Copyright© AE&M all rights reserved. 236 10 10 (UFMA), SãoLuís,MA,Brasil Universidade Federal doMaranhão Universitário Presidente Dutra, 9 Paulo (FMUSP),SãoPaulo, SP, Brasil Medicina daUniversidade deSão dasClínicas,FaculdadeHospital de 8 Porto Alegre, RS, Brasil do RioGrandeSul(UFRGS), Medicina, Universidade Federal PPG Endocrinologia,Faculdade de deClínicasPortoHospital Alegre, 7 HC-FMUSP), SãoPaulo, SP, Brasil da Universidade deSãoPaulo (IPq- das Clínicas,Faculdade deMedicina Instituto dePsiquiatriadoHospital 6 (SEMPR), Curitiba,PR,Brasil Universidade Federal doParaná deClínicas, Hospital Metabologia, 5 (UnB), Brasília,DF, Brasil Brasília, Universidade deBrasília Universitáriode do Hospital 4 Joinville, SC,Brasil Diabetes deJoinville (Endoville), 3 (Unifesp/EPM), SãoPaulo, SP, Brasil Universidade Federal deSãoPaulo Escola Paulista deMedicina, 2 (UFPE), Recife, PE,Brasil Federal dePernambuco dasClínicas,UniversidadeHospital 1 review DOI: 10.20945/2359-3997000000032 on Aug/9/2017Accepted Received onFeb/3/2017 [email protected] 50670-901 –Recife, PE,Brasil Cidade Universitária Av. Prof. MoraesRego, 1235, deMedicinaClínica Departamento dasClínicas, Hospital Lucio Vilar Correspondence to: Belo Horizonte, MG,Brasil Federal deMinasGerais(UFMG), dasClínicas,UniversidadeHospital 15 Horizonte, MG,Brasil de Belo Horizonte, Belo Casa Santa e Metabologia, 14 Ceará (UFCE),Fortaleza, CE,Brasil Cantídio, Universidade Federal do Universitário Walter Hospital 13 Campinas, SP, Brasil de Campinas(FCM/Unicamp), Médicas, Universidade Estadual Médica, Faculdade deCiências 12 Niemeyer, RiodeJaneiro, RJ, Brasil Instituto doCérebroPaulo Estadual 11 Rio deJaneiro, RJ, Brasil do RiodeJaneiro (HUCFF-UFRJ), Fraga Filho,Universidade Federal Universitário Clementino Hospital Serviço de Endocrinologia, Hospital deEndocrinologia,Hospital Serviço Serviço deEndocrinologia, Serviço deEndocrinologia, Serviço Divisão deNeurocirurgia Funcional, deEndocrinologiae Serviço deEndocrinologia Serviço Centro deEndocrinologiae Unidade deNeuroendócrino, deEndocrinologia, Serviço Unidade deNeuroendocrinologia, Serviço deEndocrinologia, Serviço Serviço deEndocrinologia, Serviço deEndocrinologia Serviço deEndocrinologia, Serviço deClínica Departamento Controversial issuesinthe surgery; temozolomide surgery; Hyperprolactinemia; prolactinomas;pseudoprolactinomas;macroprolactin;hook-effect; dopamineagonists;pituitary Keywords experience. the literatureandauthors’ issuesregardingemphasizing controversial thesetopics. This reviewisbasedondatapublishedin is toprovide areviewofthediagnosisandtreatmenthyperprolactinemia andprolactinomas, Neuroendocrinology Department oftheBrazilianSociety ofEndocrinologyandMetabolism(SBEM) cases ofmicroprolactinomasandinselectedMACs. Inthispublication,thegoalof bromocriptine. After of successful treatment, DA 2 years withdrawal should be considered in all for prolactinomas,particularly cabergoline,which ismoreeffective andbetter toleratedthan apparent idiopathichyperprolactinemia. Dopamineagonists(DAs) arethetreatmentofchoice The screeningformacroprolactinismostlyindicatedasymptomaticpatientsandthosewith so-called “hook effect”. Patients harboringcysticMACs mayalsopresentwithamildPRLelevation. among patientswithmacroprolactinomas(MACs), artificially lowPRLlevelsmayresultfromthe with PRLlevels<100 ng/mL.However, exceptionstotheserulesarenotrare.Ontheotherhand, patients with stalk dysfunction,drug-induced hyperprolactinemia orsystemicdiseasespresent ofthe presence ofaprolactinoma.Incontrast,most PRL levels>250ng/mL are highly suggestive prolactin (PRL) elevation can be useful in determining the etiology of hyperprolactinemia. Indeed, represent animportant cause ofhypogonadism andinfertility inbothsexes. The magnitudeof Prolactinomas arethemostcommonpituitaryadenomas(approximately 40%ofcases),andthey ABSTRACT Camila Viecceli Luciana A.Naves Monica R. Gadelha Mauro A.Czepielewski Luiz AugustoCasulari Luiz Antônio Araujo Lucio Vilar and Metabolism Society ofEndocrinology oftheBrazilianDepartment by theNeuroendocrinology and prolactinomas – An overview management ofhyperprolactinemia Paulo A. C. Miranda HelaneGurgelMaria 1 ,Julio Abucham 7 , Marcello D. Bronstein 4 , Antônio Ribeiro-Oliveira Júnior 3 10,11 14 , MonalisaF. Azevedo 13 , RenanM. Montenegro 4 , Malebranche B. C. CunhaNeto 7 , RaquelS. Jallad , Heraldo M. Garmes , Felipe H. G. Duarte 2 , José Luciano Albuquerque Arch EndocrinolMetab. 2018;62(2):236-63 8 8 , ManoelMartins 4 , CesarLuizBoguszewski 8 12 , Manuel dosS. Faria 13 ,Glezer Andrea , NinaR. C. Musolino 15 , CíntiaM. S. Silva 6 Arch Metab. Endocrinol 2018;62/2 , 1

, 13

,

8 ,

9 ,

6 5 , ,

10 ,

Arch Metab. Endocrinol 2018;62/2 may be direct (14).In addition,there GnRH release inhibition of hypothalamic through pulsatile secretion gonadotropin PRL levels decrease (1,3,7). Increased hypogonadismandgalactorrhea to hypogonadotropic thoserelated are in patientswithhyperprolactinemia Adapted fromRef. 1. Table 1. (13). rare extremely are carcinomas secreting adenomasinthatpopulation(12).PRL- all pituitary half of adolescent ages, they account for approximately at thepediatric and rare are Although prolactinomas (10,11). equallyaffected decade oflife,bothgendersare afterthefifth and menisestimatedtobe10:1,whereas the ageof20and50years,ratiobetweenwomen inwomen(78.2%)(9).Between with ahigherprevalence adenomas, 73.3%ofallpituitary torepresent reported havebeen districtsofBelgium,prolactinomas different three population (7,8),andinafrom of60-100permillion have anestimatedprevalence tumors (2,6) In adults, prolactinomas 40% of all pituitary tumors,accountingfor approximately pituitary secreting out(4-6). (PRL)levelshavebeenruled prolactin serum thatraise pregnancy, anddrugs hypothyroidism, primary once hyperprolactinemia most commoncauseofchronic isthe axis(1-3).Aprolactinoma hypothalamic-pituitary H INTRODUCTION Drug-induced (Table 3) Macroprolactinemia • • • • • • • Pathologic • Physiologic colorectal adenocarcinoma, etc.) gonadoblastoma; non-Hodgkinlymphoma, carcinoma; uterinecervical Ectopic prolactinproduction–Renalcellcarcinoma;ovarianteratomas; Idiopathic dorsalis; extrinsictumors, etc.), breaststimulation, etc. rings; herpeszoster, ependymoma;tabes (cervical etc.);spinalcordinjury thoracotomy;nipple Neurogenic –Chestwalllesions(burns;breastsurgery; Stalk disorders–Hastitis;seccion;traumaticbraininjury sella syndrome, etc. disease; infiltrativedisorders;metastasis;lymphocytichypophysitis;empty diseases–Prolactinomas;acromegaly;thyrotropinomas;Cushing’sPituitary metastasis; cranialradiation;Rathke’s cleftcysts, etc. meningiomas, etc.);infiltrativedisorders(histiocytosis, sarcoidosis, etc.), Hypothalamic diseases–tumors(craniopharyngiomas, dysgerminomas, insufficiency; cirrhosis;pseudocyesis;epilepticseizures hypothyroidism;adrenalinsufficiency;renal Systemic diseases–Primary Pregnancy; lactation;stress;sleep;coitus;exercise The mostcharacteristicsigns andsymptomsfound themostcommonhormone- are Prolactinomas and is the most common endocrine disorder of the of the and is the most common endocrine disorder hasmultipleetiologies(Tableyperprolactinemia 1) Causes ofhyperprolactinemia Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas non-puerperal galactorrhea (19,20).Incontrast,the non-puerperal galactorrhea inupto40-50%ofall womenwith to bepresent isestimated This so-called“idiopathicgalactorrhea” PRLlevels(18,19). cyclesandnormal menstrual ofregular inthepresence non-puerperal galactorrhea with commentingthatsomewomenpresent worth tissue (3,6,7). It is pituitary ofnormal destruction stalkor ofthepituitary iscompression occur ifthere (1-3). Hypopituitarismbeyondhypogonadismcan can also occur and seizures, hydrocephalus rhinorrhea, rarely,changes, and,more fluid(CSF) cerebrospinal symptoms,suchasheadache,visual mass effect tumor In patientsharboringmacroprolactinomas, levels(17). the libidoindependentlyoftestosterone can also reduce genders (15,16). Hyperprolactinemia infertility, andlossofbonemineralmassinboth inwomen,sexualdysfunction, and amenorrhea irregularity Hypogonadism cancausemenstrual ontestesandovaries. ofhyperprolactinemia effects PRL serum levels), andimagingstudiesof the PRL serum findings (especially laboratory clinical features, into account:medicalhistory, physicalexamination, someparameters mustbetaken hyperprolactinemia, identificationofthe etiologyof For thecorrect DIAGNOSTIC EVALUATION byanIgGand monomeric PRL(2,24-29). complex formed iscomposedofa In upto90%ofcases,macroprolactin (22,23). macroprolactinemia the conditionistermed containsmostlymacroprolactin, hyperprolactinemia of a patient with total PRL (20,21). When the serum tolessthan 20%ofthe (150-170 kDa)correspond PRL (45-60kDa)andbig-bigormacroprolactin PRL (molecularweightof23kDa),whiledimericorbig ismonomeric subjects andinpatientswithprolactinomas inhealthy form Thepredominant molecular forms. ofcirculating interms The PRLsizeisheterogeneous ISOFORMS PROLACTIN SERUM thesetopics. issuesregarding controversial emphasizing andprolactinomas, hyperprolactinemia of onthediagnosisandtreatment areview provide Endocrinology andMetabolism (SBEM) is to oftheBrazilianSociety logy Department (2,18). prolactinoma inmenishighlysuggestiveofa finding ofgalactorrhea ­ In thispublication,thegoalofNeuroendocrino 237

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 238 (4). stress obtained withoutexcessivevenipuncture samplewas aslongtheserum hyperprolactinemia, thediagnosisof confirms the upperlimitofnormal of theEndocrineSociety, asinglePRLlevel above ng/mL) totheguidelines according (1).Nevertheless, clearly elevated(>80-100 the PRLlevels are unless (33) at leastonce elevated PRLlevel should beconfirmed an inhealthyindividuals(1,3).Therefore, laboratory for a particular beyond the upper limit of normality duringthedaymay possibly be its levelsmeasured (1,2,33). Moreover, episodically, asPRLissecreted stimulation forbreast mL) (32).Thesameistrue in thePRLlevel,butitisusuallymild(<40-60ng/ past (31).Venipuncture maycauseanelevation stress towhatwasbelievedinthe to sampling,contrary prior (2,3,5). However, isnotnecessary supinerest leads to the physiological elevation of PRL levels orduetoother acuteillness, induced byexercise whilethepatient is fasted(1,4). awakening, preferably Thus, samples should be collected up to 3 hours after ofPRLoccursduringthe sleepperiod. daily production conditions, rhythm. Undernormal decline after awakening, but without atypicalcircadian peakandagradual levels duringsleep,amorning theday, throughout greatly levels canvary withhigher secretion PRL on inapulsatilemanner, issecreted Prolactin andserum influences Environmental 1.1. 1. CONTROVERSIALISSUESREGARDINGDIAGNOSIS (1,3). woman ofchildbearingagewithamenorrhea (30). Finally, nomanifestationsofthisdisease are even whenthere measuring IGF-1inallpatientswithamacroadenoma, Moreover, mustbeinvestigated by acromegaly (1,3,6). causesofhyperprolactinemia out secondary T (3-5). hyperprolactinemia in casesof asymptomatic particularly considered, shouldoftenbe formacroprolactinemia screening the (1,3,5).Furthermore, andsellaturcica pituitary Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas clearly elevated (>80-100ng/mL). atleastonce,unlessthePRLlevelsare be confirmed levels, wesuggestthatanelevated PRLlevelshould PRL can increase stress manner and as venipuncture COMMENT 1: 4 , and creatinine levels should be obtained to rule levelsshouldbeobtainedtorule , andcreatinine Stress from any source, whether psychological, any source, from Stress TSH,free In additiontoPRLdetermination, β -hCG measurement is mandatory inany ismandatory -hCG measurement As PRL is secreted inapulsatile As PRLissecreted ∼ 50% ofthetotal exceptions to these rules are not rare (1,34). notrare are exceptions totheserules with PRLlevels<100ng/mL(1,4,34).However, orsystemicdiseasespresent hyperprolactinemia drug-induced dysfunction (pseudoprolactinomas), on below. Incontrast,mostpatientswithstalk be foundinotherconditions(1,34),ascommented (3-5), although they may occasionally a prolactinoma of highlysuggestiveofthepresence 250 ng/mLare (1-5,33,34).Forexample,levels> with prolactinomas inpatients observed because thehighestvaluesare theetiologyofhyperprolactinemia determining levels The magnitudeofPRLelevationcanbeusefulin prolactin of Accuracy 1.2 of the pituitary stalk(2,40).Inthatsituation, thisso- of thepituitary (NFPA), compression from results hyperprolactinemia adenoma main etiologyisanonfunctioning pituitary whose In patientswith“pseudoprolactinomas”, of cases in behave levels pseudoprolactinomas? PRL do How 1.2.1 withPRLvalues≥500ng/nL(34). presented In thisstudy, onlypatientsharboringprolactinomas 1andTable inFigure presented are whose results 2(34). (BMSH)analyzed1234patients Hyperprolactinemia (1-3). withmildPRLelevation cystic MACsmayalsopresent (1,37-39), ascommentedonbelow. Patientsharboring ormildlyelevatedPRLlevels(<200ng/mL) normal associatedwith macroadenomas (≥ 3cm)pituitary inallcasesoflarge whichshouldbeconsidered effect”, theso-called“hook from low PRLlevelsmayresult 1000 ng/mL(35,36).Ontheotherhand,artificially (maximum diameter≥4cm),PRLlevelswillbe> In thevastmajorityofpatientswithgiantprolactinomas (4-7). typically associatedwithPRLvalues>250ng/mL (MACs)(diameter≥10mm) are Macroprolactinomas (1,33,34). 500ng/mLormore occasionally reach not infrequently, theymaybe<100ng/mL,and in PRLlevelsof100-200ng/mL,but usually result (MIC)(diameter < 10mm) microprolactinomas levels usuallyparallelthetumorsize(1,4,7).Indeed, elevation. inPRL checking PRLlevelsastheymayresult before stimulation shouldbeavoidedforatleast30minutes COMMENT 2: The BrazilianMulticenterStudyon PRL circulating In patients with prolactinomas, Vigorous exercise andnipple exercise Vigorous Arch Metab. Endocrinol 2018;62/2

Arch Metab. Endocrinol 2018;62/2 NFPAs,confirmed 33to PRL levelsrangedfrom among 64patientswith immunohistochemically these patients (41).Accordingly, study, in a recent in (> 95ng/mL)isalmostnever (<2%)encountered cases (n = 226) with NFPA, PRL > 2000 mIU/L serum (19,40). Langerhans-cell histiocytosis and metastasis sarcoidosis, Rathke´scleftcysts, such ascraniopharyngiomas, alsoincludesotherconditions pseudoprolactinomas (1,40).Theterm andprognosis natural history andhaveadistinct distincttreatments they require as diagnosisofmacroprolactinomas, differential (19). NFPAson PRL secretion the principal represent ofdopamine effect lossofthe inhibitory from result is thought to called disconnection hyperprolactinemia NFPA: adenomas. Non-functioningpituitary Adapted fromRef. 34. hyperprolactinemia intheBrazilianMulticenterStudyonHyperprolactinemia Table 2. Figure 1. Primary hypothyroidism Primary NFPA Acromegaly Drug-induced Macroprolactinemia Idiopathic Microprolactinomas Macroprolactinomas Etiology Based on a large series of histologically confirmed Based onalarge seriesofhistologicallyconfirmed PRL levels according to the etiology of the hyperprolactinemia in the Brazilian multicenter study on hyperprolactinemia (Adapted from Ref. 34). Mean PRL(ng/mL) Prolactin levels (ng/mL) according to theetiologyof

1000 1200 1400 200 400 600 800 0 nomas (n=250) 180 (14.6) 250 (20.2) Macroprolacti- 115 (9.3) 444 (36) 78 (6.3) 82 (6.6) 40 (3.2) 45 (3.6)

N (%) 1422 1422.9 ±3134.7(108-21,200) nomas (n=444) Macroprolacti- Mean PRL(range)(ng/mL)

119.5 ±112.9(32.5-404) 165.6 ±255.1(32-525) 105.1 ±73.2(28-380) 163.9 ±81.8(46-328) 74.6 ±42.4(30-253) 80.9 ±54.5(28-490) 99.3 ±57.4(28-275) 165 (n =45) Idiopathic

Prolactin levelsinhyperprolactinemicpatients(n=1234) 163 Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas nemia (n=115) Macroprolacti-

119 of hypothalamic dopamine production ( of hypothalamic dopamineproduction dopamine depletion( metoclopramide, domperidone, sulpiride, etc. ( of the dopamine receptor transcription ofthePRLgene ( mechanisms:increased different act through which is the useofdrugs, hyperprolactinemia drug- The most common cause of non-physiological of cases in hyperprolactinemia? behave induced levels PRL do How 1.2.2 immunohistochemical evaluation(Table 3)(34). 82%); however, notallpatientshadbeensubmittedto 28to490ng/mL(<100in ranged from in BMSH,among82patientswithNFPA, PRLlevels 250 ng/mL(~80%<100ng/mL)(42)Bycontrast, macroprolactinomas. orinpatientswithcystic low duetothehookeffect ng/mL. However, PRL levels may be misleadingly ng/mL, andnotinfrequently, theyexceed1000 usually>250 PRLlevelsare macroprolactinomas, Bycontrast,inpatientswith exceedinglyrare. are majorityofcases.Valuesthe great >250ng/mL modestlyelevated(<100 ng/mL)in levels are (PRL) andthus,prolactin stalkcompression, from results adenomas,hyperprolactinemia pituitary COMMENT 3: Drug-induced (n =80)

