University of Southern Denmark

MECHANISMS IN ENDOCRINOLOGY Anorexia nervosa and endocrinology: a clinical update Støving, René Klinkby

Published in: European Journal of Endocrinology

DOI: 10.1530/EJE-18-0596

Publication date: 2019

Document version: Final published version

Document license: CC BY

Citation for pulished version (APA): Støving, R. K. (2019). MECHANISMS IN ENDOCRINOLOGY: Anorexia nervosa and endocrinology: a clinical update. European Journal of Endocrinology, 180(1), R9-R27. https://doi.org/10.1530/EJE-18-0596

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European Journal of Endocrinology -18-0596 ego-syntonic neglect,ambivalence,self-starvation, etiology. Itischaracterizedbydisturbed body image, a collectionofsymptomsandisnotdefinedby an (AN) is a syndrome as it describesAnorexia nervosa Introduction clinical perspective. Considering this,theaimofpresentreviewistoprovideanupdatedoverviewmanyendocrinechanges ina with therapeutictargets.Abreakthroughinourunderstandingandtreatmentofthiswhimsicaldiseaseremains. re-nutrition, however,firstofallweneedthemtoexplorethemetabolisminanorexianervosaopennewavenues actions thatcouldoffertherapeutictargets.Weneedreliablebiomarkersforpredictingoutcomeandtoensuresafe hormones alsoarereleaseddirectlytodifferentbrainareas,wheretheymayexertbehavioralandpsychogenic and re-nutritioncombinedwithpsychometricdata.Besideswell-establishedperipheralendocrineactions,several important focusofclinicalresearchshouldbetoidentifybiomarkersassociatedwithdifferentstagesweightloss process, andtheneedforweightgainmustbebalancedagainstpotentiallyfatalrefeedingcomplications.An re-nutrition orinasettingwithsomaticcomorbidity.Electrolytelevelsmustbecloselymonitoredduringtherefeeding reactive oretiologic.Adaptivechangespotentiallymaybeinappropriateinclinicalsettingssuchasinpatientintensive are intractable.Thesyndromeisassociatedwithmultiple,profoundendocrinealterationswhichmaybeadaptive, Anorexia nervosaisasyndrome,thatcollectionsofsymptoms,whichnotdefinedbyitsetiology.Theseverecases Abstract of SouthernDenmark,Odense,Denmark of ClinicalResearch,UniversitySouthDenmark,FacultyHealthSciences,and 1 René Klinkby Støving a clinicalupdate Anorexia nervosaandendocrinology: MECHANISMS INENDOCRINOLOGY Nutrition Clinic,CenterforEatingDisorders,OdenseUniversityHospital, https://doi.org/ https://eje.bioscientifica.com Review Review are clinicalendocrinologyand epidemiologicalstudiesofanorexia nervosa. Hisresearchspecialized endocrineunitin Denmarkforpatientswithsevereanorexianervosa. areas centeratOdenseUniversityHospitalin1993.In 2010,heestablishedtheonly an interdisciplinary havingcontributed totheestablishmentof hasextensive clinicalexperience inanorexianervosa in the Regionof Southern Denmark. He of Southern Denmark, and Mental Health Services Rene KlinkbyStøving,MD,PhD,isanendocrinologistand professorineatingdisorders,University Invited Author’s profile 10.1530/EJE -18-0596 1 , 2 , 3 1 R KStøving Published by Bioscientifica Ltd. Printed inGreat Britain © 2019Theauthors 2 Endocrine EliteResearchCentre,Institute The severityvariesfrommildsubclinicalcasesto activity, depression,anxietyandemotional rigidity. ritualistic patternsoffoodintake,elevatedphysical loss ofbodyweight,obsessivethoughtsfood, endocrinology Anorexia nervosaand 3 Psychiatric ServicesintheRegion Attribution 4.0International License. This workislicensed under a Downloaded fromBioscientifica.com at01/03/201910:18:29AM (2019) Endocrinology European Journalof [email protected] Email to RKStøving addressed be should Correspondence

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European Journal of Endocrinology https://eje.bioscientifica.com present review. years ( bone metabolisminANhavebeenpublishedrecent severe illness.Asseveralcomprehensivereviewson disorders than AN, and it predominantly focuses on with AN.Thereviewdoesnotconsiderothereating yearsofclinicalwork own experiencesfromover25 AN. It is a narrative review that is combined with my each ofwhichdealswithspecifichormonesystems in the articlereferstoanumberofliteraturereviews the clinicalconsequences.Formorein-depthdiscussion of the many endocrine changeswithfocus onoverview in termsofregulationinsulin,glucoseandlipid( which reveledgeneticcorrelationswithmetabolictraits supported byarecentgenome-wideassociationstudy and weight-relatedfeaturesinAN.Thishypothesiswas in BMImayalsoinfluencedysregulationofappetite same geneticfactorsthatinfluencenormalvariation familialaccretioninAN.Hypothetically,observed the uniquely havesupportedageneticoriginforthe although thelatter remains tobeproven.Twin studies amenorrhea, thuspotentiallycreatingaviciouscircle, and intensifytheanorexia,physicalhyperactivity Butatthesametime,itmaymaintainto starvation. of corticotropin-releasinghormone(CRH)isaresponse activity havereturnedtonormal( and persistforalongtimeafterweightmotor is oftensecondary,precede theweightlosscan butit or etiologic.Forinstance,hypothalamicamenorrhea ( evenwithextremeemaciation allowssurvival starvation disturbances ( to treatment( neuroscienceapproachimproved withanevolutionary ( century that theprognosishasimprovedthroughout20th limited( treatment isstillvery pathophysiological mechanisms.Theevidencebasefor are based on symptoms, may not reflect the underlying estimated tobe1–4%( 30–50% increaseinlifetimeprevalence( markedly increaseddiagnosticheterogeneityanda the DiagnosticandStatisticalManual( criteria wererevisedin2013fortheFifthEditionof chronic enduring and fatal cases. The diagnostic 11 Review ). Theendocrinealterationscanbeadaptive,reactive The purposeofthereviewistoprovideanupdated AN isassociatedwithmultiple,profoundendocrine 14 , 6 15 ). However, sincethattheoutcomemayhave , 16 8 7 ). , , 9 17 , 10 , 18 ), andadaptationtochronicsemi- 4 ), thisaspectisomittedfrom the ). Diagnosticboundaries,which 5 ). Therewasnoevidence R KStøving 12 ). Hypersecretion 2 1 , ), leadingto 3 ), whichis 13 ).

