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Home , Hypoestrogenism, Precocious puberty, Premature thelarche

Cristiane KochiCristiane Paulo César Alves daSilva Arch Metab. Endocrinol 2016;60/2 duced bythe ) inhibitbothhypothalamus and bythetestis,andE2=,pro one, produced (T=testoster gonadalsteroids pothalamus, whereas onthehy anegativefeedback effect andexert stimulatethe stimulating ). andFSH=follicle- gland (LH=luteinizinghormone bytheanteriorpituitary ofgonadotropins the secretion of GnRH stimulating pulsatile hypothalamic secretion onsetrequires pubertal nadal (HPG)axis.Aneffective of the hypothalamic-pituitary-go inreactivation results mental, ethnic,geographic,andeconomicfactors thatincludesgenetic,metabolic,environ torial process function. Itisacomplexandmultifac of reproductive andachievement hood, withacceleratedlineargrowth P INTRODUCTION depot 11.25 mg. Monthly or 3-month depot GnRHa are effective and safe to treat CPP. ing 1-month depot leuprorelin3.75mgand7.5 mg,1-month depottriptorelin3.75mg,and3-month mulations ofGnRHa(leuprorelinandtriptorelin)areavailablecommonlyadministered,includ is along-actingGnRHanalog(GnRHa)administeredoncemonthorevery3months.InBrazil,for GnRH isadiagnosticoption.InBrazil,thetreatmentofchoice CPPandearlypuberty forprogressive basal LHvaluesareatprepubertal range,astimulationtestwithshort-acting orlong-actingmonthly in Brazil,andthecutoff values differ accordingtothelaboratoryassay. When CPPissuspectedbut the levels are not always in the pubertal range at baseline, short-acting GnRH is not readily available early . MeasurementofbasalandstimulatedLHlevelsremainschallenging, consideringthat , CPP, constitutionalgrowthandpuberty andnonprogressive acceleration,progressive and ity. due to the broad spectrum of pubertalThis occurs development, including isolated premature andaperiodoffollow-upparameters, isdesirabletodefinethe “progressive” formofsexualprecoc existing therapiesinthecountry. The diagnosisofCPPisbasedmainlyonclinicalandbiochemical therapeutic features of CPP in Brazilbased on relevant international literature and availability ofthe lenging duetolack ofstandardization. The aimofthisrevisionwas toaddressthediagnosticand Clinical andlaboratorydiagnosistreatmentofcentralprecociouspuberty (CPP)remainchal ABSTRACT Vinícius Brito Nahime therapeutic management revisiting thediagnosisand Central : Precocious puberty;sexualmaturation;-realisinghormone;luteinizinglong-actingGnRHanalog Keywords Endocrinol Metab. 2016;60(2):163-72 chological transition from childhoodtoadult chological transitionfrom andpsy isaperiodofphysical,hormonal, uberty 2 , Kopacek Cristiane 1 , Spinola-Castro Angela Maria 1 , Guerra-Júnior Gil 2 ,

2 ------1 ,

anterior . This process isnamedgonad gland.Thisprocess is decreasing mainlyingirls (5-7),butalsoinboys(8,9). is decreasing age gical studies have suggested that the initial pubertal the age of 9 years in boys. However, epidemiolo recent sexual characteristicbefore in girlsandanysecondary theageof9years before the ageof8yearsormenarche sexual characteristics before development ofsecondary intesticularvolumeboys(4). and abilateralincrease ingirls che theinitialclinicalmanifestationisthelarche odor, pubichair, ingonadar and skin oiliness, whereas che isclinicallycharacterizedbydevelopmentofaxillary Adrenar zona reticularis. DHEA sulfate) by the adrenal and DHEAS = (DHEA = dehydroepiandrosterone ofandrogens forthesecretion mone) andresponsible hor ACTH-independent(adrenocorticotropic process (1-3). arche The classical definition of precocious puberty is the isthe puberty The classicaldefinitionofprecocious a byadrenarche, isoftenpreceded Arch - - - - Accepted onMar/10/2016 Received onFeb/12/2016 [email protected] 13083-887 –Campinas,SP, Brasil “ZegferinoUniversitária Vaz” Cidade Rua Tessália Vieira deCamargo,126 Universidade deCampinas Estadual Faculdade deCiênciasMédicas, dePediatria,Departamento Gil Guerra-Júnior Correspondence to: 2 1 DOI: 10.1590/2359-3997000000144 (SBP), RiodeJaneiro, RJ, Brasil Sociedade BrasileiradePediatria (SBEM), RiodeJaneiro, RJ, Brasil de EndocrinologiaeMetabologia Pediátrica, SociedadeBrasileira Departamento deEndocrinologia, Departamento deEndocrinologia Departamento review 163 - - - - -

