the latest in pcos researchricardo azziz, m.d., m.p.h., m.b.a. chief officer of academic health &...
TRANSCRIPT
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POLYCYSTICOVARYSYNDROME(PCOS):
TheLatestinPCOSResearchRicardoAzziz,M.D.,M.P.H.,M.B.A.
ChiefOfficerofAcademicHealth&HospitalAffairs
StateUniversityofNewYork(SUNY)SystemAdministration
ResearchProfessor,HealthPolicy,Management&Behavior
SchoolofPublicHealth,Univ.atAlbany,SUNY
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COIConsultingforBayerPharma,Fractyl,LongitudeCapital,andAnsh Labs;andontheadvisoryboardforGlobalPET Imaging
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DIAGNOSIS
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Rotterdam, 2003
ROTTERDAM2003ANDAE-PCOS2006AREEXPANSIONSOFNIH1990
NIH 1990
AE-PCOS Soc., 2006
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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
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HYPERANDROGENISMINPCOSISASSOCIATEDWITHRISKOFMETABOLICSYNDROME
Shroffetal,FertilSteril88:1389-1395,2007
Age-adjustedprevalenceofMSishigherinallhyperandrogenicphenotypesofPCOS,comparedtothenon-hyperandrogenicPCOSphenotypeandtocontrols
A B C DPhenotypes
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THEIMPACTOFREFERRALBIASONTHEPHENOTYPEOF
PCOS
Ezeh et al. J Clin Endocrinol Metab. 2013; 98:E1088-96
Prev
alen
ce o
f Hirs
utis
m (%
)
Prev
alen
ce o
f Hyp
eran
drog
enem
ia (%
)
% N
on-H
ispa
nic
Whi
tes
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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
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DIAGNOSINGPCOSINADOLESCENCE• TherearenoestablishedcriteriaforthediagnosisofPCOSin
adolescents• ThediagnosisofPCOShaslife-longimplicationsandthefeaturesof
PCOSmaybelesswellestablishedinadolescents• Thus,thediagnosisofPCOSinadolescentsshouldbemadewith
greatcaution• Ifthediagnosisisunclearthenthemostprudentcoursemaybe:
– Expectantmanagementwithregular,butnotoverzealous,follow-up– Reassuranceandpatient(andfamily)education– Lifestylemodification– Treatmentofindividualsymptoms/complaints,ifneeded/desired
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EPIDEMIOLOGY
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PREVALENCESTUDIESOFPCOSAROUNDTHEGLOBE-2015
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PCOSPREVALENCEACCORDINGTONIH1990CRITERIA:AMETA-ANALYSIS
Bolzag et al, Hum Reprod 31:2841–2855, 2016
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PCOSPREVALENCEACCORDINGTOROTTERDAM2003CRITERIA:
AMETA-ANALYSIS
Bolzag et al, Hum Reprod 31:2841–2855, 2016
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PCOSPREVALENCEACCORDINGTOAE-PCOSSOCIETY2006CRITERIA:AMETA-ANALYSIS
Bolzag et al, Hum Reprod 31:2841–2855, 2016
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PATHOPHYSIOLOGY
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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
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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
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Chen et al. Diabetes 62: 2278-86, 2013
NOOBVIOUSDEFECTINPI3-K/AKT INSULIN-SIGNALINGPATHWAYINADIPOSEOFPCOS
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DYSREGULATION OFADIPOKINESECRETIONBYADIPOCYTESOFPCOSWOMEN
Chazenbalk et al. JCEM 2010; 95:935-42, and unpublished
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miR-93ISOVEREXPRESSED
ANDISNEGATIVELYASSOCIATEDWITHGLUT-4EXPRESSIONINADIPOSETISSUE
OFPCOS
Chen et al. Diabetes 62: 2278-86, 2013
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Azziz et al, Nat Rev Dis Primers. 2016;2:16057
MOLECULARMECHANISMSOFINSULINRESISTANCEIDENTIFIEDINADIPOSETISSUEOFWOMENWITHPCOS
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Azziz et al, Nat Rev Dis Primers. 2016;2:16057
MOLECULARMECHANISMSOFINSULINRESISTANCEIDENTIFIEDINMYOCYTESANDFIBROBLASTSOFWOMENWITHPCOS
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ROLEOFAMH INPCOS
Azziz et al, Nat Rev Dis Primers. 2016;2:16057
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SEVERITYOFMENSTRUALDYSFUNCTIONPREDICTSDEGREEOFIR IN494PCOS
Modified from Brower et al, J Clin Endocrinol Metab 98: E1967–E1971, 2013
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TREATMENT
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TREATMENTOFPCOS• Goalsincludetreatment&preventionof:– Dermatologicdisorders(hirsutism,acne,alopecia)– Ovulatory&menstrualdysfunction(DUB,endometrialhyperplasiaorCa)
–Metabolicabnormalities,incl.dyslipidemia,glucoseintolerance&obesity
– Infertility
• Optimumtreatmentisgenerallycombination therapy
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PCOS:CREATINGATREATMENTPLAN• Goodtreatmentplansarebasedonsoundandcompleteevaluations– Historyofthedisorder– Evaluationhistory– Treatmenthistory– Pastmedical/surgicalhistory– Familyhistory– Physicalexam– TVU/S– Laboratory
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PCOS:CREATINGATREATMENTPLAN• Rxincludes:– OCs orprogestins,forendometrialprotection/HA– Antiandrogens,forhirsutism,alopecia–Metforminformetabolicdysfunction– Ovulationinductionforinfertility– Life-stylemodification– Cosmeticcare
• PCOStreatmentgenerallyrequirescombinationRx,andlife-longcareandcounseling
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Rat
e of
Liv
e B
irths
PPCOS ITRIAL:CCVS.CC+MET VS.METFORPREGNANCY
Legro et al. N Engl J Med 2007;356:551-66
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CCVS.LETROZOLEASFIRST-LINEOVULATIONINDUCTIONININFERTILEPCOSWOMEN:
APROSPECTIVERCT
Kar. J Hum Reprod Sci. 2012;5:262-5
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Legro et al. N Engl J Med. 2014;371:119-29
PPCOS IITRIAL:CCVS.LETROZOLEFORPREGNANCY
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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
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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?
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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?
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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)
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Ong et al, 2017. Am J Chin Med 2017; 45:405-22
HERBALMEDICINESINPCOS
Berberine
Resveratrol
Paeniflorin
Ginsenosides
Cryptotanshinone
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HERBALMEDICINESINPCOS
Ong et al, 2017. Am J Chin Med 2017; 45:405-22
WenJingTang
Bushen Huatan
TianGui Caps.
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THANKYOU