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European Journal of Endocrinology -18-0102 cycles as part of predictive homeostasis, thereby humans. Circadian clockshaveadoptedgeophysical various organismsspanningfromcyanobacteria to Circadian in rhythmshavebeenwidelyobserved Introduction physiopathology anddiagnosisofCushing’s disease. the pituitary–adrenalaxisdiurnalrhythmicityaswellinvolvementofcircadianrhythmabnormalitiesin review presentsageneraloverviewoftheglucocorticoidcircadianclockmechanisms,highlightingontogeny of anatomic componentsofthehypothalamic–pituitary–adrenalaxis,whichareorganisedinahierarchicalmanner. This rhythms. Plasmaglucocorticoidcircadianvariationdependsontheexpressionofintrinsicclockgeneswithin the circadiansystem,describinginterlockingtranscription/translationfeedbackloopsessentialfornormal Physiology orMedicine,aswellTakahashi’s groupamongothers,havecharacterisedthemolecularcogwheelsof circadian rhythmicityamongmammals.Accordingly, Young, HallandRosbash,laureatesofthe 2017NobelPrizein researchers havesoughttoidentifybasicmechanismsunderlyingtheoriginandemergenceofcorticosteroid The circadianrhythmofglucocorticoidshaslongbeenrecognisedwithinthelast75 years.Sincebeginning, Abstract Preto, SaoPaulo,Brazil Departments of Ayrton Custodio Moreira diagnosis ofCushing’s syndrome circadian clock:from theontogenyto A senseoftimetheglucocorticoid MECHANISMS INENDOCRINOLOGY https://doi.org/ www.ej Review Review and thediagnosisofCushing’s syndrome axis,focusingontheglucocorticoid circadianpathophysiology ofthepituitary–adrenal rhythm received manymedicaleducation awards.Hismainresearch interestincludesthephysiologyand School. Inrecognitionofhis outstandingcontributionsasaneducatorandresearcher, hehas held severalimportantadministrativepositions,including theDeanofRibeiraoPretoMedical of SaoPaulo,Brazil.Hehaspublishedmorethan150 papersinhigh-qualityjournalsandhas and Metabolism,Department of Internal Medicine, RibeiraoPretoMedicalSchool,University Ayrton CustodioMoreira, Invited Author’s profile e-online.org 10.1530/EJE 1 Internal Medicineand -18-0102 1 1 , Sonir Rauber Antonini © 2018EuropeanSociety ofEndocrinology 2 Pediatrics, RibeiraoPretoMedicalSchool,UniversityofSaoPaulo,

A CMoreiraandothers MD, PhDisProf.ofMedicineattheDivisionEndocrinology Printed inGreatBritain . 2 and Margaret de Castro hormone release( behaviour, bodytemperature,bloodpressureand fluctuations andregulatingsleeppatterns,feeding preparing living organisms for environmental Glucocorticoid circadianclock Published byBioscientifica Ltd. 1 1 , 2 ). Downloaded fromBioscientifica.com at10/02/202102:11:10AM (2018) Endocrinology European Journal of [email protected] Email to ACMoreira should beaddressed Correspondence 179

179 :1 , R1–R18

R1 –R18 via freeaccess European Journal of Endocrinology www.eje-online.org including courtshipsinging( alterations inpupaleclosionandadultactivityrhythms, of Period ( when Konopka and Benzer described the first clock gene underlying oscillationsremainedunknownuntil1971, genetic informationfromDNAtoRNA,thenatureof rhythms may be related to the transmission of cyclic the 1960s.AlthoughHalberg( ( glucocorticoid circadian rhythmicity, bothinrats ( ( also coinedtheconceptofenvironmentalsynchronisers amplitude, peak,trough(nadir),phaseandantiphase.He circadian rhythmsintermsoftheirmeanlevels(Mesor), inphysicstodescribebiological the oscillationtheory daily cycles.Theauthoradoptedtheterminologyfrom ‘circadian’, which meansapproximately24 1950s ( syndrome hadbeenfirstdescribedduringthemid-to-late 17-hydroxycorticoid levelsinpatientswithCushing’s ( rats ( adrenal axishadbeenconfirmedinstudiesinvolving ( ketosteroids rhythm basedontheexcretionofurinary been firstdescribedbyPincusintheearly1940sasadiurnal 9 zeitgebers 5 3 11 , ). Thelackofadiurnalrhythmforplasmaandurinary ). Later, thediurnalrhythmicityofpituitary– Review Drosophila melanogaster 10 , Studies regarding postnatal emergence of The glucocorticoidcircadian rhythminhumanshad 4 12 ). ) andothermammals,includinghealthyhumans 6 ) andhumans( Per , 7 ) and introduced cosinor-based rhythmometry ) andintroducedcosinor-basedrhythmometry ). Atthattime,Halberg( ) attheperiodlocusonXchromosome 13 . Per , 15 14 locus mutations induced ). ), hadsurfacedduring A CMoreiraandothers 8 ) suggestedthat24-h 8 ) introducedtheterm h, todenote they observed afeedbackloopthatenabled they observed while identifyingnewstranscripts( molecular mappingstudiesonthe of the2017NobelPrizeinPhysiologyorMedicine,began The mammalianmolecularclockmechanism approximately 24 molecular circadian cyclesthatoscillateataperiodicityof proteins connected by feedback loops, characterising circuits involveatleasttenclockgenesandtheirtranscript molecular mechanismsforcircadian rhythms.These the present,severalstudieshaveshowncell-autonomous normal circadian behaviour( Locomotor OutputCyclesKaput),whichisessentialfor group identifiedanewgenenamed regulating circadian rhythmsinmammals,Takahashi’s proteins tocycletheirownRNA( The principal mechanism for the circadian timekeeping been extensively reviewed elsewhere ( The circadian molecular clocksysteminmammalshas loop. feedback loops:acoreloopsupportedbyanaccessory system consist of two interlocking transcription/translation cells ( Clock genesareexpressedinessentiallyallmammalian ( comprises circadian genes its modelbeingsummarisedin Glucocorticoid circadianclock Per1 During the 1980s, Young, Hall and Rosbash, recipients , Per2 22 ). Thecogwheelsofthecircadian timekeeping and Per3 h ( and phosphatases. regulated byE3ubiquitinligases, kinases The stabilityofclockproteinsis tightly to promotersofclock-controlled genes. Bmal1 regulate therhythmictranscriptionof and the accessoryloopconsistingof positive feedbackloopandalsoactivates BMAL1 generatesanautoregulatory Per2, Per3,Cry1andCry2 core loopcomprises of twointerlockingfeedbackloops.The cogwheels ofthecircadiansystemconsist molecular clockinmammals.The Schematic modelofthecircadian Figure 1 ) and cryptochromes ( ) andcryptochromes 20 Ror , . Additionally, CLOCK-BMAL1binds Downloaded fromBioscientifica.com at10/02/202102:11:10AM 21 α Clock andBmal1 . Inturn,REV-ERB andROR , 22 19 ). Fig. 1 ). Sincethemid-1990sto 18 Per . Briefly, thecoreloop ). Searching forgenes 16 179 Clock, Bmal1,Per1, 22 locusof , , :1 Clock 17 genes.CLOCK- 23 Cry1 ( ). Inaddition, Arntl), , 24 Per (Circadian and Drosophila , Rev-Erb -encoded 25 Periods Periods ) with ) with Cry2 R2 α via freeaccess

) .

