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European Journal of Endocrinology 10.1530/EJE-18-0007 (AVP) hasanimportantroleintheregulationofACTH the neurohypophysealnonapeptideargininevasopressin Besides itswell-knownantidiureticandpressoractions, Introduction patients withCDandshouldbemorewidelyappliedintheworkupofthesepatients. indicator forrecurrence.Inconclusion,thedesmopressintestisavalidtoolinbothdiagnosisandfollow-up of long-term outcome.Moreover, duringfollow-up,reappearanceofdesmopressinparadoxicalresponsewasanearly of thedesmopressinresponse,performedinearlypostoperativeperiod,wasagoodpredictorforfavorable of neoplasticACTH-secretingcellswasalsoexploitedinthefollow-uppatientswithCDundergoingsurgery. Loss failed toconfirmthisobservation.Theabilityoftheparadoxicalresponsedesmopressindepictpresence may alsohavearoleindistinguishingbetweenCushing’s disease(CD) andectopicACTHsecretion,subsequentstudies adjunctive roleofdesmopressinintheinitialdiagnosticworkupCS.Despitesomeearlydataindicatingthat this test termed ‘pseudo-Cushingsyndrome’)ACTH-dependentcortisolexcess.Severalstudieshavenowestablishedan desmopressin administrationasuitabletestenablingthedistinctionbetweenneoplasticfromfunctional(formerly vasopressin type3and/ortheaberrantexpressionof2receptorsbyneoplasticACTH-producingcells.This makes responses obtainedinhealthysubjects.Themechanismunderlyingthisparadoxicalresponseinvolvesupregulation of Cushing’s syndrome(CS),desmopressinelicitsanACTHandcortisolresponse, whichcontrastswiththeminimal minimal ornoactivityonACTHexcretion.However, inasubstantialproportionofpatientswithACTH-dependent In contrasttothenativehormoneargininevasopressin,awell-knownACTHsecretagogue,desmopressin,exerts Desmopressin isavasopressinanalogueselectivefortype2receptorsthatmediaterenalwaterretention. Abstract Department ofEndocrinology, DiabetesandMetabolism,EvangelismosHospital,Athens,Greece Dimitra Argyro Vassiliadi syndrome diagnosis andfollow-upofCushing’s The role ofthedesmopressin testinthe DIAGNOSIS OFENDOCRINEDISEASE https://doi.org/10.1530/EJE-18-0007 www.ej Review special interestonallforms of Cushing’s syndrome main fieldsofinterestinclude neuroendocrinology, adrenaldisordersandendocrine tumors,with and ChairoftheInstitutional Research BoardofEvangelismos HospitalinAthens,Greece.His Stylianos Tsagarakis Invited Author’s profile e-online.org

is theHeadofDepartment ofEndocrinology, DiabetesandMetabolism 5 and © 2018EuropeanSociety ofEndocrinology Stylianos Tsagarakis S Tsagarakis D AVassiliadi and Printed inGreatBritain . of corticotropin-releasinghormone(CRH)( ACTH and a potentiator of the ACTH-releasing activity secretion; itisbothamajordirectsecretagogue of Cushing’s syndrome The desmopressintestin Published byBioscientifica Ltd. Downloaded fromBioscientifica.com at10/01/202104:42:38PM (2018) Endocrinology European Journal of [email protected] Email to STsagarakis should beaddressed Correspondence 178 178 :5 , R201–R214

