Too much, too little, too late: Abnormal uterine bleeding

JodySteinauer,MD,MASJuly,2015

The Questions

• Toomuch(&tooearlyortoolate)– Differentialandapproachtowork‐up

– Doessheneedanendometrialbiopsy(EMB)?

– Doessheneedanultrasound?

– HowdoIstopperi‐menopausalbleeding?

– Isn’titduetothefibroids?

• Toofast:She’shemorrhaging—whatdoIdo?

• Toolittle:Aquickreviewofamenorrhea

Case 1

A46yo G3P2T1reportsherperiodshavebecomeincreasinglyirregularandheavyoverthelast6‐8months.Sometimestheycome2timespermonthandsometimesthereare2monthsbetween.LMP2monthsago.Shebleeds10dayswithclotsandfrequentlybleedsthroughpadstoherclothes.Sheoccasionallyhashotflashes.Shealsohasdiabetesandisobese.

1. Whattermdescribeshersymptoms?

2. Physiologically,whatcausesthistypeofbleedingpattern?

3. Whatisthedifferential?

1. FSH2. Testosterone&DHEAS3. Serumbeta‐HCG4. Transvaginal Ultrasound(TVUS)5. EndometrialBiopsy(EMB)

Q1: In addition to a urine pregnancy test and TSH, which of the following is the most appropriate test to obtain at this time?

Terminology: What is abnormal?

• Normal:Cycle=28days+‐ 7d(21‐35);Length=2‐7days;Heaviness=self‐defined

• Toolittlebleeding:amenorrheaoroligomenorrhea

• Toomuchbleeding:Menorrhagia(regulartimingbutheavy(accordingtopatient)ORlongflow(>7days)

• Irregularbleeding:Metrorrhagia,intermenstrual orpost‐coitalbleeding

• IrregularandExcessive:Menometrorrhagia

• Preferredtermfornon‐pregnantbleedingissues=AbnormalUterineBleeding(AUB)– Avoid“DUB”‐ dysfunctionaluterinebleeding.

Pathophysiology: Anovulatory Bleeding

Bricks&MortarEstrogen=Bricks,buildendometrium

Progesterone(P)=Mortar,stabilizes,onlyhavePifovulate

Normalmenses:WithdrawalofPcauseswalltofalldown,allatonce(orderlybleed)

Anovulation: NoPsowhenwallgrowstootall,itfalls.Itisheavywhenwallistall.Brickscanalsofallintermittently&incompletely–irregularly,irregular

Differential: AUBStep 1: Pregnant?

Pregnant

• Ectopic• SpontaneousAbortion• ThreatenedAbortion• MolarPregnancy• Trauma• Somenon‐pregnantcauses

NotPregnant• Anovulation***• Anatomic/structural**• Neoplastic*• Infectious• Iatrogenic• Non‐gynecologic

* = Most likely for this patient

PCOS Hypo/HyperThyroid

Anorexia/Over‐exercise

menopause

Peri‐menarche/Peri‐menopause

Physiologic Hyperandrogenic CNS Iatrogenic

Obesity

Causes of Anovulation

Reference: Causes of Anovulation

Pregnancy*Peri‐menarche+Peri‐menopause+Breast‐feeding*Obesity(viainsulineffectinovary)+

PCOS+Adult‐onsetcongenitaladrenalhyperplasia+

Pituitary adenoma (prolactin-secreting)*

Neuroleptic agents (via increased prolactin)*

Hypo or hyper thyroid (* or +)

Hypothalamic (stress, anorexia)*

LevonorgestrelIUD#Progestininjection*#Progestinimplant#Combinedhormonalcontraception#

*Typicallyamenorrhea#Typicallyspotting/lightirregularbleeding+Typicallyirregularheavybleeding(q1.5‐6mos)