European Journal of Endocrinology of theHPA axiscircadian rhythminnormalsubjects. system schematic representationof themulti-oscillatory factors andautonomicinnervations. and adrenalclockgenesby controllingcyclichormonal to otherhypothalamicnuclei, pinealgland,pituitary hypothalamic suprachiasmaticnucleus(SCN)clockgenes timing signalsarepropagateddownstreamfromthe are organisedinahierarchical manner( genes intheanatomiccomponentsofHPA axis,which variations dependontheexpressionofintrinsicclock rodents and non-human primates. Plasma glucocorticoid the HPA circadian rhythmhavebeenwidelystudiedin 34 animals anddeclineovertheremaining24-hperiod( onset, daytimeinhumansandnight-timenocturnal have beenreportedtooccurpriororatthetimeofactivity humans andcorticosteroneinrats.Peakconcentrations daily variationsinplasmaglucocorticoids:cortisol the best-documentedcyclicendocrineactivitiesshowing The endogenouscircadian rhythmintheHPA axisisoneof hypothalamic–pituitary–adrenal (HPA) axis Circadian rhythminthe functions ( cells andwholeorgans,therebycontrollingphysiological translate temporalinformationfromclockgenestosingle or output genes ( more thanathousandtargetgenesnamedclock-controlled and CRY proteinsbindtoE-boxeswithin thepromotersof to aperiodofexactly24 action ofthe or foodavailabilitycycles,atleastinmice( to beastronger cues ( food ingestion, temperature, rest/activity cycles and social environmental synchronisers,suchaslight–darknesscycles, timekeeping systemdependsonphoticandnonphotic respectively. Thefine-tuningofthemolecularcircadian inhibit andactivatetherhythmictranscriptionof (Nr1d1) feedback loopthatincreasesthemRNAlevelsof transcription. CLOCK-BMAL1alsoactivatesasecond then interactwithCLOCK-BMAL1,inhibitingtheirown core genes activate their target genes at E-boxes in promoters of activators of a positive feedback loop. These heterodimers and BMAL1,constitutingheterodimerictranscriptional system depends on two main clock proteins, CLOCK Review , 35 26 ). Moreover, molecularmechanismscontrolling and , 27 32 Per1 , , 28 Ror zeitgebers 33 ). Furthermore, light–darkness cycles seem ). Furthermore,light–darknesscyclesseem , zeitgeber α ). 30 Per2 . In turn, REV-ERB and ROR proteins , 31 , is to synchronise the clock system istosynchronisetheclocksystem ). Such genes are tissue specific and ). Such genes aretissuespecificand Per3 than environmental temperature thanenvironmentaltemperature h. Additionally, CLOCK,BMAL1 , Cry1

A CMoreiraandothers and Figure 2 Cry2 36 29 , 37 ). The primary ). Theprimary . These genes . These genes ). Circadian providesa Rev-Erb Bmal1 27 α ,

thalamic intergeniculateleaflet, whichalsocontribute pathway and the NPY-containing pathway from the raphe serotonergicpathway, thegeniculohypothalamic many otherregionsofthe brain,suchasthemedian Apart fromtheRHT, theSCNisalsointerconnected with is distinctfromtheCLOCK/BMAL1feedbackloop( dependent activationof that bindtoCRE-bindingprotein.Thislightsignalling- to thefactofonly response toexternallightunlike which areco-expressedinSCNcells,induced in entrainment ( involved inimageformationbutisessentialforSCNlight the photopigmentmelanopsin(Opn4),whichisnot ganglion cellsoftheretina(ipRGCs).Theseexpress retinohypothalamic tract(RHT)fromphotosensitive a bilateralinputofluminanceinformationviathe is considered complex. Themammalian SCN receives predominately argininevasopressin(AVP), angiotensinII peptide. Shellneurons,ontheotherhand,contain contains calretinin,neurotensinandgastrin-releasing also stronglyinvolvedinSCNcoupling.Thecore core neurons,isreleasedrhythmicallyfromtheand polypeptide (VIP),themostabundantneuropeptidein substantiallyacrossspecies.Vasoactivevary intestinal are distinguishedbyneurochemicalphenotypeand the core( and adorsal‘shell’region,whichreceivesinputfrom touches theopticchiasmandreceivesretinalinput, anatomic subdivisions:aventral‘core’region,which humans respectively( neuronsinmiceand and100 000 approximately 20 000 structures oftheventralhypothalamuscontaining The mammalianSCNcomprisespairedbilateral circadian rhythm SCN regulation oftheHPA axis which hasbeenextensivelyreviewedbyMorin( and increasesclockprecision( contributes tothesynchronisationofcellularoscillations cell-autonomous circadian oscillator, theSCNnetwork circadian cogwheels. Although each neuroncontains a entire SCNproviderhythmicstabilitytothemolecular normal rhythmicity. Suchnetworkpropertiesacross the contributorto and electricalsynapsesmaybetheprimary GABAergic ( neurons, whilesynapsesamongSCNneuronsaremostly with gamma-aminobutyricacid(GABA)inmostSCN and met-enkephalin.Theseneuropeptidesarecolocalised Glucocorticoid circadianclock The neuroanatomyofthecircadian rhythmsystem, 39 ). Neuronsinthecoreandshellsubregions 39 41 ). Cell–cellcommunicationviachemical , 42 Per1 ). Moreover, 38 and Downloaded fromBioscientifica.com at10/02/202102:11:10AM ). EachunilateralSCNhastwo Per1 Per2 and 39 promoterscontainCREs Per3 ). Per2 Per1 ( 179 43 and www.eje-online.org geneexpression :1 ). Thisisascribed Per2 genes, R3 43 40 via freeaccess ). ), European Journal of Endocrinology www.eje-online.org the SCN.Notably, AVP isreleasedbytheSCNduring role of AVP asan important output neurotransmitter of changes inthedorsomedial SCN( gene, which allowed the detection of diurnal AVP mRNA expressing AVP-enhanced greenfluorescentproteinfusion These dataareconsistentwiththosefromtransgenicrats SCN revealedhigherexpressionsinthemorning( ( AVP neurons,whichpeakedduringtheearlymorning showed acircadian rhythmamongimmunoreactive obtained duringtheautopsyofyounghumansubjects these SCNneurons.Basedontimeofdeath,neurons releasing