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 164 thedeve determines sical changes. In girls, ofphy bytheobservation determined are progression onset and rate of a clinical standpoint, puberty From Clinical diagnosis ging diagnosticmethods(8). withthenewgeneticand ima beingrevised currently 70%) inboys.However, theseepidemiologicaldataare (60%to frequent more organic etiologiesare whereas 90%ofthecasesingirls, 15). IdiopathicCPPrepresents listedinTableThe mainetiologiesofCPPare 1(10- Etiology CENTRAL PRECOCIOUSPUBERTY medications inBrazil. and availability of the existing literature international and therapeuticmanagementofCPPbasedonrelevant ofessentialissuesonthistopic. sents asummary withCPP.management ofchildren pre Thisrevision to the diagnosisandtherapeutic datarelevant current ofPediatricEndocrinology,Departments toexamine nology andMetabolismBrazilianPediatricSociety, Brazilian Society for Endocri from with representation was organized inSaoPaulo,Brazil,October2015, pediatric and adult . a meeting Therefore, in chosenfortheirexpertise 6participants were There PARTICIPANTS ANDOBJECTIVE (10)in: derlying physiopathologicalprocess totheun isclassifiedaccording puberty Precocious CLASSIFICATION OFPRECOCIOUSPUBERTY Guideline ofcentral precocious puberty • • The aim of this revision was to address thediagnosis wastoaddress The aimofthisrevision • nous source. –exclusivelyinboys),oran exoge nadotropin hCG (human chorionic go tumors secreting a genetic or tumoral etiology,from cell germ oradrenal gonadal sexhormones of excessivesecretion puberty: doprecocious puberty,pin-independent precocious or pseu puberty,Peripheral precocious orgonadotro earlymaturationoftheHPGaxis; cious puberty: puberty,pin-dependent precocious preco ortrue (CPP),gonadotro puberty Central precocious etiology; bleeding dueornottoahormonal orvaginal , ofthelarche, lated forms Variants development: iso pubertal of normal ------Table 1. Etiologiesofcentralprecociouspuberty others caused by like tumors, which require others caused by diseases like tumors,which require istoidentify benignconditionsfrom cocious puberty (10,16-19). found tobeabovethefamilial pattern andheightisgenerally curves, be plottedinreference condition. Height,weight,andheightvelocityshould velocity above6cm/yearcharacterizeaprogressive stage toanotherinlessthansixmonthsandaheight one from 1)(22).Aprogression maturation (Figure ofbone rate,andtheprogression events andgrowth ofpubertal chronology clinician mustknowthenormal Tanner’s classification (20,21). byMarshalland developmentisdetermined pubertal (10,16-19).Thestageoffemaleandmale genders, developmentofpubichairisassociatedwith gynecomastiamayoccur.transient pubertal Inboth inmusclemass.In40%oftheboys, tion, andincrease facial hairdevelopment,changesinbodyfatdistribu (leadingtovoicechange), growth and cricoidcartilage testicular, boyspresent totestosterone, response penile, acidification ofthevaginalpHandmucusdischarge. In ofthevaginalepithelium, with is theestrogenization aspect inthehips.Anotherimportant predominantly ofbody fat andredistribution minora, andincrease enlargement oflabiamajoraand lopment ofbreasts, CNS: system. centralnervosus dysfunction. *Mayalsoprogresstopituitary CNS abnormalities International adoption endocrine disruptors secreting sexsteroidhormones, testoxicosis, McCune-Albrightsyndrome)or simple virilizingcongenitaladrenalhyperplasia, followingressectionoftumors