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European Journal of -18-0411 context andrelevance. studies andrandomisedcontrolledtrialswhereavailableattemptedtoprovidetheinformationwithinclinical relationship exists,andwewilldescribethepotentialunderlyingmechanisms.Wehavefocusedmoreonrecent , theadrenals,reproductivesystemandbones.Ineachsection,wewillassesswhetherabidirectional appraise anddescribetheimpactofOSAonendocrinesystemincludingobesity,dysglycaemia,pituitary, the examining theeffectsofOSAtreatmentonendocrineconditionsandviceversa.Inthisreviewarticle,wewillcritically increasingly recognisedinexperimentalandepidemiologicalstudiesthereareanincreasingnumberof development orworseningofOSA.ThisbidirectionalrelationshipbetweenOSAandtheendocrinesystemhasbeen endocrine conditionsthatcanaffectobesityand/orupperairwaysanatomyandstabilityhavebeenimplicatedinthe of multiplehormonesandisimplicatedinthedevelopmentmanyendocrineconditions.Onotherhand, disruption, increasedinflammationandoxidativestress,itisnotsurprisingthatOSAhasanimpactonthesecretion impact onqualityoflife,lifeexpectancyandhealthcosts.AsOSAisrelatedtoobesityassociatedwithsleep Obstructive sleepapnoea(OSA)isacommondisorderthatassociatedwithseriouscomorbiditiesnegative Abstract Birmingham, UK Birmingham, UK,and of Birmingham,UK, University HospitalsofBirminghamNHSFoundationTrust,Birmingham,UK, University HospitalsofCoventryandWarwickshireNHSTrust,Coventry,UK, 1 Aikaterini Lavrentaki obstructive sleepapnoea Mechanisms ofdisease:theendocrinology MECHANISMS OFENDOCRINOLOGY Institute ofMetabolismandSystemsResearch,UniversityBirmingham,UK, https://doi.org/ https://eje.bioscientifica.com Review neuropathy andthepharmacology oftype2diabetesandobesity. consequences ofsleep-related disorders,obesitymanagementandcomplications,-related 2014 from the World Federation. Abd’s research has the following themes: the metabolic apnoea (OSA) in patients with and was awarded a SCOPE National in UoB. HeobtainedhisPhDin2013fromUoB,whichwas focusedontheimpactofobstructivesleep the communicationco-leadinInstituteofMetabolism andSystemsResearch (IMSR)atthe Centre ofEndocrinology, DiabetesandMetabolism (CEDAM),BirminghamHealthPartnersand atBirminghamHeartlands ,theleadfortranslationalresearchneuropathy services inthe of BirminghamNHSFoundationTrust, theleadforweightmanagementresearch anddiabetic Consultant EndocrinologistattheUniversityHospitals University ofBirmingham(UoB),anHonorary Abd ATahrani Invited Author’s profile 10.1530/EJE 6 Department ofEndocrinology,UniversityHospitalsBirmingham NHSFoundation Trust, -18-0411 isaNationalInstituteforHealthResearch (NIHR)ClinicianScientistatthe 1 , Asad Ali 5 Centre ofEndocrinology,DiabetesandMetabolism, BirminghamHealthPartners, 3 © 2019EuropeanSociety ofEndocrinology A Lavrentakiandothers 2 , Brendan G Cooper Printed inGreatBritain 3 , 4 and 3 4 Department ofRespiratoryMedicine, Institute ofClinicalSciences,University Obstructive sleepapnoea Abd A Tahrani Published byBioscientifica Ltd. 2 Department ofRespiratoryMedicine, 1 , 5 , 6 Downloaded fromBioscientifica.com at09/27/202109:41:32AM (2019) Endocrinology European Journalof [email protected] Email to A A Tahrani should be addressed Correspondence 180 180 :3 , R91–R125

R91 –R125 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com Moreover, thewell-establishedhigherOSAriskinmen or ) can alsoimprove OSA. while treatingendocrinedisorders(suchasobesity, system (suchasinsulin resistance, secretion) pressureCPAP)airway hasanimpactontheendocrine addition, OSAtreatment(namelycontinuouspositive the diurnalsecretionpatternofmanyhormones.In can be bidirectional, which is not surprising considering system haveattractedmuchattentionandtheyoften data decreasing thoughwithage( eye movement cessation and is a restorative stage slow waves,furtherdecreaseinmuscletone,possible stage N3ofNREMsleepcharacterisedbyhigh-amplitude the lossofREMandslowwavesleep(SWSordeepis microarousals andchangestosleeparchitecture, suchas rate, sympathetic activity andintrathoracic pressure, brief re-saturation, cyclical changes in blood pressure (BP), associated withrecurrentepisodesofoxygendesaturation/ this article)( see section on activity andlowmuscletone( mixed-frequency thetaEEGwaves,pronouncedeye movement (REM)sleep(characterisedbylow-amplitude, particularly duringthetransitiontosleepandrapideye (UAs) leadingtorecurrentepisodesoftheUAobstruction, OSA is characteried by instability in the upper airways that affects13–33%ofmenand6–19%women( Obstructive sleepapnoea(OSA)isacommondisorder Introduction SWS. REM,rapideyemovement; SWS,slowwavesleep. OSA hasdisruptedsleeparchitecture withlossofREMand a patientwithOSA(bottom).Please notehowthepatientwith Hypnograms andsleepstages of ahealthyindividual(top)and Figure 1 Review The interactions between OSA and the endocrine ) ( 3 , 5 , 7 ). 3 , supplementary data supplementary 4 , 5 , 6 ). Theserepeatedobstructionsare 2 )) ( 2 Fig. 1 A Lavrentakiandothers )) ( given at the end of Supplementary data Supplementary and Supplementary Supplementary 1 ). , OSA andobesityinterplay the ofOSAanditspathogenesisin have providedanoverview understanding ofthepathogenesisOSA;hence,we and viceversa.Someaspectsofthisarticlerequiresome impact ofOSAtreatmentontheendocrinedisorders relationship whenexists,aswellexplorethepotential underlying mechanismsunderpinningthisbidirectional OSA and the , and we will highlight the endocrine disorders( and mortalityassociatedwithOSAavarietyof understanding ofthepathogenesisandcomorbidities the endocrine/metabolicsysteminordertoimproveour is importanttounderstandthelinksbetweenOSAand between sexhormonesandOSApathogenesis.Hence,it vs womenalsoemphasisesthepotentialrelationship greater reductionsinAHI(based onPSG)( (LAGB) resultedingreaterweight loss(5.1vs27.8 to-severe OSA,laparoscopic adjustablegastricbanding 15 among themandrandomisedcontrolledtrials(RCTs) ( ashasbeenshown by severalstudies or bariatricsurgery pharmacotherapy weight suchaslifestyleinterventions, seems tobeevidentregardlessofthemethodlosing favourable impact ofweightlossonOSAanditsseverity withweight loss( UAs collapsibilityobserved to weight stability ( 26% (95% CI18–34%) decrease in the AHIcompared On theotherhand,10%weightlosswasassociatedwith OSA (95% CI 2.2–17) compared to weight stability ( six-fold higherriskofdevelopingmoderate-to-severe of apnoeaandhypopneaeventsperhoursleep) the apnoea–hypopnoeaindex(AHI:averagenumber was associated with 32% (95% CI 20–45%) increase in patients fromWisconsin, a10%weight gain over4 years severity. In a longitudinal study of randomly selected Weight changeshavesignificantimpactonOSAandits The impactofweightchangeonOSA population ( OSA (approx.70%)isalsohigherthanthatofthegeneral prevalence ( OSA ( Obesity isamajorriskfactorforthedevelopmentof Obstructive sleepapnoea , 16 Supplementary data Supplementary In thisarticle,wewillreviewtheinteractionsbetween In aRCT, of60patientswithobesityand moderate- 9 , , 17 10 , 18 , 1 13 11 ). , ). 12 ), which is drivingtheincreaseinOSA ). Obesityprevalenceinpatientswith 8 11 ). . ), partly due to a reduction in Downloaded fromBioscientifica.com at09/27/202109:41:32AM 180 :3 − 14.0 vs 14 kg) and ). The − R92 25.5 11 14 via freeaccess ). , European Journal of Endocrinology to obesity(highloopgain)( volume inobesitycanleadtohypoxaemia andventilatoryinstabilityinthepresenceofincreased wholebodyoxygendemanddue reduced lungvolumeresulting inreducedtrachealcaudaltraction( UA narrowing,intramuscularfatty depositsleadingtoreducedUAmusclesactivityandincreased UAmusclefatigabilityand continuous positiveairwaypressure. ObesitycanleadtoincreasedUAcollapsibilityvia parapharyngealfatdeposition, tumour necrosisfactor-alpha;IL6,interleukin-6;CNS,central nervous system;EDS,excessivedaytimesleepiness;CPAP, that mightleadtoweightgainandtheblueboxesaremechanisms ofpossibleweightlossinOSA.UA,upperairways;TNFA, obstructive sleepapnoeaanditstreatmentonweightthe underlyingmechanisms.PinkboxesarethemechanismsofOSA OSA andobesityinterplay.(A)Thepotentialmechanismslinking obesitytoobstructivesleepapnoea.(B)Thepotentialimpactof Figure 2 respectively; however, OSApersistedinmostpatientsand AHIof39.3 post- (95% CI with areductionintheAHI(WMD Wong A morerecentsystematicreviewandmeta-analysisby (by38.2events/h,95%CI:31.9–44.4)( post surgery OSA severity, by showing a significant reduction of AHI on confirmed thepositiveimpactofbariatricsurgery gastrectomy andgastricbypass( high proportionofOSAresolutionfollowingsleeve showed significantimprovementsintheAHIanda ( AHI (weight change more weightthanthosewhohadpersistentlyelevated a normalsupineAHI(i.e. post hoc behavioural conventional programme) ( (dietary,to lifestyleintervention physical activity and 95% CI events/h; between-groupdifferencewas − Review 1.9 to et al analysisofthisRCT, patientswhoachieved − − − 28.3 to5.3; 29.9, . showed that bariatric surgery wasassociated . showed that bariatricsurgery 17.4)%, − 20.2)); withthepooledmeanpre-and P − .0) ( =0.001) 23.0 ( P 28

= ± ). .8 vr2 yearscompared 0.18) over2

15.1 and12.5 − 21.0 to 19 A Lavrentakiandothers 16 < ). Otherstudiesalso 5/h) lostsignificantly , 17 ). Ameta-analysis − 15 31.6)% vs − − ± 25.1 events/h 11.5 events/h ). Inarecent . events/h 5.6 − 20 6.9 ). 19 The impactofOSAonobesityiscontroversial.One The impactofOSAonweight 27 pathogenesis, assummarisedin in OSAthistrial( of weightlosscorrelatedsignificantlywithimprovements ( onlyover32 weeks lifestyle intervention events/h; 95% CI vs in weight( resultedingreaterreductions with lifestyleintervention conduct. InanotherRCT, liraglutide3 on OSA, although these might be challenging to surgery RCTs remainneededtoaddresstheimpactofbariatric to baselineAHIOanddurationoffollow-up( there washigh between-studies heterogeneity mostly due multiple mechanismssuchasincreasedexcessivedaytime possibility isthatOSAcouldleadtoworseningobesityvia Obstructive sleepapnoea , , 20 − 28 Obesity canaffectmultipleaspectsofOSA 6.1 events/h,estimatedtreatmentdifference: , , 21 29 , 22 , 30 − , 23 5.7% vs , 31 , 24 , , 32 − 25 18 11.0 to , , − 33 ). 26 1.6%, Downloaded fromBioscientifica.com at09/27/202109:41:32AM , , 27 34 ). Inaddition,thelowlung , − 35 P 1.2,

< https://eje.bioscientifica.com , Fig. 2

0.0001) andAHI( 36 P .1) oprd to compared =0.015) ). 180 ( mg dailycombined 22 :3 , 18 23 ). Thedegree , 21 24 ). Hence, , 25 − R93 − , 12.2 26 6.1 via freeaccess , European Journal of Endocrinology https://eje.bioscientifica.com lipase inhibitionandsympathetic activation( increased energy expenditure and lipolysis via lipoprotein weight loss via increased sympathetic activity leading to ( and energyexpenditurehencecancauseweightgain and sympatheticactivityleadingtoreductionsinlipolysis reduces (satietyhormone),intermittenthypoxia gain afterCPAP arenotfullyelucidated.However, CPAP for CPAP) ( change: m compared to control (BMI change: but statisticallysignificantincreaseinBMIandweight from 25RCTs showed thatCPAP resulted inamodest loss. However, asystematicreviewof3181patients would beexpectedthatOSAtreatmentwillleadtoweight is difficultwithoutanappropriatecontrolgroup( OSA diagnosis( ofweightgainintheyearpreceding had alsoahistory 7.4 study ofpatientswithnewlydiagnosedOSAshowed longitudinally islacking.Onesmall( epidemiological evidence for an impact of OSA on weight despite theabove-mentionedplausiblemechanisms, hypercapnia-induced adipogenesis ( of theHPA axisandincreasedcortisolsecretionby could also contribute to increased fat mass by activation high-calorie foodintheafternoonandevening( sleep durationinyounghealthymen,increasedhungerfor (suppression of SWS as happens in OSA) without affecting night ( 95% CI1.80–10.77),comparedtothosewhoslept with OSA and shortsleep duration ( 48 of theseverityobesityinadolescentsandchildren( increased preferenceofcalorie-densefoodsindependent showing thattheAHIwassignificantlyassociatedwith food ( deprivation resultingincorrectivebehaviourofseeking followingenergy which wassimilartowhatobserved motivation andrewardsystembasedonfunctionalMRI, brain regionsrelatedtoemotionalresponsestimuliand restriction was associated with increased activation of the sleep durationandarchitecture ( increased orexin and neuropeptide Y levels), changes to ( sleep disruptionleadingtochangesinhungerandsatiety sleepiness (EDS)leadingtoareductioninphysicalactivity, 55 Review 2 ) andthatvisceralobesitywasincreasedinpatients forcontrolsvs0.134 , ± Nonetheless, ifOSAisacauseofobesity, thenit Furthermore, itisplausible thatOSAcanleadto 56