hormone(CRH),aswellAVP inalmosthalfof neuroendocrine neuronsthatsynthesisecorticotrophin- area ( nucleus (DMH), retrochiasmatic area and premammillary preoptic region,subparaventricularzone,dorsomedial nucleus (PVN),periventricularhypothalamicnuclei, portion of the paraventricular of input to the parvocellular efferent projectionsinrats.Themostrobustpatternconsists ( non-uniform distributionoflabelledcellsacrosstheSCN Neuroanatomical tracingstudieshavedemonstrateda variation ofneuronalfiringandhumoraloutput. to beelucidated( However, thenatureoftheseadditionalpathwaysremains control peripheralclocksindependentoftheSCNclock. In addition,recentstudiessuggestthatlightmayalso accepted, light through the RHT entrains the SCN clock. to circadian rhythmregulation ( 47 46 Review ). Moreover, AVP mRNAdiurnalvariationsinrat ). ThesestudiesdescribedthreemajorpatternsofSCN The SCN output signals are mediated by circadian 46 ). The parvocellular portionofthePVNcontains ). Theparvocellular 44 , 45 ). A CMoreiraandothers 40 49 ). Asconventionally ), corroboratingthe 48 ). light period inboth nocturnal and diurnal species. In particularly atnight( ERB destruction of clockproteins,suchas BMAIL and REV- clock mechanism.Melatonin couldinhibitproteasomal acts ontheSCN,inturndirectlyinfluencingcircadian glands ( expressing melatoninreceptors,includingtheadrenal cues frommammalianSCNtoalargenumberoftissues an importantefferentpathway, distributing temporal reflecting aninternaldarknesssignal.Melatoninisalso during thenight,inbothdiurnalandnocturnalanimals, display acircadian variation,withhighconcentrations ganglion( superior cervical in thespinalcordandnoradrenergicneuronsof neurons of the PVN, sympathetic preganglionic neurons via multisynapticpathways,includingpreautonomic melatonin synthesisinthemammalianpinealgland gland. TheSCNcontrolsthecircadian rhythmof on aneuralconnectionbetweentheSCNandpineal nocturnal anddiurnalspecies( rhythms, includingHPA axiscircadian activity, inboth explain themechanismbehind12-hreversalofcertain neurotransmitter pathwaysdownstreamoftheSCNmay interneurons in the same nuclei. The existence of different stimulates CRH-containingneuronsviaglutamatergic species, however, AVP releasedduringthelightperiod DMH nucleiviaGABAergicinterneurons.Inthediurnal inhibits CRH-containing neurons in thesubPVNand nocturnal animals,AVP releasedduringthelightperiod Glucocorticoid circadianclock α In addition,endocrinecircadian activityrelies , andinterferewithmolecular feedbackloops, 52 ). Notably, evidence has shown that melatonin RHT, retinohypothalamictract. receptor; PVN,paraventricularnucleus; arginine vasopressin;GR,glucocorticoid factors andautonomicinnervations.AVP, clock genesbycontrollingcyclichormonal pineal gland,pituitaryglandandadrenal clock genestootherhypothalamicnuclei, hypothalamic suprachiasmaticnucleus propagated downstreamfromthe manner. Circadiantimingsignalsare which areorganisedinahierarchical anatomic componentsoftheHPA axis, expression ofintrinsicclockgenesinthe glucocorticoid variationdependsonthe a multi-oscillatorysystem.Plasma pituitary–adrenal axisinnormalsubjects: Circadian rhythmofthehypothalamic– Figure 2 53 ). Downloaded fromBioscientifica.com at10/02/202102:11:10AM 51 50 ). Melatoninbloodlevels ). 179 :1 R4 via freeaccess European Journal of Endocrinology Per2 similar photoperiodicconditions reportedthat Conversely, mouse adrenalstudiesperformedunder was synchronisedwiththe peak ofplasmacortisol( Per2 the day. Furthermore,adrenalexpression Like humans, rhesus monkeys are more active during the adrenalglandsofrhesusmonkeyandrodents. in Rhythmic clockgeneexpressionhadbeenobserved to characteristiccircadian signaturesforeachtissue. a uniquecircadian expressionofclockgenes,leading each anatomiccomponentoftheHPA axispossesses Throughout thelastdecade,evidencehasshownthat Clock geneexpression intheHPA axis glucocorticoid circadian rhythm ( the effectsofplasmaACTHrhythmicityondriving circadian neuronalcontrol oftheadrenalglandsamplifies mitochondria forsteroidogenesis( thereby increasing free cholesterol transport into the adrenal cortex,possiblyviaacAMP-mediatedpathway, inputstothe andexcitatory cord andprovideinhibitory the sympatheticpreganglionicneuronsinspinal neurons, whichreceiveinputfromtheSCN,projectto ACTH ( 10-fold) circadian variation amplitudecomparedtoplasma plasma corticosteronehadamorepronounced(5-to responsiveness toexogenousACTH( studies haveshownacircadian rhythminadrenal glucocorticoid secretion( inmodulatingadrenal of directsympatheticinnervation CRH–ACTH stimuli.Morphologicaldatasupporttherole regulates adrenalcircadian activityindependentof circadian rhythmofACTHandcortisol( factors,suchasAVP,stimulatory maypossiblycontrolthe circadian rhythmicityinACTHsecretion.Thus,other infusion ofCRHinhealthymalesleadstoaretention on theadrenalcortex( action the releaseofglucocorticoidsviaitsstimulatory gland( the anteriorpituitary releasing CRHandAVP tostimulateACTHreleasefrom AVP, whiletheiraxonsprojecttothemedianeminence, PVN. ApproximatelyhalfoftheCRHneuronsco-express andmagnocellularneuronsofthe in theparvocellular glucocorticoid rhythms( adrenocorticotrophic hormone(ACTH)secretionand Review Furthermore, evidence has indicated that SCN also CRH istheprincipalneurohumoralsignalcontrolling acrophasesoccurredcloser to thedarknessphasein peakedatthebeginning of thelightphaseand 27 , 62 ). ThehypothesisisthathypothalamicPVN 57 54 61 , , 55 58 ). Inaddition,physiological 56 ). CRHismainlysynthesised , ), whichinturncontrols 59 A CMoreiraandothers 60 ). Notably, continuous ). 63 27 ). Therefore,the 60 , ). ofPer1 62 ). Notably, Per1 and and 37 ).

