermedicaltherapiesforreducingheavymenstrualbleeding.A44,47Hysterectomyisthemosteffectivetreatmentforreducingheavymenstrualbleeding.A44,47 Definitions Abnormaluterinebleedingisasymptom,notadiagnosis;thetermisusedtodescribebleedingthatfallsoutsidepopulation-based5thto95thpercentilesformenstrualregularity,frequency,duration,andvolume(Table1).7Abnormalbleedingisconsideredchronicwhenithasoccurredformostoftheprevioussixmonths,oracutewhenanepisodeofheavybleedingwarrantsimmediateintervention.5Intermenstrualbleedingisbleedingthatoccursbetweenotherwisenormalmenstrualperiods.7Useofimprecisetermssuchasmenorrhagia,metrorrhagia,anddysfunctionaluterinebleedingisnowdiscouraged. MenstrualcycletermsDescriptivetermsDefinitionFrequency(intervalbetweenthestartofeachmenstrualcycle)Infrequent>38daysNormal24to38daysFrequent<24daysRegularity(variationofmenstrualcyclelength,measuredover12months)Regular±2to20daysover12monthsIrregular>20daysover12monthsDurationofmenstruationShortened<4.5daysNormal4.5to8daysProlonged>8daysVolume(totalbloodlosseachmenstrualcycle)Light<5mLNormal5to80mLHeavy>80mLOthertermsAmenorrheaNobleedingfor90daysPrimaryamenorrheaAbsentmenarcheby15yearsofageSecondaryamenorrheaAmenorrheafor6monthswithpreviouslyregularmenstrualcyclesMenopauseAmenorrheafor12monthswithoutotherapparentcausePrecociousmenstruationMenarchebefore9yearsofage DifferentialDiagnosis Althoughtheuterusisoftenthesource,anypartofthefemalereproductivetractcanresultinvaginalbleeding.Womenmayalsomistakebleedingfromnongynecologicsites(e.g.,bladder,urethra,perineum,anus)asvaginalbleeding.Theprevalenceofconditionsthatcauseabnormalbleedingvariesaccordingtoage.Forexample,anovulationismorecommoninadolescentsandperimenopausalwomen,whereastheprevalenceofstructurallesionsandmalignancyincreaseswithage.8ThedifferentialdiagnosisofabnormaluterinebleedingispresentedinTable2.9–11 UterinebleedingCoagulopathiesFactordeficienciesPlateletdysfunctionThrombocytopeniavonWillebranddiseaseIatrogenicAnticoagulantsAntidepressantsAntipsychoticsChemotherapeuticagentsCopperintrauterinedeviceCorticosteroidsHormonalcontraceptionorotherhormonetherapyPhenytoin(Dilantin)TamoxifenInfectionAcuteorchronicendometritisPelvicinflammatorydiseaseOvulatorydysfunctionAndrogenexcessAndrogeninsensitivitysyndromeHormone-producingtumorsPolycysticovarysyndromeHypothalamic-pituitary-adrenalaxisdysfunctionCongenitaladrenalhyperplasiaCushingsyndrome/diseaseHyperprolactinemiaImmaturehypothalamic-pituitary-adrenalaxis(adolescence)Intenseexercise,stressLactationalamenorrheaOvarianfollicledecline(perimenopause)Starvation(includingeatingdisorders)ThyroiddisordersTumors,radiation,ortraumaofthepituitary/hypothalamusareaPrematureovarianfailurePregnancyAbortionAbruptionEctopicpregnancyGestationaltrophoblasticdiseaseSubchorionichemorrhageStructuralAdenomyosisArteriovenousmalformationsCesareanscardefectEndometriosisLeiomyomasMalignancyEndometrialhyperplasia/carcinomaMetastasisUterinesarcomaOutflowobstructionPolypNonuterinebleedingAdnexaMalignancyPelvicinflammatorydiseaseAnusAnalfissureHemorrhoidsInflammatoryboweldiseaseUpperorlowergastrointestinalbleedingBladder/ureters/kidneysInfectionMalignancyNephrolithiasisCervixDysplasia/malignancyEctropionEndometritisInfection(e.g.,gonorrhea,chlamydia)PolypsUrethraUrethraldiverticulaUrethralprolapseUrethritisVaginaAtrophyBenigngrowthsInfectionRetainedforeignbodyTraumaUlcerativeconditionsVulvaBenigngrowthsBlisteringdiseasesMalignancyTraumaOtherChronickidneydiseaseChronicliverdiseaseDiabetesmellitusLeukemiaSarcoidosisofthereproductivetractTuberculosisofthereproductivetractTurnersyndrome