178

European Journal of Endocrinology 10.1530/EJE-18-0062 1 therapeutist. optimistic viewforthefuturewherepituitaryadenomashouldbe‘reasonableobsession’ofasuccessful shed somelightontheinescapabledifficulties ofthecurrenttreatmentsCushing’s diseaseandtoprovidesome correlation withtheirseriouslimitationsandtheyallappeartobe‘defaultoptions’.This‘personalview’tries and laterecurrencesthatwillultimatelyrequirealternatetherapeuticapproaches.Theirhighnumberisindirect potential to‘cure’thepatientandrestoreacompletelynormalpituitaryadrenalaxis,thereareimmediatefailures One oftoday’s challengesinendocrinologyisthetreatmentofCushing’s disease:Althoughpituitarysurgeryhasthe Abstract Hôpital Cochin,FacultédeMédecineParisDescartes,Université5,Paris,France Service desMaladiesEndocriniennesetMétaboliques,CentredeRéférenceRareslaSurrénale, X Bertagna view Can wecure Cushing’s disease?Apersonal MANAGEMENT OFENDOCRINEDISEASE drugs. Chroniccortisolexcessseemstoinescapablyattract an unanticipatedandfavoritetargetfornumerousnew stage. A rare disease (for how long?) now comes to the front Introduction ‘I donotwritetosaywhatIthink, buttoknowwhatIthink.’ https://doi.org/10.1530/EJE-18-0062 www.ej Review pathophysiological mechanisms ofendocrinetumorformationandhormonehypersecretion trials withinnovativedrugs, andparticularly, developingtranslationalresearch toelucidatethe clinical careandresearch inthesefields,fromusingnewdiagnostictoolstoconducting therapeutic axisandpolypeptide hormone precursors.Heparticipatesinallaspectsof of thepituitary–adrenal France. Hisresearch interestisinendocrinetumors,adrenalcancer, Cushing’s syndrome,disorders Endocrinology ofCochinhospital,FacultédeMédecine RenéDescartes,UniversitéParis5,Paris, Xavier Bertagna Invited Author’s profile Cushing’s syndrome–anddiseaserecentlybecame e-online.org

is ProfessorofEndocrinologyandhasbeentheChief of theDepartment 5 © 2018EuropeanSociety ofEndocrinology X Bertagna Printed inGreatBritain ‘Je n’écrispaspourdire cequejepense,maispoursavoirpense’ our currentmedicaltherapies.Bycomparison,PRL-, indeed remains as an improbable frustration, resisting – adenoma – beyond surgery ACTH-secreting pituitary suddenly identifiedanew‘UnmetMedicalNeed’. the appetiteofmanypharmaceuticalcompaniesthathave Treatment ofCushingdisease Published byBioscientifica Ltd. Among the hypersecretory pituitary adenomas,the pituitary Among thehypersecretory Downloaded fromBioscientifica.com at09/28/202102:11:00AM (2018) Endocrinology European Journal of [email protected] Email to XBertagna should beaddressed Correspondence . 178 178 :5 , R183–R200 Emmanuel Berl

R183 –R200 via freeaccess 1

European Journal of Endocrinology www.eje-online.org will offersuchanoutcome. axis shouldregainitsability toreactstress. and lateeveningvalues,theoverallpituitary–adrenal its normalcircadian pattern,withnormalearlymorning be inthenormalrange,butplasmacortisolshouldresume tuning ofnormalcortisolsecretion:notonlyshouldUC the hypersecretion.Itisalsotorestoreday-to-dayfine for example,theobjectivehereisnotonlytosuppress functions, likeprolactin, In contrastwithotherpituitary Restoring anormalpituitary–adrenal axis endpoint. biochemical targetastheirprimary almost alltherapeutictrials,thesedays,usethispurely decrease UCunderitsupperlimitofnormal(ULN).And cortisol orUC).Thus,anytreatmentshould,atleast, collection(urinary to measurecortisolina24-hurinary assess ‘chronichypercortisolism’, themostwidelyusedis (‘chronic hypercortisolism’). Therearedifferentwaysto induced bychronicexcessofcirculating freecortisol array ofsignsandsymptomspossiblecomplications Cushing’s syndrome–anddiseaseisdefinedbyan Suppressing the‘chronic hypercortisolism’ ‘cured’ apatientwithCushing’s disease. should bemetsimultaneouslytoassumethatwehave On theoreticalandpracticalgrounds,severalcriteria You said…‘cure’ ‘holy grail’forCushing’s diseaseisyettobefound. adrenal axis, however,pituitary is another question. The hypercortisolism’. Lastingrestorationofa‘normal’ glucocorticoid receptor(GR)axis.( many actors,whichcomposethepituitary-adrenal- to explore all possible therapeutic strategies against the numerous investigatorsandpharmaceuticalcompanies, therapeutic approaches.Astimulatingorphan,pushing is stillsomewhatanorphanwithregardtotargeted indirectly –growthhormone(GH)-receptorantagonists. dopaminergic-somatostatin (SST)analogs,andeven– long foundtheirbrilliant‘medicalsolutions’with adenomashave GH- andTSH-secretingpituitary Review They oftensucceedinreducingthe‘chronic adenoma In contrast,theACTH-secretingpituitary However, few, ifany, ofthecurrentmedicalapproaches X Bertagna 1 ). context of‘chronichypercortisolism’. system(CNS)disturbancesinthe and centralnervous when lookingatdiabetes,highbloodpressure,osteoporosis leading toinfertility?We encounterthesamequestion hypercortisolism’ oracomplicationofhypercortisolism amenorrhea a‘clinicalfeature’associatedwith‘chronic metabolic abnormalitiesandcomplications?Issecondary between signsandsymptoms,clinicalfeatures, On a semantic point of view, should wediscriminate – – – not alwayseasytoanswerthepatient’s questions: ‘chronic hypercortisolism’ isindeedadifficulttask.It Anticipating thebeneficialeffect(s)ofsuppressing features/complications of‘chronic hypercortisolism’ Correcting theclinicalperipheral when confrontedwith‘chronic hypercortisolism’ and ( by itselfcontributestotheoverallclinicalpresentation to evaluate, in a given patient, how much cortisol excess CNS disturbances,osteoporosis.Itisnotalwayspossible Cushing’s disease:obesity, diabetes,highbloodpressure, and oftenpresentinindividualswithout(before?) induced by ‘chronic hypercortisolism’ are fairly common taken intoconsideration:many–mostclinicalfeatures Finally, the‘pre-Cushing’situationshould ideallybe – – complications: determine thereversibility–orirreversibilityof hypercortisolism’ are also importantfactors,which due tovertebracollapse…never. within days,mensesresumeweeksandheightloss impact: aftersuccessfultreatment,diabetesmaydisappear complications are not of equal significance and clinical Treatment ofCushingdisease ‘La part ducortisol’ ‘La part

osteoporosis ‘ ‘ ‘ system. irreversible damage,particularly of thecardiovascular Long-standing ‘chronic hypercortisolism’ may create syndrome. ‘catch-up’ growth ofchildren after cureofCushing’s and bonemass.( individuals, whichhelpsrestorenormalskin,muscle Tissue plasticity is aremarkable advantage in young How aboutmyexcesshair, diabetes,highbloodpressure, Shall Iresume mymenses Shall Iloseweight Furthermore, individualsubjects arenotequal Age of the patient and duration of the ‘chronic It isofobviousclinicalexperiencethatfeatures/ …?’ , Fig. 2 Fig. 1 ?’ Downloaded fromBioscientifica.com at09/28/202102:11:00AM ). ). Thebestexampleofitisthe ?’ ‘When?’

