Clinical Endocrinology. 2018;89:535–553. wileyonlinelibrary.com/journal/cen  | 535© 2018 John Wiley & Sons Ltd

Received:29April2018  |  Revised:25May2018  |  Accepted:28May2018DOI: 10.1111/cen.13753

R E V I E W A R T I C L E

Pharmacological and surgical treatment of nonreproductive outcomes in polycystic ovary syndrome: An overview of systematic reviews

Chau T. Tay1,2  | Anju E. Joham1,2  | Danielle S. Hiam3 | Moustafa A. Gadalla4,5 |  Jyotsna Pundir6,7 | Shakila Thangaratinam7 | Helena J. Teede1,2  | Lisa J. Moran1,4

1MonashCentreforHealthResearchandImplementation,SchoolofPublicHealthandPreventiveMedicine,MonashUniversity,Melbourne,Vic.,Australia2DepartmentofDiabetesandVascularMedicine,MonashHealth,Melbourne, Vic.,Australia3InstituteofHealth,ExerciseandSport,VictoriaUniversity,Melbourne, Vic.,Australia4RobinsonResearchInstitute,DisciplineofObstetricsandGynaecology,UniversityofAdelaide,Adelaide,SA,Australia5DepartmentofObstetricsandGynaecology,Women’sHealthHospital,AssiutUniversity,Assiut,Egypt6CentreofReproductiveMedicine, StBartholomew’sHospital,London,UK7BartsResearchCentreforWomen’sHealth(BARC),BartsandtheLondonSchoolofMedicineandDentistry,QueenMaryUniversityofLondon,London,UK

CorrespondenceChauT.Tay,MonashCentreforHealthResearchandImplementation,SchoolofPublicHealthandPreventiveMedicine,MonashUniversity,Melbourne,Vic.,Australia.Email:jillian.cttay@gmail.com

Funding informationNationalHealthandMedicalResearchCouncil;NationalHeartFoundationofAustralia;CREinPCOSentrylevelscholarship

SummaryBackground: Polycystic ovary syndrome (PCOS) affects up to13%womenand isassociatedwith significant complications. The quality of evidence supporting therecommendationsontreatmentofnonreproductiveoutcomesinPCOSisunknown.Objective: To summarize and appraise the methodological quality of systematicreviewsandmeta-analysesevaluatingpharmacologicalandsurgicaltreatmentsfornonreproductiveoutcomesinPCOS.Methods: A literature search from MEDLINE, EMBASE, CINAHL PLUS andPROSPEROwas performed from inception until 15th of September 2017. Articleselection,dataextractionandqualityappraisalofincludedreviewswereperformedinduplicate.Anarrativesynthesisofthefindingswasconducted.Results:Thisoverviewincluded31reviews.Thequalitywaslowfor7(23%),moder-ateforsixteen(52%)andhighfor8reviews(26%).Tworeviewsassessedpsychologi-caloutcomes.Metforminimprovedanthropometric(7of10reviews),metabolic(4of14reviews)andendocrineoutcomes (3of twelve reviews).Thiazolidinediones im-provedmetabolic (2of5 reviews)andendocrineoutcomes (oneof5 reviews)butworsenedweightgain(5of5reviews).Combinedoralcontraceptivepill(COCP)im-provedclinicalhyperandrogenism(2of2reviews).Statinsimprovedlipidprofile(3of3reviews)andtestosteronelevel(2of3reviews).Therewasnoconclusiveevidencefromincludedsystematicreviewsregardingtheuseofotherinterventions.Conclusions:Thereisreliableevidenceregardingtheuseofmetforminforanthropo-metricoutcomesandCOCPsforhyperandrogenisminwomenwithPCOSbutnotforotherinterventions.ThereissignificantgapinknowledgeregardingthemanagementofpsychologicaloutcomesinwomenwithPCOSwhichneedsfurtherevaluation.

K E Y W O R D S

meta-analysis,overview,polycysticovarysyndrome,systematicreview,treatment

1  | INTRODUC TION

Polycysticovarysyndrome(PCOS)isacommonendocrinopathyaf-fectingupto13%ofreproductive-agedwomen.1PCOSisdiagnosed

basedonthepresenceof2ofthefollowing3reproductivefeatures:menstrualorovulatorydysfunction,clinicalorbiochemicalhyperan-drogenismand/orpolycysticovarianmorphologyonultrasonogra-phywithexclusionofothercausesofhyperandrogenism.2-5Whilst

536  |     TAY eT Al.

theaetiology isnotfullyunderstood, insulinresistanceandhyper-androgenismarethe2keyhormonaldisturbancesthatunderpinthecondition.2,6,7

Polycystic ovary syndromehas a broad rangeof clinicalmani-festationsthatvaryacrossphenotypes,ethnicitiesand lifestages.Youngwomentypicallypresentwithdermatologicalcomplaints(hir-sutism or acne) or reproductive problems (oligo-/amenorrhoea orinfertility).4,8Metabolic features of PCOS include a predispositiontodevelopobesity,metabolicsyndrome,type2diabetes,hyperten-sionandnonalcoholicfatty liverdisease.9-12Psychologically,PCOSincreasestheriskofanxiety,depressionandlowqualityoflife.13-15 Thereare increasedpregnancycomplications includinggestationaldiabetes mellitus, gestational hypertension, preterm labour andpreeclampsiaandalso increased riskofendometrialneoplasia.16,17 ThesenonreproductivefeaturesinPCOScontributetoasignificanthealthandeconomicburden.18

The management of PCOS should encompass treating fertil-ity and nonreproductive outcomes such as reducing clinical symp-toms of hyperandrogenism, improvingmetabolic health, improvingpsychological well-being and preventing long-term health risks.6 Evidence-basedguidelinespublishedbytheAustralianPCOSAllianceandotherprofessionalspecialtysocietypositionstatementsrecom-mend lifestyle interventionsasfirst-linetreatmentforwomenwithPCOS.A5%-10%reductioninbodyweightiseffectiveinimprovinganthropometric, reproductive,metabolicandpsychological aspectsof PCOS.2-5,7,19,20Most guidelines discussed 3main pharmacologi-caltherapycategories,namelyinsulinsensitizers(eg,metforminand thiazolidinediones), anti-androgens (eg, spironolactone, flutamide and cyproterone acetate) and combined oral contraceptive pills(COCP).2-5,7,21,22 Bariatric surgery is also recommended for consider-ationinobesewomenwithPCOSgiventhatitisaneffectivemeansofweightreductionwhichmayimprovetheclinicalfeaturesofPCOS.2-5,7,23

However,thequalityofevidencesupportingtheserecommen-dationsforPCOS-relatednonreproductiveoutcomesisnotknown.Whiletherehasbeenan increasingnumberofsystematicreviewspublishedsummarizingtheevidenceofdifferentpharmacologicalorsurgicaltherapiesonthenonreproductiveoutcomesinPCOS,con-clusionsaredifficulttointerpretduetodiversemethodologiesandqualityofboththesystematicreviewsandtheirincludedstudies.

Theaimofthisstudywastoconductanoverviewofsystematicreviews evaluating pharmacological or surgical therapy for nonre-productiveoutcomes inwomenwithPCOS to summarize and ap-praisetheresultsandmethodologicalquality.

2  | METHODS

2.1 | Protocol and registration

This review was designed and reported in accordance with thePreferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines.24Anaprioristudyprotocolwasreg-isteredwithPROSPERO(CRD42016052649).Ethicsapplicationwasnotrequired.

2.2 | Literature search

TheelectronicdatabasesMEDLINEin-processandothernonindexedcitations(OvidMEDLINE(R)In-Process&OtherNon-IndexedCitations,OvidMEDLINE(R)DailyandOvidMEDLINE(R)1946toPresent),OvidEMBASE(EBMReviews—CochraneDatabaseofSystematicReviews2005to15September2017,EBMReviews—ACPJournalClub1991toSeptember2017,EBMReviews—DatabaseofAbstractsofReviewsofEffects1stQuarter2016,EBMreviews—CochraneCentralRegisterof Controlled Trials September 2017, EBM Reviews—CochraneMethodology Register 3rd quarter 2012, EBM Reviews—HealthTechnology Assessment 4th Quarter 2016, EBM Reviews—NHSEconomicEvaluationDatabase1stQuarter2016)andCINAHLPLUSweresearchedtoidentifyrelevantpublishedarticles.Additionalongo-ingreviewswereidentifiedfromsearchingtheinternationalprospec-tiveregisterofsystematicreviewsPROSPERO(http://www.crd.york.ac.uk/PROSPERO/).Theliteraturesearchwaslastupdatedonthe15th ofSeptember2017.The search termsused included “PCOS,” “poly-cysticovarysyndrome,”“Stein-Leventhal,”“systematic,”“review,”and“meta-analysis”withthecompletesearchstrategyforeachdatabaseprovided inAppendixS1 (found in theSupporting Information).Thesearchstrategywaslimitedtohumanstudiesonly.

2.3 | Eligibility criteria and study collection

Articleswereincludediftheymetthefollowinginclusioncriteria:originalsystematicreviewormeta-analysis;PCOSwastheprimaryfocusofthereviewwitharticlesinwhichPCOSwasasecondaryconditionassessedaspartofabroadertopicexcluded;clearsearchstrategywithatleastkeywordsortermsincluded,documentationofsearchreturnsandperformedqualityappraisaloftheincludedstudies; published in English; and published from year 2009 on-wardsgiventhiswaswhenthePRISMAstatementwaspublishedtoguidereportingofsystematicreviewsandmeta-analyses.24

The outcomes of interestwere anthropometric (weight, bodymass index (BMI), waist-hip ratio, waist circumference or bodycomposition), endocrine (total or free testosterone, sex hormonebinding globulin (SHBG), free androgen index (FAI), dehydroepi-androsteronesulphate(DHEAS),dehydroepiandrosterone(DHEA),androstenedioneorclinicalhyperandrogenism),metabolic(glucoseintolerance, surrogate markers of insulin resistance, lipid profileor blood pressure) and psychological (quality of life, anxiety ordepression).

2.4 | Study selection and data extraction

Identified articles from the literature searchwere screened in atwo-step process. First, the titles and abstracts were screenedforsuitability.Second,allarticlesthatmeettheinclusioncriteriafromthefirststepwereretrievedfordetailedfull-textassessmenttodetermineeligibility.Studyselectionwasperformed indepen-dentlyinduplicateby3investigators(C.T.T,D.S.HandL.J.M)withanydiscrepanciesresolvedbyconsensus.

     |  537TAY eT Al.