sudden death( arrest, hemolytic anemia, delirium, seizures, comaand of RFSandhypophosphatemiaarecardiacfailureor syndrome andlacticacidosis.Theclinicalmanifestations with RFS( ( intracellular spaceisbelievedtobecausedbyinsulinspikes The electrolytemovementsfromtheextracellularto relapsed withaweightdroptoBMI7.2,whichshealso the publication of that case report, the same patient withoutseveresequelae( has beensurvived corresponding to65%belowexpectedbodyweight, sex hormonesandT3.InAN,aBMIaslow7.8, growth hormone(GH)andsuppressedlevelsofleptin, characterized byincreasedsecretionofcortisoland iswelldescribed( of chronicstarvation Theoverallendocrinology allows thepatientstosurvive. characterized byanextremeadaptivemechanismthat intake duringepisodesofstarvation. term equilibriumbetweenenergyexpenditureandfood systems thatfacilitateappropriateshort-termandlong- Natural selectionhasledtotheevolutionofhormonal Adaptation The refeedingsyndrome guidelines ( is presentlynoevidencetorequire changestothecurrent by indication,leadingtheauthorstoconcludethatthere and limited by bias refeeding studies were observational on ( insulin peaks)mayallowahigherenergyintakeearly further initial restriction incarbohydrates (to prevent pdfversion/CR162.pdf underfeeding syndrome( this approach,however, isadditionalweightlossorthe energy levelisprescribed.Anunintendedconsequence of such asphosphate,magnesiumandpotassium( principally lowserumconcentrationsofintracellularions 22 or fatalcomplicationsisanecdotallyrecognized( refeeding syndrome(RFS).RefeedinginANwithserious a considerableriskduringearlyre-nutrition,termedthe and hunger disasters. However, the adaptation represents far exceedswhathaseverbeenreportedinhungerstrikes (unpublisheddata).Thisdegreeofemaciation survived endocrinology Anorexia nervosaand 28 , ). Thiamine(vitaminB1)deficiencyisalsoassociated 23 Chronic andsevereANisendocrinologically 31 , ). Asystematicreviewillustratedthat26outof27 24 29 , 25 32 ) andmanifestsasWernicke’s encephalopathy ). RFSisdefinedaselectrolytedisturbances, ). 27 , 30 .). Itiscurrentlydebatedwhether ). To low initial avoidRFS,avery Downloaded fromBioscientifica.com at01/03/201910:18:29AM http://www.rcpsych.ac.uk/files/ 180 :1 19 11 ) andis ). Since 26 20 R10 , via MULTI-PFIZER , 27 21 ). , European Journal of Endocrinology not onlyintermsofactual BMI, butalsotheshort-term evaluate insulinsensitivityand todifferentdiseasestages results are related to the different techniques used to increased ( results,from unchanged ( provided contradictory hypoglycemia. StudiesofinsulinsensitivityinANhave insulin resistanceandthuscounteractthetendencyfor below) areelevatedinAN,andbothknowntoinduce has beenassociatedwithfatalhypoglycemiainAN( ( enzymes mayriseduringtheearlyphaseofre-nutrition increased riskofhypoglycemia( of liver damage predicts low glycogen storage and thus frequent findinginliverbiopsies( and autophagy ( catabolism, dehydration,anemia,hypotension,ischemia to liverinjury, whichiswelldescribedinAN,duetoprotein hypoglycemia isunknown.Hypoglycemiamayberelated 40 administration isrequiredtomaintaineuglycemia( or repetitive, so that continuous glucose can be refractory some of these fatal cases ( hypoglycemia wasrecognizedasthecauseofdeathin described amongyoungwomenwithAN,andmanifest controls ( levels ofglucosearegenerallylowerinANthan ( inventions inmedicalhistory in ANuntilthe1960sandrepresentsoneofbizarre Insulin-induced hypoglycemiawasusedtherapeutically Adaptation Glucose metabolism BMI 12–13.Controlledrandomizedstudiesarerequired. for high risk in adults maybe should be adjusted to below purging orsomaticcomorbidity, definition thearbitrary Ifthereisnoactive risk’ patientistooconservative. negative consequences.Maybethedefinitionofa‘high overestimation oftheriskmayhavesignificantclinical pdf ( fatal complications, i.e. ‘Start low and advance slow’ for weightgainmustbebalancedagainstthepotentially monitored duringtherefeedingprocess,andneed In severeAN,electrolytelevelsmustbeclosely Clinical consequences 47 http://www.rcpsych.ac.uk/files/pdfversion/CR162. Review , ). Psychopharmacologictreatmentwitholanzapine , MARSIPAN. AccessedApril15,2015).However, an 41 The secretionofGH(seebelow)andcortisol , 42 35 ). Theincidenceofasymptomaticorsubclinical 50 , , 36 51 ). Suddenunexpecteddeathisstillwell 43 , 52 , ) ordecreased( 44 ). Marked glycogen depletion is a 37 ). Hypoglycemic coma in AN 33 R KStøving , 46 34 53 45 ). Furthermore,liver ). Ingeneral,fasting ). Theseconflicting ), andtheseverity 38 49 48 , ) to 39 ). , adaptation. low inAN,whichseemstobeappropriaterelation ( from pancreaticbetacells.TheplasmalevelsofGLP-1 secretion ofinsulin.Amylinisco-secretedwithinsulin the mucosaofdistalintestinaltractandstimulates an ongoingmeal.GLP-1issecretedfromtheLcellsin in responsetoamealandprobablylimitthesizeof glucagon-like peptide-1 (GLP-1) and amylinarereleased patients withAN. Gastrointestinal hormones suchas circumstances stressdiabetesoccursinhospitalized no published reports of how often and under what my specializedunit,buttoknowledgethereare as individualcases( onset ofinsulinresistance( thatrefeedingwasassociatedwith clamp, itwasobserved nutritional status.Usingahyperinsulinemic–euglycemic (proopiomelanocortin, POMC), ACTHsecretionis ACTH and opioids are derived from the same prohormone AN ( measurements in cerebrospinalfluid frompatientswith ( 63 normal cortisolresponsetostimulationwithACTH( of CRHhypersecretion.Thisisfurthersupportedby together withhighlevelsofcortisol,indicatingastate Adrenocorticotropic hormone(ACTH)isincreased Adaptation (HPA axis) Hypothalamic–pituitary–adrenal axis centers ( Therefore, prophylactic 5% dextrose is used in other earlier, this mayincrease the risk of refeeding syndrome. in thefirstdaysofrefeeding( intravenous10%glucose(20–40 supplementary exercise. In some centers, hypoglycemia is prevented by severe AN,especiallyduringthenightorinrelationto studied. Bloodglucoseshouldbemonitoredregularlyin or otherclinicalcharacteristicshasnotbeenfully weight loss,refeedingsyndrome,diagnosticsubtype The frequencyofhypoglycemiaanditsrelationto Clinical consequences endocrinology Anorexia nervosaand 56 64 ) butaweakenedresponsetostimulationwithCRH , , Temporary stressdiabeteshasonlybeenreported 57 64 65 , , ). Finally, CRHhypersecretionisconfirmed by 58 61 66 ) and amylin ( ). ). Thishasbeenevidentsince the1980s.As 55 ). It is observed occasionallyin ). Itisobserved Downloaded fromBioscientifica.com at01/03/201910:18:29AM 35 54 , 53 ). 