178 :5 R184 via freeaccess European Journal of Endocrinology pulmonary metastases. Thepatientfeelsthegoodof pulmonary adrenocortical cancer andalreadydetects rapidly growing young femalejustoperated from ahighlyhypersecretory thegreatandimmediateclinicalbenefitina one observes tumor.primary Itisahighly frustratingsituationwhen ofthe and evenforadrenocorticalcanceraftersurgery tumors occult ACTH-secretingectopic,non-pituitary is stillthere,andcangrowfurther. Thesameis truefor Yet, weshouldalwayskeepinmindthatthecausaltumor, or actionaregenerallynotareliablylong-termtherapy. adrenal cortisol excess, drugs inhibiting steroid synthesis adrenalectomy isadefinitive‘cure’oftumor-driven control the‘chronichypercortisolism’. Whilebilateral adrenolytic, antiglucocorticoids) can efficiently adrenals (bilateraladrenalectomy, steroidinhibitors, same timebyaunique,efficientanddefinitiveapproach. the idealpossibilityofsuppressingtwo‘enemies’at easily completelyablatetheresponsibletumor, rulingout difficult toaccessadjacenttissuesdonotalwaysallow causes –directlyorindirectlyoverproductionofcortisol. at thesametime:ahormone,cortisolandtumor, which have twoenemies,whichareinvariablypresenttogether In Cushing’s syndrome,whateveritscause,wealways Ablating theresponsible tumor other diabetesandnoosteoporosis. individual willdeveloposteoporosisandnodiabetes,the within oneindividual,organsarenotequaleither: are impressivelyreversedafterthehypercortisolismiscontrolledinyoungpatients.BMD,bonemineraldensity. Reversibility ofperipheralclinicalfeaturesaftercontrollingthe‘chronichypercortisolism’.Morphotypicandbone loss, Figure 1 Review In Cushing’s disease,treatmentsatthelevelof Anatomical constraints and tumor invasion into Cushin g X Bertagna operation whenthedoctor, atthesametime,foresees resume spontaneously, ifaftersomedelay. In thecontext of rence. function will corticotroph The suppressed pituitary always besurgicallyremoved entirely withnoriskofrecur (always) The unilateralcortisol-secreting adrenocortical adenoma (neither invasivenor‘occult’,andbenign) The tumorcanbeentirelyanddefinitivelyremoved Cushing’s syndromewithallitscauses. be met. We will consider here the whole spectrum of As stringentastheymaybe,conditionsfor‘cure’can Who canbecured? cause –isSURGERY. The only way to ‘cure’ Cushing’s syndrome – whatever its Yes wecan…sometimes! availability worldwide. have ahighsuccessrate,rapiddelayofaction,large the riskofrecurrence,becost-effective,easilyperformed, the waytoobtainit:Itshouldavoidsideeffects,minimize Not onlyisthedefinitionof‘cure’ratherstringent,butalso Ideally premises ofthecatastrophe. Treatment ofCushingdisease Two conditionsshouldbemet:

The tumor is visible, non-invasive, benign and can Cu re d Downloaded fromBioscientifica.com at09/28/202102:11:00AM 178 www.eje-online.org :5 ye ar s R185 via freeaccess - European Journal of Endocrinology www.eje-online.org of aglandactuallyboostsback itsoverallfunction:this some delay. corticotroph function willresumespontaneously, ifafter failures and/orrecurrencesarecommon. not alwaysvisible,oritcanbeinvasive,explainingthat and canoftenbesurgicallyremovedentirely. Yet, it is disease (often) the bestthingonecanhave. Cushing’s syndrome, theadrenal adenomaiscertainly cortical pre-disease state,assumingacompletereversaloftheclinical featuresinducedby‘chronichypercortisolism’. hypercortisolism. Itshowsthatassessmentofcortisolcontribution totheoverallclinicalpicturewouldrequireknow patients, withnormal–(upper, andmiddle)oralreadyabnormal(lower)clinicalparametersbeforetheoccurrenceof blood glucose(BG)areschematicallyfollowedbefore-,during-andafter‘ ‘ Figure 2 La partducortisol Review Pa Pa Pa In case of ‘immediate success’, the suppressed pituitary In caseof‘immediatesuccess’, thesuppressedpituitary The ACTH-secreting pituitaryadenomaofCushing’s It is a remarkable situation where partial resection ent 3 ent ent 2 1 LLN UL LL UL LL UL N N N N N

’… ‘cortisolcontribution’.Threecommonclinicalparameters,bodyweight(BW),bloodpressure(BP),and The tumorisalmostalwaysbenign BW BW BW Be BP BP BP fo re X Bertagna BG BG BG BW BW BW ‘occult’. Thelatternevertheless requirecarefulfollow-up which canbecuredsurgically ifdetectedearlyandnot malignant character, e.g.bronchial carcinoid tumors, displaying almostbenign outcomesdespitetheir lung). amenable to surgical cure (small-cell carcinomas of the for ectopicACTHsecretionareoftenmalignantandnot secretion (rarely) resume afterpartialhypophysectomy. is obvious,forexample,whenmensesspontaneously Treatment ofCushingdisease Cushin Rarely can they behave as very indolenttumors, Rarely cantheybehaveas very The non-pituitarytumorresponsible forectopicACTH BP BP BP cure g ’ of BG BG BG ‘chronic hypercortisolism’

Non-pituitary tumorsresponsible Non-pituitary Downloaded fromBioscientifica.com at09/28/202102:11:00AM BW BW BW , inthree‘schematic’ 178 Cure :5 BP BP BP d BG BG BG R186 via freeaccess European Journal of Endocrinology within months, the overall pituitary adrenalaxiswill within months,theoverall pituitary hours, cortisolplasmavalues droptoundetectable,and surgery.syndrome through a 30-min pituitary Within female patientfromtheunbearable featuresofCushing’s Few situationsareasrewarding as‘curing’ayoung Nothing asgood Pituitary surgery: syndrome. adenomaasthecauseof Cushing’sproducing pituitary is nowrestrictedtoCushing’s disease,i.e.anACTH- As anticipatedfromthetitle,followingdiscussion it works Pituitary surgery: hypercortisolism’. the peripheralfeatures/complicationsof‘chronic hypercortisolism, thehigher theprobabilitytocorrect for ‘cure’.Thesoonerthediagnosisandcontrolof axisisnotsufficient Restoring anormalpituitary–adrenal of ‘chronichypercortisolism’occur Surgery mustbedonebeforeirreversiblecomplications respected. ifthecompletedefinitionof‘cure’mustbe is necessary be ‘cured’(transiently?)byaunilateraladrenalectomy. exceptional patientwithahighlyasymmetricalformmay adrenalaxisisevidentlyimpossible.An normal pituitary hypercortisolism’ isalwayseasilycorrected,restoring by bilateraladrenalectomy. Althoughthe‘chronic the AIMAHsyndromesarealmostinevitablytreated McCune-Albright syndrome, theCarneycomplex, benign, but almost always bilateral lesions, seen in the cortical hyperplasiasyndromes (almostnever) remission. 1–2) allowssurgical‘cure’withlongterm,ifnotdefinitive secretion asanunfavorableprognosticfactor. and several series havehighlighted tumor-related cortisol aggressive tumors withdismalprognosis are usuallyvery disease. as metastases can occur and complicate the course of Review In allthesecases,asstatedearlier, asecondcondition The bilateralbenignACTH-independentadrenal Very rarely, earlydiagnosisofalocalizedtumor(stage The adrenal cortical carcinomas (very rarely) ‘La voieroyale’ ‘La voieroyale’… X Bertagna when These These confined osseousstructure,afewmillimetersfromvital location at the base of the brain, embedded in a semi- is indeedthe‘royalapproach…butfullofpitfalls!’. ‘Une voieroyale…semée d’embuches!’ When itworks clinical situationthatisindistinguishablefromnormal. to an overall had an early diagnosis achieve recovery or lesscompletely(seeaboveand hypercortisolism’ will disappear, at different rates, more accumulated whilstthepatientwasexposedto‘chronic normal subjects. or stimulation)willallbeundistinguishablefromthosein cortisol, theresponsetoanydynamictests(suppression return tonormal:thedailycircadian variationsofserum latter technicalreasonsmay explainthedifficultiesof believe thatthesefragments canbehomogeneous;these for research aimsandscientificallyquestionable to be ethicallyquestionable to collect‘some’fragments if onlytumoralcellsarefound; forthesereasons,itmay it raisessomedoubtonthecompletenessofsurgery misdiagnosing anothersource ACTH; ofnon-pituitary can givetheultimateproofthatwearenotmerely shortcuts: incaseofimmediatefailureapositivehistology fragmentsisseminalandshould notuseany pituitary adrenal corticaladenoma! adenomaismorecomplicated than removingan pituitary skills, thatarethedominantparameters. Removing a conditions ofeachadenoma, together withthesurgical tests, itisactually–andquitelogicallytheanatomical degree ofhypercortisolism, responsestodifferentdynamic success,suchasage,sex,durationofdisease, surgery possible featuresthatcouldbepredictiveofpituitary occur. approach’: immediatefailuresandlaterecurrencesdo entirely, isnotalwaysa‘royal surgery thepituitary because invasive adenomas cannot always beresected functions( integrity ofallanteriorpituitary the pathologicalconfirmationandrespect/restore normal surroundinggland,resectitentirely, obtain can findatinyadenoma,distinguishitfromthe something close to a miracle for me that neurosurgeons hasalwaysbeen structures likethecarotidartery…it Treatment ofCushingdisease Considering the size of the pituitary gland,itsdeep Considering thesizeofpituitary It isnotexceptionalthatyoungpatientswhohave Full pathological examination of all the removed Although manystudieshaveanalyzedthe smalladenomasarenotalwaysfound, Because very The various features/complications that have Downloaded fromBioscientifica.com at09/28/202102:11:00AM Fig. 2 The pituitary surgery surgery Thepituitary 178 ). www.eje-online.org :5 Fig. 3 ). R187 via freeaccess European Journal of Endocrinology www.eje-online.org when science(andexperts) werepointingout,inthe ofCushing’s surgery in pituitary disease patients, a time teams andtheiriconicefforts, inthelate1970s,toengage indebted totheMayoClinic ( second surgery. done: all other options remain possible, including a isthatnothing irreversiblehasbeen surgery pituitary adenomas. transcriptomic approachesinACTH-secretingpituitary transsphenoidal surgeryexploration. adenoma; Pit,preservedoverallanteriorpituitaryfunction;Pit MRI,pituitarymagneticresonanceimaging;TSSexplo, surgically removedpituitarytissue;Part.,partialremovalofthe pituitaryadenoma;PartialAdex,partialsurgeryofthepituitary surgery; Comp.,completeremovalofthepituitaryadenoma;Histo surgery at10 years;BIPSS,bilateralinferiorpetrosalsinussampling;cure,immediatecontrolofhypercortisolismafterpitui tary voie royale (definitive) cure,whilepreservingtheoverallanteriorpituitaryfunction,asshownbyoutmostseriesofarrowson left(‘ which authorizethatapartialhypophysectomy(Hypox)willremovetheentirepituitaryadenomaandleadtolong-lasting Pituitary surgery, ‘ Figure 3 Review Pit 10-year cure Taking ahistorical view, weshouldcertainlybe And yet,evenincaseoffailure,thebeauty ’). Thisisbutonepathway, amongmanyothers,alsoshown.10-year, lastingcontrolofhypercortisolismafterpituitary Comp ++ Histo + + . la voieroyale’ Part +/ + + + - Partial . Ta rgeted Histo Hy + - - po

