Continuous glucose monitoring in polycystic ovary syndrome: what interest?

Abstract

Purpose
The aim of our study was to detect subclinical abnormalities in carbohydrate metabolism in patients with polycystic ovary syndrome.
Methods
Cross-sectional study including 20 patients with PCOS diagnosed according to 5- the Rotterdam criteria. All the patients had normal carbohydrate tolerance (fasting blood 6- glucose<5.6 mmol/l, 2-h plasma glucose after a 75-g oral glucose tolerance test<7.8 mmol/l andglycated hemoglobin <5.8%). For each patient, we performed a continuous glucose monitoring over 72h, measuring the interstitial glucose every 5 minutes (288 measurements per day). We collected data about: the mean blood glucose, obtained by determining the mean values of the 288 measurements made by 24h - the mean amplitude of glycemic excursions, which is the difference between the maximum and minimum glycemic values - the time (in hours) in which the blood glucose was <0.7 g/l and / or>1.4 g/l.
Results
The mean blood glucose (over 72h) was 0.94±0.07 g/l (0.81-1.11).The mean amplitude of glycemic excursions (over 72h) was 0.81 ± 0.23 g/l (0.47-1.31).Fourteen patients (pathologic group) had subclinical glycemic abnormalities: 14 patients had glycemic values<0.7 g/l and 5 patients had also glycemic values>1.4 g/l. The mean amplitude of glycemic excursions was significantly lower (p=0.016) in the normal group (6 patients, 0.64 g/l) compared to the pathologic group(14 patients, 0.88 g/l).The other clinical and biological parameters were comparable between the two groups.
Conclusions
Our findings confirm the high frequency of subclinical abnormalities of carbohydrate metabolism in patients with polycystic ovary syndrome. A regular follow-up of these patients is necessary.

Full text

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Preprint:Pleasenotethatthisarticlehasnotcompletedpeerreview.
Continuousglucosemonitoringinpolycysticovary
syndrome:whatinterest?
CURRENTSTATUS:POSTED
ineskammoun
UniversitedeTunisElManar
ines.kammoun@fmt.utm.tnCorrespondingAuthor
ORCiD:https://orcid.org/0000-0002-8322-5621
WafaBenSaada
Departmentofendocrinologyandmetabolicdiseases,InstitutnationaldeNutrition,Tunis
HajerKandara
Departmentofendocrinologyandmetabolicdiseases,institutNationaldeNutrition,Tunis
RadhouaneGharbi
Departmentofendocrinologyandmetabolicdiseases,InstitutNationaldeNutrition,Tunis
RaniaBenSaid
Departmentofendocrinologyandmetabolicdiseases,InstitutNationaldeNutrition,tunis
ClaudeBenSlama
Departmentofendocrinologyandmetabolicdiseases,InstitutNationaldeNutrition,Tunis
ManelJemel
Departmentofendocrinologyandmetabolicdiseases,InstitutNationaldeNutrition,tunis
DOI:
10.21203/rs.2.22520/v1
SUBJECTAREAS
Endocrinology&Metabolism
KEYWORDS
polycysticovarysyndrome,carbohydratemetabolism,continuousglucose
monitoring,subclinicalabnormalities