60 , https://eje.bioscientifica.com 59 ); however, asdiscussed ) are both found to be 180 :1 mL/h) R11 via MULTI-PFIZER 62 , European Journal of Endocrinology https://eje.bioscientifica.com 83 could beusefulinthetreatment ofmajordepression( evidence thatanti-glucocorticoidtherapies preliminary was explicitlydiscussedin a recentreview( of cortisolsuppressantsshould befurtherexplored.This experimental analysis.Thus,thetherapeuticpotential remains unclearandneedstoberesolvedbyfurther AN ( CRH maybeinvolvedinapotentialviciouscircle in Clinical consequences mechanism tomaintaineuglycemia(seesectionabove). secretion (likeincreasedGHsecretion)inANisanadaptive fasting glucose ( levels inANareshowntobeinverselycorrelated cerebral effects. on circulatory levelsonly( So far, studiesonneurosteroidsinANhavebeenconducted therapeutic potential( disorders ( feedback ontheHPA axisandtobeimplicatedinanxiety novo inthebrain.Theyaresupposedtoexertanegative syndrome ( stress andhypercortisolemia instudiesonCushing´s shown thathippocampalatrophyisrelatedtochronic long-term stress. In fact, neuroimagingstudies have clearly glucocorticoid receptorsandthusmaybevulnerableto functions.Itcontainsmany a criticalstructureformemory continuing stressconditionandhighriskofrelapse( patients, thedexamethasonesuppressiontestpredicteda activity could also be pathogenic. In weight-recovered suggesting thatlowhypothalamicsomatostatinergic that the somatostatinergic tonus is impaired in AN ( action ofCRHonfoodintake( antagonists ( increased motoractivity( central microinjectionsofCRHcanleadtoanorexiaand state ofcortisolresistance.Manyanimalstudiesshowthat mechanismfora hypersecretion maybeacompensatory coping responseinacutestressfulevents.InAN,CRH glucocorticoid levelmayinduceanxietyasanappropriate anorecticeffect.Inhealthyindividuals,ahigh secondary stress andpsychologicalactivatetheHPA axiswith may alsostimulatetheurgetoexercise ( system mayinfluencehedoniceatingbehavior( preceded byactivationofthePOMCsystem.Theopioid Review , 84 Neurosteroids aresteroidsthatsynthesizedde The hippocampusbelongstothelimbicsystemandis Cortisol stimulatesgluconeogenesis,andcortisol 8 ), andthedegreeofcortisol elevation wasrelatedto ). However, sofar, thecause–effectrelationship 74 78 70 ), depression( ). Neurosteroidsmayhaveimportant ). Somatostatincounteractstheanorectic 80 ). This suggests that increased cortisol 78 ), butthisremainstobeclarified. 69 75 ) thatcanbereversedbyCRH 79 , 76 ) andcannotrevealtrue 71 R KStøving ) andAN( ), andthereisevidence 68 ). Bothphysical 77 81 ). ). Thereis 67 ) and 73 72 82 ). ), , risk byeliminatingtheadaptive bradycardiaandlow contrary, itwouldprobablyincreasethecardiovascular therapeutic effectofthyroid hormonesinAN.Onthe and yetthereisnoevidence tosupporta beneficial 101 affective disorders( effect ofimipramineinprimary antidepressant effectortoamplifythe of thyroxine, TSH or TRH was found to exert an appropriate substitution( with affectivedisturbances,whichmaypersistevenafter been provided( patients, andevidenceforcommongeneticfactorshas affective disorders in therelatives of AN of primary is wellestablished.Moreover, thereishigherprevalence weights. goal course toassessmetabolicadaptationandrecovery It maybeusefultomonitorT3levelsduringatreatment Clinical consequences even atnormalTSHlevels( metabolic rate( ( to exogenous TRH stimulation is blunted and delayed is normalorslightlydecreased,whiletheTSHresponse peripheral deiodinationofT4( (Low T3 Syndrome). Reverse T3 is elevatedfrom increased expenditure (REE)( Low levelsofthyroidhormonedecreaserestingenergy Adaptation Hypothalamic–pituitary–thyroid axis have notbeenexploredinAN. synthesis inhibitors,likeketoconazoleandmetyrapone, levels ( free cortisol excretion and early morning cortisol plasma patients, which found thatmifepristoneincreased urinary AN hasonlybeenexploredinashort-termstudyofeight Cushing’s syndrome( glucocorticoid antagonistthatisusedtherapeuticallyin for medicalabortion( ( depression andanxietymeasuresin18patientswithAN (TBG) todowngradethemetabolicrateandREE( concentrations ofT3,T4andthyroid-bindingglobulin loss is followed by adaptive decline in circulating endocrinology Anorexia nervosaand 95 85 ). Duringweightrecovery, totalT3 rises withtherising ). Mifepristone is a potent progesterone primarily used ). However, evidenceislackingforcausal relationships A relationshipbetweenANanddepressivesymptoms 88 ). To myknowledge,theeffectsofcortisol 96 98 ). InANthethyroidglandisatrophic ). Thyroiddisordersareassociated 86 89 87 Downloaded fromBioscientifica.com at01/03/201910:18:29AM ). Inaddition,itisacompetitive ). Self-starvation andweight ). Self-starvation ). Theeffectofmifepristonein 99 97 ). Exogenousadministration ). 92 , 93 180 , 94 :1 ). TheTSHlevel 90 R12 via MULTI-PFIZER , 100 91 ) , European Journal of Endocrinology at least18.5,only35%had resumed menstruation( follow-up study of 57 patients whohad reached aBMIof ofnormalbodyweight( despite recovery with AN,amenorrheapersisted in15%ofthewomen exercise. Forexample,inastudyof100adolescent girls weight recovered AN patientsdueto anxiety orexcessive Menstrual resumption typically fails in underweight. amenorrhea may have many causes,including Institute for Care Excellence (NICE) 2017). Secondary disorders: recognitionandtreatment.NationalHealth nice-org-uk.proxy1-bib.sdu.dk/guidance/ng69 ( remains aclinical hallmark ofrecovery for thediagnosisofAN( In theDSM-5criteria,amenorrheaisnolonger required Clinical consequences ( the genesisofstress-inducedhypothalamicamenorrhea and amide-relatedpeptide-3allseemtobeinvolvedin peptide peptides kisspeptin,gonadatropin-inhibitory reviewed ( in regulation of eating behavior have been thoroughly orexigenic peptides( Estradiol modulatescentralprocessesofbothsatiatingand and potentialpathogenicrolesofthesexhormones. gives rise to considerations of sex-dependent susceptibility inED( secretion duringstarvation ghrelin and cortisol levelsboth suppress gonadotropin which arebothdecreasedinAN.Inaddition,increased secretion isstimulatedbyestradiol( ofhealthysubjects( starvation LH secretionpatterncanalsobeinducedinexperimental manifests as hypothalamic amenorrhea. The immature reverse withweightgain( immature, prepubertal,low-amplitudeLHpulsesthat stress. InadultwomenwithAN,earlierstudieshaveshown reproductive systemshutsdownintimesofhungerand perspective,itisfittingthatthe From anevolutionary Adaptation Hypothalamic–pituitary–gonadal axis report ( is notaddressedintheliteratureexceptforasinglecase thyroxine treatmentinAN.Thismaybeoverlooked,asit REE. Finally, thereisaproblematicabusepotentialof 112 Review The pronouncedskewedgenderdistributioninAN ), buttheirpotentialroleinANremainsuncertain. 