105 Acromegaly (n =40)

99 In casesofnon-functioning reserpine, methyldopa Non-functioning adenomas (n =82) pituitary risperidone

80 estrogens Hypothyroidism (n =78) ), antagonism ,

), inhibition 74 haloperidol verapamil, 239 ), ,

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 240 PRL levels(45), mostoftheAAPs elicit apoor oftenassociatedwithhigh molindone, whichare the exceptionofrisperidone,amisulprideand With (45,46). toclassicalantipsychotic drugs compared side-effects andendocrinerelated fewer neurological and antipsychotic efficacy characterized byincreased (46). antipsychotics, respectively taking risperidone, olanzapine,ziprasidone, and typical in81%,35%,29%,and38%ofpatients was present antipsychotics,hyperprolactinemia patients receiving of106 (45).Inonegroup and 10%forotherdrugs antagonists, 5% for H2-receptor for antidepressants, 26% drugs, 28%forneuroleptic-like neuroleptics, class:31%for associated witheachtherapeuticdrug studies foundthefollowingratesofhyperprolactinemia (34). Other among the antidepressants representants themain were and risperidone,whiletricyclicdrugs haloperidol,phenothiazines, were involved drugs (34). Among antipsychotics, the most frequently the culpritsinalarge majorityofthecases(82.2%) (in monotherapy or in combination) were neuroleptics and (BMSH),antidepressants Hyperprolactinemia 1, 2, and3. MAO: monoamineoxidase;SSRIs: selectiveserotoninre-uptakeinhibitors. Adapted fromRefs. Table 3. fluoxetine, sibutramine),etc.(1,2,42-47)(Table 3). (opiates, fenfluramine, reuptake inhibition of serotonin cocaine, amphetamine,monoamineoxidaseinhibitors ( of dopaminereuptake heroin, morphine,enkephalinanalogs,etc. Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas • Others • Prokinetic agents • Anticonvulsivants • Antihypertensive drugs • • • Antidepressants • • Antipsychotics etc. morphine; apomorphine;heroin;cocaine;marijuana;alcohol;sibutramine, Estrogens; anesthetics;cimetidine;ranitidine;opiates;methadone; Metoclopramide; domperidone;bromopride Phenytoin Verapamil; SSRIs –Fluoxetine;citalopram;paroxetine MAO inhibitors–Pargyline;clorgyline Tricyclics – Amitriptyline; desipramine;clomipramine Atypical –Risperidone;molindone;amisulpride;quetiapine;olanzapine Typical –Phenothiazines;butirophenones;thyoxanthenes The newer atypical antipsychotics (AAPs) are The neweratypicalantipsychotics(AAPs)are In theBrazilianMulticenterStudyon Drug-induced hyperprolactinemia α -methyldopa; reserpine;labetolol tricyclic antidepressants, ), inhibition ), ng/mL) in cases of drug-induced hyperprolactinemia, hyperprolactinemia, ng/mL) incasesofdrug-induced on PRLlevels(44,47). appeartohavenoeffect andmirtazapine, bupropion including PRL level (50). Atypical antidepressants, with38ng/mLbeingthehighest hyperprolactinemia, withfluoxetine,only10(12.5%developed treated (46).Among80patients PRL toasignificantdegree elevate ofpatients,buttheyrarely small proportion risperidone (49). when aripiprazolewasusedasadjuncttherapyto Moreover, also reported PRL levels were decreased inducedbyotherAAPs(48). the hyperprolactinemia of agonist) wasshowntobeassociatedwithresolution as quetiapineandaripiprazole(adopaminepartial such theuseofdrugs at all(43,45,46).Furthermore, ornohyperprolactinemia response hyperprolactinemic its interaction and may compromise the appropriate theappropriate its interaction andmaycompromise influences antigen-to-antibody proportion relative orchemiluminescentmarker.either afluorescent The a“sandwich”testusing be quantified,thusforming epitopes of the PRL to antibodies bind to different a secondantibodyislabeled asignalgenerator. These immobilizedinasolidphase,and antibodies thatare capture through usuallyperformed They are measurements. sensitivity ofPRLandotherhormone PRL in the improved Immunometric assays have greatly issues practice? linearity our and impact effect assays hook the do How 1.2.3 range (51). domperidone discontinuation,PRLfelltothenormal withdomperidonefor3months. Following treated inayoungladywhohadbeen reported recently were (Table 3) (34).Interestingly, PRL levels of 720ng/mL 250 ng/mL(range,28-380;mean,105.1±73.2) PRL levels<100ng/mL,butin5%,theyexceeded with intheBMSH,most(64%) presented enrolled levels > 200 ng/mL (1,43-46). Among 180 cases risperidone, and phenothiazines can lead to prolactin it isalsohighlyvariable.Indeed,metoclopramide, overlap thosefoundinpatientswithprolactinomas. largelylevels < variable 100 and ng/mL, may they are isusuallyassociatedwithPRL hyperprolactinemia COMMENT 4: AlthoughPRLelevationisusuallymild(25-100 in a induce hyperprolactinemia Antidepressants Although drug-induced Although drug-induced Arch Metab. Endocrinol 2018;62/2 according to the reportable reference range of an assay reference to the reportable according workers. This means that, of laboratory the discretion at performed byphysiciansare that dilutionsordered (1,2,38).However,normal tomention it isrelevant PRL levels<200ng/mL, even ifthePRLlevelsare ³3cmandinitial in allpatientswithmacroadenomas forPRLmeasurements that dilutionsmustbeordered Inclinicalpractice,thismeans to beoverconcentrated. dilutionfor allPRLsamplessuspected forget toorder ofthe phenomenon sotheydonot aware they are that important Thus,itisextremely the hookeffect. out basistorule cannot diluteallsamplesonaroutine adenomas (1,4,37,38). lowincasesofnon-functioningpituitary remaining in PRLlevelsifthepatienthasamacroprolactinoma, in a dramaticrise (1,4). Indeed,thisstepwillresult at 1:100isthetestofchoicetounmaskthishookeffect systems usedinclinicalpractice.Dilutionofthesample Arch Metab. Endocrinol 2018;62/2 concentration ismeasuredaslow(AdaptedfromRef. 39). most of theantigen is lost with the signal antibody; thus, antigen prevent “sandwich”formation. antigen concentrations saturate both capture and signal antibodies and Figure 2. range (52,53). reference often, slightly above the manufacturer´s usuallywithinor, are results more and thereported phenomenon, also known as the prozone hook effect, iscalledahigh-dose Thisartifact higher thanreported. forthePRLconcentrationismuch result and thecorrect reported, are falselylowresults 2). Therefore, (Figure subsequently washed away antibody instead and are boundtojustone most ofthePRLmoleculesare complex tobequantifiedbythetest.Inthatsituation, actually bound in a sandwich a few PRL molecules are andthelabeledantibody when only both the capture high concentrations of PRL can simultaneously saturate oftheimmunocomplexes. Thus,extremely formation Physicians shouldkeepinmindthatlaboratories assay betweenthedifferent differs The hookeffect Schematic depictionof “hook effect.” Antigen concentrationextremelyhigh “Sandwick” Sinal antibody Antigen Capture antibody Right , When liquid phase isdiscarded, Left , Extremelyhigh Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas PRL samples coming from patients with untreated patientswith untreated PRL samplescomingfrom tothemanufacturer, 0.25-200ng/mLaccording from PRLranging (54). Inagivenassaywithreportable byclinicians confused withassaylinearityproblems the incidenceofthisphenomenon(53,54). hook theassay, and thisfacthasdramaticallydecreased to usuallynecessary highlevelsofPRLare extremely Fortunately,in measurements. withthenewerassays, dilutionsusuallycausealossofaccuracy that unnecessary itisnoteworthy 200,680 ng/mL(53).Inthisregard, tohaveaPRLvalue higherthan improbable as itisvery enoughtodetectthephenomenon, should besufficient dilution of 1:10 means that a starting this theoretically to beinducedupaPRLvalueof20,680ng/mL, isnot supposed to its manufacturer, thehookeffect For instance,consideringanassayinwhich,according at1:10. manufacturer, dilutionsmayoccasionallystart bytherespective levelsofhookeffect and itsreported argued that the binding of PRL to their receptor could argued thatthebindingof PRLtotheirreceptor (58,59). Others imaging (58) or specific treatments sellar asymptomatic (56,57), with no need to perform with macroprolactinem bythefindingthatin mostseries This iscorroborated was showntodisplaylowbiological activity(28,29,55). (1,29). Inmostofthe PRLismadeupofmacroprolactin 60% ofcirculating just or than more isaconditionwhere Macroprolactinemia routinely individuals? screening: asymptomatic in Macroprolactinemia 1.3 (53,54). measurement reported effect theobserved Otherwise, range oftheassayisreached. manually,performed anduptothepointthatlinear dilutions,evenifithastobe assays thesampleatfurther re- untilthelaboratory treatment starting from refrain cliniciansmust result. Therefore, quantification ofthe ofexact oftheimportance notaware seems thattheyare of“>2000ng/mL”,andit aresult releases laboratory 1:10 issuperimposed.Inthiscase,itcommonthatthe range,evenwhenanautomaticdilutionof reportable mayoftenfalloutof this macroprolactinomas within the normal rangeoronlymodestlyelevated within thenormal levels andprolactin macroadenoma (≥ 3cm)pituitary withalarge patientpresenting inevery considered COMMENT 5: Interestingly, hasoftenbeen thehookeffect of a treatment may be misled due to an inexact of a treatment The hook effect shouldbe The hookeffect in vitro ia, individuals are pauci- or ia, individuals are studies, macroprolactin studies,macroprolactin . 241

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 242 8to42%,withamean of individuals, it ranged from among hyperprolactinemic both genders (67), whereas 3.7% in a total of 1330 Japanese hospital workers of Scandinavia(66)and shown tobe0.2%inwomen from inthegeneralpopulationwas of macroprolactinemia (5).Thefrequency prolactin ofpituitary secretion the dopaminergic tone,whichnegativelyregulates life and lower capability to activate hypothalamic clearance,longerhalf- may beduetoitslowerrenal significant (65). isstill number ofsamplesdefinedasmacroprolactin however, withmacroprolactin; the cross-reactivity demonstrated thatsomeofthenewassaysshowlower (64). Ithasbeen differently macroprolactin method thatcannotbeusedroutinely. However, itisanexpensive and time-consuming withPEGisinconclusive (58,63). when screening andistheonlyway ofassessment the PEGprecipitation wellwith by gel filtration,which correlates isoforms diagnostictestistheseparationofThe goldstandard inatleast80%ofcases(56,63). macroprolactinemia diagnosisof enablesthecorrect PEG precipitation (56,58). Overall, monomeric hyperprolactinemia >60%pointtothediagnosisof recoveries whereas ofmacroprolactin, indicativeofthepredominance are (58,60).Recoveries <40% after PEGprecipitation monomericPRLvalues ofnormal standardization hence the needfor precipitation, also suffers However,in thesupernatant. somemonomericPRL PEG, andonlymonomericPRLwillberecovered Theoretically, with isprecipitated macroprolactin due toitslowcostandeasyworkability(63). macroprolactinemias used methodforscreening with polyethyleneglycol(PEG)isthemost dysfunction(62). (1,2), orpsychogenicerectile (61),idiopathicgalactorrhea syndrome polycystic ovary withother conditions, suchas macroprolactinemia theconcomitanceof from of symptomscouldresult (59).Moreover,of hyperprolactinemia thepresence management foran etiologicdiagnosisfortheproper withclinicalsymptomsandtheneed hyperprolactinemia levels ofmonomericPRL,leadingto“true” with high alsopresent macroprolactin, increased the originalmolecule(60). of structure be blockedbymodificationofthetertiary Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas Hyperprolactinemia related to macroprolactin tomacroprolactin related Hyperprolactinemia assaysrecognize thatdifferent It isnoteworthy and after precipitation PRL before Assaying serum However, individualswho,despite are there ​​ clinical suspicionofmonomerichyperprolactinemia, the testsconfirm Iflaboratory PRL measurement. hypogonadism andinfertility, leadingtoserum suchasgalactorrhea, tohyperprolactinemia, related complaints are in twoscenarios.Atfirst,there ofmacroprolactinemia? presence be actively investigated for the hyperprolactinemia Shouldall individuals with with macroprolactinemia? inanindividualpresenting assessment andtreatment withanadditional clinical practice:whatistheprobability issuein becomesanimportant macroprolactinemia of (58).Thishighfrequency laboratory a reference (76)and46%in113casesfrom hyperprolactinemia of16.5%in115consecutivepatientswith frequencies As anexample,twoBrazilianstudieshaveshown individuals. inhyperprolactinemic macroprolactinemia of population may explainthevariationin the frequency series(56,68-75).Thestudy 19.6%, in8European (mPRL: monomeric prolactin)(AdaptedfromRef. 6). Figure 3. 3. inFigure proposed individualsis management ofmacroprolactinemic forthe asusual.Aflowchart hyperprolactinemia is negative, investigate result the macroprolactin Ifunavailable, beguidedbytheclinicalpicture. to gel-filtrationchromatography, orifthelatteris with PEG is inconclusive,one may proceed screening ofthecondition. Ifthedue tothebenignnature investigation,follow-uportreatment, for further isnoneedit shouldguidethepatientthatthere normal, If positiveandmonomericPRLlevelsare isalwaysindicated. screening macroprolactinemia inanasymptomatic individual,hyperprolactinemia Inthissituation,facing tohyperprolactinemia. related in the absence of complaintsevaluation is requested PRL of the case. In the second scenario, serum handling for proper causes of hyperprolactinemia andpathological of physiological,pharmacological totheusualinvestigation toproceed is recommended isnotindicated,andit screening macroprolactinemia Macroprolactinemia The request for serum PRLassessmentoccurs forserum The request Flowchart tothemanagementofpatients withmacroprolactinemia Symptomatic Asymptomatic PEG precipitation No treatment No imaging mPRL after Arch Metab. Endocrinol 2018;62/2 Normal High hyperprolactinemia clinical picture Evaluate other causes for True Arch Metab. Endocrinol 2018;62/2 (range, 32.5-404; <100mg/Lin74%) among115 91%ofcases)(83),to119.5±112.9 in approximately 20-663 ng/mL (mean, 61 ± 66; < 100 ng/mL from highlyvariable: < 100 ng/mL,buttheyare levels are (83,84). inmacroprolactinemia israre disorders andmenstrual note, thefindingofbothgalactorrhea (1,61,62).Of syndrome such aspolycysticovary (74,75,85)orotherdisorders, hyperprolactinemia theconcomitance withmonomeric from result 74,76,83,84). Asmentioned,thiswouldmostly (56,58,69,70,73, patients withmacroprolactinemia inupto45%of dysfunction) havebeenreported andsexual disorders menstrual (galactorrhea, PRL autoantibodytiters(82). inanti- alongwithanincrease normoprolactinemic initially subjects whowere in macroprolactinemic maydevelop during follow-up,hyperprolactinemia PRL(82).However,development ofraisedfree without the display persistentmacroprolactinemia subjectsusually macroprolactinemic prolactinemia, cases(1,5). macroprolactinemia detectionof toavoidtheunnecessary patients, inorder inasymptomatic PRL shouldneverbemeasured (73,74,81).Conversely, treatment and inappropriate investigation causeofmisdiagnosis,unnecessary relevant a may occasionally represent Thus, macroprolactinemia byDonadioandcols.(73). patients (20%)reported in10of49 microadenoma pituitary non-secreting shiftedto microadenoma pituitary of PRL-secreting (IH).Moreover,hyperprolactinemia thediagnosis idiopathic (mean, 42.3%)ofpatientswithapparent in25to68.3% wasencountered macroprolactinemia series(73,74,81), of patients.Indeed,inthree change theinitialdiagnosisinasignificantproportion may some studies,thedetectionofmacroprolactin to (80).Bycontrast,according macroprolactinemia for thedisseminationofmedicalknowledgeabout pointingtotheneed treatment, and inappropriate investigation didnotprevent macroprolactinemia butscreening hyperprolactinemia, individuals withtrue laboratory, for costinsearching wasmore there (79). InastudyconductedinBrazilianreference and investigateotherconditionsthatjustifysymptoms outmacroprolactinemia torule others allowscreening (56,76-78),and procedure asacost-effective screening In most patients with macroprolactinemia, PRL In mostpatientswithmacroprolactinemia, tohyperprolactinemia Overall, symptomsrelated ­ ofmacro thenaturalhistory Concerning macroprolactin Some authorsadvocateroutine Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas

patients (69,70,73,74,84). 20-25%of macroprolactinemic found in approximately and, mostly, or an empty sella) maybe microadenomas Moreover, (e.g.,macroadenomas MRIabnormalities (34,56,63,69,83). overlapbetweengroups was agreat but there those with monomeric hyperprolactinemia, patientsthanin lowerinmacroprolactinemic were patients intheBMSH(33).Inmoststudies,PRLlevels levels in 80% of microprolactinomas and70%oflevels in80% ofmicroprolactinomas PRL serum useleadstonormal Bromocriptine 4and5)(Tableshrinkage (Figures 4)(19,86-89). andtumor ininducingPRLnormalization efficacy choice becauseofitsbetter tolerabilityandgreater type2(D of thedopaminereceptor countries. Cabergoline (CAB), a specific agonist Quinagolide is available in some European themostcommonlyusedworldwide.derivatives, are ergotand cabergoline (CAB),bothofwhich are (BRC)of cases(8).AmongDAs,bromocriptine 80% inapproximately andtumorgrowth secretion hormonal astheirusecontrols for prolactinomas, treatment thegoldstandard (DAs) (19).DAsare withdopamineagoniststherapy andpharmacotherapy radiation includesurgery, prolactinomas pituitary (5,24,25). to betreated doesnot need (2-7). Bycontrast,macroprolactinemia hyperprolactinemia withdrawal incasesofdrug-induced anddrug dopamine agonists(DAs)forprolactinomas, hypothyroidism, inpatientswithprimary replacement its etiologyandmayinclude,forinstance,L-thyroxine dependson ofhyperprolactinemia The idealtreatment PROLACTINOMAS TREATMENT OFHYPERPROLACTINEMIAAND and anypatientwithoutanobviouscauseforthe idiopathichyperprolactinemia, with apparent patients, subjects asymptomatic hyperprolactinemic ismostlyindicatedfor formacroprolactin screening The macroprolactinemia. from hyperprolactinemia todifferentiatemonomeric cannot beusedreliably features subjects. Clinical, radiological and laboratory of ~20%among hyperprolactinemic frequency diagnostic pitfall, with a mean cases, a laboratory COMMENT 6: hyperprolactinemia. Current availabletherapeuticoptionsfor Current Macroprolactinemia is,inmost Macroprolactinemia 2 R), isthefirst 243