1 R201 , 2 , –R214 3 , 4 via freeaccess ). European Journal of Endocrinology www.eje-online.org plasminogen activator( levels of plasma von Willebrand factor, FVIII:C and tissue von Willebrand diseaseduetoitsabilityincreasethe option forpatientswithmild hemophiliaAandtype1 pressor andoxytocineffects ( its effectiveness, long duration of action and lack of choice forcentraldiabetesinsipidus( to-pressor ratio of 4000). It became the treatment of antidiuretic butnegligiblepressoreffect(antidiuretic- for the renal V2 receptor ( DDAVP) isasyntheticanalogueofAVP thatisselective those ofLVP (nausea,abdominalpain,flushing). syndrome (EAS)( accuracybetweenCDandectopic ACTH discriminatory workup ofACTH-dependentCS( however, displacedtheuseofLVP fromthediagnostic a synergisticeffectwithCRH( cortisol inpatientswithCD( LVP andAVP stimulatedthesecretionofACTHand workup ofCushing’s syndrome(CS)wasofspecialinterest; of vasopressin analogue administration in the diagnostic pituitary disorders( pituitary evaluated inhealthysubjectsaswellpatientswith vasopressin, the porcine antidiuretic hormone), were the administrationofAVP, ormoreoftenLVP (lysine antidiuretic effects. ACTH-releasing activity( 3-(3 antagonists ( other tworeceptors( V3 (orV1b)receptor, anditisclearlydistinctfromthe vasopressinreceptorhasbeendesignatedas The pituitary same receptor, AVP alsomediatesitshemostaticeffects. kidney throughcAMP-mediatedsignaling( antidiuretic actionoccursthroughtheV2receptorsin (glycogenolysis andneoglycogenesis)effects( cascade andmediatesAVP’s pressorandhepatic The V1(orV1a)receptorstimulatesthephosphoinositol patients withCS( axis andofitssynthetic analogues intheevaluationof (HPA)physiology ofthehypothalamo–pituitary–adrenal now establishedanimportantroleofthispeptideinthe of AVP asanACTHsecretagogue,numerousstudieshave ofCRHovershadowedinitiallythesignificance discovery long beforethecharacterizationofCRH( recognized to possessACTH-releasing properties ( In fact,itwasthefirsthypothalamicfactorthat Review ′ Desmopressin (1-deamino-S- In earlystudies,ACTHandcortisolresponsesto AVP actsthoughthreedistincttypesofreceptors. -pyridyl)-Ala2, Arg8]vasopressin,possessesspecific 13 ), andavasopressinanalogue,deamino[ 8 22 ). 6 ) andlesssideeffectscomparedto 12 , 15 ); itisnotblockedbyanti-pressor 29 , 14 ), and also exerts a vasodilatory ), andalsoexertsavasodilatory 16 ) withnegligiblepressorand 26 , 17 24 17 28 ) resulting in prominent , ). The discovery ofCRH, ). Thediscovery , S Tsagarakis D AVassiliadi and ). Itisalsoatreatment 25 d 21 18 -arginine vasopressin, ) becauseofitsbetter , , 22 19 , , 7 23 27 20 ). Although the , ) becauseof ). Evaluation 11 24 9 ). Via the ) andhad , 10 5 ). Its , 6 d ), - of CRHandmuchlessthanthoseLVP ( of adverse reactions is considered low, comparable to that restrict fluidsonthedayoftest.Overall,incidence fluid intakeandcaremustbetakentoadvisepatients and inpatientswithcongestiveheartfailureonahigh Water intoxication may be a risk, particularly in children head heaviness,nausea,flushingandcoldsensation( small increasesinbloodpressureandheartrate,slight with onlyminimalandtransientsideeffects,suchas general, administrationofdesmopressiniswelltolerated demonstrating its clinical utility in patients with this of CSand,herein,wewillreviewthepublisheddata have anadjunctiveroleinthediagnosisandfollow-up workup ofCS.Itwassuggestedthatdesmopressinmay investigation of the HPA axis and more specifically for the last few decades, several groupsuseddesmopressin for the and activationoftheendothelialNOsynthase( via activationoftheendothelialvasopressinV2receptor effect, as a result of its direct effect on the endothelium, infusion (1 significant riseinACTHlevelsduringa2-hdesmopressin cortisol levels.Gaillard volunteers, andtherewerenosignificantincreasesin (4 ( various dosesinhealthyhumansubjects.Andersson In earlyclinicalstudies,desmopressinwasadministeredat ACTH-releasing activityandasynergisticeffectwithCRH. V3 receptor,pituitary despite 34 At variancewithanACTH-releasingeffectseeninrats( healthy subjects Desmopressin effect onACTHsecretion in intriguing disorder. desmopressin wasreportedin 12ofthe20studiedsubjects. plasma cortisolafterthei.v. administrationof4 and Juhos( evidence ofadisturbedHPA axis.Inthestudy ofRado not exhibitsignificantresponses todesmopressin,despite with depressionwasincluded;interestingly, they alsodid 68% respectively. Inthesamestudy, agroupofpatients cortisol levelsinonly2ofthe15subjectsby58%and ( to thetwoagentsseparately. InthestudybyMalerbi but toamuchlesserextentthanthesumofresponses ACTH comparedtotheresponseseenwithoCRHalone, CRH (oCRH), desmopressin increased the response of Cushing’s syndrome The desmopressintestin 16 35 μ ), desmopressinhasnosignificantaffinityforthehuman ) investigated the effect of two desmopressin doses ), administration of 10 g and16 ng/kg/min). Whenco-administeredwith 36 μ g) givenintravenouslyin17youngmale ) anaverageincreaseof6.9 et al Downloaded fromBioscientifica.com at10/01/202104:42:38PM . ( μ g ofdesmopressin increased 2 ) observed aslightalbeitnot ) observed in vitro evidence for a weak 178 :5 ± 32 1.7 ). Overthe μ g/dL in 30 R202 μ ο et al ). In g of vine et al 31 33 via freeaccess ). . ,

