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D Kim and others PRL cut-offs and tumor size 182:2 177–183 Clinical Study reduction

Prolactin ≤1 ng/mL predicts macroprolactinoma reduction after therapy

Correspondence Daham Kim, Cheol Ryong Ku, Kyungwon Kim, Hyein Jung and Eun Jig Lee should be addressed Department of Internal Medicine, Institute of Endocrine Research, Yonsei University College of Medicine, to C R Ku Seoul, Korea Email [email protected]

Abstract

Objective: The association between level variation and size reduction remains unclear. This study aimed to determine the prolactin level cut-off predictive of a tumor size reduction. Design: Retrospective cohort study. Methods: We reviewed medical records of patients with prolactinoma who received primary cabergoline therapy and for whom complete data on pituitary assays and sellar MRI at baseline and 3 months post treatment were available. We tested whether the certain prolactin level after 3 months post treatment predicted better response. Results: Prolactin levels normalized in 109 (88.6%) of 123 included macroprolactinoma patients. The mean tumor size reduction was 22.9%, and patients in the lowest prolactin tertile (≤0.7) had the highest frequency of tumor size reductions of ≥20% (73.7 vs 52.9% and 45.9% in tertiles 2 (>0.7 to 2.6) and 3 (>2.6 to 20), P = 0.015). Patients with prolactin levels ≤1 ng/mL exhibited larger tumor size reductions vs those with prolactin levels of 1–20 (27.2 ± 18.3% vs 19.5 ± 13.9%, P = 0.014), 1–10 (19.3 ± 13.7%, P = 0.017) and 1–5 ng/mL (19.2 ± 14.3%, P = 0.039). A multivariable logistic regression analysis revealed that a prolactin level ≤1 ng/mL at 3 months and high-dose cabergoline therapy were significantly associated with tumor size reductions of≥ 20% (odds ratio (OR): 2.8, 95% confidence interval (CI): 1.2–6.7, P = 0.017; OR: 2.0, 95% CI: 1.0–3.9, P = 0.043). European Journal of Endocrinology Conclusions: A prolactin level ≤1 ng/mL at 3 months after cabergoline treatment was correlated with a significant tumor size reduction in patients with macroprolactinoma. This finding may help clinical decision making when treating macroprolactinoma patients.

European Journal of Endocrinology (2020) 182, 177–183

Introduction

Prolactinomas are the most commonly occurring pituitary The first line of therapy involves medical management adenomas, accounting for approximately 40% of all with such as and pituitary tumors and 50–60% of all functional pituitary cabergoline. Surgical resection is generally reserved for tumors (1). These tumors cause headaches, visual patients who are unresponsive or intolerant to medical dysfunction, , and hyperprolactinemia therapy. Cabergoline, a specific D2 receptor , is the (2). Patients with prolactinoma typically exhibit the first choice of treatment because of its superior efficacy clinical features of hyperprolactinemia, including gonadal and better tolerability (3). The recommended cabergoline dysfunction, , and . dosage for initiation is 0.25–0.5 mg twice a week, whereas Serum prolactin level normalization and tumor the usual weekly maintenance doses range from 0.25 to shrinkage are the major goals of prolactinoma treatment. 3.0 mg (4).

https://eje.bioscientifica.com © 2020 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-19-0753 Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 11:48:25AM via free access