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 244 patients withprolactinomas. BCR: bromocriptine (AdaptedfromRef. 34). Figure 6. in naïvepatientswithmacroprolactinomas(AdaptedfromRef. 34). Figure 5. concerning efficacyandtolerability(AdaptedfromRef. 34). Figure 4. (10,19,88). forD its bettertoleranceandhigher affinity from results ofCABprobably better performance 6 and7)(34,88). The toBCR(Figures resistance inpatientswithintoleranceor effective is alsovery ishigherinnaïvepatients,butthedrug effectiveness is achievedin85%ofpatients(3,86-88).CAB withCAB,thisgoal whereas macroprolactinomas, Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas 100% 100% 20% 40% 60% 80% 20% 40% 60% 80% 20% 40% 60% 80% 0% 0% 0%

Naive patients normalization 91% Comparative efficacy of CAB and BCR in inducing tumor shrinkage Comparative efficacyofCAB and BCR ininducingtumor shrinkage Efficacy of cabergoline on the normalization of PRL levels in 238 Efficacy ofcabergolineonthenormalization ofPRLlevelsin238 86% irpoatnm n=11 Macroprolactinoma (n=117) Microprolactinoma (n=121) Comparison of cabergoline (CAB) and bromocriptine (BCR), PRL 83% Cabergoline (n=40)

euto 0 Completedisappearance Reduction >50% 67% 80%

p =0.048

A n=28 BCR(n=304) CAB (n=238) BCR-intolerant Resistance 59% 10%

88% patients

81% 18%

Bromocriptine (n=43)

BCR-resistant Side-effects 22% patients 61%

43% 57%

50%

p =0.034

35%

Intolerance 8% BCR-responsive

100%

14% patients 100%

2 R Multicenter StudyonHyperprolactinemia (BCR) amongpatientswithmacroprolactinomasfromtheBrazilian Table 4. bromocriptine (BCR)(AdaptedfromRef. 34). effective notonlyinnaivepatientsbutalsothoseprevioiuslytreatedwith Figure 7. patients; CAB, in10-15%(34,88-91). ofthe one-third size byatleast50%inapproximately prolactinoma (CAB), in10-15%.BCRfails todecrease ofpatients;cabergoline one-quarter in approximately levels prolactin (BCR) fails to normalize Bromocriptine or2.0mg/weekofcabergoline) (89,90). bromocriptine conventional dosesofmedication(7.5mg/day sizeby≥50%withmaximal macroprolactinoma PRLlevelsandtodecrease tonormalize includes failure adopted thedefinitionsuggestedbyMolitch,which have many experts therapy (2,4,88-91).Currently resistance todopamineagonist(DA) the definitionof for conceptshavebeenproposed arbitrary Different dopamine to resistance the agonists? manage to How 2.1 hyperprolactinemia. and themanagementofpsychotropic of prolactinomas to the treatment aspects related In thistopic,wewillcoverchallengingorcontroversial 2. CONTROVERSIALISSUESREGARDINGTREATMENT Adapted fromRef. 34. 10% 20% 30% 40% 50% 60% 70% 80% 90% Complete tumordisappearance Tumor reduction>50% PRL normalization Outcome 0%

Naive patients 80% (n =40) Comparative efficacyofcabergoline(CAB)andbromocriptine Concerning macroprolactinomashrinkage, cabergolineis

57% uo hikg 0 Completedisappearance Tumor shrinkage>50% BCR-intolerant 40% (n =47) patients

21%

(n =117) Arch Metab. Endocrinol 2018;62/2 57.5% 77.8% 80% CAB BCR-resistant (n =20) 30% patients

0% (n =133)

34.7% 58.7% 59.4% BCR

BCR-responsive 40% (n =10) patients - induced p-value

0.034 0.048 0.042 20%

Arch Metab. Endocrinol 2018;62/2 induced byhigh dosesofCAB(seebelow) (88,90). valvulopathy theriskofcardiac regarding a concern is,however, theCABdose(90).There continue toincrease doses notto isnoreason higherdoses,there from effects conventional beyond and no adverse is a continued response As long as there DA the of dose the Raising twice(90,98). andhasonlybeenreported rare more to CAB is much to BCR in a patient resistant the response (90,97).Bycontrast, thepituitary slower eliminationfrom binding sites,alongertimeoccupyingthereceptor, anda fordopamine to cabergoline’s possessingahigheraffinity toBCR,butthismaybedue inpatientsresistant effective (30,90,96,97). ItisnotclearwhyCABshouldbeso withsometumor sizechange and upto70%respond to BCR, 50-80%ofpatientsresistant approximately PRLlevelsin in normalizing CAB. CABiseffective BCRto switchingfrom patientsaddress in resistant switchingdopamineagonists Most ofthedataregarding DA another to Switching (34,88,90,96,97). withotherdrugs treatments (4)radiotherapy;and(5) experimental tumor resection; andtolerate;(3)surgical patient continuestorespond the dose of the DA beyond conventional doses if the therapy include(1)switchingtoanotherDA;(2)raising to DA for patients with resistance The approaches Treatment (95). ortestosterone therapywithestrogen replacement isduetotheconcomitantuse ofhormone DA resistance (94). In some cases, the development of prolactinoma Rarely, ofa maybemalignanttransformation there (90). Mostcommonly, thisisduetononcompliance. atalaterpointintime tothesedrugs become resistant (90). the abilityofdopaminetoinhibitPRLsecretion couples theD that Moreover, intheGprotein isadecrease there number of D inthe ina4-folddecrease transcription, resulting in D is rather associated with a decrease toD affinity absorptionordrug toDAs.Drug explainresistance anumberofpotentialmechanismsto are There mechanisms Pathogenetic Patients who initially respond to a DA may rarely toaDAmayrarely Patients whoinitiallyrespond 2 R are not involved (90). DA resistance notinvolved(90).DAresistance R are 2 R to adenylyl cyclase, further decreasing decreasing R toadenylylcyclase,further 2 Rs on the cellmembrane(92,93). 2 R gene Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas (72%), asfollows:in3(12%)patients,withupto4 ofPRL levels wasachieved in 18patients normalization 3months,upto9mg/week.Overall, tolerated, every theCABdoseasneededand increasing progressively toCAB3mg/weekby refractory of 25prolactinomas evaluated the management cols. (101) prospectively recently, More of thosewithmicroadenomas. and Vilar and10% levels in18%ofpatientswithmacroadenomas PRL unabletonormalize 7 mg/week)ofCABwerestill and cols.(100)foundthatdoses>2.0mg/week(upto 96% atthehighestdoseof12mg/week(99).DiSarno at 3,6,and9mg/week,respectively,reaching finally to 35, 73, and89% gradually increased normalization mg per week (range 3-12mg/week). The rate of PRL within 12 months,with a meandose of CAB of5.2 ± 0.6 of the PRL levels achieved normalization resistance, tohaveDA that 25of26patients(96.1%)considered titration ofCAB,Onoandcols.(99)documented levels to normal islimited (4,89,90). levels tonormal restoring PRL in itsefficacy tumor growth, controlling in below). Indeed,although it canalsobeeffective toradiotherapy (see seem to be thelessresponsive tumors,prolactinomas Among thefunctioningpituitary Radiotherapy and 5.3%withmedication(104). ofPRLwasonly7.8%withoutmedication normalization MulticenterStudy,European therateofpostoperative without medicationandin27%withmedication.Inthe ofPRLin42% inanormalization resulted that surgery toBCR,quinagolideorCAB in 26patientsresistant medication. Similarly, Primeauandcols.(102)found without dopamine agonist medication and in 15% with ofPRLin36% in a normalization resulted that surgery either BCRorCAB,Hamiltonandcols.(102)reported to toDA(6,102-104).Of61patients resistant response the mayimprove evidence thatdebulkingsurgery is also some is available (4,90). There neurosurgeon and an experienced their tumorispotentiallyresectable if Patients canalwaysundergo transsphenoidalsurgery surgery Debulking detected(101). were abnormalities ­ tolerated, andnosignificantechocardio doses>7mg/week. CABwaswell benefitted from in 6(24%)patients,with6-7mg/week.Nopatients mg/week; in9(36%)patients,with5and Using an individualized, stepwise approach ofdose Using anindividualized,stepwiseapproach graphic valve 245

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 246 and shouldonlybeperformed the therapyof lastresort as its use is generally regarded the toxicity of the drug, totemozolomide.Given responded macroadenomas PRL-secreting found that12of20(75%) resistant Reviewing such cases, Whitelaw and cols. (119) prolactinomas. large DA-resistant aggressive, some very It hasalsobeenfoundtobemoderatelysuccessfulin tumorssince2006(117,118). malignant pituitary or ofaggressive successfully used in the treatment (90).prolactinomas DA-resistant in patients with aggressive lanreotide and usefulthantheSSTR2-agonistsoctreotide more activity atSSTR5(116),itwouldbepotentially only has substantial as pasireotide (115). Therefore, ofPRLsecretion totheregulation with respect subtype5(SSTR5)isthemost important receptor tumors. The somatostatinin cases of DA-resistant (114)andcabergoline (113)orlanreotide octreotide onthesuccessfulcombinationtherapyof reports havebeen few tumors(90),andthere PRL-secreting (90,112). prolactinomas in two males with DA-resistant reported was recently inhibitor, anaromatase successful useofanastrozole, maximal dosesofDA(110,111).Inaddition,the levels despite who persistedwithlowtestosterone patients ofhypogonadisminprolactinoma the recovery in SERM clomiphenewasalsoshowntobeeffective when tamoxifenwasadded(90,109).Theuseofthe intumorsizeandalowering ofPRLlevels a decrease with have been shown to respond macroprolactinomas invasive resistant” few patients with “bromocriptine Accordingly, experimentalapproach. an interesting a inhibitorsinmenmightbe in womenoraromatase theuseofSERMs through prolactinomas in resistant endogenousestrogens apoptosis (108).Thus, reducing cell membrane(107).Moreover, may block estrogen in thenumberofD decrease (105), stimulation ofmitoticactivity (106), and a onPRLgenetranscription effects including direct multiple mechanisms, of dopamine agonists through women notwillingtoconceive(4,19,90). formenandpremenopausal often allthatisnecessary therapy is replacement to DAs, hormonal resistant Of note,ifoneisdealingwithmicroprolactinomas drugs Other Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas Temozolomide, anoralalkylatingagent, hasbeen notusefulforSomatostatin analogsgenerallyare intheeffectiveness maycauseadecrease Estrogens 2 receptors on the lactotroph onthelactotroph receptors mTOR and tyrosine kinaseinhibitors(3,120). mTOR andtyrosine suchas antagonists(3),andantiblasticdrugs, receptor analogues anddopamineD the useofchimericmolecules(somatostatin trials are oftemozolomideafter0.5-2.5years(90,119). effects thesuppressive tumorsescapefrom aggressive very (90,119).Unfortunately,tumor control manyofthese andradiotherapyfor ofDAs,surgery after thefailure still debated(see below)(10,121). asinthosewithParkinson’sdiseaseis prolactinomas valvulopathy in patients with cardiac clinically relevant toCAB(~12%vs~4%)(87).compared intolerance isalsosignificantlyhigherwithBCR, discontinuationduetocompleterate oftreatment continued useinmanypatients(34,88,121).The or withdosereduction (34,88), andtheyresolve duration andofshorter lesssevere, less frequent, generally are for BRC, but CAB adverse effects ofCABissimilartothatreported The safetyprofile (~25%) (121). (~30%), anddizzinessor vertigo include nauseaorvomiting(~35%),headache (34,88,121). Themostcommonadverseevents mild tosevereheadaches, whichmayrangefrom etc.) butalsoposturalhypotension,dizzinessand symptoms (e.g.,constipation,nausea,vomiting, DAs? of gastrointestinal frequently more of sideeffects, profile safety the in spectrum abroad DA therapyoftenprecipitates differences there Are 2.2 approach is successful in at least 70% of patients. approach This andnoadverse effects. continued response isa first,as long asthere should be performed inthedose toCAB,astepwiseincrease resistance inatleast50%of cases.Facedwith normalization with cabergoline (CAB), which leads to prolactin shouldbeswitchedtotreatment bromocriptine COMMENT 7: tumor growth evenunderDAtherapy.tumor growth aggressive temozolomide canbeindicatedtocontrol hasfailed.Radiation and when themedicaltreatment tothedopamineagonist(DA) aresponse improve may additionalbenefits.Debulking surgery provide In ourexperience,doses>7mg/weekdonot Other treatment strategiesundergoing clinical Other treatment Whether CAB is associated with an increased riskof Whether CABisassociated with anincreased Patients with resistance to Patients withresistance Arch Metab. Endocrinol 2018;62/2 2 receptors) (2,3),PRL receptors) Arch Metab. Endocrinol 2018;62/2 taking thedrug. thanthosenot susceptible toimpulsivity disorders more withhigher dosages)were on CAB(particularly on theappearanceofICDsand concludedthatpatients randomized studyaimingto assesstheimpactofCAB recently, Barakeandcols.(135) conductedtheonly adenomas(134).More with nonfunctioningpituitary totheircounterparts compared disorder impulse control likelytodevelopan tobe9.9timesmore reported withDAshavebeen treated males withprolactinomas Inanotherstudy, treatment. on CABforprolactinoma ofICDinpatients a10%prevalence reporting review compulsive buying(133). and CAB(132);anddepression months afterstarting three ofpsychiatricdisorder history without aprevious CAB(131);psychosisinapatient just afterstarting CAB (130);gamblingandcompulsivesexualbehavior (126); compulsivegamblingoneyearafterstarting psychosis inapatientwithundiagnoseddepression CAB(125); afterstarting subject withbipolardisorder ina mania (123,129);withpsychoticfeatures suchasafirstepisodeof have describeddisorders withCAB(123-133). Thesereports patients treated inprolactinoma ICDs andotherpsychiatricdisorders buying (126). disorder, compulsive sexual behavior and compulsive explosive include gambling,kleptomania,intermittent tooneselforothersandcan or ultimatelyharmful excessiveand/ urges toengageinbehaviorsthatare lessthan1%to3% (122,123). thought torangefrom patientsisnotknownbut inDA-treated side effects mania (3,5,122-125).Theexactincidenceofthese (ICDs),and disorders psychosis, impulsivecontrol hallucinations,nightmares, concentration, nervousness, anxiety,somnolence, anorexia, insomnia,impaired includingdepression, psychiatric adversesideeffects, cause dopamine antagonists (7). Theseagentscanrarely tothatofthe theoppositeeffect exerts DA treatment hyperactivity thatoccursinthesecases(43,46,47). duetothesupposeddopaminergic and schizophrenia suchaspsychosis ofpsychiatricdisorders treatment classicallyusedforthe quetiapine, sulpiride)are Dopamine antagonists(e.g.,haloperidol,olanzapine, psychiatric cause disorders? agonists dopamine Do 2.3 In 2011, Martinkova andcols.(128)publisheda In 2011,Martinkova havebeenpublishedfocusingon Few reports resisting in characterizedbydifficulties ICDs are Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas based onthisgenestudy(137). perspectivetoselectpatientsforCABtreatment future demonstratinga systemside-effects, of centralnervous intheoccurrence could explainindividualdifferences ABCB1 is aP-gpsubstrate(137).Thisstudydemonstratedthat studyshowedthatCAB substances.Arecent harmful itagainst substances outof the brainand protect certain totransport inorder transporter as anefflux tissuesthatacts intumorcellsandnormal expressed the encoded by (P-gp). This protein, P-glycoprotein studies in Parkinson's disease reporting on an increased onanincreased studies inParkinson's diseasereporting andclinical However, havebeencasereports there toother DAs(141,142). compared a loweraffinity (BRC)has bromocriptine a potentagonist,whereas andactas instance, CAGandPGLshow highaffinity for affinities; withdifferent to 5-HT2Breceptors and, finally, valvulardysfunction(141,142).DAsbind valvethickening proliferation, mitogenesis, fibroblast valves, whichinducesacascadeofeventsinvolving onheart abundantlyexpressed (5-HT2B) receptors, 2B involves theactivationof5-hydroxytryptamine (140).Theunderlyingmechanism failure risk ofheart derived DAspramipexoleisassociatedwithahigher withCAB,andthenon-ergot- evidence thattreatment andmoderate valvularregurgitation risk ofcardiac CAB andpergolide (PGL)isassociatedwithahigher withhighdoses of evidencethattreatment now strong is ofpatients, there disease (138,139).Inthisgroup published in2007involvingpatientswithParkinson’s twoarticles valvulardisease(HVD)emerged from heart the therapeuticuseofdopamineagonists(DAs)with endocrinologists about a possible association between relevance? its with is among signsthatcauseconcerns The mainwarning what – associated agonists disease dopamine valvular heart of Risk 2.4 psychiatric disorders before prescribing DAsandto prescribing before psychiatric disorders therapy. toexclude important Itseemstherefore oraggravatedbydopamineagonist(DA) triggered maybe disorders symptoms andimpulsivecontrol COMMENT 8: of psychiatricdisorders. toorwithahistory followuppatientsprone carefully Psychiatric effects of CAB can be modulatedby Psychiatric effects ABCB1 genepolymorphisms(withlossoffunction) gene (136), is a membrane transporter gene(136),isamembranetransporter In susceptiblesubjects,psychotic 247