…‘theroyalapproach’.Thisschemeresumesthedeterminantsofasuccessfulpituitarysurgery, - x 2 X Bertagna ) andSanFrancisco( Foun Comp d ++ Histo + + . Partial Part + +/ Not + + Expl TS - . S fo o Hy un Clinical Histo po d + - - x Non invasive - 3 ) Partial outcome Comp. ++ Found + + + a straightforward or desirablesituation. a straightforward options. Onthecontrary, hehastoomany, which isnever the endocrinologistisnotdeprived ofothertherapeutic hasfailed,orisjudgednotfeasible, surgery When pituitary ‘default options’ All othertherapeuticapproaches are hypothalamus ( highest rankedjournals,the‘possible’causalroleof Histo Treatment ofCushingdisease Accessible or Ad − Part +/ + + + , positiveornegativeimmunohistochemistryforACTHin ex - . In Expl TS va Not sive S o Seen fo un 4 d Contra Comp. ). Non- Histo ++ + + PIT MR And/or Accessible indications Part + +/ + + Downloaded fromBioscientifica.com at09/28/202102:11:00AM - Partial . Ta I Not seen rgeted Found Histo Hy + - - po -

x Comp. BIPS 178 ++ Histo + Expl + TS :5 Partial S S o Part Not + + +/ + + - . fo Hy un Histo po d R188 x + - - - via freeaccess La European Journal of Endocrinology – – options aretried: the disease;andthisisparticularlytruewhennewmedical Cushing’s diseasepatientsisdifficultduetothenatureof Assessing theefficacyofanytherapeuticoption in medical treatments The ‘inescapable’limitationsofthe – – – – inescapable limitations: bilateral totaladrenalectomy…allareassociatedwith radiotherapy,(Mifepristone), pituitary and,eventually of synthesis,adrenolytic),theglucocorticoidreceptor (dopaminergic, SSTanalogs),theadrenalcortex(inhibitors

Review ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ to recruit more patients, it is useful to have cases with to recruitmorepatients,itis usefultohavecaseswith endpoint.Yet,UC isalogicalprimary ithaslimitations: a raredisease. It isdifficulttorecruitalarge numberofpatientswith most often Reduce/eliminate the‘chronichypercortisolism’… function Never restoreanormalpituitary–adrenal Often addadverseevents(AEs) third) disease: They almostalwayscreateasecond(andsometimes Medical treatment targeting the pituitary Medical treatmenttargetingthepituitary ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ hypercortisolism’. much lowersuccessratestocontrolthe‘chronic of 100%–allothertherapeuticoptionshave does nothaveaunexpectedrateofsuccess Apart fromtotalbilateraladrenalectomy–which axis. pituitary–adrenal None oftheseapproachescanrestoreanormal treatment. other possiblesideeffectswithchronicMitotane Significant gastrointestinalandCNSAEs,many Diabetes isabigconcernwhenusingPasireotide. with itsownpropensiontogrow, ifnotirradiated. adenoma, Leaving thefirstdisease,pituitary insufficiencywithradiotherapy Pituitary many difficulties toadapt the treatment (see below). (progesterone blockade)withMifepristone.Andthe mineralocorticoids), and even a third one to glucocorticoids(excessandrogen, The inescapablefeaturesofgeneralresistance insufficiency. fine tuning of daily dosage, risk of adrenal synthesis, andtheproblemsofexcessprecursors, Adrenocortical blockadewithinhibitorsofsteroid after bilateraladrenalectomy. Addison’s diseasewiththeadrenolyticMitotaneor X Bertagna – – – – Medical treatmentstowardsthepituitaryadenoma Treatment ofCushingdisease

⚬ ⚬ ⚬ diabetes, highbloodpressure,gonadaldysfunction)are consequences…not ‘UC’!Theselatterfeatures(obesity, point, thepatientsactuallycomplainofperipheral end Whereas itislogicaltomeasureUCastheprimary carried outsofarhavebeenuncontrolled. Cushing’s disease,most–ifnotalltherapeutictrials However, becauseofthesupposedintrinsicseverity particularly important to design‘well-controlled’ trials. Because ofthesespecificfeatures,itwouldbe of hypercortisolism isnotrelatedtoitsseverity( authors stateinparallelpublicationsthatthe‘degree’ Cushing’s diseasepatients( knowing thelargespontaneousvariabilityofUCin to its baseline value. Something rather controversial, the ULN,butisreducedbyhalformoreincomparison a treatment,countingpatientswhoseUCremainsabove UC. Surprisingly, somestudiesalsoassesstheefficacyof where spontaneousfluctuationsmaysimplynormalize mildly elevatedUC,downto1.5-foldULN,arange Yet, inhibiting tumorACTHsecretion. through theSST2andSST5subtypereceptors, adenoma, to act directly at thelevel of the pituitary PasireotideThe somatostatin(SST)analogisassumed Cushing-related clinicalconsequences/complications. in theneedtomedicallymanagetreatmentof evaluate, aspreciselyheorshecan,thedecrease often treatedsymptomatically, andonemayhaveto more difficulttoevaluate,alsobecausetheyaremost ⚬ ⚬ ⚬ ƒ ƒ by morethan50%.Raisingtwonewquestions: who didnotnormalizebutdroppedtheirinitialUC ‘mild’ Cushing’s diseaseorcountingthosepatients become betterwhenconsideringonlypatientswith normal UC ( Only between25and40%ofthepatientsachieve Cholelithiasis mayoccur. to improvetheirclinicalsituation. treatment whilstreceivingthatismeant require theadditionofasupplementalantidiabetic undesirable in these patients, who may even and/or developorworsendiabetes.Thisishighly Close to80%ofpatientshave‘hyperglycemia’ ƒ ƒ disease withoutdiabetesor normalUCwith Is itbettertohavemild,untreated, Cushing’s Cushing’s disease. is nottheonlydeterminant to theseverityof What is‘mild’Cushing’s disease?UCvalue 7 ). Not unexpectedly, the figures Downloaded fromBioscientifica.com at09/28/202102:11:00AM 5 ), and when the same ), andwhenthesame 178 www.eje-online.org :5 R189 6 ). via freeaccess European Journal of Endocrinology www.eje-online.org cortisol inescapablyincreasesACTH plasmalevels,withconsequencesonbothmineralocorticoids andandrogens. The hormoneturmoilofCYP11B1 blockadeinCushing’s diseaseanditsperipheralconsequences. Thebeneficialdecreaseof Figure 4 – – Cabergoline

Review ⚬ Yet, subtype, inhibitingtumorACTHsecretion. adenoma, through the D2 receptor at the pituitary The dopamineagonistissupposedlyactingdirectly Obesit ObesityH ⚬ Fat ƒ response afterafewmonthsoftreatment( some patientsseemtoescapethistherapeutic of Cushing’s diseasepatients.Forunknownreasons, receptor agonistcannormalizeUCinabout30% studies havereportedthatthisdopamineD2 The efficiencyrateseemstoberatherlow. Several ƒ y as atherapeutictarget(seeupper)? What istherationaleof50%decreaseinUC cholelithiasis? Cushing’s diseaseornormalUCwith diabetes? Isitbettertohave mild, untreated, Sugar DiabetesI DiabetesI Improved (Corsol GlucoCor Protein Muscle. Muscle. Bone Bone Skin Skin /Cured

Immunit ) . nfecon nfecon X Bertagna y Depression Depression CNS 8 ). MineraloCor (DOC/ Balance ACTH Salt Vessels K Vessels K HB BP P – – – drawbacks. secretion, theirmodesofactioninescapablycreateserious can evidentlylower–andevencontrolthecortisolover Inhibitors ofsteroid biosynthesis Medical treatmentstargetingtheadrenalcortex Treatment ofCushingdisease Aldo