ThemostcommoncausesofabnormaluterinebleedingaredescribedwiththeacronymPALM-COEIN.5TheetiologiesinthePALMgroup(polyp,adenomyosis,leiomyoma,malignancyandhyperplasia)arestructuralandcanbeimagedorbiopsied.TheetiologiesintheCOEINgroup(coagulopathy,ovulatorydysfunction,endometrial,iatrogenic,nototherwiseclassified)arenonstructural.Theseetiologiesarenotmutuallyexclusive,andpatientsmayhavemorethanonecause. POLYP Thelifetimeprevalenceofendometrialpolypsrangesfrom8%to35%,andtheirincidenceincreaseswithage.12Intermenstrualbleedingisthemostcommonpresentingsymptom,butmanypolypsareasymptomatic.Physicalexaminationfindingsaretypicallyunremarkable,exceptforcasesinwhichthepolypsprolapsethroughthecervix.13Althoughtheycandevelopintomalignancy,approximately95%ofsymptomaticpolypsarebenign,andtheriskofmalignancyisevenlowerinpremenopausalwomen.14 ADENOMYOSIS Thepresenceofendometrialtissueinthemyometriumisknownasadenomyosis.Itsprevalencerangesfrom5%to70%,anditsassociationwithabnormaluterinebleedingisunclear.15Manypatientsareasymptomatic,butthosewhohavesymptomstypicallyreportpainful,heavy,orprolongedmenstrualbleeding.Examinationmayrevealadense,enlargeduterus. LEIOMYOMA Leiomyomas(alsocalledfibroids)arebenigntumorsarisingfromtheuterinemyometrium.Theirprevalenceincreaseswithage;theyareeventuallyfoundinupto80%ofallwomen.16Mostleiomyomasareasymptomatic,butbleedingisacommonpresentingsymptomandtypicallyinvolvesheavyorprolongedmenses.Largerleiomyomasaremorelikelytobeassociatedwithabnormaluterinebleeding.17Patientsmayreportpelvicpainorpressure,andonexaminationtheuterusmaybeenlargedorirregularlycontoured.MoreinformationonthediagnosisandtreatmentofleiomyomasisavailableinapreviousAmericanFamilyPhysicianarticle(https://www.aafp.org/afp/2017/0115/p100.html). MALIGNANCYANDHYPERPLASIA Abnormaluterinebleedingisthemostcommonsymptomofendometrialcancer.18Althoughtheprevalenceofendometrialcancerincreaseswithage,closetoone-fourthofnewdiagnosesoccurinpatientsyoungerthan55years.19Long-termunopposedestrogenexposureistheprimaryriskfactor(Table3).18,20Bleedingpatternsinpatientswithuterinemalignancyarehighlyvariable.MoreinformationonthediagnosisandmanagementofendometrialcancerisavailableinapreviousAmericanFamilyPhysicianarticle(https://www.aafp.org/afp/2016/0315/p468.html). RiskfactorRelativeriskMajorLong-termuseofunopposedestrogen10to20Hereditarynonpolyposiscolorectalcancer(Lynchsyndrome)6to20Estrogen-producingtumor>5MinorObesity2to5Nulliparity3Polycysticovarysyndrome3Historyofinfertility2to3Latemenopause2to3Tamoxifenuse2to3Type2diabetesmellitus,hypertension,gallbladderdisease,orthyroiddisease1.3to3 COAGULOPATHY Approximately20%ofpatientswithheavymenstrualbleedinghaveableedingdisorder,andtheprevalenceinadolescentgirlswhobleedheavilyisevenhigher.21–23VonWillebranddiseaseandplateletdysfunctionarethemostcommoncoagulopathiesassociatedwithabnormaluterinebleeding.24Inadditiontoheavymenstrualbleeding,adolescentswithbleedingdisordersmayreportirregularmenstrualbleeding.25 OVULATORYDYSFUNCTION Avarietyofendocrinedisorderscanleadtoovulatorydysfunction(Table2).9–11Infrequentorabsentovulationduringthefirstfewyearsaftermenarcheandduringperimenopauseiscommonandnotnecessarilyasignofunderlyingpathology.26Menstrualbleedingcausedbyovulatorydysfunctionisoftenirregular,heavy,orprolonged. ENDOMETRIAL