1.5 45 , 49 57 kg weightgainover12 months, butthesepatients , − ). Inaddition,disruptionofsleeparchitecture 46 0.096 , 37 58 ). This is supported by cross-sectional studies 54 , , 38 ). Themechanismsbehindtheweight 59 53 ±

, 0.718 , ), hencequantifyingtheimpactofOSA 39 60 ) (leptin resistance, increased , , 61 kg forcontrolsvs0.417 ). ± 0.273kg/m 40 A Lavrentakiandothers , < 41 5 51 2 h/night) (OR, 4.40, n , forCPAP; weight − 3 prospective =53) 42 , 0.018 52 , 43 ). However, 62 , ± ± 44 , 0.243kg/ 50 0.718kg 63 Fig. 2B ). Sleep ). OSA ). The ≥ 7 h/ 47 ). , summarise theevidenceregardingT1D. will focusmostlyonpre-diabetes/T2Dbutwealso common inpatientswithT1Daswell.Inthissection,we However, it is now increasingly recognised that OSA is research in this field has focused on pre-diabetes/T2D. As obesityisamajorriskfactorforOSA,muchofthe OSA anddysglycaemia that requiresfurtherinvestigations. to lipolysis( CPAP onincreasinggrowthhormone(GH)levelsleading this mightbeopposedtoacertaindegreebytheimpactof weight gainbyinhibiting sympathetic activity ( the balancebetweentheseopposingmechanismstowards maintenance inpatientswithOSA.CPAP treatmenttilts impacts ofweightgainandlossispotentially net effects of theabove-mentioned opposing mechanisms/ prevention. onT2D or incombinationwithlifestyle intervention, of longdurationtoassessthe impactofCPAP, onits own OGTT ( and thatCPAP loweredthe2-hglucoselevels following in impairedglucosetolerancestatuscomparedtonoCPAP syndrome) suggested that CPAP resultedin improvements with obesity(BMI CI 1.02–1.99)( studies that defined OSAas AHI 95% CI:1.27–1.75),whichremainedsignificanteven in after adjustment for age, sex and BMI (adjusted RR: 1.49, showed thatOSAwasanindependentriskfactorforT2D recent meta-analysisofeightstudies(63,647participants) independent riskfactorforthedevelopmentofT2D. A populations ( criteria usedtodefineOSAanddifferencesinstudy estimates isduetodifferentdiagnosticmethodsand with OSA(15–30%)( severe OSA),andahighprevalenceofT2Dinpatients in patientswithT2D(8.5–86%,23.8–70%moderate-to- 5 sectional studiesshoweda high prevalence of OSA (mild: risk factorforOSAandT2D( ( be associatedwithvariouscomorbidities,includingT2D In generalpopulationstudies,OSAhasbeenshownto Epidemiology Obstructive sleepapnoea 9 ≤ ), whichisnotsurprisingsinceobesityacommon AHI Longitudinal studieshavealsoshownthatOSAisan 73 <

15; moderate:15 ). However, thereremainsaneedforlarge RCTs 64 67 ). Theabove,however, isonlyahypothesis 72 , ). AsmallRCTof12 weeks in80patients 68 > , 45 kg/m 69 7 , , 66 Downloaded fromBioscientifica.com at09/27/202109:41:32AM 70 ). Thisvariationinprevalence , ≤ 2 71 AHI andmostlywithmetabolic ). ≥ 5 (adjusted RR: 1.42; 95% < 7

30; severe:AHI , 180 65 :3 ). Severalcross- Fig. 2 R94 ), but ≥ 30) via freeaccess European Journal of Endocrinology to othertissues( which pancreatic dysfunction andIRviaincreased oxidativestress( (based onIVGTT)( secretiondespitereductionsinsensitivity 75.4–98%) resultedinblunted,ratherthanincreased, IH (24.3 experimental studies in healthy adults showed that 5 death ( in IR, intermittent hypoxia(IH)andsleepfragmentation to There are several putative mechanisms linking Mechanisms: OSAleadingtodysglycaemiaandT2D with pre-diabetes(RCT)( severe OSAwithoutdiabetes(uncontrolledtrial)( β in patients with T2D ( found inamorerecentstudy( despite adjustment for obesity ( and higher AHIwas associated with lower tolerance test (IVGTT))compared to healthycontrols; index duringfrequentsamplingintravenousglucose had a lower without diabetes,patientswithmoderate-to-severeOSA examined in theliterature. In one study of patients − (mean differenceinHOMA-IR: showed afavourableeffectofCPAP onIRvsnoCPAP recent meta-analysisofsixRCTs ofadultswithoutdiabetes In supportoftherelationshipbetweenOSAandIR,a EDS vswithoutdespitebeingmatchedforBMI( between OSAandIRwasonlyevidentinpatientswith studies asBarcelo inthe different associations between IRand OSA observed Variation inEDSmightcontributetothevariation that therelationshipisnotdependantonobesity( between OSAandIRwaspresentinleanmen,suggesting the studiesshowedanassociation( variations in the definitions of OSA and IR, but most of between OSAandIRhadconflictingresults,dueto dysfunction ( by theeffectsofOSAoninsulinresistance(IR)and The impactofOSAonincidentT2Dislikelytobemediated OSA andinsulinresistance -cell function in compliantpatients with moderate-to- 0.11, Review Fig. 3 β In rodentmodels,IHhasbeenshowntoincrease The impactofOSAon -cell dysfunctionanddysglycaemia( P 83 . .0) ( =0.008) events/h, averageoxygensaturation90.6%,range ) andimpair β -cell function (measured using the disposition 7 ). Studiesthatexaminedtherelationship 87 77 β -cells arelessabletohandle compared , ). t al et 88 85 80 , ). ChronicIHcanleadto β 89 -cell function( 82 . showedthattheassociation ). Similar to IR, CPAP improved ), andincreasedinflammation ). β -cell functionismuchless 79 − 78 A Lavrentakiandothers 0.43; 95%CI: ) andinanotherstudy ). Similar results were β -cell function 65 ). Theassociation 84 33 ). Resultsfrom β ) summarised -cell function − 74 0.75 to 81 β β β , -cell -cell -cell h of 76 75 86 ) or ). ). ),

acoustic stimuli of varying intensity and frequency for acoustic stimuli of varying changing sleep duration or REMsleep) was achieved via suppression of SWS(withoutawakening the subjects, experimental studyofyounghealthyadults,all-night fat depositionintheliverandmusclerustingIR( can increasefreefattyacid(FFA) releaseleadingtoectopic structures, ILandTNFA) ( macrophagesincrown-like to M1-proinflammatory (increased CD8 was anindependentpredictor forincidentwitnessedsleep and possibleOSAprospectively andshowedthatHOMA-IR longitudinal studyassessed therelationshipbetweenIR of OSAinpatientswithT2D arecurrentlyunknown.One 1.83) ( OSA, especiallyiftheywerewomen(1.43;95%CI:1.11– further patientstreatedwithinsulinhadhigherrisk of hazard riskofincidentOSA1.53(95%CI:1.32–1.77)and based studyof151,194participantswithT2Dshowed a without T2Dremainsunclear. Recently, apopulation- is higherthananage-andobesity-matchedpopulation T2D aswedetailedabove,butwhetherthisprevalence studies showedahighprevalenceofOSAinpatientswith OSA hasnotreceivedmuchattention.Manycross-sectional widely studied,theimpactofT2Danddysglycaemiaon While theimpactofOSAonglucosemetabolismhasbeen The impactofdysglycaemiaonOSA 105 ( between OSAandT2D,whicharesummarisedin neurohormonal mechanismsareinvolvedinthelinks in cortisollevels( increased sympatheticactivityandinsomecaseschanges sensitivity and release (based on IVGTT) ( of 8–13 sensitivity (by25%, which issimilartoaweightgain three nights( to theeffectsofOSAonglucosemetabolism( muscle ( liver anddownregulation of HIF1a and HIF2a in skeletal which was accompanied by upregulation of HIF1a in the skeletal muscleandadiposetissue,butnotintheliver in insulin receptorexpressionandphosphorylation effects ( also bemediatedbyhypoxia-induciblefactor(HIF) The impactsofchronicIHandoxidativestressonIRcould Obstructive sleepapnoea 30 , , Changes insleeparchitecture canalsocontribute 39 106 114 , 92 kg) without a compensatory increaseininsulin kg) withoutacompensatory 93 , 51 107 ). In addition, the incidence and natural history ). Inaddition,theincidenceandnaturalhistory ). In rodents, 35 days ofchronicIH decreased ). Inrodents,35 days ). , 65 , 94 108 , ). Thisresultedinareductioninsulin + 96 cytotoxic T-cells recruitment, shift β , -cell functionwereassociatedwith , 109 94 97 , , , Downloaded fromBioscientifica.com at09/27/202109:41:32AM 98 95 110 90 , ). Inaddition,severalother 94 , , 99 111 91 ). These changes in insulin , https://eje.bioscientifica.com ). Inaddition,chronicIH 100 , 112 , 180 101 , 113 :3 , 102 ). , 94 103 ). Inan , Fig. 3 R95 104 90 via freeaccess ). ,