European Journal of Endocrinology 42% thatwasdeemedborderline). Similarresultsshowing patients withadrenalCS(albeit onehadaresponseof also patients with long-standing CD), but not in the 8 dependent adrenalhyperplasia (presumablyrepresenting patients withCDandinthe twopatientswithACTH- a 40–45%increase)wasseeninall but oneofthe16 variation atbaselineconcentration(corresponding to of morethanfourtimestheintra-assaycoefficient of independent hypercortisolism. Acortisolincrement CS of various etiologies, including patients with ACTH- responses todesmopressin(5or10 Malerbi Cushing’s syndrome Desmopressin effect inpatientswith of healthyhumansubjects. a negligibleornoACTH-releasingactivityinthemajority response, it seems that desmopressin administration has investigation andalsothecriteriatodefineapositive (continuous infusionvsbolusinjection),thetimeof studies thatrelatestothedose,modeofadministration ( appreciable responsestodesmopressininhealthysubjects 40 exogenously administeredCRHinhealthysubjects( reporting a potentiating effect of desmopressin on activation, given a few studies CRH-mediated pituitary desmopressin administeredintheafternoonreflectsa effectof levels. Itisthereforepossiblethattheobserved higher endogenousCRHlevelscomparedtothemorning early afternoonisaperiodofHPA axisquiescencewith on thebasisofbothACTHandcortisoloutput.The subjects weredeemed‘responders’to10 response to 10 and 15 producing maximal responses,and a significantcortisol significant ACTHresponsetoallthreedoses,with10 were administeredintheearlyafternoon;theyreporta three differentdosesofdesmopressin(5,10and15 ACTH-releasing potential.InthestudyofScott of desmopressinadministrationmightinfluenceits (0.4 much largerdosesofdesmopressinwereadministered a moderateeffectofdesmopressinoncortisollevels,but desmopressin hadnoeffect.Williams subjects. In the same study, intranasal administration of after administration of LVPthan that observed to the same increase,however,The observed wasconsiderablylower 2 Review , ). Mostofthesubsequentreportsfailedtodemonstrate 31 To summarize,despitesomevariabilitybetween μ g/kg). Itshouldbenotedthatthetimeofday , 39 t al et , 40 . ( , 41 31 , ) werethefirsttoevaluatecortisol 42 , 43 , μ 44 g doses. Overall, 11 of the 18 ). S Tsagarakis D AVassiliadi and μ g) inpatientswith et al μ g desmopressin . ( 37 ) reported et al . ( 38 39 μ μ g) ), g , adenomas orothertypesofACTH-producingtumors( because ofaconstitutional overexpression in corticotroph due toahypercortisolism-induced upregulation( the V3receptorispresentinhighconcentrations,either (V1b) receptormaydemonstratesomeactivitywhen desmopressin, despiteitslowcross-affinitywiththeV3 have tobeconsidered.Oneproposedmechanismisthat activity ontheV3receptor. Therefore,othermechanisms of CRH,desmopressindoesnotseemtohaveconsiderable V3receptorandbypotentiatingtheaction the pituitary vasopressin inducesACTHsecretionbyactingdirectlyon ACTH-dependent CSisnotfullyelucidated.Although paradoxical response to desmopressin in patients with 55 studies. dose of10 ACTH-dependent CS were conducted. To this end, a fixed test’ (DT) in the diagnosis and differential diagnosis of a seriesofstudiesexploring thevalueofa‘desmopressin and cortisol response to desmopressin and, consequently, ACTH-dependent CSdemonstrateaparadoxicalACTH mechanism, asubstantialproportionofpatientswith number ofreportedcasesissmall. compared toothers,alsoremainselusivebecausethe tumor typesaremorelikelytoresponddesmopressin expression oftheV2Rremainsunclear. Whether some in vivo patients withEAS,however, thefrequencyofpositive of thefourcases.Duetolimitednumberstudied examined, whereas the V3R mRNA was expressed in three presence oftheV2RmRNAinallfourtumorsthatwe been documented ( in EAStumorsthatareresponsivetodesmopressinhasalso patients withEAS.EctopicexpressionoftheV2receptors results inpositivecortisolandACTHresponsesmost of nonspecificvasopressinanalogs,suchas LVP or AVP tumors ( commonly expressedinectopicACTH-secreting(EAS) corticotrophin tumors( the expressionorV2receptorinmostofstudied ACTH-secreting cells( the V2receptorisexpressedaberrantlybyabnormal 58 ( dependent CSwerereportedinmanysubsequentstudies administration ofdesmopressininpatientswithACTH- enhanced ACTHandcortisolresponsesfollowingthe Cushing’s syndrome The desmopressintestin 31 ) ( , , 59 Despite thelackofconcreteknowledgeabout The mechanismofsuchanexaggeratedandthus The V3receptorhasbeenreportedtoalsobe 35 Tables 1 ). Another, probablyadditional,mechanismisthat responsestodesmopressinaswelltheectopic , 41 57 µg ofdesmopressingiveni.v. wasusedinmost , ) and explains the fact that administration 43 and , 44 2 , ). 55 45 , , 59 58 58 46 Downloaded fromBioscientifica.com at10/01/202104:42:38PM ); infact,Dahia , ). , 60 47 ). We demonstrated ( , 48 , 49 178 , 50 www.eje-online.org :5 , 51 t al et , 52 . reported , 55 53 R203 56 ) the , ) or 57 54 via freeaccess , , European Journal of Endocrinology www.eje-online.org Review

Table 1 The desmopressin stimulation in patients with Cushing’s disease (CD), suspected Cushing’s syndrome (CS) or pseudo-Cushing’s syndrome (PCS) and healthy subjects.

Suspected CS/PCS Performance Study Patients with CD, R/TN (%) R/TN (%) Conditions Healthy subjects, R/TN (%) Criteria Sensitivity (%) Specificity (%) S Tsagarakis D AVassiliadi and (31) 15/16 (94%) 2/15 (13%) %ΔCort >40–45% 94 87 (35) 14/14 (100%) 4/11 (36%) Depression 2/20 (10%) %ΔCort >36% 100 90 vs controls 64 vs depressed (41) 13/16 (81%) 0/4 (0%) %ΔCort >20% and %ΔACTH >50% 81 100 (43) 10/10 (100%) 0/11 (0%) %ΔACTH >150% 100 100 (44) 21/25 (84%) 3/20 obese (15%) %ΔCort >20% 84 85 23/25 (92%) %ΔACTH >50% 92 85 (47) 66/76 (87%) 1/30 (3%) Alcohol 5/31 normal (16%) ΔACTH >27 pg/mL 87 91 dependence, 3/36 obese (8%) depression, PCOS (52) 17/19 (90%) 2/15 (13%) %ΔACTH >35% and ΔACTH 90 87 >20 pg/mL Cushing’s syndrome The desmopressintestin (49) 22/27 (82%) 2/23 (7%) Central obesity, – ΔACTH >27 pg/mL 82 90 PCOS, depression, alcohol dependence (46) 13/15 (87%) 0/15 (0%) %ΔACTH >50% and/or 87 100 %ΔCort >20% (53) NR/52 NR/28 NR/31 ΔACTH >27 pg/mL 75 90 cortisol >12 μg/dL and ΔACTH 90 92 >18 pg/mL (54) NR/30 NR/18 NR/12 cortisol >12 μg/dL and ΔACTH 97 100 Downloaded fromBioscientifica.com at10/01/202104:42:38PM >18 pg/mL (50) NR/68 NR/56 – ACTH peak >71.8 pg/mL 91 95 ΔACTH ≥37 pg/mL 88 97