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Abstract
Purpose
Theaimofourstudywastodetectsubclinicalabnormalitiesincarbohydratemetabolisminpatients
withpolycysticovarysyndrome.
Methods
Cross-sectionalstudyincluding20patientswithPCOSdiagnosedaccordingto5-theRotterdam
criteria.Allthepatientshadnormalcarbohydratetolerance(fastingblood6-glucose<5.6mmol/l,2-h
plasmaglucoseaftera75-goralglucosetolerancetest<7.8mmol/landglycatedhemoglobin<5.8%).
Foreachpatient,weperformedacontinuousglucosemonitoringover72h,measuringtheinterstitial
glucoseevery5minutes(288measurementsperday).Wecollecteddataabout:themeanblood
glucose,obtainedbydeterminingthemeanvaluesofthe288measurementsmadeby24h-themean
amplitudeofglycemicexcursions,whichisthedifferencebetweenthemaximumandminimum
glycemicvalues-thetime(inhours)inwhichthebloodglucosewas<0.7g/land/or>1.4g/l.
Results
Themeanbloodglucose(over72h)was0.94±0.07g/l(0.81-1.11).Themeanamplitudeofglycemic
excursions(over72h)was0.81±0.23g/l(0.47-1.31).Fourteenpatients(pathologicgroup)had
subclinicalglycemicabnormalities:14patientshadglycemicvalues<0.7g/land5patientshadalso
glycemicvalues>1.4g/l.Themeanamplitudeofglycemicexcursionswassignificantlylower
(p=0.016)inthenormalgroup(6patients,0.64g/l)comparedtothepathologicgroup(14patients,
0.88g/l).Theotherclinicalandbiologicalparameterswerecomparablebetweenthetwogroups.
Conclusions
Ourfindingsconfirmthehighfrequencyofsubclinicalabnormalitiesofcarbohydratemetabolismin
patientswithpolycysticovarysyndrome.Aregularfollow-upofthesepatientsisnecessary.
Background
Polycysticovarysyndrome(PCOS)isoneofthemostcommonfemaleendocrinopathies,witha
prevalenceofaround15%inwomenofchildbearingage[1].Thisdualreproductiveandmetabolic
diseasecanberesponsibleforhyperandrogenism,fertilityandmenstrualcycledisorders,obesity,

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diabetesmellitus(DM),dyslipidemia,hypertension,andevenendometrialcancer[2].Insulin
resistance(IR)appearstobethelinkbetweenthesedifferentanomalies.
VeryfewstudieshaveexaminedtheglycemicprofileofpatientswithPCOSandwithoutclear
alterationsinglycoregulation.Thesestudies[3,4]havedemonstratedtheexistenceofsubclinical
glycoregulationabnormalities,whichmaysubsequentlyleadtoastateofglucoseintoleranceoreven
toDM.
Theaimofourstudywastodetectsubclinicalabnormalitiesinglucosemetabolisminpatientswith
PCOSbyusinga72-hourcontinuousglucosemonitoring(CGM).
Methods
Weconductedacross-sectionalstudythatincluded20patientswithPCOS,followedatthe
departmentofendocrinologyandmetabolicdiseasesoftheNationalInstituteofNutrition(Tunis).We
chosethisnumberofparticipantswithreferencetotheliteraturesincethestudiesmadeonthis
subjectdidnotexceed10to45patients.
Thetotaldurationofrecruitmentwas08months(fromApriltoNovember2013).
I-Patients:
InclusionCriteria
Age:18-45yearsold
DiagnosisofPCOSconfirmedaccordingtotheRotterdam2003criteria[5],bythepresenceofatleast2
ofthe3followingcriteria:
-Clinical(hirsutism)and/orbiological(totaltestosterone>2nmol/l)hyperandrogenism
-Dysovulation:occurrenceoffewerthan9menstruationsperyear
-PCOSechographiccriteria:ovarianvolume>10mland/orthepresenceof≥12follicles(2-9mm)on
oneorbothovaries.
Normalcarbohydratetoleranceattestedby:
-Fastingbloodglucose(FBG)<5.6mmol/land
-2-hplasmaglucose<7.8mmol/l(aftera75-goralglucosetolerancetest)and
-Glycatedhemoglobin(HbA1c)<5.8%.
InformedConsent
Non-InclusionCriteria
Otheretiologiesofhyperandrogenismand/ormenstrualdisorders,includingcongenitaladrenal
hyperplasia,androgen-secretingtumors,Cushing'ssyndrome,hyperprolactinemiaandhypothyroidism.
Pregnantorbreastfeedingwomen
Patientswhotook,inthe3monthsprecedingthestudy,drugsinterferingwiththecarbohydrate
metabolism(corticotherapy,estrogens,metformin).