Datacollectedfromtheeligiblearticlesincludedauthorship,pub-licationyear,countryofauthors’origin,typesofstudyeligibleforthesystematicreview,dateofliteraturesearch,languagerestriction,ad-herencetoasystematicreviewguideline,presenceofmeta-analysis,the authors’ interpretation of quality assessment of the includedstudies,numberofincludedstudiesandparticipantsinvolvedandtheParticipant,Intervention,Comparison,OutcomesandStudies(PICOS)frameworkofthestudy. If theauthorsdidnot interpretthequalityoftheincludedstudiesnorsummarizetheoverallqualityoftheen-tirestudy,thesectiononqualityassessmentwasbedocumentedas“unclear.”Dataextractionwasconductedindependentlyinduplicate(C.T.T,L.J.MandM.A.G)withanydiscrepanciesresolvedbyconsensusanddiscussionwithathirdinvestigator(D.S.H).

2.5 | Quality assessment (AMSTAR)

The Assessing the Methodological Quality of Systematic Reviews(AMSTAR)toolwasemployedtoappraisethequalityoftheincludedsystematic reviews.25,26 AMSTAR evaluates the methodological as-pectsof systematic reviewsusing11 items: (i) theprovisionofanaprioridesign,(ii)duplicationofstudyselectionanddataextraction,(iii)conductionofacomprehensiveliteraturesearch,(iv)inclusionofgreyliteratureinthereview,(v)availabilityofalistoftheincludedandex-cludedstudies, (vi)descriptionof thecharacteristicsof the includedstudies, (vii) clear documentation of the scientific quality of the in-cluded studies, (viii) considerationof the scientificqualityof the in-cludedstudiesinformulatingconclusions,(ix)appropriateanalysisofresultsdependingonheterogeneity,(x)assessmentofpublicationbiasand(xi)considerationofconflictofinterestofboththesystematicre-viewandtheincludedstudies.26Eachitemwasgiven1pointifitwasdeterminedas“yes”and0point if itwasdeterminedas“no”or“notapplicable.”The reviewswerecategorizedas lowquality if the totalAMSTARscorewas≤3,moderatequality ifthetotalAMSTARscorewasbetween4to7,andhighqualityifthetotalAMSTARscorewas≥8.

Qualityassessmentofalleligiblesystematic reviewswascon-ductedindependentlyinduplicate(C.T.T,L.J.MandM.A.G)withanydisagreements resolvedby consensusanddiscussionwitha thirdinvestigator(D.S.H).

2.6 | Data synthesis

Anarrativesynthesisoffindingsfromtheincludedreviewswasper-formed.Resultswerepresentedaccordingtothedifferenttypesofintervention.Statisticallysignificantoutcomesofinterestwerepre-sentedifameta-analysiswasperformedbythereview.

3  | RESULTS

3.1 | Literature search

The electronic database search retrieved 978 articles, and an addi-tional60wereidentifiedfromPROSPERO.Afterremovingthedupli-cates,831articlesremainedforscreening.Atotalof564articleswere

excluded after reviewing the title and abstract leaving 267 articlesavailableforfull-textevaluation.Atotalof140articleswereeligibleforanalysisofwhich33wererelatedtotreatmentofnonreproductiveoutcomes.Ofthese,2articleswereapriorversionofasystematicre-view,andtherefore,weonlyincludedthemostrecentpublications.27,28 Finally,31systematicreviewswereincludedinthisstudy.ThePRISMAflowdiagramis illustrated inFigure1.The listofexcludedarticles isavailableinAppendixS2(foundintheSupportingInformation).

3.2 | Study characteristics

ThestudycharacteristicsandPICOframeworkoftheincludedsys-tematicreviewsaresummarizedinTable1.ThecountryoforiginoftheauthorsincludedChina(n=11),29-39Australia(n=6),40-45UnitedKingdom (n=5),43,45-48 the United States of America (n=4),49-52 India (n=3),44,52,53 Canada (n=3),50,54,55 Brazil (n=2),41,56 Iran (n=2),40,54Columbia(n=1),46Greece(n=1),57Italy(n=1),57Spain(n=1),58Scotland(n=1),59Luton(n=1),48Netherlands(n=1)41 and Saudi Arabia (n=1).46 Thirteen reviews explicitly included rand-omizedcontroltrials(RCTs)only29-32,34,36,38,42,43,46,53,57,59;5reviewsincluded RCTs and phase-1 data of cross-over trials39,41,44,45,52; 2 reviews included RCTs and prospective trials50,56; 2 reviews in-cluded RCTs and observational studies49,58; 1 review included RCTs, comparative studies and case series with >5 patients55; 2 reviews includedallclinical trials40,54;3 reviews includedall studytypes35,48,51;and3reviewsdidnotstateaninclusioncriteriaforthestudytype.33,37,47Fifteenreviewsdidnotsetalanguagerestrictionin their literature search30,31,39-41,43-46,49,50,52,56-58; 11 reviews re-strictedtheirsearchtoEnglishpublicationsonly32,34-38,42,51,53,55,59; 1reviewrestricteditslanguagetoEnglishandPersian54; 1 review re-stricteditslanguagetoEnglishandChinese33;and3reviewsdidnotstateifanylanguagerestrictionwasapplied.29,47,48Twelvereviewsreportedfollowingaguidelineongoodpracticeinconductingsys-tematic reviews30,31,35,39,41,44-47,53,57,58; 25 reviews included meta-analyses29-38,41-47,49-53,55-57; and18 reviewsdidnotprovideaclearstatementastotheoverallqualityassessmentoftheincludedarti-cles.31,33,34,36,37,41-44,47,51-58Thenumberofstudiesincludedineachsystematic review ranged from1 to35, and the total participantsrangedfrom16to3992.Eighteen(58%)ofthesystematicreviewshadlessthan10studiesincludedintotal.29-32,36,38-42,44,46-48,52,56,57,59

3.3 | Methodological quality of systematic reviews

TheAMSTARscoresoftheincludedsystematicreviewsareprovidedinAppendixS3(foundintheSupportingInformation).Majorityoftheincludedsystematicreviewswereoflow(n=7;23%)42,47,48,54,55,58,59 to moderate quality (n=16; 52%)29-34,36,37,39,40,43,49-51,53,56 withonly8gradedhighquality (n=8;26%).35,39,41,44-46,52,57Commonlyunreported itemswereconsiderationof conflictof interestof theincludedstudies(n=28;90%),presenceofanaprioristudydesign(n=23; 74%), a list of the excluded articles (n=23; 74%), inclu-sionofgrey literature (n=22;71%),duplicationofstudyselectionor data extraction (n=21; 68%), formulation of study conclusion

538  |     TAY eT Al.

basedonthescientificqualityoftheincludedstudies(n=18;58%)andconductionofacomprehensiveliteraturesearch(n=18;58%).Assessmentofpublicationbiaswasnotappropriatelyperformedin9 reviews (29%),documentationof thescientificqualityof the in-cluded studieswasunsatisfactory in6 reviews (19%), andhetero-geneitywasnot taken intoaccountby2 reviews (6%).All reviewsreportedthestudycharacteristicsoftheincludedstudies.

3.4 | Types of intervention

The typesof treatments assessedweremetformin, thiazolidinedi-one,oralcontraceptivepills(OCP),anti-androgens,statins,orlistat,bariatric surgery and antidepressants. Nonconventional therapiessuchasvitaminD,inositol,N-acetyl-cysteineandantioxidantswerealsoincludedinthisreview.

3.4.1 | Insulin sensitizer: metformin

Sixteen reviews evaluated the efficacy of metformin(Table2).29,30,32,34-36,38,41,43,45,46,49,53,56,57,59 Five were rated highquality,10wereratedmoderatequality,and1wasratedlowquality.

A total of 174 trials and10525 adolescent and adult participantswere involved.

Anthropometricoutcomeswereassessedby10reviews.Sevenreviews (n=3 comparing metformin vs thiazolidinediones,29,30,34 n=2 comparing metformin vs placebo,45,53 n=1 comparing met-forminvsCOCPs46andn=1comparingcombinationtherapywithmetformin and clomiphene citrate vs clomiphene citrate alone)59 reportedresultsfavouringmetforminintermsofBMIand/orwaist-hipratio.Therewasnosignificantdifferenceinanthropometricout-comeswhenmetforminwascompared toacarbose38ororlistat,56 orwhencombinationtherapywithmetforminandstatinwascom-pared to metformin alone.36 Endocrine outcomes were assessedby 12 reviews. Three reviews (n=2 comparingmetformin vs pla-cebo45,53 and n=1 comparing metformin and clomiphene citratevsclomiphenecitratealone59) reportedreductions intestosteronewhenusingmetformin.Therewasno significantdifference in en-docrine outcomes whenmetformin was compared to acarbose,38 OCP,46vitaminD,32,57thiazolidinediones,29,30,34orlistat,56inositol43 or combination therapy with statin.36 Metabolic outcomes wereassessed by 14 reviews with 4 reviews reporting beneficial out-comes favouringmetformin for theprevalenceof type2diabetes

F IGURE  1 Studyselectionprocess

     |  539TAY eT Al.

mellitusorprediabetes(n=1comparingmetforminvsOCP),46totalcholesterol and low-density lipoprotein (LDL) (n=1 comparingmetformin vsOCP),46 blood pressure (n=2 comparingmetforminvs placebo),45,53 triglycerides (n=1 comparing metformin vs pla-cebo,53n=1comparingmetforminvsthiazolidinediones),34glucose(n=1comparingmetforminvsplacebo),45 insulin (n=1comparingmetforminvsplacebo)45andglucose/insulinratio(n=1comparingmetformin vs placebo).53No significantmetabolic outcomesweredetected when comparing metformin to vitamin D,32,57 orlistat,56 inositol,43 acarbose38 orwith the additionofmetformin to folliclestimulatinghormone (FSH)-containinggonadotrophinovulation in-ductionorclomiphenecitrate.59Psychologicaloutcomeswerenotassessedbyanyoftheabovereviews.