Primarydisordersofendometrialhemostasistypicallyoccurinthesettingofpredictableovulatorycyclesandarelikelyduetovasoconstrictiondisorders,inflammation,orinfection.Endometrialdysfunctionispoorlyunderstood;therearenoreliablediagnosticmethods,anditshouldbeconsideredonlyafterothercausesareexcluded.5 IATROGENIC Avarietyofmedicaltreatmentscanprovokeabnormaluterinebleeding.Hormonalcontraceptionisthemostcommoncauseofiatrogenicuterinebleeding(i.e.,breakthroughbleeding).5Othercausativeagentsincludenoncontraceptivehormonetherapy,drugsthatinterferewithsexsteroidhormonefunctionorsynthesis(e.g.,tamoxifen),anticoagulants,anddopamineantagonists(e.g.,tricyclicantidepressants,someantipsychotics). NOTOTHERWISECLASSIFIED Thiscategorycontainspoorlyunderstoodconditions,raredisorders(e.g.,arteriovenousmalformations),andconditionsthatdonototherwisefitintotheclassificationsystem,suchascesareanscardefects,whichcancausepostmenstrualspottingwhenbloodcollectsinthenichecausedbythescar. DiagnosticEvaluation Theapproachtopatientspresentingwithabnormaluterinebleedingincludesassessingforhemodynamicinstabilityandanemia,identifyingthesourceofbleeding,pregnancytesting,anddeterminingwhetherevaluationforendometrialcarcinomaisindicated(Figure1).6,18,26–30Thebroaddifferentialdiagnosisnecessitatesadetailedhistoryandphysicalexamination. BLEEDINGHISTORY Adescriptionofthebleedingpatternshouldbeelicited,includingfrequency,duration,regularity,andvolume.Heavymenstrualbleedingisdefinedasmorethan80mLoftotalbloodloss,butquantitativeassessmentisimpracticalinroutineclinicalpractice.Historicalcluessuchaspassingbloodclotsorchangingpads/tamponsatleasthourlysuggestheavymenstrualbleeding.31Ahistoryofpostcoitalbleedingmayindicatecervicitis,ectropion,or,rarely,cervicalcancer,whereasabdominopelvicpainmaysuggestinfection,structurallesions,orendometriosis. Cliniciansmayunderestimatetheprevalenceofcoagulopathiesamongpatientswithabnormaluterinebleeding.32Theseconditionsshouldbeconsideredinwomenwithafamilyhistoryofabnormalbleedingorapersonalhistoryofheavymenstrualbleedingsincemenarche,orsymptomssuchasfrequentbruising,bleedinggums,epistaxis,postpartumhemorrhage,orbleedingwithsurgicalanddentalprocedures.27 PHYSICALEXAMINATION Anexaminationofthepelvis,includingspeculumandbimanualexaminations,isanimportantaspectoftheevaluationofabnormaluterinebleeding.Careshouldbetakentoexamineallpotentialbleedingsites,includingtheurethra,perineum,andanus.Cervicalcancerscreeningshouldbeperformedifitisnotuptodate.Pelvicexaminationcanbedeferredinadolescentsifthepatientisnotsexuallyactive,neithertraumanorinfectionissuspected,andtheresponsetoinitialtreatmentisadequate.33 LABORATORYTESTING Allpatientswithabnormaluterinebleedingshouldbeevaluatedforpregnancywithaurineorserumhumanchorionicgonadotropintest,andforanemiaandthrombocytopeniawithacompletebloodcount.6Thyroidfunctionshouldbeevaluatedinpatientswithsignsorsymptomsofthyroiddisease,oriftheinitialworkupdoesnotrevealalikelycause.6,28,34Additionalhormonaltests(e.g.,prolactin,androgens,estrogen)areindicatedonlyifhistoryorexaminationfindingssuggestaspecifichormonalcause.26,28Theplateletcount,prothrombintime,andpartialthromboplastintimecanbeinitialscreeningtestswhenableedingdisorderissuspected,butresultsmaybenormalinwomenwithvonWillebranddiseaseorotherbleedingdisorders.Diagnosingableedingdisordertypicallyrequiresadditionaltesting,ofteninconsultationwithahematologist.27 