(Renin ⚬ ⚬ ?W YET: overproduce cortisol( to cortisolandtherebyloweringtheadrenals’ability CYP11B1, blockingtheconversionof11-deoxycortisol Both drugsdirectlyinhibitthemajorcortisol-producing Metyrapone andLCI699. ) ⚬ ⚬ Cushing’s diseaseinanotherpatientwithnowtwo These chronic treatments transform a patient with dopaminergic drugs,itisgenerallywelltolerated. Other thantheadverseeffectscommontoall . ) LH Downloaded fromBioscientifica.com at09/28/202102:11:00AM 9 , Androgen 10 (DHEA) ). Amenorrhea Amenorrhea Testo Hirsusm Hirsusm Inferlity Inferlity orse

While all these drugs 178 ? s :5 Improved Testo Impotence Impotence Libid Libid o o R190 ? via freeaccess - European Journal of Endocrinology morning (08h00)andmidnight cortisolrangesareindicated.F, cortisol;UC,24-hurinarycortisol. and inapatientunderaninhibitor ofsteroidsynthesisadministeredsymmetricallytwicea day (dottedline).Normalearly The titratingapproach.theoretical continuousplasmalevelsofcortisolinanuntreated Cushing’s diseasepatient(solid line) Figure 5 Review corsol (F ⚬ ⚬ (salivary) ⚬ Plasma ⚬ ƒ The challengeofdrugdosageadjustment: balance? excess inbothsexes.Whatwillbetheultimate androgen infemalesandmineralocorticoid associate bettercortisolcontrolwithworsening As exemplifiedin secreting adenoma. ACTH- diseases: CYP11B1blockadeplusapituitary ƒ • limitations ( disease patient. This approach has serious chronically normalizeUCofagivenCushing’s exactly therightdoseofmedicationthatwill glucocorticoid: Theconcept,here,istofind daily tothepatient, without supplemental has toadministertheappropriatedoseofdrug, A ‘titrating’approach isproposed • ⚬ disease patients( of dailycortisolproductionCushing’s How tocopewithspontaneousfluctuations ⚬ ) 08h00 pituitary adrenalaxis. pituitary Normal UCdoesnotmeannormal Fig. 5 i. 4 Fig. ): 5 )? , theoverallresultmay X Bertagna wherethedoctor 24h00 Treatment ofCushingdisease Inh . Untreated CD Ste.Syn.CD • • ⚬ ⚬ ⚬ ⚬ 08h00 Dayme (AI)? How torecognize/avoidadrenalinsufficiency ⚬ ⚬ ⚬ ⚬ well’ time apatientwillcomplainof‘notfeeling Early andmildAIwillbesuspected each pressure drop,electrolyteschanges…). (vomiting, abdominalpain,briskblood diagnosis ofAI,andnotwaitforacuteAI particularly ifwewanttomakeanearly specific, manifestations are not very Clinical judgment is key. Yet, the clinical cortex beresponsiveenough? corticotroph cells?Ifso,willtheadrenal the reactivatedperi-tumoralnormal ACTH, that from the tumor or that from these patients?Will ACTHrise?Which How abouttheresponsetostressin restored (seefurther). The normal circadian rhythm cannot be non-specific; decreased blood pressure stomach discomfortarejustcompletely . Many symptoms like fatigue and Downloaded fromBioscientifica.com at09/28/202102:11:00AM Mornin Late Mornin UC Late UC night F: night F: gF gF 178 : : : : www.eje-online.org

:5 Low(normal) Normal High High(normal High High R191 ) via freeaccess European Journal of Endocrinology www.eje-online.org indicated. F, cortisol;UC,24-hurinary cortisol. supplemented withcortisolin the morningandatnoon(arrows).Normalearly(08h00) andmidnightcortisolrangesare (solid line)andinapatientunder aninhibitorofsteroidsynthesisadministeredsymmetrically twiceaday(dottedline)and The blockandreplaceapproach. Thetheoreticalcontinuousplasmalevelsofcortisolinanuntreated Cushing’s diseasepatient Figure 6 Review corsol (F (salivary) Plasma ⚬ ⚬ ) syndrome’ the ill-definedlabel‘cortisolwithdrawal normal cortisollevels,somewillinvoke symptoms thatlooklikeAIbuthave really help:Becausesomepatientshave Measuring cortisollevelsdoesnot drugs some patientsstillonantihypertensive possibly beabenefitofthetreatmentand might nothelpsomuchsinceitcould It was anticipated that obtaining a normal ACTH, andthus,fairlystableintheday. treatment, itisstilldrivenbythetumor production ispartiallyhamperedbythe cortisollevels.Although salivary) as a ‘normal range’ for plasma (and/or titrating approach,thereisnotsomething no complaints!Furthermore,undera patients withlowplasmacortisoland F 08h00 . Andthereversealsohappens, X Bertagna Administered F F Endogenous F 24h0 Treatment ofCushingdisease Under Fsubstuon Untreated CD 0 ƒ ƒ • supplemented withcortisol( secretion istotallysuppressed,andthepatient dose of medication, to the point that cortisol proposed A ‘Blockandreplace’ approach isalternatively • ⚬ ⚬ ⚬ 08h00 The advantages: ⚬ ⚬ ⚬ the cortisolsupplementationschedule. circadian rhythm,byproperly adjusting but alsoanormal–althoughartificial We canrestorenotonlya normal UC fluctuations oftheendogenouscortisol. We eliminate the problem of day-to-day the patientisinAI…he(she)is. We donothavetowonderwhetheror ( ( cortisol ‘high’ latenightserum(salivary) cortisoland morning serum(salivary) UC wouldbeattheexpenseof‘low’early 11 5 Fig. : here the doctor administers a large ). Da ), asconfirmedinFleserius’paper y me Downloaded fromBioscientifica.com at09/28/202102:11:00AM Morning Late Morning UC Late UC night F: night F: F: F: 178 Fig. 6 : :

:5 Normal Normal

High High(normal) Normal High ): R192 via freeaccess European Journal of Endocrinology – – The adrenolytic Mitotane – – –

Review ⚬ ⚬ ⚬ ⚬ ⚬ Yet, ( hypercortisolism inamajorityofpatients,ca.80% in theadrenalcortex.Mitotanesuppresses directed againstACAT 1,whichisfoundpredominantly to beincorrelationwithitsactionbeingexquisitely cells. Itsratherspecificactionattheadrenalseems cholesterol esterinsteroid-secretingadrenocortical increased apoptosisduetoaccumulationoffree through arecentlyfoundmechanism( Mitotane induceslong-lastingadrenolyticaction Yet, lowering theadrenals’abilitytoproducecortisol( the start of the overall steroid biosynthetic pathway, The drug directly inhibits several enzymes mostly at Ketoconazole. 14 ⚬ ⚬ ⚬ ⚬ ⚬ which isrendereddifficult in faceofalteredsteroid corticosteroid supplementation, theadjustmentof needfor adrenalectomy’, witha mandatory It willmostofteninduce astateof‘chemical bioavailability. It hasaslowonsetofactionandhighlyvariable approaches. we usethe‘Titrating’ orthe‘Blockandreplace’ are encountered with the drug adjustment, whether As withMetyraponeandLCI699,thesameproblems gonads, particularlytheandrogens. decrease allsteroidsynthesisincludingintothe that ofa‘spillover’mechanismwherethedrugcan biologically activeprecursorsofcortisol,butrather no morethatofpotentialexcessdeleterious steroid biosyntheticpathway, theproblemis Because theblockadeissituatedearlyonin ACTH-secretingadenoma! plus apituitary diseases: ‘high’blockadeofsteroidbiosynthesis Cushing’s diseaseinanotherpatientwithnowtwo This chronictreatmenttransformsapatientwith ). • • ⚬ ⚬ The drawbacks: ⚬ ⚬ deficiency. hyperplasia due to 11-beta-hydroxylase mutations, causing congenital adrenal by patientswithinactivatingCYP11B1 and androgens in women – as exemplified levels of precursors, mineralocorticoids CYP11B1 inhibitionwillinducehigher created. The inescapableAI,evenifitispurposely X Bertagna 13 ) involving 12 ). – receptor: Mifepristone Medical treatmenttargetingtheglucocorticoid – – – Treatment ofCushingdisease