-19-0753 European Journal of Endocrinology https://eje.bioscientifica.com the retrospectivenatureofthis study. requirement forinformedconsent waswaivedbecauseof Board of Severance Hospital (No. 4-2019-0400). The of Helsinkiandwasapproved bytheInstitutionalReview was conductedinaccordancewiththe1964Declaration of 221identifiedpatientswereenrolled( third month of cabergoline treatment. Accordingly, 217 transsphenoidaladenomectomy beforethe underwent cabergoline treatment.We excludedpatients who data,andsellarMRIfindingsat3monthsafter and sellarMRIfindingsatbaseline,follow-upprolactin hormone assaydata was available:completepituitary included patients for whom the following information tests, andneuroimaging. tests, routinebiochemicalanalysiswiththyroidfunction medications, physicalexaminationfindings, out byassessingtheclinicalhistory, includingcurrent causesofhyperprolactinemiawereruled secondary sellar MRI( adenomason level abovethenormalrangeandpituitary was madeifapatientpresentedwithserumprolactin November 2011 and June 2017. A diagnosis of prolactinoma drug therapy atSeverance Hospital between primary prolactinoma who were treated with cabergoline as a We reviewedthemedicalrecordsofpatientswith Patients Patients andmethods size reductionsinpatientswithmacroprolactinoma. potential useofprolactincut-offvaluestopredicttumor determined. Therefore, this study aimed to evaluate the prolactin normalizationcut-offvalueshavenotyetbeen following 3monthsofcabergolinetreatment. below thenormalrangeevenafternormalization to cabergoline( useful for predicting long-term responses and resistance prolactin normalizationafter3monthsoftreatmentare assessments basedonthetumorvolumereductionand ( in 81%ofpatientsreceiving0.25–2mgcabergolineweekly macroprolactinoma, normoprolactinemiawasachieved with microprolactinoma( the normalizationofprolactinlevelsin95%patients cabergoline twiceweeklyfor12–24monthsresultedin 6 ). Cabergoline treatment is very effective,andresponse ). Cabergolinetreatmentisvery Clinical Study To evaluate the relationships among parameters, we Differences intumorsizereductionwithinthe In apreviousstudy, treatmentwith0.125–1.0mg 8 ). Beforeconfirmingaprolactinomadiagnosis, 7 ). However, prolactinlevelsmaydecrease 5 ). Inanotherstudyof D Kimandothers Fig. 1 ). Thisstudy adenomectomy; 3mf/u,3-monthfollow-up. resonance imaging;PRL,prolactin;TSA,transsphenoidal Flow chartofthestudy.CAB,cabergoline;MRI,magnetic Figure 1 In allcases,oralcabergolinewasinitiatedatalowdose Treatment andresponseassessment the meansizereductionof macroprolactinomapatients set thetumorsizereduction cut-offvalueaccordingto 3 monthsofcabergolinetreatment)/initial tumorsize.We was calculatedasthe(initial tumorsize macroprolactinoma ( 1 ng/mL.Thesecriteriawereusedtoclassifypatients( mL, andthelowerlimitofdetectableprolactinlevelwas mL. Thelowerlimitofnormalprolactinlevelwas5ng/ defined astheachievementofaconcentration 3.66 and3.77%,respectively. Prolactinnormalizationwas coefficients ofvariationforprolactinconcentrations were overcome apotentialhook effect.Thewithin-runandtotal assay wasrepeatedaftera1:100serumsampledilutionto if theprolactinvalueswerenotashighexpected, of detectionfortheprolactinassaywas0.25ng/mL,and kits (BeckmanCoulter, Brea,CA,USA).Thelowerlimit chemiluminescence using commercial months. The serum prolactin levels were measured using initiation toensureasufficientperiodofdrugexposure. dose wasmaintainedfor3monthsaftertreatment to amaintenancedosewithin2–4weeks( (0.5–1 mg/week),andthedosagewasgraduallyincreased classify prolactinomasasmicroprolactinoma( maximum tumordiameterwasmeasuredandused to system (Achieva; Philips, Best, The Netherlands). The General Electric,Minneapolis,MN,USA)or3.0-Tesla accepted criteria. Although ourassaykitismoresensitive,weusedgenerally reduction PRL cut-offsandtumorsize A responseevaluationwasconductedafter3 Sellar MRIwasperformedusinga1.5-Tesla (Signa; ≥ 10 mm)( Downloaded fromBioscientifica.com at09/26/202111:48:25AM 8 ). Atumorsizereduction 182 − :2