102 110 ). , 111 ). Recentlydiscoveredhypothalamic 109 1 ). Neuroendocrinesexdifferences ) although menstrual resumption ) althoughmenstrualresumption 103 ). ThealteredLHpulsatility 104 R KStøving 107 105 ). Thegonadotropin , ) andleptin( 108 113 ). https://www- ). In a 1-year ). Ina1-year . Eating . Eating 106 114 ), ). ). did notuniquelypredictmenstrualresumption( this leptintherapy( menstrualcycleswith of eightsubjectsachievedovulatory follicles and elevated plasma estradiol levels ( of theovaries,increasednumberandsizesdominant leptin increasedpulsatileLH,resultinginanenlargement hypothalamic amenorrhea,administrationofexogenous quite lowBMI;inafewcases,evenlowerthanBMI14( small minorityofpatients,menstruationmayrecoverata inAN( to BMIinpredictingmenstrualrecovery wasnotsuperior by dualenergyX-rayabsorptiometry function ( of the subjects wereexpected to resumetheir menstrual at aBMIof19orbodyfatpercentage of23,only50% BMI levelsandbodyfatpercentages wascalculated,and The predicted probability ofresuming menses at various of AN ( not use oral contraceptives and had a history This isinlinewithastudyof113adultwomenwhodid perinatal lethality in women with a history ofANindicate perinatal lethalityinwomen withahistory miscarriages, cesareandeliveries, prematurebirthsand common inAN( perception ( attitudes towardeating,eatingbehaviororbodyshape independently ofweightchanges,butitdidnotaffect estradiol improvedthetendencytoexperienceanxiety weight ( anxiety inwomenwithANindependentofbody has beenassociatedwithmoreseveredepressionand these symptomsinAN.Forinstance,hypoandrogenemia and itispossiblethatdeficiencyinsexhormonesworsens adolescents withAN( with cyclicprogesteroneincreasedboneaccrualratesin that transdermalphysiologicalestrogenreplacement IGF-1 ( IGF-1, although transdermal estrogen did not suppress with estrogen’s suppressiveeffectonhepaticsynthesisof ( consistently foundinsufficientevidencetosupportthis estrogen preparations on bone health in women with AN several systematicreviewsexaminingtheeffectoforal alleviated by substitution with estradiol. However, atrophy could theoretically be of starvation-related membranes and bone mass. Some of these consequences and well-knownrolesinmaintainingmuscle,mucous this isnotanoptionintreatmentofAN. as exogenousleptinalsoreducesfatmassandappetite, endocrinology Anorexia nervosaand 14 , In athletic women with slight underweight and In athleticwomenwithslightunderweight Unplanned pregnanciesappear toberelatively Anxiety anddepressionarewell-knownfeaturesofAN, Both estrogenandtestosteroneplayimportant 117 118 ). Thelackoffavorableeffectscouldbeassociated 120 12 ). Inlinewiththis,an18-monthRCTshowed 121 ). InadolescentgirlswithAN,transdermal ). Furthermore, body composition measured ). Furthermore,bodycompositionmeasured ). 122 115 , 119 123 ). InAN,however, increasedleptin Downloaded fromBioscientifica.com at01/03/201910:18:29AM ). ). Reportsofincreasedrisk for https://eje.bioscientifica.com 180 :1 115 116 12 ). Three ). In a ). Ina ), and R13 via MULTI-PFIZER 12 12 ). ). European Journal of Endocrinology https://eje.bioscientifica.com but astherewasno control group,itisnot possible to ( rhGH for2 years growth failureanddelayed puberty weretreatedwith investigated. Ten girlswithearly-onsetANandsubsequent The therapeuticeffectsofGHinANhasonlybeenscantily Clinical consequences however, PAPP-A hasnotyet beenstudiedinAN. and releasesbioactiveIGF( promoting enzymewithinthetissuesnearIGFreceptor of IGF-binding proteins, PAPP-A functionsasagrowth- widely expressedinmultipletissues.Bycleavingasubset abundant inthecirculation ofpregnantwomenandis IGF-1 ( is increasedandinverselycorrelatedwiththelevelof GH effects( inhibits transcription5whichisamediatorofintracellular from hepatocytes,adipocytesandmyocytes,FGF21 the secretionoffibroblastgrowthfactor21(FGF21) a stateoflowenergyavailability( (through increasedlipolysis)tomaintaineuglycemiain in ANisthusadaptivethroughitsgluconeogenicrole of euglycemia(seeabove).ThestateGHresistance of thehigherGHandlowerIGF-1levelsismaintenance potent stimulator of gluconeogenesis, a beneficial effect ( Circulating levelsoftotal ultra-filtrated( in ANandshouldalsobeconsideredthetreatment. and viceversa( by refeeding ( be correlatedwiththeweightlossinANandarereversed process ( controls, denoting marked irregularity of the GH release significantly higherGHapproximateentropyscoresthan GH secretion( daily pulsatileGHsecretionandbasal(non-pulsatile) burst durationareincreasedinAN,withmarkedlyhigher burstfrequency,resistance. Secretory burstmassand pattern,andANisastateofacquiredGH secretory The metabolic effects of GH are related to its pulsatile Adaptation Growth hormone(GH)axis pregnancy andoftheirchildren( the needforcarefulmonitoringofthesewomenduring 50 Review ) IGF-1levelsaregreatlydecreasedinAN.AsGHisa Placental-associated proteinprotein-A(PAPP-A) is 131 125 ). 130 ). ThealterationsinGHsecretionappearto 125 125 127 ). ExpectedlyinAN,thelevelofFGF21 , 126 133 ). Furthermore,womenwithANhad ). Insomniaisarecognizedsymptom ). GH pulsatility is affected by sleep ). Increase in height was observed, ). Increaseinheightwasobserved, 132 R KStøving 114 129 ). To myknowledge, , ). Fastingstimulates 124 128 ) . ) andbioactive Adaptation Ghrelin secretion asapotentialetiologic factorinAN( studies havefailedtoreveal any polymorphisminghrelin acylated/desacylated ghrelin. So far, genetic association and short-termweightgain ledtoanincreasedratioof concentration decreaseswithweightgain( level of ghrelin is elevated in AN and the plasma was recentlyprominentlyreviewed( The broadpharmacologicalpotentialofghrelinpathways separate hormonethroughanunknownreceptor( in micelackingGOAT ( ghrelin (GOAT) is theonly known enzyme capable of acylating acylated ghrelinstimulatesappetite( is presentinacylatedanddesacylatedforms,only neurons are ablated in mice ( as evidencedbytherapidarrestoffeedingwhenthese These pathwaysareessentialfornormalfeedingbehavior, agouti-related protein(AgRP)andneuropeptideY(NPY). orexigenic pathways produced by thetwoneuropeptides, effect isstimulationoffoodintakeviaactivation initial characterizationasaGHsecretagogue.Itsstrongest exerts multiple physiological effects that go far beyond its gastric cells. Ghrelin cross the blood–brain barrier and Approximately 70%ofcirculating ghrelinissecretedby trial incriticallyillpatientsintensivecareunits( patients hasbeenseverelyquestionedbyamulticenter the safety of GH treatment in hypercatabolic GH-resistant hardly beoftherapeuticbenefitincachexia.Furthermore, treatment led to a further decrease in fat mass, which can not increasethelevelofIFG-1( times thedoseusedtotreatGH-deficientpatientsdid ( with BMI17.4 21 to28 and enduringANwhothenincreasedbodyweightfrom peptide-2 wasadministratedtoonepatientwithsevere ( nutritional interventions separate thepotentialeffectofrhGHfromthat levels inrestrictiveandbinge-purgesubtypesofAN( ( and theplasmalevelofobestatinisalsoincreasedinAN ( 146 endocrinology Anorexia nervosaand 135 149 147 ). Moreover, pulse amplitude is increased the secretory Numerous studieshaveshownthatthecirculating ); however, supraphysiologicdosesgreaterthanfive ). Somestudieshavereporteddifferencesinghrelin , 148 in vivo kg over 14 months ( kg over14 months ). Obestatiniscleavedfromacylatedghrelin, , as indicated by theabsence of acyl ghrelin ±