European Journal of Endocrinology https://eje.bioscientifica.com patients withT2Dandthuscan haveanegativeimpactonOSA( independent predictorsofincident witnessedapnoeassuchasHOMA-IR,hypertriglyceridaemia andsmokingarealsocommonin with T2Disoftenassociated weightgain( improvements inglycaemiccontrol mighthaveafavourableimpactonOSA.Furthermore,treatment intensificationinpatients be relatedtotheseverityofhyperglycaemiaindependently obesityandsmoking( 117 pulmonary volumesandfunctionscomparedtohealthyindividuals whichcouldaffectUAstability( ventilatory driveandcentralrespiratoryresponsestohypercapnia ( mechanism inpatientswithpre-diabetesordiabetesisautonomic neuropathy,whichmightimpactonUAinnervation( predictor ofthedevelopmentandprogressionNAFLD( subsequent effectsoninsulinsensitivity( (NAFLD) andprogressiontosteatosisinthosepatients,due ectopicfataccumulationandhepaticinflammation,with CPAP ( signalling, resultsincarotidbodychemosensoryreflexandhencetoincreasedsympatheticactivity( increased sympatheticactivitywhichcancontributetotheIR( ( CPAP onIR( Interestingly, CPAPtreatmentcaninterruptmostoftheabove-mentionedpathwayswhichmightexplainfavourableeffects of oxidative stressandinflammation),increasedghrelin,leptinreducedadiponectin( pituitary–adrenal (HPA)axis,changesinthegrowthhormone(GH)/IGFhyperaldosteronism(viahypokalaemia,increased inflammation leadingtoIRan hypothalamic-pituitary-adrenal axis;T2D,type2diabetes.IHandsleepdisruptionresultinincreasedoxidativestress SWS, slowwavesleep;CB,carotidbody;FFA,freefattyacid;ROS,reactiveoxygenspecies;NAFLD,nonalcoholicliverdisease; HPA, The potentialbidirectionalrelationshipandtheunderlyingmechanismsbetweenobstructivesleepapnoeatype2diabetes. Figure 3 97 Review , , 98 118 104 , 99 , 119 , , 100 105 96 , 120 ). However,theimpactofCPAPonleptinandadiponectinhasnotbeenconsistentbetweendifferentstudies , ). AnothermechanismthatlinksOSAtodysglycaemiaistheincreased riskofnonalcoholicfattyliverdisease 101 , 121 ). Furthermore,patientswithOSA(duetorecurrentmicroarousals,thelossofSWSandIH( ) anddiffusioncapacityforcarbonmonoxide( β -cell dysfunction.Inaddition,OSAcanleadtodysglycaemiaviaactivationofthehypothalamus– A Lavrentakiandothers 106 , 107 124 ). Arecentmeta-analysisofninecohortstudiesshowedthatOSA wasa ), whichcouldleadtothedevelopment orworseningofOSA( 107 ). Ontheotherhand,dysglycaemiacouldleadtoOSA.Oneplausible 6 , 108 109 Obstructive sleepapnoea 112 ). , 30 110 , 113 , 102 ). Inaddition,T2Disassociatedwithreduced , 122 ). TheIH,viaoxidativestressanditsimpactonHIF , 123 123 ). TheimpactofT2Donthelungsseemsto ), whichraisesthepossibilitythat Downloaded fromBioscientifica.com at09/27/202109:41:32AM 40 111 , 103 48 , , ), thatisreversibleby 112 90 , , 91 180 113 , 10 92 :3 , 114 , , 59 125 93 )) have , , 115 ). Other 94 6 ), , , 95 116 R96 ). , via freeaccess European Journal of Endocrinology ( correlated withHbA1cbetter thantheAHIduringNREM tends tooccurlaterduringsleep andtheAHIduringREM have animportantimpacton glycaemiccontrolasREM et al night comparedtobelow4 CPAP; thepositiveRCTshowedCPAP usageof5.2 difference betweentheseRCTs wascompliancewith explain the conflicting results.However, an important these RCTs betweenthe CPAP andthecontrol armto changes inweightoranthropometricsmeasures in ( duration (3vs6 months) of CPAP hadbaselineHbA1cof7.6%)( of 7.3%,whiletheRCTthatshowedpositiveeffects example oneofthenegativeRCTs hadabaselineHbA1c population ( conflicting resultscouldbeduetodifferencesinstudies was no change in HbA1c in the control group ( − loweredHbA1cby RCT showedthatCPAP for6 months CPAP hadnoimpactonHbA1c( showed conflicting results. Two ofthese RCTs showedthat HbA1c overtheshortterm( glycaemic variability, postprandialglucoselevelsand parameters inpatientswithT2D. possibility thatOSAtreatmentmightimproveglycaemic adjustment forconfounders)( during REM sleepand not during NREM sleep (after between AHIandHbA1cwasonlyevidentforthe Interestingly, onestudyshowedthattherelationship severity iscorrelatedwithworseglycaemicmeasures( OSA 0.7–3.7%)( (difference inHbA1cbetweenpatientswithandwithout patients withoutOSAdespiteadjustmentforconfounders , glycaemic variability and HbA1c compared to showed thatpatientswithOSAhadworsefastingplasma Several cross-sectional studies in patientswithT2D OSA andglycaemiccontrolinT2D OSA inpatientswithT2D 129 117 worsening ofOSAassummarisedin dysglycaemia/diabetes canleadtothedevelopmentor 1.31; 95%CI1.13–1.51)( years(OR: apnoea (notformallydiagnosedOSA)over6 82 0.4% (95% CI: Review , , , Several uncontrolledtrialsshowedthatCPAP improved Several possiblemechanismsmakeitplausiblethat . ( 136 118 130 138 ). Hence,thereisstillaneed forwell-designed , , 119 131 , 140 β , -cell reserve), baselineglycaemiccontrol(for -cell reserve), , 120 132 ). LongerCPAP durationpernightmight − 7 , 0.7% to ). , 121 133 , 122 , 115 138 134 − 65 , 0.04%; h/night inthetrialbyWest 123 ). ). Therewerenosignificant , , 137 135 , 138 A Lavrentakiandothers 136 124 ). However, threeRCTs Fig. 3 P ). Inaddition,OSA , .2) hl there while =0.029) ). Thisraisedthe , 139 125 ( ), whileanother , 7 139 126 , 11 140 ) orstudy , , 127 115 ). These , h per , 128 116 7 ). , , T2D asshownin macro- and microvascular complications in patientswith that OSAcouldleadtothedevelopmentorprogressionof Several plausiblemechanismshaveledtothehypothesis OSA andvascularcomplicationsinpatientswithT2D in patientswithT2D. whether CPAP can (or cannot) improve glycaemic control RCTs oflongerCPAP durationtoanswerthequestion randomised to early ( CPAP inanRCTwhichpatientswithT2DandOSAwere of after3 months reductions inBPlevelswereobserved and diastolic ( systolic (mean change: monthslowered newly diagnosedOSA,CPAP for9–12 studyshowedthatinpatientswithT2Dand observational with T2D has not been studied widely. A retrospective OSA on DR is more related to disease progression rather with maculopathy( systematic review also suggested that OSA was associated OSA wasassociatedwithgreater DRseverity( (DR), butthattherewassome evidencetosuggestthat that OSAwasassociatedwithdiabeticretinopathy studies concludedthattherewasnoconvincingevidence been publishedalthoughseveralareongoing. studieshave were cross-sectionalandnointerventional and autonomicneuropathy( neuropathy, chronickidneydisease(CKD),retinopathy related microvascularcomplicationsincludingperipheral patients withT2D. RCT publishedregarding the impactofCPAP onCVDin BMI and hypertension ( 3.74, with diabetesmellitus(adjustedHR:2.03,95%CI:1.10– inpatients cerebrovascular events(MACCEs)over3 years associated withincreasedriskofmajoradversecardiacand (PCI),OSAwas had percutaneous intervention coronary ( 1.4–9.0; HR: 2.2;95%CI:1.2–3.9; disease(adjusted artery OSA predictedincidentcoronary and anormalbaselineexercise echocardiographytest, ( disease artery 95% CI:1.03–6.42)butnotwithcoronary ofstroke(adjustedOR:2.57; between AHIandahistory ( Obstructive sleepapnoea 150 149 148 The relationshipbetweenOSAandCVDinpatients A recentsystematicreviewof15cross-sectional OSA hasbeenshowntobeassociatedwithdiabetes- ). In another recent study of 1311 patients who ). Inalongitudinalstudyin132patientswithT2D ). ThesleepAHEADstudyshowedanassociation P

= P 0.023) afteradjustmentforage,sex,ethnicity,

<

.1 vramda olwu f49 years 0.01) overamedianfollow-upof4.9 − 3.69, Fig. 4 152 < − 1 week) or late (1–2 months) CPAP ( ). Itisplausiblethattheimpact of 5.53 to 141 Downloaded fromBioscientifica.com at09/27/202109:41:32AM − 151 6.81, 95% CI: P

, = ). There is no interventional ). There is no interventional 142 0.01) andheartfailure(3.5; 71 https://eje.bioscientifica.com − ). Mostofthesestudies , 1.85) BP ( 143 180 , 144 :3 − 9.94 to , 145 147 , 152 ). Similar 146 − ). The R97 3.67) ). via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com after adjustmentforpotential confounders(adjusted DR (18.4%vs6.1%; without OSAtodevelop pre-proliferative/proliferative months, patientswithOSAwere morelikelythanpatients ( (adjusted OR:2.7,95%CI:1.2–5.9, OR: 2.3;95%CI:1.1–4.9; associated withsightthreateningDR(STDR)(adjusted proliferative DR( was associatedwithprogressiontopre-proliferativeand was notassociatedwiththedevelopmentofDRbut longitudinal study in patients with T2D in which OSA with T2DandOSA.Thisissupportedbyarecent vulnerable totheeffectsofIHthatoccurinpatients demands overnightwillmaketheretinaparticularly of hyperglycaemia)( than thedevelopmentofdisease(whichisafunction PARP activationandimpairedmicrovascularfunctioncomparedwithpatientstype2diabetesonly( Our ownworkhasshownthatpatientswithOSAandtype2diabeteshaveincreasedoxidativenitrosativestress OSA andhyperglycaemiasharesimilarmolecularconsequencesincludingoxidativestress,PKCactivationAGEproduction. in OSA.Recurrentarousalsalsoactivatethesympatheticnervoussystemandthusleadtoendothelialdysfunction( and theincreaseintransmuralpressuregradientsovervesselwallscouldalsocontributetoendothelialdysfunctionobserved responsible foratherosclerosis,whichinturncanalsoexacerbateoxidativestress( induced byoxidativestressleadtohypertension.Bothhypertensionandinflammationpromoteendothelialdysfunction exacerbate oxidativestress.Thisviciouscircleleadstocardiovascularmorbidity.Sympatheticoveractivityandthedecrease inNO induces inflammation,whileincreasedproinflammatorycytokines,adhesionmoleculesandprocoagulantactivitiescan andinflammationplayakeyroleinOSAthedevelopmentofassociatedcardiometabolicmorbidities.Oxidative stress glyceraldehyde 3-phosphatedehydrogenase.(A)Obstructivesleepapnoeaanditscardiometabolicconsequences.IH,oxidative protein kinaseC;AGE,advancedglycationendproduct;PARP,polyADPribosepolymerase;AR,aldosereductase;GAPDH, C-reactive protein;IH,intermittenthypoxia;NO,nitricoxide;NOx,totalnitrateandnitrite;OSA,obstructivesleepapnoea; PKC, microvascular complications(B)-AdaptedwithpermissionfromTahrani (A) MechanismsrelatingOSAtocardiovasculardisease-AdaptedwithpermissionfromJullian-Desayes Figure 4 153 Review ). After a median follow-up of 43.0 (IQR: 37.0–51.0) 153 P ). Inthislongitudinalstudy, OSAwas

= 7 ). Theincreasedretinaloxygen 0.02), whichremainedsignificant P .3) n maculopathy and =0.035) A Lavrentakiandothers P .1 a baseline at =0.01) OSA vswithout(49.3 vs23.8%, with T2D,CKDprevalence washigherinpatientswith CI: 1.13–2.64)( OSA andCKDinpatientswith T2D(pooledOR:1.73,95% cross-sectional studies, there was an association between assessing theimpactofCPAP onDRareongoing. improvement intheoedema( associated withimprovementinvisualacuitybutwithout individuals withOSAandsignificantmacularoedema was CPAP treatment by anotherproof-of-conceptstudythatshowed non-compliant patients ( to developpre-proliferative/proliferativeDRcompared to were compliantwithCPAP weresignificantlylesslikely in thisstudy, patientswithmoderate-to-severeOSAwho OR: 5.2;95%CI:1.2–23.0; Obstructive sleepapnoea In asystematicreviewoftwolongitudinalandten et al . ( 131 ) inpatientswithtype2diabetes.CRP, 140 155 ). Inaddition,intrathoracicpressureswings ≥ 2.5 ). Inalongitudinalstudyin patients /ih PPoe months in h/night CPAP over 6 Downloaded fromBioscientifica.com at09/27/202109:41:32AM 153 ). Thisfindingwassupported P .3 ( =0.03) 141 154 et al ). 180 ). Currently, RCTs 153 . ( P :3 145

< ). Interestingly .0) which 0.001), 140 ) and ). (B)Both R98 via freeaccess European Journal of Endocrinology prevalence of OSA in patients with T1D and cardiac normal BMI( in whichOSAwaspresent in 32%ofthepatientswith shown inacross-sectionalstudy of199patientswithT1D mechanism forthehighprevalence ofOSAinT1Das 16.7% (95%CI:1.1,34.5)( severe OSA (AHI between studies ( (31.2–72.6) reflectingthesmallsamplesizevariation among adultpatientswithT1D,butthe95%CIwaswide the prevalence of OSA (defined as AHI of developingOSA( patients withT1Dwhichmightfurtherincreasetheirrisk studies suggestthatobesityprevalenceisincreasingin rather thanobesity( in T1Dmightbemorerelatedtoautonomicneuropathy particularly thatsomerecentstudiessuggestOSA is increasinginterestinOSApatientswithT1D, much lessattentionthaninT2D( patients with T2D, examining OSA in T1D received As patientswithT1Dtendtobeleanorleanerthan OSA andT1D and itscomplicationsareongoing. between OSAandCPAP ondiabetes-relatedneuropathy T2D. CohortstudiesandRCTs assessingtherelationship both large and small fibre neuropathy in patients with ( offootulcerationinpatientswithT2D and ahistory fibredensity(basedonskinbiopsies), epidermal nerve ( adjustment (OR:2.82;95%CI:1.44–5.52; (60 vs 27%, Screening Instrument(MNSI)vspatientswithoutOSA peripheral neuropathy based on the MichiganNeuropathy sectional study, which showed that OSA is associated with neuropathy inpatientswithT2Dwasexaminedacross- P having OSA( − vs without OSA (median: 2.5 (0.7)years,eGFRdeclinewasgreaterinpatientswith macro-albuminuria ( also associated with lower eGFRand more micro- and (adjusted OR:2.64,95%CI:1.13–6.16, remained significantafteradjustmentforconfounders 141 143

1.6%; = Review 0.02) werepredictorsoflowerstudy-endeGFR( Autonomic neuropathy was suggested as one potential In asystematicreviewoffour studies ( The relationshipbetweenOSAandperipheral ). ThesestudiessuggestthatOSAwasassociatedwith ). In addition, OSA wasassociated with lower intra- − 7.7 to5.3%), P B 161

< =

0.001), which remained significant after − ). Andanotherstudyshowed ahigher 3.8, 160 ≥ 159 15) in the same meta-analysis was 156 158 ). The prevalence of moderate-to- P P