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 248 prevalent in patients takingBRC, whilemore observed was oftracetricuspidregurgitation higher prevalence withBRCforcomparison. Notably,patients treated a ofprolactinoma was thefirsttoinclude agroup (150). 90% ofpatientswithoutamurmur inthe valvular lesionwasshownonechocardiogram andnoclinicallysignificant functional murmurs), in10%ofcases(allwere audible systolicmurmur detectedan echocardiography examination before takingcabergoline. Cardiovascular with prolactinoma assessed40patients of thisstudyalsoprospectively of0.11%(150).Theauthors inaprevalence resulting disease was identified in only two out of 1,811 patients, andthickenedvalve,clinicallyrelevant a restricted associatedwith regurgitation of moderateorsevere definition ofCAB-associatedvalvulopathyasthetriad followed bytheauthors(150).Utilizingprecise 40patients 21studiesandfrom analyzed datafrom systematicreview (149).Anotherrecent regurgitation valve inmitraloraortic observed were differences patients takingCAB.No significant hyperprolactinemic in of mild-to-moderatetricuspidvalveregurgitation risk studies with1,398individualsfoundanincreased of CABinHVD.Ameta-analysissevenobservational dedicatedtoinvestigating therole sectional studieswere asshowninthestudybyGuand cols.(148). results, istheimpactofexaminerbiasin to beconsidered (146,147).Anotherfactor mass indexandhypertension withageandisinfluencedby gender,increases body ofvalvular regurgitation because theprevalence young ormiddle-agewomen(146).Thisisimportant predominantly withDAsare treated abnormalities whilepatientswithendocrine with multipledrugs, usuallyontherapy older than60yearsofagewhoare includemen in Parkinson’s disease predominantly mg ofCABperweek)(145).Moreover, moststudies than3 more than thoseusedinendocrinology(rarely 10-foldhigher approximately mg ofCABperday)are (at least 3 cumulative doses of DAs used in neurology thatmustbehighlighted.First,thedailyand groups betweenthese CAB, despitethestrikingdifferences withDAs,especially HVD inendocrinepatientstreated abouttheriskof animmediateconcern disease brought BRC (143,144). with reactions inpatientstreated fibrotic non-cardiac and andcardiac valvularregurgitation risk ofabnormal Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas A BrazilianstudybyBoguszewski andcols.(151) most cross- In patientswithhyperprolactinemia, As expected, the findings inpatients with Parkinson's cardiac valve regurgitation. Similarly, valveregurgitation. cardiac 19patients theriskofsignificant doesnotincrease in prolactinomas and cols.(154)concludedthat5yearsofCABtherapy of valvular dysfunction. Auriemma a higher prevalence calcification inCABusersthatwasnotaccompaniedby ofvalvular prevalence 2 yearsandfoundanincreased ( treated and cols.(153)followedpatientswithprolactinomas valves.Delgado damage causedbyDAstocardiac longitudinal studieshaveshedlightonthepotential (152). BRC orCABwasreported witheither treatment onlong-term with prolactinomas ofsubclinicalHVDinpatients prevalence increased inasubsequent studyinwhichan was confirmed notclinicallysignificant(151).Thisobservation were findings alltheseechocardiographic users; nevertheless, inCAB observed were and ahighermitraltentarea trace-to-mild tricuspidandtracemitralregurgitation to screen for valvular heart disease. Of note, with for valvular heart to screen with CABshouldhavean annualechocardiogram treated (FDA) advicethatpatients withprolactinoma Administration challenge theUSFood and Drug (158). study inpatientswithacromegaly valveshasalsobeennoticedinalongitudinal on cardiac mg/week (99,110). 3to12 detected despitetheuseofdosesrangingfrom ­ significant echocardio dosesofCAB,no tostandard toberesistant considered cumulative doses. useoflow dysfunction andthesafetyoflong-term high cumulativedosesinthedevelopmentofvalvular role of the (157), confirming in hyperprolactinemia riskofHVDinParkinson’sdisease butnot increased and theNetherlands,CABwasassociatedwithan theUnitedKingdom,Italy,study involvingdatafrom HVD (156).Inamulti-country, nestedcase-control risk ofclinically significant associated withan increased is oritstreatment thathyperprolactinemia not support outinDenmarkdid studycarried nationwide cohort thesafetyofCABinendocrinepatients.A confirmed follow-up (155).Population-based studies have also inthe grades norsymptomaticdiseasewasobserved regurgitation Neither asignificantchangeinvalvular withDAs. during 5yearsofcontinuoustreatment followedinCuritiba,Brazil, were with prolactinomas Beyond the cross-sectional investigations, Beyond thecross-sectional The findingsoftheabovementioned studies ofCABtherapy The absenceofadetrimentaleffect patients In twostudiesinvolving51prolactinoma n = 45) or not treated ( = 45)ornottreated graphic valve abnormalities were were graphic valveabnormalities Arch Metab. Endocrinol 2018;62/2 n = 29)withCABfor Arch Metab. Endocrinol 2018;62/2 costs(4,6,88). treatment valves, and consequencesincardiac potential long-term ofmedicaltreatment, because oftheadverseeffects therapy, shouldbeconsidered withdrawaloftreatment still notclear(4,6,10).Despite theneedforlong-term is welltoDAs,theoptimal durationoftreatment very respond Although it is well known that prolactinomas how? and when Why, – Why, often? how agonist and how dopamine the when, of Withdrawal 2.5 with thepatient(121,150,154). maintained basedonclinicaljudgmentanddiscussion or reduced such cases,therapymaybeinterrupted, othercausesofvalvulopathies. In etiologies from evaluation isindicated to distinguish CAB-induced duringfollow-up,further detectedorprogress are of the therapy (121,154). Importantly, if valve lesions notanindicationforcessation are echocardiography individuals, ashighlightedbysomeauthors(146,147). findingsinolder echocardiographic in interpreting specialattentionshouldbegiven years. Nevertheless, aftertheageof50 who maintaincabergoline treatment than3mgperweek,orthose 5 yearsatadoseofmore than with anaudiblemurmur, formore thosetreated forpatients shouldbereserved that echocardiograms examinationand byaclinicalcardiovascular screened thatsuchpatientsshouldbe and cols.(150)proposed review,based onthefindingsoftheirsystematic Caputo recently, onayearlybasis(90).More echocardiogram >2mg/weekwithan assessing allpatientsreceiving recommend becomesignificant,someexperts effects atwhatdoselevelthesevalve as itisuncertain (90,145,156).However, valveabnormalities cardiac riskof doesnotappeartobeanyincreased there week, usuallyusedinpatientswithprolactinomas, conventional dosesofcabergoline, i.e.,upto2mg/ cabergoline atdosesupto2mg/week. forpatients receiving would notberecommended evaluation doses.Thus,anechocardiogram standard withDAsin treated chronically diseases whoare orother endocrine patients withhyperprolactinemia abouttheriskofvalvulopathyin major concerns COMMENT 9: Subclinical valvular abnormalities detectedby Subclinical valvularabnormalities Current available data do not support availabledatadonot support Current Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas patients, the overall remission rate after the withdrawal patients, the overall remission (162-170). variable results afterDAwithdrawalwith rates ofhyperprolactinemia 2003, several studies have evaluated the recurrence reduction (161,162).Since a significanttumorsize and duringtreatment period ofnormoprolactinemia criteria forCABwithdrawal,includingaprolonged attributedtostricterselection rates ofthisstudywere (162).Thehighersuccess 66 and47%,respectively ratesof this studyto8yearsdocumentedremission of thoseharboringaMAC(161).Anextension withdrawn in70%ofpatientswithaMICand64% (161) demonstratedthatCABcouldbesuccessfully studybyColaoandcols. 2003, alandmarkprospective rateof20.6%afterBCRdiscontinuation.In a remission 2002, aBrazilianstudybyPassosandcols.(160)showed withdrawal havebeenpublishedsince1979(159).In 0.001) (172). CAB withdrawal(p< likelytobenefitfrom more were withdrawal reduction intumorsizebefore significant a thelowestCABdoseandpresented who received (p= 0.587).Patients ofeffect years showednotrend longerthan 2 CABtreatment (p =0.006),whereas success withdrawalwasassociatedwithtreatment before tothelowestlevel strategies, aCABdosereduced adjustingforoptimalwithdrawal meta-regression meta-analysis(172).Inarandomeffects random effects ratewas65%bya recurrence the hyperprolactinemia patients submittedtoCABwithdrawalfoundthat for agradualDAwithdrawal(4). onMRI may becandidates no visibletumorremnant foratleast2yearsandwhohave normoprolactinemia thatpatientswho haveattained in 2011recommended prior todiscontinuationoftherapy(171). ofthetumorwasachieved in allpatients reduction than50% was alsohigherinstudieswhichagreater rate duration (16%)(p=0.01)(153).Theremission treatment in comparison to studies with a shorter washigher(34%) theremission months oftreatment, studies) (p=0.07)(171).Instudieslastingover24 was used(35%in4studies)versusBRC(20%12 wasfoundinstudies in whichCAB rate ofremission ahigher (171).Furthermore, for macroprolactinomas and 16% 21% for microadenoma hyperprolactinemia, of DAtherapywasonly21%,32%foridiopathic In ameta-analysisof19studieswithtotal743 after DA Studies on persistentnormoprolactinemia A meta-analysis from 2015thatonlyevaluated A meta-analysisfrom bytheEndocrine Society The guidelinesprovided 249

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 250 ratewasexperiencedby MAC). Ahigher remission was 46%(65%incasesofMIC and36%insubjectswith rate Dogansen andcols.(169), theoverallremission (167-169).Intheseries by compared and BCRwere whenCAB discontinued (161-169). The same was true is than thosewithMICswhentreatment remission alowerriskofhyperprolactinemia MACs presented with theseparameters(168-172). eveninpatientswhopresented wasobserved recurrence withdrawal.However,MRI before hyperprolactinemia of low doses of CAB, and lack of a visible tumor on PRLlevels,theuse DA withdrawalincludesuppressed oftenassociatedwithasuccessful parameters more (4,6,10,19).Overall, studies havebeencontradictory ofthese afterstoppingDAs,butthe results remission remission? of soughtthe predictors Several studiesintheliterature of predictors the are What 30%ofpatients(173,174). approximately after 2additionalyearsoftherapymaybesuccessfulin demonstrated thatasecondattemptatCABwithdrawal ofthese studieshave for atleast2years.Theresults receiving additional CABtherapy the firstwithdrawal, after ofhyperprolactinemia in patientswithrecurrence the outcomeofasecondattemptatCABwithdrawal Two independentstudies(173,174)haveinvestigated often? How cessation (170). foratleast12months after CAB maintained remission (73%) 11.2) months,indicatingthatahighpercentage withdrawal patientsatamediantimeof3.0(range;2.9- in3(27%)post- observed were hyperprolactinemia of with CABforatleast5years(170).Recurrences treated in 11 patients with macroprolactinomas recently, discontinuationwasevaluated treatment toBCR(55%vs.36%)(169).More CAB, compared ratewasfoundwith MAC) (169).Ahigherremission was 54%(35%incasesofMICand64%subjectswith rate (23 MACsand44MICs),theoverallrecurrence yrs) orinitialadenomasize(168).Among67patients duration ofCABtherapy(upto3yrs,5yrsor> oftheprevious 12 monthsin34(45.9%),regardless within occurred with CABfor≥3years,recurrences Among 74 patients (19MACsand 55 MICs) treated 27%to54%(168-170). CAB withdrawalrangedfrom Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas In the great majorityofstudies,patientsharboring In thegreat ratesafter studies,therecurrence recent In three after DAwithdrawal(4,6,88). PRL levels radiotherapy also favor persistent normal and surgery pituitary (176,177).Previous remission toassessthepossibilityofhyperprolactinemia pregnancy (177). Thus, DA withdrawal has been suggested after rateofhyperprolactinemia therecurrence not increase levels in68%ofpatients.Moreover, did breastfeeding ofPRL wasassociatedwithnormalization pregnancy after pregnancy. that Auriemma andcols.(176)reported PRLconcentrations serum spontaneously normalize andpostmenopausalpatients. among premenopausal wassimilar ofhyperprolactinemia rate ofrecurrence Colaoandcols.(163)showedthatthe Nevertheless, influences t (169). vs. 56%)andMAC(45%27%),respectively withCABvs.BCR,forbothMIC(86% patients treated currently is indicated in extremely rare cases(6,88,178). rare isindicatedinextremely currently and inaccessible via thetranssphenoidal approach fortumors craniotomymustbereserved (88), whereas andmostmacroprolactinomas microprolactinomas forboth ofsurgical approach golden standard prolactinomas? for the (TSS)represents Transsphenoidal surgery surgery of role the is What 2.6 low(<10%)(88,160,162,169). isvery tumor growth the risk of recurrence, In cases of hyperprolactinemia within 24monthsofDAdiscontinuation(162-173). observed were all studies, all recurrences virtually 3months)(164-169).In of PRLlevels(e.g.,every the patientshouldbesubjectedtoastrictermonitoring withinthefirstyear,Most patientsrelapse duringwhich (171,172). 1 to5yearsaftercessationoftreatment studies. Generally, for thepatientshavebeenobserved The follow-upafterDAwithdrawalhasvariedindifferent after followedup be withdrawal? patients should long How recommended tograduallytapertheCABdose. recommended withdrawal,itis drug the lowestdoseofCAB.Before ofPRLlevels<10ng/mLandtheuse presence inthe tumor orharboringsmallremnants, withoutvisible and thosewithmacroprolactinomas inallpatientswithmicroprolactinomas considered cabergoline (CAB)withdrawalshouldbestrongly COMMENT 10: There are fewstudiesshowingthatsomepatientsmay are There afactorthat Menopause mightbeconsidered he reduction ofPRLlevels(175). he reduction Following two years of treatment, Following two years oftreatment, Arch Metab. Endocrinol 2018;62/2 Arch Metab. Endocrinol 2018;62/2 one. lower doseof CAB thanthepresurgical aftersurgical debulking, usinga PRL normalization toCAB achieve resistance many patientswithpartial (185). macroprolactinomas and38%of148073% of1211microprolactinomas ofPRLlevelstobeachievedinapproximatelycontrol series, includingatleast100patients,hasshownthe 13published from the analysisofsurgical results recently, (88).More of 18%and23%,respectively rate (MACs),witharecurrence macroprolactinomas (MICs)andpatients withmicroprolactinomas onaveragein74.7%and34%of levels, occurred ofPRL definedasthenormalization remission, than50 series, initial surgical involving more review tumor sizeandinvasiveness(6,121).Inaliterature PRLlevels(<200ng/mL), and serum increased moderatelyexperience oftheneurosurgeon, the are treatment forprolactinoma surgery of successful determinants The most important Efficacy Adapted fromRefs. 6, 10, and19. Table 5. (179,184). the diagnosisofCSFrhinorrhea accuratetoolforconfirming isavery nasal secretions As tostoptheleak(181). DA toallowtumorre-growth strategy toCSFleakagewouldbethewithdrawalof (183).Anadditional treatment occur duringlong-term (182).However,rhinorrhea thiscomplicationcanalso administrationandthe diagnosis of ofdrug the start the useofDA,withameantime3.3monthsbetween related to fluidleakagewere 90% ofcasescerebrospinal review,DA therapy(180-182).Ina recent than more arapidtumorshrinkageinducedby from sinus orresult spontaneously duetotumorinvasionofthesphenoid ofCSFleaks (179).Thelattercanoccur surgical repair management ofsymptomaticapoplexy(178)andthe the particularly complications oftheprolactinomas, Cerebrospinal fluidleakduringadministrationofdopamineagonists Persistent opticchiasmcompression Resistance todopamine-agonists Intolerance todopamineagonists apoplexy Pituitary Increasing tumorsizedespiteoptimalmedicaltherapy β Notably, studies(102,104), asshownintworecent are Additional indicationsforTSSsurgery 2-transferrin isonlyfoundinCSF,2-transferrin itsdetectionin Indications for surgery inprolactinomas Indicationsforsurgery Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas mass effects, has been reported either to further worsen eithertofurther hasbeenreported mass effects, as a consequence of surgery before macroadenomas Hypopituitarism, commonly found in patients with 1%ofsurgeries onMACs(121,187,188). approximately to occur in and has been reported DIisrare permanent (121).Incontrast, andmacroadenomas both micro- diabetes insipidus(DI)isquitecommonwithTSSfor (121,186-188).Transient1.9% ofcases,respectively to occur in 0.1%, 0.2%, 0.1%, 0.1% and reported havebeen fluidrhinorrhea palsy andcerebrospinal vascular injury, meningitis/abscess,oculomotor loss,stroke/ 3.3%to31.2%(88,121).Visual from rateranges themortality with giantprolactinomas, those In patientswithlarge tumors,particularly 3.4% (88,121). morbidity rate being approximately ratebeingatmost0.6%andthemajor the mortality infrequent, TSS for MIC are Complications from Safety of RT guidancetodeliverhigh thatuses stereotactic RT (191).Stereotactic over thetarget isaform area multiple non-overlappingbeams ofX-raysthatintersect “conventional radiotherapy” (CRT), involvestheuseof beamradiotherapy,(189). External toas alsoreferred techniques beamradiotherapyand stereotactic external (4,6,88). casesofmalignantprolactinomas rare the very bysurgery, casesnotcontrolled resistant aswellin in DA- RT tumor growth isonlyindicatedtocontrol hypopituitarism at 10-20 years (121,191). Therefore, associated withahighriskofradiation-induced radiotherapy (RT) (88,189,190). Moreover, it is ofpatientssubmittedto one-third approximately occursinonly tumors,PRLnormalization pituitary amongthemostradioresistant are As prolactinomas for radiotherapy of prolactinomas? role the is What 2.7 (102-104). aftersurgery or toimprove leakage. fluid such assymptomaticapoplexyorcerebrospinal andacutetumorcomplications, medical treatment; by withoutfastimprovement and visualimpairment withchiasmalcompression macroprolactinomas orintolerancetodopamineagonists; with resistance isindicated forpatients transsphenoidal approach, COMMENT 11: Historically, withboth patientshavebeentreated Surgery, usuallybythe 251