between adrenocorticalclockgenesandtheregulation elements of the murine promoter, indicating a direct link of CLOCK/BMAL1 heterodimers to expression was transcriptionally regulated by the binding corticosterone profiles in mice ( with alate-daytimeacrophaseinaccordanceplasma regulator ofsteroidogenesis,possessedcircadian variation revealed thatSTAR mRNAandprotein,arate-limiting gland( via thepituitary adrenal oscillatorswasindependentofSCNsignalling hypophysectomy, indicatingthattheactivityof genes intheratadrenalglandremainedunalteredafter the circadian rhythmicityofthe did not show an obvious circadian rhythm. Moreover, adrenal gland( both the and of thecanonicalclockgenes( synchrony withthepeakofcorticosterone( access Bmal PVN displayedanevidentcircadian rhythminphase with expressions intheSCN.Moreover, the PVNwhilebeinginantiphasewiththeirrespective period ( period, whereas SCN, rhythm andwereinantiphasewitheachother. Inthe glandshowed aclear expressions intheanteriorpituitary as thoseinadrenalclockgenes.However, glandwerenot asevident gene expressioninthepituitary Interestingly, diurnalrhythmsinplasmaACTHand Bmal Per1 Moreover, Per1 onset ofthedarknessperiodandwasinphasewith the corticosterone rhythm acrophase occurred atthe glandandSCN.Amongadultratsfed pituitary circadian rhythms of clock genes in theadrenal gland, They subsequentlycomparedhormonerhythmswith and c-fos and corticosteronesecretion,thefunctionalexpressionof cortex. a well-organisedlevelofrhythmicitywithintheadrenal glucocorticoid circadian rhythm was also dependent on of steroidogenesis( Glucocorticoid circadianclock Girotti Our groupshowedthatamong ratsthathadfood expression in the adrenal cortex and in phase with and , Bmal Rev-Erb circadian gland. expressionintheanteriorpituitary circadian expression( Crh Per1 ad libitum 68 , clockgenesineachcomponentoftheHPA axis. Per2 glomerulosa and Bmal Pomc ). These genes also showed a clear rhythm in et al α ) exhibitedacircadian expressionpatternin expressionrhythmsintheadrenalglands. Per2 temporalexpressionwasinantiphasewith . ( and 65 Bmal 36 and those that had restricted food ). However, acrophasesoccurredduringthelight 67 ) examined the 24-h pattern of ACTH Star and peaksoccurredduringthedarkness ). Thesestudiesindicatedthatthe Downloaded fromBioscientifica.com at10/02/202102:11:10AM andtheexpressionof 66 fasciculata ). Additionalfocusedanalyses 36 Bmal1 ). Clock 67 ). Notably, Per1, Per2 , Crh and zonesofthemouse Cry1 179 Star expressioninthe www.eje-online.org :1 , Cry2 Per1 upstream Per2 64 and transcripts , ). Majority STAR ad libitum and Per1, Per2 Per2 Bmal1 gene , Pomc Bmal R5 Star, Per3 cis via freeaccess ,

European Journal of Endocrinology www.eje-online.org through acetylation( proteins modulatetheactivity andbioavailabilityofGRs Per2 reset circadian rhythmsofperipheralclockgenes reciprocal interaction.Daily variationsincorticosteroids genes and GR expression in peripheral tissues possess a been reviewedelsewhere( variability inglucocorticoidsensitivityhavealready The molecularmechanismsofhumanGRactionand receptors orbytranslocationintothemitochondria. which arepossiblymediatedbymembrane-localised actions, GRsalsoexertrapid,non-genomiceffects, human tissuesandorgans( nuclear receptorsuperfamilyandisexpressedinalmostall glucocorticoid receptor(GR),whichbelongstothe diverse effectsviaaspecificintracellularreceptor, the tissues ( impactonclockgenephasesinperipheral regulatory formaintaininghighamplitudewithno is necessary A recentstudy suggested thatcorticosteroid rhythmicity systems( cardiovascular andimmune/inflammatory white adiposetissues,lungs,kidneys,bone,skin,blood, well asperipheraltissues,suchtheliver, gut,muscles, gland( terminalis, hippocampusandpituitary such as the PVN,pineal gland, central amygdala, stria glucocorticoids influencebrainregionsoutsidetheSCN, reset peripheralclockgeneexpression( circadian variationsignals fromtheSCNpacemakerto asahumoralsignalthattransduces while alsoserving axis, regulateabroadspectrumofphysiologicfunctions Circulating glucocorticoids, theend-effectorsofHPA circadian signal Circulating glucocorticoidsasa are propagateddownstreamfromtheSCNtoHPA axis. clock geneexpression,althoughthemaintimingsignals component of the HPA axishasadistinctive circadian Taken together, thesestudiesdemonstratethat each to produce a daily rhythm in circulating glucocorticoids. mechanism regulatingcorticosteronereleasecooperate dependent steroidogenesis and the SCN-driven central al et on-going photoperiod to feedingschedulesinatissue-specificmanner, despite gene expressionintheSCN,PVNandARCresponded intheSCN,PVNandARC.Inaddition,clock observed access, differentphasesinclockgenesexpressionwere Review At thecellularlevel,glucocorticoidsexerttheir , . ( Bmal1, Cry1 70 74 ) demonstrated that in mice, adrenal clock- ). and 79 Cry2 zeitgeber , 75 71 . Meanwhile,CLOCK-BMAL1 77 , ). Inaddition,Lamia( 76 , ( 78 ). Inadditiontogenomic A CMoreiraandothers 69 ). Additionally, clock ). Recently, Chung 71 , 72 , 59 ). Thus, 73 ), as Per1, 59 80 ). ) endocannabinoid interface via activation of theG-protein- steroid actioninthePVNinvolvingglucocorticoid– corticotrophsthroughrapid neurons andpituitary exert rapidnegativefeedbackmediatedbyGRsinCRH loop thatresetstheactivatedHPA axis.Glucocorticoids gland,establishinganegativefeedback anterior pituitary CRH secretioninthePVNandACTH tissue cortisolconcentrations( or vice-versa,playanimportantroleintheregulationof which interconvert inactivecortisoneintoactivecortisol, type 211- Furthermore, the relative activities of both type 1 and of glucocorticoid circadian rhythm inperipheraltissues. tuned molecularfeedbackloopthatmodulatestheeffects crosstalk betweenclockgenesandGRsprovidesafinely the transcriptionalresponsetoglucocorticoids.The