= ). .0) ( =0.002) ). Afteranaverage follow-up of 0.044) andhigherAHI( ). Inaddition,epidemiological 160 − 6.8%; IQR: ). A Lavrentakiandothers 156 157 ). Afteradjustment, P ). However, there .2. S was OSA =0.02). n − ≥ 186 patients), =186 16.1 to 2.2 vs 5) was 51.9% P B =0.003) 156 = − 4.6, ). play animportantroleinthewell-establishedlinks bidirectional ( The links between OSA and RAAS activation are potentially system (RAAS) OSA andtherenin–angiotensin–aldosterone large well-designedstudiesareneeded. of OSAinpatientswithT1Dremainpoorlyexploredand 167 functioninadultpatientswithT1D( pulmonary monoxide ( gas exchangewithlowerdiffusingcapacityforcarbon volumes (FVC, PEF, MMEF) ( children andadolescentswithT1Dincludinglowermean might contributetothehighprevalenceofOSAin but without neuropathy (67 vs 23%) ( autonomic neuropathycomparedtopatientswithT1D 0.58–2.07, but without OSA (mean difference: 1.32 significantly higher PAC vspatientswithhypertension separately, patients withhypertensionandOSAhad examined inpatientswith andwithouthypertension dL; 95%CI: in patientswithOSAvsno(meandifference:0.95 towards higherplasmaaldosteroneconcentration(PAC) CI: 2.00–4.79, those withoutOSA(meandifferenceof3.39 significantly higherinpatientswithOSAcompared to 2.48, (PRC) (meandifference0.95 CI: activity (PRA)(meandifference:0.17 no significantrelationshipbetweenOSAandplasmarenin patients withhypertension ( included middleagemenandeightofthem (mostly studies andtheyincludedarelativelysmallsamplesize analysis included 14 studies, all but one were case–control between OSAandRAASactivation( patients withoutOSA( aldosteronism (PA) inpatientswithOSAcomparedto some studiessuggestedahigherprevalenceofprimary of the RAAS due to cyclical/IH ( patients with OSA is mainly attributed to the activation hypertension-RH) ( between OSAandhypertension(particularlyresistant Obstructive sleepapnoea − , A recentmeta-analysishasexaminedtherelationship The pathophysiology of in 0.22 to0.55, 168 P .3 ( =0.23) < ). Thenaturalhistory, impactandpathogenesis 100, range:12–120)( P 165 .05 ( =0.0005) − 0.16 to2.07, i. 5 Fig. 174 ). Therearesimilarfindings ofimpaired P

< P ). However, angiotensinIIlevelswere

Fig. 5 .00) ( 0.00001) = 0.40)) orplasmareninconcentration ). Hyperaldosteronismmightalso 174 173 Downloaded fromBioscientifica.com at09/27/202109:41:32AM ) ( ). ). 9 P 174 , .9 ( =0.09) 169 ng/mL (95%CI: 174 174 ). Themeta-analysis found https://eje.bioscientifica.com , 163 170 ). Therewasatrend ). Thestudiesgenerally 174 ng/mL perhour(95% 180 , , 172 162 164 171 ). However, when 174 :3 ). In addition, ng/dL; 95% CI: ). Other factors ) and impaired , ). Themeta- 172 ng/L; 95% , − 173 0.58 to R99 ). 166 ng/ via freeaccess , European Journal of Endocrinology https://eje.bioscientifica.com further byoedemaduetofluiddisplacementduringrecumbencyovernightparticularlyinpatientswithRH( fluid retentionresultinginUAoedema,increasedresistanceandcollapse( non-significant trend.TheincreasedriskofOSAinpatientswithhyperaldosteronismisplausibleduetosodium and rodent models( ( activation ofthecarotidbodybyangiotensinIIandresultedinincreasedreninaldosteronelevelsleadingto BP aldosteronism; MR,mineralocorticoidreceptors.Inrodentstudies,IHpromotedangiotensinIandAT1expression,increased the mechanisms. IH,intermittenthypoxia;RAAS,renin–angiotensin–aldosteronesystem;RH,resistanthypertension;PA,primary The potentialbidirectionalrelationshipbetweenobstructivesleepapnoeaandhyperaldosteronismtheplausiblelinking Figure 5 aldosterone (based on 24 monthsofCPAP resultedingreaterreduction that 6 randomised toCPAP ( 179 angiotensin II and aldosterone levels ( hypertension (mostlyRH)showedthatCPAP lowered patients withRHandhyperaldosteronism( ( significantly with aldosteronelevels PAC andurinary analysis, anotherstudyshowingthattheAHIcorrelated OSA and PAC ( anti-hypertensives didnotaffecttherelationshipbetween measurements; however, ameta-regressionshowedthat be attributedtothemedicationusedpriorRAAS definition ofOSA( heterogeneity, which could bedue to variations in the 159 r =0.568, Review ). OneRCTinwhich117 patientswithRHwere , Several uncontrolledstudiesinpatientswith The above-mentionedmeta-analyseshadhigh 169 , 170 P =0.0009; ). Inaddition,oxidativestresshasbeenshowntoincreasetheactivationofmineralocorticoidreceptors(MR)in 171 174 ). WhetherOSAisassociatedwithreninactivationsremainstobeexploredasthecurrentstudiesshowa ). Supporting the findings of this meta- 174 r n =0.533,

= ). Theheterogeneitycanalso 57) vsnoCPAP ( P .0, epciey in respectively) =0.002, A Lavrentakiandothers h ) compared 176 n 175 0 showed =60) , ). 177 , 178 , is shownin impact ofOSAontheRAAS and themechanisticpathway ( difference: aldosterone levelscomparedtono/shamCPAP (mean the above-mentionedRCT)showedthatCPAP lowered studies and two RCTsobservational (did not include with worse hypoxia ( nocturnal BP, notusingspironolactoneandwithpatients those withuncontrolledhypertension,nondipping in on loweringaldosteronewasparticularlyevident in showed onlyatrend( P difference: to thecontrolgroupinper-protocolanalysis(mean hyperaldosteronism might leadtoorworsenOSA Obstructive sleepapnoea 181 .2) ( =0.027) On theotherhand, RAAS activationand Chronic IHseemstoplayanimportantroleinthe ). 159 180 − − Fig. 5 , 0.236, 95%CI: 3.3 176 ). However, the intention-to-treat analysis μ ( , g/24 177 172 180 , , h; 95%CI: 178 176 Downloaded fromBioscientifica.com at09/27/202109:41:32AM ). A recent meta-analysis of three P ). Thismighthavebeenworsened

= , 0.07). TheimpactofCPAP 177 − 0.45 to , 178 − , 159 180 6.1 to 182 , :3 − 178 , 0.02, 183 ). − 0.4 , 184 P =0.034) μ g/24 h; R100 , 185 via freeaccess ). European Journal of Endocrinology ( sleep (whichisconsistentwith theriseinearlymorning) levels followedbyincreased cortisolsecretioninlate onset andSWSareassociated withadeclineincortisol and iscloselyrelatedtosleep stages( Cortisol secretionhasawell-describedcircadian rhythm (HPA) axis OSA andhypothalamic–pituitary–adrenal 189 usually resolvewithCPAP treatmentorweightloss( and series,theclinicalbiochemicalfeatures are rare but have been reported in multiple case reports phaeochromocytoma) ( of acatecholaminesecretingtumour(i.e.pseudo- features ofphaeochromocytomawithoutthepresence with hypertensionandtheclinicalbiochemical is importanttonotethatpatientswithOSAcanpresent CVD risk and that CPAP compliance is often not optimal. needed, particularlythatOSAisassociatedwithincreased RCTs assessingtheimpactofMRantagonistsonOSAare OSA arescreenedforPA ( of PA recommend that patients with hypertension and guidelines oftheEndocrineSocietyonmanagement be usefulinpatientswithhypertensionorPA andOSA. worsen OSAandsuggestthataldosteroneantagonistscan studies support the notion that hyperaldosteronism could from 22.5(14.7)to12.3(12.1)( ( patients withPA whohadPSGs,havingMRantagonists P the AHIbyameanof (one RCT)andconcludedthatspironolactonereduced systematic reviewandmeta-analysisfoundthreestudies 39.8 improvedOSAseverity(basedonPSG)(AHI: for 8 weeks) study inpatientswithRH,spironolactone(25–50 associated withlowerAHI( study ofpatientswithRH,spironolactonetreatmentwas 95% CI: 1.3–2.6) ( diabetes mellitus and heart failure (adjusted OR: 1.8; hyperaldosteronism afteradjustmentforage,sex,BMI, and hyperaldosteronism compared to those without developing OSAwashigherinpatientswithhypertension study,retrospective cohortregistry-based theriskof via multiplemechanismsasdetailedin n 194

< Review

= .00) ( 0.00001) , 13) oradrenalectomy( Although notdirectlyrelatedtoRASactivation,it Finally, duetothelinksbetweenOSAandPA therecent ). Ontheotherhand,cortisol mightimpactonsleep ± 190

19.5 vs22.0 , 191 ). 175 ). Furthermore, in a small study of 20 ± 186 . events/h; 6.8 − ). Moreover, in a cross-sectional 21.12 (95%CI: 110 173 n 187 ,

= ). Furthermore, well-designed 189 7) resultedinAHIreduction ). Inanotheruncontrolled A Lavrentakiandothers , P 190

< P .2 ( =0.02) .5 ( 0.05) , − 191 192 27.47 to ). Thesecases 188 , i. 5 Fig. 185 193 ). Arecent mg daily ). These ). Sleep − . Ina 14.77, 110 , to obeseandleancontrols( stimulation werehigherin patients withOSAcompared Another studyalsoshowedthatACTHresponsestoCRH activation comparedtoobesecontrols( while theothershowedthatOSAwasassociatedwithHPA between patientswithOSAandobesecontrols( one showednodifference in mean24-h plasma cortisol 24-h cortisolprofilereportedcontradictingresultsas point measurements( measurements over24 However, onlytwoofthesestudieshadplasmacortisol HPA activationinpatients with OSAin6/7studies ( to eitherobeseorleancontrol,therewasnoevidenceof studies thatcomparedcortisollevelsinpatientswithOSA respectively) ( levels: and ODIcorrelatednegativelywithmorningcortisol even suggestedthatOSAmightinhibittheHPA axis(AHI relationship between OSA and the HPA axis, while some with variabilityincompliance.Somestudiesshowedno without OSA,smallsamplesizesandshortCPAP duration profile), variabilityinmatchingbetweenpatientswithand obesity, thesamplingfrequency(singletimepointvs24-h conflicting resultsduetotheconfoundingeffectsof The impactofOSAonHPA axisiscontroversialwith OSA andHPAaxisactivation SWS andpromotesnocturnalawakening( architecture, for example, HPA axis hyperactivity inhibits on cortisol levels (blood or salivary) ( on cortisollevels(bloodor salivary) eight uncontrolledstudies assessed theimpactofCPAP ofCPAP ( this deficitwascorrectedafter3 months with OSAcomparedtoobesecontrols( (ONDST) wassignificantlylesspronouncedinpatients following overnightdexamethasonesuppressiontest cortisol inhibition OSA vs obese controls, the salivary cortisolwasnotdifferentbetweenpatients with salivary stimulation. Carneiro be relatedtothedynamicresponsesHPA inhibitionor simply relatedtobasalor24-hcortisolprofilesbutmight aspect isthattheimpactofOSAonHPA axismaynotbe of the sleep architecture ( nocturnal HPA activationwhenthereisIHanddisruption with OSAandobesityvsobesecontrols,consistent levels between23:00 study byVgontzas necessarily be consistent over the 24-h period, as the Obstructive sleepapnoea In thesameabove-mentioned systematicreview, However, theimpactofOSAonHPA axismaynot r = − 0.444, 195 , 196 et al P h and07:00 .0 and =0.002 199 , . showedthatmeanplasmacortisol t al et 197 h, whiletheresthadsingletime Downloaded fromBioscientifica.com at09/27/202109:41:32AM 201 ). Thetwostudiesthatmeasured , . showed that although basal 202 198 ) ( Fig. 6 ). ). Inasystematicreviewof https://eje.bioscientifica.com h werehigherinpatients ). Another important r 180 = 196 − 199 201 :3 0.381, 193 ). Interestingly, ). Fivestudies ). ). P =0.011 R101 200 196 199 via freeaccess ). ), ). European Journal of Endocrinology https://eje.bioscientifica.com HOMA score,serumcortisol remainedindependently vs 23%, to age-,gender-andBMI-matched controls( was higherinwomen with active CS ( exogenous) ( with Cushing’s syndrome(CS)(whetherendogenousor Several studieshaveshownthatOSAiscommoninpatients OSA inpatientswithCushing’ssyndrome 212 (even whenbrief),sleeprestrictionandIH( be mediatedviamechanismsrelatedtonightawakenings single time points. The effects of OSA on the HPA axis can can lowercortisol24-hprofileratherthanlevelsat particularly nocturnallyandthatCPAP (14 days to3 months) there isevidencethatOSAassociatedwithHPA activation lowered after2 monthsofCPAP ( blood cortisollevelscomparedtocontrols,whichwere women whichshowedthatOSApatientshadhigher24-h in arecentstudyofnonobesemenandpostmenopausal relationship betweenOSAandHPA axiswereaddressed The confoundingeffectsofobesityandgenderonthe cortisol inmenandwomenwithobesityOSA( days,showedthatCPAP canlowermorningsalivary 14 were over3-monthperiod.Aslightlylongerstudyof that showedpositiveimpactofCPAP oncortisolwhich this studywasovera1-weekperiod,unlikethestudies any effecton24-hcortisolprofile( study showedthat8 negative studies( more frequentlyduringthe24 showed favourable impacts of CPA measuredcortisol ( (blood andsalivary) three studiesshowedthatCPAP loweredcortisollevels showed noimpact( Review , Overall, while the studies showed conflicting results Overall, whilethestudiesshowedconflictingresults 213 , P 214 .0) ( =0.003) 217 , 215 ). The prevalence of OSA (based on PSG) , 199 216 218 h ofCPAP pernightdidnothave ). However, arecentin-laboratory ) asshownin 76 201 ). AftercontrollingforBMI and , , 196 206 , , A Lavrentakiandothers 51 203 207 h comparedtothe ). Fig. 6 , ). Thestudiesthat 208 204 n . 5 compared =35) ). Nonetheless, , 51 205 n 0 (50% =30) , 210 ), while , 209 211 ). , including obesity, T2Dandhypertension)(4.11vs1.70per controlled (matched for age, sex and comorbidities at increasedriskofdevelopingOSAcomparedtomatched cohort studyshowedthatpatientswithCS( to obesity( the relationshipbetween CS andOSAarenotonlyrelated associated withAHI( of thesurgicalintervention. and adrenal)inordertoensurethesafety (both pituitary in patientswithCSwhenconsidering surgical treatment anaesthetists needtobeaware ofthehighriskOSA is active.Inaddition,endocrinologists,surgeonsand CS islifelongorsimplyrelatedtotheperiodwhere examine whethertheincreasedOSAriskinpatientswith treatment ontheincidenceandseverityofOSA to ( can induceUAmyopathyleadingtocompromisedUAs patients with CS ( spaces) mayalsoplayaroleintheincreasedriskofOSA in (in theperitoneum,mediastinumandparapharyngeal In addition to obesity, hyperglycaemia, IR and ectopic fat above-mentioned studiesthatobesityisnottheonlyfactor. relationship betweenCSandOSA,itisclearfromthe for theworseninginAHI( suggesting mechanismsotherthanadiposityresponsible correlate withchangesinweightandneckcircumference steroid treatment)( by 56%comparedtocontrols(withmildOSAbutno of prednisolone(10 OSA ( diagnosis ofCS( starting separatingclearlyfromthefirstyearafter in thisstudy, forOSAdevelopment curves thesurvival slightly higherriskinmenvswomen( thousand person/year;HR2.82,95%CI:1.67–4.77),with Obstructive sleepapnoea Fig. 6 Future studies need to assess the impact of CS While obesitymightplayanimportantroleinthe ) ( n

