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European Journal of Endocrinology -18-0667 in decreaseprolactinlevels, tumorshrinkageand through bindingandactivation ofD2receptors,resulting bothersome ( , infertility, testosteronedeficiency inmenor microprolactinomas resultinginoligomenorrhea, for all macroprolactinomas and for symptomatic tumors( functioning pituitary of ,whicharethemostcommontype of therapy (DAs)constitutetheprimary Introduction therapy canmitigatethepotentialharmsassociatedwithICDsinthesepatients. regularly evaluatetreatedpatientsforthedevelopmentofICDs.EarlydetectionICDsanddiscontinuation DA on DAtherapymustbeawareofthispotentialadverseeffect, counselpatientsregardingpertinentsymptomsand implications forpatients’well-beingandfamily. Endocrinologistsandotherphysiciansinvolvedinthecareofpatients in patientstreatedwithDA,includingthosehyperprolactinemia.ThedevelopmentofICDscanhaveserious identification andmanagementofICDsinpatientsonDAarediscussed.Inconclusion,awidevarietycan occur mechanisms underlyingthedevelopmentofICDsinthissettingarereviewed.Inaddition,strategiesforearly risk factorsfortheemergenceofICDsinpatientstreatedwithDAarediscussedandputativepathophysiologic article, wesummarizeavailabledataonICDsinpatientswithhyperprolactinemiaaswellotherdisorders.Possible assembling objects).Thesebehaviorscanhavedevastatingeffects onpatients’lifeandfamily. Inthepresentreview stealing, hypersexualityandpunding(repetitiveperformanceoftasks,suchascollecting,sorting,disassembling and A varietyofICDsmayoccurinpatientstreatedwithDA,includingcompulsiveshopping,pathologicgambling, A growingbodyofevidencehasidentifiedimpulsecontroldisorders(ICDs)aspossibleadverseeffects ofDAtherapy. an importantroleinthetreatmentofneurologicdisorders,includingParkinson’s diseaseandrestlesslegssyndrome. Dopamine agonists(DAs)representacornerstoneinthemanagementofpatientswithhyperprolactinemiaand have Abstract Harvard MedicalSchool,Boston,Massachusetts,USA 1 Maya Barake agonists: howmuchshouldweworry? hyperpolactinemia treated withdopamine control disorders inpatientswith MANAGEMENT OFENDOCRINEDISEASE Clemenceau MedicalCenter, Beirut,Lebanonand https://doi.org/ https://eje.bioscientifica.com Review Dopamine agonists exert their therapeuticeffect 10.1530/EJE 1 , Anne Klibanski -18-0667 2 6 ). © 2018EuropeanSociety ofEndocrinology 1 ). Treatment isindicated 2 M Barakeandothers and Nicholas A Tritos 2 Neuroendocrine Unit,MassachusettsGeneralHospitaland Printed inGreatBritain 2 patients withmacroprolactinomas orasubsetofpatients considered. However, thisisoftennot possibleinmany the opticchiasm,gradualtreatment withdrawalmaybe by morethan50%overbaseline is and thetumorisnolongervisibleonscanorshrinks When prolactinlevelsremainnormalforatleast2 years United States)( and (the last one is not available in the patients. Available DAincludecabergoline, restoration ofgonadalfunctioninthemajoritytreated impulsivity Dopamine agonistsand Published byBioscientifica Ltd. 1 ). Treatment withDAisoften prolonged. Downloaded fromBioscientifica.com at10/01/202102:27:31AM (2018) Endocrinology European Journal of [email protected] Email to NATritos should beaddressed Correspondence 179 179 > 5 :6