R/TN(%), responders/total number tested (%); CD, Cushing’s disease; CS, Cushing’s syndrome; PCS, pseudo-Cushing syndrome; PCOS, polycystic ovaries syndrome; NR, not reported; %ΔCort, ((peak

cortisol-basal cortisol)/basal cortisol) × 100%; %ΔACTH, ((peak ACTH-basal ACTH)/basal ACTH) × 100%; ΔACTH, peak ACTH-basal ACTH; B cortisol, baseline cortisol. 178 :5 R204 via freeaccess European Journal of Endocrinology subjects, ofspecialinterest istheperformanceofthis or neoplastic,ACTH-dependent hypercortisolism. major challenge is to differentiate these groups from ‘true’ but withhormonaltestingthat isnotclearlydiagnostic.A central obesity, hypertension,hirsutism,irregular menses, patients withseveralclinicalfeaturesresemblingCSlike disease or uncontrolled diabetes mellitus. It also refers to conditions suchasalcoholism,depression,chronickidney to ‘physiologic’HPA axisactivation( because they cause a state of chronic hypercortisolism due that affectthespecificityofclassicdiagnostictests, definition. Ithasbeenusedtocharacterize conditions ‘pseudo-Cushing’ isprobablyamisnomerandhasbroad patients withtheso-called‘pseudo-CS’(PCS).Theterm dependent hypercortisolism isilldefined,suchasin discrimination betweenfunctionalandneoplasticACTH- is particularlyusefulespeciallyinsituationswherethe response, mostlydepictingneoplasticcellsandthusit axis. Thedesmopressin response representsan aberrant tests, whichassessfunctionalalterationsoftheHPA is distinct from that of the commonly used screening pathophysiological basisoftheresponsetodesmopressin it asuitabletestforthediagnosisofCS.Infact, without ACTH-dependenthypercortisolism, makes The lackofresponsetodesmopressininsubjects Cushing’s syndrome The desmopressin testinthediagnosisof ( ( ( ( ( Study diagnosis ofACTH-dependentCushing’s syndrome. Table 2 ((peak ACTH-basalACTH)/basalACTH) %ΔCort, ((peakcortisol-basalcortisol)/basalcortisol) CD, Cushing’s disease;EAS,ectopicACTHsyndrome;NR,notreported; ( ( ( ( 45 51 55 52 44 43 41 42 31

Review ) ) ) ) ) ) ) ) )

Thus, besidestheevaluation oftheDTinhealthy Patients withCD 10/10 (100%) 19/22 (86%) 21/26 (81%) 19/26 (73%) 17/19 (89%) 23/25 (92%) 13/16 (81%) 14/17 (82%) 15/16 (94%) (sensitivity The desmopressinstimulationinthedifferential NR/149 Responders/total number 83%) tested Patients withEAS (%) 4/9 (44%) 3/5 (60%) 2/5 (40%) 3/4 (75%) (specificity NR/21 62%) 0/3 0/3 0/1 0/1 × 100%.

S Tsagarakis D AVassiliadi and 61 %ΔACTH %ΔACTH %ΔCort %ΔCort %ΔCort Criteria %ΔACTH %ΔACTH %ΔACTH %ΔCort %ΔACTH and/or %ΔCort %ΔACTH %ΔACTH ΔACTH ). Thisisthecasein × 0% %ΔACTH, 100%; > > > > > > > > > > > 20% 20% and 20% and 40–45% 20 pg/mL > > 32% 50% 50% 35% and 50% 150% 50% 35%