= 217 7 h a S eoeadatr3 months 17) whohadPSGbeforeandafter3 , 218 219 ). ArecentTaiwanese population-based , 222 ACTH, adrenocorticotropichormone. CRH, corticotropin-releasinghormone; hypercortisolism withOSAdevelopment. Possible mechanismslinking OSA toHPAaxisdysregulation.(B) Possible underlyingmechanismslinking OSA andHPAaxisdysregulation.(A) Figure 6 217 219 220 R mg dailyormore),AHIworsened ). 2 , ). Similarly, inpatientswithout : 77.8%, 221 ). ThisincreaseinAHIdidnot Downloaded fromBioscientifica.com at09/27/202109:41:32AM 220 ). Moreover, hypercortisolism ). P

<

0.001), suggestingthat 180 219 :3 ). Interestingly n 3 were =53) R102 via freeaccess European Journal of Endocrinology later) ( increased riskofUAcollapsibility inpatientswithacromegaly( correlated totheAHIandIGF1 levels( and acromegaly( MRI andnasopharyngoscopythat showedthetonguebaseanduvulatobemainsiteof UAobstructioninpatientswithOSA compromise ofUAsinpatientswithacromegaly( secondary toincreasedglycosaminoglycandeposition,collagen andtissueoedemamacroglossiacontributetothe retroposition ofthetonguebasewithcaudaldisplacement thehyoid( collapsible UAs.Patientswithacromegalyhaveverticalgrowth ofthemandible,whichleadstopharyngealobstructiondue acromegaly toOSAarerelatedtheanatomicalchangesthat occurasaresultofGHexcessleadingtonarrowerandmore linking GHexcess(redarrows)anddeficiency(blue withOSAdevelopment.Themaincausalmechanismslinking OSA andGH/IGFaxis.(A)Possibleunderlyingmechanismsfor OSAleadingtoGH/IGFaxisdysregulation.(B)Possiblemechanisms Figure 7 activity ( expression, possiblyduetomodulationofsomatostatin dependent suppressionofGHreleaseandmRNA by CPAP ( and stimulated GH and IGF1 levels, which are improved suggest thatOSAisassociatedwithsuppressionofbasal OSA) ( during SWS(bothofwhicharedisruptedinpatientswith axis asGHsecretionisincreasedaftersleeponsetand architecture can lead to dysregulation of the GH/IGF OSA-associated chronicIHanddisruptionofsleep OSA andthedysregulationofGH/IGFaxis or worseningcanbefoundin relation ofGHexcessanddeficiencytoOSAdevelopment ofOSAimpactonGH/IGFaxisaswellthe Summary OSA andGH/IGFaxis Review In rodents,IHwasshowntocausearecoverabledose- 219 223 226 , 225 236 , 224 ). Inhumans,OSAwasshowntobeassociated ). , 237 ). Overall,studiesinrodentsandhumans 216 ), IRanddysglycaemia( ). Inaddition,theuvuladiameter correlatedtotheseverityofUAcollapseandtonguemeasurements Fig. 7 A Lavrentakiandothers 216 . , 230 219 ). TheweaknessofUAmuscles (sternohyoidmuscle)alsocontributestothe , 224 226 , 238 , 227 ). , 228 235 , 229 ). Otherfactorsincludehypothyroidism, largegoitres(detailed , increases inIGF1levelsandadecreaseIGFBP1 pulse frequencyafter12 weeks oftreatmentwithfurther GH concentration,massofsecretedperpulseand IGF1 levels,totalandpulsatileGHsecretion,mean severe OSA showed thatCPAP vs sham CPAP increased a recentRCTin65middle-agedmenwithmoderate-to- improvement inSWS( CPAP treatment;thisimprovementcorrelatedwiththe 10 every plasma levelsandsecretionrate(bloodswerecollected one night without CPAP and one night with CPAP, GH study ofpatientswithOSAwhowereexaminedfor between OSA and the GH/IGF1 axis. In an experimental ( men withOSA,butincreasedfollowing 3 months of CPAP fasting IGF1levelscorrelatednegativelywiththeODIin increased following one night of CPAP ( with amarkedreductioninGHbloodlevels,which by week24( Obstructive sleepapnoea 195 230 In supportoftheimpactOSAonGH/IGFaxis, , ). Sleepdisruptionalsoplaysaroleintherelationship 225 231 ). Inaddition,softtissuethickening/swelling, , min overnight)werereducedandincreasedafter 232 228 , 233 ). Furthermore,othertreatmentsthatcan , 234 ). Thisissupportedbyastudyusing 227 Downloaded fromBioscientifica.com at09/27/202109:41:32AM ). https://eje.bioscientifica.com 180 :3 64 ). In addition, R103 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com (1/507) ( on OGTTgivinganacromegaly prevalenceof0.2% IGF1 levels,ofwhichninepatients suppressedGHlevels with OSAshowedthattenpatients (1.97%)hadelevated reduce theOSA-relatedsurgicalrisks( with somatostatinreceptorligandspreoperatively to thickness and OSA should be treated severe pharyngeal addition, the guidelines recommended that patients with recommended evaluatingallpatientsforOSA( Society ClinicalPracticeGuidelineforacromegaly on acromegaly-relatedcomorbidities,the2014Endocrine cardiomyopathy ( comorbidities suchashypertensionandheartfailure/ might playanimportantroleinotheracromegaly-related improved byCPAP inaRCT( OSA contributed to IR in patients with acromegaly, which although this was not adjusted for obesity. Inaddition, and OSAvsacromegalyonly( tolerance orT2Dwashigherinpatientswithacromegaly acromegaly alone( or IGF1levelsbetweenpatientswithOSA of acromegaly, despitethattherewerenodifferencesinGH few patientsundergoPSGinclinicalpractice( inItaly),only acromegaly andOSA(asshownbyasurvey ‘Although cliniciansseemtobeawareofthelinksbetween evaluation andtheconsiderationofCPAP ( controlled acromegalyhavepersistentOSAthatrequired OSA, upto40%(range:21–58%( studies ( ( prevalent inpatientswithactiveacromegaly(45–80%) Many cross-sectionalstudiesshowedthatOSAishighly OSA andacromegaly IGF1 levelscomparedtotheleancontrol( matched control despite that both these groups had lower were lowerinpatientswithOSAcomparedtotheweight- can recoverwithweightloss( secretion, IGF1levelsandperipheralGHsensitivity, which (particularly visceral)islinkedtoareductioninGH between OSAandGH/IGF1dysregulationasobesity levels ( have alsobeenshowntoimproveIGF1andIGFBP3 improve OSA,suchasadenotonsilectomyinchildren, 231 Review On theotherhand,arecentstudyof507patients As aresultofthehighprevalenceOSAanditsimpact In addition,OSAcontributedtotheadverseoutcomes Obesity isapotentialconfounderfortherelationship ), withanaverageprevalenceof69%inPSG-based 229 239 232 ). ). Thesefindingssuggestthat screeningfor ). AlthoughloweringGH/IGF1improves 238 236 ). ). Thepresenceofimpairedglucose 230 n 237 A Lavrentakiandothers : 10/17vs5/19)( ). However, IGF1levels ). Furthermore,OSA 231 234 )) ofthosewith ). + 96 acromegaly vs ). 235 233 234 ). , 236 234 ). In ), ). patients withacromegaly, itisnotsurprisingthattreating Considering thatOSAisdrivenbytheexcessofGH/IGF1in The impactofacromegalytreatmentonOSA 249 ( OSA inpatientswithacromegalyaresummarised ( apnoea (SA)canalsooccurinthecontextofacromegaly although we have focused here on OSA, central sleep Clinical PracticeGuidelineforacromegaly( IGF1 levelsisrecommendedaspertheEndocrineSociety hyperhidrosis andhypertension),thenmeasurementof as T2D,debilitating arthritis, carpaltunnel syndrome, of acromegalyoracromegaly-associatedconditions(such However, ifinadditiontoOSA,thereareotherfeatures acromegaly inOSAshouldnotberoutinelyperformed. (either aftersurgery, radiotherapyand/ormedicaltherapy) acromegaly aftercomplete/partial biochemicalcontrol et al not presentatbaseline22%) ( by Chemla even whenOSAwasnotpresentatbaselineasshown with acromegalyfollowingachievingnormalIGF1levels might requireCPAP. Infact,OSAmightoccur in patients acromegaly havepersistentmoderate-to-severeOSAthat IGF1 levelscanimproveOSA,butmanypatientswith curing acromegalyorsignificantimprovementsinGH/ pegvisomant ( somatostatin analogues ( in patientswithacromegalyfollowingtreatment moderate OSArange( improvements inAHIbuttheaverageremained withsignificant reduced from45.8to28%by6 months improved OSA( volumeincreasedsignificantly,airway accompaniedwith postsurgery,1 month thetongueareadeclinedwhile had remissionfollowingtrans-sphenoidalsurgery, at study of24patientswithacromegaly (20 withOSA)who of whetheracromegalywascuredornot( resolution oftheSAsyndromeinallpatientsregardless acromegaly, trans-sphenoidaladenomectomyresultedin with SAsyndrome(obstructiveorcentralEDS)and under control( OSA to persist or even worsen after acromegaly is brought acromegaly canimproveOSA,butitisalsocommonfor Obstructive sleepapnoea 231 240 , . showedthatAHIincreased in55.5%ofpatientswith The mechanismsleadingtothehighprevalenceof The above-mentionedstudiesclearlyshowthat , ), butfarlesscommonthanOSA( 250 234 , , 251 240 et al , 261 252 , . (OSAcuredin57%,newOSAthatwas 241 256 234 , , 262 253 , ). TheprevalenceofsevereOSAwas ). Inasmallstudyofsixpatients 242 256 ). , Downloaded fromBioscientifica.com at09/27/202109:41:32AM 254 246 , ). Similar results were observed ). Similarresultswereobserved 243 ). , 249 , 263 244 , 257 ). Similarly, Castellani , 180 245 , 236 258 :3 , 255 ). 246 , 259 239 ). Inanother , , 247 ). Finally, 260 R104 , Fig. 7 ) and 248 via freeaccess ,