Physiologic Hyperandrogenic CNS Iatrogenic

Reference:  AUB Differential 

Uterus:Myoma,polyp,adenomyosis,atrophy

Cervix:polyp,atrophy,trauma

Vagina:atrophy,trauma

Uterus:Hyperplasia,cancer

Cervix:Dysplasia,cancer

Ovary:hormoneproducingtumor

Uterus:Endometritis,PID

Cervix:Cervicitis

Vagina:Vaginitis(eg Trich)

Coagulopathy(vWD),severerenalorliverdz,GIorGUsource

Non-Gynecologic

Infectious

Neoplastic

Anatomic

Hormonal

Not Pregnant

Anovulation

Not Pregnant

Initial Work‐up:  Menometrorrhagia

• Always:Urinepregnancy

• Usually:TSH

• Maybe:Hct,r/ocoagulopathy

• Maybe:EMB(EndometrialBiopsy)

• Maybebutlater:TransvaginalUltrasound

• Usuallynotnecessary:FSH,LH,Testosterone,Estradiol

Does she need an EMB?

EndometrialCancerFacts• 4thmostcommoncancerinwomen;averageage61but25%occurinpremenopause

• 10%ofpost‐menopausalwomenwithbleedinghavecancer

• Presentsatearlystagewithbleeding;rareintheabsenceofbleeding.Vastmajorityeffectivelytreatedwithsimplehysterectomy

• Riskfactor=Increasedestrogen(longh/oanovulatione.g.PCOS,obesity).Protective=smoking,OCP’s

The Problem

• Irregularbleedingiscommon

• Endometrialcancerisrelativelycommon

• Riskpredictionmodelsarenotuseful

• LittleevidencetoguideusregardingwhentodoEMB

• ACOGguidelines(expertopinion)recommendbiopsyinMANYwomen

ACOG, July 2012

ACOGPracticeBulletin128,DiagnosisofAUBinReproductive‐AgedWomen

Perimenopause

• Averages4years

•12%suddenlystopmenstruating

•18%havelonger,heaviermenses

•70%haveshort,irregularmenses

ShouldwethereforeperformEMB onallbut12%of

women?

The Evidence…

• Oneprospectivecohortstudyof1000womentotestlessaggressiveEMBClinicalPathway

• AlleligibleforbiopsyusingACOGguidelines.Onlybiopsiedthosethatwerepost‐menopausalorhadatleast1riskfactor(n=570)

• Nocancers/hyperplasiain2yrs f/uinthosethatweren’tbiopsied.(under‐poweredtoanswerthisquestion)

Dunn,JReprodMed. 2001Sep;46(9):831‐4

A Rational Approach to EMB

• Naturalhistory:Endometrialcancertakesmanyyearstodevelopprogressingfromnoatypia toatypia priortoinvasion.Wehavetimetodetectit.

• Bleedingpatterncues:Cancer&hyperplasiapresentmostcommonlywithmenometrorrhagia,sometimeswithintermenstrual bleeding.Rarelywithregularly‐timedmenses.

• Progestins (IUD,progestin‐onlypill)havebeenshowntotreathyperplasiaandcancer.

A Rational Approach to EMB

Post‐Menopause:ALLwomenWITHANY BLEEDING(except4‐6monthsafterstartingHRT)

Recentonsetirregularbleeding: Considertreatingfirstandifbleedingnormalizes,noneedEMB

>50: Allwomenwithrecurrent,irregular bleeding(considernotdoingifperiodslightandspacingout)

45‐50: Recurrentirregularbleedingplus>1riskfactorOR>6mosmenometrorrhagia

<45:Longhistory(>2yr?>5yr?)ofuntreatedanovulatory bleeding(eg PCOS)

Otherreasons:Papwithatypicalglandularcellsorendometrialcells(ie ifpapnotdoneattimeofmenses).

EMB isnotperfectlysensitivesofurtherevaluationmandatoryif:

1.PersistentAUB afternegativeEMB

2.PersistentAUB after3‐6monthsofmedicaltherapy

A Rational Approach to EMB (cont’d)

Do all women with AUB need an ultrasound?