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II.Methodology:
1.Datacollected:
Foreachpatient,weperformedaclinicalexaminationandmetabolicassessmentwithfasting
insulinemia(FI)andcalculationoftheHOMA-Rindexbytheformula:
HOMA-R=(FBG(mmol/l)*FI(μIU/ml))/22.5
Wealsorealized,foreachpatient,aCGMover72hours.ThedeviceusedwastheMedtronicMinimed
CGMS.Itconsistsofanimplantableelectrodeintheabdominalsubcutaneoustissue,connectedtoa
computersystemthatstoresallthevaluesofthemeasuredsignal.Theimplantedsystemmakesit
possibletoobtainaninterstitialglucosevalueevery5minutes(288measurementsperday).
Inordertoobtainanoptimalrecording,4capillarybloodglucoseperday(beforethe3mealsand
beforebedtime)weremeasuredtocalibratethesystem.
Theimplantationofthedevicewasperformedinallpatientsatthesametime(between9amand
11am).Weaskedthemtomaintaintheireatinghabitsandtheirusualprofessionalandphysical
activities.
FromtheCGM,wenoted:
Themeanbloodglucose(MBG,expresseding/l)obtainedbydeterminingtheaveragevaluesofthe288
measurementsmadeby24h.
Themeanamplitudeoftheglycemicexcursions(MAGE,expresseding/l)representedbythe
differencebetweenthemaximumandminimumvaluesofthebloodglucoselevels
Thelengthoftime(inhours)whenbloodglucosewas<0.7g/land/or>1.4g/l.
Wethendividedourpatientsinto2groups:
Patientsinwhombloodglucoselevelswerestillbetween0.7and1.4g/lduring72hours:normalCGM
group
Patientsinwhombloodglucoselevelswereoutsidetheselimits:pathologicalCGMgroup
Wecomparedtheclinicalandbiologicalparametersofthesetwogroups.
Informedconsentwasobtainedfromallparticipantsincludedinthestudy.
2-Dataanalysis:
Wecalculated:
simpleandrelativefrequencies(percentages)forqualitativevariables.
meansandstandarddeviationswithdeterminationofextremevaluesforthequantitativevariables.
Thecomparisonofmeansonindependentserieswasperformedusingthenon-parametricMannand

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Whitneytest.
ThecomparisonofpercentagesonindependentserieswasperformedbythePearsonchi-squaretest,
andincaseofnon-validityofthistest,byFisher’sexactbilateraltest.
Thestudyofthelinkbetween2quantitativevariableswasmadebySpearman'scorrelation
coefficient.
Forallstatisticaltests,thethresholdofstatisticalsignificancewassetatp<0.05.
Results
Themeanageofourpatientswas26.2±6.6years(18to45years).ThemeanbodymassindexBMI
was32.9±8.7Kg/m²(20-55).Twentypercentofourpatientswereoverweightand65%wereobese.
ThemeanvalueofMBG(over72hours)was0.94±0.07g/l(0.81-1.11).
ThemeanvalueoftheMAGE(over72hours)was0.81±0.23g/l(0.47-1.31).
Thebloodglucoselevelsremainedbetween0.70and1.40g/lduringthe72hoursoftherecordingin
6casesamongour20patients.
Fourteenpatientshadbloodglucose<0.70g/lduringtherecording,fiveofwhomhadbloodglucose
<0.50g/landfiveotherpatientshadalsoabloodglucoselevel>1.40g/l(Figure1).Hypoglycemia
wasasymptomaticandnotfeltbypatients.
Thelengthoftimespentoutsidethepreviouslyfixedlimits(<0.7or>1.4g/l),expressedinhours,is
detailedintable1.
TheMBGandMAGEvalueswerenotsignificantlycorrelatedwiththedifferentclinicalandbiological
parametersstudied(BMI,waistcircumference,FBG,HbA1c,FIandHOMAindex).
Wedividedourpatientsinto2groupsbasedonCGMdata:
NormalCGMgroup:patientsinwhombloodglucoselevelswerealwaysbetween0.7and1.4g/lduring
the72hours(n=6)
PathologicalCGMgroup:patientswhohadbloodglucoselevelsoutsidetheselimits(n=14)
Wefoundnosignificantdifferencebetweenthese2groupsconcerningBMI,waistcircumference,
presenceofacanthosisnigricans,menstrualdisorders,familyhistoryofdiabetes,FBG,HbA1c,FI,
HOMAindex,andtotaltestosterone(table2).
ThevalueoftheMBGwasalsocomparableinbothgroups(0,97±0,05vs0,93±0,07g/l).However,

