POLYCYSTICOVARYSYNDROME(PCOS):

TheLatestinPCOSResearchRicardoAzziz,M.D.,M.P.H.,M.B.A.

ChiefOfficerofAcademicHealth&HospitalAffairs

StateUniversityofNewYork(SUNY)SystemAdministration

ResearchProfessor,HealthPolicy,Management&Behavior

SchoolofPublicHealth,Univ.atAlbany,SUNY

COIConsultingforBayerPharma,Fractyl,LongitudeCapital,andAnsh Labs;andontheadvisoryboardforGlobalPET Imaging

DIAGNOSIS

Rotterdam, 2003

ROTTERDAM2003ANDAE-PCOS2006AREEXPANSIONSOFNIH1990

NIH 1990

AE-PCOS Soc., 2006

COMPARINGTHEPHENOTYPESOFPCOSBYNIH1990,ROTTERDAM2003,ANDAE-PCOS2006

Phenotypes

Characteristics A B C DHirsutism/HA Ö Ö Ö

Ovulatory Dysfunction Ö Ö Ö

Polycystic ovaries Ö Ö Ö

NIH 1990 Ö Ö

Rotterdam 2003 Ö Ö Ö Ö

AE-PCOS 2006 Ö Ö Ö

HYPERANDROGENISMINPCOSISASSOCIATEDWITHRISKOFMETABOLICSYNDROME

Shroffetal,FertilSteril88:1389-1395,2007

Age-adjustedprevalenceofMSishigherinallhyperandrogenicphenotypesofPCOS,comparedtothenon-hyperandrogenicPCOSphenotypeandtocontrols

A B C DPhenotypes

THEIMPACTOFREFERRALBIASONTHEPHENOTYPEOF

PCOS

Ezeh et al. J Clin Endocrinol Metab. 2013; 98:E1088-96

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PHENOTYPESINWOMENWITHPCOSIDENTIFIEDINREFERRALVS.UNSELECTEDPOPULATIONS:SYSTEMATICREVIEWANDMETA-ANALYSIS

Liznevaetal,F&S106:1510--1520,2016

• Phenotype A: 50% in referral vs. 19% in unselected*• Phenotype B: 13% in referral vs. 25% in unselected*• Phenotype C: 14% in referral vs. 34% in unselected*• Phenotype D: 17% in referral vs. 19% in unselected

*Significant difference

DIAGNOSINGPCOSINADOLESCENCE• TherearenoestablishedcriteriaforthediagnosisofPCOSin

adolescents• ThediagnosisofPCOShaslife-longimplicationsandthefeaturesof

PCOSmaybelesswellestablishedinadolescents• Thus,thediagnosisofPCOSinadolescentsshouldbemadewith

greatcaution• Ifthediagnosisisunclearthenthemostprudentcoursemaybe:

– Expectantmanagementwithregular,butnotoverzealous,follow-up– Reassuranceandpatient(andfamily)education– Lifestylemodification– Treatmentofindividualsymptoms/complaints,ifneeded/desired

EPIDEMIOLOGY

PREVALENCESTUDIESOFPCOSAROUNDTHEGLOBE-2015

PCOSPREVALENCEACCORDINGTONIH1990CRITERIA:AMETA-ANALYSIS

Bolzag et al, Hum Reprod 31:2841–2855, 2016

PCOSPREVALENCEACCORDINGTOROTTERDAM2003CRITERIA:

AMETA-ANALYSIS

Bolzag et al, Hum Reprod 31:2841–2855, 2016

PCOSPREVALENCEACCORDINGTOAE-PCOSSOCIETY2006CRITERIA:AMETA-ANALYSIS

Bolzag et al, Hum Reprod 31:2841–2855, 2016

PATHOPHYSIOLOGY

SNPSANDGENESASSOCIATEDWITHPCOSINGWASSTUDIESASOF2016# Locus SNP* Gene Description Population

Chromosome21 2p16.3 rs13405728 LHCGR Luteinizinghormone/choriogonadotropin receptor Chinese,Surinamese,European,