tumor sizeafter 7 ). Thelatter < 10 mm)or < 20 ng/ 178 8 via freeaccess ). European Journal of Endocrinology Female, Age (years) Table 1 dose thanthoseinthemicroprolactinomagroup.Moreover, macroprolactinoma groupreceivedahighercabergoline than in the microprolactinoma group. Patients in the of treatmentwerehigherinthemacroprolactinomagroup serum prolactinlevelsatthebaselineandafter3months All patientswithmicroprolactinomawerefemale.The mean agethanthoseinthemicroprolactinomagroup. Patients inthemacroprolactinomagrouphadanolder microprolactinoma andmacroprolactinoma,respectively. prolactin normalization.Ninety-fourand123patientshad of cabergoline treatment, 92.2% of the patients achieved diagnosis, andmost(82.0%)werefemale.After3months in The characteristicsofthe217includedpatientsareshown Patient characteristics Results dose (mg/week),andprolactin (years), sex(female),initialtumorsize(mm),cabergoline ( independently associatedwithtumorsizereductions logistic regressionanalysiswasusedtodeterminevariables linear-by-linear association,asappropriate.Amultivariable group comparisons were performed using the mean values were performed using Student’s expressed asmeans as numbersandpercentages. Continuousvariablesare statistical analyses.Categoricalvariablesarepresented SPSS Statisticsversion23(IBMCorp.)wasusedforall Statistical analysis cabergoline treatment. who achievedprolactinnormalizationafter3monthsof CAB, cabergoline;PRL,prolactin. PRL normalization, Size reduction(%) After 3months Initial Tumor size(mm) After 3months Initial Prolactin (ng/mL) CAB dose(mg/week) ≥ Clinical Study 20%) based on observed characteristics of patients (age characteristicsofpatients(age 20%) basedonobserved Table 1 n (%) Characteristics ofthestudypatients. . The patients had a mean age of 35 years at . The patients had a mean age of 35 years at n (%) ±