Becauseolderageisanimportantriskfactorforendometrialcancer,allpatientswithabnormaluterinebleedingwhoare45yearsoroldershouldundergoendometrialsampling.18Youngerwomenshouldundergosamplingiftheyhaveahistoryofunopposedestrogenexposure,ifmedicalmanagementfails,orifbleedingsymptomspersist.6Office-basedendometrialbiopsyisthepreferredapproach,withhysteroscopicdilationandcurettagereservedforinstancesinwhichofficesamplingfails,isinadequate,orcannotbeperformed.35Blindsamplingmaymissfocallesions,sohysteroscopicdilationandcurettageshouldbeperformedifsymptomspersistdespitenormalbiopsyresults.18 IMAGING Indicationsforpelvicimagingincludeabnormalitiespalpatedonbimanualexaminationorsymptomsthatpersistdespiteinitialtreatment.6Transvaginalultrasonographyisthefirst-lineapproachformostpatients,althoughsalineinfusionsonohysterography(theinfusionofsterilesalineintotheendometrialcavitywhiletransvaginalultrasonographyisperformed)isbetteratdetectingintracavitarylesions.36Routineuseofmagneticresonanceimagingisdiscouragedbutcanbeconsideredifsonographicimagingisinadequate.6 Management Multiplefactorsshouldbeconsideredwhenchoosingamongtreatmentoptionsforabnormaluterinebleeding(Table4),37–42includingthecauseandacuityofthebleeding,fertilityandcontraceptivepreferences,medicalcomorbidities,adverseeffects,cost,andrelativeeffectiveness.Iftheunderlyingcauseofbleedingcanbeidentifiedandtreated,symptomsmayresolvewithouttheneedforadditionalintervention.Anemiaisanindicationfortreatment,asisbleedingthatnegativelyaffectsthepatient'squalityoflife.Becauseexposuretounopposedestrogenincreasestheriskofendometrialcancer,treatmentofanovulatoryabnormaluterinebleedinginvolvesinducingovulatorycyclesoradministeringsupplementalprogesteronetoantagonizeestrogen'sproliferativeeffectontheendometrium. DrugSuggesteddosageNotesAcutebleedingConjugatedequineestrogenHemodynamicallyunstable:25mgintravenouslyevery4to6hoursforupto24hoursFollowtreatmentwithaprogestintoprovokewithdrawalbleeding;donotuseinpatientsatincreasedriskofthrombosisHemodynamicallystable:2.5mgorallyevery6hoursfor21daysEstrogen-progestinoralcontraceptives1monophasicpillcontaining35mcgofethinylestradiolorally3timesdailyfor7daysOtherregimensalsoeffective;donotuseinpatientsatincreasedriskofthrombosisProgestinsNorethindrone,5mgorally3timesdailyfor7daysOtherhigh-doseoralprogestinsarealsoeffectiveTranexamicacid10mgperkgintravenouslyevery8hoursor20to25mgperkgorallyevery8hoursFasteronsetifgivenintravenously;donotuseinpatientsatincreasedriskofthrombosisChronicbleedingDepotmedroxyprogesterone(Depo-Provera)150mgintramuscularlyor104mgsubcutaneouslyevery13weeksUnscheduledbleedingisacommoninitialadverseeffect,butone-halfofpatientsbecomeamenorrheicafter12monthsofuseEstrogen-progestinoralcontraceptives1monophasicpillcontaining35mcgofethinylestradioldailyOtherroutes(transdermalpatch,intravaginalring)arelikelyalsoeffective;regimenswithnoorfewerhormone-freeintervalsmaybemoreeffectiveLevonorgestrel52-mg(20-mcg-per-day)intrauterinedevice(Mirena)Effectivenessdataarebasedprimarilyontrialsinvolvingthe20-mcg-per-daydevice;effectonbleedingsuppressionmaywanebeforecontraceptiveeffectivenessexpiresNonsteroidalanti-inflammatorydrugsNaproxen,500mgorally2timesdailyOtheroralnonsteroidalanti-inflammatorydrugsarealsoeffective;administeronlywhilepatientisbleeding;donotuseinpatientswithcoagulopathyProgestinsNorethindrone,2.5to5mgorallyoncedailyOtheroralprogestinsarealsoeffective;administrationduringonlythelutealphaseissignificantlylesseffectivefortreatingheavybleedingTranexamicacid(Lysteda)1,000to1,500mgorally3timesdailyFasteronsetifgivenintravenously;donotuseinpatientsatincreasedriskofthrombosis