European Journal of Endocrinology 292 placebo, GH treatment increased IGF1 from 168 and dysglycaemia who were randomised to either GH or In a12-monthdouble-blindRCTof40menwithobesity IGFBP3 levels(2.4 IGF1 levels(108 ( BMI atbaselineandtheGH-treatedgroupwereyounger that theGH-treatedvs-untreatedgroupshadsimilar received GHreplacement(3.3vs0.9%, theSAincidencewasgreateringroupthat 2.3 years patients withGHDshowedthatafterameanfollow-up of study ofGH-treated( status ( post treatment: 28.2/h vs 28/h), regardless of baseline OSA hadnoimpactonAHI(prevs replacement for6 months another studyof19patientswithGHDshowedthatGH worsened theOSAbutimprovedcentralSA( from 6.3to14.6( 4.4 to0.1( the medianobstructiveAHIdecreasedsignificantlyfrom afterstoppingGHtreatment GHD showedthat6 months serum IGFI:351 received GHreplacement(mediandose:2 show amixedpicture.Insmallstudyoffivemenwho replacement wasexcessive.Thestudiesintheliterature properties ofGH( OSA duetoareductioninadiposity(stronglipolytic GH replacement in patients with GHD might improve GH replacementandOSA ( or hypothalamic delivered to the underlying pituitary obesity asaresultofsurgicalorradiotherapytreatment increased obesityeitherduetoGHDorhypothalamic with aprevalenceof63%,whichismainlyduetothe acromegaly. commoninadultswithGHD OSAisvery OSA ismuchlessexaminedinGHDcomparisonto OSA inadultswithGHdeficiency(GHD) GH/IGF1 ( acromegaly treatmentregardlessofthenormalisation fibrosis ( BMI and/orirreversiblecraniofacial-skeletaldeformities/ is probably due to multiple factors including increased ( 231 269 Review ± ). OSApersistencefollowingacromegalytreatment ). However, theGH-treated grouphadhigherbaseline

117 265 231 µg/L, the AHI from 31 264 ). Still, in a large observational longitudinal ). Still,inalargeobservational 265 P ). Hence,OSAevaluationisneededpost

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266

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0.9 vs2.1 , n 267

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25 and the ). However, n ± =442) 2 to 72 269 ). tissue (basedonCT)( sectional area,whilereducedabdominalvisceraladipose neck transversediameter, circumference andtotalcross- Interestingly, GHtreatmentinthisstudyincreased ( for OSAinthispopulationhasbeenrecommended 1:10,000–25,000 livechildren),andasaresult,screening (PWS) arealsoathighriskofhavingOSA(prevalence: Children andpatientswithPrader–Willi syndrome OSA inPrader–Willisyndrome distribution (increasingneckcircumference). increasing IGF1levelsorviaaffectingadiposetissue the development or worsening of pre-existing OSA via of newOSA.However, GHreplacementmightresultin GH replacement on pre-existing OSA and the development ODI from18 279 /OSA, havebeenreported intheliterature( in patients with PWS,associated with sleep-disordered that suddendeathearlyinthecourseofGHreplacement CPAP ( criteria forrhGHinitiation,tillthepatientistreatedwith guidelines considered untreated severe OSA as an exclusion GH initiation( follow-up exceptinthosewhoworsenedshortlyafter that GHreplacementdidnotworsenAHIduringthe ( of adenotonsillarhyperthophyfollowingGHtreatment ( patients followingGHreplacementovertheshortrun study suggestingthattheAHIworsensinasubgroupof replacement ( (i.e. OSAworsened)in50%ofthecasesfollowingGH end ( the treatmentandcontrolgroupatbaselineorstudy the AHI,andtherewasnodifferenceinAHIbetween weeks) did not worsen term treatment with rhGH (6 with PWSisdebatable.Salvatoni collapsibility( all leadingtoairway (obesity and scoliosis causing lung volume restriction) alveolarhypoventilationhypotonia andsecondary UAsmusclesabnormalities withsmallairways, increased viscosityofUAssecretions,craniofacial PWS islikelytobemultifactorialdueGHdeficiency, Obstructive sleepapnoea 273 273 271 , Hence, more data are required to assess the impact of The impactofGHreplacementonOSAinchildren ). However, longer term follow-up (2 years) showed ). However, longer termfollow-up(2 years) ), whichinpartcouldbeduetothedevelopment ). The highprevalenceofOSAinpatientswith 280 272 276 ). ). Nonetheless,inthisstudy, theAHIincreased , 277 ± 272 ). Thisisparticularlyimportantconsidering 274

14 to29 ). Similarresultswereshowninanother , 275 270 ). Asaresult,the2013consensus Downloaded fromBioscientifica.com at09/27/202109:41:32AM ± ). 1 (all 21 https://eje.bioscientifica.com et al P values 271 180 . showedthatshort- :3 ). ≤ 0.001) ( R105 270 278 via freeaccess ). , European Journal of Endocrinology https://eje.bioscientifica.com with suspectedOSA,the prevalence ofHashimoto’s with OSA ( did notshowahighprevalence ofSHinpatients was younger and leaner ( was recruitedfromsleep and the control group studies havepotentialselectionbiasasthepopulation prevalence ofSHwashigherinOSAvscontrol,butthese general population( patients withsevereOSAwas4.7%whichissimilartothe as itshowedthattheprevalenceofraisedTSHin813 ( patients withOSAcomparedtowithout evidence thathypothyroidismismorecommon in While studiesarenotconsistent,overall,thereisno Hypothyroidism inpatientswithOSA about therelationshipbetweenOSAandSH. department ( heavier andthepatientsarerecruitedfromrespiratory in patients with untreated SH despite that SH patients were with normal thyroid functions was higher (75%) than that selection bias as the prevalence of OSA in healthy controls PSG) ( 53% ofpatientswithuntreatedSHhadOSA(basedon study( (SH); onesmallobservational relationship betweenOSAandsubclinicalhypothyroidism relationship. studies includingRCTs areneededbeforeconfirmingthis OSA, whichimproveswithLT4 treatment.However, larger This suggests that hypothyroidism can leadto/worsen SWS%: 18.4(7.2–25.2)vs28.2(15–33.4), (TpO treatment improvedhypoxaemiaandsleeparchitecture 2.1 (0.8–4.6))( improved theAHI(fromamedianof14.3(7.4–33.6)to had evidenceofOSA(AHI one study, 30%ofpatientswithrecentlydiagnosedOH improved withlevothyroxine4(LT4) treatment( abnormalities (,choking,apnoeaperiods),which overt hypothyroidism(OH)hadnocturnalbreathing decade of life) found that 25–50% of patients with studies(501patientsintheir4th–5th interventional andfive A recentsystematicreviewofoneobservational OSA inpatientswithhypothyroidism (HPT) axis OSA andhypothalamic–pituitary–thyroid 284 Review There islackofgood-qualitydataregardingthe , 2 285 sat 283 ). Arecentstudyalsosupportedthisconclusion < ). However, theseresultsarelikelytorepresent 90%: 14% (2.2–19.9) vs 0.2% (0–1.7), 290 283 282 ). In a study of 245 euthyroid patients ). Hence,currentlywecannotbecertain ). Inaddition,inthelaterstudyLT4 286 ). Somestudiesshowedthatthe 287 ≥ 5 basedonPSG)andLT4 , 288 A Lavrentakiandothers , n 289 0) hwd that showed =108) ). Other studies P

< .5 ( 0.05) P 281

< 0.05; 282 ). In ). lean, andthereweremoremenintheOSAgroup( to controls ( of NTIS (defined as normal TSH and low FT3) compared moderate-to-severe OSA( A recentcross-sectionalstudyshowedthatpatientswith OSA andnon-thyroidalillnesssyndrome(NTIS) 297 in worsening ofOSAviamultiplemechanismssummarised Hypothyroidism canleadtothedevelopmentor Mechanisms linkingOSAandthyroiddisorders severity ofOSA( prevalence ofHashimoto’s increasedwithworsening in patientswithOSA(basedonPSG)( was32.2%inpatientswithoutOSAvs46.8% reporting ahigherprevalence ofOSAinmenvswomen. initially broughttoattention bytheconsistently The interactionbetweensex hormonesandOSAwas gonadal (HPG)axis OSA andthehypothalamic–pituitary– the impactoftreatingoneorother. the complexrelationshipbetweenOSAandHPTaxis groups and RCTs are needed to enable us to understand However, cohort studieswithwell-matchedcontrol need totakethepresenceofOSAintoconsideration. and cliniciansinterpretingthethyroidfunctionresults clinically. Inaddition, OSA can beassociated with NTIS a lowthresholdtotestforthyroiddisordersifindicated function resultsinpatientswithOSA. account thepossibilityofNTISwheninterpretingthyroid ( OSA mightleadtoNTIS,butthisstudywasnotcontrolled levels inpatientswithNTISsupportingthenotionthat 304 contribute totheassociationbetweenOSAandNTIS( and low-gradeinflammation,resultingfromOSA,canalso 3-inactivating T3andT4( downregulation of deiodinase1andenhancing deiodinase prevalence ofNTISinpatientswithOSA,possiblyvia ( nocturnal hypoxemiacomparedtopatientswithoutNTIS Within theOSAgroup,patientswith NTIShadworse Obstructive sleepapnoea 301 301 Fig. 8 , ). CPAP hasbeenshowntoimproveFT3 for5 months In summary, SAandthyroidspecialistsneedtohave ). However, it is important the clinicians take into ). ThissuggeststhatIHcouldplayaroleinthehigh 298 ( , 232 299 n ,

= , 281 300 60) (10.4 vs 0%), but the control group was 291 , ). 282 ). , 284 Downloaded fromBioscientifica.com at09/27/202109:41:32AM 302 n

= , 125) hadahigherprevalence ). Inaddition,oxidativestress 291 , 292 180 , P 293 0.03) ( =0.03) :3 , 294 , 291 295 R106 ). The , 301 303 296 via freeaccess ). , , European Journal of Endocrinology (based onDXA)( weight lossbyreducingleanmass ratherthanfatmass rather thanfatmass.Inaddition, LT4treatmentcauses seems toberelatedexpanded watercompartment matched controlled( OH areabout5–7 kgheaviercomparedtoeuthyroid between OHandOSAasstudieshaveshownthatpatientswith ( The diaphragmweaknesscanbeimprovedbyLT4treatment contributing toOSAdevelopment/worsening( hypothyroidism, whichresultinareductionlungvolumes been showntobeweakerinrodentsandhumanstudies also beenreported( expression inrodentstudiesandneuropathyhumans,has in hypothyroidism,duetoalteredmyosinheavychain with LT4treatment( CB inrodentswithhypothyroidism( (D1)expressioninthebrainstemand human studies( chemosensors’ responsetohypoxia/hypercapniainanimaland can alsoresultinbluntedventilatorydriveandimpaired ( can beresolvedfollowingthyroidectomyorLT4insomecases laryngeal oedemaduetoreducedvenousreturn;bothofwhich obstruction, especiallyinsupineposition,andbyincreasing 263 of thyroidstatus)cancauseUAobstructionandcollapse( architecture inanuncontrolledstudy( swelling andimprovedAHI,nocturnalhypoxaemiasleep support ofthismechanism,LT4treatmentreducedsofttissue infiltration (myxoedemainthemoresevereform)( (in tongue,neck,andpharynx)causedbymucopolysaccharides can leadtoincreasedUAcollapsibilityduesofttissueswelling Mechanisms linkingOSAandhypothyroidism.Hypothyroidism Figure 8 253 256 Review ). It causes narrowing of the UA by direct mechanical ). ItcausesnarrowingoftheUAbydirectmechanical ). Finally, obesity could be potentially another link ). Finally,obesitycouldbepotentiallyanotherlink , 264 , 265 , 266 256 271 ). Hypothyroidism (especially when severe) ). Hypothyroidism(especiallywhensevere) ). This is possibly due to decreased ). Thisispossiblyduetodecreased , 256 217 270 272 ). Impaired UA dilator muscle function ). ImpairedUAdilatormusclefunction , ). However, this weight-increase in OH ). However,thisweight-increaseinOH ). 268 ). Furthermore, the diaphragm has ). Furthermore,thediaphragmhas 267 A Lavrentakiandothers 254 ), and can be reversed ), andcanbereversed ). (regardless ). Goitre(regardless 253 , 256 256

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256 ). ). ,

(67.2 for LH(24.9 and mean levels with OSA had lower area under the curve non-significant ( However, adjustment for BMImade these associations with O SWS, higherAHI(basedonPSG)andmoresleeptimespent (based onquartiles)wereassociatedwithsignificantlyless older men( a cross-sectionalanalysisofprospectivestudyhealthy due toaltered gonadotropin synthesis and release ( OSA isassociatedwithhypogonadotropichypogonadism In men polycystic ovariansyndrome(PCOS)( were associatedwithloweredOSAriskinwomen in postmenopausalwomenandoralcontraceptives replacementtherapyreducedtheriskofOSA was higherthanthatinpremenopausalwomen; the prevalenceofOSAinpostmenopausalwomen in menworsens/increasestheriskofhavingOSA, includingthattestosteronereplacement observations This relationshipwasfurtheremphasisedbyseveral (approximately byseven events perhour),mainly replacement in this RCT resulted in worsening RDI the othertreatmentafter8-week washout.Testosterone or matchingoil-basedplacebo andthencrossedoverto intramuscular testosteroneesters(500,250and were randomised to receive three injections of weekly menaged RCT in which healthy ambulatory testosterone ( was greaterforthosewhousedinjectablevstopical P (16.5% (95%CI:15.1–18.1)vs12.7%11.4–14.2), received testosteronereplacementvsthosewhodidnot 2-year riskofincidentOSAwasgreaterinpatientswho did notreceivetestosteronetreatment( were matchedbasedonageandcomorbidities to menwho of OSA at baseline and received testosterone replacement, members,aged40–64 years, service military whowerefree risk ofdevelopingOSA.Inacohortstudy, 3422ofUS Patients receivingtestosteronereplacementareatincreased Testosterone replacementandOSA found inotherstudies( group wasleanernumerically( P Obstructive sleepapnoea

< = .0) ( 0.001) 0.003) compared to healthy controls, but the control 2 sat n 312 < =1312, ± 90% after adjustment for age and race ( 312 UL s 43.4 vs 10.2IU/L ). Interestingly, theincreasedriskofOSA 307 ). Thisisalsosupportedbyasmall ± ≥ mlL s 113.3 vs 11.5nmol/L ). Otherstudiesshowedthat patients 65 years old),lowertestosteronelevels 309 Downloaded fromBioscientifica.com at09/27/202109:41:32AM , 310 308 https://eje.bioscientifica.com ± , 311 9.5IU/L, ). Similarfindingswere 180 ). 65 312 :3 , 305 ). Theabsolute ± P

26.8nmol/L, < ). .0) and 0.005) > 0 years 60 306 R107 307 ). In mg) via freeaccess ).