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 252 complication is radiation- years (197). Another rare has been estimated to be 0.8% at 10 optic neuropathy radiation-induced yr (196).Therateofpresumed 2.0%at 10yr,from to2.4%at20 yr, and8.5%at30 second braintumorshasbeen demonstratedtorange 21% at20years(121,195). Thecumulativeriskof 4%at5yearsto11%10and radiation, from of CVA thetimeof from hasbeenfoundtoincrease injury. Theincidence brain tumorandopticnerve accidents(CVAs),include cerebrovascular asecond (103,176,177). AdditionalcomplicationsofCRT new deficienciescanappeareven20yearslater to ariseinthefirst5yearsafterradiationtreatment, decade (193,194).Althoughhypopituitarismtends deficiency withinthefollowing hormone pituitary radiotherapy willdevelopatleastoneanterior pituitary than50%ofpatientsreceiving (121). More complications with thedevelopmentofseveralsevere The useofconventionradiotherapy(CRT) isassociated Safety fractions (88,189-191). CRT or, RT wheneverpossible, stereotactic inmultiple (192). Inthissituation,patientsshouldbeoffered chiasmortracts cm, orwithin3mmoftheopticnerves, option unless the tumor is largertreatment than 3-4 some series(189,191),butnotinall(192). in hasbeenreported withradiosurgery normalization timetohormonal (88,189,190). Moreover, ashorter thanwithCRT withradiosurgery to belessfrequent thought Thus, radiation-inducedcomplicationsare tissuein thetumorvicinity. brainandnerve normal unchanged. remained or in 90.3%, the tumor volume decreased whereas radiosurgery, 23.3%achievedPRLnormalization, submitted to gamma-knife patients with prolactinomas (88). IntheseriesbyWan andcols.(190),ofthe176 be similar(34.1%forCRT vs.31.4%forradiosurgery) seems to rate of both approaches overall normalization concluded that the withCRTtreated or radiosurgery inpatientswithprolactinomas normalization hormonal regarding oftheliterature review A comprehensive Efficacy in multiplefractions(191). or doses of radiationinasingle fraction (radiosurgery) Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas Currently, hasbeentherecommended radiosurgery techniquesdeliverlessradiationto Stereotactic definitive conclusions(121). todraw required series andwithlongfollow-upsare toCRT.compared However,studiesoflarge further (88,191,199). reported of casessecondbrainmalignancieshavealsobeen loss,aswellahandful and worsenedfacialsensory (121,198). Clinicaldeteriorationduetovisualfieldloss ofpatients one-third inapproximately occurring has beenfoundtobethemostcommoncomplication, 0.2-0.8%(88,121). ofapproximately prevalence braintissue,witha ofthesurrounding induced necrosis are unresponsive to theabovementioned therapies unresponsive are that prolactinomas (TMZ) hasbeenusedinaggressive ofeugonadism (200). Temozolomideand restoration of the PRL level normalization tumor volume control, therapeutic goalsinpatients withGPs,whichinclude and radiotherapy, the toreach maybenecessary agonists (DAs)aloneorincombinationwithsurgery (200,203). mandatory function evaluation is usually necessary, and pituitary visualtestingis formal Therefore, also bepresent. (204-207). Panhypopituitarism may hydrocephalus such asorbitalinvasion,epistaxisorobstructive adenoma, other atypicalmanifestationsforapituitary alterationsand headaches, aswellotherneurological respectively,the optic chiasm and/or cranial nerves, and of defects and/orophthalmoplegiaduetocompression men thaninwomen(203).GPsoftencausevisualfield in aggressive usuallymore (200,201). Thesetumorsare commonlyfoundinmiddle-agedmen more they are to 4cm(200-202). thanorequal tumors withamaximumdiametergreater usuallydefinedas (GPs),theyare giant prolactinomas managed? be should is no consensusonthedefinition of Although there prolactinomas giant How 2.8 possible, preference should be given to stereotactic shouldbegiventostereotactic possible, preference bysurgery. casesnotcontrolled resistant Whenever inDA- tumorgrowth only indicatedtocontrol radiationtherapyis side-effects, potentially severe COMMENT 12: techniques These data suggest the greater safety of radiosurgery safetyofradiosurgery These datasuggestthegreater radiosurgery,In patients receiving hypopituitarism Different therapeutic approaches, suchasdopamine therapeutic approaches, Different and only2-3%ofallprolactinomas, GPs represent . Due to its low efficacy and Due toitslowefficacy Arch Metab. Endocrinol 2018;62/2 Arch Metab. Endocrinol 2018;62/2 couldalsobe therapy (4,206,214). Neurosurgery fluid during DA apoplexy or leakage of cerebrospinal to some acute complications such as be restricted orshould (debulkingsurgery) prolactinoma resistant topatients withDA- approach multidisciplinary ofthe aspart shouldbeconsidered Neurosurgery Surgery only aminorityofpatients(211-213). andtumorvolumeshrinkagein of normoprolactinemia these patients, some authors described the persistence BRCwithdrawnin in patientswithGPs.Concerning aboutCABwithdrawal nodataintheliterature are DAwithdrawal,there 2.5to7mg.Regarding from atweeklydosesranging PRLnormalization reached andcols.(210),10of16patients(62.5%) by Vilar of20months(209).Intheseries a medianinterval in11/18(61%)patientswithin PRL normalization achieved (208). AmongGPs≥6cm,DAtreatment (n=100)(p 0.19) no giantmacroprolactinomas patients withGPs(n=26)andby66%of wasachieved by55%of and >50%tumorreduction GP patients.ThecompositegoalofPRLnormalization of>50%intumorvolume87%the in thereduction ofPRLlevelsin68%and inthenormalization resulted the seriesbyEspinosaandcols.(208),CABtreatment toBCR(34,88).In and bettertolerabilitycompared efficacy medical management of GPs due to its greater DAforthe (200). Cabergoline (CAB)isthepreferred thePRLlevelin60%ofcases and tonormalize intumorvolume)74% ofthecases > 65%reduction intumor diameteror the tumormass(>30%decrease or evengetworse(200-202). visualfielddefectsdonotimprove shrink andifsevere ifthetumorsdonot may occasionallybenecessary (e.g.,within15to30days) In thissetting,earlysurgery (200-202). monitoring of the visual fieldismandatory However, ofvisualabnormalities. in thepresence close optioninpatientswithGPs,even first-line treatment the ofthetumorsize,itisconsidered rapid reduction As medical therapy in most cases causes a marked and agonists Dopamine (88). giant prolactinomas should beapriorityinthemanagementofpatientswith commonly invasivebehavior, ofmasseffects control (117-119). Due to thelarge tumor volume and The use of DA for GPs seems to reduce significantly The useofDAforGPsseemstoreduce Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas Temozolomide (200-202). masseffects surgery, regarding particularly withDAtherapyand do notachievediseasecontrol Radiotherapy shouldbeusedinpatientswithGPswho Radiotherapy toDAtherapy(102,104). tumor response the mayalsoimprove (88,121). Debulkingsurgery tomasseffects thesymptomsrelated toimprove order istodebulkthetumorin cases, thegoalofsurgery inthese experience. Therefore, or theneurosurgeon’s ofthesurgical techniqueemployed curative, regardless ishardly surgery with giantandinvasiveprolactinomas, usually thefirstchoice,evenforGPs(200).Inpatients is Thetranssphenoidalapproach during DAtreatment. orevenworsen that do notshowanyimprovement visualfielddefects forpatientswithsevere considered hyperprolactinemia (6,10,88). Hyperprolactinemia (6,10,88). Hyperprolactinemia hyperprolactinemia to hypogonadismrelated the hypogonadotropic mostlydueto among womenwithprolactinomas, frequent very are anovulation andinfertility Chronic pregnancy? involving and challenges the prolactinomas manage to How 2.9 (117,119). mg/m doseis150–200 mentioned.Thestandard previously modalities despitethemultiple treatment mass effects of interms uncontrolled thatremain prolactinomas giant of DNAandcanbeusedinaggressive methylation through cytotoxiceffects agent thatexerts Temozolomide is an oral alkylating chemotherapeutic multiple conventional treatment modalities. multiple conventionaltreatment ofthe regardless ofmasseffects interms controlled not ofGPsthatare forthesubgroup be reserved therapy. Radiotherapyand/ortemozolomideshould have alarge tumorloaddespitedopamine agonist of thesepatients,especiallyinpatientswhostill ofthemanagement aspart should beconsidered Surgery to thoseforsmallermacroprolactinomas. compared oftenrequired, cases, buthigherdosesare reduction inthemajorityof and significanttumor levels ofprolactin enablesnormalization as thisdrug (GPs), choice forpatientswithgiantprolactinomas COMMENT 13: 2 for 5 days, repeated every 28-daysinacycle every for5days,repeated Cabergoline isthetherapyof 253

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 254 with ­ 30 days after drug within half-life andcanbedetected inthecirculation takingintoaccount thatCABhasalong Nevertheless, is con­ discontinued assoonpregnancy inpregnancy,(121,216). Asageneralapproach DAsare lacking in humans animal models, butsuchdataare studies (103);CABhasbeenshowntodosoin theplacentainhuman BRC hasbeenshowntocross fetus the in safety DAs withaDA(217,219). treatment boundaries andusuallytowaitatleast1yearunder atumorwithinthesellar toobserve it ismandatory Thus, in patients withexpansivemacroprolactinomas, withBRCforatleast12months. in patientstreated ­ duringpreg riskoftumorgrowth a reduced (217). However, andcols.(218)noted Holmgren isupto35% withclinicalrepercussion tumor growth theriskof contrast, inpatientswithmacroadenomas, trimester. clinicallyevery In should bemonitored DAcanbewithdrawn,andthepatient confirmation, afterpregnancy islessthan5%;therefore, tumor growth the chance of clinicallysignificant microprolactinomas, that mighthavecausedtumorshrinkage(216).In levels andthediscontinuationofdopamineagonist ofthesehighestrogen effect of boththestimulatory asaresult canenlarge duringpregnancy Prolactinomas growth Tumor (216,217). andthepoten­ embryogenesis isthefetalexpo­ point ofconcern to visualdisturbancesandheadache.Thesecond leading the tumorbecauseof high levels of estrogens, ovulation induction(216,217). may be used for gonadotropins citrate or recombinant clomiphene in cases with microprolactinomas, control women withtheuseofDA.Inabsencehormonal is, however, in most ovaries (216).Fertility restored onthe effects direct through production progesterone and estrogen (215).PRLcanalsodecrease release nuclei ofthehypothalamus,whichstimulatesGnRH and periventricular in the arcuate made by neurons thegeneration of kisspeptin, a protein of suppressing appearstobemediatedbyanearlierstep This effect ofGnRH(14). thesuppression through and frequency (LH)pulseamplitude the luteinizinghormone decreases Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas During pregnancy, the primary concern is growth of During pregnancy, isgrowth concern the primary drawal, early fetal exposure is drawal, early fetal exposure tial risk of malformations tial riskofmalformations sure toDAinearly sure firmed (216). firmed nancy difference was found among the three groups (216). groups wasfoundamongthethree difference Overall,no newborns. andmalformed pregnancies, multiple births, premature atterm, births miscarriages, intheUSgeneralpopulation,regarding and pregnancies inducedbyCAB induced byBCRwith968pregnancies 6239pregnancies outcomesdatafrom has compared this issue,Molitch (216) (216,217,219). Addressing aconcern underDAuseare dopaminergic braincircuitry damagetothefetus(216). purpose withnoapparent in clinical practice, CAB has often been used forthis induction(4).However,authorized DAforpregnancy of theEndocrineSociety, withBRCbeingtheonly bytheGuidelines (217),asrecommended pregnant women willing to become in hyperprolactinemic therationalforBRCpreference (216). Thesefactsare induced by CAB and BRC, respectively pregnancies toBRC:~950vs.~6200 isstilllimitedcompared drug unavoidable (217).Moreover, theexperiencewiththis malformations, when used for pregnancy induction when usedforpregnancy malformations, or riskfor abortions associated withincreased apparently are safe forthefetus;noneof these drugs developmental dis­ and twocasesofpervasive andfoundtwocasesofseizures followed 61children conti­ inachievingcomplete fluency andonecaseofdifficulty described two cases ofslight delay inverbal children years, respectively. Leb­ followedfor41monthsand12 five and83children in Ono andcols.(225)didnotfindanyabnormalities (223)and described.Bronstein ceived onCABwere ofphysicaldevelopmentwasobserved. impairment pu­ andanotheronewithprecocious sclerosis with tuberous was onecaseofidio­ during12to240months, andthere up 70children, followed Bronstein conceived duringBRC treatment, (222). pre-eclampsia death bysevere hasshown12healthybabies andonefetal pregnancy withtheuseofCABduring theentire 15 pregnancies (217,220,221). Recently,deformity a compilation of one caseofundescendedtestisandtalipes pregnancy,BRC usethroughout whichhavedisclosed 100casesof onlydataonapproximately are there drawn atupto6weeksofpregnancy. Intheliterature, berty (223).Intwootherstudies(217,224),no berty The potential fetal malformation and im­ The potentialfetalmalformation In summary, BCRandCABseemtobeequally con­ In fourstudies,thefollow-upsofchildren thelong follow-up of children Concerning In the vast majority of cases, the DAwaswith­ nence. Moreover, Stalldeckerandcols.(227) pathic hydrocephalus, onechild pathic hydrocephalus, be and cols. (226) following 88 Arch Metab. Endocrinol 2018;62/2 pairment of the ofthe pairment order. Arch Metab. Endocrinol 2018;62/2 evidence oftumor enlargement (216). inapatientwithheadachesorother falsely reassuring worry. By contrast,thelackofarisein PRL maybe maycauseunnecessary enlargement andtherefore (216). AriseinPRLmay wellnotindicatetumor can occurwithoutachange inthePRLconcentration rise withtumorenlargement, andtumor enlargement levels risewithgestation,butPRLdonotalways women,PRL misleading (216,217).Indeed,innormal of PRLlevelsisnodiagnosticbenefitandcanbe weeks) (216,217,219). advanced (e.g., > 37 is sufficiently if the pregnancy ofthebaby, mightbedelivery approach alternative duringthesecondtrimester(216,217).An preferably ­ neuro treatment, withclinical andwithout improvement to masseffects with MICs or MACs experiencing symptoms related evalu­ Clinical evalua­ (217,219). shouldbeevaluatedbyanexpert pregnancy with expanding MACs,DAmaintenance throughout instead (217,219,222).Ontheotherhand,inpa­ couldbeused intolerance, CAB,althoughoff-label, totheclinicalfindings(217).In casesofBCR related ­ BRC reintroduc and after thefirsttrimester, shouldbeperformed, complaints, sellarMRIwithoutcontrast,preferably and visualimpair followed eachtrimester, withattentiontoheadache (MACs)should be enclosed macroprolactinomas the physician’sandpatient’sdecision(217). surgical debulking,dependson indication ofprevious ­ oritsreintro pregnancy tumors, thechoiceofBRCmain­ expanded or invasive allowance. In previously pregnancy shrink­ Assessment oftumor or enclosed macroadenomas. inpatientswithmicroadenomas isconfirmed pregnancy 8. The DA should be withdrawn as soon as is Figure ­ duringpreg management ofprolactinoma byGlezerandcols.(217)forthe An algorithmproposed approach best The (216,218,223). theconception should bediscontinued30daysbefore women. Ideally, hyperprolactinemic in infertile CAB Notably, duringpregnancy, periodicchecking (MICs) or Patients with microprolactinomas ation each trimester are indicated.In patients ation eachtrimesterare age in macroadenomas is mandatory before before ismandatory age inmacroadenomas tion monthly and neuroophthalmological tion monthlyandneuroophthalmological tion is indicated if tumor growth is tion isindicatediftumorgrowth ­ ­ment (217).Inthepres surgery should be performed, shouldbeperformed, surgery duction if needed, or else the duction ifneeded,orelsethe tenance throughout tenance throughout nancy is shown nancy isshown ence ofthose tients Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas imaging) (AdaptedfromRef. 217). pregnancy (PRL: prolactin; BCR: bromocriptine; MRI: magnetic resonance Figure 8. not require DA during pregnancy (216-219). DAduringpregnancy not require risk,anditisallowedinpatients whodid tumor growth 10to68% (217). studies was27%,rangingfrom ­ afterpreg remission hyperprolactinemia andapoptosis. The medianrateof of tumor necrosis caninduce areas duringpregnancy levels ofestrogen (216,217).Ithasbeensuggested thathigh pregnancy asymptomatic tumorenlargement mayoccurduring mayoccur.disappearance, afterpregnancy Moreover, orevencompletetumor becausereduction, reassessed After pregnancy, PRLlevelsandtumorsizeshouldbe Follow-up Macroprolactinoma multiple pregnancies, or congenitalmalformations multiple pregnancies, disease, trophoblastic ectopicpregnancies, abortions, inspontaneous not beenfoundtocauseany increase forlessthan6weeksofgestationhas to thesedrugs exposure induction. Indeed,short-term pregnancy seem tobeequallysafeforthefetus,whenused COMMENT 15: pregnancy throughout maybeused or headachecomplaints,thedrug andvisualand/ in patientswithmarkedgrowth or cases harboringinvasivemacroprolactinomas inselected Nevertheless, isconfirmed. pregnancy andshouldbediscontinuedassoon pregnancy toinduce a dopamineagonistisonlynecessary COMMENT 14: macroprolactinoma Microprolactinoma and intrasellar Breastfeeding doesnotseemtobeassociated with Breastfeeding BRC mantainanceevaluated Headache and/orvisual Algorithm suggestedfortheprolactinomamanagementduring in individualcases impairment Clinical follow-upeachmonth+ evaluation 3/3months Clinical follow-up In thelarge majorityofcases, Bromocriptine andcabergoline Bromocriptine Neurophtalmologic . months each 3 without contrast Sellar MRI levels reassedafterdelivery Sellar MRIandPRLserum nancy in eight serum levelsreassed Sellar MRIandPRL failure orapoplexy Medical treatment reintroduction Neurosurgery after delivery BRC . 255

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 256 trial,adjunctive useful. Indeed, inaplacebo-controlled cases, usingaripiprazoleas adjunctive therapymaybe (46-48). In these antipsychotics may be inappropriate antipsychotic suchasaripiprazole orotheratypical switching toadifferent on antipsychotictreatment, onPRL(e.g.,risperidone)(43,46). effects with robust to antipsychotics as alternatives may also serve drugs these (43,46).Therefore, ofthosetreated subgroup only amildelevationinPRLlevels,and olanzapine, lurasidone, asenapine, or clozapine, cause antipsychotics, suchasquetiapine, Other atypical (46,228). antipsychotic-induced hyperprolactinemia therapyforpatientswith it maybeusedasalternative them(46,228).Thus, levels and may oftendecrease onPRL agonist,ithasaneutraleffect D2 receptor AAPs other or Because theatypicalantipsychoticaripiprazoleisapartial aripiprazole to Switching and (ii)addingDAtherapy(41). on PRLlevels(41,209-211) (AAPs) withaloweffect toaripiprazoleorotheratypical antipsychotics drug include(i)switchingtheoffending hyperprolactinemia psychotropic-induced patients withconfirmed lesion (4,46). exclude ordiagnoseasellarregion to of therapy, MRIshouldbeperformed thenpituitary doesnotcoincidewiththeinitiation hyperprolactinemia ofpsychiatricsymptomsand iftheonsetof of arelapse cannotbesafelywithdrawn duetotherisk the drug consultation withthepatient’spsychiatrist(4,46).If substitute themedicationshouldalwaysbemadein the decision to withdraw or PRL (4). Nevertheless, is suspected and then remeasuring hyperprolactinemia ifpsychotropic-induced drug with analternative for3daysorsubstituting discontinuing thedrug urgently (4,44).EndocrineSocietyGuidelinessuggest started whenthesemedicationsare possible, particularly PRL, butinthemajorityofcases,thisisnotpractically medicationsknown toincrease psychotropic starting Ideally, abaselinePRL levelshouldbeobtainedbefore (1). orpseudo-prolactinoma macroprolactinemia, hypothyroidism, primary such prolactinomas, etiologyfor thePRLelevation, may haveanalternative hyperprolactinemia psychotropic-induced apparent It shouldalwaysbekeptinmindthatpatientswith psychotropic-induced the hyperprolactinemia? manage to How 2.10 Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas However, in patients who are clinically very stable stable However, clinically very inpatientswho are forsymptomatic proposed approaches The different most antipsychotics come from D most antipsychoticscomefrom of mechanisms of action. Indeed, the therapeutic effects DA andantipsychoticmedicationsmayhaveopposing isnotwellstudied(46,47). induced hyperprolactinemia of antipsychotic- The use of DA in the treatment therapy DA Adding andpsychoticsymptoms(230,231). microprolactinomas tumorsizeintwopatientswith levels andinreducing PRL innormalizing showntobeeffective recently adjunctive aripiprazoletherapy(49). levels wa ofPRL normalization induced hyperprolactinemia, trialinvolvingpatientswithrisperidone- controlled recently,More inadouble-blind,randomized,placebo- (229). than80%ofpatients with schizophrenia in more hyperprolactinemia drug-induced aripiprazole normalized used cautiously, indosesaslowpossible(46). itshouldbe Nevertheless, induced hyperprolactinemia. toBCRinthemanagementofantipsychotic- preferable to itshigherspecificityfortheD Due or adjunctivetreatment. aripiprazole as an alternative with severe (2 the underlyingpsychiatricdisorder didnotimpair symptomsapparently hyperprolactinemic of with lowdosesofCABorBCRforthetreatment to 6 months, the association of dopamine antagonists 8 weeks bipolar patients and had a duration ranging from and contrast, in5studiesthatinvolved174schizophrenic onhaloperidol. By in apatientwithschizophrenia treatment when BCR was added for macroprolactinoma Andrade andcols.(235)describedasimilarsituation symptoms.Likewise, Santos of thehyperprolactinemic forthetreatment patients whenCABwasintroduced schizophrenic induced psychoticexacerbationinthree acabergoline- instance, Changandcols.(234)reported For is, however, thisconcern. littleevidencetosupport orexacerbationofpsychosis(46).There trigger relapse and ofantipsychotic drugs theeffectiveness may reduce thatDAtherapy isaconcern (232,233). Thus,there in patients who do not respond to the first approach. tothefirstapproach. in patientswho donotrespond therapy. DAtherapyat low doses can be used cautiously oradjunctive the useofaripiprazoleasan alternative wouldbe antipsychotic-induced hyperprolactinemia COMMENT 16: Very interestingly, aripiprazoletherapywas DA therapy should therefore be reserved for patients forpatients bereserved DA therapyshouldtherefore s encountered in 46% of patients who received in46%ofpatientswhoreceived s encountered hyperprolactinemia The best approach for symptomatic forsymptomatic The bestapproach Arch Metab. Endocrinol 2018;62/2 2 who fail to respond to to who fail to respond receptor, CABwouldbe 2 receptor antagonism antagonism receptor 36-240). Arch Metab. Endocrinol 2018;62/2 20. 19. 18. 7. 1 16. 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES w relevant tothisarticle nopotentialconflictofinterest Disclosure:

as reported. as reported.