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R287 –R296 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com or gambling,withlowregard fortheirpotentialnegative an individualtoperformcertain behaviorslikeshopping Impulsivity hasbeendefined astheurgeexperiencedby Impulsivity andimpulsecontrol disorders articles withnolanguagelimitation. hyperprolactinemia, prolactinomas.We included relevant impulsivity, impulsecontroldisorders,dopamine agonists, inception upuntilJuly2018.We usedthe keywords electronic databasesPubMedandMEDLINEfromtheir A reviewofavailableliteraturewasperformedusingthe Methods hyperprolactinemia. therapy, withemphasisondatainpatientstreatedfor on impulsivityandICDsinpatientsreceivingDA therapy( been associatedwithICDsintheabsenceofdopamine in theabsenceoftherapy, hyperprolactinemiahasnot symptomatology (anxiety, ,apathy, ) to PDpatients,whomayexperiencepsychiatric disorders (ICDs)becamerecognized( namely increasedimpulsivityandimpulsecontrol association betweenDAandpsychiatricmanifestations, with dopamineagonists( risk ofclinicallysignificantvalvulardiseaseinassociation echocardiographic studiesdidnotsuggestanincreased the treatmentofhyperprolactinemia,mostevidencefrom with the 5-HT2B ( proposed mechanismforthiseffectisdruginteraction and the treatment duration was at least 6 months ( used inpatientswiththisadverseeffectexceeded 3 disease (PD)( the publicationofdatainpatientswithParkinson’s risk ofcardiac-valveregurgitationwasraisedfollowing for someergot-deriveddopamineagoniststoincreasethe with theD1receptor( the 5-HT1 receptor and orthostasis, through interaction gastrointestinal (),thoughttobemediatedthrough The most common treatment-related adverse events are treatment period,concernforlong-termsafetyarises. effect profile.However, withthepotentialforaprolonged levels despitesmalltumorsize( with microadenomaswhodonotnormalizeprolactin Review The aimsofthepresentarticlearetoreviewdata Throughout theyears,concernsregardingan Dopamine agonistsgenerallyhaveafavorableside- 5 , 6 11 ). However, thedailycabergolinedose ). 4 ). Inthepastdecade,potential 8 , 7 9 ). In the usualdoses used for ). 2 , M Barakeandothers 3 ). 10 ). Incontrast 5 ). The mg restless legsyndrome,while designedforthestimulation 21 immediate rewardandincrease impulsivechoices( postulated topromotebehaviors withthepossibilityof receptors withinthemesocorticolimbic systemis increasing dopaminelevelsorstimulating in mediatingreward-relatedbehavior. And as such, ( projecting to the and the frontal cortex the ventraltegmentalarea,pathwayinvolvesneurons mesocorticolimbic pathway. With cellbodieslocatedin they allsharethesamebiologicsubstratewithin have beenclassifiedaspsychiatricconditionsamongthe Manual ofMentalDisorders,FifthEdition(DSM-V),ICDs assembling objects).IntheDiagnosticandStatistical of tasks,suchascollecting,sorting,disassemblingand (), (repetitiveperformance , stealing(),hairpulling include compulsive shopping, pathologic gambling, problems forthepatientandhisorherfamily. significant andlastingsocial,financialinterpersonal wellbeing ( person’s dailyliving,interpersonalrelationsandsocial condition becomesadisorderwhenitinterfereswiththe health related.Asinotherpsychiatricderangements,the harms fortheindividual,whetherfinancial,socialor for animmediatereward,disregardingthefuturepotential impulse toperformacertainactivitywiththepotential psychiatric disorderscharacterizedbyfailuretoresistan consequences ( Task andtheExperientialDiscountingTask ( or delayedrewards,includingtheBalloonAnalogRisk actual risk-takingbehaviororchoicebetweenimmediate tests alsoincludecomputerizedvalidatedinstrumentswith the BarrattImpulsivenessScale( include theBehavioralInhibition/Activationsystemand different domains.Examplesofexistingquestionnaires , planningandsubdivideimpulsivityinto questionnaires measureresponsestoreward,punishment, through more objective psychometric tests. Available better quantifiedusingself-reportquestionnairesand literature addressingthisproblem.Impulsivitycanbe there maybesubstantialheterogeneityintheavailable for subjectivityintheevaluationofsuchdisorders, different ICDsdoexist,however, duetothepotential of addictivedisorders( ( ‘Disruptive, ImpulseControl,andConductDisorders’ impulsivity Dopamine agonistsand 19 13 ). Dopamineagonistsused for thetreatmentofPDor ). Thisdopaminergicpathwayhasbeenimplicated ). Pathologicgamblinghasbeenclassifiedaspart While ICDsmayhavedifferentclinicalpresentations, Depending onthepursuedimpulse,ICDsmay 13 ). Indeed,ICDshavethepotentialtoresultin 12 ). Impulsecontroldisorders are aclassof Downloaded fromBioscientifica.com at10/01/202102:27:31AM 13 ). Formaldefinitionsforthe 14 , 15 179 , 16 :6 ). Psychometric 17 , 18 ). R288 20 via freeaccess , European Journal of Endocrinology Reporting System,collected between2003and2012, retrospective analysisofdata fromtheFDAAdverseEvent was reported,rangingbetween 7.1and11.4%( 34.8% ( of ICDs in PD treated with a DA ranged between 2.6 and eating ( population, exceptforhypersexualityandcompulsive statistically significantwhencomparedtoacontrol hypersexuality and7%punding( 5% pathologicgambling,11%compulsiveeating,3% specific ICDswereasfollows:9%compulsiveshopping, prevalence ofanyICDwas17%,whilethefrequencies of study evaluatingICDsinrestlesslegssyndrome(RLS),the was reported in a large Asian study ( than oneICD( hypersexuality (3.5%).Ofnote,3.9%ofpatientshadmore followed bygambling(5%),compulsiveeating(4.3%)and commonly reported ICD was compulsive shopping (5.7%) or moreICDsinPDpatientswas13.6%( conducted intheUSAandCanada,prevalenceofone of PD.Inthelargestcross-sectionalDominionstudy dopamine agonistswereapprovedforthetreatment Impulse controldisorderswerereportedasearly Prevalence disorders otherthanhyperprolactinemia Impulse control disorders inParkinson’s diseaseand receptors ( agonist treatmentoccursviaexcessivestimulationofD3 postulated that the development of ICDs with dopamine limbic system, in thefrontalcortex and the thalamus. Itis D2 receptors,but are alsohighlyexpressedwithin the ( istheD2receptor releasefromthepituitary the responsible for inhibiting mediated throughD2receptoractivation( and thesubstantianigra.Anti-Parkinsonianeffectis caudate nucleus,theputamen,nucleusaccumbens namely D2 and D3. D2 receptors are localized within the is mediatedthroughbindingtodopaminereceptors, ( may alsoincreaseimpulsivitythroughstimulationofthe through activationofthetuberoinfundibularpathway in ICDs.Similarly, DAusedtotreathyperprolactinemia receptors withintherewardmesolimbictract,resulting control of motor function, may also stimulate dopamine of thenigrostriataldopaminergicpathwayinvolvedin 23 Review ). D3receptorsarepresentintheregionscontaining Dopamine actionindiverseavailablepathways 28 19 ). Inarecentsystematicreview, theprevalence ). In RLS, a typically lower prevalence of ICDs 22 , 24 26 19 , 25 ). AcomparableoverallICDprevalence , 20 ). , 21 ). M Barakeandothers 27 28 ). In a case–control ). Resultswere 26 22 ). Themost ). Similarly, 19 ). Ina as withtheirfamilies. Even whenphysicians are aware their presenceduringdiscussionswithpatients,aswell undetected unlessphysiciansspecificallyinquireabout treated withaDA,theprevalencewas12.4%( ICD prevalencewas 51.5%, while inthose who were never patients whoeveruseda DA inthefollow-upperiod, the 5-yearcumulativeincidenceofICDswas46.1%.In ( yearsoftherapy from 19.7%atbaselineto32.8%5 for theoccurrenceofanICD.ICDprevalenceincreased formally evaluatedyearlyusingsemistructuredinterviews yearsandwere PD werefollowedannuallyforupto5 In anewlypublishedlongitudinalstudy, 411patientswith were derivedfromcross-sectionalandretrospectivestudies. with restlesslegssyndrome( in Parkinson’s disease,while23.8%wereseeninpatients 61.7% ofICDsreportedamongpatientsonDAoccurred psychological traitswerefound tocorrelatewiththe general ( also anindependentpredictor fordevelopinganICDin hypersexuality onDA,allwere men( in apublishedseriesof15PDpatientsdeveloping and eating were more frequent in women ( more commonlyinmen,whilecompulsiveshopping ( ICD groupwereyoungerage,smokingandsinglestatus morefrequently inthe demographic factorsobserved who remainedfreeofthisadverseeffect.Significant developing ICDs were compared to PD patients Patient related Risk factors and measuretheseverityofICDsymptoms( (QUIP-RS), hasbeenstudiedandvalidatedtodiagnose Compulsive DisordersinParkinson’s Disease-RatingScale questionnaire, namedtheQuestionnaireforImpulsive- determine thepresenceofanICD.InPD,aspecific caregivers( if physicianshadnotinterviewed an ICD would have been missed in more than half of cases disclose them.IntheseriesbyWeiss tendency togamble),individualsmaynotspontaneously disorders (includingchangesinsexualbehavioror the personalnatureofsomesymptomsthese than 50% of patients who suffer from anICD; due to of thisadverseevent,itmayremainunknowninmore impulsivity Dopamine agonistsand 29 26 ). Among the 306 patients without an ICD at baseline, ). Amongthe306patientswithoutanICDatbaseline, ). Hypersexualityandcompulsivegamblingoccurred Although ICDsarenotrareinPD,theymaygo Up untilrecently, epidemiologicdataregardingICDs The presenceofamental illnessorofcertain Screening instrumentsmaybehelpfultoobjectively 19 ).