⚬ ⚬ ⚬ ⚬ ⚬ ⚬ countries asacontragestive),wasalsofoundtobean anti-progesterone drug(andpresentlyusedinmany Mifepristone (RU486),originallydevelopedasan Yet, action, indeedshowedsomeefficacy. original therapeutic approach,opposingglucocorticoid was improved,aswellcognitionandqualityoflife.This 5.7%; insulinresistancedecreased,glucosemetabolism relation to cortisol action: Mean body weight dropped benefit wasobtainedtowardssomeperipheralfeaturesin in anopen-label,multicenterstudydesign.Aclear 300 and1200 ( surgery persisting Cushing’s diseaseafterfailureofpituitary mellitus or hypertension. Among them, 42 patients had various causesofCushing’s syndromeandtype2diabetes in USA:theSEISMICstudyselectedadultpatientswith The firstsystematicapproachwasrecentlyperformed including patientswithCushing’s disease. efficacious inoccasionalcasesofCushing’s syndrome, Several papers had initially suggested that it could be ( anti-glucocorticoid drugpotentiallyactiveinman 17 ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ It hasnumerousAEs( patient, thebenefitsaremostoftenonlytransient. Although itsefficacymaylastforyearsinagiven replacement. 5a-dihydrotestosterone rather than testosterone patients develophypogonadismthatrequires by 5-alpha-reductaseactivity( Through strong inhibition of androgen activation 3-fold increasedcortisolreplacementdose. ( CYP3A4-mediated rapidinactivationofcortisol transport andmetabolism.Mitotaneinduces rather non-specific–actions ofcortisol? make clinicaljudgmenton theperipheral–and How tomonitordrugdosage, whenwecanonly to long-termmifepristoneadministration)? actually increased sevenfold on average in response endogenous cortisolbecomesmeaningless(UC How toevaluatethetreatmentefficacy when had longbeenanticipated: oversecretion inCushing’s disease,severalproblems the pathophysiologicalmechanismofACTH Given themodeofactiondrugand ). 15 ), whichmeansthatpatientsrequirea2-to 18 ). A single oral dose of mifepristone, between ). A single oraldose of mifepristone, between mg perday, wasadministeredfor24 weeks, Downloaded fromBioscientifica.com at09/28/202102:11:00AM 16 ). 178 www.eje-online.org :5 15 ), male R193 via freeaccess European Journal of Endocrinology www.eje-online.org – – – The inescapablelimitationsofpituitaryradiotherapy – – – – – – With allmedicaloptions

Review ⚬ ⚬ ⚬ ⚬ ⚬ although itfurtherprogresses withtime.Thereisno of follow-up. It israrelybetterthan50%attwoyears, depending onthedosesadministered andtheduration hypercortisolism’ widelybetween series, vary and successratesforcontrolling the‘chronic In allcases,itsactiononthetumorproceedsslowly, Yet, beam therapy)( (gammaknifeor proton or bystereotaxicradiosurgery classically byconventionalfractionatedradiotherapy as welltumorgrowth.Itcanbeperformedeither radiotherapymaycontrolACTH oversecretion, Pituitary The necessityforalife-longtreatment? A variablesuccessrate. The contraindicationinpregnantfemale. tumor.the pituitary The needtocarefullyfollowthepotentialgrowthof A fairlylargearrayofspecificAEs. axis. pituitary–adrenal None ofthesemedicaloptionscanrestoreanormal ⚬ ⚬ ⚬ ⚬ ⚬ some autonomouscortisolsecretion( incidentalomas withnoCushing’s syndromebut plasma valuesintheparticularsituationofadrenal the day further lowersthe morning nadir of cortisol might beofhelp:Metyraponegivenattheend Asymmetrical administrationofsteroidinhibitors rhythm andnormalresponsetostress). include noriskofadrenalcrisis,normalcircadian controlled, a normal axis is not restored (that would Even inthosepatientswhosehypercortisolism is with plannedpregnancy? myometrium, andofcoursebeingnon-compatible mifepristone inwomen,itsadverseeventsonuterus How tocopewiththeantiprogesteroneactionof edema? if un-opposed, will be creating hypokalemia and act atthemineralocorticoidreceptorandthereby, cortisol and11-deoxycortiosterone(DOC)thatcan the mineralocorticoid actions of both increased the inescapableandchronicACTHincrease How toavoid the possible side effects induced by cortisol levels? and to treat it, in the presence of high circulating How torecognizeanddiagnoseadrenalinsufficiency, 20 ). X Bertagna 19 ). – bilateral adrenalectomy The inescapablelimitationsof – – – – – – – Treatment ofCushingdisease

The majoradvantageofthissurgicaloptionis with modernradiotherapytechniques. has beenreported,althoughtheseareprobablylower Finally, apotentialriskofcerebrovascularcomplications adverse effect. minimizesthis evidence thatstereotaxicradiosurgery occurs inupto50%ofthepatients.Thereisno functions not ‘spared’,andfailureofsomepituitary tissueis Also, withradiotherapythenormalpituitary steroid synthesis. combined withmedicaltherapy, usuallyinhibitorsof used alone.Inmanycases,radiotherapyhasbeen good optionwhenarapidcureisneeded,atleast approach.Therefore,itisnota stereotaxic radiosurgery clear evidence that better outcome is obtained with the when DonNelsonestablished ‘his’syndrome.Nelson essential toolswhichwereobviously lackinginthe1950s MRI, availability ofACTHmeasurement andpituitary minimized inthemodernera, becauseofthecommon the probabilityoffull blown Nelson’s syndrome is tumor,The pituitary ofcourse,isstillpresent.However, adrenal insufficiency. need foradaptation,educationandtheriskofacute mineralocorticoids, anditsunavoidableconstraints, life-long steroidcoveragewithglucocorticoidsand These patientsbecomeAddisonian:theywillneed Yet, ( (transsphenoidal surgery) after a–somewhatlessmajorsurgicalprocedure clearly improved,andsimilartoorbetterthanthat that the quality of life of these operated patients was to referral centers. Several recent serieshave shown difficult surgicalprocedure,whichshouldberestricted zero, butwithsomedefinitivemorbidity. Itisindeeda and experienced teams have reported mortality rates of The laparoscopicsurgicalapproachisnowthestandard, operation. caused byadrenalreststhathaveescapedthesurgeon years afteratotalbilateraladrenalectomy. Thisis to thepointthat‘chronichypercortisolism’ mayrecur resume someendogenouscortisolsecretionsometimes patients. Rarepatients,lessthan10%,however, may The success, furthermore, is permanent, in almostall immediately. hypercortisolism’ with a successrateof100%, its unequaled efficacy tocontrol the ‘chronic Downloaded fromBioscientifica.com at09/28/202102:11:00AM 21 ). 178 :5 R194 via freeaccess European Journal of Endocrinology 486 ormifepristone;RX,pituitary radiotherapy;SOM,somatostatinanalog;TSS,transsphenoidal surgery. bilateral adrenalectomy;CAB, cabergoline; KTZ,ketoconazol;LCI,LCI699orosilodrostat;LYS, mitotane;MET, metyrapoe;RU,RU options forCushing’s disease, andtheircombinations,thetoo-manyindividualdifferences betweenpatients.ADX, total Squaring thecircle:The‘cushingame’ …insearchofthe‘tayloredtreatment’.Orhowtointerface thetoo-manytherapeutic Figure 7 radiotherapyandtreatedconcomitantlywith pituitary reduce adverseevents.Forexample,patientsundergoing adrenal axis( treatments, actingatdifferentlevelsofthepituitary– Many authorshavethoughtfullycombinedseveral Why notcombine! Review RU be avalidated,ornecessary, procedure. adrenalectomy has been debated, but does not seem to by pregnancy. radiotherapyafter Preventivepituitary early stages are manageable and (4) itisnot accelerated MRIfollow-up;(3)whenitoccurs,the and pituitary variable; (2)itcanbedetectedearlybyplasmaACTH that: (1) corticotroph tumor progression is highly become symptomatic.Recentstudies( before thetumorhasextendedtopointthatit in allpatientsundergoingbilateraladrenalectomy precisely followthe‘corticotrophtumorprogression’ following bilateraladrenalectomy. Currently, wecan ACTH-producing adenoma progression of a pituitary Syndrome wasoriginallydefinedbyinvasivetumor RX LYS ADX (« Treatment The Options i. 7 Fig. Cushingame» ), soastoimproveeffectivenessand MET TSS SOM KTZ X Bertagna ) CAB LCI 22 ) haveshown – – in ratherconvincingstudies,twocontrastingsituations: awaiting forthefulleffectofradiationtherapy. some sortofsteroidsynthesisinhibitororMitotane,while Treatment ofCushingdisease

to threedifferentdrugs,startingwithpasireotidefirst, disease (notsevere)were‘sequentially’treatedwithup In an opposite situation, patients with classic Cushing’s action, eliminatingtheriskofescapephenomena. time when Mitotane had started its delayed adrenolytic metyrapone could be withdrawn after a few weeks, at a initial UCwithinafewdays.Bothketoconazoleand proved highlyeffective, normalizing extremelyhigh ‘simultaneously’ administered( doses ofMitotane,acting as aslowadrenolyticwere acting atdifferentstepsofsteroidogenesisandsmall two steroidinhibitors,ketoconazoleandmetyrapone, embolism,etc.),a‘tritherapy’wasused.The pulmonary out anysurgicalapproach(cardiacfailure,recent In patientswithsevereCushing’s disease,ruling (15 of17)wereeventuallycontrolled(UCnormalized). ( adding cabergolineandfinallyketoconazole,asneeded 24 Two ‘combination’approacheshavebeendocumented ). Under this sequential approach, most patients ------Severity Drug cost Drug availabilit Follow Preference Distance Pregnancy Sex Age Need Tumor Prior treatments patient for rapid -up threat Downloaded fromBioscientifica.com at09/28/202102:11:00AM The : dowe (shots? success y 23 178 have time ). This‘cocktail’ www.eje-online.org :5 pill s? R195 ) ? via freeaccess European Journal of Endocrinology www.eje-online.org disease patients ( published guidelines for the treatmentofCushing’s remarkable thatinoneof thelatest(amongmany) therapeutic options,itisnotreassuringatall. As alreadystated,whenagivendiseasehassomany each individualpatient’ And attheendtreatment shouldbe:‘tailored in – – These conditions evidently definethetherapeutic strategy: – – – disease: Several factorscontributetotheseverityofCushing’s When are limitationscounterbalancedbyseverity? identified andselected( given patient,thebestpossiblecombinationhastobe her imaginationinasortof‘Cushingame’where,for disease, anexperiencedendocrinologistcanusehis/ With somanyoptionsnowavailabletotreatCushing’s