AlthoughTVUS isthebestimagingchoiceforpelvicpathology(ie betterthanMRI,CT)….• 80%withheavymenstrualbleedinghavenoanatomicpathology

• Incidentalfindingssuchasfunctionalovariancystsandsmallfibroids(~50%)areoftenfoundleadingtoanxietyandunnecessarytreatments

• SO….treatfirst,TVUS iftreatmentfails

What about U/S instead of EMB for post‐menopausal bleeding?

Transvaginal Ultrasound

• Measureendometrialstripe

• Abnormal=>4mm(or5)

• Non‐specific:myomas,polypsalsocausethickEM

• Operatorskillmandatory

• NOTUSEFULPRE‐MENOPAUSE

TVUS EMB

96% Sensitivity 94%

61% Specificity 99%

99% NPV 99%

40‐50% Furtherw/unecessary

?<5%

CanofferpatientchoiceaslongaseitherisquicklyavailableandpatientunderstandsshemayneedEMBafterU/S

TVUS vs EMB to Detect Cancer (in post‐menopausal women)

Q1: In addition to a urine pregnancy test and TSH, which of the following is the most appropriate test to order at this time?

1. FSH2. Testosterone&DHEAS3. Serumbeta‐HCG4. Transvaginal

Ultrasound5. EndometrialBiopsy

A46yo G3P2T1reportsherperiodshavebecomeincreasinglyirregularandheavyoverthelast6‐8months.Sometimestheycome2timespermonthandsometimesthereare2monthsbetween.LMP2monthsago.Shebleeds10dayswithclotsandfrequentlybleedsthroughpadstoherclothes.Sheoccasionallyhashotflashes.Shealsohasdiabetesandisobese.

EMB=“Disordered Proliferative”. How do I stop the bleeding?

MedicalNSAID’sTransexamic AcidOralE+PE+Ppatch,ringHRT(lowerdoseE+P)HRTpatchOralProgestinProgestinIUDIMProgestinGnRH agonist

SurgicalEndometrialablation

(D&C/Hysteroscopy)

Hysterectomy(failedmedicalmanagement)

Disorderedproliferative=Anovulation

Non‐hormonal Treatment: NSAID’s

• 5daysaroundtheclock(eg 600mgtid)

• ManydosagesandtypesproveneffectiveinmultipleRCT’s todecreaseblding by~40%

• Usealoneorwithothertherapies

DON’TFORGETNSAIDs!

First Line Hormonal Treatments

• Firstchoice:Levonorgestrel IUD– >80%reductioninbloodloss,decreasedcramping,prevents/treatshyperplasia,highlyeffectivebirthcontrol

– Veryfewcontraindicationstousing– Bloodlossandsatisfactioncomparabletoablation,satisfactioncomparabletohyst.

• 2nd choice:combinedcontraceptives(pill,patch,ring)orprogestininjection– Proventodecreaseirregularperi‐menopausalbleeding– Anytypeok,20mcgpreferredforwomen>40– Estrogencontraindications:smokers>35,HTN,complicatedDM,multipleRFforCAD,h/oDVT,migraines

Second Line Hormonal Options

• CyclicProgestins:– LesseffectivethanNSAID’sandLevo IUD– 21‐daytherapymoreeffectivethan10‐daybutpoorlytolerated

• HT(post‐menopausaldosing):– MoredifficulttogaincyclecontrolcomparedwithOCP– SamecontraindicationsasCombinedHormonalContraception

Transexamic Acid

• Anti‐fibrinolytic;availableinEuropeformanyyears‐availableinUS2011

• Expensive$170percycle

• InRCT’s,moreeffectivethanNSAID,cyclicprovera.– LesseffectivethanMirena.ImprovesQOLby80%by3rdcycle

• Dose:2tabstid for5days(3900mg)

• Risks:TheoreticriskofVTE.Noincreaseinlargestudies.ContraindicatedinthosewithhistoryoforriskfactorsforVTE.UnknownifsafeinconjunctionwithCHC.