3.4.2 | Insulin sensitizer: thiazolidinediones

Fivereviews29-31,34,45evaluatedtheefficacyofthiazolidinedionesinwhichonewashighqualityand4weremoderatequality(Table2).Atotalof74trialsand5282participantswithPCOSwereinvolved.All5reviewsassessedtheanthropometric,endocrineandmetabolicout-comesofthiazolidinediones(n=3comparedwithmetformin,29,30,34 n=2comparedwithplacebo).31,45BMIwassignificantlyincreasedwith thiazolidinediones in all 5 reviews while endocrine benefits(reducedfreetestosterone)werereportedinonereviewwhencom-paredtometformin.34Formetabolicoutcomes,onereviewshowedimprovedfastingglucoseandinsulinincomparisonwithplacebo,31 one review showed improved fasting insulin and homoeostaticmodelassessmentofinsulinresistance(HOMA-IR)whencomparedto metformin,30 and one review showed worsened triglycerideswhencomparedtometformin.34Psychologicaloutcomeswerenotassessedbyanyoftheabovereviews.

3.4.3 | Insulin sensitizer: inositol

Three reviews43,45,48 evaluated the efficacy of inositol (Table2).The reviewswereof low (n=1),moderate (n=1)andhigh (n=1)quality.Atotalof62trialswith5072womenwithPCOSwerein-volved. In all 3 reviews, inositol was compared against placebo.Anthropometric outcomes were reported by 2 reviews with onereview reporting reduced BMI and waist-hip ratio.48 Endocrineoutcomeswereassessedbyall3reviewswith2ofthesereportingbenefits(testosterone,DHEASorandrostenedione).43,48Metabolicoutcomeswerealsoassessedbyall3reviewswith2reviewsreport-ingreducedinsulin,43,48onereviewreportingreducedglucoseandHOMA-IR,43 and one review reporting improved blood pressure,triglycerides and high-density lipoprotein (HDL).48 Psychologicaloutcomeswerenotassessedbyanyoftheabovereviews.

3.4.4 | Hormonal therapy: combined oral contraceptive pill

The efficacy of COCPs was assessed by 4 reviews46,49,50,58 (Table3) of low to high quality (n=1 high, n=2moderate, and

n=1 low). Results from88 trials involving3722 adolescent andadult women with PCOS were analysed. Anthropometric out-comes were reported by one review with COCP being associ-atedwitha lesserreductionofBMIcomparedwithmetformin.46 Endocrineoutcomeswereassessedby2reviewswithonereport-ing greater acne reduction when compared to metformin46 and one review reporting general improvement in clinical hyperan-drogenismwhenusingCOCPasmonotherapyor in combinationwithmetformin.58 Two reviews assessedmetabolic outcomesofwhichonereviewreportedthatCOCPusewaslesseffectivethanmetformininreducingtheprevalenceofdysglycaemia,totalcho-lesterolandLDL,46andonereviewreportedthatCOCPusewasassociatedwith increasedHDL and triglycerides comparedwithbaseline.50Psychologicaloutcomeswerenotassessedbyanyoftheabovereviews.

3.4.5 | Hormonal therapy: anti- androgens

Onehigh-qualityreviewevaluatedthesideeffectsofanti-androgensandtheirefficacyonmetabolicoutcomes(Table3).49Nosignificanteffectsonmetabolicoutcomeswerereported.

3.4.6 | Weight loss therapy: orlistat

Orlistatwasevaluatedbyonemoderatequalityreviewincompari-sonwithplacebo,metforminorotheranti-obesitydrugs56(Table4)where9trialsand602adolescentandadultwomenwithPCOSwereinvolved.Meta-analysisofthestudiescomparingorlistattoplacebowasnotpossiblebutthesystematicreviewreportedimprovementsin anthropometric (BMI, weight, waist circumference or waist-hipratio), endocrine (testosterone) andmetabolicoutcomes (triglycer-ides,HDL,LDL,HOMA-IRandinsulin).Meta-analysisofthestudiescomparingorlistattometforminshowednosignificantdifferences.56 Psychologicaloutcomeswerenotassessedbytheabovereview.

3.4.7 | Weight loss therapy: bariatric surgery

TheeffectofbariatricsurgeryinwomenwithPCOSwasevaluatedin 2 low-quality reviews47,55 (Table4). They involved 19 trials and2394participantswithandwithoutPCOS.Bothreviewscomparedthesamegroupofwomenbeforeandafterbariatricsurgery.Bothreviewsassessedanthropometricandendocrineoutcomesandre-portedreductionsinBMI,percentageofexcessweightlossandhir-sutism.47,55Metabolicoutcomeswereassessedbyonereviewandshowedreductionsinbloodpressure,improvementindyslipidaemia,normalizationofglucose levels, improvementofglycaemiccontrolandresolutionoftype2diabetesmellitus.47Psychologicaloutcomeswereassessedbyonereviewandreportedbenefitsindepression.47

3.4.8 | Other therapy: statins

Three reviews evaluated the efficacy of statins36,42,44 (AppendixS3, found in the Supporting Information) with rating of one low,

540  |     TAY eT Al.

TABLE 1 Studycharacteristics

Aut

hor (

y)Co

untr

yIn

clud

ed s

tudy

type

Dat

e of

last

lit

erat

ure

sear

chLa

ngua

ge

Syst

emat

ic

revi

ew

guid

elin

e fo

llow

ed

Met

a-

anal

ysis

pe

rfor

med

Num

ber o

f in

clud

ed

pape

rs

Tota

l num

ber

of in

clud

ed

part

icip

ants

Popu

latio

n an

d PC

OS

diag

nost

ic c

riter

ia

AlKhalifahetal

(2016)

46Canada,Saudi

Arabia,Columbia,

UnitedKingdom

RCTs

15-Jan

All

Yes

Yes

417

0Adolescents(11-19y)

ESHRE/ASRM

Aminietal(2015)54

Iran

Experimentalor

quasiexperimental

trials

13-Nov

English,

Persian

No

No

1183

4Ir

ania

n ESHRE/ASRM

Azadi-Yazdietal

(2017)

40Iran,Australia

Clinicaltrials

17-Jan

All

No

No

618

3Diagnosticcriterianotstated

Bordewijketal

(2017)

41Netherlands,

Australia,Brazil

RCTsandphase1of

cross-overtrials

16-Sep

All

Yes

Yes

526

4Anovulatorywomen

undergoingovulationinduction

withFSHESHRE/ASRM

Butterworthetal

(2016)

47UnitedKingdom

Notstated

15-Mar

Notstated

Yes

Yes

626

4ESHRE/ASRM

Domecqetal

(2013)

49UnitedStates

RCTsandcomparative

observationalstudies

11-Apr

All

No

Yes

2213

35Diagnosticcriterianotstated

Duetal(2012)31

China

RCTs

12-Jun

All

Yes

Yes

828

6ESHRE/ASRM

Duetal(2012)29

China

RCTs

12-Feb

Notstated

No

Yes

626

7ESHRE/ASRM

Duetal(2012)30

China

RCTs

11-Nov

All

Yes

Yes

627

8ESHRE/ASRM

Fangetal(2017)32

China

RCTs

15-Dec

English

No

Yes

950

2ESHRE/ASRM

Galazisetal

(2011)

48UnitedKingdom,

Luton

Allstudytypes

10-Jul

Notstated

No

No

847

9Diagnosticcriterianotstated

Gaoetal(2012)42

Australia

RCTs

11-Sep

English

No

Yes

425

4Diagnosticcriterianotstated

Gilletal(2014)59

Scotland

RCTs

13-May

English

No

No

412

9Clomipheneresistantwomen

Diagnosticcriterianotstated

Graffetal(2016)56

Brazil

RCTsandprospective

studies

15-May

All

No

Yes

960

2Withoutpre-existingdiabetes,

13-44y

ESHRE/ASRM

Halperinetal

(2011)

50Canada,United

States

RCTsandprospective

cohorts

10-Apr

All

No

Yes

3579

8Withoutpre-existingdiabetes,

13-44y

ESHRE/ASRM

Heetal(2015)51

UnitedStates

Allstudytypes

15-Jan

English

No

Yes

30 (7regarding

intervention)

3182

(2

83

includedfor

intervention)

ESHRE/ASRM

Jiaetal(2015)33

China

Notstated

14-Sep

English,

Chinese

No

Yes

1723

97ESHRE/ASRM

     |  541TAY eT Al.

Aut

hor (

y)Co

untr

yIn

clud

ed s

tudy

type

Dat

e of

last

lit

erat

ure

sear

chLa

ngua

ge

Syst

emat

ic

revi

ew

guid

elin

e fo

llow

ed

Met

a-

anal

ysis

pe

rfor

med

Num

ber o

f in

clud

ed

pape

rs

Tota

l num

ber

of in

clud

ed

part

icip

ants

Popu

latio

n an

d PC

OS

diag

nost

ic c

riter

ia

Lietal(2011)34

China

Parallel-group

designedRCTs

10-May

English

No

Yes

1045

9Diagnosticcriterianotstated

Mendozaetal

(2014)

58Spain,Italy

RCTs,nonrandomized

studiesand

noncontrolled

studies

13-Oct

All

Yes

No

2715

89Diagnosticcriterianotstated

Mengetal(2016)35

China

Allstudytypes

15-Dec

English

Yes

Yes

34 (7regarding

interven-

tion)

3117

(1

41

includedfor

intervention)

ESHRE/ASRM

Pateletal(2017)53

Indi

aRCTs

16-May-

English

Yes

Yes

1459

316-45y(excludepregnancyor

clomipheneresistant)

Diagnosticcriterianotstated

Pergialiotisetal

(2017)

57Greece

RCTs

16-Sep

All

Yes

Yes

964

7Diagnosticcriterianotstated

Pundiretal(2017)43

UnitedKingdom,

Australia

RCTs

16-Aug-

All

No

Yes

1060

1Diagnosticcriterianotstated

Ravaletal(2011)44

India,Australia

RCTsandphase1of

cross-overtrials

11-Jul

All

Yes

Yes

424

4ESHRE/ASRM

Skublenyetal

(2016)

55Canada

RCTs,comparison

studies,andcase

series>5patients

Notstated

English

No

Yes

1321

30WomenwithorwithoutPCOS

Diagnosticcriterianotstated

Sunetal(2015)36

China

RCTs(excludingtrails

comparingstatins

withOCPorother

statins)

14-Oct

English

No

Yes

928

2Diagnosticcriterianotstated

Tangetal(2012)45

UnitedKingdom,

Australia

RCTsandphase1of

cross-overtrials

11-Oct

All

Yes

Yes

4439

92Oligo-oranovulatory

ESHRE/ASRM

Thakkeretal

(2015)

52India,UnitedStates

RCTsandphase1of

cross-overtrials

13-Sep

All

No

Yes

891

0ESHRE/ASRM

Xueetal(2017)37

China

Notstated

16-Apr

English

No

Yes

1685

5ESHRE/ASRM

Zhangetal(2014)38

China

RCTs

13-Sep

English

No

Yes

626

3ESHRE/ASRM

Zhuangetal

(2013)

39China

RCTsandphase1of

cross-overtrials

12-Jun

All

Yes

No

116

ESHRE/ASRM

RCT,randomizedcontroltrials;ESHRE,EuropeanSocietyofHumanReproductionandEmbryology;ASRM,AmericanSocietyforReproductive

Medicine;OCP,oralcontraceptivepill.