1974;39(5):928-35. in plasmaandpituitaryextracts. JClinEndocrinolMetab. Suh HK,Frantz AG. Size heterogeneityof human prolactin Neurol. 2014;124:185-95. Romijn JA. Hyperprolactinemiaandprolactinoma.Handb Clin Obstet GynecolSurv. 1983;38(12):689-700. Sakiyama R,QuanM.Galactorrhea andhyperprolactinemia. Am Fam Physician. 2012;85(11):1073-80. Huang W, Molitch M.Evaluationandmanagementofgalactorrhea. sexual dysfunction.JSex Med.2007;4(5):1485-93. al. Effect ofhyperprolactinemia inmalepatientsconsultingfor Corona G,MannucciE,Fisher AD, Lotti F, Ricca V, BalerciaG,et Res. 1985;22(3):196-203. Fossati P. Hyperprolactinemiaandsexual function inmen.Horm Buvat J, Lemaire A, Buvat-HerbautM,Fourlinnie JC,Racadot A, Natl Acad Sci USA. 1994;91(4):1244-7. Procfrom GT1 neuronal cell lines through prolactinreceptors. gonadotropin hormone-releasinghormonereleasebyprolactin Milenkovi J ClinEndocrinolMetab.2011;96(12):3649-60. Heaney AP. Pituitarycarcinoma:difficult diagnosisandtreatment. in children andadolescents.HormRes. 2009;72(4):197-205. Fideleff HL,BoqueteHR,SuárezMG, M.Prolactinoma Azaretzky J Endocrinol.2003;148(3):325-31. features and response to cabergoline in hyperprolactinemia. Eur Somma C,etal.Genderdifferences intheprevalence,clinical Colao A, Sarno AD, Cappabianca P, Briganti F, R,Di Pivonello 2016. p.15-29. Endocrinology, 6thed.).RiodeJaneiro: GuanabaraKoogan; (editor). In: Vilar L,editor. EndocrinologiaClínica,6a ed. (Clinical R,Colao Auriema R,Pivonello A. Prolactinomas. In: Vilar L Endocrinol Metab.2006;91(12):4769-75. sectional studyintheprovince ofLiege,Belgium.JClin Beckers A. Highprevalenceofpituitaryadenomas:across- Daly AF, RixhonM, Adam C,Dempegioti A, Tichomirowa MA, prolactinomas. Pituitary2005;8(1):3-6. Ciccarelli A, Daly AF, Beckers A. The epidemiologyof Lancet. 1998;352:1455-61. Colao A, Lombardi G. Growth hormone and prolactin excess. Am. 2015;44(1):71-8. Glezer A, BronsteinMD.Prolactinomas. EndocrinolMetabClinN Metab. 2012;97(7):2211-6. hyperprolactinemia andnegative sellarimaging.JClinEndocrinol Glezer A, BronsteinMD. Approach tothepatient withpersistent guideline. JClinEndocrinolMetab.2011;96(2):273-88. hyperprolactinemia: An Endocrine Society clinical practice Montori VM, Schlechte JA, etal.Diagnosisandtreatmentof Melmed S,CasanuevaFF, Hoffman AR, KleinbergDL, 2010.Philadelphia: Saunders/Elsevier; p.333-57. In: DeGrootLJ, Endocrinology. Jameson JL,editors. 6thed. of prolactinsecretionandprolactinomas. Bronstein MD.Disorders 2016. p.3-14. Endocrinology, 6thed.).RiodeJaneiro: GuanabaraKoogan; In: Vilar L,editor. EndocrinologiaClínica,6aed.(Clinical hiperprolactinemia (Diagnosticevaluation of hyperprolactinemia). Vilar L,NavesLA,FleseriuM. Avaliação diagnósticada hyperprolactinemia. Arq BrasEndocrinolMetab.2014;58(1):9-22. Vilar L,FleseriuM,BronsteinMD.Pitfallsinthediagnosisof ć L,D’Angelo G,Kelly PA, Weiner RI.Inhibitionof Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas 28. 27. 26. 25. 24. 23. 22. 21. 40. 39. 38. 37. 36. 35. 34. 33. 32. 31. 30. 29. Thirunavakkarasu K,DuttaThirunavakkarasu P, SridharS,Dhaliwal L,Prashad Biochem Biophys Res Commun.1989;165(1):299-305. is covalently boundtoimmunoglobulininhumanamnioticfluid. Heffner LJ, GramatesLS, Yuan RW. A glycosylatedprolactinspecies Endocrinol Metab.2005;90(5):3036-44. in macroprolactinemiaduetoanti-PRLautoantibodies.JClin Immunoglobulin Gsubclassesandprolactin(PRL)isoforms Hattori K, Nakaya N,Ikekubo Y, Kitagawa K,Inagaki C. 1995;80(8):2342-6. macroprolactinemia orprolactinoma.JClinEndocrinolMetab. monomeric prolactinwithanimmunoglobulinGinpatients Some formsofbigprolactinbehaveasacomplex Cavaco B,Leite V, Santos MA, Arranhado E,Sobrinho LG. Metab. 1996;81(2):586-90. women andtheheterogeneityofitsetiologies.JClinEndocrinol Hattori N. The frequency ofmacroprolactinemiainpregnant apituitarytumor.presenting like Am JMed.1985;78(2):346-50. Jackson RD, Wortsman J, Malarkey WB. Macroprolactinemia Metab. 1985;61(2):258-64. hyperprolactinemia and normal menses. J Clin Endocrinol a largemolecularweightprolactininwomenwithidiopathic Jackson RD, Wortsman J, Malarkey WB. Characterizationof physiological significance.Endocr Rev. 1995;16(3):354-69. Sinha YN. Structuralvariantsofprolactin:occurrence and 94:114-21. Pseudoprolactinomas. Trans Am ClinClimatol Assoc. 1983; Randall RV, Scheithauer BW, Laws,ERJr, Abboud CF. 303. case report and review of literature. Endocr Pract. 2002;8(4):296- Frieze TW, MongDP, Koops MK. “Hook effect” inprolactinomas: case report. Neurosurgery. 1998;42(4):913-5. low serumprolactin:thepitfallof “high-dose hookeffect”: Barkan AL, Chandler WF. Giantpituitaryprolactinomawithfalsely 2006;79(1):41-3. serum prolactin:thesignificanceof‘hookeffect’. JNeurooncol. ES, etal.Giantinvasivepituitaryprolactinomawithfalselylow Fleseriu M,Lee M,PineyroMM,SkugorReddy SK,Siraj Endocr Pract. 2010;16(1):42-6. Giantprolactinoma andeffectiveness of medical management. Acharya SV, GopalRA,MenonPS,Bandgar TR, ShahNS. Diabetes MetabDisord.2013;12(1):3. Giantprolactinoma: case report and review of literature.J Rahmanian M,MeybodiHA,LarijaniB,Mohajeri-Tehrani MR. Endocrinol Invest. 2008;31(5):436-44. results of a Brazilian multicenter study with 1234 patients. J R Jr, etal.Diagnosisandmanagementofhyperprolactinemia: Vilar L, Freitas MC,Naves LA, Casulari LA, Azevedo M, Montenegro Clin North Am. 2001;30(3):585-610. Molitch ofprolactinsecretion.EndocrinolMetab ME.Disorders prolactin levels.IntJGynaecolObstet.1985;23(6):459-62. Ferriani RA,Sá MFS.Effect ofvenipuncturestressonplasma the collection? Arq BrasEndocrinolMetab.2006;50(3):569-70. Evaluation ofplasmaprolactinlevels:isitnecessarytorestbefore JH, Vieira JGH,Oliveira Tachihana T, MacielRMB,Hauache OM. Endocr Pract. 2007;13(4):396-402. growth hormoneandprolactinwithuseofcabergolinetherapy. ofadenomascosecreting Coelho CE.Substantialshrinkage Vilar L, Czepielewski MA, Naves LA, Rollin GA, Casulari LA, Biochem Med(Zagreb).2012;22(2):171-9. Macroprolactinemia: new insights in hyperprolactinemia. Kasum M,Oreskovic S,ZecI,Jezek D, Tomic V, Gall V, etal. infertile women.Endocrine.2013;44(3):750-5. GR, GainderS,etal.Macroprolactinemiainhyperprolactinemic 257

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 258 60. 59. 58. 57. 56. 55. 54. 53. 52. 51. 50. 49. 48. 47. 46. 45. 44. 43. 42. 41. Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas molecule inmacroprolactinemia. JEndocrinol.2006;190(2):287-93. Anti-prolactin (PRL)autoantibody-binding sites(epitopes)onPRL Hattori N,Nakayama Y, Kitagawa K,Ishihara T, Saiki Y, Inagaki C. pitfall? Endocrine.2012;41(2):169-70. Bronstein MD.Editorial:ismacroprolactinemia justadiagnostic studies. ClinEndocrinol(Oxf).2002;57(3):327-31. Screening for macroprolactinaemia and pituitary imaging Hauache OM,Rocha AJ, Maia AC Jr, MacielRM, Vieira JG. hyperprolactinaemia. ClinEndocrinol(Oxf).1992;37(4):365-72. Friesen HG.Characterizationofbig,bigprolactininpatientswith Leite V, CosbyH,Sobrinho LG,Fresnoza MA, Santos MA, 2005;90(7):3927-32. of routinescreeningformacroprolactin.JClinEndocrinolMetab. Gibney J, Smith TP, McKenna TJ. The impactonclinicalpractice J ClinEndocrinolMetab.2006;91(3):1048-55. bioassay. viaitshomologousreceptorinanew sensitive activity Goffin V, etal.Humanmacroprolactindisplayslowbiological Glezer A, Soares CR, Vieira JG,Giannella-NetoD,RibelaMT, distinct confoundingentities.Pituitary. 2016;19(4):458-9. Oliveira A Jr. Hookeffect andlinearrangeinprolactinassays: do Carmo Dias Gontijo M, de Souza Vasconcellos L, Ribeiro- Clin EndocrinolMetab.2013;27(6):743-4. Stenman UH. Pitfalls in hormone determinations. BestPract Res macroprolactinomas. ClinEndocrinol(Oxf).1996;44(3):305-9. be missedbyimmunoradiometricassay in patientswith St-Jean E,BlainF, ComtoisR.Highprolactinlevelsmay domperidone. Arch EndocrinolMetab.2016;60 (Suppl.3):S22. Very highprolactinlevelsassociatedtochronic therapywith Vilar L,Lyra R, Albuquerque JL,Lyra R, Vilar CF, DinizET, etal. with fluoxetine. JClinPsychiatry. 2006;67(6):952-7. duringtheacutephaseoftreatment disorders major depressive Klibanski A, etal.Serum prolactin levelsamongoutpatientswith Papakostas GI,MillerKK,Petersen T, SE, KG,Hilliker Sklarsky placebo-controlled trial. Am JPsychiatry. 2007;164(9):1404-10. aripiprazole, forantipsychotic-induced hyperprolactinemia:a al. treatmentwithadopaminepartialAdjunctive agonist, Shim JC,ShinJG,Kelly DL, Jung DU, Seo YS, LiuKH,et Pharmacother. 2003;37(2):206-8. hyperprolactinemia with substitution of quetiapine. Ann Kunwar AR, Megna JL. Resolution of risperidone-induced 2014;55(1):29-36 hyperprolactinemia: aclinical review. Psychosomatics. Ajmal A, Joffe H,Nachtigall LB.Psychotropic-induced survey. JClinPsychopharmacol. 2008;28(6):686-90. Antipsychotic- inducedhyperprolactinemia: across-sectional Johnsen RA, E, Kroken Abaza M,OlbergH,Jørgensen HA. pharmacovigilance database. Therapie. 2003;58(2):159-63. hyperprolactinemia: acase-non-casestudyfromthenational Petit A, PiednoirD,Germain ML, Trenque T. Drug-induced hyperprolactinemia. Ther ClinRiskManag.2007;3(5):929-51. La Torre D,Falorni A. Pharmacologicalcausesof 2013;9(8):955-68. and therapeuticconsequences.Expert OpinDrugMetab Toxicol. induced hypo- andhyperprolactinemia: mechanisms, clinical Voicu V, Medvedovici A, Ranetti AE, R 61 (Suppl.3):S11. patients withhyperprolactinemia. Arch EndocrinolMetab.2017; IS, etal.Demographic,clinical,andlaboratorialfeaturesof770 Vilar L, Albuquerque JL, Vilar CF, Ferreira LA,CardosoIRA,Inacio macroadenoma. ClinEndocrinol(Oxf).2006;65(4):524-9. 226 patientswithhistologicallyverifiednon-functioningpituitary disconnection hyperprolactinaemia needre-definition? Astudyof Ansorge O, MestonN,etal.Dothelimitsofserumprolactinin Karavitaki N, Thanabalasingham G,ShoreHC, Trifanescu R, ă dulescu F Ş . Drug- 67. 66. 65. 64. 63. 62. 61. 79. 78. 77. 76. 75. 74. 73. 72. 71. 70. 69. 68. Hattori N,Ishihara T, Saiki Y. Macroprolactinaemia:prevalenceand Invest. 1995;55(2):139-47. molecular weightprolactin(150-170 kDPRL).Scand JClinLab T, Torjesen P. Frequency ofhyperprolactinaemia duetolarge Bjøro T, MørkridL, Wergeland R, Turter A, Kvistborg A, Sand Metab. 2010;54(9):856-62. with polyethylene glycolprecipitation. Arq BrasEndocrinol monomeric formdoesnoteliminatescreeningformacroprolactin AO, etal.Hyperprolactinemia: new assaymorespecific forthe Vieira JGH, Tachibana TT, Ferrer CM,deSá J, BiscollaRP, Ana Hoff Endocrinol Metab.2002;87(12):5410-5. prolactin (macroprolactin)bycommercialimmunoassays.JClin variability inthedetectionofprolactinseracontainingbig Smith TP, Suliman AM, Fahie-Wilson MN,McKenna TJ. Gross 1998;44(8):1758-9. as ascreeningmethodformacroprolactinemia.ClinChem. experience and validation of polyethylene glycol precipitation Vieira JGH, Tachibana TT, ObaraLH,MacielRMB.Extensive macroprolactinemia. JClinEndocrinolMetab.1996;81(7):2512-4. of psychological erectiledysfunctionbecauseofthepresence Guay AT, Sabharwal P, Varma S,Malarkey WB. Delayeddiagnosis Endocrinol (Oxf).2014;80(4):616-8. women underinvestigation forpolycysticovary syndrome.Clin CR, Kobayashi NK,etal.Evaluationofmacroprolactinemiain259 Hayashida SA, Marcondes JA, Soares JM Jr, Rocha MP, Barcellos I, Chang-Verdugo R,Chinolla-ArellanoLZ.Frequency of Leaños-Miranda A, Ramírez-Valenzuela KL, Campos-Galicia and pathogenicsignificance.ClinDev Immunol.2012;2012:167132. Shimatsu A, Hattori A. Macroprolactinemia:diagnostic, clinical, solution. South MedJ. 2006;99(11):1206. Fahie-Wilson M. The macroprolactinemiaproblem andits hyperprolactinemia. Arq Bras EndocrinolMetab.2007;51(1):86-91. al. Prevalence ofmacroprolactinemiaamong115 patientswith Vilar L,MouraE,Canadas V, Gusmão A, Campos R,Leal E,et 2015;172(6):687-95. strategy fromthestudyof222patients.EurJEndocrinol. Raverot G,etal.Macroprolactinaemia:abiologicaldiagnostic Parlant-Pinet L,Harthé C,Roucher F, Morel Y, Borson-ChazotF, Endocrine. 2012;41(2):327-33. al. Clinicalandradiologicalfindingsinmacroprolactinemia. D, Isik S,Berker Tutuncu YA, OzuguzU, F, Gokay ErdenG,et radiological features.EurJClinInvest. 2007;37(7):552-7. Spada A, etal.Patients withmacroprolactinaemia:clinicaland Donadio F, Barbieri A, Angioni R,Mantovani G,Beck-Peccoz P, Neurosurg. 2008;18(3):223-7. differential diagnosisofhyperprolactinemic patients. Turk A, Polat G,etal. The importance ofmacroprolactinemiainthe Ba 2005;60(4):190-7. significance and characterization ofthecondition. ActaClinBelg. Hooghe-Peeters EL, Velkeniers B.Macroprolactinemia: clinical Theunissen C,DeSchepper J, Schiettecatte J, Verdood P, macroprolactinaemia. ClinEndocrinol(Oxf).2003;59(3):339-46. Beckett GJ. Clinicalandradiologicalfeaturesofpatientswith Strachan MW, Teoh WL, Don-Wauchope AC, Seth J, Stoddart M, patients. JClinEndocrinolMetab.2002;87(2):581-8. Enjalbert A, etal.Macroprolactinemiarevisited:astudyon106 Vallette-Kasic S,Morange-Ramos I,Selim A, GunzG,MorangeS, glycol. Ann ClinBiochem. 1997;34:252-8. of ascreeningtestbasedonprecipitationwithpolyethylene hyperprolactinemia inadistrict generalhospitalandevaluation Fahie-Wilson MN,Soule SG.Macroprolactinemiacontributionto (Oxf). 2009;71(5):702-8. ClinEndocrinol aetiologies inalargegroupofhospitalworkers. ğ dato ğ lu C,Ba ğ dato ğ lu OT, MusluN,Köseo Arch Metab. Endocrinol 2018;62/2 ğ lu A, Da lu A, ğ tekin Arch Metab. Endocrinol 2018;62/2 97. 96. 95. 94. 93. 92. 91. 90. 89. 88. 87. 86. 85. 84. 83. 82. 81. 80. B, etal.Prolactinomas resistanttostandard dopamine agonists Colao A, DiSarno A, Sarnacchiaro F, Ferone D, DiRenzo G, Merola Nat ClinPract EndocrinolMetab.2006;2(10):552-61. Olafsdottir A, Schlechte J. Managementofresistant prolactinomas. Metab. 1987;64(2):391-4. macroadenoma: possiblerolefor estrogen.JClinEndocrinol Testosterone-related exacerbation ofaprolactin-producing Prior JC,Cox TA, Fairholm D,Kostashuk E,NugentR. 1997;82(9):2962-5. of proto-oncogeneexpression.JClinEndocrinolMetab. carboplatin andetoposide;immunocytochemical analysis PH. Metastaticprolactinoma:effect ofoctreotide,cabergoline, Hurel SJ, Harris PE,McNicol AM, Foster S, Kelly WF, Baylis mRNA levels.EurJEndocrinol.2012;166(3):383-90. correlated withreductionofdopamineD2receptorlongisoform Usui T, etal.Resistance todopamineagonistsinprolactinomais Shimazu S,Shimatsu A, Yamada S,InoshitaN,Nagamura Y, to dopamineagonists.Neuroendocrinology. 2009;89(2):163-70. differentially andresistant expressedinprolactinomasresponsive Passos VQ, Fortes MAHZ,Giannella-NetoD,BronsteinMD.Genes bromocriptine. ClinEndocrinol(Oxf).1994;41(6):821-6. hyperprolactinaemic patients whoare resistant to or intolerant of CW.Vilar L,Burke Quinagolideefficacy andtolerabilityin Neurooncol. 2014;117(3):421-8. Molitch ME. Management of medically refractory prolactinoma.J Pituitary. 2005;8(1):43-52. Molitch ME.Pharmacologicresistanceinprolactinomapatients. treatment ofprolactinomas.EndocrRev. 2006;27(5):485-534. Gillam MP, Molitch MP, Lombardi G,Colao A. Advances inthe Study Group.NEnglJMed.1994;331(14):904-9. of hyperprolactinemic amenorrhea. CabergolineComparative comparison ofcabergolineandbromocriptineinthetreatment Webster J, PiscitelliG,Polli A, Ferrari CI,IsmailI,Scanlon MF. A controlled trialsandmeta-analysis.Pituitary. 2011;14(3):259-65. hyperprolactinemia: asystematic reviewofrandomized bromocriptineinthetreatmentof CR. Cabergolineversus dos Santos Nunes V, El DibR, Boguszewski CL, Nogueira Diabetes. 2013;121(4):201-5. prevalence and clinical significance. Exp Clin Endocrinol K, etal.Macroprolactinemiainpatientswithprolactinomas: Elenkova A, Genov N, Abadzhieva Z, Kirilov G, Vasilev V, Kalinov Endocrinol Metab.2017;61 (Suppl. 3):S8. study.macroprolactinemia: resultsfromaprospective Arch E, etal.ClinicalandMRIfindingsamong 120 patients with Vilar L, Vilar CF, Albuquerque JL,GadelhaPS, Thé AC, Trovão Minerva Endocrinol.2007;2(2):79-86. with macroprolactinemiaormonomerichyperprolactinemia. et al.Clinicalandlaboratoryfeaturesgreatlyoverlap in patients Vilar L,NavesLA, Freitas MC,Lima M, Canadas V, Albuquerque JL, macroprolactinaemia. EurJEndocrinol.2012;166(4):625-9. Hattori N, Adachi T, Ishihara T, Shimatsu A. The naturalhistoryof 2014;58 (Suppl1):S17-18. with idiopathichyperprolactinemia. Arq BrasEndocrinolMetab. MM, etal.Prevalence ofmacroprolactinemiaamongpatients Vilar L,GadelhaPS,Rangel FilhoF, Siqueira A, Viana KF, Fonseca Health. 2009;12(6):930-4. costs inpatientswithelevatedserumprolactinlevels. Value identifying macroprolactinemiaonhealth-careutilizationand de Soárez PC,Souza SC, Vieira JG,Ferraz MB. The effect of 2013;2013:478282. etiology andclinicalmanifestations.IntJEndocrinol. with menstrualirregularities, galactorrhea, and/orinfertility: macroprolactinemia inhyperprolactinemic womenpresenting Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas 103. 102. 101. 100. 99. 98. 114. 113. 112. 111. 110. 109. 108. 107. 106. 105. 104.