> 20% considered. OfnoteinthestudybyTirabassi sensitivity oftheDTtothatwhenwholecohortwas abnormal biochemicaltestandshowedasimilar CD, definedashavingatleastonenormalorborderline 53 not usuallyposediagnosticproblems.Two studies( hypercortisolism, whereaspatientswithfull-blownCSdo difficulties in distinguishing them fromnon-neoplastic it isusuallyCD,andespeciallythemildercases,thatbear however, ismorerelevanttotheclinicalchallengessince CD, whereasnopatientswithEASwereincluded.This, ACTH-dependent CSandinparticularpatientswith noted thatallstudieswereconductedinpatientswith proposed cut-offsarepresentedin assessing thediagnosticperformanceofDTand be subjectedtotestingforthepresenceofCS.Studies test particularlyinpopulationswhoaremorelikelyto than didtheovernightdexamethasonesuppressionand the DT distinguished mild CD fromPCS more accurately the thresholdforDexa-CRHtestto110 as havingUFC obtained inasubgroupofpatientswithmildCD,defined were leading toaspecificityof90%.Similarobservations 81.5%, the rate of false positives was substantially lower non-responders totheDT, resultinginasensitivityof On theotherhand,althoughsomeCDpatientswere in afalse-positiverateof21%andspecificity62.5%. exceed thethresholdof38 cortisol increasesthatwereminorbutstillsufficientto suppression ofcortisolafterdexamethasoneordueto subjects hadapositiveDexa-CRHtest,duetoeithernon- benefit. Atthesametime,asubstantialnumberofPCS alone, sothatadministrationofCRHwasnoadditional Dexa-CRH testafterthedexamethasonesuppression with CD already exceeded the diagnostic cut-off of the with CSand23PCS( diagnostic abilityoftheDTwiththistestin32patients and PCS.PecoriGiraldi CRH) testiswidelyusedforthedistinctionbetweenCD midnight serumcortisoltests. high specificitywhilethe latterpaneliscompromised panel combinesatestofhigh sensitivitywithatest inferior. Thisis attributable to thefact that theformer combination ofDSTwithDexa-CRH testswasstatistically suppression test(DST)and theDT, whereasthe outcome was obtained by combining the dexamethasone in thesamestudy( of sensitivity. However, Bayesian analysis, performed dL) improveditsspecificityto82%butattheexpense Cushing’s syndrome The desmopressintestin ) performedaseparateanalysisofpatientswithmild Currently, thedexamethasone-suppressedCRH(Dexa- < ml2- (250 690 nmol/24-h 49 ), showedthatthebestdiagnostic et al Downloaded fromBioscientifica.com at10/01/202104:42:38PM 49 . comparedretrospectivelythe nmol/L (1.4 ). Ofnote,allbut2patients 178 al 1 Table www.eje-online.org μ :5 μ g/24-h). Raising g/dL), resulting nmol/L (4 . Itmustbe et al. R205 ( 53 μ 49 via freeaccess g/ ), , European Journal of Endocrinology www.eje-online.org positive cortisolresponseand 3positiveACTHresponses CD and5patientswithEAS). OnepatientwithEAShada in patientswithACTH-dependent CS(17patientswith CRH testand,also,toacombined testusingbothagents ability ofthedesmopressintothat discriminatory proven EAS( an increasingnumberofpositiveresultsinpatientswith ACTH riseof120%.Subsequentstudies,however, identified applied, however, afairlyhighthresholdforthepercent to desmopressin,whereasall10patientswithCDdid;they reported thatnoneofthe3patientswithEASresponded the singlepatientwithsuspectedEAS.Sakai ACTH responsein14of17patientswithCDbutnot in Colombo in thedifferentialdiagnosisofACTH-dependentCS. to studiesaimingevaluatetheroleofdesmopressin indicate CD, in analogy to the response to CRH, and led suggested thatapositiveresponsetodesmopressinmight initially included wereunresponsive.Thisobservation proven and two patients with suspected EAS that were In thestudy by Malerbi Cushing’s syndrome diagnosis ofACTH-dependent The desmopressin testinthedifferential the Dexa-CRHis‘ suppressed cortisollevelsafterthelow-doseDST, where useful inpatientswithalowclinicalsuspicionbutnon- especially in these situations. The DT can be particularly and thusitmayrepresentagoodsecond-linetest positive (likeinPCS)orfalse-negative(mildCD)results even wherethefirst-linetestshaveahighrateoffalse- for thesepatients. affected, makingthedesmopressintestaplausiblechoice metabolism ( use ofmedicationsthatinterferewiththedexamethasone established thatthespecificityofDSTisaffectedby responders testedpositivetotheDT. Inaddition,itiswell diagnosis ofACTH-dependentCS.Incontrast,nonethe the useofDexa-CRHtestmayleadtoerroneous do nothavefullysuppressedbaselineACTHlevelsand with clinicallyovertadrenalCS,manyofthesepatients patients respond to this test ( we recentlyreportedthatasignificantnumberofsuch with incidentallydiscoveredbilateraladrenalnodules; specificity oftheDexa-CRHisalsohamperedinpatients by thelowspecificityofDexa-CRHtest.Infact, Review Overall, theDThasagooddiagnosticperformance, et al Table 2 63 . ( ), whereastheresponsetoDTisnot 41 a priori ) demonstratedapositivecortisoland ). NewellPrice ’ positive. et al 62 . ( ). In contrast with patients 31 S Tsagarakis D AVassiliadi and ) theonlypatient with et al . ( 48 ) comparedthe et al . ( 43 ) also CRH andV3(V1b)orV2receptorsinmanycorticotroph Based onthehypothesisthatco-overexpressionof in healthysubjects( dependent CS, as opposed to what was previously reported desmopressin onACTHreleaseinpatientswithACTH- evidence foraconsiderableCRH-potentiatingactionof ACTH, comparedtoeachcompoundalone,providing greaterpercentageThey observed increasesofcortisoland Newell Price adenomas butnotintumorssecretingACTHectopically, adenomas commonly express the CRH receptor ( ability ofbothtests.IncontrasttoEAStumors,corticotroph desmopressin withCRHmayimprovethediscriminatory the twogroupsofCDandEASpatients. there wasnogoodcriterionthatcandistinguishbetween analysisshowedthat with CDandEAS.Infact,ROCcurve ACTH responsestothedesmopressintestbetweenpatients and foundasignificantoverlapofthepercent cortisoland in 3ofthe5patientswithhistologicallyconfirmedEAS EAS respondtotheDT; positiveresponses weobserved EAS ( results inacohortof29patientswithCDandfive 2 outof5patientswithEASandincasereports( desmopressin werealsoreportedbyTerzolo the DTcomparedtoCRHtest.Positiveresponses to theDTresultinginlowerdiscriminatingaccuracyof during anACTHnadirmay result inafalse-negative ratio the neoplasticcorticotrophs andthereforesampling diagnostic becauseofintermittent ACTHsecretionfrom between thecentralandperipheral samplesisnotalways hypersecretion ( and ectopic ACTH diagnosis between pituitary-derived accurate diagnosticprocedureforthedifferential It iswellestablishedthatBIPSSrepresentsthemost Bilateral InferiorPetrosal SinusSampling(BIPSS) negative CRHtest,islimited. adjunctive test totheCRHtest,especiallyinpatients with The utilityofthecombineddesmopressin-CRHtestasan DT in the differential diagnosis of ACTH-dependent CS. regarding thedifferentialdiagnosisbetweenCDandEAS. is considered,butstillwithonlyamoderateperformance, when theACTH(butnotcortisol)percentage increment desmopressin-CRH test performed better thanDT alone, either peptidealone.Inourcohort( for thedifferentialdiagnosisofCDfromEAS,than desmopressin andCRHappearedtoyieldbetterresults Cushing’s syndrome The desmopressintestin Overall, theavailabledatadonotsupportaroleof Another intriguinghypothesiswasthatcombining 55 ), alsoindicatedthataproportionofpatientswith et al 64 . ( 42 ). However, thebasal ACTH gradient ) combineddesmopressinwithCRH. 2 ). Moreover, thecombinationof Downloaded fromBioscientifica.com at10/01/202104:42:38PM 178 55 :5 ), thecombined et al 60 . ( 57 R206 52 ). Our , 59 ) in via freeaccess ). European Journal of Endocrinology differential diagnostic tests and in particular to CRH patients withnegativeresults totheroutinenon-invasive improve thediagnosticsensitivity ofBIPSS,especiallyin combined administrationof desmopressinwithCRHmay especially whenCRHisunavailable ( expensive alternativeACTHstimulantduringBIPSS, desmopressin maybeanequallyeffectiveandless BIPSS were100%. analyzed, thesensitivity, specificityand accuracyof to testswithCRHand/orhigh-doseDSTwereseparately results (16 withCDand2EAS)contradictory and, importantly, whenonlythesubgroup of18patients had diagnosticcentral-to-peripheralACTHgradients All 8patientswithCDwhowereunresponsivetoCRH without compromisingitsspecificity, whichwas100%. 62% forthebasalcentral-to-peripheralACTHgradients) the sensitivityofprocedureto98%(compared proven EAS,thatthisamplifiedstimulationimproved patients ( alone. We subsequentlydemonstrated,inastudyof54 BIPSSwithCRHstimulation patients whounderwent in central ACTHlevels compared tothelevelsobserved combined desmopressin/CRHstimulusresultsinhigher larger numberofpatients( and CRHduringBIPSSin6patientswithCD.Ina after thecombinedadministrationofdesmopressin corticotroph adenomas ACTH output from pituitary In this context,Kaltsas these agentsduringBIPSSmayimproveitssensitivity. ( and CRHonthereleaseofACTHinpatientswithCD 75 which involvesaround10–20%ofpatientswithCD( responsiveness ofsomecorticotrophadenomastoCRH, 72 low butstillconsiderable rate offalse-negativeresults( in thevariousstudiesrangesfrom88to100%,owinga the useofCRHstimulation. when comparedtothenumberofsubjectsstudiedwith number, however, ofstudiedsubjectsissmall,especially for CRH(92.1–97%),withanexcellentspecificity. The and reported a sensitivity comparable to that reported desmopressin instead of CRH during BIPSS ( ACTH stimulantduringBIPSS.Afewstudiesused standard BIPSSprocedure( the diagnostic sensitivity of this test and is part of the ( 65 42 Review ). Onthebasisofsynergisticeffectdesmopressin , ). StimulationofACTHsecretionwithCRHimproves ), itwashypothesizedthattheadministrationofboth 73 Altogether, the available data support that Although BIPSSisahighlyaccuratetest,itssensitivity Desmopressin hasalsobeenusedasanalternative ). One reason for a false-negative gradient is poor 78 ), including 7 patients with histologically t al et 65 77 , 66 . ( ), weconfirmedthatthe S Tsagarakis D AVassiliadi and , 76 67 ) reported a higher ). 79 ). Moreover, the 68 , 69 , 70 74 71 ) , , remission ( with higherpostoperative cortisol levelsachievelate ( patients withlowearlypostoperative cortisollevelsrecur postoperative cortisol level,aconsiderable number of Although the most widely applied criterion is a low early and CRH test ( sphenoidal surgery (TSS)isthebesttherapeuticoptionfor sphenoidal surgery suboptimal immediateandlong-termcurerates,trans- postoperative assessmentofpatientswithCD.Despitethe Of particularinterestistheapplicationofDTin Cushing’s disease follow-up ofpatientswith The desmopressin testinthepostoperative stimulation ( heparinize patientsundergoingBIPSSwithdesmopressin risk ofthromboembolism( a procedure associated with a minor but not negligible associated withhypercoagulation ( half thehemostaticdose( administered desmopressindoseduringBIPSSisroughly more dataonpatientswithEASarerequired.Althoughthe stimulus mightresultinthelossofspecificity, butcertainly, testing. Sofar, thereisnoevidencethatamorepotent ( the HPA axis ( of low postoperativecortisollevels,timetorecovery predictors oflong-termoutcome;undetectableorvery Numerous studiesaimedtoidentifypostoperative planning of follow-up of patients with CD in remission. is importantforthepostoperativemanagementand patients according to their long-term risk of recurrence The recognitionofearlyprognosticmarkersthatcanstratify long-term outcome postoperative periodasaprognostic markerofthe The desmopressin testintheimmediate follow-up asanearlymarkerofrecurrence. period asapredictoroflong-termoutcomeandduring evaluated bothduringtheimmediatepostoperative and lifelong follow-up. In this context, the DT has been initially controlledpatients( successful TSS,recurrences may occurinupto66%of for macroadenomas( between 70and90%( patients withCD( Cushing’s syndrome The desmopressintestin 90 87 ) andasmallalbeitsignificant numberofpatients ), normalcortisol suppression by dexamethasone ( 91 83 ). Thus,noneofthecurrently widelyused 85 ). 86 , , 86 64 89 ), normal late-night salivary cortisol ), normal late-night salivary ). Remission rates following TSS vary ). RemissionratesfollowingTSSvary ) have been used in this context. 64 64 Downloaded fromBioscientifica.com at10/01/202104:42:38PM ). However, evenafterinitially , 84 82 80 ) andisconsiderablylower ), itisadvisedtoroutinely 64 ), consideringthatCSis ), necessitatingfrequent 81 178 ), andthatBIPSSis www.eje-online.org :5 R207 88 via freeaccess ) European Journal of Endocrinology www.eje-online.org in these patients if the DT becomes negative, a watchful hypocortisolism butundergo delayedremission.Infact, of thesmallsubsetpatients whodonotdisplayearly early postoperativeperiodled inthecorrectassignment preoperative desmopressin responsivenessduringthe advantage oftheDTwasthatlosspositive of loworundetectablecortisollevel.Anadditional was superiorfromthemorecommonlyusedcriterion Notably, inthisseries,thepredictiveability oftheDT ( 10.6–448.5) at 60 months (95% confidenceinterval, administration, had ahazard ratio for recurrence of 24.7 of and asensitivityof68%topredictlong-termrecurrence. with aspecificityof95%,positivepredictivevalue77% patients, the negative prognostic value of the DT is 92% data reportedinthesestudies,comprisingatotalof116 dL) topredictthelong-termoutcome.Combining increments concludedsimilarcut-offvalues(7–7.4 studies ( robust. Inthisline,itisofnotethatinfourindependent criteria thatrelyonabsolutevaluesorincrementsaremore ‘positive’ results.Thus, instead ofpercentage changes, in significant percentage increases providing erroneously and evensmallvariations, within theassayCV, mayresult are usuallylowinthosewhoweresuccessfullyoperated during the immediate postoperative period, cortisollevels positive desmopressinresponse.Itshouldbenotedthat, also needed on the applied criteria of what constitutes a compromised thepredictingabilityoftest.Cautionis it islikelythatinclusionofdesmopressinnon-responders preoperative responsetodesmopressin( performed. Moreover, afewstudiesdonotreportonthe recurrence and,thepostoperativetimingthatDTwas of response,theappliedcriteriaforremissionand however, amongthestudieswithregardstodefinition 57 to100%,respectively. Thereisconsiderabledisparity, greatlyfrom20to100%and detect recurrencevary of thestudies,whereassensitivityandspecificityto from 76to100%,beingabove90%inthevastmajority the reported negative predictive value of the test ranges Table 3 the usefulnessofDTinthisregardarepresented increased risk for relapse. The existing studies that assessed of residualneoplastic corticotrophs, and hence,an HPA axis,exploitsitsuniqueabilitytodetectthepresence all the other tests that assess thefunctional activity of the remission ( markers isaccurateenoughinthepredictionoflong-term Review ≥ We recentlyreportedthatanincrease in serumcortisol The useoftheDTpostoperatively, atvariancewith 7.4 . Inthesestudies( μ 93 g/dL frombaseline,followingdesmopressin 64 , 97 ). , 98 , 99 ), assessmentofabsolutecortisol 92 , 93 , S Tsagarakis D AVassiliadi and 94 , 95 , 92 96 , , 94 97 , , 97 98 ), and , 99 99 μ g/ ), ).