Egyptian,Indian,Arabic2 rs2268361 FSHR Follicle-stimulatinghormonereceptor- possibleassociationwith

erectiledysfunctionEuropean,Arabic,Chinese

3 rs2349415 European,Arabic,Chinese4 2p21 rs13429458 THADA Thyroidadenomaassociatedprotein– increaseofluteinizing

hormoneandtestosterone.European,Chinese

5 2q34 rs1351592 ERBB4 Receptortyrosine-proteinkinaseerbB-4 EuropeanChromosome5

6 5q31.1 rs13164856 RAD50 DNArepairproteinRAD50 EuropeanChromosome8

7 8p32.1 rs804279 GATA4 TranscriptionfactorGATA-4protein EuropeanChromosome9

8 9q33.3 rs2479106* DENND1A DENN domain-containingprotein1A protein– mediationofendocytosis

Chinese,European

9 9q22.32 rs4385527 C9orf3 Chromosome9openreadingframe3/aminopeptidaseO– cleavageofN-terminalaminoacid;possibleassociationwitherectiledysfunction

Chinese,European

Chromosome1110 11p14.1 rs11031006 FSHB Follitropin subunitbeta/Follicle-stimulatinghormonebetasubunit Chinese,European11 11q22.1 rs1894116 YAP1 Yes-associatedprotein1– activatestranscription Chinese,European12 rs11225154 Chinese,European

Chromosome1213 12q13.2 rs705702* RAB5B/SUOX RASoncogeneprotein/sulfiteoxidase– associatedwithinsulinand

glucoselevelChinese,European

14 12q14.3 rs2272046 HMGA2 High-mobilitygroupAT-hook2protein– possiblytranscriptionalregulatingfactor

Chinese,European

15 12q21.2 rs1275468 KRR1 Smallsubunitprocessomecomponenthomolog EuropeanChromosome16

16 16q12.1 rs4784165 TOX3 TOXhighmobilitygroupboxfamilymember3– transcriptionfactor Chinese,EuropeanChromosome19

17 19p13.3 rs2059807 INSR Insulinreceptorgene Chinese,EuropeanChromosome20

18 20q13.2 rs6022786 SUMO1P1 Pseudogene1 Chinese*Reportedsignificancep

BMIINWOMENWITHPCOSIDENTIFIEDINREFERRALVS.UNSELECTEDPOPULATIONS:

SYSTEMATICREVIEWANDMETA-ANALYSIS

Liznevaetal,F&S106:1510--1520,2016

Overall, in this small analysis, referral PCOS subjects had a greater BMI as compared with local controls, which was not immediately apparent or was less severe in women with PCOS detected in unselected populations

Chen et al. Diabetes 62: 2278-86, 2013

NOOBVIOUSDEFECTINPI3-K/AKT INSULIN-SIGNALINGPATHWAYINADIPOSEOFPCOS

DYSREGULATION OFADIPOKINESECRETIONBYADIPOCYTESOFPCOSWOMEN

Chazenbalk et al. JCEM 2010; 95:935-42, and unpublished

miR-93ISOVEREXPRESSED

ANDISNEGATIVELYASSOCIATEDWITHGLUT-4EXPRESSIONINADIPOSETISSUE

OFPCOS

Chen et al. Diabetes 62: 2278-86, 2013

Azziz et al, Nat Rev Dis Primers. 2016;2:16057

MOLECULARMECHANISMSOFINSULINRESISTANCEIDENTIFIEDINADIPOSETISSUEOFWOMENWITHPCOS

Azziz et al, Nat Rev Dis Primers. 2016;2:16057

MOLECULARMECHANISMSOFINSULINRESISTANCEIDENTIFIEDINMYOCYTESANDFIBROBLASTSOFWOMENWITHPCOS

ROLEOFAMH INPCOS

Azziz et al, Nat Rev Dis Primers. 2016;2:16057

SEVERITYOFMENSTRUALDYSFUNCTIONPREDICTSDEGREEOFIR IN494PCOS

Modified from Brower et al, J Clin Endocrinol Metab 98: E1967–E1971, 2013

TREATMENT

TREATMENTOFPCOS• Goalsincludetreatment&preventionof:– Dermatologicdisorders(hirsutism,acne,alopecia)– Ovulatory&menstrualdysfunction(DUB,endometrialhyperplasiaorCa)