s . d . Statistical comparisons of the . Statisticalcomparisonsofthe 490.2 34.6 19.5 10.9 13.7 Total ≤ 8.7 2.2 178 (82.0) 200 (92.2) 1 ng/mL). D Kimandothers ± ± ± ± ± ± ± ( n 10.7 17.7 9.2 10.4 26.4 1344.7 0.7 = 217) t -test, and -test, and χ 2 test or test or Microprolactinoma 115.9 31.9 16.1 91 (96.8) 94 (100) 2.0 6.1 7.3 4.1 the endofthisarticle).Patientsinlow( significant linear relationship was observed between significant linear relationship was observed prolactin levelandtumorsizereduction;however, no was performedtoevaluatetherelationshipbetween reduction of22.9%.Simplelinearregressionanalysis who achievedprolactinnormalizationhadameansize of cabergolinetreatment.Macroprolactinomapatients prolactin normalizationcut-offvalueafter3months Next, wecomparedtumorsizereductionswithinthe Tumor sizereductionaccordingtoprolactinlevel who achievedprolactinnormalization. included onlypatientswithmacroprolactinoma exact sizechangesinsmalltumors,ourfurtherevaluations in themicroprolactinomagroup.Asitisdifficulttomeasure reduction wasgreaterinthemacroprolactinomagroupthan prolactin normalization.However, thepercentage ofsize 88.6% ofthoseinthemacroprolactinomagroupachieved 96.8% of patients inthemicroprolactinomagroup and Table 1, see section on level relativetoacut-offof5ng/mL(Supplementary treatment intotwogroupsaccordingtotheirprolactin prolactin normalizationafter3monthsofcabergoline We classifiedmacroprolactinomapatientswhoachieved cut-off of5ng/mL Tumor sizereductionclassifiedbyaprolactinlevel vs 3:73.7%52.9%45.9%, the prolactinlevelandtumorsizereduction(tertiles1vs2 alinearrelationshipbetween size reduction,weobserved size reduction cut-off value at 20% according to the mean prolactin normalizationintotertilesandsetthetumor However, whenwedividedpatientswhoachieved these variables( reduction PRL cut-offsandtumorsize ± ± ± ± ± ± ± 7.3 0.6 19.0 1.8 1.5 7.4 72.8 ( n = 94) r = Macroprolactinoma − 0.1, supplementary materials supplementary 776.3 Downloaded fromBioscientifica.com at09/26/202111:48:25AM 22.1 14.6 18.6 12.2 36.7 β 2.4 109 (88.6) = 84 (68.3) − ± ± ± ± ± ± ± 0.5, 95%CI: 16.2 10.7 11.6 34.1 1734.0 12.3 0.8 https://eje.bioscientifica.com P =0.015; ( 182 n = 123) :2 Table 2 ≤ − 5, 1.3 to0.2). n 2 and =82) given at ). < < < < < < P value 0.013 0.001 0.001 0.012 0.001 0.001 0.001 0.001 0.039 179 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com CAB, cabergoline;PRL,prolactin. CAB dose(mg/week) Size reduction(%) After 3months Initial Tumor size(mm) After 3months Initial Prolactin (ng/mL) Female, Age (years) using aprolactincut-offvalueof1ng/mL. Table 3 P the degreeofsizereduction(27.2 dose. However, thetwogroupsdifferedsignificantlyin serum prolactinlevel,initialtumorsize,andcabergoline of women( n low ( prolactin level cut-off level of 1ng/mL. Moreover, the cabergoline treatmentintotwogroupsaccordingtoa achieved prolactin normalization after 3 months of Next, weclassifiedmacroprolactinomapatientswho level cut-offof1ng/mL Tumor sizereductionclassifiedusingaprolactin treatment. of tumorsizereductionafter3monthscabergoline similar cabergolinedosesanddidnotdifferinthedegree and initialtumorsize.Moreover, thetwogroupsreceived not differintermsoftheinitialserumprolactin level mean ageatdiagnosisandproportionofwomendid high prolactingroups( Size reduction (classified bytertiles). normalization after3monthsofcabergolinetreatment among macroprolactinomapatientswhoachievedprolactin Table 2 PRL, prolactin. PRL levelsaregiveninunitsofng/mL. ≥ < =0.014;

= 20% 20% Clinical Study 60) had a similar mean age at diagnosis and proportion ≤ 1, n (%) n Macroprolactinoma patientswhoachievedprolactinnormalization after3monthsofcabergolinetreatment,classified Percentage ofcaseswithsizereductions Fig. 2A

= Table 3 49) andhighprolactingroups( 28 (73.7%) 10 (26.3%) 1st tertile (PRL n = 38) ). Asawiderangeofprolactinlevelswas ) anddidnotdifferintermsoftheinitial ≤ 0.7, > 5–20 ng/mL, 18 (52.9%) 16 (47.1%) ( 2nd tertile > 702.9 0.7 to2.6, n 22.9 13.4 17.4 36.1 Total = 34) 2.3 3.3 79 (72.5) ± ± ± ± ± ± ± D Kimandothers ± ( n 0.8 16.4 9.4 10.4 4.4 1725.4 11.9 = 109)

18.3% vs19.5 n 20 (54.1%) ( 3rd tertile 17 (45.9%)