marker ofrecurrence The desmopressin testduringfollow-upasanearly follow-up periodsareneededtoconcludeonthispoint. surgery. Therefore, larger prospective studies withlonger is small,andtheymayoccurmanyyearsaftersuccessful overall numberofrecurrencesinthepublishedstudies the DT, however, maybehamperedbythefactthat accurate appreciationofthepositivepredictivevalue foratimelydetectionofrecurrence.The surveillance outcome whileitspersistencenecessitatesclose A lossoftheparadoxicalresponseindicatesafavorable postoperative follow-upplanningofpatientswithCD. period, intheassessmentoflong-termoutcomeand role of the DTperformed in the immediate postoperative surgery. repeat waiting approachmaysavethemfromunnecessary or UFCin71%ofthepatients. Recently, Ambrogio increase inmidnightcortisol (eitherserumorsalivary) desmopressin in17patients) andthatthisprecededthe to vasopressinanalogue stimulation(including with recurrentCDultimately hadapositiveresponse Bou Khalil hormonal documentation of recurrence by 4–39 months. follow-up and, importantly, thispreceded clinical and DT becamenegativeafter‘cure’butreappearedduring al et months).Ambrosi however, was rathershort(upto36 throughout, 2ofthemrecurred.Thelengthfollow-up, at thefirstpostoperativemonthandremainedpositive with ‘normalization’ofcortisollevelshadpositiveDT remained negativeandnonerelapsed,whereas5patients considered as‘cured’hadnegativepostoperativeDTthat responsiveness todesmopressinovertime;14patients changes in the during follow-up. They did not observe CD inpost-surgicalremissionwithrepeatedDTs hypercortisolemia. patient exposure to the detrimental effects of severe andprevents biochemical testsallowstimelyintervention manifestations orthedevelopmentofclearlypathological before thereappearanceoffullspectrumclinical test abnormalities.Earlyrecognitionofrecurrence a ratherlowdiseaseactivitywithmarginalbiochemical when relapsingfollowing TSS remainforalongtimein early stageisalsochallenging.SeveralpatientswithCD least insomecases,documentationofrecurrenceatan In additiontothedifficultiesindiagnosingCD,at Cushing’s syndrome The desmopressintestin Altogether, theexistingdatasupportacomplementary Colombo . ( 100 , et al 101 t al et . ( ) describedthreepatientsinwhomthe 102 . ( ) alsoreportedthat17of20patients 93 Downloaded fromBioscientifica.com at10/01/202104:42:38PM ) evaluated19patientswith 178 :5 R208 et al via freeaccess . European Journal of Endocrinology