In theDominionstudy, PDpatients Downloaded fromBioscientifica.com at10/01/202102:27:31AM 25 ). et al 24 179 https://eje.bioscientifica.com ). Malegenderwas ., thedetectionof :6 26 31 30 29 ). Similarly, ). ). ). R289 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com Dominion study( ICDs ( relationship wasobtainedbetween DAandfrequencyof free ofanICD( were exposedtohighercumulative DAdosesthanthose ICDs amongPDpatients,individualswhodeveloped compulsive eating( shopping, gamblingandhypersexualitybutnotfor of theDAandoddsratiofordevelopingcompulsive betweenthedose dose–response relationshipwasobserved conductedamong1167PDpatients, apositive survey Dose anddurationofDA was forpramipexoleandropinirole( were associatedwithICDs,butthestrongestassociation , bromocriptine,rotigotineandapomorphine) all FDA-approvedDAs(,, ( likely explainstheirmorefrequentimplicationinICDs system, isat least 100 morethan for D2,which for theD3receptor, primarilylocalizedwithinthelimbic in PD( the D3dopaminereceptorandarecommonlyprescribed ropinirole ( for anICDwastheDApramipexole,followedby Type ofDA Treatment related substantial functionalimpairment( with higherfrequencyofmotorcomplicationsandamore others, relatedtheoccurrenceofanICDtothosepatients are linkedtoICDprevalence( younger ageatonsetofPDandalongerdiseaseduration Disease related shopping andgambling( specific association of with compulsive related to specific ICDs but not to others, including the of ICDs,certainpersonalitytraitsweremorecommonly decision-making tasks( ineffective copingskillsandinabilitytoperformwellin include obsessive-compulsive symptoms, novelty seeking, Other traitspotentiallyrelatedtoICDdevelopment an ICD,ascomparedtothosewhodidnot( was significantlyhigherinPDpatientswhodeveloped depressive oranxietytraitsonpsychological surveys the prevalenceofadepressiveoranxietydisorder prevalence ofanICDinseveralstudies( 24 Review ). Similarly, inthesystematicreviewbyGrall-Bronnec, 32 25 ). Such a relationship was not observed in the inthe ). Sucharelationshipwas not observed ). Indeed,theaffinityofbothdopamineagonists 25 In theFDAreport,strongestsafetysignal ). Bothdrugsshareapreferentialaffinityfor 32