> = 2.6 to20, n 27) had a similar = 37) > 1–20 ng/mL, ± ≥ 20% 13.8%, P 0.015 Low group value 902.9 27.2 13.3 18.2 38.3 2.5 0.4 35 (71.4) ± ± ± ± ± ± ± (PRL 1.2–6.7, after 3 months of cabergoline treatment (OR: 2.8, 95% CI: in patients whose prolactin levels decreased to cabergoline dose(OR:2.0,95%CI:1.0–3.9, increased significantlyincasesthatreceivedahigh that theoddsratio(OR)forsizereductionsof reduction of 70% ofpatientsinthelowgroupachievedatumorsize 3 monthsofcabergolinetreatment.However, morethan patients inthehighgroupachievedthisoutcomeafter size reductioncut-offvalueat20%,lessthanhalfofthe respectively; P group ( size reductiondifferedsignificantlyfromthoseinthelow ( to prolactinlevelsof inthehighgroup,wenarrowedrangethis observed long-term responseandresistancetocabergoline( after 3monthsoftreatmentisusefulforpredictingthe the tumorvolumereduction and prolactinnormalization well-tolerated approach.Aresponseassessmentbasedon settings, cabergolinetreatmentisaneffective,safe,and inclinicalpractice( adenoma observed Prolactinoma is the most commonly occurring pituitary Discussion cabergoline treatment. even ifprolactinlevelshadnormalizedafter3monthsof tumor sizereduction in patientswithmacroprolactinoma, prolactin levelto However, differences within the prolactin normalization reduction PRL cut-offsandtumorsize n 0.8 18.3 8.8 10.2 0.3 2380.8 12.0 .1 ad 27.2 and =0.017

= ≤ 33). For both narrowed highgroups, the degrees of A multivariablelogisticregressionanalysisrevealed 1, n = 49) ≤ P 1 ng/mL, =0.017; ≥ Fig. 2B 20% (Supplementary Table20% (Supplementary 2). < 1 ng/mLwascorrelatedwithasignificant Table 4 High group n ± and 9 27.2 =49; >

18.3% vs19.2 1 to10( 539.6 Downloaded fromBioscientifica.com at09/26/202111:48:25AM 19.5 13.6 16.7 34.4 ). Therefore,areductioninthe 2.2 5.7 44 (73.3) C ). Whenwesetthetumor ± ± ± ± ± ± ± ( > 0.7 13.9 9.9 10.6 4.7 881.7 11.7 1 to20, n ± 0 and =50)