542  |     TAY eT Al.

TABLE 2 Resultsofsystematicreviewsregardinginsulinsensitizers

Revi

ews

AM

STA

RQ

ualit

y of

in

clud

ed s

tudi

esO

utco

mes

ass

esse

dCo

mpa

rison

Sign

ifica

nt re

sults

Metformin

AlKhalifahetal

(2016)

46High

Verylowtolow

Anthropometric

BMI

MetforminvsOCP

Anthropometric

BMI(WMD−4.02,95%CI−5.23to−2.81)

Reproductive

Hirsutism,acne,

testosterone

Reproductive

Acnescores(W

MD0.3,95%0.05to0.55)

a

Metabolic

Dysglycaemia,

cholesterol,TG,

HDL,LDL

Metabolic

Dysglycaemia(riskratio0.41,95%CI0.19to

0.86)

Cholesterol(W

MD−43.23,95%CI−64.15to

−22.32)

LDL(WMD−35.5,95%CI−57.45to−13.33)

Psychologic

–N

A

Bordewijketal

(2017)

41High

Unclear

Anthropometric

–Metformin+

ovulation

inductionvs

ovulation

induction

Reproductive

–

Metabolic

Insulin,glucose

Psychologic

–

Mengetal

(2016)

35High

RCTs:lowto

moderateriskof

bias;observa-

tionalstudies:

highriskofbias

Anthropometric

–Metforminvsno

treatment

NA

Reproductive

–

Metabolic

–

Psychologic

–

Pergialiotisetal

(2017)

57High

Unclear

Anthropometric

–Metformin±vitD

vsvitaminD

NA

Reproductive

DHEAS,SHBG

Metabolic

Glucose,insulin

Psychologic

–

Tangetal

(2012)

45High

Verylowtolow

Anthropometric

BMI,waist-hipratio

Metforminvs

plac

ebo

Anthropometric

Waist-hipratio(MD−0.01,95%CI−0.01to

0.00)

Reproductive

Testosterone,SHBG

Reproductive

Totaltestosterone(MD−0.60,95%CI−0.73to

−0.48)

Metabolic

BP,glucose,insulin,

cholesterol,TG

Metabolic

SystolicBP(MD−3.59,95%CI−5.13to−2.04)

Glucose(MD−0.15,95%CI0.25to−0.06)

Insulin(MD−3.51,95%CI−6.50to0.53)

Psychologic

–

Domecqetal

(2013)

49Moderate

RCTs:lowto

moderateriskof

bias;observa-

tionalstudies:

highriskofbias

Anthropometric

–Metformin(no

comparators)

NA

Reproductive

–

Metabolic

–

Psychologic

–

(Con

tinue

s)

     |  543TAY eT Al.

Revi

ews

AM

STA

RQ

ualit

y of

in

clud

ed s

tudi

esO

utco

mes

ass

esse

dCo

mpa

rison

Sign

ifica

nt re

sults

Duetal(2012)29

Moderate

High

Anthropometric

BMI

Metforminvs

thiazolidinediones

Anthropometric

BMI(SMD−0.4,95%CI0.16to0.65)

Reproductive

Testosterone

Metabolic

Glucose,HOMA-IR

Psychologic

–

Duetal(2012)30

Moderate

Verylowtolow

Anthropometric

BMI

Metforminvs

pioglitazone

Anthropometric

BMI(SMD−0.25,95%CI0.01to0.49)

Reproductive

Testosterone,hirsutism

Metabolic

Insulin(SMD0.37,95%CI−0.61to−0.13)a

HOMA-IR(SMD0.32,95%CI−0.57to−0.06)a

Metabolic

Glucose,insulin,

HOMA-IR

Psychologic

–

Fangetal

(2017)

32Moderate

Lowtomoderate

riskofbias

Anthropometric

–Metforminvs

vitaminD

NA

Reproductive

–

Metabolic

Cholesterol,TG,HDL,

LDL,insulin,glucose,

QUICKI,HOMA-IR

Psychologic

–

Graffetal

(2016)

56Moderate

Unclear

Anthropometric

BMI,weight,waist

circumference

Metforminvs

orlistat

NA

Reproductive

Testosterone

Metabolic

Insulin,HOMA-IR,

cholesterol,TG,HDL,

LDL

Psychologic

–

Lietal(2011)34

Moderate

Unclear

Anthropometric

BMI

Metforminvs

thiazolidinediones

Anthropometric

BMIat3-mo(SMD−2.47,95%CI−3.33to−1.62)

BMIat6-mo(SMD−0.70,95%CI−0.76to

−0.65)

Reproductive

Hirsutism,androsten-

edione,testosterone,

DHEA

Reproductive

Freetestosterone(SMD0.36,95%CI−0.03to

−0.69)

a

Metabolic

Glucose,insulin,

HOMA-IR,HDL,LDL,

TG

Metabolic

TGat6-mo(SMD−1.13,95%CI−1.68to−0.57)

Psychologic

–

TABLE 2 (Continued)

(Con

tinue

s)

544  |     TAY eT Al.

Revi

ews

AM

STA

RQ

ualit

y of

in

clud

ed s

tudi

esO

utco

mes

ass

esse

dCo

mpa

rison

Sign

ifica

nt re

sults

Pateletal

(2017)

53Moderate

Unclear

Anthropometric

BMI,waist-hipratio

Metforminvs

plac

ebo

Anthropometric

BMI(MD−1.18,95%CI−2.0to−0.36)

WHR(MD−0.02,95%CI−0.03to0.00)

Reproductive

Hirsutism,testosterone,

freetestosterone,

FAI,SHBG,DHEAS

Reproductive

Testosterone(MD−14.32,95%CI−26.80to

−1.85)

Metabolic

Bloodpressure,

cholesterol,TG,HDL,

LDL,

glucose,insulin,

glucose/insulinratio,

HOMA-IR,

QUICKI

Metabolic

SystolicBP(MD−4.92,95%CI−7.51to−2.33)

DiastolicBP(MD−1.51,95%CI−2.23to−0.79)

TG(MD−10.74,95%CI−17.93to−3.56)

Glucose/insulinratio(MD2.28,95%CI1.16to

3.41)

Psychologic

–

Pundiretal

(2017)

43Moderate

Unclear

Anthropometric

–Metforminvs

inositol

NA

Reproductive

Androstenedione,

testosterone,DHEAS,

SHBG

Metabolic

Insulin,glucose,

glucose/insulinratio,

HOMA-IR

Psychologic

–

Sunetal(2015)36

Moderate

Unclear

Anthropometric

BMI

Metformin+statin

vsmetformin

Metabolic

Totalcholesterol(SMD−1.28,95%CI−1.59to

−0.97)

LDL(SMD−0.74,95%CI−1.03to−0.44)

TG(SMD−1.37,95%CI−2.46to−0.28)

Reproductive

Testosterone,andros-

tenedione,DHEAS,

SHBG,FAI

Metabolic

Cholesterol,LDL,HDL,

TG,glucose,insulin,

HOMA-IR

Psychologic

–

Zhangetal

(2014)

38Moderate

Poor

Anthropometric

BMI

Metforminvs

acarbose

NA

Reproductive

Hirsutism,testosterone

Metabolic

TG,HDL

Psychologic

–

TABLE 2 (Continued)

(Con

tinue

s)

     |  545TAY eT Al.

Revi

ews

AM

STA

RQ

ualit

y of

in

clud

ed s

tudi

esO

utco

mes

ass

esse

dCo

mpa

rison

Sign

ifica

nt re

sults

Gilletal(2014)59

Low

3high,1low

Anthropometric

BMI

Metformin+

clomiphenevs

clomiphene

Anthropometric

2trials:BMIwasdecreased

Reproductive

SHBG,testosterone

Reproductive

2trials:testosteronewasdecreased

Metabolic

Insulin

Psychologic

–

Thiazolidinediones

Tangetal

(2012)

45High

Verylowtolow

Anthropometric

BMI,waist,hipratio

Rosiglitazonevs

plac

ebo

Anthropometric

BMI(MD+0.68,95%CI0.40to0.96)

Reproductive

Testosterone,SHBG

Pioglitazonevs

plac

ebo

NA

Metabolic

BP,glucose,insulin,

cholesterol,TG

Psychologic

–

Duetal(2012)31

Moderate

Unclear

Anthropometric

BMI

Thiazolidinediones

vsplacebo

Anthropometric

BMI(SMD+0.39,95%CI0.13to0.66)

Reproductive

Hirsutism,testosterone

Metabolic

Insulin(SMD−0.81,95%CI−1.5to−0.12)

Glucose(SMD−0.55,95%CI−1.06to−0.05)

Metabolic

Glucose,insulin

Psychologic

–

Duetal(2012)30

Moderate

Verylowtolow

Anthropometric

BMI

Pioglitazonevs

metformin

Anthropometric

BMI(SMD0.25,95%CI0.01to0.49)

a

Reproductive

Hirsutism,testosterone

Metabolic

Insulin(SMD−0.37,95%CI−0.61to−0.13)

HOMA-IR(SMD−0.32,95%CI−0.57to−0.06)

Metabolic

Glucose,insulin,

HOMA-IR

Psychologic

–

Duetal(2012)29

Moderate

High

Anthropometric

BMI

Thiazolidinediones

vsmetformin

Anthropometric

BMI(SMD0.4,95%CI0.16to0.65)

a

Reproductive

Testosterone

Metabolic

Glucose,HOMA-IR

Psychologic

–

TABLE 2 (Continued)

(Con

tinue

s)

546  |     TAY eT Al.