interact withGRsinaligand-dependentmannertooppose showed thatbothcircadian co-regulators, the morningthanatnight( confirmed thattheSCNwas metabolicallymoreactivein squirrel monkeyfoetusesduring latefoetaldevelopment the daily place at the end of gestation. Accordingly, evaluation of ofgestation ( 25th week gestation. Moreover, thePVNisalreadyformedat week of almost completed between the 18th and 30th humans ( sheep hasbeenextensivelydescribed( rhythms in foetal and neonatal rats, hamsters and axis. AlthoughtheontogenyofSCNandcircadian follows thegradualmaturationofSCNandHPA The developmentoftheglucocorticoidcircadian rhythm circadian rhythm The ontogenyoftheglucocorticoid plasma glucocorticoids. of theHPA axisresultinarobustcircadian rhythmof molecular and physiological oscillations at multiple levels corticosteroids. Thesereciprocalinteractionsbetween via feedbackloopsinvolvingclockgenes,proteinsand clock genesineachanatomiccomponentoftheHPA axis of the HPA among axis, synchronisation can be observed ( and CRHtranscriptionduetomRNAproteinturnover include theinhibitionofpro-opiomelanocortin(POMC) dependent signallingpathway( scanty dataareavailableforprimates( Glucocorticoid circadianclock 83 ). Thus, besides the classical neuroendocrine regulation Glucocorticoids havealsobeenwellknowntosuppress 14 89 C-labelled deoxyglucoseutilisation patternsin β -hydroxysteroid dehydrogenaseisoenzymes, , 90 ). HumanfoetalSCNneurogenesisis Downloaded fromBioscientifica.com at10/02/202102:11:10AM 89 ), while RHT maturation takes 91 ). Inaddition,lightinduced 81 82 ). ). Thedelayedeffects 179 87 :1 84 , Cry1 , 88 85 ), primarily and , 86 , Cry2 R6 87 via freeaccess ), , European Journal of Endocrinology review onthecircadian cogwheeldevelopmentofthe cues ratherthanthefoetalcircadian system( entrained by gene rhythmsinthefoetalSCNcould,theoretically, be These studiessuggestedthatthedevelopmentofclock low amplitude but significant rhythmicity at E21 ( However,observed. genes relatedtocellularactivity( E19, whereasrhythmicexpressionsof confirmed theabsenceof utilising foetalratSCNsamplingvialasermicrodissection fromP3toP10andthereafter( observed in the rat SCN at E19, whereas a clear oscillation was no detectable 97 during foetalandneonatalperiodsinmammals( the presence of circadian rhythmicity in SCN clock genes also developafterbirth( locomotor activity, drinkingandplasmacorticosterone P10 inrats,whilecircadian rhythmsoftemperature, and maturationoflightsignallingarecompletedaround 87 neurogenesis beingcompletedonlyafterbirth( prenatally, whiletheratSCNdevelopsgraduallywith clock isalreadyfunctioningandresponsivetolight data provideevidencethattheprimateSCNcircadian weeks( foetuses atagestationalageof29–35 as heartrateandfoetalmovements,arepresentinhuman circadian rhythms of several physiological functions, such afterconceptioninhumans( 24 weeks gene expressioninbabooninfantsatagesequivalentto a robustincreaseinSCNmetabolicactivityand Review ). Duringthefoetalstage, ). In addition, ipRGC projection to theSCN via the RHT Molecular studies have supported evidence regarding Per1, Per2,Cry1 Rev-Erb Per2 α oscillationsdrivenbymaternal and 84 , 86 Per2 Bmal1 in situ and , 94 and A CMoreiraandothers c-fos ). expressionsexhibited hybridisationfound Bmal1 , Bmal1 Rev-Erb Avp 92 95 ). Furthermore, generhythms and , rhythmsat 98 96 α andother 93 84 ). Another ). Astudy Vip ). These , 95 85 ) were , , Per1 98 96 86 ). , ,

and steroidogenesis-relatedgenes( Cry2 Bmal1, Per1,Per2,Per3,Cry1, and its relationship with theadrenalrhythmicity of on theemergenceofratpostnatalcorticosteronerhythm rhythmometry, we had recently conducted a refined study Applying appropriateprotocolsandusingcosinor-based from theearlypostnatalperioduntiladulthood( on postnataldaysP30,P22,P21orP16( studies. Accordingly, suchaneventhadbeenfoundtooccur acrossdifferent acrophase, hasbeendeterminedtovary in neonatalrats,withavespertineplasmacorticosterone foetuses attheendofgestation( amongcapuchin monkey plasma DHEAS, were observed and adrenal glands, as well as a circadian rhythm of expressions of in the foetal rat SCN, robust oscillatory that observed than thoseinthepositivefeedbackloop( feedback loopofthecoreclockbecomerhythmicearlier non-primate SCNdemonstratedthatgenesinthenegative with eye opening in pups at P14. We also demonstrated which waswellknowninadultrats,hadbeenassociated P14, P16,P21andP24.Inourexperiments,thisrhythm, Conversely, at anocturnalacrophasehadbeenobserved was subsequentlyascribedtothetimeofbreastfeeding. had neverbeenpreviouslydescribed.Thisnovelfinding earlypostnatalages well asamorningacrophase,atvery P1 untilP12( corresponding to07:00–11:00 rhythm withamorningacrophase(betweenZT0andZT2, 24-h period.Accordingly, plasmacorticosteronecircadian overa P16, P21andP24weredecapitatedat4-hintervals our study, ratpupsatpostnatalagesP1,P3,P6,P12,P14, Glucocorticoid circadianclock The establishmentoftheHPA axiscircadian rhythm Fig. 3 Bmal-1, Per-2, Cry-2 Endocrinology. 2017;158(5):1339–1346). and CorticosteroneRhythmin Male Rats. Expression oftheAdrenalClock Genes Postnatal OntogenyoftheCircadian (Reproduced withpermissionfrom: Black barsrepresentthedarkphase between peakandmesorconcentrations. interval oftheacrophase.*Differences line: cosinecurveand95%confidence days P1toP24.Dottedline:mesor;solid time 0,4,8,12,16and20onpostnatal corticosterone concentrationsat corticosterone inrats.Plasma Postnatal ontogenyofcircadianplasma Figure 3 ). Plasmacorticosteronerhythmicity, as Downloaded fromBioscientifica.com at10/02/202102:11:10AM h) had been observed from h) hadbeenobserved 100 and and Star ). 179 Ror and Clock www.eje-online.org 11 :1 α /Rev-Erb , 12 Mc2r in the SCN 99 , 101 ). Unlike zeitgeber ) inrats 103 α , genes Clock, 102 R7 ). In via freeaccess ).