18.3% vs19.3 182 n ± = 60) 14.3%, :2 > P 1 to5ng/mL 1 .4) and =0.043) ). Insuch < P < P ± 1 ng/mL =0.039, value 0.076 0.014 0.884 0.470 0.001 0.315 0.825 0.088 13.7%, ≥ 180 20% 7 via freeaccess ). European Journal of Endocrinology CAB, cabergoline;CI,confidenceinterval. Prolactin CAB dose(mg/week) Initial tumorsize(mm) Sex (female) Age (years) of 1ng/mL. cabergoline treatment,classifiedusingaprolactincut-offvalue achieved prolactinnormalizationafter3monthsof reductions of Table 4 stalkdiseasemaydecreasethisinhibition and or pituitary released fromthehypothalamus;therefore,hypothalamic normally inhibitedbydopamine,aneurotransmitter sufficient factorfordiagnosis.Prolactinproductionis adenoma isconsistentwithprolactinoma,itnota hyperprolactinemia withtheexistenceofapituitary , asellarMRIisindicated( hyperprolactinemia, renalorhepaticinsufficiency, and causes. Afterrulingoutpregnancy, ,drug-related toidentifythepossible workupisnecessary laboratory to cabergolineinpatientswithprolactinoma. prolactin normalizationcut-offvalueasanearlyresponse This studyisthefirsttocomparedifferenceswithin strong predictive factor oftumor reduction ( after 3monthsofcabergolinetreatmentwasasignificantly revealed thatareductioninprolactinlevelto outcome. Amultivariablelogisticregressionanalysis who achievedaprolactinlevel reduction cut-offvalueat20%,morethan70%ofpatients of cabergolinetherapy. Whenwesetthetumorsize who achievedaprolactinlevel tumor sizereductionwassignificantlygreaterinpatients normalization cut-off value andfound that thedegree of we analyzedtumorsizereductionswithintheprolactin cut-off valuehavenotbeenidentifiedpreviously. Here, Clinical Study When hyperprolactinemiaisconfirmed,aclinicaland ≤ Multivariable logisticregressionanalysisofsize 1 ng/mL ≥ 20% inmacroprolactinomapatientswho Odds ratio 2.8 2.0 1.0 0.7 1.0 < < D Kimandothers 1 ng/mLafter3months 1 ng/mLachievedthis 1.2–6.7 1.0–3.9 0.1–1.1 0.2–2.0 0.9–1.0 95% CI 3 ). Although < 1 ng/mL P 0.017 0.043 0.935 0.480 0.154 ≥ value 20%). diagnosis basedonthenatureofdisease,ratherthan ( majority ofpatientsdonotachievetumorsizereductions dopamine agonisttreatmentinpatientswithNFPA, the Although serumprolactinlevelscanbereducedby stalkandcausehyperprolactinemia. compress thepituitary adenoma (NFPA),nonfunctioning pituitary which may to discriminateprolactinomafromhyperprolactinemic induce anincreaseinprolactinlevels( effects thanthatassociated with bromocriptine,thedrug is associatedwith a lower incidence of unpleasant side administration onlyonceor twiceweekly. Asthisdrug Cabergoline hasalonghalf-life, whichenablesitsoral drug. in thisstudyreceivedcabergolineasaprimary agonist, drugcompliance,anddose.Allthepatients cannot completelyreplacesellarMRI. level to ruled outclinically. Therefore,areductionin theprolactin thus, hyperprolactinemicNFPAs cannotbecompletely always consistentinpatientswithprolactinoma,and between theserumprolactinlevelandtumorsizeisnot in apatientwithlargemacroadenoma.Theassociation effect whenprolactinvalues are notashighexpected dysfunction ( from normallactotrophs because of hypothalamicstalk prolactinoma, whichwouldinhibitprolactinsecretion be suggestiveofhyperprolactinemicNFPA ratherthana adenoma withamodestlyelevatedprolactinlevelwould the tumor size. Therefore, a radiologically diagnosed large the serumprolactinlevelgenerallyparallelsachangein forothertumors.Inprolactinoma,achangein surgery of anaccuratemedicaltreatmentforprolactinomaor and hyperprolactinemicNFPA iscriticaltotheprovision predict abetterresponse. to It ismeaningfulthatareductionintheprolactinlevel pathologic confirmation,andsomemayhavehadNFPA. reduction PRL cut-offsandtumorsize 10 < ). In this study, most patients received a clinical Responses to dopamine agonists vary by thetypeof Responses todopamineagonistsvary The differential diagnosis between prolactinoma 1 ng/mLafter3monthsofcabergolinetherapycan < 1 ng/mLafter3monthsofcabergolinetherapy 11 ). We mustalsoconsiderapotentialhook org/10.1530/EJE-19-0753 figure isavailableat prolactin. Afullcolourversionofthis ( 10 ng/mL( (B) Prolactinlevel level prolactin levelsat3months.(A)Prolactin Tumor sizereductionsaccordingtothe Figure 2 n = 49) vs ≤ Downloaded fromBioscientifica.com at09/26/202111:48:25AM 1 ( n = 49) vs > n 1 to5ng/mL( = 50). (C)Prolactinlevel https://eje.bioscientifica.com ≤ > 1 ( 1 to20ng/mL( 182 https://doi. n = 49) vs :2 9 . n ). Itisdifficult = 33). PRL, > 1 to n ≤ = 60). 181