• Sideeffects:Minimal

Surgical Treatments

• D&C,Hysteroscopy:– Notreallyatreatment.Temporaryreductioninbleeding.Diagnostic,notcurative(exceptifpolypremoved).

• EndometrialAblation– Reducesbutdoesn’teliminatemenses– ~25%repeatablationorhyst in5years– Mustruleoutcancerfirst– Can’tbedonein>12weekuteriorforwomenwhowantfertility

Perimenopausal/AnovulatoryBleeding: Summary

R/opregnancy,thyroiddz

EMBifmeetscriteria

Treatfirstasifanovulatory bleeding:– NSAID’s+– Hormones(Levo IUD,CHC,DMPA)

Ifpersists:– U/Stocheckforanatomiccauses(andEMBifnotalreadydone)

– Discusssurgicaloptionsforbleedingrefractorytomedicalmanagement.

Case 2: Is it the fibroids?

SamehistoryasCase1exceptshehasfibroids….

A46yo G2P2womanpresentsstatingthatherfibroidsarecausingirregularbleeding.

Shehasaknownfibroiduterusandcomplainsofincreasinglyirregularandheavyperiods.Sometimestheycome2timespermonthandsometimesthereare2monthsbetween.LMP 2monthsago.Shebleeds10dayswithclotsandfrequentlybleedsthroughpadstoherclothes.Sheoccasionallyhashotflashes.Shealsohasdiabetesandisobese.

Onexam,heruterusis16weekssizeandirregular.

Fibroids…...

• Verycommon 80%ofhysterectomyspecimens(doneforanyreason)and~75%haveonU/Satage50.

• 2‐3foldhigherincidenceinblackwomen

• About50%areasymptomatic

• Growslowlyuntilmenopauseandthendecreaseby~50%(canstillcausebleedingpost‐menopause)

Fibroid Symptoms

• Bleeding– Usuallynormal ormenorrhagia(heavybutregular).Fibroidsstretchendometrium=moreblding

– Occasionallymenometrorrhagiaifsubmucous orintracavitary(Fibroidsdistortendometriumsoitcan’teverbestable=constantblding)

• Pressure(notpain)• Dysmenorrhea

Heavy,irregularbleeding

NoeffectHeavy,regularbleeding

Is the bleeding due to the fibroids? 

• Fibroidsarecommoninlater40s• Anovulationiscommoninlater40s• Theincreasedbleedingseenwithfibroidsistypicallyduetoincreasedvolumeordistortionoftheendometrium

• Therefore:Decreasetheamountofendometriumbytreatingasanovulatory bleeding.Thisoftenworks.

AUB with Known Fibroids: Work‐up and Treatment

• R/ocancer(using“rationalemb algorithm”andpregnancy(don’tblamefibroidsforthebleeding)

• NSAID’sandhormones

• Ifnobetter,blamethefibroids!

• +/‐ Lupron‐‐asabridgetomenopauseorpre‐optoshrinktoobtainlessinvasiverouteofhysterectomy

• Surgicaltherapies(hysteroscopic resectionif<3cm,myomectomy,hysterectomy,UAE)

Hysterectomy

• Veryhighpatientsatisfaction(90%)(higherthanablation)

• Improvedqualityoflife,sexualsatisfactionanddecreasedpain

• Increasedlongtermrisksofprolapse,incontinence

Uterine Artery Embolization

• Benefits:40%decreaseinsize,75‐90%improvedbleeding

• Unknown:Willtheyre‐grow?In5yrf/uofRCT,25%hadhysterectomy

• Notfor:womenwhowantfertility• A“major”non‐surgicalprocedure:

– Requireshospitalizationforpaincontrol,– ~2weekstoreturntofullactivities(duetopainandfever)

– Risks:emergenthyst (1‐2%),5%expelmyoma throughcervix,40%havefever

Case 3… Too Fast

41yearoldwomanpresentswithdizzinessandheavyvaginalbleedingfor2weeksstraight.