. efamnsee Hfr1 weeks 0.4 self-administeredGHfor12 139 Downloaded fromBioscientifica.com at01/03/201910:18:29AM ). Desacylghrelinmayactasa 133 134 ). IntranasalGH-releasing 137 ). InanRCTtenpatients 135 ). Circulating ghrelin 138 141 180 ). Importantly, the ). Oacyltransferase , :1 142 50 , 143 151 , 144 ). , 152 136 , R14 140 150 via MULTI-PFIZER 145 ). ). ), ). , European Journal of Endocrinology (THC) intakeinhumans described short-termeffects interest anddebate. Old studiesoftetrahydrocannabinol million hitsinGoogleand demonstratesahugepublic A search for‘medicalcannabis’givestodaymorethan 6 Adaptation The endocannabinoidsystem potential ofghrelinagonisminAN. obviously basisforfurtherexplorationofthetherapeutic oftreatment ( during 4 weeks agonist; however, therewasnosignificant weightgain sensation. Gastric emptying was shortened by the ghrelin out of10patientsdroppedduetoanincreasedhunger stable patientswithAN(BMI17.7 relamorelin, wasrecentlytestedinanRCTof22chronic, with diabetic gastroparesis ( improvements overplaceboin23hospitalizedpatients receptor agonist,ulimorelin,demonstratedsymptomatic commoninAN( is very nausea andotherformsofgastrointestinaldiscomfort show promisingresults( disease to cancer and chronic obstructive pulmonary treatment oflossappetite.SmallRCTs incachexiarelated appetite-stimulating responsetochronicstarvation. Increased ghrelin secretion seems an appropriate adaptive Clinical consequences moderate andhighMCTsupplementation( in bodyweightdidnotdiffersignificantlybetweenlow, a dose-dependentmanner( increased thelevelofacylated(active)ghrelinlevelsin medium-chain triglyceride (MCT) supplementation studies. Inanotherstudyof30patientswithsevereAN, that studycannotbedrawnbutshouldinspiresubsequent group andblindingoftheinvestigators, conclusions from in AN,andduetolackofarandomized,placebo-controlled measurement by visual analog scale has not been validated decreased inthreeofthefivepatients( increased in four of the five patients, whereas body weight hungermeasuredbyavisualanalogscale intervention, ( twice adaypreprandiallyfor2 weeks supraphysiologic dosesofghrelin(3 five patients with restrictive severeAN (BMI 10.2–14.6), studyhasbeenpublished.Inapilotof intervention Review In theory, ghrelinagonismoffersanapproachin To myknowledge,onlyoneexperimental 158 155 154 ). AnRCTwiththeghrelin 159 , 160 156 ). However, theincrease R KStøving ). The ghrelin agonist, ). Despitethis,thereis , ± 157 :) ( 0:4) μ g/kg) wereinfused 153 ). Gastroparesis, 153 160 ). Duringthis 154 ). Appetite ), where3 ). enetne eodte4 weeks.Duringthe4-week been extendedbeyondthe 4 that trial( inthelastweekof the highestweightgainwas observed gaining effect( a statistically, buthardly clinically, significantweight- low-dosage dronabinol(10 of 24patientswithsevereandenduringANfoundthat randomized double-blind, controlled crossoverstudy occasionally tube-fedduringthetrial( the diazepamgroup,althoughparticipantswere gain intheTHCgroupwasslightlyhigherthanthat in randomized trialof11patientswithAN( and highdosesofTHCwerecomparedinanon-blinded reviewed ( The therapeuticperspectivesinANhavepreviouslybeen Clinical consequences or asdysregulatedrewardprocesses. appropriate (butinsufficient)adaptationtomalnutrition units. Anincreasedlevelcouldbeinterpretedbothasan measured inafewsmallpopulationsbyresearch ( controls inperipheralendocannabinoidresponsetomeals weight-recovered AN patients differed from healthy palmitoylethanolamide ( 2-arachidonoylglycerol, oleoylethanolamideand concentrations oftheendocannabinoidsanandamide, and interoceptiveimpairment. special interestinAN( and hedonicfoodrewards( pathway implicated in processing appetitive motivation amygdala andorbitofrontalcortex),whichconstitutesa mesolimbic rewardsystem(midbrain,striatum,insula, 1 wasnegativelycorrelatedwithBMIthroughoutthe disorders, theavailabilityofcannabinolreceptor and fattissue).Itwasrecentlyshownthatineating (intestinal system and pancreas) and adipogenesis (liver evaluation offoods(limbicsystem),gutsignaling functions (hypothalamusandhindbrain),hedonic both centralandperipheral,beingrelatedtointegrative related neuralandhormonalcircuitry atseverallevels, characterized indetail.Thesystemhasarolefeeding- minor weightgains. related ( intake ( in termsofelevatedhungerratingsandincreasedfood patients with AN suffer from universal anhedonia ( endocrinology Anorexia nervosaand 166 The endogenouscannabinoidsystemhasbeen Patients with AN have high peripheral ). Sofar, however, endocannabinoids haveonlybeen 161 164 169 171 , ) cachexia,clinicaltrialshaveshownonly 162 ). Inanoldstudy, theeffectsofdiazepam ), indicatingthattreatment shouldhave 171 ). However, incancer( ). Itshouldbenoted,however, that 166 Downloaded fromBioscientifica.com at01/03/201910:18:29AM 166 ) inviewoftheconsensusthat 165 gdiy vr4 weekshad mg daily)over4 , ). Thehedonicrolesareof https://eje.bioscientifica.com 168 ). Moreover, seven 180 170 :1 170 163 ). Anadd-on, ). Theweight ) andAIDS- R15 via MULTI-PFIZER 167 ) European Journal of Endocrinology https://eje.bioscientifica.com of post-traumaticstresssyndrome overtime( level ofvasopressinwasnot relatedtothedevelopment of soldiers( sensitivity toADH( levels of ADH in cerebrospinal fluid and enhanced pituitary depression hasbeenfoundtobeassociatedwithelevated evidence of this is thoroughly reviewed ( and responsestostress( involved insocialbehavior, sexualmotivation,depression released directlyintothebrainwhereitisconsidered to be osmoregulation andarterioleconstriction,vasopressin is and polydipsia( vasopressin secretion,withclinicalsymptomsofpolyuria has also beendocumented in AN dueto defective pathogenic interpretation( and oralcontraceptives,however, whichconfounds terms ofpharmacologictreatmentwithantidepressant ability) ( concentrating and afterwaterdeprivation(lowerurinary ADH levelsdespitelowerplasmasodiumandosmolality) showed alteredosmoregulationbothatbaseline(normal 179 hormone secretion(SIADH)mayalsobeimplicated( 177 seizures. Purgingbehavioristhedominantcause( such as vomiting, altered level of consciousness and commoninAN( very arginine vasopressin and argipressin. Hyponatremia is Vasopressin is also referred to as antidiuretic hormone, Adaptation Vasopressin anhedonia andmotorrestlessnessinAN. in modulation of both feeding behavior and the anxiety, enduring AN.Theremaystillbeprospectsforcannabinol should thusbedone,especiallyinpatientswithsevereand a beneficial effecteither. Further explorative research cannabinol inAN.However, theyhavenotruledout so farhavenotconfirmedatherapeuticpotentialfor physically active( dronabinol (daily15 and arecentclinicalcasestudyusinghigherdoseof This contrastswithanimalexperimentalstudies( physical activitymonitoredbyaccelerometer( treatment, dronabinol was associated with increased Review , ); although the syndromeofinappropriate antidiuretic In additiontotheestablishedendocrineeffectson clinicaltrialsconducted The twosmall,preliminary 180 182 , 181 n ). Thestudypopulationwasheterogenicin