tochronicexposuresexsteroidhormones(latetreatmentof Secondary Genetic causes Idiopathic encephalitis, sarcoidosis, tuberculosis), radiation, perinatalasphyxia, trauma Acquired diseases*: processes(abscess, inflammatory meningitis, meningomyelocele, lobe, ectopicposteriorpituitary duplication pituitary dysplasia, , spinabifida, vascularmalformation, Other congenitalmalformations: suprasellarcyst, arachnoidcyst, septo-optic dysgerminoma, craniopharyngioma* LH-secreting adenoma, , neurofibroma, non-hCGsecreting Tumors: astrocytoma, ependymoma, opticorhypothalamicglioma, Hypothalamic hamartoma Chromosomal abmormalities Inactivating mutationsintheMKRN3gene(familialCPP) Activating mutationsintheKISS1RandKISS1genes The mainobjectiveofevaluating patientswithpre To puberty, evaluateapatientwithprecocious the Arch Metab. Endocrinol 2016;60/2 - - Arch Metab. Endocrinol 2016;60/2 and nonprogressive CPP,and nonprogressive (develop andearlypuberty acceleration,progressive andpuberty titutional growth cons thelarche, andincludes isolatedpremature broad developmentisvery ofpubertal because thespectrum diagnosisofCPPmay bechallenging the differential stage.Ingirls, tion aboutheight,weight,and pubertal useful inthediagnosisoffamilialCPP(10,16-19). onsetandsimilarcasesinthefamily,pubertal maybe aboutfamilyhistory,Information includingthe age at hypothalamichamartomas. nic etiologies,particularly manifestations belowtheageof4yearssuggestorga diagnosis.However, clinical not helpfulindifferential tite changes.Theageatonsetofsignsandsymptomsis of headache and psychological, visual, or appe currence suchastheoc diseasesandinformation neurological toidentifyprior important or ointments.Itisalsovery and useofcreams tions, accidentalingestionofdrugs, infec ofperinataltrauma,previous conditions, history nostic step,andinvestigationshouldincludethebirth the followingcharacteristicsmustalwaysbeevaluated: immediate and objective management. Patients with Tanner (22). Figure 1. ChronologyofsexualmaturationandgrowthspurtduringpubertyinbothgendersaccordingtoMarshall& Tanner (20,21)stages. Adapted from The clinical history mustalwaysbetheinitialdiag The clinicalhistory • The physical examination must include informa • lial geneticchannel. gender and age and/or height above the fami Height velocity above the expected valuefor ders; of secondary sexualcharacteristicsinbothgen of secondary Early onsetand/oraccelerateddevelopment Growth velocity Event Hair 1 0 1 1 2 1 ± 2 2 3

years Age (years) 1 Female 3 4 1 4 1 5 5 1 6 1 7 ------Growthvelocity isolated development of breast tissue,withoutotherpu isolated development ofbreast tothe refers thelarche axis.Premature of gonadotropic These conditions occur independent of the reactivation etiology.vaginal bleedingdueornot toahormonal and prepubertal or adrenarche thelarche premature puberty,mon variantsofprecocious suchasisolated It isessentialtodiscriminatebetweenCPPandcom Differential diagnosisofprecociouspuberty logy (10,16-19). ofovarianetio puberty ted withperipheralprecocious whichisassocia nosis ofMcCune-Albrightsyndrome, andoftenjaggededgesmayindicate thediag irregular (associated withopticglioma).Café-au-laitspots related toCPP and gestive oftype1neurofibromatosis sug edges,whichare café-au-lait spotswithregular and ofneurofibromas also investigatethepresence funduscopic evaluation. The physical examination must and ofheadcircumference, examination, measurement CPP include neurological idiopathic andneurogenic diagnosisof mination thatmayhelpinthedifferential assessmentsduringphysicalexa talia. Otherimportant tothevirilizationofgeni testis isdisproportional concomitant testiculardevelopment,orthesizeof in peripheralpuberty, occurswithout penilegrowth ten indicativeofactivationtheHPGaxis,whereas boys) (23,24).Inboys,testiculardevelopmentisof ages of8and9yearsingirls10 sexualcharacteristicsbetweenthe ment ofsecondary Testes Event Penis Hair 1 0 1 1 2 1 2 Age (years) 1 3 1 Male 2 3 ± 4 3 1 2

