ManagingPCOSataYoungAgeAmbikaAshraf,MDAssociateProfessor

PediatricEndocrinology

Disclosures• Otsuka– Researchgrant• Merck– Researchgrant• ThrasherResearchFund

EducationObjectives1) UnderstandthediagnosisofPolycysticOvary

Syndromeinteenagers2) Beawareoftheconditionsthatcanbemislabeled

asPCOS3) Describethecomponentsofmanagement4) DiscussthemetabolicconsequencesofPCOSin

teenagers

PolycysticOvarySyndrome• Mostcommonsymptoms:• Menstrualirregularity• Infrequentmenses(oligomenorrhea >45days, <8cycles/year)• Primaryamenorrhea(nocyclebyage15or3yearsafterbreastdevelopment)• Secondaryamenorrhea(absentmenses >90days)• Canhave‘regular’periodswithoutovulation(10-15%)• Frequentheavybleeding(<21days)*** Persists2yearsbeyondmenarche

PolycysticOvarySyndrome• Othercommonsymptoms:• Hirsuitism- terminalhairgrowthinamalepattern- darkcoarse• Acne- severe,cystic- occuralongjawline,back,chest

• Obesity:inUS~2/3rd ofpatientswithPCOS-ObesityunmasksoramplifiesPCOS

RosenfieldRL.NEnglJMed2005;353:2578-2588.

The Ferriman–Gallwey Scoring System for HirsutismVisual grading over 9 body areas

Otherassociatedskinconditions• Acanthosisnigricans:neck,groin,skinfolds,underarms.Frominsulinresistance

• Rarelyalopecia:scalphairthinninginmalepattern

PCOSinadolescents- DiagnosticCriteria

• Onlyneed2criteria:• Hyperandrogenism:clinicalorbiochemical*Centraltodiagnosis• Menstrualirregularities:thatpersists>2yearsafteronsetoffirstperiod

• Absenceofanotherunderlyingendocrinopathy

Required

Hyperandrogenism Clinical/biochemical

X

Oligo-/amenorrhea Persistent XPCOmorphology Maybenormal NO

PCOS“Look-alikes”• Adolescence• Hypothyroidism• Hyperprolactinemia• OvarianFailure• Obesity• CushingSyndrome/Disease• HypothalamicDysfunction• Non-classicalCongenitalAdrenalHyperplasia• Androgen-SecretingTumor

PCOS“Look-alikes”• Non-classicalCongenitalAdrenalHyperplasia• Resultsinmenstrualirregularitiesandhyperandrogenism• Enzymedefectinsteroidpathway(adrenalandovary)• Measure17-hydroxyprogesteronetodiagnose

PCOS“Look-alikes”• Androgen-secretingTumor(adrenalorovariantumors)• Consideriftotaltestosteroneis>200ng/dL• Unusualsymptoms:voicedeepening,clitoromegaly,malepatternbalding• Rapidonsetofsymptoms• Mayneedpelvicultrasound(ovaries)andCTScan(adrenals)

PCOS“Look-alikes”• CushingSyndrome/Disease• Cortisolexcess• FromACTH-producingtumor• Fromcortisol-producingtumor• Steroidexposure• Clinicalfeatures:-Obesity-Hypertension-Striae-Muscleweakness

Laboratoryevaluation• SerumTestosterone:totalandfreeVariabilityofassays,diurnalfluctuations,lackofwelldefinedadolescentcut-offpointsTestosteronereachadultlevelsbyage15Reliableassay:LCMS/MS

• FSH/LH/estradiol• TSH,FT4• Prolactin• 17-hydroxyprogesterone• DHEAS• Midnightsalivarycortisol• Urine24-hrfreecortisol• Pelvicultrasound

Evaluatingassociatedrisks• Bloodpressure• Bodymassindex• Signsofinsulinresistance:acanthosis,skintags• Increasedabdominaladiposity• Diabetesscreening• 5-10foldincreasedriskofdiabetes• impairedglucosetolerance30-35%

• Cholesterolissues:hightriglyceride,lowHDL,highLDL• Screenfordepression,anxiety,panic,poorbodyimage,eatingdisorders

• Screenforfattyliverdisease:liverenzymes• Sleepapnea

Whentodoultrasound?1. Ifsuspicionofovarianoradrenaltumor:markedly

elevatedtestosterone,rapidonsetofseverevirilization,ifthereispainorapalpablemass

2. Toevaluateanatomy:Inpatientswhoneverhadacycle3. CystsinPCOS(maybenormalinadolescence):

- Arrestedfollicles(>12)- Lessthan10mminsize- Donotcausediscomfort,painorswelling- Increasedovarianvolume>10cm3 (withoutacystordominantfollicleineitherovary)- NoneedforUSmonitoring