Review extremely difficulttoassess. and evaluationof‘adrenalinsufficiency’episodesare not expectadramaticclinicalchange,anddrugefficacy situations areparticularlydifficulttomanage:wedo discordance, i.e. relatively mild. These not uncommon biological counterparts(UC),whichappearinsharp of long-standingundiagnosedhypercortisolism with and possibleAEs.Somepatientshaveseverestigmata medical optionsincomparisonwiththeirtolerance it isnotobvioustoanticipatethebenefitofvarious In contrast,in‘mild’formsof‘chronichypercortisolism’, failsorseemswithouthope. surgery adrenalectomy mayappearlegitimateifthepituitary ‘combined’ medicalapproachorevenarescuebilateral hypercortisolism isvitally needed,thelimitationsofa When anurgentandrapidcontrolofthe immediate probleminthemajorityofcases. The tumoralthreat,althoughthisisrarelyan may haveaccumulatedovertheyears. ofdebilitatingfeatures/complications,which recovery unknown for years; a late diagnosis will not allow total The durationofthedisease,whichmayhavebeen complications. through infectious,cardiovascular, psychiatric actually beanimmediatevitalthreattosurvival, The highlevelsofcirculating cortisol,whichmay Cushing’s diseasepatientsaredifferent;anditis 25 ), with the official support ofthe Fig. 7 ) –adifficultgame. X Bertagna who endurethemaleficenceofdisease,and–withtime ‘guideliners’ –whocancope!However, forthepatient, Cushing’s disease’. dose andcombinationofmedicaltreatment modalitiesfor individual patient.Future studiesshouldexaminetheoptimal be targetedatdifferent levelsandshouldbetailored ineach same Journal( Fig. 7 therapies’. of medication;gender;age;andtheavailabilitymedical the method of delivery,personal history; side effects, and cost interactions); the patient’streat; other medications (drug–drug control; thesizeandlocationofresidual tumors;theurgencyto account patient preferences; treatment goals; biochemical curative, the choice of second-line therapy must take into eventually state American EndocrineSociety, aselectedgroupofexperts, adenoma. cause ofCushing’s disease:TheACTH-secreting pituitary better thanthatwhichspecifically controls/ablatesthe For obvioustheoreticalreasons,notreatmentshouldbe The pituitaryadenomaisareasonable obsession needed! All this ‘progress’ means one thing: more progress is Some progress, recently Future directions can be,stillhaslimitations. – realizethatmedicine,asmodernand Treatment ofCushingdisease ⚬ ⚬ ⚬ ⚬ Really adifficultgame!Forthedoctor–and Just anotherconclusion,inreview, inthe ⚬ ⚬ ⚬ ⚬ , ‘Squaringthecircle’). different fromMetyrapone. AEs, butstillunderdevelopment,andnotradically to bepromisingintermsofefficacyandlowrate LCI 699isanewCYP11B1inhibitor, whichseems mode ofaction. with somerestrictionsitsnot-so-easynew Mifepristone was authorizedintheUnited States, efficiency rate. for adrugactingdirectlyatthepituitary, withalow Pasireotide obtainedthefirstofficialauthorization surgical risk. small taking a laparoscopic approach with very Total bilateraladrenalectomyisnowperformed (Otherconsiderationscouldevenbeadded 26 ): ‘When surgery isnotpossibleornon- ‘When surgery ‘Medical therapyforCushing’s diseasecan Downloaded fromBioscientifica.com at09/28/202102:11:00AM 178 :5 ‘personalized’ R196 via freeaccess it European Journal of Endocrinology iodide symporter;RAI,radioactive iodinetherapy;X,themoleculartargettobefoundin ACTH-secretingpituitaryadenoma. Comparing thepathophysiologies ofthetoxicthyroidadenomaand‘toxic’ACTH-secreting pituitaryadenoma.NIS,sodium Figure 8 What otherendocrinetumorshavetaughtandteachus pituitary surgery/radiotherapy? Can weimprovetheefficiency ofthe Review of transiently ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ƒ ƒ secreting pituitary adenoma’: secreting pituitary The ‘toxicthyroidnodule’andtheACTH- More focusedradiotherapeuticaltechniques? endoscopy andbettermicroscopicvisualization? More efficientsurgicalapproaches,through imaging ofthepituitary? Better andmoreprecise(andintra-operative)MRI ƒ ƒ Ablation restorenormalfunction This non-surgicalapproachisfeasiblebecause; axis. fully normalpituitary–thyroid hyperthyroidism, and subsequently, restores a outpatients alwaysanddefinitelyeliminatesthe A singledoseof RAI (radioactive iodine) in rewarding as treating a toxic thyroid nodule. grail’. Nothingisaseasy, ascostless,and endocrine tumorthathaslongfoundits‘holy The toxicthyroidnoduleisahypersecretory phenot Conserve -a suppressed adenom thyroid nd specific- Surger To Benign Clonal yp RA NIS xic ic dn I features X Bertagna y a orma normal cell l : s: Treatment ofCushingdisease of transientl ƒ Ablation restorenormalfunctio ƒ • • • • • • • adenoma’ ofCushing’s disease( more than the ‘toxic ACTH-secreting pituitary Nothing resembles the ‘toxic thyroid nodule’ • • • • • • • Targeting through X A benign,clonaltumor, withinanegative overall thyroidfunction. ofthe This willallowsubsequentrecovery tumoral thyroidcellsarepreserved. a negativefeedbacksystem,normal,non- At thesametime,becauseitallhappensin targeted way. efficacy ofRAItherapyinaspecific,organ- within thetumorcells,enhancing symporter (NIS) allows RAI to accumulate The expressionofthesodium-iodide differentiated phenotypicfeatures. many ofitsnormal(and rather specific) A tumorbenignenoughthatithaskept tumor We knowwearedealing with aclonal, benign differentiated phenotypicfeatures(GPCR mostofitsnormal Which hasconserved feedback system( Conserve AC phenot ys - TH-secreting adenoma and specific- «T pituitar uppresse Surger Benign Clonal Downloaded fromBioscientifica.com at09/28/202102:11:00AM oxic yp X ? ic dn 27 y features » y ). orma dn 178 ormal cell www.eje-online.org :5 l Fig. 8 ? ). n R197 s: via freeaccess European Journal of Endocrinology www.eje-online.org Review ⚬ ⚬ ƒ ƒ ƒ ƒ tumor…may provideuswithnewtargets On theotherhand,acquired phenotype ofthe ƒ ƒ ƒ ƒ • • adenomas. Theonlyreported, sofar, recurrent nevertheless rarelyconcern ACTH-secreting the roleof With regard tothepituitary, weknowabout new medicaltreatments( provide thetherapeutistwithtargetsforefficient melanoma, Tyr-kinase mutatedGISTs, now biology issometimesofhelp:BRAF-mutated Better knowledgeofthe‘modified’tumor identified ( RET, theMAPkinasepathwayshavelongbeen thyroid tumors, the role of BRAF mutations, in mostpheochromocytomas( hypoxia andMAPkinasespathwaysareinvolved signaling pathway, respectively( activations ofthecAMPpathwayorcalcium syndrome orConn’s adenoma,throughthe adrenocortical adenomas leading to Cushing’s and highly differentiated tumors such as leading totumorgrowth.Thisistrueforbenign have clearlypointed-outmolecularmechanisms In manycases,germlineorsporadicmutations tumors pathophysiology. in themolecularunderstandingofendocrine Major progresshasbeenmadeinthelastyears • • the ACTHcellshouldhelp:Hopefully, most Better knowledgeofthenormal‘biology’ allow totakecontrolofthetumor, medically. Yet! The tumor ( adrenocortical functionafterablationofthe Resuming completelynormalpituitary being ratherspecific( prohormone convertases). Some of them expression, glucocorticoidreceptivity, such approach,yet! adenomas,no In ACTH-secretingpituitary dopaminergic treatmentoftheseadenomas. adenomas isthebasisforhighlyeffective DA2-R expressioninPRL-secretingpituitary as a basis for RAI treatment, maintained maintained NIS expression in thyroid tumors the most efficacious treatments: Besides the judiciously takenintoconsiderationtodirect – phenotype.Insomecasesitmaybe kept manyfeaturesoftheirinitial–normal –arebenignandhave true forthepituitary endocrine tumors–andthisisparticularly 29 32 grail Menin ). ). isstilltobefound,whichwould and X Bertagna 28 AIP 33 ). ). mutations,which 31 ). Inmalignant 30 ). The And downstream ofthepituitaryadenoma before theemergenceof‘personalizedmedicine’! endocrine tumorswhichhavefoundtheir‘holygrail’long and morerecently, oftheprolactinomaareparadigmatic approaches. Theexamplesofthe‘toxicthyroidnodule’, andcouldpossiblybeusedfortherapeutic been preserved highly differentiatedtumorsthose‘natural’targetsthathave repertoire ofnormalphenotypictraitsthese benign and with potentialnewandefficienttherapeuticapproaches. adenomasandprovideus of ACTH-secretingpituitary that wouldatthesametimeexplainpathophysiology It isindeedimportanttodiscovernewmoleculartargets Treatment ofCushingdisease ⚬ ⚬ ⚬ Yet, we shouldnotneglect to search aswellwithin the ⚬ ⚬ ⚬ patients. could possiblybeobtained inCushing’s disease on liver( ACTH plasmalevelsbuthas no–orlittleeffect compound hasbeensynthesized whichdecrease is dissociatedondifferenttargetcells.Sucha molecules the‘glucocorticoid’actionofwhich have been developed with theidea to create new SElective GlucocorticoidReceptorAgonists(SEGRA) SEGRA rebound effect? cortisol secretion?Shouldweanticipate an ACTH maintained ( precursor problem.Aldosteronesecretionnormally extreme specificityofthemodeaction;no immediate response;noexpectedAE,duetothe R, wouldtheoreticallyaddseveraladvantages: of theadrenallyexpressedACTHreceptorMC2- Inhibiting thedirectactionofACTHatlevel Anti-ACTH (MC2-Rantagonists) Yet, moreto belearnt. effect, lessAEduetoitsbetteradrenalspecificity). with itssupposedadvantagesoverMitotane(faster increase aswithMetyraponeorLCI699).Together liver AEaswithKetoconazole,noriskofprecursor advantages overthecurrentssteroidinhibitors(no of ACAT1 ( common modeofactionthroughtheinhibition Mitotane andATR 101bothapparentlysharea ATR-101 SDHs control of the EGF-R might be a clue! correlate yet, although it may suggest that is thatof adenomas mutation in ACTH-secreting pituitary genesaremuchmorerarelyinvolved. 37 ). Oneimmediatelyseesthe benefit that 36 USP8 35 ). Yet, howtopreciselymonitorthe ). ATR-101 might have unique Downloaded fromBioscientifica.com at09/28/202102:11:00AM ( 34 ), whichhasnotherapeutic 178 :5 Cables R198 via freeaccess , European Journal of Endocrinology References sector. grant fromanyfundingagencyinthepublic,commercialornon-for-profit conferences andscientificboards.Thisworkdidnotreceiveanyspecific pharmaceutical companies(HRA-Pharma,Novartis,IPSEN)foractivitiesin In thelastthreeyears,authorhashadfinanciallinkswithfollowing Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest endocrinological challenge. ‘minute’ adenomasremaina‘huge’,and‘long-lasting’, not knowhowtotakecontrolofthemmedically:These surgery,‘cured’ thefirstpatientsbypituitary westilldo discovered thecauseofhisdisease( adenomas pituitary ‘… Conclusion 5 4 3 2 1 Review Striking clinical effects ⚬ Petersenn S, Newell-Price J,Findling JW, Gu F, Maldonado M, Sen K, Krieger DT, Amorosa L&Linick F. Cyproheptadine-induced Tyrrell JB, Brooks RM,Fitzgerald PA, Cofoid PB,Forsham PH& Salassa RM, Laws ERJr, Carpenter PC&Northcutt RC. Bertagna X &Guignat L.ApproachtotheCushing’s diseasepatient High variability in baseline urinary freecortisolvaluesinpatients High variabilityinbaselineurinary Salgado LR, Colao A,Biller BM&Pasireotide B2305StudyGroup. 293 remission ofCushing’s disease. 753–758. microadenomas. pituitary Wilson CB. Cushing’s disease.Selective trans-sphenoidal resectionof disease. Transsphenoidal microadenomainCushing’s removalofpituitary (https://doi.org/10.1210/jc.2012-3200) ofClinicalEndocrinologyandMetabolism Journal with persistent/recurrenthypercortisolism surgery. after pituitary Forty yearsafterSalassa’s andTyrrell’s ( ⚬ the rare malignant pituitary tumors. the raremalignantpituitary researchers. Temozolomide has its use restricted to steroid biosynthesisareinthebasketofimaginative the glucocorticoidreceptortype2,newinhibitorsof expression andtumorgrowth,newantagoniststo tyrosine kinase activity to decrease POMC gene transcription, antagonistsofSF1,inhibitorsEGF-R POMC gene,retinoicacidtoinhibitgene oligonucleotides preventingtranscriptionofthe New somatostatinanalogs,shortinterferingRNA And… 893–896. Mayo ClinicProceedings (https://doi.org/10.1056/NEJM197510302931802) ’ as Harvey Cushing stated when he as Harvey New England Journal ofMedicine New EnglandJournal 1978 New England Journal ofMedicine New EnglandJournal … 53 X Bertagna produced 24–28. 38 ). 2013 … 98 by minute 2 , 1307–1318. 3 1978 ) groups 1975 298