4 years 4 5 Guideline ofcentral precocious puberty 5 1 5 5 1 6 1 7 165 ------

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 166 ted inmostcases. Dependingonclinical variablesand nosis ofCPP, GnRHstimulationtestisnotwarran range does not exclude the diag in the prepubertal (16,27,28).Althoughabasal LHvalue pubertal dered consi > 0.3IU/L(ICMA,ECL) inbothgendersare monly used.BasalLHvalues >0.6IU/L(IFMA)or themostcom (ECL). Ofthese,ICMAandECLare minescence (ICMA),andelectrochemiluminescence (IFMA), immunochemilu ding immunofluorometric available,inclu levelsare gonadotropins to measure methodswithhighsensitivity (16). Severallaboratory methodology valueandlaboratory ding onthecutoff mainly ingirls,variesbetween60and100%,depen fordiagnosisofCPP, LHatbaselinemorning serum tivation ofthegonadalaxis(10,15).Thesensitivity todocument theac -acting GnRHisrecommended LH) atbaselineand/orafterstimulationwithshort (mainly ofgonadotropins measurement Laboratory assessment Hormonal diagnosis Laboratory age andpelvicultrasoundingirls(10,16,26). levels, bone can be limited to basal hormonal puberty andimagingassessmentofisolatedvariants ratory Labo conducted inthesepatientswithisolatedforms. shouldbecarefully progression indicators ofpubertal investigation. Clinical further nuous bleeding requires manifestation ofCPP. or conti Inaddition,recurrent thefirst represents vaginalbleedingrarely prepubertal action.Ofnote, it isdependentornotofhormonal if generally benign,acyclicandmustbedifferentiated , with no other signs of puberty, are Isolatedprepubertal vanced boneagemightbepresent. mustbeexcluded.Ad cream, topical corticosteroids testosterone, causes, suchascontactwithtransdermal tumors)andother genital hyperplasia,adrenocortical con (adrenal sulfate). Inthiscondition,adrenal (mainlyDHEAand adrenal-derived concentrationsof duetoincreased hairgrowth axillary is defined by the development of pubic or adrenarche follow-up(25).Premature ce theneedforlong-term whichreinfor of theageinitialclinicalpresentation), CPP (independent 13% of them developed progressive thelarche, onoutcomeofgirlswithpremature cohort over several months. In the largest It usually regresses ofadultheight. vanced boneage,withoutimpairment and ad signs, such as accelerated linear growth bertal Guideline ofcentral precocious puberty ------GnRH (intravenous gonadorelin, 100µg)maybere GnRH (intravenousgonadorelin, astimulationtestwithshort-acting their progression, CPP,sensitivity andlargetheir low considering over (27,28,30-38). summarized in Tableactivation of the HPG axis are 2 values of basal or GnRH-stimulated LH that indicate necessity ofGnRHstimulationtest.Thedistinctcutoff basal LHof0.3U/LasindicativeCPP, avoidingthe of ICMA andECLIA,wesuggestconsiderthecutoff CPP in62.7%ofgirlsand71.4%boys(31).Using byIFMA,wasable todiagnosis 0.6 U/L,measured cost savings (31). We demonstrated that basal LH > GnRH test,whichisunfeasibleinmanycenters,with change inclinicalpracticeavoidingthenecessityof mayfacilitate dataandthisapproach local normative using in thediagnosisofCPPshouldbeinterpreted sensitivity (31).TheauthorsstatedthatbasalLHlevels with100% specifity and 90.5% dicated no progression whilebasalLH≤0.2IU/Lin progression of pubertal found thatabasalLH level ≥0.3IU/Lwas indicative in 57girls(31).Basedonanalgorithm,theauthors progression clinicalpubertal say (ICMA),topredict trated theabilityofbasalLH,assessedbysensitiveas CPP mustbehighlighted.ACanadianstudydemons ofbasalLHinthe diagnosisof theimportance reasons, and unavailabilityofGnRHainsomecenters.Forthis the high cost, risk of local reaction of this strategy are clinically suspectedcases(29,30).Thedisadvantages thebiochemical diagnosisofCPPin nativeto confirm long-acting GnRHanalog(GnRHa)maybeanalter to 