26 Different studies concluded that a ). A positive non-linear dose–response ). Apositivenon-lineardose–response ). The influence of treatment duration ). Theinfluenceoftreatment duration 27 ). In another survey investigating investigating ). Inanothersurvey 19 21 , I 21 n a multicenter cross-sectional n amulticentercross-sectional ). ). Whenlookingatsubtypes 19 ). Certainstudies,butnot M Barakeandothers 19 19 ). ). 19 19 ). Namely, , 21 , 26 ). psychiatrist. It has been proposed that all patients who with cautionandclosefollow-upbythepatients’ individuals withaffectivedisorders,DAsshouldbeused higher predisposition to develop an ICD, including as thebestfirststepinmanagement.Inpatientswith Prevention oftheoccurrenceanICDcanbeconsidered Management dose–effect relationshipbutnoclearcut threshold( positively associatedwithICDprevalence,asignificant treatment doseanddurationwereindependently of PDpatientsonDAsclarifiedthisassociation.Both studies wereinconsistent,arecentlongitudinalfollow-up correlation ( ICD occurrence, while others did not find a significant showing arelationbetweenlongertreatmentdurationand trials includedinasystematicreview, withsomestudies on theriskofanICDwasinconsistentamongretrieved adverse effects( and eachmedicationisassociated withitsownpossible use ofthesespecificmedications havebeeninconsistent, inhibitors andatypicalantipsychotics. Effectsfromthe as antidepressantdrugs,including serotoninreuptake dugs, includingvalproicacidandtopiramate,aswell who developedanICDcomprisecertainanti-epileptic options ( behavioral therapy and specific pharmacological with possibleexacerbationoftheICD( However, more recentreportshadinconsistentresults discontinuation ofDAtherapypost-operatively( a suitablesolution,mainlybyallowingreductionor Initial casereportssuggestedthatthismethodmaybe to helpwithICDcontrolyieldedcontroversialresults. stimulation totreatPDwhilecuttingbackonDAtherapy the occurrenceofDAwithdrawalsyndrome( come attheexpenseofmotorfunctiondeteriorationand after treatmentdiscontinuation( on ICDsinPD,resolved50%ofpatients1 year of theICD( with remissionorsignificantsymptomaticimprovement DA orstopit.Thishasbeenassociated,incertainstudies, first considerationwouldbetodecreasethedoseof financial andsocialproblems( allow earlydetectionbeforetheoccurrenceofsignificant be counseledaboutthispotentialsideeffect, in orderto are prescribedaDAaswelltheirfamilies(ifpossible) impulsivity Dopamine agonistsand Other potentialtherapeuticoptionsincludecognitive Attempts atresortingtosubthalamicdeepbrain In theeventthatanICDoccursinaPDpatient, 19 ). MedicationsadministeredtoPDpatients 21 19 , ). While the findings of cross-sectional ). Whilethefindingsofcross-sectional 19 33 , ). Inthelongitudinalfollow-upstudy 21 , 30 Downloaded fromBioscientifica.com at10/01/202102:27:31AM ). 30 ). 29 ). However, thismay 179 35 :6 ). 19 ). 29 R290 ). 34 via freeaccess ). European Journal of Endocrinology cabergoline; EDT, ExperientialDiscounting Task; MIDI,MinnesotaImpulseDisorderInterview. BART, BalloonAnalog RiskTake; BIS11,BarrattImpulsivenessScale; BIS/BAS,BehavioralInhibition/ActivationSystem;BRC,bromocriptine; CAB, questionnaire. *Four-part questionnaireincluding:Modifiedhypersexuality questionnaire,MIDI,modifiedSouthOaksGamblingScreen, punding Bancos Barake Martinkova Author, year Table 1 are stilllacking.Currentevidenceismostlyderivedfrom of ICDsinDA-treatedhyperprolactinemicindividuals gambling whenswitchedtocabergoline( treated withbromocriptine,andsubsequently, compulsive aged womanwhodevelopedcompulsiveshoppingwhile 39 with bromocriptineaswellcabergolineuse( were reportedthereafter, inbothmenandwomen, baseline afterwithdrawaloftheDA( with cabergoline( was a50-year-oldmanwithmicroprolactinomatreated and hypersexualitydespitelowtestosteronelevels;this a secondcaseofICDinpatientwithpathologicgambling stopping themedication( cabergoline ( afterstarting who developedpathologicgambling1 year reported on a 38-year woman with a microprolactinoma hyperprolactinemia wasfirstpublishedin2007.Davie An association between DA use and impulsivity in Prevalence Impulse control disorders inhyperprolactinemia 2014 ( 2014 ( et al Review , 40 Accurate epidemiologic surveys ontheprevalence Accurate epidemiologicsurveys ., 2011( , 44 43 et al. et al 41 ) ) Studies onimpulsecontroldisordersorimpulsivityinhyperprolactinemia.