Revi

ews

AM

STA

RQ

ualit

y of

in

clud

ed s

tudi

esO

utco

mes

ass

esse

dCo

mpa

rison

Sign

ifica

nt re

sults

Lietal(2011)34

Moderate

Unclear

Anthropometric

BMI

Thiazolidinediones

vsmetformin

Anthropometric

BMIat3-mo(SMD2.47,95%CI−3.33to−1.62)a

BMIat6-mo(SMD0.70,95%CI−0.76to−0.65)a

Reproductive

Hirsutism,androsten-

edione,testosterone,

DHEA

Reproductive

Freetestosterone(SMD−0.36,95%CI−0.03to

−0.69)

Metabolic

Glucose,insulin,

HOMA-IR,cholesterol,

TG,HDL,LDL

Reproductive

TGat6-mo(SMD1.13,95%CI−1.68to−0.57)a

Psychologic

–

Inositol

Tangetal

(2012)

45High

Verylowtolow

Anthropometric

BMI,waist,hipratio

D-chiro-inositolvs

plac

ebo

NA

Reproductive

Testosterone,SHBG

Metabolic

BP,glucose,insulin,

cholesterol,TG

Psychologic

–

Pundiretal

(2017)

43Moderate

Unclear

Anthropometric

–Inositol(myo-or

di-chiroisomers)

vsplacebo

Reproductive

Androstenedione(SMD−1.6,95%CI−2.3to

−0.6)

Totaltestosterone(SMD−3.3,95%CI−5.1to

−1.5)

DHEAS(SMD−3.2,95%CI−5.7to−0.6)

Reproductive

Androstenedione,

testosterone,DHEAS,

SHBG

Metabolic

Insulin(SMD−2.1,95%CI−3.2to−0.9)

Glucose(SMD−1.0,95%CI−1.7to−0.2)

HOMA-IR(SMD−1.8,95%CI−2.6to−1.0)

InsulinAUC(SMD−1.6,95%CI−2.8to−0.4)

Glucose/insulinratio(SMD2.9,95%CI2.2to

3.6)

Metabolic

Insulin,glucose,

glucose/insulinratio,

HOMA-IR

Psychologic

–

Galazisetal

(2011)

48Low

4low,4high

Anthropometric

Notspecified

D-chiro-inositolvs

plac

ebo

Anthropometric

2trials:improvedBMI,waist-hipratio

Reproductive

Reproductivesteroids

Reproductive

3trials:reducedtestosterone

Metabolic

BP,cholesterol,insulin

sensitivity

Metabolic

3trials:reducedinsulin,BP,TG

Psychologic

–1trial:increasedHDL

NA,notavailable;MD,meandifference;WMD,weightedmeandifference;SMD,standardizedmeandifference;CI,confidenceinterval;BMI,bodymassindex;SHBG,sexhormonebindingglobulin;FAI,

freeandrogenindex;DHEA,dehydroepiandrosterone;DHEAS,dehydroepiandrosteronesulphate;BP,bloodpressure;HDL,high-densitylipoprotein;LDL,low-densitylipoprotein;TG,triglycerides;

HOMA-IR,homoeostaticmodelassessmentofinsulinresistance;QUIKI,quantitativeinsulinsensitivitycheckindex;AUC,areaunderthecurve;OCP,oralcontraceptivepill.

a Resultslessbeneficialthancomparator.

TABLE 2 (Continued)

     |  547TAY eT Al.

TABLE 3 Resultsofsystematicreviewsregardinghormonaltherapies

Revi

ews

AM

STA

RQ

ualit

y of

in

clud

ed s

tudi

esO

utco

mes

ass

esse

dCo

mpa

rison

Sign

ifica

nt re

sults

Oralcontraceptivepills

AlKhalifahetal

(2016)

46High

Verylowtolow

Anthropometric

BMI

OCPvs

metformin

Anthropometric

BMI(WMD4.02,95%CI−5.23

 to−2.81)

a

Reproductive

Hirsutism,acne,testosterone

Reproductive

Acnescores(W

MD−0.3,95%

 0.05to0.55)

Metabolic

Dysglycaemia,cholesterol,TG,HDL,

LDL

Metabolic

Dysglycaemia(riskratio0.41,

 95%CI0.19to0.86)

a

Cholesterol(W

MD43.23,

 95%CI−64.15to−22.32)

a

LDL(WMD35.5,95%CI−57.45

 to−13.33)a

Psychologic

–

Domecqetal(2013)49

Moderate

RCTs:lowto

moderaterisk

ofbias;

observational

studies:high

riskofbias

Anthropometric

Weight,BM

IOCP(no

com

para-

tor)

NA

Reproductive

–

Metabolic

Fastingglucose,postprandialglucose,

glucosetolerancetest,random

glucose,areaunderthecurveof

glucose,glucose/insulinratio,

HOMA-IR,QUICKI

Psychologic

–

Halperinetal(2011)50

Moderate

17high,9

moderate,16

low

Anthropometric

–Pre-vs

post-OCP

Metabolic

HDL(SMD0.46,95%CI0.14to

0.78)

TG(SMD0.55,95%CI0.17to

0.93)

Reproductive

–

Metabolic

Insulin,glucose,cholesterol,TG,HDL,

LDL,hyperinsulinemiceuglycaemic

clamp(m-value),glucose/insulinratio,

HOMA-IR

Psychologic

–

Mendozaetal

(2014)

58Low

Unclear

Anthropometric

BMI,weight

OCP±

metformin/

anti-

androgen

(no

clea

r co

mpa

ra-

tor)

Reproductive

Relievedhyperandrogenismafter

6 m

o

Reproductive

Hirsutism,acne,seborrhoea,testoster-

one,DHEAS,SHBG,FAI,

androstenedione

Metabolic

Combinationwithmetformin

moreeffectiveinreducingIR

Metabolic

BP,cholesterol,TG,HDL,LDL,glucose,

insulin,HOMA-IR

Psychologic

–

(Con

tinue

s)

548  |     TAY eT Al.

onemoderateandonehighquality.Resultswerederived from17trials and 780 participantswith PCOS. Statinswere evaluated ei-therasastandalone therapycomparedtoplaceboorascombina-tiontherapywithmetformincomparedtometformin.All3reviewsreported improvements inmetabolic outcomes (n=3 for the lipidprofile36,42,44 and n=1 for insulin),42 and 2 reviews reported im-provementinendocrineoutcomes(testosterone).42,44Theeffectsofstatinsonanthropometricoutcomeswerenotsignificant(n=2).36,44 Psychologicaloutcomeswerenotassessedbyanyofthereviews.

3.4.9 | Other therapy: vitamin D

Seven reviews evaluated vitamin D32,33,37,40,51,54,57 (Appendix S3,foundintheSupportingInformation)eitherasmonotherapyvspla-ceboormetformin,ascombinationtherapywithmetforminvsmet-forminorcomparingtheeffectsofbeforeandaftervitaminD.Onlyonereviewhadahighratingwhilethemajorityofthereviews(n=5)wereofmoderatequality,andonereviewwasoflowquality.Atotalof75trialsand5701participantswomenwithPCOSwereinvolved.

Five reviewsassessedendocrineoutcomeswith2 reviewsre-portingbenefitsDHEAS(n=1comparingvitaminDvsplaceboandvitaminDwithmetformin vsmetformin)57 or testosterone (n=1comparingvitaminDvsplacebo).40Metabolicoutcomeswereas-sessedby6reviewswith4reviewsreportedbenefitsasreductionsinHOMA-IR(n=1comparingvitaminDvsplaceboorcombinationtherapyvsmetformin),57totalcholesterol(n=1comparingvitaminDvsplacebo)57or triglycerides (n=2comparingbeforeandaftervitaminD).37,51One review reported significant improvements inblood pressure for vitamin D vs placebo.54 Anthropometric out-comeswereassessedbyonereviewwhichdidnotshowanysignif-icantresults.54Psychologicaloutcomeswerenotassessedbyanyofthereviews.

3.4.10 | Other therapy: N- acetyl- cysteine

Two reviews52,54 evaluated the efficacy of N-acetyl-cysteine ofwhichone reviewwasof highquality andone reviewwasof lowquality(AppendixS3,foundintheSupportingInformation).Atotalof19trialswith1744participantswithPCOSwereinvolved.Bothreviewsassessedanthropometric,endocrineandmetaboliceffectsof N-acetyl-cysteine in comparison with placebo or metformin.One review reported improvements in anthropometric anthropol-ogy (reducedBMI,weight andwaist-hip ratio) andmetabolic out-comes (improved lipidprofile, reduced fastingglucose, insulinandHOMA-IR).54Psychologicaloutcomeswerenotassessedbyanyofthereviews.

3.4.11 | Other therapy: antidepressants

One high-quality review39 aimed to investigate the efficacy ofantidepressants in PCOS (Appendix S3, found in the SupportingInformation)andidentifiedonestudyinvolving16womenwithPCOScomparingfluoxetine(antidepressant)andsibutramine(anti-obesityRe

view

sA

MST

AR

Qua

lity

of

incl

uded

stu

dies

Out

com

es a

sses

sed

Com

paris

onSi

gnifi

cant

resu

lts

Anti-androgens

Domecqetal(2013)49

Moderate

RCTs:lowto

moderaterisk

ofbias;

observational

studies:high

riskofbias

Anthropometric

–Anti-

androgen

(no

com

para-

tor)

NA

Reproductive

–

Metabolic

Fastingglucose,postprandialglucose,

glucosetolerancetest,random

glucose,areaunderthecurveof

glucose,glucose/insulinratio,

HOMA-IR,QUICKI

Psychologic

–

NA,notavailable;WMD,weightedmeandifference;SMD,standardizedmeandifference;CI,confidenceinterval;BMI,bodymassindex;SHBG,sexhormonebindingglobulin;FAI,freeandrogenindex;

DHEAS,dehydroepiandrosteronesulphate;BP,bloodpressure;HDL,high-densitylipoprotein;LDL,low-densitylipoprotein;TG,triglycerides;IR,insulinresistance;HOMA-IR,homoeostaticmodelassess-

mentofinsulinresistance;QUIKI,quantitativeinsulinsensitivitycheckindex;OCP,oralcontraceptivepill.

a Resultslessbeneficialthancomparator.

TABLE 3 (Continued)

     |  549TAY eT Al.