Priortothis,occasionalirregularperiodsbutnothinglikethis!

Hemoglobin=9

Acute Menorrhagia Treatment

ABC’sandStopthebleeding!• ConsiderEDfortransfusion• Estrogen—2‐4OCPs(30‐35mcgE2)

– Increasesfibrinogen,factorsV,IX,plateletaggregation.“Covers”denudedareasinuterus

– OralaseffectiveasIV(souseoral)

• Givewithanti‐emetic• SmallRCTsuggestshigh‐doseprovera maybeeffectiveas

well,20mgtid• Ifnoteffective,options:D&C,Foleybulbtamponade,

emergencyhysterectomy

OCP Taper

• Don’twanttogive2‐4OCP’s perdayandthenstopsuddenlyb/cwillhavelargewithdrawalbleed

• Taper:4x4days,3x4days,2x4daysthen1 perdayfor1‐2months(66‐96pillsrequired).

• Instructnottotakeplacebosandgiveatleast3packsofpillsatonce.

• Givewithanti‐emetic,splitbid(i.e.2bidratherthan4allatonce)

What about too little bleeding?

Sevenquestionsinevaluationof2° amenorrhea

1. Pregnant?2. Excessivehairgrowthoracne? PCOS3. Overweight? Obesity‐inducedanovulation4. Breastsecretions? Hyperprolactinemia5. Verythin,over‐exercise,stress? Functional

hypothalamicamenorrhea6. Hotflashes? Prematureovarianfailure7. Pregnantrecentlycomplicatedwithinfectionoruterine

surgery(D&C)? Asherman’s syndrome

Size of words reflects frequency.

WORK‐UP:  Amenorrhea

• Always:– Urinepregnancytest.

– IfNeg:TSH&PLN

• Ifhotflashes:– FSH

• Ifhirsute/obese:

– Usuallynofurthertestingneeded.(Ifdeepvoiceorclitoromegaly:testosterone.Iffamilyhistoryhirsutism oronsetatpuberty:17OH‐P)

Reference: Progestin Challenge Test

• Progestinchallengetest:(10mgProverax10days)– Bleedingafterconfirmsendogenousestrogenispresent

– Distinguisheshypothalamicamenorrhea(nobleedingorjustspots)fromPCOS(fullwithdrawalbleed)

• Estrogenchallengetest:(Premarin 2.5mgqd x3wksthenProverax10days)distinguisheshypothalamicamenorrhea(fullwithdrawalbleed)fromAsherman’s (nobleedingorjustspots)

Amenorrhea Treatment

1. PCOS Protecttheendometrium!(fromhyperplasiaduetounopposedE2) combinedcontraceptives,DMPA,LNGIUD

2. Obesityinducedanovulation same

3. Hyperprolactinemia duetomicroadenoma OCPsornothing,Bromocriptine ifdesirespregnancyortotreatsxs

4. Functionalhypothalamicamenorrhea‐‐ protectthebones!(fromlackofE2) estrogen‐containingcontraceptives

5. Prematureovarianfailure same

6. Asherman’s syndrome Hysteroscopy

Conclusions

• Diagnosis:consideranovulationeveninwomenwithfibroids.

• Work‐up:Alwaysruleoutpregnancy.Usually:TSH,PLN,?HCT,?EMB,TVUSifinitialtreatmentfails.

• Treatment:allbleedingtreatedsimilarly;NSAID’splushormones.Considerothercausesandtreatmentsifthisdoesn’twork.Preventhyperplasiawithprogestin‐dominanthormones.

• Persistentabnormalbleedingrequirescontinuedwork‐upevenifEMBand/orultrasoundarenegative.