Treatment ofCushingdisease 18 17 16 15 14 13 12 10 11 9 8 7 6 Fleseriu M, Biller BM,Findling JW, Molitch ME,Schteingart DE, Bertagna X, Bertagna C,Luton JP, Husson JM&Girard F. Thenew Hahner S &Fassnacht M.Mitotaneforadrenocorticalcarcinoma Chortis V, Taylor AE, Schneider P, Tomlinson JW, Hughes BA, Sbiera S, Leich E,Liebisch G,Sbiera I,Schirbel A,Wiemer L, Coste J,BouKhalil R,Silvera S,Guignat L, Baudry C, Castinetti F, Guignat L,Giraud P, Muller M,Kamenicky P, Drui D, Bertagna X, Pivonello R,Fleseriu M,Zhang Y, Robinson P, Taylor A, Daniel E, Aylwin S, Mustafa O,Ball S,Munir A,Boelaert K, Pivonello R, DeMartino MC,Cappabianca P, DeLeo M,Faggiano A, Colao A, Petersenn S,Newell-Price J,Findling JW, Gu F, Guarnotta V, Amato MC,Pivonello R,Arnaldi G,Ciresi A, Fleseriu M, Pivonello R,Young J, Hamrahian AH,Molitch ME, SEISMIC StudyInvestigatorsinclude: mifepristone,aglucocorticoid Gross C &onbehalfoftheSEISMIC StudyInvestigators.The org/10.1210/jcem-59-1-25) of ClinicalEndocrinologyandMetabolism steroid analogRU486inhibitsglucocorticoid actioninman. treatment. Metabolism and androgenreplacement. 5 therapy inadrenocorticalcancerinducesCYP3A4andinhibits O’Neil DM, Libé R,Allolio B,Bertagna X,Bertherat J en.2015-1367) Endocrinology reticulum stressandapoptosisinadrenocorticalcarcinoma cells. Sterol-O-Acyl transferase1triggeringlipid-mediatedendoplasmic Matysik S, Eckhardt C,Gardill F, Gehl A 167 patients fromasinglecenter. Efficiency andtoleranceofmitotaneinCushing'sdisease76 Guibourdenche J, Abbas H,Legmann P, Bertagna X&Bertherat J. jc.2013-3628) and Metabolism Cushing’s disease:isitworthatry? Caron P, Luca F, Donadille B,Vantyghem MC 138–148. prospective, phaseIIstudyinCushing’s disease. Osilodrostat, apotentoral11 Watson CE, Maldonado M,Hamrahian AH,Boscaro M 2616) Metabolism multicenter studyin195patients. of metyraponeintreatingCushing’s syndrome:aretrospective Chortis V, Cuthbertson DJ,Daousi C,Rajeev SP 2009 treated bysurgery. with thedopamineagonistcabergolineinpatientsunsuccessfully treatment ofCushing’s disease:effectivenessofchronictreatment Lombardi G, Hofland LJ,Lamberts SW&Colao A.Themedical org/10.1056/NEJMoa1105743) ofMedicine New EnglandJournal A 12-monthphase3studyofpasireotideinCushing’s disease. Maldonado M, Schoenherr U,Dipl B,Mills D,Salgado LR doi.org/10.1007/s12020-016-0914-9) severity ofCushing’s syndrome. al Trementino L, Citarrella R,Iacuaniello D,Michetti G,Simeoli C (https://doi.org/10.1111/cen.12259) with Cushing’s disease. Shimizu C, Tanaka T, Shimatsu A,White T, Hilliard A 99 concept study. patients withCushing’s disease:resultsfromamulticenter, proof-of- a potent11 α . The degree of urinary hypercortisolism. Thedegreeofurinary isnotcorrelatedwiththe -reductase, explainingtheneedforpersonalizedglucocorticoid 1375–1383. 473–481. 94 223–230. (https://doi.org/10.1007/s11102-015-0692-z) 2015 2013 Current OpinioninInvestigationalDrugs β -hydroxylase inhibitor, cortisolin normalizesurinary 2015 (https://doi.org/10.1530/EJE-12-0358) 2014 Journal ofClinicalEndocrinologyandMetabolism Journal (https://doi.org/10.1210/jc.2013-2117) 98 100 (https://doi.org/10.1210/jc.2008-1533) Journal ofClinicalEndocrinologyand Metabolism Journal 156 161–171. 4146–4154. 99 3895–3908. Clinical Endocrinology 1623–1630. Downloaded fromBioscientifica.com at09/28/202102:11:00AM Journal ofClinicalEndocrinologyand Journal β European Journal ofEndocrinology European Journal (https://doi.org/10.1210/jc.2012-2851) -hydroxylase inhibitor:22-week, 2012 Endocrine (https://doi.org/10.1210/jc.2015- Journal ofClinicalEndocrinologyand Journal Journal ofClinicalEndocrinology Journal (https://doi.org/10.1210/ (https://doi.org/10.1210/ 366 1984 et al 914–924. 2017 178 . Mitotaneinhibits 2014 59 et al www.eje-online.org :5 et al 55 25–28. Pituitary 2005 . Ketoconazolein 564–572. 80 (https://doi. . Effectiveness et al 261–269. et al et al 6 (https://doi. 2016 386–394. . Mitotane . et al . LCI699, R199 (https:// Journal Journal 2014 2012 . 19 et