TABLE 4 Resultsofsystematicreviewsregardingweightlosstherapies

Revi

ews

AM

STA

RQ

ualit

y of

in

clud

ed s

tudi

esO

utco

mes

ass

esse

dCo

mpa

rison

Sign

ifica

nt re

sults

Bariatricsurgery

Butterworthetal

(2016)

47Low

Unclear

Anthropometric

Percentageofexcess

weightloss

Pre-vspostbariatric

surgery

Anthropometric

1trial:improvedpercentageof

excessweightloss

Reproductive

Hirsutism

Reproductive

2trials:improvedhirsutism

Metabolic

T2DM,bloodpressure,

cholesterol,TG,HDL,

LDL,glucose

Metabolic

3trials:improvedglycaemicprofile

(resolutionofT2DM,improvement

ofglycaemiccontrol,ornormaliza-

tionofglucoselevels)

2trials:improvedbloodpressure

Psychologic

Depression

Psychologic

1trial:improveddyslipidaemia

1trial:improveddepression

Skublenyetal(2016)55

Low

Unclear

Anthropometric

BMI,weight,percentage

ofexcessweightloss

Pre-vspostbariatric

surgery

Anthropometric

Percentageofexcessweightloss

(weightedmean57.2%,range33%

to75%)

MeanBM

Iimprovedfrom46.3to

34.2

Reproductive

Hirsutism

Reproductive

Hirsutism(OR0.12,95%CI0.04to

0.36)

Metabolic

–

Psychologic

–

Orlistat

Graffetal(2016)56

Moderate

Unclear

Anthropometric

BMI,weight,waist

circumference

Insulin,HOMA-IR,

cholesterol,TG,HDL,

LDL

Anthropometric

8trials:reducedBMIand/orweight

5trials:reducedwaist-hipratioor

waistcircumference

Reproductive

Testosterone

Reproductive

7trials:reducedtestosterone

Metabolic

Insulin,HOMA-IR,

cholesterol,TG,HDL,

LDL

Metabolic

4trials:improvedlipidprofile(TG,

HDL,LDL)

5trials:reducedHOMA-IRand/or

insulin

Psychologic

–

OR,oddsratio;CI,confidenceinterval;T2DM,type2diabetesmellitus;BMI,bodymassindex;HDL,high-densitylipoprotein;LDL,low-densitylipoprotein;TG,triglycerides;HOMA-IR,homoeostaticmodel

assessment(ofinsulinresistance).

550  |     TAY eT Al.

drug).Nosignificantdifferenceswerereportedbetweentreatmentsforanthropometric,endocrineormetabolicoutcomes.Nostudyas-sessingpsychologicaloutcomeswasfound.

3.4.12 | Other therapy: acarbose

Acarbosewas compared against placebo in onemoderate qualityreviewincluding6trialsand263womenwithPCOS(AppendixS3,found in the Supporting Information).38 Acarbose was associatedwith improvement in endocrine (testosterone) and metabolic (tri-glyceride andHDL) outcomes.No significant change in anthropo-metric outcomeswas detected. Psychological outcomeswere notassessedbythereview.

3.4.13 | Other therapy: antioxidants

One low-quality systematic review assessed the efficacy of anti-oxidants54 (AppendixS3, found in theSupporting Information) in-volving 11 trials and 834 Iranianwomenwith PCOS. This reviewreportedonetrialforsoyvsplacebowhichimprovedendocrineout-comes(DHEASandtestosterone);onetrialforfolicacidvsplacebowithout any significant outcome; 3 trials for omega-3 vs placebowhichimprovedmetabolicoutcomes(increasedHDL,reducedtotalcholesterol, total cholesterol/HDL ratio, LDL/HDL ratio, triglycer-ides,LDL,glucose, insulinand insulin resistance);andone trial forzincvsplacebowhichimprovedendocrine(testosterone)andmeta-bolic outcomes (HOMA-IR, cholesterol, triglycerides and LDL).54 Nosignificantimprovementsinanthropometricoutcomeswerere-ported.54Psychologicaloutcomeswerenotassessedbythereview.

4  | DISCUSSION

This is thefirstoverviewofsystematic reviewsassessingpharma-cologicalorsurgicalinterventionsfornonreproductiveoutcomesinwomenwithPCOS,anditdemonstratesalackofhigh-qualitysys-tematicreviewsormeta-analysespresentingdatafromhigh-qualitystudies.

There isdiversity in thequalityof identified reviews in regardtotheuseofmetformin.MostdemonstratedareductioninBMIorwaist-hipratio,andsomereportedbenefitsinmetabolicoutcomesincludingbloodpressure,triglycerides,markersofglucosetoleranceandinsulinresistanceincomparisonwithplaceboorCOCP.Efficacyin hyperandrogenism is less convincing.Our findings support cur-rentevidence-basedguidelinesandspecialitysocietypositionstate-ments where metformin is recommended for women with PCOSwhofailedtoachievetargetweightlosswithlifestylemanagementorthosewithimpairedglucosetoleranceortype2diabetesmellitus,anditisalsonotrecommendedasatreatmentforhirsutismoracneduetoalackofefficacy.2,3,5,7,21,22,60

We report that thiazolidinediones were more effective thanmetforminorplaceboinreducingmarkersofinsulinresistance.30,31 Onlyoneof5reviewsshowedsuperiorityforthiazolidinedionesin

reducing testosterone.34 However, these benefits come with theprice of increased weight which is contradictory for PCOS giventhe high prevalence of obesity and the negative impact onmeta-bolic, endocrine and reproductive outcomes. Thiazolidinedionesmayalsoincreaserisksofbladdercancerandosteoporosis.2,5,7,61,62 Consideringtheserisks,thiazolidinedionesarenotrecommendedasroutinetreatmentforwomenwithPCOS.2,3,5,7,21,22

WereportherethattheCOCPwastheonlytreatmentmodalitythatimprovedclinicalhyperandrogenism.TheuseofCOCPwasnotassociatedwithworseninginsulinresistanceinthisreview.46,49,50,58 TheeffectsonlipidprofileweremorecontroversialasthepositiveeffectofincreaseinHDLmaybeoffsetbyanunfavourableincreaseintriglyceride.50Notably,thereviewbyDomecqetal49didnotre-portanythromboembolicorcardiovasculareventswithCOCPuse.There is consensus in recommendingCOCPs as first-line pharma-cological therapy foracne,hirsutismandoligo-/amenorrhoeawithcareful consideration of the potential risk of increased venousthromboembolism extrapolated from evidence from the generalpopulation.2,3,5,21Althoughpreviousstudieshaveraisedconcernsofworseninginsulinresistanceandtriglycerides,thereisnoavailableevidenceofincreasedcardiovasculareventswithlong-termusewithCOCP.2,7,63-65There is inadequateevidence tocompareor recom-mendspecificCOCPpreparationsorhormonalcomponents.

Whileanti-androgenshavebeenusedwidelytotreathirsutism,especially inpatientswherehirsutism isnot resolvedbyCOCPorwhereCOCPiscontraindicatedorpoorlytolerated,ourstudyfailedtofindanyevidence.2,3,21,60Theonlyreviewweretrievedfocusedon reporting the adverse events where flutamide was associatedwith hepatotoxicity in 2 case series.49One reason for the lack offindingsinourstudyislikelyrelatedtoourrestrictionpublicationsafter2009.Two reviewsbySwigloetal andBrownetal involving12and9RCTs,respectively,concludedthatanti-androgensareaneffectivetreatmentofhirsutismbuttheevidenceisweak.66,67BothreviewsincludedRCTsofsmallsamplesizes(14to82participants)andhighlightedtheneedofmorewell-designedRCTsinvestigatingtheuseofanti-androgensinwomenwithPCOS.

WeightlosstreatmentsinPCOSwereexploredby3reviewsinourstudy.Tworeviewsinvestigatingbariatricsurgerywereoflowqual-itywhich impactsontherobustnessoftheirresults.47,55WereportthatinwomenwithPCOS,bariatricsurgery-inducedweightloss,im-provedhirsutism,bloodpressure,glycaemicandlipidprofile.Orlistatimprovedanthropometric,endocrineandmetabolicoutcomeswhencomparedtoplacebobutnotmetformin.56However,weacknowledgethat there isencouragingevidence inthegeneralpopulationshow-ing that bariatric surgery improves weight loss andmetabolic out-comessuchasglycaemiccontrol,lipidprofileandbloodpressure.68-70 Bariatricsurgerywasrecommendedasasecond-linetherapytoim-provefertilityoutcomesinwomenwithPCOSbytheevidence-basedAustralianguidelineandtobeconsideredinmorbidlyobesewomenwithPCOSbytheEuropeanSocietyofEndocrinology.2,4Otherso-cieties concluded that better quality trialswith long-term data arerequiredbeforeincorporatingbariatricsurgeryintotheirrecommen-dationsforwomenwithPCOS.5,20Wefoundthatstatins,afamilyof

     |  551TAY eT Al.

cholesterol-loweringdrugs,areeffective in improvingthe lipidpro-file.36,42,44Giventhelackofdefinitebenefitsintreatmentofhyper-androgenaemiaoranovulation,paucityofdatainreproductive-agedwomenandconsideringthedisadvantageoftype2diabetesdevel-opment, statinsare reserved forwomenwithPCOSwhomeet thestandardindicationsforlipid-loweringtherapy.5,7,22,71

Ourreviewincludedseveralnonconventionalinterventionsthatarenot recommendedbyanyguidelinesor specialty societyposi-tion statements. Although the evidence is not robust, there maybesomebenefitswiththeuseofvitaminDandinositol.WefoundseveralmoderatequalityreviewsassessingvitaminDdemonstratedreductionsintriglycerideandtestosteronelevels.Onehigh-qualityreviewbyPergialiotisetalreportedbeneficialeffectsofvitaminDinreducingDHEAS, insulinresistanceandcholesterol.57 Inositol isa nutritional supplementwith proposed insulin-sensitizing charac-teristics.5,43,48Asreportedhereinlowtomoderatequalityreviews,they may have advantageous effects in nonreproductive-relatedendocrine andmetabolic outcomes including improving biochemi-calhyperandrogenismandinsulinresistance.Noconclusioncanbemade regarding the use of acarbose, N-acetyl-cysteine, soy, folicacid,omega-3orzincinwomenwithPCOSasthenumberofstudiesinvolvedislimited.