Table 3 The postoperative desmopressin test in predicting long-term recurrence of CD. Review

No of patients No of patients with initial with recurrence Positive Timing of Study remission tested tested Time of follow-up preoperative DT postoperative DT Criterion for postoperative DT NPV PPV Sensitivity Specificity

(93) 19 2 1–36 months 19 1, 6, 12, 18, 24 and ΔCort >7.3 μg/dL 100 40 100 82 36 months (96) 64 3 2–54 months 64 5–6 days %ΔACTH >30% 100 17 100 75 (95) 164 18 6–148 months 164 4–6 days %ΔACTH >30% 92 16 56 65 150 17 %ΔCort >20% 90 17 24 85 (98) 17 5 24–141 months NR 3–6 months Peak ACTH ≥22 pg/mL 92 100 80 100 %ΔACTH >35% NA NA 80 75 Peak cortisol >12.7 μg/dL 92 80 80 92 %ΔCort ≥14% NA NA 100 67

ΔCort >7 μg/dL 92 80 80 92 S Tsagarakis D AVassiliadi and (97) 41 11 20–161 months 41 15–30 days ΔCort >7 μg/dL 83 100 46 100 (92) 39 15 24–123 months NR 6 months ΔACTH >9 pg/mL 95 78 93 83 (94) 38 10 18–180 months NR 3 months %ΔACTH >21% and positive cortisol increment 84 37 70 57 (99) 39 7 12–199 months 39 6 months ΔCort >7.4 μg/dL 97 86 86 97 37 7 ΔACTH >52 pg/mL 94 83 71 97 39 7 % ΔCort >63% 96 50 86 81 37 7 %ΔACTH >111% 96 55 86 83 (103) 43 10 2–23 years 39 ΔACTH >27 pg/mL 76 33 20 86