= ). Astudyof12patients(BMI15.2 907) deployedtocombatzones, theplasma 181 174 185 ). mg), whichalleviatedtheurgetobe ). 175 ). However, inaprospectivestudy ) andmayleadtocomplications 182 183 ). Partialdiabetesinsipidus ). Animalexperimental R KStøving 184 ). In humans, ± 186 172 173 178 176 0.6) ). ). ) , ,

meta-analysis ( disease; however, thiscouldnotbeconfirmedinarecent section below)levelscouldbebiomarkersforpsychiatric a frequentadverseeffect. lacking ( are oftenprescribedinANalthoughtheevidenceis will haveseriousconsequences( dehydration sincefluidrestrictioninthissituation It isparticularlyimportanttorecognizehypotonic carefully resolved,ascorrectionaltherapywilldiffer. caseofhyponatremiamustbeThe causeofevery Clinical consequences had littleattentioninANresearch. and depressioninANremainstobeexaminedhas The potentialpathogenic role ofvasopressininanxiety significant reduction inbingeeating orbodyweight ( combined with anenergy-restricted diet showedno ( measurements ofoxytocinreflectcentralrelease( ( publication bias andquestionable provoking trialswererecentlycriticallyreviewedfor affect eatingbehavioraswell( possess anxiolyticandantidepressanteffects( and empathy ( psychological effects such as attachment ( application of oxytocin has been claimed to exert In numeroushumanexperimentalstudies,intranasal centrally projectingneuronsdirectlytobrainareas. is welldocumentedthatoxytocinalsoreleasedfrom gland,it oxytocin secretedfromtheposteriorpituitary Besides theestablishedperipheralendocrineactionsof Adaptation Oxytocin study reportedhighermethylation ofthereceptorgene receptor genehavebeeninvestigated inafewstudies.One the anxietyinducedbymeals ( 17.7 postprandial serum level of oxytocin in 13patients (BMI that returntonormalduringrefeeding( levels ( Studies onoxytocininANhavereportedlowercirculating endocrinology Anorexia nervosaand n 194