120minutesafterthefirstapplicationofamonthly 30 inBrazil),LHmeasurement le (whichisfrequent GnRHisunavailab commended. Whenshort-acting sociation with thephysiologicalminipuberty. atthisagein as oftenincreased caution sincetheyare with below theageof2yearsshould beinterpreted inchildren hormones andsexsteroid of gonadotropins (10). Levels puberty diagnosis ofperipheralprecocious suggestthe theystrongly loworsuppressed, levels are FSH isnotusefulinthediagnosisofCPP, butwhenthe of basal or GnRH-stimulated mended. Measurement male gender, ofβ-hCGisalwaysrecom measurement CPP, LHlevels.Alsointhe whichisestablishedfrom diagnosisbetweencentralandperipheral differential the todetermine butinsufficient puberty precocious totalTissensitivetodiagnose (26). Inboys,serum children andpubertal prepubertal lap betweennormal In girls, serum levels of E2 are notusedtodiagnose levelsofE2are In girls,serum Arch Metab. Endocrinol 2016;60/2 ------Arch Metab. Endocrinol 2016;60/2 wever, an experiencedexaminer this methodrequires end-diastolic flowdivided bytheflowvelocity).Ho betweenthepeak systolicand (adifference rine artery sment isbasedonthepulsatility index(PI)oftheute CPP. andprogressive thelarche premature Thisasses diagnosisbetweenisolated to establishadifferential useful Dopplerfindingsare graphy anduterineartery Some studieshavedemonstratedthatpelvicultrasono girls. 40%ofprepubertal mal findingsinapproximately nor andovarianfolliclesare (16).Microcysts puberty parametertoevaluategirlswithprecocious laboratory stimulationandmaybeanadditional dicate hormonal rian volume>1.8mLanduterinelength3.4cmin method todetectcystsandneoplasticlesions.Anova mine theuterineandovarianvolume,isasensitive puberty,nosis ofprecocious butingirls,ithelpsdeter (41,42). Pelvicultrasonographyisnotusedinthediag adultheight celerated BA,sincethelatteroverestimate overthosethatuseac average BAshouldbepreferred this methodhaslowaccuracy. Bayley-Pinneautablesfor height bytheBayley-Pinneaumethod(40),although adult significant.BAisusedtopredict it isconsidered deviations(SD), ceeds eitheroneyearortwostandard BA isoftenadvanced,andwhentheadvancementex puberty,monly used(39).Inpatientswithprecocious andPyle’sis the mostcom thods, ofwhichGreulich me minant wrist and hand and estimated by different (BA)isobtainedwithanX-rayofthenondo Imaging ICMA: immunochemiluminescence;IFMA: immunofluorimetric;ECLIA: eletrochemiluminescence;SC: subcutaneous;IV: intravenous;F: female;M: male;N/A: notavailable. Table 2. CutoffvaluesofbasalandGnRH-stimulatedLHfordiagnosiscentralprecocious puberty Neely andcols., 1995(32) Author Bizarri andcols., 2014(38) Pasternak andcols., 2012(34) Houk andcols., 2009(33) Brito andcols., 2004(30) Brito andcols., 1999(27) Sathasivam andcols., 2010(35) Lee andcols., 2013(36) Resende andcols., 2007(28) Freire andcols., 2013(37) Method ECLIA ECLIA ICMA ICMA ICMA ICMA ICMA ICMA IFMA IFMA IFMA IFMA IFMA Basal LH(IU/L) ------> 0.2 1.05 0.83 0.15 N/A 0.6 0.6 0.1 0.3 0.6 0.2 0.1 resonance imaging (MRI) (10,44). Computed tomo resonance bymagnetic inallpatients,preferably be performed system(CNS)should assessment ofthecentralnervous of CPP, confirmation (43). After laboratory anatomical development is reached, revert orstabilize thesexual revert development is reached, ageforpubertal the sexualmaturationuntil the normal aimstointerrupt puberty ofprecocious The treatment Objectives andindications of pubertalarrest patientsandtheirfamilies. inaffected considered cases (12).Inthesescases,geneticcounselingshouldbe radic CPP, MKRN3 spo 30% offamilies(45)whileinpatientswithapparently In familialCPP, foundinabout MKRN3defectswere sents the most common genetic cause of CPP (Table 1). several geographicalorigins(12).Infact,MKRN3repre MKRN3 mutationshavebeenidentifiedinfamiliesfrom andinactivating onGnRHsecretion effect inhibitory therapeutic