). Interestingly, Almanzarreportedonamiddle- ., , 42 36 ) Cross-sectional Cross-sectional Cross-sectional Study design ). Her symptoms resolved 2 months after ). Hersymptomsresolved2 months group) (1 control groups) (2 control 37 ). Similarly, hisbehaviorreturnedto

36 ). In2009,Falhammarreported

participants Number of M Barakeandothers 37 147 30 20

). Afewothercases

38 ). Four-part screening Self-report Screening ICD Screening methodfor positive answers patients with interview of survey* +telephone by postal questionnaire sent (BART/EDT) based tests 11) +computer- (BIS/BAS, BIS questionnaires (MIDI) questionnaire et al 38

, .

despite thelackofevidentICDs( the attentionsubscaleofBarrattImpulsivenessScale, with DAshadahigherscoreinonemeasureofimpulsivity, questionnaires andcomputer-basedtasks.Patientstreated validated psychometrictests,includingbothself-report ( lesionsandnormoprolactinemia one withpituitary untreated hyperprolactinemia( on DAs compared to two control groups, one with for impulsivity, including10hyperprolactinemicpatients an ICD( ( consecutive patientswithprolactinomastreatedDAs toscreenforICDsintwenty used astructuredinterview hyperprolactinemia ( 3.5% oftheseeventsoccurredinpatientstreatedfor of DA-associatedICDsreportedtotheFDAfoundthat studies. In2014,aretrospectiveanalysisof1580events retrospective reviews,casereportsandcross-sectional with non-functioning adenomas (mean age 56.9 years) ( with non-functioningadenomas(meanage56.9 years) years),ascompared to 70patients (mean age 54.6 with prolactinomascurrentorpastuseofDAs survey, Bancos impulsivity Dopamine agonistsand n 42

= ) ( 10) inacross-sectional pilot study( In subgroup ICD prevalence NA 2 (10%) ICD patients with Number of 3.7% (27.7% vs not onDA men onDAvs prevalence in analysis, ICD 17.1% (24.68% vs on DA on DAv/snot al 1 Table (%) 42 P ). In2014,weformallyscreened30individuals =0.01) P =0.03) ). Two patients(10%)werediagnosedwith et al . evaluatedimpulsivityin77patients No association 53% onCAB(median Positive association All patientsexcept1 Quinagolide Bromocriptine Cabergoline DA type/dose DA between type/dose 26.25 mg/week) BRC (mediandose 1 dose dose andEDTscore between cabergoline 1.1 mg) on CAB(meandose 150 µg/day 7.5–15 mg/day 4 mg/week 25 mg/week), 29%on

Downloaded fromBioscientifica.com at10/01/202102:27:31AM ). In2011,Martinkova

43 n ). Inparallel,inapostal

= 10) andasecond 179 https://eje.bioscientifica.com :6 Hypersexuality Higher scorein Hypersexuality Pathologic Compulsive ICD type vs notonDA more withDA significantly 11 subscale ofBIS the attention gambling eating 43 ). We used R291 t al et 44 via freeaccess ). .