= 7), an8-weekRCTwithnasaloxytocinapplication It hasbeensuggestedthatADHandoxytocin(see In patients with binge eating disorder and obesity ). Itwasalsoquestionedwhetherperipheral ±

0.3) has beensuggested to be adaptive to decrease 196 188 , 197 ), andSIADHresultinginhyponatremiais 189 191 , 198 ). , ) and lower concentrations in CSF 192 Downloaded fromBioscientifica.com at01/03/201910:18:29AM ). Furthermore, oxytocin may 200 193 post hoc ). SNPsoftheoxytocin 187 180 ). Severalthought- ). Antidepressants :1 190 interpretations 199 ), generosity ). Increased 192 194 ) and R16 195 via MULTI-PFIZER ). ). European Journal of Endocrinology considered inanyoftheabove-mentioned studies.Besides in the short-term nutritive status, which is in fact not resultscouldbeduetovariations many contradictory adaptive rather than pathogenic roles ( dissolved after restorationofbody weight, indicating circulatingconcluded thatmostoftheobserved alterations AN havebeencomprehensivelyreviewed,anditwas was notincludedinthatstudy( measured inonestudyofAN,althoughacontrolgroup GLP-1 receptor. To myknowledge, ithassofaronlybeen product oftheglucagonprecursorthatco-activates level ofGLP-1inAN( satiety. LikePYY, reportsofthe therearecontradictory mediating processes related to glucose metabolism and gut peptide that acts as ahormone and neurotransmitter, other studies( be increasedinsomestudies( Plasma levelsofPYYinANareparadoxicallyreportedto partly byreducingappetitestimulationghrelin( believed toplayaroleinmealterminationandsatiety, concentrations of CCK ( reportsaboutbasal and postprandial serum contradictory the CSFremainsunchanged( ghrelin, seethesectionabove.InAN,CCKlevelin act toincreasesatietyanddecreasefoodintake.For grows. Exceptforghrelin,allthementionedhormones longandstill the listofidentifiedguthormonesisvery peptide-1 (GLP-1), oxyntomodulin and ghrelin; however, cholecystokinin (CCK),peptideYY(PYY),glucagon-like long-term energybalance.Themostwell-studiedare appetite controlandinfluencebothshort-term neurons inhypothalamic and brainstem centersof motility andsecretion,gutpeptidesactdirectlyon Besides theirmanylocaleffectsongastrointestinal Adaptation Gut peptides human studies. experimental datahavenotyetbeentranslatedtoclinical oxytocin pathwaysinANremainsunknown.Animal The clinicalconsequenceoftheabovefindingson Clinical consequences disorder symptoms( in AN( Review The potentialpathogenicrolesofguthormonesin 201 ) andassociationswiththeseverityofeating 211 , 212 202 ). GLP-1issupposedtobeabrain- 57 ). 204 , 58 , , 205 144 213 214 203 R KStøving , , ). Oxyntomodulinisa 206 210 ). ) whereasthereare , ), butdecreasedin 207 215 , 208 , 216 ). PYY is ). The 209 ).