European Journal of Endocrinology https://eje.bioscientifica.com testosterone ( of REM)mightexplainthe linkbetweenOSAandlow hence, thedisruptionofsleep architecture inOSA (loss are relatedtolowertestosterone concentrations( REM (fewersleepepisodesandlatency obesity ( mechanisms includingIH,sleepfragmentationand hypercapnia ( did notinfluencechemo-responsivenesstohypoxia/ mechanistic study, androgenblockadewith flutamide studies showingconflictingresults.Inoneinteresting these mechanismsarenotwellprovenwithmultiple on theneuromuscular control of UA ( anabolic effects(leadingtoUAnarrowing)andaneffect apnoea threshold),reducedsensitivitytohypercapnia or response tohypoxaemia(leadingCO include alteredventilatorresponsessuchasincreased replacement leadstoOSA,butpostulatedmechanisms ( contribute totheincreased/worseningOSAinmenwith mass and increased visceral adiposity, which can Low testosteroneinmencanleadtolossofmuscle Mechanisms replacement ( recruitmentthresholdfollowingtestosterone ventilatory be as a result of time-dependent changes in hyperoxic weeks( 18 weeksbutnotat and onnocturnalhypoxaemiaat7 by 10.3events/h(95%CI,0.8–19.8events/h; in whichtestosteronereplacementworsened the ODI of 1000 diet andwererandomisedtointramuscularinjections shown inaRCTof67menwhoreceivedhypocaloric pharmacokinetics profilesoftheseagents. developing or worsening OSA due to the variations in the replacement haveadifferentialimpactontheriskof It isunclearwhetherdifferentmethodsoftestosterone replacement inmenwithuntreatedsevereOSA( guidelines recommendedagainsttheuseoftestosterone As aresult,theEndocrineSocietyclinicalpractice and incident or worsening OSA ( studies suggestedalinkbetweentestosteronereplacement on RDIandhypoxiaparameters( hyoxaemia measures, while placebo had minimal effects during non-REM (NREM) sleep and worsenednocturnal Review In addition,OSAcanimpacttheHPGaxisviaseveral The effectsoftestosteronecanbetimelimitedas mg testosteroneundecanoateorplacebo( 306 , 319 193 320 325 310 ). Thistime-dependenteffectsmight 321 ). ). ). , 326 , 322 ). Testosterone levels peak during ). Itisunclearhowtestosterone A Lavrentakiandothers 314 313 323 , ). Severalother , 315 324 2 levelsbelow , ). However, 316 P =0.03) , 323 319 318 317 )); ), ), ). ). peak in progesterone secretion ( luteal phaseinhealthypremenopausal womenwiththe response ( receptor in rodent led to reduced hypoxic ventilator the brainstem ( via theeffectsofprogesteroneandoestradiolonCB can influencebreathingnotonlyviaandrogensbutalso compared tomen.Basedonanimalstudiessexhormones OSA impactontheHPGaxisinwomenislesswellstudied In women impact onSHBGwasnotreported( CPAP improvedtestosteronelevelsalongwithLH,butthe other study, patientshadhypogonadismatbaselineand the impact of free testosterone was rather limited. In the was associatedwithincreasedSHBG,whichsuggeststhat In oneofthesestudies,theincreaseintotaltestosterone of CPAP ontestosteronelevelsexcepttwostudies,which short. Theuncontrolledstudiesmostlyshowednoeffects hypogonadism at baseline and the CPAP duration was testosterone levels,butthestudyparticipantsdidnothave 334 found in treatment (CPAP andsurgical)onHPGaxiscanbe free testosteroneorSHBGlevels( 95% CI: compliance (standardisedmeandifference(SMD) had noeffectsontestosteronelevelsdespitegoodCPAP of CPAPmeta-analysis, an average of 6 months treatment men showingthepaucityofavailabledata( studieswithatotalsamplesizeof232 observational meta-analysis in2014foundonlytwoRCTs andfive with alimitednumberofstudiesintheliterature.A CPAP effectsontheHPGaxisinmenremainscontroversial The impactofOSAtreatmentontheHPGaxis was superiortoCPAP inregardstoED( measurements ( function despitethelackofimpacthormonal beneficial impactsonscoresforsexualanderection and theimpactonfreetestosterone. and needtoensureadequateCPAP treatmentduration response between men withand without hypogonadism future trialsneedtoconsiderthepotentialdifferencein impact ofCPAP onHPGaxisinmenremainsunclearbut showed that CPAP increased testosterone levels ( Obstructive sleepapnoea , Summary ofthetrialsassessing impact ofOSA Summary It isimportanttonotethatCPAP mightstillhave 335 − ). ThetwoRCTs showednoeffectofCPAP on Table 1 0.63 to0.34)( 339 ) andlowerUAresistancewas foundinthe 332 338 ( 195 , ). In addition, lack of progesterone 333 , 205 327 ). However, intwoRCTs sildenafil Downloaded fromBioscientifica.com at09/27/202109:41:32AM , ). CPAP alsohadnoeffectson 328 , 340 327 329 ). On the other hand, ). , Table 1 180 330 336 :3 , , 331 337 ). Hence,the 327 , ). 332 ). Inthis Table 2 = R108 − , 0.14, 333 via freeaccess ). , European Journal of Endocrinology

Table 1 Non-randomised trials examining the effects of OSA treatment (CPAP/surgery) on the hypothalamic–pituitary–gonadal (HPG) axis 229( , 239, 350, 351, 352, 353, Review 354, 355, 356, 357). Data are presented as mean or mean ± s.d.

Intervention CPAP Total testosterone Free testosterone group OSA severity duration HG at LH (IU/L) (nmol/L) (nmol/L) SHBG (nmol/L) Study n Age BMI Controls (AHI baseline) (months) baseline Pre-CPAP Post-CPAP Pre-CPAP Post-CPAP Pre-CPAP Post-CPAP Pre-CPAP Post-CPAP (195) 43 NA NA NA Severe 3 No NA NA 14.4 ± 1.2 17.0 ± 1.1* 0.512 ± 0.047 0.509 ± 0.035 19.8 ± 1.9 22.7 ± 2.0* (328) 16 51.3 32 32a Severe (43.3 ± 4.7) 7 No 3.0 (1–5) 4.0* (1–7) 17.7 ± 1.8 16.7 ± 2.1 0.5 ± 0.07 0.43 ± 0.04 13.7 ± 1.9 27.1 ± 6.5 (n = 7) (n = 3) (n = 7) (n = 3) (329) 5 49.5 31.7 NA Severe 9 Yes 2.1 ± 0.8 2.6 ± 0.2 2.9 ± 6.7 2.6 ± 11.3* NA NA NA NA (330) 67 56.2 33.7 NA Severe 6 No NA NA 20.7 ± 7.45 20.1 ± 7.32 NA NA NA NA (331) 27 65.4 32 NA Severe 3 No NA NA 12.7 ± 4.5 11.9 ± 3.5 0.26 ± 0.07 1 month: 32.3 ± 11.6 1 months: (median: 43) 0.23 ± 0.06 31.1 ± 13.2 3 months: 3 months: A Lavrentakiandothers 0.25 ± 0.05 31.1 ± 12.5 (333) 53 43.87 28.71 NA Severe 3 No 5.99 ± 2.50 5.82 ± 2.38 13.45 ± 5.48 14.05 ± 5.18 NA NA NA NA (334) 32 47.4 31.3 60b Severe 1 Yes 4.1 ± 1.8 6.3 ± 2.1* 4.5 ± 1.4 12.1 ± 3.5* NA NA NA NA (55.9 ± 12.9) (335) 12 9c Moderate- severe UPP, 3 months No NA NA 13.31 ± 1.07 16.59 ± 0.72* NA NA NA NA post surgery

aBMI and age-matched; bBMI matched, but were leaner; cBMI matched but were younger; *statistically significant. AHI, apnoea–hypopnea index; BMI, body mass index; CPAP, continuous positive airway pressure; HG, hypogonadism; LH, luteinizing hormone; NA, not applicable; SHBG, sex hormone binding globulin; UPP, uvulopalatopharyngo-plasty. enlargement/tonsillectomy ( 1/3 ofadolescentgirlswithPCOShadprevioustonsillar development asdetailedinarecentstudyshowingthat plausible thatinsomecasestheOSAcouldprecedePCOS dysfunction inwomenislacking( Unlike inmen,evidenceforCPAP’s impactonsexual women comparedtomatchedcontrols( , satisfactionandpain)inpre-postmenopausal dysfunction (FSFIscore:desire,arousal,lubrication, this areaareneeded. small uncontrolledstudyshowednoeffect( remains to be explored in large studies, and since one ( combined oestrogen–progesteronevsoestrogenalone saturations women not taking HRT and less time spent in oxygen prevalence ofmoderate-to-severeOSAcomparedto in postmenopausalwomenwasassociatedwithlower ( 17-OH-progesterone, progesteroneandoestradiol > sexual functionandisassociatedwithPCOS. OSA has a negative effect on female sex hormones and on didnothave higher prevalenceofOSA studies showedthatwomen withPCOSandincreased the higher OSA prevalence in womenwith PCOS, three considered toimpactOSApathogenesis, contributingto cohorts wererecruitedfromspecialisedclinics( controls camefromgeneralpopulationwhileexposed (class II),andthereisahighlevelofselectionbiassince came fromtheUnitedStatesinwomenwithobesity was significantheterogeneityamongstudies,moststudies development ( main riskfactorsofOSA,andthus,PCOSprecedesOSA both ofwhichareexpectedsinceobesityandage 12.13) andinadultwomencomparedtoadolescents, with PCOScomparedtolean(OR:3.96,95%CI:1.29– OSA prevalencewassignificantlyhigherinobesewomen regardless ofthePCOSdefinitionused( (95% CI: 22.4–51.0) of women with PCOS had OSA from ourgroup(15studies, with PCOS.Arecentsystematicreviewandmeta-analysis OSA ishighlyprevalentinwomenofreproductiveage OSA andpolycysticovariansyndrome(PCOS) did notdiscusstheimpactofOSAonpregnancy. Obstructive sleepapnoea 342 341 10/h wasassociatedwithlowermorninglevelsof Similar tomen,OSAhasbeenassociatedwithsexual It is also interesting that although androgens are nachr f5 oe 2–2 yearsold),AHI In acohortof53women(24–72 ). TheimpactofCPAP ontheHPGaxisinwomen ). However, hormone replacement (HRT) < 90%, particularly in womenwho received 347 ). However, inthismeta-analysis,there Downloaded fromBioscientifica.com at09/27/202109:41:32AM 348 n

= https://eje.bioscientifica.com ). 568) showedthat36.1% 346 180 ). Inthisreviewwe 347 :3 343 ). Inaddition, 330 , 344 347 ) RCTs in ) ( R109 ). Itis 345 via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com Review

Table 2 Randomised controlled trials examining the effects of OSA treatment (CPAP/surgery) on the hypothalamic–pituitary–gonadal (HPG) axis 229( , 239, 350, 351, 352, 353, 354, 355, 356, 357).