European Journal of Endocrinology https://eje.bioscientifica.com of theprolactinoma,four patients inthesamestudy either testosteronereplacement orsurgicalresection despite asimilarincreasein testosteronelevelsthrough this patientpopulation( potentially contributetothe higherhypersexualityin to improvementinerectilefunction,whichcouldalso in prolactinlevelsinducedbyDAtherapymaycontribute testotoxicosis’ ( hypersexuality. effect wastermed‘dopa- Thisobserved of rewardpathwaysbytheDAmighthaveinduced levelstonormal,alongwithstimulation that therelativelyrapidincreaseandrestoration of disruptive hypersexuality( were treatedwithaDAandsubsequentdevelopment of recently reportedoneightmenwithprolactinomaswho by DeSousa hypersexuality andmalegenderhasbeenhypothesized was foundbetweenwomeninbothgroups( adenomas. Concurrently, nodifferenceinICDprevalence likely todevelopanICDthanmenwithnon-functioning prolactinomas treatedwithaDAwere9.9timesmore recounted byBancos occurrence ofanICDinassociationwithDAswas Patient related Risk factors or moreICDs,assuggestedintheliterature( testosterone replacement( had hypogonadism,whichwasappropriatelytreatedwith Only one out of the ten patients reporting hypersexuality different fromthenon-functioning adenoma group( ICD and the only type whose prevalence was significantly al et cannot bedefinitivelyestablished.InthestudybyBancos commonly inducedbyDAsinprolactinoma patients hypersexuality. WhethertheseparticularICDsaremore Case reportsmainlydescribedcompulsivegamblingand gambling, shopping,eating,pundingandhypersexuality. prolactinomas treated with DAs, including compulsive association withtheuseofaDA( men, butnotwomen,hadahigherICDfrequencyin associated withDAuse( studied accordingtothetypeofICD,hypersexualitywas (24.68%) than in the control group (17.1%). When was non-significantly higherinDA-treated patients and 26.25 The medianweeklydoseoftheDAwas1 Review A potentialassociationbetweenaspecifictypeofICD, A varietyofICDtypeswerereportedinpatientswith ., hypersexualitywasthemostcommonlyreported mg forbromocriptine.TheprevalenceofICDs t al. et 45 ). Itwasalsosuggestedthatadecrease A strikinggendereffectonthe ( et al. 45 ). Inacaseseries,theauthors P ( 45 45 44

= 44 0.03). Insubgroupanalysis, , ). Theauthorshypothesized ). Patientscandevelopone ). Intheirsurvey, menwith 46 M Barakeandothers ). Ontheotherhand, 44 ). mg forcabergoline 44 37 ). , 38 , 41 44 ). ). control group( betweenpatientstreatedwithDAsandthe observed difference intheprevalenceofpsychiatricdisorderswas studybyBancos cross-sectional observational have aknownpsychiatricbackground.Similarly, inthe DAs ( compulsive shopping, then compulsive gambling on ofdepressionwhoinitiallydeveloped woman withhistory disorders isnotclear. Almanzarreportedonamiddle-aged with certainpredisposingpsychologictraitsorpsychiatric replacement ( patients with hypogonadism who receive testosterone has beennoevidenceofhypersexualitydevelopingin normal testosterone levels. It should be noted that there ICD didnothavehypogonadismatbaselineandhad the DA.Moreover, twopatientswhodevelopedthis the causativefactorforICDwaslikelyexposureto showed noevidenceofhypersexuality, suggestingthat as compared to PD, whereinDAs commonly used explain thelowerICDprevalence inhyperprolactinemia, are relativelyselectiveD2agonists, whichmightpartly prevalence of ICDs. Both cabergoline and bromocriptine compared toD2receptors, isassociatedwithahigher been postulatedthathigheraffinitytoD3receptors, as treatment durationhasnotbeenclearlyestablished.It versus anotherandataspecificdosethresholdorcertain Whether ICDsareinducedmorefrequentlybyoneDA is alsousedinthetreatmentofhyperprolactinemia. United States,quinagolide,anon-ergotdopamineagonist, and fewersideeffects( cabergoline duetohigherefficacy, easierdosing schedule and cabergoline,withageneralpreferentialuse of treatment of hyperprolactinemia include bromocriptine Treatment related tumor sizeorprolactinlevelandICDrisk. prolactin levelswithoutanevidentrelationshipbetween with eithermacro-ormicroprolactinomasandvariable Disease related starting cabergoline( gambling, majordepressionandparanoiddelusionsafter reported byDaviewasdiagnosedwithbothpathologic unmasked bytheDAtherapyisnotclear. Thepatient disease orapredispositiontodeveloponethatwas with theICD.Whethertheyalreadyhadanundiagnosed are newlydiagnosedwithapsychiatricproblemalongside impulsivity Dopamine agonistsand Whether ICDsoccurmorecommonlyinpatients 38 ). Otherreportedcasesintheliteraturedidnot 47 44 ). ). Someprolactinomapatients,however, ICDs have been reported in patients 36 In manycountries,DAusedinthe 1 ). ). Incertaincountriesoutsidethe Downloaded fromBioscientifica.com at10/01/202102:27:31AM 179 :6 t al et R292 ., no via freeaccess