Ourstudyhasseveralstrengths.Beinganoverviewofsystem-atic reviews,we collated evidence of interventions for PCOS in anonbiased and systematic manner.We reported our findings fol-lowingthePRISMAguidelinesutilizingrigorousmethodologywithduplication in all study tasks.However,we note study limitationsincludingthediverseAMSTARqualityoftheincludedreviewsandthe lackof clear interpretationof thequalityof individual studieswithintheincludedsystematicreviews.However,performingaddi-tionalqualityassessmentofmorethan350includedstudieswouldbeunfeasible.Wealsoexcludedpublicationsbeforeyear2009asanattempttofilteroutreviewsthatdidnotfollowthePRISMAguide-lines.AssomeinterventionsforPCOShavebeenusedfordecades,wemayhaveexcludedsignificantearlierstudies,albeitpotentiallyoflowerquality.Inourstudy,wefoundthatonlyanti-androgenswereaffectedbythislimitation.66,67

Lastly, quality of future systematic reviews may be strength-enedbyaddressingreportingconflictofinterestofincludedstudies,registering for an apriori protocol andprovides a list of excludedstudies.Wealsoidentifiedsignificantgapsinknowledgeregardingthelackofdataonpsychologicaloutcomesintreatmentofwomenwith PCOS.We retrieved included psychological outcomes as anoutcomeofinterestonlyin2reviews39,47despitethewidelyknownincreasedprevalenceofdepression,anxietyandlowerqualityoflifeinwomenwithPCOSwhichfuturestudiesshouldaddress.72

5  | CONCLUSIONS

This overview of systematic reviews consolidates the evidence oftreatmentoptionsfornonreproductiverelatedoutcomesinwomenwith PCOS.We call attention to the lack of studies investigating

psychological outcomes in any intervention in womenwith PCOSwarrantingfurtherexamination.Overall,wenoteevidenceformet-forminandCOCPuseinnonreproductiveoutcomesinPCOS,cautionagainstthiazolidinedionesandhighlightthatfurtherresearchiswar-rantedinanumberofinterventionssuchasstatins,bariatricsurgery,vitaminDorinositoltoclarifyoutstandingclinicalgaps.

ACKNOWLEDG MENT

ChauTTayissupportedbyaCREinPCOSentrylevelscholarship,HelenaJTeedeissupportedbyanNHMRCPractitionerFellowship,AnjuEJohamissupportedbyaNHMRCEarlyCareerFellowshipandLisa JMoran is supportedbyaNationalHeartFoundationFutureLeaderFellowship.

CONFLIC T OF INTERE S T

Nothingtodeclare.

ORCID

Chau T. Tay http://orcid.org/0000-0001-6228-2654

Helena J. Teede http://orcid.org/0000-0001-7609-577X

Anju E. Joham http://orcid.org/0000-0002-6307-2568

Lisa J. Moran http://orcid.org/0000-0001-5772-6484

R E FE R E N C E S

1. BozdagG,MumusogluS,ZenginD,KarabulutE,YildizBO.Theprev-alenceandphenotypicfeaturesofpolycysticovarysyndrome:asys-tematicreviewandmeta-analysis.Hum Reprod.2016;31:2841-2855.

2. ConwayG,DewaillyD,Diamanti-KandarakisE,etal.Thepolycysticovarysyndrome:apositionstatementfromtheEuropeanSocietyofEndocrinology.Eur J Endocrinol.2014;171:P1-P29.

3. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on wom-en’s health aspects of polycystic ovary syndrome (PCOS): theAmsterdam ESHRE/ASRM-Sponsored 3rd PCOS ConsensusWorkshopGroup.Fertil Steril.2012;97:28-38.e25.

4. TeedeH,MichelmoreJ,McCallisterV,NormanRJ.Evidence-basedguidelinefortheassessmentandmanagementofpolycysticovarysyndrome.PCOSAustralianAlliance2011.

5. LegroRS,ArslanianSA,EhrmannDA,etal.Diagnosisandtreatmentofpolycysticovarysyndrome:anEndocrineSocietyclinicalprac-ticeguideline.J Clin Endocrinol Metab.2013;98:4565-4592.

6. ShorakaeS,BoyleJ,TeedeH.Polycysticovarysyndrome:acom-monhormonalconditionwithmajormetabolicsequelaethatphysi-ciansshouldknowabout.Intern Med J.2014;44:720-726.

7. GoodmanNF,CobinRH,FutterweitW,etal.AmericanAssociationof Clinical Endocrinologists, American College of Endocrinology,and Androgen Excess and Pcos Society Disease State ClinicalReview: Guide to the Best Practices in the Evaluation andTreatment of PolycysticOvary Syndrome – Part 2.Endocr Pract. 2015;21:1415-1426.

8. TeedeH,DeeksA,MoranL.Polycysticovarysyndrome:acomplexcondition with psychological, reproductive and metabolic man-ifestations that impacts on health across the lifespan.BMC Med. 2010;8:41.

552  |     TAY eT Al.

9. MoranLJ,MissoML,WildRA,NormanRJ.Impairedglucosetoler-ance,type2diabetesandmetabolicsyndromeinpolycysticovarysyndrome: a systematic review and meta-analysis. Hum Reprod Update.2010;16:347-363.

10. SetjiTL,HollandND,SandersLL,PereiraKC,DiehlAM,BrownAJ.Nonalcoholic steatohepatitis and nonalcoholic fatty liver diseaseinyoungwomenwithpolycysticovarysyndrome.J Clin Endocrinol Metab.2006;91:1741-1747.

11. Lim SS, Davies MJ, Norman RJ, Moran LJ. Overweight, obesityand central obesity in women with polycystic ovary syndrome:a systematic review and meta-analysis. Hum Reprod Update. 2012;18:618-637.

12. deGroot PC,DekkersOM, Romijn JA,Dieben SW,HelmerhorstFM.PCOS,coronaryheartdisease,strokeandtheinfluenceofobe-sity: a systematic review andmeta-analysis.Hum Reprod Update. 2011;17:495-500.

13. DokrasA,Clifton S, FutterweitW,WildR. Increased prevalenceof anxiety symptoms inwomenwith polycystic ovary syndrome:systematicreviewandmeta-analysis.Fertil Steril.2012;97:225-230.e2.

14. BarryJA,KuczmierczykAR,HardimanPJ.Anxietyanddepressioninpolycysticovarysyndrome:asystematicreviewandmeta-analysis.Hum Reprod.2011;26:2442-2451.

15. BazarganipourF,Taghavi SA,MontazeriA,AhmadiF,ChamanR,KhosraviA.Theimpactofpolycysticovarysyndromeonthehealth-relatedqualityoflife:asystematicreviewandmeta-analysis.Iran J Reprod Med.2015;13:61-70.

16. Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, FauserBC, Macklon NS. A meta-analysis of pregnancy outcomes inwomen with polycystic ovary syndrome. Hum Reprod Update. 2006;12:673-683.

17. HaoulaZ,SalmanM,AtiomoW.Evaluatingtheassociationbetweenendometrial cancer and polycystic ovary syndrome.Hum Reprod. 2012;27:1327-1331.

18. Azziz R, Marin C, Hoq L, Badamgarav E, Song P. Health care-relatedeconomicburdenofthepolycysticovarysyndromeduringthe reproductive life span. J Clin Endocrinol Metab. 2005;90: 4650-4658.

19. LimSS,NormanRJ,DaviesMJ,MoranLJ.Theeffectofobesityonpolycysticovarysyndrome:asystematicreviewandmeta-analysis.Obes Rev.2013;14:95-109.

20. MoranLJ,PasqualiR,TeedeHJ,HoegerKM,NormanRJ.Treatmentof obesity in polycystic ovary syndrome: a position statementoftheAndrogenExcessandPolycysticOvarySyndromeSociety.Fertil Steril.2009;92:1966-1982.

21. Escobar-MorrealeHF,CarminaE,DewaillyD,etal.Epidemiology,diagnosisandmanagementofhirsutism:aconsensusstatementbytheAndrogenExcessandPolycysticOvarySyndromeSociety.Hum Reprod Update.2012;18:146-170.

22. Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessmentofcardiovascularriskandpreventionofcardiovasculardiseaseinwomenwith the polycystic ovary syndrome: a consensus state-ment by the Androgen Excess and Polycystic Ovary Syndrome(AE-PCOS)Society.J Clin Endocrinol Metab.2010;95:2038-2049.

23. Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F,Sancho J. San Millan JL. The polycystic ovary syndrome as-sociatedwithmorbid obesitymay resolve afterweight loss in-duced by bariatric surgery. J Clin Endocrinol Metab. 2005;90: 6364-6369.

24. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group.Preferred reporting items for systematic reviews and meta-analyses:thePRISMAstatement.BMJ. 2009;339:b2535.

25. SheaBJ,BouterLM,PetersonJ,etal.Externalvalidationofamea-surementtooltoassesssystematicreviews(AMSTAR).PLoS ONE. 2007;2:e1350.

26. SheaBJ,GrimshawJM,WellsGA,etal.DevelopmentofAMSTAR:ameasurementtooltoassessthemethodologicalqualityofsystem-aticreviews.BMC Med Res Methodol. 2007;7:10.

27. TangT,LordJM,NormanRJ,YasminE,BalenAH.Insulin-sensitisingdrugs (metformin, rosiglitazone,pioglitazone,D-chiro-inositol) forwomenwith polycystic ovary syndrome, oligo amenorrhoea andsubfertility.Cochrane Database Syst Rev.2009:CD003053.

28. TangT,LordJM,NormanRJ,YasminE,BalenAH.Insulin-sensitisingdrugs (metformin, rosiglitazone,pioglitazone,D-chiro-inositol) forwomenwith polycystic ovary syndrome, oligo amenorrhoea andsubfertility.Cochrane Database Syst Rev.2010:CD003053.

29. Du Q, Wang YJ. Comparative efficacy of thiazolidinedionesand metformin for polycystic ovary syndrome. Saudi Med J. 2012;33:954-961.

30. DuQ,WangYJ,YangS,WuB,HanP,ZhaoYY.Asystematic re-viewandmeta-analysisofrandomizedcontrolledtrialscomparingpioglitazoneversusmetformininthetreatmentofpolycysticovarysyndrome.Curr Med Res Opin.2012;28:723-730.

31. DuQ,YangS,WangY-J,WuB,ZhaoY-Y,FanB.Effectsofthiazoli-dinedionesonpolycysticovarysyndrome:ameta-analysisofran-domizedplacebo-controlledtrials.Adv Ther.2012;29:763-774.

32. FangF,NiK,CaiY,ShangJ,ZhangX,XiongC.EffectofvitaminDsupplementationonpolycysticovarysyndrome:asystematicre-viewandmeta-analysisofrandomizedcontrolledtrials.Complement Ther Clin Pract.2017;26:53-60.

33. JiaX-Z,WangY-M,ZhangN,etal.EffectofvitaminDonclinicalandbiochemicalparametersinpolycysticovarysyndromewomen:ameta-analysis.J Obstet Gynaecol Res.2015;41:1791-1802.