European Journal of Endocrinology www.eje-online.org Endocrinology. 2017;1581339–1346). Genes andCorticosteroneRhythm inMaleRats. Ontogeny oftheCircadianExpression oftheAdrenalClock the darkphase(Reproducedwith permissionfrom:Postnatal and 20onthepostnataldaysP1 toP24.Blackbarsrepresent corticosterone concentrationsat Per2 indicate theacrophaseand95%confidenceintervalof expression duringpostnataldevelopmentinrats.Circles Acrophases ofplasmacorticosteroneandclockgene Figure 4 mothers approachthelittertofeedtheirpupsduring Although adultratactivityispredominantlynocturnal, of adrenalclockgenesandcorticosteronesecretion( maternal environment,entrainingthecircadian rhythm cues forpupsbeforeP10mayhavebeenderivedfromthe after P10( and clockgeneexpressionrhythmicityarecompletedonly antiphase ( rhythm ofplasmacorticosterone,whereasBmal1wasin and across allpostnataldevelopmentalages.Accordingly, clock gene acrophases in adrenal tissues was observed glands ( profile aspreviouslydescribedforadultratadrenal ( early neonatalperiodsandbecamevespertinenocturnal acrophases advanced by approximately 10 acrophase. FromP14, genes fromP3,whereas in themRNAexpressionof circadian variations,aswellamorningacrophase, 103 Review , The relationship between plasma corticosterone and Cry1 ), whichwasconsistentwiththeadultcircadian Per3 36 circadian profileswereinphasewiththecircadian , 86 Cry1 ). Fig. 4 ), wehypothesisedthattheexternalrhythmic and ). ConsideringthatratSCNmaturation Rev-Erb Rev-Erb Bmal1 α expressionsandplasma Bmal1 zeitgeber , α A CMoreiraandothers presentedanocturnal Per2 , Per2 , time0,4,8,12,16 Per3 , h compared to Per3 and and Bmal1 103 Cry1 Cry1 Per2 ). ,

rhythm ( development oftheplasmacorticosteronecircadian in adrenalclockgenes,whichissynchronywiththe progressive postnatalmaturationofcircadian variations rats. Taken together, thesedatasuggestthatratsexhibit a motor activitycanalsoactassynchroniseragentsinadult In additiontolight,dailypatternsoffoodingestionand may shift from maternal and nonphotic to photic cues. phase, theentrainmentofratadrenalcircadian variations the foetaladrenalglands( Bmal1 plasma cortisolcircadian rhythminchildrenagedbetween subsequent postnatalweeks remainsunsolved. morning glucocorticoidpeak anditsmaintenancein after birth,thequestionregarding theonsetofearly human samplescollectedduringthefirstfewhours ( to day/nightcyclestakingplaceaftertheneonatalperiod secretion maybepresentatbirth,despitesynchronisation birth seemstoinducere-entrainment,circadian cortisol in allinfantsofthesameage.Inaddition,giventhat increase lateringestationandmaynotuniformlyoccur These datasuggestthatcircadian cortisolsecretionmay neonates collected18–24 insalivasamplesfrom 119healthy had beenobserved rhythmicity incortisoland17 exogenous day/night cycles ( displayed a cortisol rhythm, which was not coupled to study showedthat2outof10healthytermneonates circadian clocksystems functionprenatally. Another term ( concentrations wasdemonstratedinhumanfoetusesat plasma cortisol of a 24-h rhythm in umbilical artery glandoradrenalgland.Thepresence as thebrain,pituitary rhythm havebeenconductedonhumanfoetaltissues,such its relationshipwiththeontogenyofcortisolcircadian However, nostudiesregardingclockgenerhythmicityand in differentcomponents of theHPA axis( its relationshipwithcircadian expressionofclockgenes ontogeny ofthepostnatal glucocorticoid rhythm and however, maternal melatonin seems to be a corticosterone levels ( in ratfoetaladrenalglandsparallelwithdecreasing may synchronise identified assynchroniseragents.Furthermore,melatonin milk melatoninlevelsduringnight-time( stimulation duringbreastfeeding( light phase.Themother’s bodytemperatureandtactile Glucocorticoid circadianclock 112 Previous datahavedescribed theemergenceof Studies invariousspecieshaveaddressedthe ). Althoughtheaforementionedstudiesinvolved and 109 103 ), suggestingthatthehumanSCNandadrenal Per 2 ). expressioninthefoetalSCNbutnot Per2, Bmal1 106 Downloaded fromBioscientifica.com at10/02/202102:11:10AM h or25–55 , 100 107 110 and ). Duringthelatepostnatal ). In capuchin monkeys, ). However, nocircadian α StAR -hydroxyprogesterone 104 179 h afterbirth( expressionphases ), aswellhigh :1 87 105 , zeitgeber 108 ), maybe , 111 103 R8 for via freeaccess ). ). European Journal of Endocrinology should havebeenmaintained forconsecutiveweeks point outthatdailycortisol variationsinourstudies weeks postnatal( emerged 2–16 individual circadian rhythmintermandpreterminfants age of8postnatalweeks,similar toterminfants.However, cortisol circadian rhythminpreterminfantsatamedian ( cortisol levels correlation between plasma and salivary ( cortisol in preterm infants remains controversial salivary 2 or4 weekspostnatal. infants presentedacircadian cortisolrhythmasearlier individuals ( among healthy addition, variability had been observed postnatal, which was earlier than previously thought. In rhythm appears in healthy term infants at least 1 month cortisolcircadianthese dataconfirmthatsalivary using multilevel analysis calculations ( level ( significantly higherthanthemedianeveningcortisol ( assay variation from the morning value taken as 100% night valueswerelessthanthreetimesthemeanintra- definitions ofcircadian rhythmicitywereassumedwhen with asteadydeclinethroughouttheday( the amplitudebetweenmorningandeveningvalues rhythms. Onedefinitionofcircadian rhythmicitywas to thedifferentmathematicaldefinitionsofcircadian divergences could have been due infants. The observed numberofhealthyterm after birthandhadavarying months weeksuntil12 night, startedcollectionfrom2 many timesaday, includingmorning,afternoonand the firstandthirdmonthoflife( wherein adult-likerhythmbecameapparentwasbetween cortisol from healthy term infants found that the mean age or stressfortheinfant( obtained viaanon-invasiveprocedurethatcausesnopain at homemanytimesadayoverconsecutivedaysand protocols, given that saliva samples are easier to collect free cortisol that has been used as a tool in longitudinal cortisol measurements, an index of plasma with salivary This limitation had been overcome during the last decades difficulties inobtainingserialbloodsamplesfrominfants. circadian variationsappearcouldbeascribedtotheethical human studiesregardingtheagewhereinplasmacortisol and thirdmonthoflife( 1 and3 years ( 120 120 117 Review Nevertheless, the correlation between plasma and All aforementionedstudiesperformedsalivasampling Four previouslongitudinalstudiesthatusedsalivary ) while also showing the appearance of a salivary ) whilealsoshowingtheappearanceofasalivary , ), whenthemedianmorningcortisollevelwas 121 119 ). Accordingly, a ourgroupwasabletoobserve ) orwhendifferentmethodswerecompared 117 13 ). Indeed,approximately30%ofnormal ), 6 months ( 115 , 113 34 14 ). , ) andbetweenthesecond 116 A CMoreiraandothers 122 114 , ). Itisimportantto 117 ). Discrepanciesin 118 , 118 ). Altogether, 116 , 119 ). Other ). and theonsetofsleeprhythm( cortisolrhythm between theappearanceofasalivary regularity ( cortisolrhythmandbehavioural development ofsalivary and postnatalenvironmentalsynchronisers. was likely to occur given that the twins shared prenatal of acortisolcircadian rhythmbetweeneachtwinpair. This genetic influence, indicating synchronyintheemergence coefficients suggestagreaterenvironmentalratherthan ( and dizygotictwinpairsat7.87.4 weeks, respectively cortisolrhythmemergenceinmonozygotic of salivary we didinourprotocol.We asimilarage alsoobserved not specify whether the rhythmhadbeen maintained, as month.However, theydid level atacorrectedageof1 cortisol circadian rhythm in preterm infants on a group recently, Ivars in ordertobeconsideredanestablishedrhythm.More postulating a tonic mode of cortisol release ( burstlike modeofcortisolsecretion withouttheneedfor accounted for by an amplitude-modulated, random the nyctohemeralpattern of cortisolsecretioncanbe concentration profilesin healthy subjectsrevealedthat deconvolution technique.Analysisof24-hplasma had beenwelldescribedusingawaveform-independent peaks over24 leading toameanofapproximately10cortisolsecretory in theamplitudeofACTHsecretionthroughoutday, around midnight.Thispatternismaintainedbychanges (CAR) ( morning awakening,termedcortisolawakeningresponse variation withplasmalevelspeakingshortlyafter Normal humanadultcortisolsecretionfollowsadiurnal Cushing’s disease Cortisol circadian variationin thereafter. 