IsPCOSthewrongname?• Thecystsin“PCOS”areanultrasoundfinding• Canbemisleading

• NIH-calledmeeting2013“ThenamePCOSisadistractionthatimpedesprogress.Itistimetoassignanamethatreflectsthecomplexinteractionsthatcharacterizethesyndrome”

• E.g.FemaleMetabolicReproductiveSyndrome

TheSyndrome• MenstrualIrregularities• AndrogenExcess• Hirsutism• Acne

• Infertility• Cardio-metabolicConsequences• Diabetes• CardiovascularDisease

• Depression

UnderlyingcauseofPCOS• Notwelldefined:complexpolygenic• Affects5-10ofevery100adolescents• Higherprevalenceinobeseadolescents• Associatedwithinsulinresistancein50-70%ofpatients:- Increasedinsulinlevels- Decreasedinsulinsensitivity/resistanceà increasemalehormoneeffects

• Inherentabnormalityofsteroidproduction(dysregulatedhyperactivityofcytochromeP450c17αenzymaticactivity)inovariesandadrenalgland

• Manygenesimplicated• Lowbirthweight• Precociouspuberty

Overproductionofandrogensfromtheadrenalglandsandovaries

ImbalanceofLHandFSHfromthepituitarygland

Insulinresistance

RapidGnRH pulses

Understandingpathophysiology• Insulinresistance(IR)àplayacardinalroleinthepathogenesisofPCOSandhyperandrogenism

• Desynchronization ofLHandFSHsecretionfromthepituitaryglandà highLH,lowFSH-LowFSH:abnormalfolliclematuraiton/anovulation-HighLH:stimulatestestosteroneproductionfromthecacells

• Overproductionofandrogensfromtheadrenalglandsandovaries

Treatment• Symptomatic• NoCure• MainGoalsofTreatment:

ØMenstrualregulation:lifestylechanges,OCP,metforminØ Improveinsulinresistance:lifestylechanges,metforminØReducemalehormoneeffects:lifestylechanges,OCP,metformin,spironolactone,skintreatments

Treatment:MenstrualRegulation• Combinedoralcontraceptives=1st linetherapy• Predictablecycles,improvesacne• Improveshirsuitism:noticeablein6months• Protectendometriumfromprolongedestrogen• NoevidenceforOCPincreasingriskfordiabetes• Improveslipids• Continueuntil5yearsaftermenarcheorhaslostasubstantialamountofweight

Treatment:Insulinresistance• Insulinsensitizer:Metformin-Ifdiabetic,prediabetic, orhasimpairedglucosetolerance orwhennosuccesswithoutmedication

- 30%reductioninprogressiontodiabetes-1500-2000mg/day-Maycauseweightlossinsome-Mayimprovemenstrualirregularity- Reducetestosteroneby20-25%

-Otherdrugs–notapproved• NoadequatelypoweredRCTsofarinadolescents

Lifestylemodification• Maintainingoptimalbodyweight• Exercise:30minutesofmoderate-vigorousphysicalactivity• 5-10%weightlossà canimprovemenstrualfunction• Reducesdiabetesriskandothermetabolicabnormalities

• Behaviormodification• Maintainingselfcontrol• Assessingdepressionandanxiety

• Diet (nodietisshowntobesuperior)• Calorierestricteddiet• Manyrecommendlowercarbohydratediet,lowglycemicloaddiet

Hirsuitism:pharmaceuticalRx• Combinedoralcontraceptive=1st line• Takesawhiletoseeeffect(6monthsà alteredhairshafts)

• Spironolactone• Antiandrogen:reducehairgrowth, preventnewgrowth,alreadypresentfolliclesmaynotregress• Antihypertensive,adiuretic(can↑K)• Teratogenic:mayaffectformationofmalegenitaliaoffetusà needreliablecontraception

• Otherantiandrogens:flutamide,finasteride- notusedinteens• Topicaleflornithine (vaniqa)

Treatment:HirsutismCosmeticManagementOptions• Mechanical• Shaving• Waxing• Creams• Electrolysis• Depilatories

• Lasertreatment• Worksasfollicularmelaninabsorbsthelaserwavelength,selectivethermaldamage• Besttocombinewithamedicaltreatment

Multi-DisciplinaryApproach• MenstrualRegulation• Hirsutism• Obesity• Monitoringforcardio-metabolicrisk• Regularfollow–up

PediatricEndocrinologyPediatricGynecology

DermatologyPrimaryCareNutritionist

FamilysupportMotivation

Importanceofearlydiagnosis

Timelyinitiationoftherapy

Improvedqualityoflife

Summary• PropermanagementcanimprovePCOS• Beawareoftheconditionsthatcanbe

mislabeledasPCOStoensureanaccuratediagnosis

• PCOSisasyndromeandtreatmentisamulti-facetedapproach