European Journal of Endocrinology including maritaldiscord( developed problemsintheir personalrelationships, eight menreportedwiththis ICDondopaminergictherapy implications ofhypersexuality aremany. Sixoutofthe and bankruptcy( financial burdens,includingmajorlosses,debts or gamblingareoftenassociatedwithsignificant personal and/orprofessionallife.Compulsiveshopping behaviors thatcouldbedetrimentaltothepatient’s In manyinstances,DA-inducedimpulsivityresults in Implications years thereafter( treatment initiation ( occurrence ( treatment durationandimpulsivityscoresorICD their hypersexualitywithDAdosereduction( ( therapeutic dosemayhelpalleviateincreasedimpulsivity risk of ICD ( no relationshipwasfoundbetweentreatmentdoseand with highertreatmentdose( test andcabergolinedose,indicatinghigherimpulsivity performance intheExperientialDiscountingTask (EDT) pilot study, anegativecorrelationwasobtainedbetween ICD increaseswithdoseescalationisnotclear. Inour 15–25 12 men).Menwhoweretakingbromocriptineon with mostpatientsbeingon0.5–1 DAs, patients were on cabergoline (0.5–2.25 Similarly, inthecaseseriesofmenwithhypersexualityon a relativelylowdoseofcabergoline(0.5–1 developed hypersexualityintheBancosstudy, sixwereon commonly useddosesofDAs.Amongthetenpatientswho the literature,increasedimpulsivitywasreportedat range ofDAsusedinhyperprolactinemia.Indeed, reported withquinagolide( Pathologic gamblingandhypersexualityhavealsobeen sequentially withthesuccessiveuseofbothdrugs( one casestudy, twodifferentICDswereinduced available withbothcabergolineandbromocriptine.In DA-induced impulsivityinprolactinomapatientsare receptor subtypes(D1,D4,D5)( affinity andhavelowerforotherdopamine cabergoline also bind D3 receptors with substantial D3 receptors( (pramipexole andropinirole)havepreferentialaffinityfor 40 Review ). Fouroutofeightmenhadadecreaseorresolution In available studies, no relation was observed between In availablestudies,norelationwasobserved ICDs seemtooccuracrossthetherapeuticdose mg daily( 43 44 19 , 44 ). On the same matter, decreasing the 36 , 45 25 36 ). ICDswerebothreportedsoonafter , ). Whetherthe risk ofdevelopingan 37 ). However, bothbromocriptineand , 45 37 , 38 ) (De Sousa 2017) or months to , , 38 45 42 40 , ). Theyoftenhadfinancial , , 43 45 45 41 M Barakeandothers ). IntheBancosstudy, ). ). ). Similarly, the social 48 mg weekly(5outof ). Casereportson mg weekly)( mg weekly), 45 ). 44 38 ). ). agonist ( several (up to 3) months after stopping the dopamine behavioral changes and cessation of impulsive behavior reported intheliterature,whereinpatientshaddramatic success ofthismanagementstrategyisconsistentwithcases recognized istostoporatleastdecreasetheDAdose.The However, thenextbeststep,onceconditionis management of patients withDA-induced impulsivity. There arenopublishedtreatmentguidelinesforthe Management use andgambling( incited byhighrisksexualbehavior, includingillegaldrug online dating.Fewpatientsalsohadillicitactivities losses fromreducedworkperformanceandsometimes , topiramate,valproate andzonisamide( and appearedtobebeneficial incasestudies,including developing impulsivity, fewmedicationshavebeentried been usedinhyperprolactinemic patients.InPDpatients pharmacologic therapiestargeting impulsivityhavenot however, had additionalaffectivesymptoms( by Daviealongsidetostoppingcabergoline;hispatient, uniformly effective.Escitalopramwastemporarilyused condition ( needed due to the significant psychosocial burden of the therapy (CBT)( These includepsychotherapyandcognitivebehavioral help inthemanagementofDA-inducedimpulsivity. two patientswithhypersexuality( DA dosereduction,asreportedinafewcases,including or completeresolutionoftheICDmaybepossiblewith replacement), dependingontheclinicalscenario( replacement (includingoralcontraceptivesorandrogen orhormone surgery may includetranssphenoidalpituitary forDAwithdrawal ( treatment strategiesshouldthenbeconsideredwhile adenoma afterwithdrawalofDAtherapy. Alternative potential increase in size of a prolactin-secreting pituitary consequences ofrecurrenthyperprolactinemiaor or cessation on ICDs have to be balanced against the the managementofpatientswhodevelopICDs. of DAtherapyappearstobethemosteffectivestrategyin cabergoline andbromocriptine( seem beneficial, asICDshavebeenreportedwithboth the DA( ICDs maypersistinsomepatientstakinglowdosesof reduction alone may not be sufficient in other cases, as impulsivity Dopamine agonistsand Additional non-pharmacologictherapiesmight However, thebeneficialeffectsofDAdosereduction 45 36 ). SwitchingfromoneDAtoanotherdoesnot , 40 37 ). Specificpsychotropictherapiesarenot , 40 45 37 ). Family interventions mayalsobe ). Familyinterventions ). Similarly, adecreaseinimpulsivity , 45 Downloaded fromBioscientifica.com at10/01/202102:27:31AM ). 