31 and34 weeks postconceptionandcontinuetomature system andtheHPA axisbecomefullydevelopedbetween complex neuroanatomicalpathways,theclockgene development, includingsleeppatterns,suggestthatthe between cortisol circadian rhythm and behavioural stage inhumandevelopment.Moreover, theassociation circadian maturationof theHPA early axis at avery children ( between nappingandcortisollevelsonlyamongolder another studydemonstratedanegativecorrelation Glucocorticoid circadianclock 124 Ivars ). The heritability index and intraclass correlation 126 125 123 t al et ), anddecreasingthereafter, reachinganadir ). Taken together, allthesedataconfirm ). Ourstudy, however, aparallelism observed h ( et al . foundnocorrelationbetweenthe 127 . ( 123 , 128 Downloaded fromBioscientifica.com at10/02/202102:11:10AM ) describedthedevelopmentofa , 129 ). The oscillatory pattern ). Theoscillatory 122 ) ( 179 Fig. 5 www.eje-online.org :1 ). Inaddition, 130 ). This R9 via freeaccess European Journal of Endocrinology www.eje-online.org 22 in rodentsandnon-primatemammals( observed that oscillate ataperiodicityof approximately 24 on theexpressionofintrinsic clockgenesintheHPA axis cortisol concentrations in humans probably also depend burstactivity,secretory circadian ACTHandplasma ACTH-specific amplitudeand/orfrequencythatcontrol tonic glucocorticoidsecretionmode( rhythmic circadian variations,eliminatingtheideaofa cortisol secretion integrates random cortisol pulses with dynamic conceptregardingthephysiologicalmode of Endocrinology 200052:423–426). relationship tosleepactivityinpreterminfants.Clinical emergence ofsalivarycortisolcircadianrhythmandits (solid triangles)(Adaptedwithpermissionfrom:The salivary cortisolinthemorning(opencircles)andatnight diurnal sleeptime(opencircles).(B)Meanconcentrationof time (solidsquares),nocturnalsleeptriangles)and activity inpreterminfants.(A)Meanvaluesoftotal24-hsleep Ontogeny ofsalivarycortisolcircadianrhythmandsleep Figure 5 Review ). AbnormalitiesintheHPA axiscircadian rhythmwere A CMoreiraandothers 130 ). Asidefromthe 20 h, as , 21 , cortisol levelstodropatlateevening( variationandthefailureofplasma 24-h cortisolsecretory 133 inpatientswithCushing’sbeen observed disease( mean pulsatileACTHamplitudebutnotfrequencyhad patients withCushing’s disease.Accordingly, increased subjects, abnormalitiesintheHPA axisweredescribedin normal circadian ACTHandcortisolsecretioninhealthy syndrome) havebeenconductedtodate. Cushing’s ACTH-dependentCushing’s disease(pituitary of ourknowledge,nomolecularstudiesonclockgenesin and noapparentCushingoidphenotype( than wild-typemiceandshowednormalglucosetolerance daily fluctuation.Inaddition, mice demonstratedelevatedglucocorticoidlevelswithno levels withnocircadian rhythm( Per1- mutatedclockgenes.Indeed, inmicecarrying observed which returned to normal after pituitary adenomectomy which returnedtonormalafter pituitary cerebrospinal fluidCRHcompared tonormalsubjects, patients withCushing’s diseaseexhibitedlowerlevels of plasma orcerebrospinalfluid cortisol.Ontheotherhand, is inoppositiontothecircadian for patternobserved rhesus monkeys( volunteers ( acrophase andanearlymorningnadirinhealthy fluid CRHlevels,whichwasdescribedtohaveanevening vein CRH,published studies haveadoptedcerebrospinal petrosal sinuses ( is difficultto measure inplasma and evenin theinferior reflects thecircadian releaseofhypothalamicCRH,which with abnormallyhighcortisollevels( while 43%exhibitedpersistentdiurnalvariationalbeit cortisolcircadiandisease completelylostsalivary rhythm, ( Cushing’s disease may exhibit cortisol circadian variation or ectopicACTHorigin.However, somepatientswith hallmark ofpatientswithCushing’s syndromeofadrenal ( incorticotropinomas glucocorticoid resistanceobserved significant abnormalitiesthatcouldexplaintherelative of CRH,AVP, ACTHandGRgeneshavenotshown metabolitesduringasuppressiontest( urinary to dose-dependentlysuppresscirculating cortisolorits demonstrated by thefailureof low-dose dexamethasone feedback.Thisfeatureis the glucocorticoidinhibitory of corticotropinomas includes thepartial resistance to to thesealterations,anotherremarkablecharacteristic Glucocorticoid circadianclock 140 137 ). Thisdisruptionledtotheabsenceofnormal Simultaneous with the detailed characterisation of the Thus far, investigationsonthestructureandexpression , , and 138 141 , , Per2 139 142 145 -null miceshowedelevatedcorticosterone ). Thelossofcortisolcircadian rhythmisa ). Indeed, 57% of patients withCushing’s ), similartothepatterndescribedin 146 144 ). Notably, theCRHcircadian pattern ). Thus, as asubstitute for portal Downloaded fromBioscientifica.com at10/02/202102:11:10AM Per1 Brd 131 127 179 miceweresmaller 143 ), whereas , :1 134 132 ). HPA activity ). Inaddition ). To thebest 135 , Per1 136 R10 129 ). via freeaccess Brd ,

European Journal of Endocrinology night salivary cortisol(LNSC)levels( night salivary suppression tests(1 freecortisol(UFC), low-dose dexamethasone of urinary Cushing’s syndromehavebeenbasedonmeasurements clinical featuresofCushing’s disease( metabolismalterationsand leading tointermediary dysregulation oftheclocksysteminperipheraltissues, circadian rhythmcontribute tohypercortisolism andthe in corticotrophsandthedisruptedglucocorticoid Thus, incorticotropinomas,theglucocorticoidresistance majority of the patients with Cushing’s syndrome ( Indeed, themelatonincircadian rhythmismaintainedin influence ofthemelatoninrhythm,cannotberuledout. from sympatheticadrenalmodulations,aswellthe levels. However, thepotentialroleofcircadian inputs in suchpatientsevenwithabnormallyhighcortisol explain themaintenanceofcortisolcircadian rhythm control oftheSCNcircadian clockgenes,whichwould from theadenomawouldbestillunderrelative reduced CRH secretion. In such cases, ACTH secretion a numberofpatientswithCushing’s diseaseexhibitonly portal veiniscompletelyabolished.Ontheotherhand, circadian rhythmoncecircadian CRHreleasein the that patientswithCushing’s syndromelosetheircortisol causes reducedCRHconcentrations. tumour ( dogs with hyperadrenocorticism due to an adrenocortical reduced inpatientsreceivingsteroidtreatment( ( 147 Review Biochemical strategies to establish a diagnosis of Based ontheaforementioneddata,wehypothesised , 148 149 ). CRHlevelsinthecerebrospinalfluidwerealso ). These data suggestthat hypercortisolism mg overnightorlonger)andlate- A CMoreiraandothers Fig. 6 151 ). , 152 148 , ) and 153 150 ). ).