management(26).MKRN3hasapotential basis oftheCPP, withnoimplicationondiagnosisand logy ofCPP, is indicated andmayelucidatethegenetic ( history,3 molecularstudy ofthemakorinring-finger In allcasesofidiopathicCPPwithorwithoutfamilial studies Molecular hamartomas. calcified ones,butithaslowsensitivitytodetectsmall graphy ofthebrainmayidentifyCNStumors,mainly ) gene, recently implicated in the genetic etio MKRN3) gene,recently 0.1 mg/m Leuprorelin acetate20ug/kgSC Leuprorelin acetate3.75mg Gonadorelin 100ugIV Gonadorelin 100ugIV Gonadorelin 100ugIV Gonadorelin 100ugIV Gonadorelin 100ugIV Gonadorelin 100ugIV 2 , maximumof0.1 mgSC GnRH N/A defects were detected in about 8% of detectedinabout8%of defects were Guideline ofcentral precocious puberty LH peakafterGnRH(IU/L) 3.3 (M);4.2(F) 4.1 (M);3.3(F) 9.6 (M) 6.9 (F) 5.0 (F) 10.0 N/A 8.0 7.0 5.0 5.0 4.9 5.0 167 - - - -

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. for BAbelow-2;lossofheightpotentialduringfol height belowthetarget height(±8.5cm);SD 168 recommend 28 days.Although someAmericangroups intramuscularlyorsubcutaneouslyevery administered toa3.75mg 100 µg/kg.Inpractice,this corresponds CPPis75- studies. ThedoseofGnRHa usedtotreat of CPP hasbeendemonstratedbyseveral the treatment andsafety on most commonlyused,and their efficacy the are acetate (LA)andtriptorelin GnRHa, leuprorelin bythegonads(28,48).Ofavailable hormones ofsexsteroid theproduction suppress which inturn ofthesehormones, theproduction GnRHa suppresses chronically,LH andFSHbutwhenitisadministered tially, of GnRHastimulatesthesynthesisandsecretion (46-48).Ini (“down-regulation”) GnRH receptors theamountof endocytosisandreducing promoting withendogenousGnRH, peting forGnRHreceptor half-life. GnRHaactsontheanteriorpituitary, com its degradation,whichprolongs toprotease is resistant stabilityandduration, withmore in thepituitary synthetic decapeptidethatbindstotheGnRHreceptor ofchoiceforCPPisGnRHa (15,44),a The treatment Treatment ofcentralprecociouspuberty may bebeneficial(24,47). (44).Inearlyandfastpuberty,seizures) arrest pubertal emotionalimmaturity,disorders, mentalretardation, (behavioral exclusivelyforpsychosocialreasons arrest ofpubertal no consensusabouttherecommendation ofCPP. pattern to evaluatethe“progressive” is There CPP. Aperiodof3-6monthsfollow-upcanbeuseful ornot forthedecisiontotreat crucial BA advanceare dataand low-up (44)].Clinicalandanthropometric height belowthe2.5 offinal [prediction finalstature potential ofabnormal periodthannormal), tal stagetoanotherinashorter onepuber from development(progression pubertal ofanyetiology, puberty sive precocious accelerated (10,44,46). menarche ofearly tothe occurrence cancer)related (mainly breast tion ofsexualactivity, cancer andestrogen-dependent theriskofsexualabuse,earlyinitia age, andreduce her family. atanearly pregnancy Italsohelpstoprevent te the psychosocial adjustment of the patient andhisor andpromo target height),avoidbodydisproportions, heightpotential(withintherangeof the normal characteristics, delaytheskeletalmaturation,preserve Guideline ofcentral precocious puberty Pubertal arrest is indicatedinpatientswithprogres arrest Pubertal th percentile; prediction offinal prediction percentile; ------

dose has failed to show superior clinical results toini dose hasfailedtoshowsuperiorclinicalresults higher GnRHadoses(200-300µg/kg),amonthly7.5mg advantages includetheabolishmentofperiodicsubcu over 1-monthand3-monthdepotGnRHa(52).The 50mg)hasadvantagesand disadvantages ths ( leases therapeuticdosesofGnRHafor12to24mon 2. ted inFigure ispresen ofCPPtreatment mg) dosages.Aflowchart depot (3.75mgor7.5mg)3-month(11.25 may beinitiallyobtainedwith1-month arrest Pubertal therapeuticresults. satisfactory andbrought adherence, dosingconvenienceand CPPhasimproved mg totreat of3-monthdepotLA11.25 approval Brazil, therecent stilllacking(49-51).In