several smallstudieshavebeenpublished( the gut-brainaxisisgutmicrobiota.Inrecentyears, the humeralpathways,apotentiallyimportantplayerin yet clarified.Speculatively, theymightcontributetothe andrefeeding,buttheirexactrolesarenot to starvation The gutpeptidesprobablyplayacriticalpartinadaptation Clinical consequences AN ( of ClpBhasbeenfoundtobeincreasedinpatientswith and anxietysignaling( neuropeptide which are supposed to be involved in satiety as amimeticof produced inthegutbacteria,andClpBhasbeenidentified Caseinolytic proteaseb(ClpB)isanexampleofapeptide The exploration of this essential area is still in its infancy. specifically relatedtoAN( 220 of 61hospitalizedpatients with AN(BMI14.8 fat percentage ( non-addictive exercisers, evenwhenadjustedforbody were lowerinmenwithexercise addictioncompared to food. Thisissupportedbythefindingthatleptinlevels physical activityseemsappropriatetofacilitatefinding perspective,anincreased drivefor an evolutionary data mustbetranslatedtohumanswithcaution,from hyperactivity ( as leptinadministrationpreventsstarvation-induced that leptindeficitisimplicatedinthisphenomenon motoric hyperactivity ( in animals hasconsistently been reported to induce toburncalories( just compensatory compulsive exercise iscommon inAN( (both freeandboundleptin)( stimulus thatincreaseswithrefeedingandrecovery an appropriateadaptationtoreduceanorexigenic in AN( most extensivelystudied.Reducedserumlevelsofleptin homeostasis, andappetiteregulation.Leptinisbyfarthe tissue andmodulateenergyexpenditure,glucose Adipokines arecytokinesthatsecretedbyadipose Adaptation Adipokines influence theoutcome. maintenance of disordered eating behavior and may also endocrinology Anorexia nervosaand ) aswell13reviewsfocusingonthemicrobiota 228 229 ). ) reflectdecreasedfatmassandappeartobe 236 238 α , -melanocyte-stimulating hormone,a ). However, anaccelerometricstudy 237 227 ). Although animalexperimental Downloaded fromBioscientifica.com at01/03/201910:18:29AM 235 ). Remarkably, theplasmalevel 221 ), and there is evidence , https://eje.bioscientifica.com 230 222 , , 233 180 231 223 , :1 ). Extensiveand , 234 232 224 217 ). Starvation ). Starvation ) andisnot , , 225 ± 218 .) did 2.0) , R17 , 226 via MULTI-PFIZER 219 ). , European Journal of Endocrinology https://eje.bioscientifica.com of whiteadiposetissue,making itmetabolicallyactive containing protein5,isamyokine involvedinbrowning anxiolytic effects( persons indicated that exercise exertsantidepressant and effects ofexercise. Forinstance,ameta-analysisof42,264 a linkbetweenthemyocyteandbeneficialmental effects ( adipokines, theyhaveautocrine,paracrineandendocrine in responsetomuscularcontractionsand,likethe Myokines areproducedandreleasedbymusclecells Adaptation Myokines sensitizing adiponectin may aggravate this problem ( metabolism) clinical challenge, as mentioned above (section axis the sectionabove(section The therapeuticpotentialofleptinisbrieflydiscussedin Clinical consequences results ( studies onvisfatininANhavesofarproducedconflicting to thecircular levelsofadiponectin andleptininAN,the networks. In contrast energy and body-weight regulatory adipocyte differentiationandismetabolicallyactivein tissue. Liketheotheradipokines,itisimplicatedin the pathogenesisofAN( suggested thathyperadiponectinemiacouldcontributeto food intake( expenditure andfattyacidoxidationbyreducing of adiponectinreducesbodyweightbyenhancingenergy body weight. In humanstudies,peripheral administration administration ofadiponectinhasbeenshowntodecrease ( adiponectin in AN, which decrease during refeeding this, most studies found increased circulating levels of correlated to BMI and body fat mass ( sensitizing properties.Serumlevelsarenegatively isoforms with specific receptors ( thoroughly reviewed ( physical activity( not revealaclearassociationbetweenleptinlevelsand 52 Review , ). Inaddition,severehypoglycemiacanbeaserious Irisin, previouslynamedfibronectin typeIIIdomain- Visfatin ismainlysynthesizedinabdominaladipose The adaptiverolesofadiponectininANhavebeen 243 251 247 , 244 , , . Hypothetically, theincreasedlevelofinsulin- 245 252 248 ). Inanimalstudies,intracerebroventricular ). Based on these observations, ithasbeen ). Basedontheseobservations, ). Themyokinesarebelievedtorepresent , 249 239 252 ). ). ). 240 240 ). Adiponectin exists in several Hypothalamic–pituitary–gonadal Hypothalamic–pituitary–gonadal , 246 R KStøving ). 241 ) and has insulin- 242 ). In linewith Glucose 250 ). Clinical consequences anxiety. by multiplefactorssuchasnutritivestatus,exercise, and 257 levels ofBDFNinANhaveshownconflictingresults( modulated thermogenesis( of BDNFinanimalsenhancedphysicalactivityand belongs tothefamilyofmyokines.Intracerebralinfusion neurotrophic growth factors found in the brain, but it also catabolism inthesepatients. to healthycontrols( to beaffectedbyexercise inpatientswithANcontrast energy throughlessbrowningofwhitefat.Itisfoundnot represents anotheradaptivemechanismtoconserve reported tobedecreasedinAN( and capableofincreasingthermogenesis.Irisinhasbeen firstly toexploremetabolism inANtoopennewavenues to be translated to human studies. We need biomarkers important animalexperimental dataonoxytocinremains related peptide-3, myostain, follistatin and PAPP-A. The peptide,andamide- kisspeptin, gonadatropin-inhibitory Several ‘new’peptidesremaintobestudiedinAN,e.g. classical metabolicparameterssuchasT3andinsulin. should alsoberelatedtotheplasmaconcentration of of exercise needstobeconsidered.Potentialbiomarkers andlevels relative weightchangeoverthepast1–4 weeks the currentnutritionalstatus,e.g.expressedasshortterm not enoughtoincludeBMIintheinterpretationbutalso research. endocrinologicallystudyofAN,itis Inevery and tothestageofdiseaseshouldbekeptinthis perspectives needed. Strongattentiontotheevolutionary useful clinicalbiomarkers,howevermuchresearch isstill as hormones mentionedabovehavethepotentialtoserve assess theirpsychometricproperties.Severalofthemany stages ofbothweightlossandrefeeding,thento should betoidentifybiomarkersassociatedwithdifferent severe AN.Animportantfocusofclinicalresearch inAN Nearly alltheendocrinesystemsareprofoundlyalteredin Clinical Conclusions excessive exercise andanxiety inAN. important inourunderstandingofstarvation-induced e.g. myostainandfollistatin,theycouldprovetobe in AN.Severalmyokinesremain to bestudied in AN, At thispoint,myokineshavenoclinicalconsequences endocrinology Anorexia nervosaand , Brain-derived neurotrophicfactor(BDNF)isoneofthe 258 ), indicatingthattheserumlevelsareinfluenced 254 Downloaded fromBioscientifica.com at01/03/201910:18:29AM ), possiblyduetothemuscle 255 ). Studiesoncirculating 253 180 ) andthusprobably :1 R18 via MULTI-PFIZER 256 , European Journal of Endocrinology References the references. Claire Margaret Gudex is thanked for skilled proofreading and review of Acknowledgements the public,commercialornot-for-profitsector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict no perceived asprejudicingtheimpartialityofthisreview. is there that declare author The Declaration ofinterest be takenintoconsideration. systematic reviews.Thisweakenstheevidenceandshould work withAN,andarenotgeneratedbymeta-analysesof years of clinical own experiences from more than 25 excluded. Theconclusionsareinfluencedbytheauthors but commonlyreferencedolderpublicationswerenot weremainlyselected, and reviewsfromthepast15 years language articlesindexedinMedLine.Originalstudies This isanarrativereviewbasedexclusivelyonEnglish Limitations disease isstillawaited. in ourunderstandingandtreatmentofthiswhimsical outcome andtoensuresaferefeeding.Abreakthrough of therapeutictargets,andsecondlyforpredicting 3 6 5 4 2 1 Review Mancuso SG, Newton JR,Bosanac P, Rossell SL,Nesci JB& Steinhausen H-C. The outcome of anorexia nervosa inthe20th Steinhausen H-C. 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