via freeaccess European Journal of Endocrinology www.eje-online.org

27 26 25 24 23 22 21 20 19 Review Gicquel C, LeBouc Y, Luton JP, Girard F&Bertagna X. Feelders RA &Hofland LJ.MedicaltreatmentofCushing’s disease. Nieman LK, Biller BMK,Findling JW, HassanMurad M,Newell- Feelders RA, deBruin C,Pereira AM,Romijn JA,Netea-Maier RT, Kamenicky P, Droumaguet C,Salenave S,Blanchard A,Jublanc C, Assié G, Bahurel H,Coste J,Silvera S,Kujas M,Dugué MA,Karray F, Thompson SK, Hayman AV, Ludlam WH,Deveney CW, Loriaux DL Starke RM, Williams BJ, Vance ML &Sheehan JP. Radiationtherapy Debono M, Harrison RF, Chadarevian R,Gueroult C,Abitbol JL& Journal ofClinicalEndocrinologyandMetabolism Journal Monoclonality ofcorticotrophmacroadenomasinCushing’s disease. (https://doi.org/10.1210/jc.2012-3126) ofClinicalEndocrinologyandMetabolism Journal org/10.1210/jc.2015-1818) Endocrinology andMetabolism an EndocrineSocietyClinicalPracticeGuideline. Price J, Savage MO&Tabarin A. Treatment ofCushing’s syndrome: (https://doi.org/10.1056/NEJMc1000094) in Cushing’s disease. Lely AJ Hermus AR, Zelissen PM,vanHeerebeek R,deJong FH,der 2011 Cushing’s syndrome. as analternativetorescueadrenalectomyforsevereACTH-dependent et al Gautier JF, Brailly-Tabard S, Leboulleux S,Schlumberger M,Baudin E 2007 Nelson’s syndrome. progression afteradrenalectomyinCushing’s disease:areappraisalof Dousset B, Bertherat J,Legmann P sla.0000251578.03883.2f) Annals ofSurgery adrenalectomy forCushing'sdisease:a10-yearexperience. & Sheppard BC.Improvedqualityoflifeafterbilaterallaparoscopic MED.0b013e32833ab069) Diabetes andObesity disease: anevidence-basedreview. forthetreatmentofCushing’sand stereotacticradiosurgery 3461–3469. secretion. in adrenalincidentalomapatientswithmildautonomouscortisol Newell-Price J. Resettingtheabnormalcircadian cortisolrhythm jc.2011-3350) and Metabolism patients withCushing’s syndrome. receptor antagonist,producesclinicalandmetabolicbenefitsin . Mitotane,metyrapone,andketoconazolecombinationtherapy 96 92 et al 2796–2804. 172–179. Journal ofClinicalEndocrinologyand Metabolism Journal . Pasireotidealoneorwithcabergolineandketoconazole (https://doi.org/10.1210/jc.2017-00823) 2012 2007 2010 Journal ofClinicalEndocrinologyandMetabolism Journal (https://doi.org/10.1210/jc.2011-0536) 97 New England Journal ofMedicine New EnglandJournal Journal ofClinicalEndocrinologyandMetabolism Journal 245 2039–2049. 17 790–794. 356–364. 2015 Current OpinioninEndocrinology, et al 100 Journal ofClinicalEndocrinology Journal (https://doi.org/10.1210/ (https://doi.org/10.1097/01. X Bertagna . Corticotrophtumor (https://doi.org/10.1097/ 2807–2831. 1992 2013 Journal ofClinical Journal (https://doi.

75 98 362 472–475. 425–438. 2017 1846–1848. 102

Accepted 20February2018 Revised versionreceived7February2018 Received 30January2018

Treatment ofCushingdisease 33 32 31 30 29 28 38 36 35 37 34 Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Reincke M, Sbiera S,Hayakawa A,Theodoropoulou M,Osswald A, Devji T, Levine O,Neupane B,Beyene J&Xie F. Systemictherapy thyroidcarcinoma.Integrated genomiccharacterizationofpapillary Fishbein L, Leshchiner I,Walter V, Danilova L,Robertson AG, Bertagna X. Geneticsofadrenaldiseasesin2014:genetics Guilhaume B, Bertagna X,Thomsen M,Bricaire C,Vila-Porcile E, de Keyzer Y, René P, Beldjord C,Lenne F&Bertagna X. Cushing H. The basophil adenomas of the pituitary bodyandtheir Cushing H. Thebasophiladenomasofthepituitary Clark AJ, Forfa R,Hussain M,Jerman J,McIver Ed,Taylor D & LaPensee CR, Mann JE,Rainey WE,Crudo V, Hunt SW3rd& Schäcke H, Schottelius A,Döcke WD,Strehlke P, Jaroch S, trials. systematic reviewandnetworkmeta-analysisofrandomizedclinical for previouslyuntreatedadvancedBRAF-mutatedmelanoma:a Cancer GenomeAtlasResearch Network. org/10.1016/j.ccell.2017.01.001) and paraganglioma. Comprehensive molecularcharacterizationofpheochromocytoma Johnson AR, Lichtenberg TM,Murray BA,Ghayee HK,Else T nrendo.2014.215) Reviews Endocrinology improves understandingofadrenocorticaltumours. (https://doi.org/10.1210/jcem-66-5-1056) ofClinicalEndocrinologyand Metabolism Journal disease: resultsin64patientsandlongtermfollow-upstudies. Transsphenoidal forthetreatment ofCushing’s surgery pituitary Olivier L, Racadot J,Derome P, Laudat MH,Girard F 2265.1998.00560.x) Endocrinology hormone receptorgenesincorticotrophtumours. Overexpression ofvasopressin(V3)andcorticotrophin-releasing 137–195. clinical manifestations. Chan L. ACTHantagonists. 1775–1788. and intheadrenalcortexofdogs. acyltransferase 1,inducesapoptosisinH295Radrenocorticalcells Hammer GD. ATR-101, aselectiveandpotentinhibitorofacyl-CoA Nature Genetics al Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K,Saeki Y jamaoncol.2016.4877) effects. receptor agonistleadstoseparationoftherapeuticeffectsfromside of transactivationfromtransrepressionbyaselectiveglucocorticoid Schmees N, Rehwinkel H,Hennekes H&Asadullah K.Dissociation . MutationsinthedeubiquitinasegeneUSP8causeCushing’s disease. JAMA Oncology PNAS (https://doi.org/10.1210/en.2015-2052) 2004 1998 2015 101 49 47 Cancer Cell 2017 2015 475–482. 31–38. 227–232. Bulletin oftheJohnsHopkinsHospital Downloaded fromBioscientifica.com at09/28/202102:11:00AM 3 11 Frontiers inEndocrinology 366–373. 77–78. (https://doi.org/10.1038/ng.3166) 2017 (https://doi.org/10.1046/j.1365- Endocrinology 31 (https://doi.org/10.1038/ (https://doi.org/10.1001/ 181–193. Cell 178 2014 1988 :5 2016 Clinical (https://doi. 159 2016 Nature et al 66 157 1056–1064. 676–690. .

7 1932 101. R200 et al . 50 via freeaccess et et