CD, Cushing’s disease; DT, desmopressin test; NA, no available data; NR, not reported; %ΔCort, ((peak cortisol-basal cortisol)/basal cortisol) × 100%; %ΔACTH, ((peak ACTH-basal ACTH)/basal ACTH) × 100%; ΔACTH, peak ACTH-basal ACTH. the collectionofthreeorfoursamplesonsuccessivedays from significantwithin-patientvariabilitynecessitating surgical recurrence of CD, with the caveat that it suffers to beoneoftheearliestabnormalitiesindicatingpost- cortisolhasbeenreported increase inlate-nightsalivary recurrence by21 months. Amongbiochemicalmarkers,an yearsaftersurgery, precedingdocumented positive 3 DT. patient recurreddespiteaclearlynegativepostoperative to frankhypercortisolism. In our study ( who subsequently developed recurrence, even years prior whereas aresponsetodesmopressinreappearedinpatients became positive in 9) ofpatientson long-term remission, DTcontinuedtobenegativeinthemajority(it surgery; ACTH levels.Allbut6patientsdidnotrespondtoDTafter response wasdefinedasanincreasebyatleast27 aftersurgery. Positive subjected toDTforup20 years negative preoperativeDT)inremissionafterTSSthatwere ( may bemorerelevantduring follow-up,whenHPA axis dexamethasone isnotthat crucial. However, theCDDT and thus,theneedforfurther suppressionbyadding postoperative period, the HPA axis is already suppressed, In patients with successfully treated CD in the early due to stress. cells and any response that can be observed ( coupled dexamethasone-desmopressin test –CDDT) administration beforeperformingtheDT(theso-called ( subjects mayrelatetostressinducedbytheprocedure responses innormal test. Infact,someoftheobserved modification that aimsto improve the specificityof the Performing theDTafterdexamethasonesuppressionis a Coupled dexamethasone-desmopressin test(CDDT) of CD. may progressovertimeandleadtoclinicalreappearance indicates persistence of pathological corticotrophs that a truerecurrence,whereasearlypostoperativepositivity postulate thatreappearanceofpositivitytoDTrepresents evaluation ofsuccessfullyoperatedpatientswithCD.We supporting aroleofrepeatedDTaspartthelongitudinal term follow-up,earlierthanothermarkersofrecurrence, that apositiveresponsemightreappearduringlong- interest. comparing thesetwomarkerswouldbeofparticular cortisolarescarcesalivary ( ( Cushing’s syndrome The desmopressintestin 103 105 44 104 ). Basedonthis, it wassuggested that dexamethasone Overall, theexistingdata,althoughlimited,indicate T ) reportedon43patientswithCD(including 4 with ) isexpectedtosuppressthenormalcorticotroph ). Datacomparing postoperative DT andlate-night his patienthadrepeatedDTs andthetestbecame Downloaded fromBioscientifica.com at10/01/202104:42:38PM 102 , 105 178 ) andfuturestudies www.eje-online.org :5 99 ), also one pg/mL in R209 via freeaccess European Journal of Endocrinology www.eje-online.org preoperative andpostoperative investigationofpatients be morewidelyincorporated asanadjunctivetoolinthe these patients. It is therefore suggested that the DT should evidence thatitmayaidthe postoperativeassessmentof are inconclusive.Furthermore, thereisaccumulating insight favoringthediagnosisofCDwhenothertests fact, due to its high specificity the DT provides further and postoperativefollow-upofpatientswithCD.In makes theDTausefuladditionaltoolindiagnosis property, however, todepictcorticotrophneoplasticcells EAS, whereBIPSSremainsthegoldstandard.Itsunique DT isnotusefulforthedifferentiationbetweenCDand undergoing neoplastictransformation.Thatbeingso, receptor expressionthatdevelopinACTH-producingcells they areonlyassociatedwithchangesinvasopressin not relate to a functional activation of the HPA axis, but In contrast,thepositiveresponsestodesmopressindo found incasesoffunctional activation oftheHPA axis. not surprisingtoobtainresultsoverlappingwiththose tests todetectneoplasia-relatedcortisolexcess,itis status oftheHPA axis.Therefore,whenapplyingthese freecortisolexcretionarebasedonthefunctional urinary cortisoland suppression, midnightserumorsalivary largely duetothefactthattestslikedexamethasone due toahighrateofindeterminateresults.Thisis available diagnostictestsiscompromisedbyimprecisions challenge. Thediagnosticperformanceofmostcurrently of therapeuticoutcomeCSrepresentacontinuing There isnodoubtthatthediagnosisandassessment Conclusions markers ofrecurrence. earlierthanother the positivityofCDDTwasobserved aftersurgery. Mostimportantly,first 3 years aswithDT, a worsepositivepredictivevalue,whenperformedinthe predicting thelackofrecurrence(100%NPV),albeitwith follow-up, however, theCDDTwasmoreaccuratein DT andCDDTintheearlypostoperativeperiod;during same group( of CDDTinmostpatients.Asubsequentstudybythe (no cleardefinitionisgiven)followedthepositivity treated byTSS.Inthisstudy, thelossofcircadian rhythm 89% specificitytopredictrecurrencein38CDpatients and ACTHlevelsaftertheCDDThad100%sensitivity reported thatanincreaseofmorethan50%incortisol the conventionalhormonaltests.Castinetti was exploredasatooltodetectrecurrenceearlierthan functionality is gradually restored. In this context, CDDT Review 94 ) reportedsimilarperformanceofthe S Tsagarakis D AVassiliadi and t al et . ( 105 ) References the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagencyin Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest its exactrole. with CS;additionallargeprospectivestudieswillestablish

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