resistance orintolerancetodopamineagonists.Pituitary. in hyporesponsive prolactinomas:analysisofpatients with Hamilton DK, Vance ML,Roulos PT, LawsER.Surgicaloutcomes 2012;166(5):779-86. in dopamineagonist-resistantpatients.EurJEndocrinol. surgery in prolactinomas: improvement of hormonal control Primeau V, Raftopoulos C,MaiterD.Outcomesoftranssphenoidal 2017;49:EP975. of cabergoline-resistant prolactinomas. Endocrine Abstracts. The useofincreasingdosescabergolineinthemanagement Vilar L, Vilar C, Albuquerque JL,GadelhaP,Thé AC, Trovão E,etal. 53(1):53-60. prolactinomas. ClinEndocrinol(Oxf).2000; dopaminereceptortype2agonists,inthetreatmentof selective Cerbone G,etal. The effect ofquinagolideandcabergoline,two Di Sarno A, LandiML,MarzulloP, DiSomma R, C,Pivonello 93(12):4721-7. prolactinomas in150 patients.JClinEndocrinolMetab. 2008; al. Prospective studyofhigh-dosecabergolinetreatment Ono M,MikiN,Kawamata T, MakinoR, Amano K,Seki T, et Pract. 2011;17(3):e55-8. in twopatientswithcabergolineresistantprolactinomas.Endocr Iyer P, Molitch ME.Positive prolactinresponsetobromocriptine Metab. 1997;82(3):876-83. respond tochronic cabergolinetreatment.JClinEndocrinol 2017;49:EP841. prolactinoma – a case report.an aggressive Endocrine Abstracts. al. Effect oftheadditionlanreotide autogeltothetreatmentof Vilar L, Vilar C, Albuquerque JL,GadelhaP, Thé AC, Trovão E,et Pituitary. 2011;14(4):351-7. in acaseofdopamine-agonist resistant macroprolactinoma. Efficacy ofthecombinedcabergoline andoctreotidetreatment Fusco A, Lugli F, Sacco E, L, BianchiTilaro A, Angelini F, et al. J ClinEndocrinolMetab.2002;87(10):4447-51. an aromataseinhibitorinthetreatmentofagiantprolactinoma. high dosesofcabergolineandacombinationtestosterone Gillam MP, Middler S,Freed DJ, Molitch ME. The novel useofvery agonist treatment.EurJEndocrinol.2009;161(1):163-9. by clomipheneinmaleswithprolactinomasunderdopamine Ribeiro RS, Abucham J. Recovery hypogonadism of persistent 3):S28. cabergoline therapy. Arch EndocrinolMetab.2017;61 (Suppl. of hypogonadism inmalepatientswithprolactinomasunder Thé AC, etal. The roleofclomiphenecitrateintheresolution Vilar L, Vilar CF, Aroucha PT, Albuquerque JL, Gadelha PS, pituitary adenomas.Neuroendocrinology. 1982;34(5):339-42. administration on prolactin release by invasive prolactin-secreting Lamberts SWJ, Verleun T, OosteromR.Effect oftamoxifen Cell Biol.2001;116(3):215-22. apoptosis in lactotrophs induced by bromocryptine. Histochem Aoki MDP, Aoki A, MaldonadoCA.Sexual dimorphismof ovariectomized rats.Endocrinology. 1986;119(6):2484-9. in the anterior pituitary of the number of dopamine receptors Pasqualini C,BojdaF, Kerdelhue B.Directeffect ofestradiolon Nature. 1975;255(5508):497-8. secretion and mitosis in prolactin cells. bromocriptine on in vivo Lloyd GM,MearesJD,Jacobi J. Effects ofoestrogenand gene. JBiolChem.1982;257(5):2133-6. Maurer RA.Estradiolregulatesthetranscriptionofprolactin 2012;167(5):651-62. cabergoline: amulticenterstudyof92patients.EurJEndocrinol. P, Vilar L,etal.Prolactinomas resistanttostandarddosesof Vrooner L,Jaffrain-Rea M-L,Petrossians P, Tamagno G,Chanson 2005;8(1):53-60. 259

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 260 133. 132. 131. 130. 129. 128. 127. 126. 125. 124. 123. 122. 121. 120. 119. 118. 7. 11 116. 115. Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas

Psychosomatics. 2013;54(4):387-91. inapatientwithprolactinoma. induced impulsecontroldisorders Almanzar S, Zapata-Vega MI, Raya JA. Dopamine agonist- 2012;24(4):E54. with undiagnoseddepression.JNeuropsychiatry ClinNeurosci. Bilal L,ChingC.Cabergoline-induced psychosis inapatient 2009;190(2):97. hypersexuality incabergoline-treatedprolactinoma.MedJ Aust. Falhammar H, Yarker JY. Pathological gambling and Neuropsychiatry ClinNeurosci.2007;19(4):473-4. therapy inapatientwithpituitaryprolactinoma.J Davie M.Pathological gambling associatedwithcabergoline 2012;53(6):595-600. episode mania. Psychosomatics.Cabergoline associatedwithfirst Harris YT, Harris AZ, DeasisJM,Ferrando SJ, Reddy N, Young RC. Neuropharmacol. 2011;34(5):179-81. medication inpatientswithpituitaryadenomas.Clin P. associated withdopaminergic Impulsecontrol disorders Martinkova J, Trejbalova L,Sasikova M,BenetinJ, Valkovic approaches. Mov Disord.2015;30(2):150-9. inParkinson’sdisorders andfuture disease:Controversies Chaudhuri K, Brown RG, et al. Management of impulse control Samuel M,Rodriguez-Oroz M, Antonini A, Brotchie JM,Ray 2012;24(4):E54. with undiagnoseddepression.JNeuropsychiatry ClinNeurosci. Bilal L,ChingC.Cabergoline-inducedpsychosis inapatient bipolar Idisorder:acasereport. Asian JPsychiatr. 2016;22:94-5. M. Cabergolinecaninducemaniawithpsychotic featuresin Rovera C,Cremaschi L, Thanju A, Fiorentini A, MauriMC,Serati 2010;207(4):645-59. Psychopharmacologyrelated impulsecontrolbehaviors. (Berl). V, choice etal.Impulsive andresponseindopamineagonist- Voon V, Reynolds M,Ekanayake B, Brezing C,GalleaSkaljic 2016;6(3):229-23. induced manicepisode:casereport. Ther Adv Psychopharmacol. Yüksel RN,ElyasKaya Z,DilbazN,Cingi Yirün M.Cabergoline- dailymed/drugInfo.cfm?id=31309. Accessed on: April 7, 2017. Information. 2010 Available from:http://dailymed.nlm.nih.gov/ National LibraryofMedicine.DailyMedCurrent Medication 2016;15(4):503-12. of treatmentsforprolactinomas.Expert OpinDrugSaf. Auriemma RS,GrassoLF, R,Colao Pivonello A. The safety resistant totemozolomide. Pituitary. 2012;15(1):37-43. Honnorat J, et al. New targeted therapies in pituitary carcinoma Jouanneau E, Wierinckx A, DucrayF, Favrel V, Borson-ChazotF, 2012;76(6):877-86. dopamine agonist-resistantprolactinomas.ClinEndocrinol(Oxf). Eva P, King AP, etal. Temozolomide inthemanagementof D, Whitelaw BC, Dworakowska Thomas NQ, Barazi S, Riordan- reports. NeurooncolPract. 2016;3(3):188-95. carcinomas andatypicaladenomas:systematicreviewofcase Ji Y, Vogel RI,Lou E. Temozolomide treatmentofpituitary Pituitary.2017;20(2):261-6. andwhenshoulditbeused? treating pituitarytumours Halevy C, Whitelaw BC.Howeffective istemozolomide for antisecretory profile.EurJEndocrinol.2002;146(5):707-16. release inhibitingfactor(SRIF)receptorbindingandaunique a novel somatostatinpeptidomimeticwithbroadsomatotropin Bruns C,Lewis I,BrinerU, Meno-Tetang G, Weckbecker G.SOM230: 1999;84(9):3268-76. subtypes inhumanprolactinomas.JClinEndocrinolMetab. andfunctional expressionofsomatostatinreceptor Quantitative Jaquet P, QouafikL, Saveanu A,GunzG,Fina F, DufourH,etal. 139. 138. 137. 136. 135. 134. 151. 150. 149. 148. 147. 146. 145. 144. 143. 142. 141. 140. Engl JMed.2007;356(1):29-38. Dopamine agonistsand the risk of cardiac-valve regurgitation. N Schade R, F,Andersohn SuissaS,Haverkamp W, GarbeE. Parkinson’s disease.NEnglJMed.2007;356(1):39-46. Valvular heart diseaseandtheuseofdopamineagonistsfor Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G. patients with PRL adenomas. Eur J Endocrinol. 2012;167(3):327-35. ABCB1 predictsideeffects oftreatmentwithcabergolinein A, Stalla GK, et al. Polymorphisms of the drug transporter gene Athanasoulia AP, C,IsingM,Brockhaus Sievers AC, Yassouridis Proc invivo. Natl activity Acad Sci US A. 2000;97(7):3473-8. correlation ofoneallelewithP-glycoprotein expressionand multidrug-resistance gene: multiple sequence variations and J, Johne A, etal.Functional polymorphismsofthe human 136.Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller 2014;17(2):150-6. agonist therapy for hyperprolactinemia: a pilot study. Pituitary. KK, etal.Investigation inpatientsondopamine ofimpulsivity M,Evins Barake AE, Stoeckel L,Pachas GN,Nachtigall LB,Miller 2014;80(6):863-8. pituitary adenomas:acase-controlstudy. ClinEndocrinol(Oxf). dopamine agonist-treatedprolactinomasandnonfunctioning D, Nippoldt inpatientswith TB. Impulsecontroldisorders Bancos I,Nannenga MR,Bostwick JM,SilberMH,Erickson with prolactinomas. Pituitary. 2012;15(1):44-9. bromocriptine ontheriskofvalvular heart diseaseinpatients de Souza AM, Azevedo M. A comparisonofcabergolineand Boguszewski CL,dosSantos CM,SakamotoKS,MariniLC, Lancet DiabetesEndocrinol.2015;3(11):906-13. prolactinoma: asystematicreview andadditionalclinicaldata. to detect cabergoline-associated valvulopathy in patientswith Caputo C,Prior D,Inder WJ. The needforannualechocardiography observational studies.Herz.2013;38(8):868-80. of fibrosisandinsufficiency ofcardiacvalves.Meta-analysis De Vecchis R,EspositoC, Ariano C.Cabergolineuseandrisk reporting bias?ClinEndocrinol(Oxf).2011;74(5):608-10. disease andlow-dose dopamineagonisttherapy:anartefact of Gu H,Luck S,Carroll PV, Powrie J, J. Chambers Cardiacvalve in healthy subjects.CircJ. 2011;75(11):2699-704. Prevalence andcorrelates ofphysiological valvularregurgitation al. et H,Takada OzakiT, I, Y, H,TodaOkura Yamagishi A, Yamabe two-dimensional echocardiography. Am Heart J. 1989;117(3):636-42. echocardiography inpatientswithstructurallynormalhearts by Thomas JD,etal.Prevalence ofvalvularregurgitationbyDoppler Choong CY, Abascal VM, Weyman J, Levine RA,GentileF, Metab. 2010;95(3):1025-33. of dopamineagonistsinhyperprolactinemia. JClinEndocrinol Valassi E,Klibanski A, BillerBM.Potential cardiacvalveeffects 2009;24(3):344-9. use andtheriskofvalvularheart disease.Mov Disord. Tan LC,NgKK, Au WL, Lee RK,Chan YH, Tan NC.Bromocriptine Cardiol Rev. 2002;10(6):334-6. valvular heart diseasesubsequenttobromocriptinetreatment. Serratrice J, DisdierP, HabibG, Viallet F, Weiller PJ. Fibrotic Pathol. 2010;38(6):837-48. Elangbam, C.S.Drug-inducedvalvulopathy: anupdate. Toxicol 2007;356(1):6-9. Roth BL. Drugs and valvular heart disease. N Engl J Med. 2015;29(12):985-98. disease: asystematicreviewofobservationalstudies.CNSDrugs. dopamineagonistuseinpatientswithParkinson’sergot-derived regurgitation andheart failureassociatedwithergot-andnon- Tran T, Brophy JM,SuissaS,Renoux C.Risksofcardiacvalve Arch Metab. Endocrinol 2018;62/2 Arch Metab. Endocrinol 2018;62/2 167. 166. 165. 164. 163. 162. 161. 160. 159. 158. 157. 156. 155. 154. 153. 152. single centerexperience. Pituitary. 2012;15(1):25-9. prolactinomas andoutcomeofdopamine agonistwithdrawal: a Karathanassi E,KitaM.Long termfollow-up ofpatientswith Anagnostis P, Adamidou F, Polyzos SA, Efstathiadou Z, (Oxf). 2011;75(6):819-24. commonly especiallyinmacroprolactinoma. ClinEndocrinol dopamine agonisttherapyinpatients withprolactinomaoccurs Recurrence ofhyperprolactinaemia followingdiscontinuationof Barber TM, Kenkre J, Garnett C, Scott RV, Byrne JV, Wass JA. agonist withdrawal. ClinEndocrinol(Oxf).2010;72(4):507-11. determining the remission ofmicroprolactinomasafter dopamine Huda MS, Athauda NB, Teh MM,Carroll PV, Powrie J. Factors therapy. JClinEndocrinolMetab.2009;94(7):2428-36. hyperprolactinemia after withdrawal of long-term cabergoline Kharlip J, Salvatori R, Yenokyan G, Wand GS.Recurrence of (Oxf). 2005;63(1):26-31. therapy insubjectswithmicroprolactinomas.ClinEndocrinol Long-term remission followingwithdrawal ofdopamineagonist Biswas M, Smith J, Jadon D, McEwan P, Rees DA, Evans LM, et al. 2007;67(3):426-33. term withdrawal of cabergoline therapy. Clin Endocrinol (Oxf). F, etal.Predictors ofremissionhyperprolactinaemia after long- Colao A, Di Sarno A, Guerra R, Cappabianca P, E, Pivonello Caranci 2003;349(21):2023-33. tumoral and nontumoral hyperprolactinemia. N Engl J Med. Lombardi G. Withdrawal oflong-termcabergolinetherapy for Colao A, DiSarno A, CappabiancaP, DiSomma R, C,Pivonello 87(8):3578-82. bromocriptine withdrawal. JClinEndocrinolMetab.2002; term follow-up ofprolactinomas:normoprolactinemiaafter Passos VQ, Souza JJ, MusolinoNR,BronsteinMD.Long- (Copenh). 1979;92(3):413-27. bromocriptine inpatientswithprolactinomas. Acta Endocrinol suppression ofprolactinsecretionafter long-termtreatment with Eversmann T, Fahlbusch R, Rjosk HK, von Werder K. Persisting Metab. 2012;97(9):E1714-E19. on cardiac valves inpatients with acromegaly. J Clin Endocrinol et al.Noevidenceofadetrimentaleffect ofcabergolinetherapy Maione L,GarciaC,Bouchachi A, Kallel N,MaisonP, Salenave S, Drug Saf. 2012;35(2):159-71. hyperprolactinaemia: amulti-country, nestedcase-controlstudy. with dopamineagonistuseinParkinson’s diseaseand K, MazzagliaG,etal.Riskofcardiacvalveregurgitation Trifirò G,MokhlesMM,Dieleman JP, van Soest EM, Verhamme study. JClinEndocrinolMetab.2012;97(5):1629-34. with hyperprolactinemia: anationwide population-based cohort CM, Norrelund H,etal.Heart valvediseaseamongpatients Steffensen C,MaegbaekML,LaurbergP, M,Kistorp Andersen Metab. 2014;58(Suppl 5):S172. disease inpatientswithprolactinomas. Arq BrasEndocrinol long-term treatmentwithdopamineagonistsonvalvularheart Zaccaron BA,Sena RH,Souza AM, Boguszewski CL.Safety of 2013;169(3):359-66. valve diseaseinpatientswithprolactinomas.EurJEndocrinol. C, etal.Safety oflong-termtreatmentwithcabergolineoncardiac R,PeroneAuriemma RS,Pivonello Y, GrassoLF, Ferreri L,Simeoli 2-year follow-up study. Clin Endocrinol(Oxf).2012;77(1):99-105. in patientstreatedwithdopamineagonistsforprolactinomas,a Holman ER,etal.Changesinheart valvestructureandfunction Delgado V, BiermaszNR,van Thiel SW, NA, EweSH,Marsan treatment. EurJEndocrinol.2012;167(1):17-25. prolactinomas onlong-termbromocriptineandcabergoline prevalence ofsubclinicalcardiacvalvefibrosisinpatientswith Elenkova A, ShabaniR,Kalinov K,Zacharieva S.Increased Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas 174. 173. 172. 171. 170. 169. 168. 186. 185. 184. 183. 182. 181. 180. 179. 178. 177. 176. 175. A, Salvatori R.Second attempt towithdrawcabergolinein Kwancharoen R, Auriemma RS, Yenokyan G, Wand GS,Colao worthwhile? Front Endocrinol(Lausanne).2015;6:11. in patientswithprolactinomasafter attempt: afailedfirst isit da Fonseca MM,etal.Second attempt ofcabergolinewithdrawal Vilar L, Albuquerque JL,GadelhaPS,Rangel FilhoF, Siqueira AM, systematic reviewandmeta-analysis.Pituitary. 2015;18(5):745-51. strategy inprolactinomapatientstreatedwithcabergoline:a Hu J, ZhengX,Zhang W, Yang H.Current drugwithdrawal Clin EndocrinolMetab.2010; 95(1):43-51. of dopamine agonists: systematic review and meta-analysis. J Pereira AM. Recurrence of hyperprolactinemia after withdrawal OM,Lagro J, Burman P,Dekkers Jørgensen JO, Romijn JA, remission after withdrawal. ClinEndocrinol(Oxf).2017;86(2):207-13. associated with macroprolactinomas and analysisof factors Suzuki H,etal.Long-term resultsofcabergolinetherapyfor Watanabe S, Akutsu H, Takano S, Yamamoto T, E, Ishikawa and when?Pituitary. 2016;19(3):303-10. of dopamineagonisttherapyinprolactinomas:Inwhich patients Dogansen SC,Selcukbiricik OS, Tanrikulu S, Yarman S. Withdrawal prolactinomas. JEndocrinolInvest. 2016;39(12):1377-82. of recurrencewithdrawal factors in and possible predictive Recurrence ofhyperprolactinemia followingdopamine agonist Sala E,BellavitiButtoni P, Malchiodi E, Verrua E,CarosiG,etal. volume. JClinEndocrinolMetab.2003;88(10):4709-19. mortality, morbidity, andtheeffects ofhospital andsurgeon intheUnitedStates,1996–2000: surgery forpituitarytumors 2nd FG,Klibanski Barker A, Swearingen B. Transsphenoidal 2009;23(5):575-96. Colao A. The prolactinoma. BestPract Res ClinEndocrinolMetab. via agarose gelelectrophoresis.LabMed.2015;46(1):26-33. Anani WQ, OjerholmE, Shurin MR. Resolving transferrin isoforms 1989;32(5):346-9. bromocriptine treatmentformacroprolactinomas.SurgNeurol. Cerebrospinal fluidrhinorrhea occurring inlong-term Bronstein MD,MusolinoNR,BenabouS,MarinoRJr. review oftheliterature.NeurosurgFocus. 2012;32(6):E2. inthesettingcerebrospinal fluidleakage ofpituitaryadenomas: Lam G, Mehta V, ZadaG. Spontaneous and medicallyinduced 2000;52(1):43-9. invasiveprolactinomas.Clin Endocrinol(Oxf). for massive IA. CSFrhinorrhoea followingtreatmentwithdopamineagonists Leong KS,Foy PM,Swift AC, Atkin SL,HaddenDR,MacFarlane pii:bcr12.2008.1383 Case Rep. 2009;2009. as thepresentingfeatureofaninvasivemacroprolactinoma.BMJ F, Guilfoyle M, et al. Spontaneous cerebrospinalfluid rhinorrhoea Mankia SK, Weerakkody RA, Wijesuriya S,Kandasamy N,Finucane Am JRhinol.2002;16(1):17-23. Lund VJ. Endoscopicmanagementofcerebrospinalfluidleaks. prolactinomas. JClinNeurosci.2015;22(11):1785-91 WW, LawsER Jr. Current indications for the surgical treatment of Smith TR, HulouMM,HuangKT, Gokoglu A, CoteDJ, Woodmansee on 73patients.ClinEndocrinol(Oxf).2014;80(5):642-8. Outcome ofprolactinomaafter pregnancyandlactation:astudy Domingue ME,DevuystF, Alexopoulou O, CorvilainB,MaiterD. lactation. JClinEndocrinolMetab.2013;98(1):372-9. study onrecurrence ofhyperprolactinemia after pregnancyand M, etal.Results ofasingle-center observational10-year survey Auriemma RS,Perone Y, DiSarno A, GrassoLF, Guerra E,Gasperi Endocrinol (Oxf).2001;54(3):295-300. on prolactin levels in patients with hyperprolactinaemia. Clin S,PageKarunakaran RC, Wass JA. The effect ofthemenopause prolactinomas: apilotstudy. Pituitary. 2014;17(5):451-6. 261