–Metabolicabnormalities,incl.dyslipidemia,glucoseintolerance&obesity

– Infertility

• Optimumtreatmentisgenerallycombination therapy

PCOS:CREATINGATREATMENTPLAN• Goodtreatmentplansarebasedonsoundandcompleteevaluations– Historyofthedisorder– Evaluationhistory– Treatmenthistory– Pastmedical/surgicalhistory– Familyhistory– Physicalexam– TVU/S– Laboratory

PCOS:CREATINGATREATMENTPLAN• Rxincludes:– OCs orprogestins,forendometrialprotection/HA– Antiandrogens,forhirsutism,alopecia–Metforminformetabolicdysfunction– Ovulationinductionforinfertility– Life-stylemodification– Cosmeticcare

• PCOStreatmentgenerallyrequirescombinationRx,andlife-longcareandcounseling

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PPCOS ITRIAL:CCVS.CC+MET VS.METFORPREGNANCY

Legro et al. N Engl J Med 2007;356:551-66

CCVS.LETROZOLEASFIRST-LINEOVULATIONINDUCTIONININFERTILEPCOSWOMEN:

APROSPECTIVERCT

Kar. J Hum Reprod Sci. 2012;5:262-5

Legro et al. N Engl J Med. 2014;371:119-29

PPCOS IITRIAL:CCVS.LETROZOLEFORPREGNANCY

EMERGINGTHERAPIESINPCOS1)NeurokininB(kisspepetin-neurokininBorNKB)receptorantagonistsa)ToreduceLHandLH-stimulatedTlevels

i) AZD4901 (Astra-Zeneca,nowMillendo)ii) ESN364 (EuroScreen)

2) 17b-hydroxysteroiddehydrogenase,Type5(AKR1C3)inhibitorsa)Tosuppressandrogenbiosynthesis

i) KDT501 (KinDex Therapeutics)

3)NitricOxide(NO)synthesisstimulationa)Toimproveendothelialfunction

i) N-acetylcysteine(NAC),aloneorwithCCand/ormetforminii)L-Arginine,aloneorwithOCPs,CCormetforminiii)Solubleguanylatecyclase(sGC)stimulators

EMERGINGTHERAPIESINPCOS4)DENND1A (akaconnecdenn 1)inhibition

a)TodecreaseCYP17 andandrogenbiosynthesisi) AntiDNEEN1A.V2 IgG

5)IncreasingFSHa)Modifiedlonger-actingFSH

i) Follitropin Delta(Ferring)

6)IncreasingSHBG levelsa)RecombinantSHBG

a)Serono

7)Antiandrogensa) ARantagonist

i) BAY1161116 (Bayer)ii)Others?

EMERGINGTHERAPIESINPCOS8)Insulinsensitizers

a)Glucagon-likepeptide(GLP)-1agonists/stimulatorsi) Long-actingglucagon-likepeptide(GLP)-1receptoragonist(Liraglutide)ii) EnhancementofGLP-1actionviainhibitionofphosphodiesteraseenzyme(PDE)-4

b)Inositolsi)D-chiro-inositolormyo-inositolaloneii)D-chiro-inositol+myo-inositol(Ovasitol fromTheralogix)

c) NovelTZDs?

9)Aromataseinhibitorsa) Letrozoleb)Others?

10)Micro-RNAmodulationa)miR-93inhibitionb)Others?

EMERGINGTHERAPIESINPCOS11)Acupuncture

a) Asystematicreview&meta-analysisincluding27RCTs noted(Joetal,2017):i)Alowlevelofevidence thatacupunctureimprovesovulation&menstruationrateii)Alow/verylowlevelofevidence thatacupunctureasanadjuncttomedicationimprovesLH,LH/FSH ratio,TT,fastinginsulin,andpregnancyrates

12)ElementalSupplementationa)Chromium

i) JDSTherapeutics

13)FenugreekSeedExtract(Furocyst)

Ong et al, 2017. Am J Chin Med 2017; 45:405-22

HERBALMEDICINESINPCOS

Berberine

Resveratrol

Paeniflorin

Ginsenosides

Cryptotanshinone

HERBALMEDICINESINPCOS

Ong et al, 2017. Am J Chin Med 2017; 45:405-22

WenJingTang

Bushen Huatan

TianGui Caps.

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