Abnormal Uterine BleedingMitra A. Razzaghi, MD

Womens Integrated Services in HealthWISH

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ObjectivesQuick review terminology and etiology of AUBWork up for AUB - most important stepsNew trend in treatment of most common causes of AUBNew non-invasive and minimally invasive technologyOrganize the madnessQuick practical summary on how to diagnose and treat AUB

Case 56 y/o AA lady, presents for follow up on hospital admission for asthma exacerbation in Las Vegas. Asthma is now controlled. By the way she also had 5 days of moderate vaginal bleed which has stoppedShe is G2P2, postmenopause for past 4 years, no significant gyn history. She was on combination HRT for severe hot flashes which stopped 2 yrs agoPatient reluctant to have any studies doneWhat to do?

AUB - OverviewCommon problem in ambulatory medicine30% of outpatient gyn visitsBroad differential diagnosisMuch of the evaluation and treatment can be done by internists

AUB: Is uterus the origin?RectalUrethralVulvarVaginal wallCervixUterusFallopian tube or ovary

Non-Uterine Genital SourcesVaginal trauma- external/internalVaginitisVaginal atrophyCervical polypsCervicitis

TerminologyMenorrhagia bleeding >80cc/cycleMetrorrhagia light bleed, irregular intervalsAmenorrhea absence of periods x 3 usual cycle lengthsOligomenorrheaIntervals >35 daysMenometrorrhagiaHeavy bleed >80 ml, irregular intervals

Abnormal Uterine Bleeding (AUB) StructuralLeiomyomaPolypsCarcinomaPregnancy complicationsDysfunctional (DUB)OvulatoryAnovulatory

Diagnostic toolsHistory and physical including pelvic examBeta-HCGPap testScreening for STIs if indicatedBlood tests as indicatedEndometrial samplingPelvic ultrasound (transabdominal and transvaginal (TVUS)Saline Infused Sonohystogram (SIS)Hysteroscopy

Endometrial samplingFast and easy to do -may be tricky in postmenopausal women Minimal discomfort for patientShould be done in almost all AUB patients over age 35Provides important informationComparable results with diagnostic D&CBest time at or beyond day 18 of cycle

Treatment based on Biopsy ResultsPolypHysteroscopy or D&CObservation sometimes acceptableEndometritisHyperplasia without atypiaCyclic or continuous progestinRepeat EMBX in 3-6 monthsRefer to Gyn if hyperplasia persistsAtypia or carcinomaDisordered endometrium, stromal collapse, proliferative or secretoryTreat based on bleeding pattern

Saline Infused Sonohystogram (SIS)IndicationSuspect intra-cavity lesion (polyp, fibroid)Endometrial thickness eval with TamoxifenHow it is doneVaginal Ultrasound first4 mm catheter guided into uterus through cervical osSmall balloon or plug keeps the catheter in place20 cc saline infused with vaginal transducer in placeDistension of the uterine allows visualization

Hysteroscopy

Endometrial polyp

Systemic Diseases causing AUB

Thyroid diseaseChronic liver diseaseCushing syndromeRenal diseaseEmotional or physical stressExcessive exercisesmoking

Common medications causing AUBHormones (including Tamoxifen)AnticoagulantsPhenytoinAntipsychotics (Olanzapine, Risperidone)Tricyclic antidepressantsCorticosteroidsAntibiotics (toxic epidermal necrolysis or Stevens-Johnson Syndrome)

Polycystic Ovarian SyndromeAffects 10% of women in the USDefinition by NIH Consensus, 1990:Oligo- or anovulationHyperandrogenismExclusion of other causes of hypergonadism and menstrual irregularityRotterdam Criteria, 2003:Exclusion of other causes of hypergonadism and menstrual irregularity

and 2 of following 3 criteria

AnovulationHyperandrogenismPolycystic ovaries by ultrasound

PCOS - PathophysiologyElevated LH and insulin levelsCombination enhances ovarian androgen productionHigh androgen levels lead to abnormal follicular development and function

PCOSClinical manifestationsIrregular mensesAndrogen excessObesityAcanthosis nigricansMedical complicationsEndometrial cancerInsulin resistance/DiabetesInfertilityCoronary artery disease (CAD)Obstructive sleep apnea (OSA)Non-Alcoholic steatohepatitis (NASH)

PCOS - DiagnosisClinical diagnosis based on NIH criteriaUltrasound results using Rotterdam criteriaRule out other causesMenstrual irregularitiesPregnancyHyperprolactinemiahypothyroidismAndrogen excessHyperprolactinemiaNonclassical adrenal hyperplasiaAndrogen secreting tumors

PCOS - Work upRule out other etiologiesTSH, Prolactin, B-HCG, FSH17-OH ProgesteroneTestosterone level (

PCOS - TreatmentConcentrate on metabolic syndrome and risk reductionTreatment of unopposed estrogenNeed at least 3-4 endometrial shedding a year if not on any other treatmentAndrogen excess treated with OCP, spironolactone, or Eflomithine