and specificityof93.3%forthediagnosisCushing’s range at23:00 levels thatwerealmostentirelyoutsidethenormal with Cushing’s syndromeexhibitedhighercortisol cortisollevelssuchthatpatients in morningsalivary with Cushing’s syndromerevealedasubstantialoverlap between normal volunteers, obese patients and patients with Cushing’s syndrome( suitable screeningprocedurefordeterminingpatients cortisolwasahighly studies clearlyshowedthatsalivary syndrome beensuggested( until themid-1980shaditsusefordiagnosingCushing’s established duringthelate1970s( functionhadbeen the evaluationofpituitary–adrenal Cushing’s syndromehasincreasedovertime( absence ofcortisolcircadian rhythm,inthescreeningof measurements, a simple test that evaluates the presence or As willbefocusedinthepresentreview, theuseofLNSC overnight improved the diagnostic accuracy of Cushing’s saliva collectionat23:00 ( measurement aftera1 cortisol syndrome isthesubstitutionofplasmaforsalivary strategy toimprovethediagnosticaccuracyofCushing’s been confirmed using meta-analysis ( 160 of Cushing’s syndromein adults ( increased midnightserumcortisollevelsinthediagnosis that elevatedLNSClevelsareanexcellentsubstitutefor syndrome ( Glucocorticoid circadianclock 156 , The importance of salivary steroidanalysisfor The importanceofsalivary , 161 157 , ). Basedonpreviousstudies,thecombinationof 162 143 ) andchildren( h. Thisdifferenceresultedinasensitivity ). Indeed,severalstudieshaveconfirmed retinohypothalamic tract. paraventricular nucleus;RHT: system inperipheraltissues(5). PVN, the glucocorticoidreceptor(GR) andclock (3b) deregulatetheinteraction between circadian rhythmandhypercortisolism cortisol rhythm.Disruptedglucocorticoid concentrations (4)andleadstoabnormal increased cortisol(3a)reducesCRH to increasedACTHsecretion(2).Inturn, to cortisolnegativefeedback(1),leading Corticotropinomas arepartiallyresistant physiopathology ofCushing’s disease. dysregulation ofclockgenesinthe Abnormal cortisolcircadianrhythmand Figure 6 mg dexamethasonesuppressiontest Downloaded fromBioscientifica.com at10/02/202102:11:10AM h andafter1 156 158 163 , 157 , , 164 143 143 ). Subsequently, two 179 155 mg dexamethasone 165 ). Thesedatahave ). Acomparison www.eje-online.org :1 , ). However, not , 157 166 154 , ). Another 158 ). , R11 159 via freeaccess , European Journal of Endocrinology www.eje-online.org Metabolism 2014;992045–2051. Cushing’s Syndrome.JournalofClinicalEndocrinology & Performance thanUrinaryFree CortisolintheDiagnosisof permission from:Late-nightSalivary CortisolHasaBetter confirming thesuperiorityof LNSC. (Reproducedwith Cushing’s disease,whereasLNSCfailedinonly2.3%, (43 represents thecut-off valuesforLNSC(350 43 patientswithCushing’s disease(CD).Thedottedline (LNSC) andurinaryfreecortisol three concurrentandconsecutivelate-nightsalivarycortisol urinary freecortisolinCushing’s disease.Individualvaluesof Diagnostic performanceoflate-nightsalivarycortisoland Figure 7 LNSC samplingisrecommended.Altogether, thesedata LNSC ( despitehighvariabilityfor syndrome hadbeenobserved either currentorearly-stagerecurrenceofCushing’s UFC. ThesuperiorityofLNSCoverUFCfordiagnosing LNSC wasbetterindiagnosingCushing’s diseasethan confirmedthat receiver-operating characteristiccurves disease, whereasLNSCfailedinonly2.3%( UFC failedtodiagnose18.6%ofpatientswithCushing’s patients withCushing’s diseasefor3consecutive days. of LNSC and UFC using simultaneous samples of 43 the variability, reproducibility and diagnostic performances the differentassaysused( between reports because of diagnostic performance vary cortisol diagnostic cut-offs and to highlight that salivary syndrome inadultsandchildren( Review μ In amorerecentprospectivestudy( g/24 168 h). UFCfailedtodiagnose18.6%ofpatientswith , 169 ). Consideringthevariability, atleastthree 151 ( , UFC) samplesobtainedfrom 165 A CMoreiraandothers 143 , 167 , 163 168 ). ng/dL) andUFC ). Itisimportant ), wecompared i. 7 Fig. ). The The feedback loops between clock genes and their Concluding remarks rhythm inpatientswithCushing’s disease( phenomenon overlayingthedisruptedcortisolcircadian represent adistinctandadditionalphysiopathological awakening. ThissubtledysfunctionoftheHPA axismay disease, whichcanberelatedtohypercortisolism upon showed bluntedCARinpatientswithactiveCushing’s levels within30–45 cortisol ( appears to be superimposing the circadian rhythm of of thedisease( UFC seems to occur later during the natural progression is anearlymarkerforCushing’s disease,whileincreased cortisolcircadianindicate thatlossofsalivary rhythm marker ofCushing’s disease. cortisolcircadiansalivary rhythmseems tobeanearly Cushing’s disease.Fordiagnosticpurposes,an abnormal metabolism andclinicalfeaturesof in intermediary dysregulation intargettissues, leadingtoalterations rhythm contributetohypercortisolism andclocksystem in corticotrophs and the disrupted cortisol circadian In corticotropinomas,theglucocorticoidresistance postnatal. infants becomesapparentataround1 month prenatally, cortisol circadian whilesalivary rhythmin primates isalreadyfunctioningandresponsivetolight of theSCNandHPA axis.TheSCNcircadian clockin development ofwhichfollowsthegradualmaturation in theplasmaglucocorticoidcircadian rhythm,the between molecular and physiological oscillations result turn interact reciprocally with GRs.Theseinteractions SCN pacemaker to reset peripheral clock genes, which in asatransducerofcircadianalso serving signalsfromthe of the HPA axis, regulate physiologic function while Circulating glucocorticoids, whicharetheend-effectors cyclic hormonalfactorsandautonomicinnervations. andadrenalcircadianpituitary clockgenesbycontrolling downstream fromtheSCNtootherhypothalamicnuclei, circadian rhythmof the HPA axis is propagated thousand clock-controlledtargetgenes.Theendogenous transcript proteins bind to the promoters of more than a environmental synchronisers.Clockgenesandtheir timekeeping system dependson photic andnonphotic Moreover, thefine-tuningofmolecularcircadian rhythm withaperiodicityofapproximately24 transcript proteinsdetermineaself-sustainedcircadian Glucocorticoid circadianclock Moreover, adistinctphenomenontermedCAR 170 , 171 168 ). 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