34. Li XJ, Yu YX, Liu CQ, et al. Metformin vs thiazolidinediones fortreatment of clinical, hormonal and metabolic characteristics ofpolycystic ovary syndrome: ameta-analysis.Clin Endocrinol (Oxf). 2011;74:332-339.

35. MengY,ChenX,PengZ,LiuX,SunY,DaiS.Associationbetweenhighserumhomocysteinelevelsandbiochemicalcharacteristicsinwomenwithpolycysticovariansyndrome:asystematicreviewandmeta-analysis.PLoS ONE. 2016;11:e0157389.

36. Sun J, YuanY, Cai R, et al. An investigation into the therapeuticeffects of statinswithmetformin on polycystic ovary syndrome:a meta-analysis of randomised controlled trials. BMJ Open. 2015;5:e007280.

37. XueY,XuP,XueK,etal.EffectofvitaminDonbiochemicalparam-eters inpolycysticovarysyndromewomen:ameta-analysis.Arch Gynecol Obstet.2017;295:487-496.

38. Zhang YY, Hou LQ, Zhao TY. Effects of acarbose on polycysticovary syndrome: a meta-analysis. Exp Clin Endocrinol Diabetes. 2014;122:373-378.

39. ZhuangJ,WangX,XuL,WuT,KangD.Antidepressantsforpolycys-ticovarysyndrome.Cochrane Database Syst Rev.2013:CD008575.

40. Azadi-Yazdi M, Nadjarzadeh A, Khosravi-Boroujeni H, Salehi-Abargouei A. The effect of vitamin D supplementation on theandrogenic profile in patientswith polycystic ovary syndrome: asystematicreviewandmeta-analysisofclinicaltrials.Horm Metab Res.2017;49:174-179.

41. Bordewijk EM, Nahuis M, Costello MF, et al. Metformin duringovulation induction with gonadotrophins followed by timed in-tercourse or intrauterine insemination for subfertility associatedwith polycystic ovary syndrome. Cochrane Database Syst Rev. 2017;1:CD009090.

42. Gao L, Zhao FL, Li SC. Statin is a reasonable treatment optionfor patients with Polycystic Ovary Syndrome: a meta-analysisof randomized controlled trials. Exp Clin Endocrinol Diabetes. 2012;120:367-375.

43. PundirJ,PsaroudakisD,SavnurP,etal.Inositoltreatmentofanovu-lationinwomenwithpolycysticovarysyndrome:ameta-analysisofrandomisedtrials.BJOG.2018;125(3):299-308

     |  553TAY eT Al.

44. RavalAD,Hunter T, StuckeyB,Hart RJ. Statins forwomenwithpolycysticovarysyndromenotactivelytryingtoconceive.Cochrane Database Syst Rev.2011:CD008565.

45. TangT,LordJM,NormanRJ,YasminE,BalenAH.Insulin-sensitisingdrugs (metformin, rosiglitazone,pioglitazone,D-chiro-inositol) forwomen with polycystic ovary syndrome, oligo amenorrhoea andsubfertility.Cochrane Database Syst Rev.2012:CD003053.

46. Al Khalifah RA, Florez ID, Dennis B, Thabane L, Bassilious E.Metforminororal contraceptives foradolescentswithpolycysticovariansyndrome:ameta-analysis.Pediatrics. 2016;137:e20154089.

47. ButterworthJ,DeguaraJ,BorgC-M.Bariatricsurgery,polycysticovarysyndrome,andinfertility.J Obes.2016;2016:1-6.

48. Galazis N, Galazi M, Atiomo W. D-Chiro-inositol and its signifi-cance inpolycysticovarysyndrome:asystematicreview.Gynecol Endocrinol.2011;27:256-262.

49. DomecqJP,PrutskyG,MullanRJ,etal.Adverseeffectsofthecom-montreatmentsforpolycysticovarysyndrome:asystematicreviewandmeta-analysis.J Clin Endocrinol Metab.2013;98:4646-4654.

50. Halperin IJ,KumarSS,StroupDF,LaredoSE.Theassociationbe-tweenthecombinedoralcontraceptivepillandinsulinresistance,dysglycemiaanddyslipidemiainwomenwithpolycysticovarysyn-drome: a systematic review and meta-analysis of observationalstudies.Hum Reprod.2011;26:191-201.

51. HeC,LinZ,RobbSW,EzeamamaAE.SerumvitaminDlevelsandpolycysticovarysyndrome:asystematicreviewandmeta-analysis.Nutrients.2015;7:4555-4577.

52. ThakkerD,RavalA,PatelI,WaliaR.N-acetylcysteineforpolycysticovarysyndrome:asystematicreviewandmeta-analysisofrandom-izedcontrolledclinicaltrials.Obstet Gynecol Int. 2015;2015:817849.

53. Patel R, Shah G. Effect of metformin on clinical, metabolic andendocrineoutcomesinwomenwithpolycysticovarysyndrome:ameta-analysis of randomized controlled trials.Curr Med Res Opin. 2017;33:1545-1557.

54. Amini L, Tehranian N, MovahedinM, Ramezani Tehrani F, ZiaeeS.AntioxidantsandmanagementofpolycysticovarysyndromeinIran:asystematicreviewofclinicaltrials.Iran.2015;13:1-8.

55. SkublenyD,SwitzerNJ,GillRS,etal.Theimpactofbariatricsur-geryonpolycysticovarysyndrome:asystematicreviewandmeta-analysis.Obes Surg.2016;26:169-176.

56. GraffSK,MarioFM,ZiegelmannP,SpritzerPM.Effectsoforlistatvs. metformin onweight loss-related clinical variables in womenwithPCOS: systematic review andmeta-analysis. Int J Clin Pract. 2016;70:450-461.

57. Pergialiotis V, Karampetsou N, Panagopoulos P, Trakakis E,PapantoniouN.TheeffectofVitaminDsupplementationonhor-monalandglycaemicprofileofpatientswithPCOS:ameta-analysisofrandomisedtrials.Int J Clin Pract. 2017;71:e12957.

58. Mendoza N, Simoncini T, Genazzani AD. Hormonal contracep-tive choice for women with PCOS: a systematic review of ran-domized trials and observational studies. Gynecol Endocrinol. 2014;30:850-860.

59. Gill S, Gemmell A, Colleran R, ZanuriN,O’BrienH, PoobalanA.Doesmetformincombinedwithclomiphenecitrateimprovefertil-ityrelatedoutcomesinclomipheneresistantwomenwithPCOS:asystematicreview.Middle East Fertil Soc J.2014;19:81-88.

60. GoodmanNF,CobinRH,FutterweitW,etal.AmericanAssociationofClinicalEndocrinologists,AmericanCollegeofEndocrinology,andAndrogen Excess and Pcos SocietyDisease State Clinical Review:Guide to the Best Practices in the Evaluation and Treatment ofPolycysticOvarySyndrome-Part1.Endocr Pract.2015;21:1291-1300.

61. Berberoglu Z, Yazici AC, Demirag NG. Effects of rosiglita-zone on bone mineral density and remodelling parameters inPostmenopausal diabetic women: a 2-year follow-up study. Clin Endocrinol (Oxf).2010;73:305-312.

62. Turner RM, Kwok CS, Chen-Turner C, Maduakor CA, Singh S,Loke YK. Thiazolidinediones and associated risk of bladder can-cer: a systematic review and meta-analysis. Br J Clin Pharmacol. 2014;78:258-273.

63. CostelloMF,ShresthaB,EdenJ,JohnsonNP,SjoblomP.Metforminversus oral contraceptive pill in polycystic ovary syndrome: aCochranereview.Hum Reprod.2007;22:1200-1209.

64. AmiriM,RamezaniTehraniF,NahidiF,KabirA,AziziF,CarminaE.Effectsoforalcontraceptivesonmetabolicprofileinwomenwithpolycystic ovary syndrome: a meta-analysis comparing productscontaining cyproterone acetatewith third generation progestins.Metabolism.2017;73:22-35.

65. KorytkowskiMT,MokanM,HorwitzMJ,BergaSL.Metabolicef-fectsoforalcontraceptives inwomenwithpolycysticovarysyn-drome. J Clin Endocrinol Metab.1995;80:3327-3334.

66. SwigloBA,CosmaM,FlynnDN,etal.Clinical review:antiandro-gensforthetreatmentofhirsutism:asystematicreviewandmeta-analyses of randomized controlled trials. J Clin Endocrinol Metab. 2008;93:1153-1160.

67. BrownJ,FarquharC,LeeO,ToomathR,JepsonRG.Spironolactoneversusplaceboorincombinationwithsteroidsforhirsutismand/oracne. Cochrane Database Syst Rev.2009:CD000194.

68. ColquittJL,PickettK,LovemanE,FramptonGK.Surgeryforweightlossinadults.Cochrane Database Syst Rev.2014:CD003641.

69. QiL,GuoY,LiuCQ,HuangZP,ShengY,ZouDJ.Effectsofbariatricsurgeryonglycemicandlipidmetabolism,surgicalcomplicationandqualityoflifeinadolescentswithobesity:asystematicreviewandmeta-analysis.Surg Obes Relat Dis.2017;13:2037-2055.

70. RicciC,GaetaM,RausaE,AstiE,BanderaF,BonavinaL.Long-termeffectsofbariatric surgeryon type IIdiabetes,hypertensionandhyperlipidemia:ameta-analysisandmeta-regressionstudywith5-yearfollow-up.Obes Surg.2015;25:397-405.

71. PreissD,SeshasaiSR,WelshP,etal.Riskofincidentdiabeteswithintensive-dose compared with moderate-dose statin therapy: ameta-analysis.JAMA.2011;305:2556-2564.

72. ChingHL,BurkeV,StuckeyBG.Qualityof lifeandpsychologicalmorbidity inwomenwith polycystic ovary syndrome: bodymassindex,ageandtheprovisionofpatientinformationaresignificantmodifiers.Clin Endocrinol (Oxf).2007;66:373-379.

SUPPORTING INFORMATION

Additional supporting information may be found online in theSupportingInformationsectionattheendofthearticle.

How to cite this article:TayCT,JohamAE,HiamDS,etal.Pharmacologicalandsurgicaltreatmentofnonreproductiveoutcomesinpolycysticovarysyndrome:Anoverviewofsystematicreviews.Clin Endocrinol (Oxf). 2018;89:535–553. https://doi.org/10.1111/cen.13753