Adenomyosis:Benign histological finding of endometrial glands into myometrial wallCauses pain, menorrhagia and large uterus during reproductive years

Uterine Leiomyoma

Uterine Leiomyoma (Fibroids)Most common gynecological tumor20-40% of reproductive age women Cause unknownSymptomsMenorrhagiaPelvic pressure/painDecreased fertilityImprovement after menopause or other hypoestrogenic states

Uterine FibroidsIncreased riskNulliparityObesityETOH useBlack-American ethnicityGenetic/Familial predisposition

Reduced riskPregnancyCombination OCPDepo-ProveraTobacco use

Uterine FibroidsAsymptomaticExpectant managementMildly symptomaticOCPNSAIDsUseful in idiopathic menorrhagiaDo not reduce blood loss caused by fibroidsMay alleviate cramping

Uterine Sparing Treatment for FibroidsHormonalUterine artery embolizationMR directed ultrasound (ExAblate)MyomectomyHysteroscopic resectionLaparoscopic myomectomy

GnRH AgonistsMost effective medical therapyDown regulates pituitary GnRH receptorsProfound decline in ovarian steroid production35-65% size reduction, mostly within first 3 monthsReturn to pretreatment size after discontinuationIdeal treatment before surgical excisionInduces menopause

RaloxifeneSelective estrogen receptor modulatorPostmenopausal: reduces fibroid volumePremenopausal: conflicting dataCombination with GnRH agonist70% vs. 40% reduction in size with GnRH agonist aloneSide effectsVenous thromboembolismVasomotor symptoms

Other TherapiesDanazoleAndrogenic steroidInhibits pituitary gonadotropin secretionSide effects: weight gain, acne, oily skinMifepristone (RU-486)AntiprogestinSide effects: vasomotor symptoms, 25% hyperplasiaLevonorgestrel-releasing IUDContraindications: uterine distortion, submucosal intracavitary fibroids

Uterine Artery Embolization UAE

Uterine Artery Embolization-UAE

Disadvantages of UAEPainful!!!Reduces bleeding more than bulkPedunculated fibroids cannot be embolizedNot definitiveCan induce menopauseNot recommended for women who desire fertilityIR data skewed- minimal long term follow up

MR Guided Ultrasound (ExAblate)MRI maps the fibroidsHigh frequency ultrasound heats the fibroidSize decreases by 13%80% decreased symptomsContraindicated if pregnancy is desiredLower complication compared to UAE

Uterine Leiomyoma

ExAblate

Limitations of MR-US AblationFew sites in the US - available in DenverCannot go through scars, bladder, bowelLimited to smaller fibroidsNo fertility dataLimited long term data (8 years)

Abdominal MyomectomyMajor surgeryComplications significantly higher than hysterectomyLong recoveryRecurrence rate 50%Small chance of uterine perforation in subsequent pregnancy

Laparoscopic MyomectomyOnly for pedunculated or subserosal fibroidsAdvanced laparoscopic techniques requiredVery limited availability

Hysteroscopic myomectomySuitable for submucous or intracavitary fibroidsLimited by size and location of the tumorHigh recurrence rateRequires advanced hysteroscopic skills

Hysterectomy

Laparoscopic HysterectomyLaparoscopic assisted vaginal hysterectomyLaparoscopic sub-total hysterectomyTotal laparoscopic hysterectomy

Treatment of Dysfunctional Uterine Bleeding

OCP- New FormulationsChewable tablet35 ug Ethinyl Estradiol+ 0.4 mg Norethindrone75 mg Ferrous Fumarate in placebo24/4 day regimenShorter hormone-free intervalFDA indication for PMDD84/7 day regimen12 weeks active pill + 7 days placeboFour menstrual periods per yearMenstrual migraine, dysmenorrhea12 weeks active pill + 7 days 10 ug Ethinyl Estradiol

Contraindication to OCPPrevious thromboembolic event or strokeHistory of estrogen-dependent tumorActive liver diseasePregnancyUncontrolled hyperlipidemiaOlder than 35 and smokes >15 cigarettes per dayOlder than 40 not contraindicated but progestin preferredAvoid Desogestrel-containing OCP if risk factors for VTE

ProgestinsCommonly used oral forms:Medroxy progesterone (Provera) cheaper but has PMS-like side effectMicornized progesterone (Prometrium)Norethindrone (Aygestin) Megestrol (Megace)Cyclic progestin (e.g. Provera 14 days on 14 days off)Continuous progestin:Norethindrone Minipill 0.35 dailyDepo-Provera (new SC form) or progesterone Implant (Implanton)Levonorgestrel IUD (Mirena)

Levonorgestrel IUD (Mirena)T-shaped polyethylene with a collar containing 52 mg of levonorgestrelVisible on X-RayEffective up to 7 years, approved for 5As effective as endometrial ablation for treatment of menorrhagiaMay also decrease the risk of PID