1 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com 24 monthsoftreatment( increased thelikelihoodof prolactinoma shrinkageafter normal range(asdetermined bythesumofscore) achieve aprolactinlevelbelow thelowerlimitof In apreviousstudy, cabergolinetherapy intendedto Therefore, we could not clarify long-term outcomes. MRI findings and not by dividing patients into groups. periodic prolactinmeasurementsandfollow-upsellar Cabergoline doseadjustmentswereperformedbasedon decisions and notaccording to a standard study protocol. design, thedrugdosesweredeterminedbyclinical macroprolactinoma cases.Becauseoftheretrospective confirmation, andlimitationofthepatientsample to retrospective single-centerdesign,absenceofpathological valvular regurgitation( dose cabergolinebecauseofthepotentialriskcardiac Caution mustbeexercised intheprotracteduseofhigh- apoplexy( leakage, chiasmalherniation,andpituitary rare, these adverse eventsinclude cerebrospinal fluid of dopamineagonists should beconsidered. Although resistance, theadverseeffectsassociatedwithhighdoses for overcomingmay be more effective and necessary can beexpected.Althoughhigh-dosecabergolinetherapy standard doses,amoresignificanttumorsizereduction to cabergolinetreatmentismoreprominentwithsimilar prolactinoma. levels shouldbeconsideredduringthetreatmentof of causality, thesideeffectsassociatedwithlowprolactin further studiesareneededtounderstandthedirections metabolic disturbancesinmen( in women and sexual dysfunction and psychological or is associated with ovarian dysfunction medical problems.However, somestudiessuggestthat people withlowprolactinlevelsdonothaveanyspecific influences morethan300separateprocesses,most and pancreaticdevelopment( essential roles inmetabolism, regulation, mammals (usuallyfemales)toproducemilk.Italsoplays can considerthetumortobehighlyresponsive. size reductioncorrespondstothedoseofcabergoline,we macroprolactinoma treatment( ranged from2to3mg/week,whichareusuallyeffectivefor 0.3 mg/week,95%CI:0.0–0.6).Thecabergolinedoses did notdifferbetweenourstudygroups(meandifference: frequently moreeffective.However, thecabergolinedose compliance ratemaybesuperior( Clinical Study This studyhadseverallimitations,includingits Our studydemonstratedthatiftheprolactinresponse Prolactin isbestknownforitsroleinenabling 19 ). 20 ). Pathologicconfirmation 13 14 D Kimandothers 11 ). Ifthedegreeoftumor 15 ). Althoughprolactin , , 12 16 ). Higherdosesare , 17 ). Although 18 ). to treatment.Therefore,ourresultscanbeusedhelp cabergoline treatment can predict an even better response suggests that a prolactin level prolactin levels,comparedwithbromocriptine.Ourstudy with fewersideeffectsandmoreeffectivelynormalizes is thefirstchoiceofdrugtherapybecauseitassociated who received single-agent therapy. Currently, cabergoline of arelativelylargenumberpatientswithraredisease our studyislimitedtopatientswithmacroprolactinoma. microprolactinoma. Therefore,theclinicalapplicationof of significanttumorsizereductionsinpatientswith cabergoline treatmentismaintained even intheabsence patients withmacroprolactinoma,althoughclinically, ( exhibiting resistance orintolerance to dopamineagonists whereas surgicaltreatmentisindicatedonlyforthose the firstlineoftreatmentforpatientswithprolactinoma, was notpossibleinthisstudybecausemedicaltherapyis language editing. English for (www.editage.co.kr) Editage thank to like would authors The Acknowledgement and (MSIP Government Korean the MOHW; No.NRF-2017M3A9E8029720). by funded and (NRF) Foundation Research National the of Program Development Technology Medical and Bio the by supported was K R C (NRF-2018R1D1A1B07050637). Education of Ministry the by funded (NRF), Korea of Foundation Research the National through Program Research Science Basic the by supported was K D Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Declaration ofinterest EJE-19-0753 at paper the of version online the to linked is This Supplementary materials in patientswithmacroprolactinoma. months ofcabergoline treatment predicted better response a reductionintheprolactinlevelto responsiveness inpatientswithprolactinoma.Moreover, of cabergolinetreatmentwasausefulpredictor In summary, prolactin normalization after 3months Conclusion guide clinicaldecisionmaking. reduction PRL cut-offsandtumorsize 3 ). Furthermore,weanalyzedtheprolactincut-offsin The mainstrengthofourstudy was theenrollment . 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Accepted 26November2019 Revised versionreceived13November2019 Received 24September2019

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