EMERGENTTREATMENT Occasionally,abnormaluterinebleedingisofsufficientquantityordurationthatemergentattentionisrequired.Forhemodynamicallyunstablepatients,uterinetamponadeusingaFoleycatheterorgauzepackingcanachieverapidbuttemporarycontrolofbloodloss.43Furtheremergencyinterventionsforhemodynamicallyunstablepatientsincludeintravenousestrogen,dilationandcurettage,uterinearteryembolization,and,rarely,hysterectomy.Medicaltherapy(e.g.,oralestrogen,combinedoralcontraceptives,oralprogestins,intravenoustranexamicacid)isusuallyadequatefortreatinghemodynamicallystablepatientswithseverebleeding. NONEMERGENTTREATMENT Awiderrangeofmedicalandsurgicaloptionsareavailablefortreatmentofnonemergentuterinebleeding(Table4).37–42Toavoidsurgicalrisksandpreservefertility,medicalmanagementisthefirst-lineapproachformostpatients.44Amongmedicaltherapies,the20-mcg-per-dayformulationofthelevonorgestrel-releasingintrauterinesystem(Mirena)ismosteffectivefordecreasingheavymenstrualbleeding(71%to95%reductioninbloodloss)andisaseffectiveashysterectomywhenquality-adjustedlifeyearsareconsidered.39,45–47Estrogen-progestinoralcontraceptivesareeffective(35%to69%reduction)andcanalsobeusedtoregulatebleedinginpatientswithovulatorydysfunction.39,48Continuousdosingoforalprogestinsisanothereffectivehormonaltreatmentoption(87%reduction),butlong-termpatientsatisfactionislow.39,49Twoeffective,well-tolerated,nonhormonalchoicesareoraltranexamicacid(Lysteda;26%to54%reduction)andnonsteroidalanti-inflammatorydrugs(10%to52%reduction).39,50Botharetakenonlywhenthepatientisbleeding,andtranexamicacidhastheaddedbenefitofbeingsafewhilethepatientisattemptingtoconceive. Hysterectomyisthedefinitiveandmosteffectivetreatmentforabnormaluterinebleeding,andityieldsahighlevelofpatientsatisfaction.44,47,51Alessinvasive,lower-risksurgicaloptionisendometrialablation,whichisaseffectiveasthelevonorgestrel-releasingintrauterinesystem.47Avarietyofablativetechniquesareavailable,andallareequivalentintermsofbleedingoutcomesandpatientsatisfaction.52Myomectomyanduterinearteryembolizationaretreatmentoptionsforleiomyomas,andendometrialpolypscanbetreatedwithpolypectomy.Exceptformyomectomyandpolypectomy,surgicalinterventionsforabnormaluterinebleedingarecontraindicatedinpatientswhowishtopreservefertility. ThisarticleupdatespreviousarticlesonthistopicbySweet,etal.53;Albers,etal.54;andOrielandSchrager.55 DataSources:APubMedsearchwascompletedinClinicalQueriesusingthekeytermsabnormaluterinebleeding,heavymenstrualbleeding,irregularmenstrualbleeding,menorrhagia,metrorrhagia,anddysfunctionaluterinebleeding.Thesearchincludedmeta-analyses,randomizedcontrolledtrials,clinicaltrials,andreviews.AlsosearchedweretheAgencyforHealthcareResearchandQualityevidencereports,ClinicalEvidence,theCochranedatabase,andUpToDate.Searchdates:August21,2017,andNovember10,2018. ContinueReading Advertisement MoreinAFP MoreinPubmed ArticleSections Copyright©2019bytheAmericanAcademyofFamilyPhysicians. 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