Implanon (contraceptive implant)Serum level of etonogestrel detectable within hours of insertionRelatively rapid return of fertility - 3 monthsContinuous protection for 3 yearsAppropriate for women after 4th postpartum weekEasy insertion and removal by physicianDoes not protect against STI

Balloon AblationUses hot liquid is balloon to treat uterine liningMinimally invasive, inserted through cervixProcedure is quick, uterine lining is treated for 8 minutesUterine lining will slough off like a period in 7-10 days

Advantages of AblationMany patients report decreased bleeding and are satisfiedMinimal recovery timeLow complication rateEasy to perform

Disadvantage of AblationNo long term studiesMay not be definitivePatient selection is the key!Works best with normal shaped cavityOften inappropriately performedHigh failure rate with adenomyosis and fibroids

Postmenopausal bleedingAtrophy 59%Polyp 12%Endometrial cancer 10%Endometrial hyperplasia 9.8%Hormonal effect 7%Cervical cancer

Endometrial Hyperplasia

Adenocarcinoma

Postmenopausal bleedingHistory and physical to direct clinician towards 4 groupsNeoplasmAtrophyMedicationsForeign bodyCervical cytology very importantMean age for cervical cancer 52.2Visible lesion needs biopsy even if pap is normal

Postmenopausal bleedingEvaluation to includePap testTransvaginal UltrasoundEndometrial biopsy if endometrial thickness 5mm or higherEMBx

Special considerationsIntrauterine infection Rare in this age groupThink malignancyOccasionally due to cervical stenosisPost Radiation TherapyCan be late effectObliterative endarteritis, tissue necrosisHemorrhagic cystitis or proctitisDisease of adjacent organsDiverticulitis can fistulize into uterine

Quick Practical Summary

AUB Initial approachHistory and physical - pelvic examRule out pregnancyDetermine bleeding pattern

Bleeding patternsNormalInterval 21-35 daysDuration 2-7 daysAmount 12 days consider irregular regardless of cyclic patternAcute Severe BleedingContraceptive related

Irregular bleeding - PerimenarcheUp to 2 years after menarcheImmature hypothalamic-pituitary-ovarian axisReassuranceIf not enough: OCP or progestin

Irregular bleeding non-pregnantTSH, Prolactin if oligomenorrhea>35 or unopposed estrogen: EMBX, consider TVUSConsider causeEndometritisMedicationsAdvanced systemic diseasePCOS If no desire for pregnancyOCP low -> highProgestins: oral, injection, implant, IUDIf persists TVUS, EMBxHave to scratch your head more? Refer to our Gyn friends

MenorrhagiaBlood loss of >80 ml per cyclePoor correlation of actual loss with pts perception of excessive bleedMay try hormonal therapyOCP if not contraindicatedProgestins including Levonorgestrel IUD or Provera 10 mg 14 days on 14 days offNSAIDs- 400mg Ibuprofen TID x 4 days start the day before mensesIf inadequate response TVUS or SISEMBX if endometrial thickness >10mmSurgical options if Polyp or submucosal myomaMRI if possible adenomyosisScreen for Von Willebrand disease early if suspected

Severe Acute BleedingOrthostatic hypotension or Hgb

Severe Acute BleedingHemodynamically stableOral Premarin 2.5 mg qid +antiemeticStudies: TVUS, TSH, CBC, CoagsD&C if no response after 4 doses or bleed >1 pad per hourAfter bleeding stopped: OCP(monophasic) QID x4 days TID x 3 days BID x 2 days QD x 3 weeks One week off then cycle on OCP for at least 3 monthsDont forget oral Iron!

Peri-menstrual SpottingPre and post menstrual ( 35 years of age : Endometrial biopsy warranted

OCP Associated BleedingBreakthrough Bleeding common with low dose OCPIf persistent for 3 months, switch to high doseScreen for GC/CT (common in young females)If persistent rule out structural cause (TVUS/SIS or hysteroscopy)AmenorrheaRule out pregnancyMay continue same pill (no risk of hyperplasia)May switch to higher estrogen OCP

Bleeding Associated with IUDRule out endometritisEmpiric therapy acceptableCommon for first 4-6 months of useCopper IUDOne cycle of OCP or10 mg Medroxyprogesterone x 7 daysTrial of NSAIDsProgesterone-releasing IUDOne cycle of OCP

If bleeding persists consider removal of IUD

Depo-Provera Associated BleedingSpotting common, no treatment necessaryIf persistent irregular bleed7-day course of estrogen:1.25 mg Premarin daily orEstradiol 1mg daily orEstrogen patch e.g. Climara 0.1mg

Maybe repeated if bleeding recurs

Back to our casePelvic exam normalAll labs normal - not pregnant!Pap smear HGSILTVUS normal, Endometrial thickening 5 mmColposcopy normalECC and EMBx normalGood news from cytology review!!!Conclusion

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