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theMAGEvaluewassignificantlylowerinthegroupwithnormalregistration(0.64vs0.88g/l,p=
0.016).
Discussion
Inour20patientswithPCOSwhohavehadCGM,thebloodglucosevaluesremainedintherangeof
0.70-1.40g/linonly6patientsduringthe72hoursofrecording.Alltheother14patientshadblood
glucoselevelslessthan0.70g/l.Thiswouldberelatedmostprobably,tohyperinsulinismsecondary
toinsulinresistanceinthesepatients.Nevertheless,wefoundnosignificantdifferencebetweenthese
2groupsconcerningclinical,metabolicorhormonalparameters.
ThisisthefirstTunisianstudytoassesstheresultsofCGMinpatientswithPCOS.However,ourstudy
hassomelimitations.Itismainlytheabsenceofacontrolgroupwhichcouldnotbeincludedfor
financialreasons.
Theassociationbetweenhyper-androgenismandmetabolicdisorderswasfirstdescribedbyAchard
andThiersin1921[6].Subsequently,severalepidemiologicalstudiesconfirmedthehighprevalence
ofcarbohydratetoleranceabnormalitiesinwomenwithPCOS[7,8].Indeed,theriskofDMis
multipliedby7inthesepatients[9].
AccordingtotheAmericanDiabetesAssociation(ADA),diabetesscreeningisrecommendedinPCOS
patients,astheriskofprogressiontoDMis2-3%peryear.Thisscreeningismadebya75-goral
glucosetolerancetestorHbA1cdeterminationaccordingtotheADAin2018[10].
CGMcanrecordinterstitialglucosevaluesrangingfrom0.4to4g/l.Itismoresensitiveinthe
detectionofstrongglycemicvariations[11].Itwasinitiallyusedindiabeticsubjects.Currently,itis
alsousedinhealthysubjects,pregnantwomen[12,13]andeveninthecardiacintensivecareunit
[14],toevaluatetheeffectofBMI,somefoods,physicalactivity,andstressonbloodglucoselevels
variations[13].CGMisalsousedtodiagnoseearlyglycemicabnormalitiesinallhighriskpatients
[15].
AChinesestudythatperformedCGMin434healthyvolunteers[16]chosetherangeofnormalblood
glucosebetween0.70and1.40g/l.AnotherItalianstudythatincluded15healthyvolunteers[13]
setthenormalrangeofbloodglucosebetween0.70and1.25g/l.Inourstudy,wechosetheinterval

7
between0.70and1.40g/l,sincethepopulationoftheChinesestudy[16]wasimportantand
especiallybecauseinthisstudy,thetimespentoutsidethenormalrangewaslessthan1hourover
theentire72hours.Thisintervalwouldthereforereflectthephysiologicalvariationsofbloodglucose.
AnotherChinesestudy[3]performedcontinuousbloodglucoserecordingin20patientswithPCOS
(withnormalcarbohydratetolerance)and20age-matchedhealthywomenwithnormalmenstruation.
MBGandMAGEwerecomparableinbothgroups.Incontrast,thepeakingtimeofpost-breakfast
plasmaglucoselevelofthePCOSgroupwassignificantlylongerthanthatofthecontrolgroup.CGM
diagnosedanabnormalmodeofdailyglucosechangecharacterizedbyadelayedpeakofpost-
breakfastplasmaglucoselevel.
Athirdstudy[4]alsoperformedCGMin45patientswithPCOSwithnormalglucosetoleranceand45
age-matchedcontrolsfemale.Postprandialbloodglucosewassignificantlyhigherinpatientswith
PCOS.
Ourstudyhighlightssomeglycemicdisordersthatcouldpredictapre-diabetesconditioninpatients
withPCOS.Thesedisordersareundetectableonoralglycemictolerancetestandunpredictableby
otherclinicalandbiologicalparameters.Larger-scalecontrolledstudiesareneededtobetterclarify
thesedata.
Conclusion
PCOSisacommonendocrinepathologyinwomenofchildbearingage.Themetabolicdisordersare
frequentinthesepatients.Theaimofourworkwastolookforsubclinicalabnormalitiesin
carbohydratemetabolismusinga72hoursCGM,in20normoglycemicpatientswithPCOS.
TheCGMhasindeedhighlightedsomedisorders,especiallyalowbloodglucoseandevenauthentic
asymptomatichypoglycaemia(<0.50g/l).Thisprofilecouldpredictapre-diabetescondition.
Weemphasizetheimportanceofearlydiagnosisandregularscreeningofmetabolicanomaliesin
patientswithPCOS.TheCGMmightbeinterestingforearlydetectionofsubclinicalglycemic
disorders.
ListOfAbbreviations
ADA:AmericanDiabetesAssociation