36 , 38 37 40 , , , 179 42 40 45 https://eje.bioscientifica.com ). Thus,cessation :6 ). Suchmeasures ). However, dose 36 ). Specific 1 19 R293 , 2 , 40 , 3 via freeaccess ). ). European Journal of Endocrinology https://eje.bioscientifica.com more closely. In addition, longitudinal follow-up is caregivers to identify patients at risk and follow them to thedevelopmentofthis adverseeventwouldhelp hyperprolactinemia. Establishing risk factors predisposing the occurrenceofimpulsivityandICDsinpatientswith variable treatmentdosesareneededtobetterunderstand Longitudinal, prospectivestudiesoflargersamplesizeand Future directions identified problem. awareness amongpatientsandprovidersofthisrecently Updating theseimportantreferenceswouldhelpraise to developanICDwithintheirprescribinginformation. package insertsdonotcontainawarningonthepossibility events withdopaminergictherapy( of prolactinomasdonotaddressICDsaspotentialadverse prevention ofseriousconsequences. and physician, hopefully resulting in early intervention then bepromptlydetectedandreportedtothetreating for use in hyperprolactinemia ( questionnaire forICDscreeninginPDcouldbevalidated them withtheirphysicians( and thepossiblereluctance of patients to openlyaddress and sensitivenatureofsomeICDs,suchashypersexuality, reduce communicationdeficitsarisingfromthepersonal during clinicvisitsmayevenbeconsideredandcould questionnaires toscreenforheightenedimpulsivity during follow-up. The use of written then regularlyquestionpatientsaboutthispotential to impulsivitypriorinitiationofaDA.Theyshould patients andtheirfamiliesaboutpossiblebehaviorsrelated aware ofthispossibleadverseevent. or at least mitigated if both clinicians and patients are developing anICDonDAtherapycanonlybeprevented The potentiallydevastating,yetreversible,effectsof Awareness andprevention(implicationsforpractice) mitigate hyperprolactinemia( thathaspartialDAactivityandmayoften prolactin secretion.Ofnote,however, aripiprazoleisan antagonists wouldbecounterproductivewithregardsto is notknown;however, theuseofmostdopamine can beconsideredinpatientswithhyperprolactinemia used withvariableresults( Selected anti-psychoticsandanti-depressantswerealso Review Current guidelinesonthetreatmentandmanagement In practice,physiciansshouldroutinelycounselboth 19 45 1 ). Whetherthesetherapies 31 ). ). Thecurrentlyavailable M Barakeandothers ). Emerging ICDs would 2 , 3 ). Similarly, DA studies aremethodologicallyconsideredtobeoflower and cross-sectionalstudies.Whilethesetypesof evidencecomesfromcasereports,retrospective primary with hyperprolactinemiaandPD. needed aswellphenotypicdifferencesbetweenpatients hyperprolactinemia andtothelowertherapeuticdoses different dopaminereceptorselectivityofDAsusedin with neurologic disorders, potentially due to the of thisadverseeventseemslowerthaninpatients heightened impulsivityandICDs.Theprevalence is associatedwiththepotentialfordevelopmentof The use of DA in the treatment of hyperprolactinemia Conclusions once itoccurs. required toidentifythebesttreatmentstrategyforanICD treatment strategies. developing ICDsaswelldevise effectivescreeningand studies areneededtobetter identifypatientsatriskof to facilitateearlydetection. Longitudinal, prospective adverse eventiscriticalamongendocrinologistsinorder alternatives. Increasingawarenessofthispotential and thepotentialrisksofmoreinvasivesurgical undoubted benefitsofDAtherapyinhyperprolactinemia (treatment cessation), canbe challenging due to the this population,thoughapparentlystraightforward patients isstillnotclear. Management of ICDsin predisposing factorsdoexistinhyperprolactinemic initiation orseveralyearsintotherapy. Whether individual receiving higherdoses,eithershortlyaftertreatment and bromocriptinetreatmentdosesamongthose been describedbothinpatientsonstandardcabergoline devastating, socialandfinancialconsequences.ICDshave ICD hasbeenassociatedwithvariable,butpotentially has beenmostlyreportedinmen.Occurrenceofan compulsive gambling and hypersexuality. Thelatter on DA therapy for prolactinomas, most commonly patients. AvarietyofICDshavebeenreportedinpatients of manifestationsICDsamonghyperprolactinemic endocrine community, possiblyrelatedtounderreporting and ICDsinhyperprolactinemicpatients. strengthens the putative association between DA therapy the association between DA and ICDs in several studies nevertheless thepresenceofconsistentfindingsregarding quality than prospective, randomized controlled trials, impulsivity Dopamine agonistsand In thecaseofhyperprolactinemicpatients, Awareness ofthisproblemislikely low inthe Downloaded fromBioscientifica.com at10/01/202102:27:31AM 179 :6 R294 via freeaccess European Journal of Endocrinology References final version. All authorsparticipatedindraftingthismanuscriptandapprovedofthe Author contributionstatement the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagencyin Funding perceived asprejudicingtheimpartialityofthisreview. 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