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 262 206. 205. 204. 203. 202. 201. 200. 199. 198. 197. 196. 195. 194. 193. 192. 191. 190. 189. 188. 187. Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas report andreview ofliterature.JPediatr Neurosci.2011;6(2):134-7. clinical presentationina first child withgiantprolactinoma: Case Chaurasia PK, Singh D, Meher S, Saran RK, SinghH.Epistaxisas and skullbaseextension. AJR Am J Roentgenol. 1998;170(1):194-6. Levy RA,QuintDJ. Giantpituitaryadenomawith unusualorbital Neurosurg. 2002;97(2):299-306. prolactinomas: clinicalmanagement andlong-termfollowup.J RK, Shrivastava Arginteanu MS,King WA, Post KD.Giant 1997;82(7):2102-7. study.Jand proliferationmarker ClinEndocrinolMetab. related difference inthegrowthofprolactinomas:aclinical Delgrange E, Trouillas J, Maiter D, Donckier J, Tourniaire J. Sex- 2014;170(6):R213-27. challenges inmanaginggiantprolactinomas.EurJEndocrinol. Maiter D,DelgrangeE. Therapy ofendocrinedisease:the 2013;170(1):31-8. F, etal.Giant prolactinomasinwomen.EurJEndocrinol. Delgrange E,Raverot G,BexM,BurmanP, DecoudierB,Devuyst 2013;79(4):447-56. prolactinomas: thetherapeuticapproach. ClinEndocrinol(Oxf). Moraes AB, SilvaCM, Vieira NetoL,GadelhaMR.Giant invasive prolactinomas.Pituitary. 2013;16(1):68-75. knife stereotacticradiosurgeryfordrugresistantorintolerant Liu X,Kano H,KondziolkaD,Park KJ, Iyer A, ShinS,etal.Gamma prolactinomas: long-termresults.Pituitary. 2015;18(6):820-30. Gamma Kniferadiosurgeryformedicallyandsurgicallyrefractory Cohen-Inbar O, XuZ,Schlesinger D, Vance ML,SheehanJP. efficacy andtoxicity. Radiother Oncol.2009;93(3):597-601. Whittle IR,etal.Radiotherapy forpituitaryadenomas:long-term Erridge DS,Stockton SC,Conkey D,Strachan MW, StathamPF, Endocrinol Metab.2005;90(2):800-4. for pituitary adenoma: updateafter an additional 10 J Clin years. second braintumorafter surgeryandradiotherapy conservative Minniti G, Traish D, Ashley S,Gonsalves A, BradaM.Riskof Neurooncol Pract. 2014;1(1):22-8. cerebrovascular accidentsinpatientswithpituitaryadenoma. Brada M,Burchell L, Ashley S, Traish D. The incidenceof Endocrinol (Oxf).1989;31(3):363-73. Radiation-induced hypopituitarism isdose-dependent.Clin Littley MD,ShaletSM,BeardwellCG,Robinson EL,Sutton ML Phys. 1994;30(3):557-65. IntJRadiattreatment outcomeandprognosticfactors. OncolBiol SB, Simpson WJ. Radiation therapyforpituitaryadenoma: Tsang RW, BrierleyJD,Panzarella T, GospodarowiczMK,Sutcliffe pituitary adenomas.JClinEndocrinolMetab.2009;94(9):3400-7. et al.Long-term resultsofstereotacticradiosurgeryinsecretory Castinetti F, Nagai M,MorangeI,DufourH,CaronP, Chanson P, 2017;110(4):854-60. patients treated in a single institution. Cancer.consecutive radiosurgery forpituitaryadenomas:long-termresultsof125 The efficacy offractionatedradiotherapyandstereotactic Kong DS,Lee JI,LimdoH,KimKW, ShinHJ, NamDH,etal. cases. JExpClinCancerRes. 2009;28:36. for secretorypituitaryadenomas:experiencein347consecutive Wan H,ChihiroO, Yuan S.MASEP gamma kniferadiosurgery secreting pituitarytumors.Pituitary. 2012;15(2):135-45. Hamrahian AH, HatipogluB,SuhJH.Radiotherapy forprolactin- 189.Sheplan OlsenLJ, Robles Irizarry L,ChaoST, Weil RJ, macroadenomas. JNeurosurg1984;61(3):577-80. function followingtranssphenoidalresectionofpituitary Nelson Jr AT, Tucker JrHS, Becker DP. Residual anterior pituitary Br JNeurosurg.2004;18(5):507-12. sphenoidal surgery:ourexperienceandareviewoftheliterature. N,RaySudhakar A, Vafidis JA. Complicationsafter trans- 214. 213. 212. 211. 210. 209. 208. 207. 226. 225. 224. 223. 222. 221. 220. 219. 218. 217. 216. 215. TH. Endoscopicendonasalcomparedwithmicroscopic Komotar RJ, RM,Raper Starke DM, Anand VK, Schwartz experience. Brain Tumor Res Treat. 2013 ;1(2):71–7 for the treatment of invasive prolactinoma: the single institute Kyung Rae C,Kyung-Il J, HyungJinS.Bromocriptinetherapy patients usingbromocriptine.HormRes.1986;23(3):167-76. N. Extrasellarprolactinomas:successfulmanagementof24 Sieck JO, NilesNL,JinkinsJR, Al-Mefty O, S, el-Akkad Woodhouse limitations ofthemedicaltreatment.EndocrJ. 1998;45(4):529-37. after bromocriptinetherapyongiantprolactinomas:effects and Saeki SunamiK, N,NakamuraM, Yamaura A. Surgicalindication 59 (Suppl.1):S21. response totreatmentin16 cases. Arch EndocrinolMetab.2015; Thé AC ,etal.Giantprolactinomas:clinicalmanifestationsand Vilar L, Albuquerque JL,GomesB,GadelhaPS,Lopes IGA, Pituitary. 2016;19(4):429-36. prolactin-secretingpituitaryadenomas. andaggressive massive et al.Giantprolactinomaslargerthan60mminsize: acohort of Shimon I, Sosa E,Mendoza V, Greenman Y, Tirosh A, Espinosa E macroprolactinomas? Endocrine.2015;52(3):652-9. M. Giantprolactinomas:aretheyreallydifferent fromordinary Espinosa E, Sosa E, Mendoza V, Ramírez C, Melgar V, Mercado prolactinoma. ClinMedInsightsCaseRep. 2012;5:115-8. and hypothalamus involvement: acutepresentationofagiant S, Alkatari hydrocephalus,Aljohani N.Obstructive fifth nerve 2010;73(2):236-42. goline in hyperprolactinaemic women. Clin Endocrinol(Oxf). 100 pregnancies initiated undertreatmentwithcaber Lebbe M,HubinontC,BernardP, MaiterD.Outcome of Metab. 2010;95(6):2672-9. in womenwithmicro-andmacro­ High-dose cabergoline therapy for hyperprol­ Ono M,MikiN, Amano K,Kawamata T, Seki T, MakinoR,etal. Gynecology andObstetrics1988. RiodeJaneiro, Brazil.p.9. treatments. Program oftheSecond World Con­ Krupp P, C,Richter Monka K. The safetyaspectsofinfertility 2005;8(1):31-8. Bronstein MD.Prolactinomas andpregnancy. Pituitary. pregnancy. Endocrine.2014;47(1):64-9. Glezer A, BronsteinMD. Prolactinomas, cabergoline, and Steril. 1981;36(4):524-6. prophylactic therapyinprolactinomaduringpregnan­ Canales ES,GarciaIC,Ruiz JE,Zárate A. Bromocriptineas HormRes.mothers. 1985;22(3):239-46. Loria Y..Follow-up ofchildren bornofbromoc­ Raymond JP, Goldstein E, KonopkaP, Leleu MR,MerceronLE, inpregnancy.Nattumors Rev Endocrinol.2011;7(5):301-10. Bronstein MD,Paraiba DB,Jallad RS.Managementofpituitary 1986;111(4):452-9. prolactin andontumourgrowth. Acta Endocrinol(Copenh). with prolactinoma--effect ofpregnancyandlac­ Holmgren U, Bergstrand G, Hagenfeldt K, Werner S. Women 2016;41(3):341-50. MD. Pregnancy andpituitary adenomas.MinervaEndocrinol. Glezer A, Jallad RS,Machado MC,Fragoso MC,Bronstein 2015;172(5):R205-13. the pregnantpatientwithaprolactinoma.EurJEndo­ Molitch ME.Endocrinologyinpregnancy:managementof Neuroendocrinol. 2014:26(12):898-908. lactation-induced suppressionofkisspeptinexpression.J of kisspeptinneuronsinthemousebrainanditsrole Brown RS,Herbison AE, Grattan DR.Prolactin regulation adenomas. Pituitary. 2012;15(2):150-9. transsphenoidal andopentranscranialresectionofgiantpituitary Arch Metab. Endocrinol 2018;62/2 prolactinomas. JClinEndocrinol actinemic infertility tation onserum riptine-treated gress of cy. Fertil crinol. ­ Arch Metab. Endocrinol 2018;62/2 234. 233. 232. 231. 230. 229. 228. 227. 2008;30(4):378-80. exacerbation inschizophrenic patients.GenHospPsychiatry. Chang SC,ChenCH,LuML.Cabergoline-inducedpsychotic substantia nigrainschizophrenia. BrainRes. 1994;299(1):152-4. Owen R,F, Poulter M,Crow TJ. in DopamineD2receptors 2010;7(6):18-23. Yanofski J. The dopaminedilemma.Psychiatry (Edgmont). Diabetes MetabCaseRep. 2016;2016:160028. prolactinoma withtheantipsychotic drugaripiprazole. Endocrinol IC,SchubartBakker CD,ZelissenPM.Successfultreatmentofa Metab CaseRep. 2015;2015:150100. in awomanwithcabergoline-inducedmania.EndocrinolDiabetes Burback L.Managementofamicroprolactinomawitharipiprazole 2015;1(2):172-7. blind, randomised, placebo-controlled trial. B J Psych Open. aripiprazole in risperidone-inducedhyperprolactinaemia: double- Raghuthaman G, Venkateswaran R,KrishnadasR. Adjunctive Clin Neuropharmacol.2016;39(6):288-94. hyperprolactinemia: amulticenter, study. open-label,prospective switching toaripiprazole forresolvingantipsychotic-induced Comparing the effectiveness and safety of the addition of and Yoon HW, Lee JS,Park SJ, Lee SK,Choi WJ, Kim TY, etal. re­ fetal develop­ Boero L,etal.Effects ofcabergolineonpregnancyandembryo- Stalldecker G,GilMSM,GuitelmanMA, Alfieri A,BallarinoMC, view oftheliterature.Pituitary. 2010;13(4):345-50. ment: retrospective studyon103ment: retrospective pregnanciesanda Controversial issuesinthemanagementofhyperprolactinemia andprolactinomas 240. 239. 238. 237. 236. 235. multicenter study. Psychiatry ClinNeurosci.2010;64 (1):19-27. eight-week randomized, single-blind, placebo-controlled, bromocriptine onantipsychotic drug-inducedhyperprolactinemia: Lee MS,Song HC,NaH, Yang J, Ko YH, Jung IK,Joe SH.Effect of 2013;21(4):332-41. in schizophrenic patients.ExpClinPsychopharmacol. on hyperprolactinemia, psychopathology, andsexualfunctioning Dimopoulou K, Tzebelikos E,Lykouras L.Effects ofcabergoline Kalkavoura CS,Michopoulos I, Arvanitakis P, Theodoropoulou P, a pilotstudy. JClinPsychiatry. 2004;65(2):187-90. Cabergoline treatmentofrisperidone-inducedhyperprolactinemia: Cavallaro R, Cocchi F, Angelone SM, Lattuada E, Smeraldi E. Endocrinol Invest. 2000;23(11):765-70. hyperprolactinemia inpatientswithpsychotic J disorders. cabergoline inthemanagementofrisperidone-induced Tollin SR.Useofthedopamineagonistsbromocriptine and tolerability ofcabergolinetreatment.Clin Ter. 2007;158(2):121-6. hyperprolactinemia in youth with schizophrenia: efficacy and Mazza M,DiMichele V, etal.Risperidone-inducedsymptomatic Pollice R,DiGiovambattista E, Tomassini A, DiPucchio A, review oftheliterature.CaseRep Med.2010;2010:573252. schizophrenia in a patient with prolactinoma: a case report and insights inthemanagementofantipsychotics inthetreatmentof Santos Andrade EH,Pan PM,daSilvaPF, Gadelha A. New 263

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