CPAP arm CPAP Total testosterone (nmol/L) LH (IU/L) Control duration CPAP HG at Exposed cohort Control group Active NCPAP Sham CPAP Study n Age BMI arm (n) (MONTHS) compliance baseline Pre-CPAP Post-CPAP Pre-CPAP Post-CPAP Pre-CPAP Post-CPAP Pre-CPAP Post-CPAP (205) 52 NA NA 49a 1 Yesc No 13.5 ± 5.8 13.2 ± 4.7 14.4 ± 5.0 12.9 ± 4.4* 5.99 ± 2.55 5.81 ± 2.42 6.07 ± 2.70 5.34 ± 3.00* (332) 27 51 9 32 3 20b 2.5 Yesd No 16.0 4.7 16.2 5.2 19.1 6.9 17.9 5.8 NA NA NC NA

± ± ± ± ± ± A Lavrentakiandothers

Data are presented as mean or mean ± s.d. aSham CPAP; boral appliance; cfor both cohorts (5.4 and 4.6 h); d25/27 effective treatment; *statistically significant. AHI, apnoea–hypopnea index; BMI, body mass index; CPAP, continuous positive airway pressure; HG, hypogonadism; LH, luteinizing hormone; NA, not applicable; s.d., standard deviation; SHBG, sex hormone binding globulin; UPP, uvulopalatopharyngo-plasty. was worseintheOSAgroup( were notdifferentbetweenthetwogroupsbuthirsutism compared to the alter group ( total ,LDLandtriglycerideslowerHDL) CI: 0.67–2.11, tolerance (2 BP (4.63 systolic BP(10.8 IR (HOMA-IR: MD circumference (MD:10.93 (mean difference:6.01 only showed that the earlier group had higher BMI women withPCOSandOSAvs compared tomen. the lowcirculating androgenlevelsinwomenwithPCOS consistent acrossthestudies( OSA severityandhyper-androgonaemiawerenot compared tocontrols,andtherelationshipbetween spinal fracturescomparedto menspent O 67 years,menwhospent rather than OSA studies examinedconditions thatarerelatedtoOSA OSA might increase the risk of fractures, although these in patientswithOSA,severalstudiessuggestedthat demographics. obesity, CVDriskfactors,CKD,CVD,gout andsocial this studywasadjustedforage,gender, diabetesstatus, CI: 1.69–4.44)overthe6-yearfollow-up( years vs1.00/1000person-years,adjustedHR:2.74,95% both men and women (incidence rate: 2.52/1000 person- was greater in patients with OSA vs control in matched controls(age,sexandindexdate),theriskof of 1377patientswithnewlydiagnosedOSAand22,655 with OSA( studies showedanincreasedriskofosteoporosisinpatients conflicting results( between OSA and bone mass density (BMD) showed Although cross-sectional studies assessing the relationship OSA andbonemetabolism in such asobesity( and didnotaccountforimportantpotentialconfounders included wererelativelysmall,athighriskofselectionbias, Obstructive sleepapnoea 2 saturations Fig. 9 In anothermeta-analysisfromourgroupcomparing Consistent withtheincreasedriskofosteoporosis Several mechanisms link PCOS to OSA as summarised ( mmHg 95% CI: 1.06–8.21), impaired glucose 350 355 h plasmaglucoseonOGTT: MD ). , < I 356 349 2 90% hadincreasedriskofincident non- per se

= mmHg 95%CI:6.21–15.39), diastolic 0%) andworselipidsprofile(higher ). Inalargeretrospectivecohortstudy ). = 351 2.23, 95% CI:1.41–3.06; . In a study of 2911 men older than kg/m Downloaded fromBioscientifica.com at09/27/202109:41:32AM , ≥ 352 10% oftheirsleeptimewith 2 cm, 95%CI:8.03–13.83), 349 , 95%CI:4.69–7.33),waist 347 , 349 353 ). However, thesestudies ). Thiscouldbedueto ). The levels , 180 354 < :3 1% ofsleeptime 355 ); longitudinal ). TheHRin = 2.23, 95% I 2 R110 =0%), via freeaccess European Journal of Endocrinology severe snoring(acommonOSA symptom)wasassociated ( napped daily( study therewasanincreased riskoffallsinwomenwho HR: 1.33,95%CI:0.99–1.78)andsimilartotheprevious (age-adjusted HR:1.29,95%CI:1.02–1.65;fully-adjusted hip fracturescomparedtowomenwhodidnotnapdaily napping wasassociatedwithincreasedriskofincident 69 years orolderfor6 years foundthatself-reported daily longitudinal studythatfollowedup8101womenaged (relative risk:1.25,95%CI:1.04–1.51)( also higherinthegroupwithnocturnalhypoxaemia In thesamestudy, therelativeriskofhaving relative hazards:1.42,95%CI:0.94–2.15, with O of OSAandPCOSentities( sympathetic activationallofwhichcanleadtoaviciouscycle comorbidities areoxidativestress,endothelialdysfunctionand associations betweenOSAandPCOS.Othercommon common inbothdisordersandcancontributetothe worsening orthedevelopmentofOSA( and dysglycamiainwomenwithPCOScancontributeto causing/or worseningPCOSphenotype( can influenceGnRHandgonadotropinspulsatility,leadingto While, IHandsleepfragmentationcanimpactHPGaxis or leadtobluntedventilatorchemo-responsiveness( (as aresultofanovulation)canincreaseUAcollapsibilityand/ with PCOSandrogensexcessalonglowerprogesterone to playaroleinthisbidirectionalrelationship,aswomen from Kahal clinical interactionsandunderlyingpathophysiology.Adapted Obstructive sleepapnoeaandpolycysticovarysyndrome; Figure 9 n Review

= 3220) andmen( 2 saturation et al . withpermission.Sexhormonesarethought 358 < ). Inarecentcohortstudy, women 90% over 7 years follow-up (adjusted n

= 322 99 gd4 yearsandolder, 2969) aged40 ). A Lavrentakiandothers 322 322 ). Obesityis ). Inaddition,IR P 357 .4) ( =0.047) ≥ ). Another 1 fallwas 322 ). 357 ). potential mechanismbetweenOSA andbonedisease. 375 have detrimentaleffectsonbonemassandfracturerisk( impact ofOSAonbonemetabolism( and GHinOSAtheassociatedIRcouldalsocontributeto had noeffectonPTH( (19.34 Furthermore, serum25-hydroxyvitaminDwasfoundtobelower OSA, hypoxaemia plays an important role as has been shown by OSA, hypoxaemiaplaysanimportantroleashasbeenshownby resorption markers.Aswithotherendocrineconsequencesof parathormone; BMD,bonemineraldensity;BRMs, OSA andbonemetabolism.GH,growthhormone;PTH, Figure 10 concentrations (19.21 ( P levels higher(62.57 Melatonin hasbeenshowntoincreaseBMDinaRCT( due tofrequentnocturnalawakeningandlightexposure( lower melatoninserumlevelscomparedtopeoplewithoutOSA patients withOSAmighthavechangedmelatoninprofileand profile couldalsocontributetotheimpactofOSAonbones,as leading tobonemassloss( activation increaseboneresorptionandinhibitformation Other mechanismsincludinghyperleptinaemiaandsympathetic lead tohigherriskofosteoporosisandfractures( result inincreasedinflammationandoxidativestressthatcan HIF2a) andVEGF( differentiation viaHIFtranscriptionfactorfamily(HIF1aand increase osteoclastsandinhibitosteoblasts’growth Cauley with similarnon-significant trendinmen( women (adjustedHR:1.68, 95% CI:1.16–2.43, with increasedriskoffractures over10-yearfollow-upin Obstructive sleepapnoea 345

< 0.0001) in patients with OSA compared to healthy controls 0.0001) inpatientswithOSAcomparedtohealthycontrols , ). CPAP for seven nights increased 25-hydroxyvitamin D ). CPAPforsevennightsincreased25-hydroxyvitaminD 376 ± et al 9.54 ng/mL vs32.83 , 377 . and IH in human cell cultures and rodents can . andIHinhumancellculturesrodentscan ), and as OSA increases the risk of T2D, then T2D is a ), andasOSAincreasestheriskofT2D,thenT2Disa 333 ± 29.97 pg/mL vs40.05 , ± 345 334 9.45 vs21.03 ). The suppression of the gonadal axis ). Thesuppressionofthegonadalaxis , 341 335 Downloaded fromBioscientifica.com at09/27/202109:41:32AM ± 16.93 ng/mL, , , 342 336 ). Changes in melatonin ). Changesinmelatonin , https://eje.bioscientifica.com 337 342 ± 9.50, ). In addition, IH can ). Inaddition,IHcan ). T2D in particular can ). T2Dinparticularcan 180 ± P 31.12 pg/mL, 31.12 pg/mL, F

= 8.32, < :3 0.0001) and PTH 0.0001) andPTH 338 359 , P ). 339 344

P < =0.006), 0.01) but 0.01) but 374 , ). ). 343 R111 340 , ). ). ). ). via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com the relationshipbetweenOSA andSH,theimpactof replacement onOSAinpatients withhypothyroidism, on OSAaswellcentral SA, theimpactofthyroxine patients withCS,thelong-term impactofGHreplacement ofOSAanditsresponsetotreatmentin the naturalhistory treatment onOSA,theeffectsofOSAHPA axisand of OSAondiabetes-relatedoutcomes,theimpactPA impact of diabetestreatment on OSA as well asthe impact available: theimpact of OSA and CPAP onweight, the to eitherno,minimalorinconsistentevidencecurrently the followingneedtobeexploredinfuturestudiesdue in the circadian rhythm. In particular, our review found disorders suchasshortsleepdurationandmisalignment system andtheinteractionbetweenOSAothersleep in clinical studies, the diurnal nature of the endocrine the difficultyinachievinggoodcompliancewithCPAP studies inmanyareas.Thisisfurthercomplicatedby due tothelackofwell-designedcohortandinterventional knowledge gapsinthefieldatamechanisticlevelandalso driveaswellautonomicdysfunction. ventilatory muscles,changestochemosensitivityand upper airway body adiposity, narrowingoftheUAs,weakening system onOSAwasmostlymediatedviaincreasedupper and oxidativestress.Whiletheimpactofendocrine activation, theelevatedBPandincreasedinflammation mediated byintermittenthypoxaemia,sympathetic The impactofOSAontheendocrinesystemwasmostly varied dependingontheendocrinesystemexamined. relationships endocrine systemalthoughtheobserved multiple bidirectional interactions between OSA and the In thisreviewwehavedemonstratedthatthereare Summary andconclusion 368 summarised in OSA on bone turnover, bone density and fracture risk 128 CTXlevelssignificantly(211 adjusted urinary Furthermore, CPAP loweredthecreatinine- for3 months independently ofage,BMIandothervariables( CTX the AHIwasindependentlyassociatedwithurinary patients withOSAcomparedtocontrolsinmenand type IcollagenCTX)hasbeenshowntobehigherin markers (suchasserumC-terminaltelopeptideof and fracturesinpatientswithOSA,boneresorption Review , ± Our reviewalsoshowsthattherearemultiple Several mechanismsmightexplaintheimpactof Consistent withtheincreasedriskofosteoporosis 369 59 μ , g/mmol/creatinine; 370 , 371 Fig. 10 , 372 ( , 361 373 , ). 362 P

< , .1 ( 0.01) A Lavrentakiandothers 363 , 364 360 , ). 365 , 352 366 ± 0 vs 107 , , 360 367 ). ,

EJE-18-0411 This islinkedtotheonline version ofthepaperat Supplementary data safety ofthegeneralanaesthesiaandsurgicalprocedures. association andtreattheOSAinordertoimprove that areassociatedwithOSAneedtobeawareofthis involved in the treatment of the endocrine conditions Furthermore, clinicians,surgeonsandanaesthetists the successfultreatmentofendocrinecondition. status needtobeclarifiedbyformaltestingfollowing Cushing’s, acromegalyorhypothyroidism)andthatOSA by curingtheunderlyingendocrinedisorder(suchas conditions shouldnotassumethatOSAwouldrecover and theimpactofCPAP onbonemetabolism. CPAP in women with PCOS and men withhypogonadism methods ofreplacementonOSA,theimpactOSAand long-term testosteronereplacementandthedifferent References Health. Service, theNationalInstitute for Health Research ortheDepartmentof those ofthe author(s) and not necessarily thoseofthe National Health Health ResearchintheUK.Theviewsexpressedthispublication are A A Tahrani is a clinician supported by the National Institute for Acknowledgements Research intheUK(CS-2013-13-029;2013). Clinician Scientist receiving funding from theNationalInstitute for Health in the public, commercial or not-for-profit sector. But A A Tahrani is a NIHR agency funding any from grant specific any receive not did research This Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest Obstructive sleepapnoea 4 3 2 1 Epstein LJ, Kristo D,Strollo PJJr, Friedman N,Malhotra A,Patil SP, McNicholas WT. Diagnosisofobstructivesleepapneainadults. Chokroverty S, Thomas RJ&Bhatt M. Senaratna CV, Perret JL,Lodge CJ,Lowe AJ,Campbell BE, inadults. the evaluation,managementandlong-term careofobstructivesleep Ramar K, Rogers R,Schwab RJ,Weaver EM doi.org/10.1513/pats.200708-118MG) Proceedings oftheAmerican ThoracicSociety Elsevier HealthSciences:Philadelphia,PA, USA,2013. org/10.1016/j.smrv.2016.07.002) review. obstructive sleepapneainthegeneralpopulation:asystematic Matheson MC, Hamilton GS&Dharmage SC.Prevalenceof Finally, clinicianstreatingpatientswithendocrine . Sleep MedicineReviews Journal ofClinicalSleepMedicine Journal Downloaded fromBioscientifica.com at09/27/202109:41:32AM 2017 34 70–81. Atlas ofSleepMedicineE-Book 2008 et al 180 https://doi.org/10.1530/ (https://doi. . Clinicalguidelinefor :3 5 2009 154–160. 5 263–276. (https:// R112 via freeaccess . European Journal of Endocrinology

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