8
BMI:bodymassindex
CGM:continuousglucosemonitoring
DM:diabetesmellitus
FBG:Fastingbloodglucose
FI:fastinginsulinemia
HbA1c:glycatedhemoglobin
IR:Insulinresistance
MAGE:meanamplitudeoftheglycemicexcursions
MBG:meanbloodglucose
PCOS:Polycysticovarysyndrome
Declarations
Ethicalapprovalandconsenttoparticipate:Thestudywasapprovedbytheethicscommitteeof
theNationalNutritionInstituteofTunis.Writteninformedconsentwasobtainedfromallparticipants.
Consentforpublication:NotApplicable
Availabilityofdataandmaterials:Thedatasetsusedand/oranalysedduringthecurrentstudy
areavailablefromthecorrespondingauthoronreasonablerequest
CompetingInterests:Theauthorsdeclarethattheyhavenocompetinginterests
Funding:Thisresearchdidnotreceiveanyspecificgrantfromanyfundingagencyinthepublic,
commercialornot-for-profitsector.
Authorscontributions:IKparticipatedintheconception,designofthework,interpretationofdata
andrevisionofthefinalmanuscript.WBShavedraftedthework.HKparticipatedintheconception
andanalysis.RGparticipatedinthewritingofthemanuscript.RBSparticipatedintheacquisitionof
data.CBSsubstantivelyrevisedthemanuscript.MJparticipatedintheacquisitionofdata.Allauthors
readandapprovedthefinalmanuscript.
Acknowledgements:NotApplicable
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Tables
Table1.Timespentoutsidethelimitsof0.7-1.4g/l
1stday 2ndday 3dday Totalof72hours
G>1,40g/l(n=5) 0,04±0,17H 0,08±0,3H 0,3±0,6H 0,14H
G<0,70g/l(n=14) 2,7±3H 0,93±1,52H 0,08±0,24H 1,23H

Table2:ComparisonbetweennormalandpathologicalCGMgroup
 NormalCGMGroup(n=6) PathologicalCGMGroup
(n=14) p
Age(year) 26±8,2 21,3±7,4 ns
BMI(Kg/m²) 32,1±10 33,2±8 ns
Waistcircumference(cm) 97,5±16,3 97,7±15,4 ns
Acanthosisnigricans(n) 2 7 ns
Menstrueldisorders(n) 4 12 ns
Familyhistoryofdiabetes(n) 2 2 ns
FBG(mmol/l) 5,1±0,26 5±0,47 ns
HbA1c(%) 5,4±0,2 5,3±0,4 ns
FI(µUI/ml) 11,2±8,5 24,14±20 0,08
HOMAIndex 2,5±1,9 5,4±4,6 ns
Testosterone(nmol/l) 2±0,7 2,4±0,6 ns
n:numberns:notsignificant

Figures

11
Figure1
Continuousglucosemonitoringshowingsubclinicalglycemicabnormalitiesinourpatients
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