are follow-upresults long-term withthoseofmonthlyGnRHa.However,compared andsafety several studiesdemonstratingtheirefficacy lable, suchasLA11.25mg,22.5and30with withtrimonthlydosingbecameavai nient preparations conve years,more (49).Inrecent arrest tiate pubertal 150 mgper month (depotintramuscular injection) bone mineralloss.MPA 50mgto dosagevaries from developmentof cushingoidhabitus,and hypertension, (ACTH)suppression, hormone adrenocorticotrophic in MPA mimeticaction resulting hasaglucocorticoid 2enzyme(16,19).Inaddition, dehydrogenase teroid by inhibiting 3 betahydroxys gonadal steroidigenesis thalamic pulsegenerator, inhibits and it also directly byacting on hypo release bits central gonadotropin have nobeneficialimpactonfinalheight. MPA inhi but progression, CPA usefulinblockingpuberty are (CPA) therapeutic options. Both MPA represent and acetate(MPA)xyprogesterone acetate or (53). In thesecases, medro secretion the hormonal impairs theabsorptionofGnRHathatfailsto suppress terized bythedevelopmentofasterileabscess,which charac tion shouldbegiventolocalallergic reaction, inintensity. maybemild tosevere These effects Atten andrarely,hyperprolactinemia, anaphylaxis(10,44). and vasomotor symptoms due to vaginal bleedingafterthefirstGnRHadose,nausea, tions (5%-10%ofthecases),headache,abdominalpain, and includelocalallergic reac infrequent are effects in Brazil. of thistherapy. optionisstillunavailable Thistreatment themainundesirable sideeffects and localinfectionare attheimplantsite,spontaneous extrusion, of reactions taneous orintramuscularadministration,buttherisk A subdermal implant of prolonged actionthatre implantofprolonged A subdermal GnRHa are generallywelltolerated,and theirside GnRHa are Arch Metab. Endocrinol 2016;60/2 ------ACTH and cortisol suppressing effect, laboratory hy laboratory effect, suppressing ACTH andcortisol symptoms andgynecomastiainthemale.Duetoits Arch Metab. Endocrinol 2016;60/2 nical treatment, signs of intracranial hypertension, or signsof intracranial hypertension, nical treatment, to cli large lesions associatedwithepilepsyrefractory for isreserved therapy forhypothalamichamartomas clinical therapywithGnRHa (10,11,15,54).Surgical doesnotpreclude cell tumors.Treatment withsurgery as chemotherapyorradiotherapy, forgerm reserved are modalities,such (11,54).Othertreatment formations mal CPP is indicated forbothcongenital and acquired of localreaction. notavailableor,RHa are asabove-mentioned,incase onlywhenGn therapeutic optionsmustbeconsidered situation(16,19).Ofnote,these attention instressful special can occur with CPApoadrenalism use,deserving mg/m The usual CPAsecretion. 50 to 100 daily oral doses are gonadotropin suppressing level,partially the pituitary actionat pheral tissuesandanadditionalprogestational in peri for its competing with testosterone (16,19).CPAprogression activity, hasantiandrogenic inblockingpuberty nistration, andestablishedefficacy Advantages ofMPA includeitslowcost,easilyadmi Figure 2. Treatment flowchartofprogressivecentralprecociouspuberty(CPP)with along-actingGnRHanalog(GnRHa). Surgical treatment of CNS lesions associated Surgicalwith treatment 2 (16). CPA side effects include gastrointestinal (16).CPA includegastrointestinal sideeffects Adequate control 1-month depotGnRHa3.75mg28/28days Trimonthly clinicalandlaboratorialmonitoring 3-month depotGnRHa11.25mg12/12weeks(84days) Clinical andlaboratorialdiagnosisofprogressiveCPP ------3 –6months rare cases of tumor growth, when a differential diag whenadifferential casesoftumorgrowth, rare kedly (below 4 cm/year), recombinant human growth humangrowth kedly (below4 cm/year),recombinant mar (10). Whentheheightvelocityreduces reevaluated carefully puberty etiological diagnosisoftheprecocious inGnRHadosemusthavethe persists afteranincrease that control with inadequateclinicaland laboratory GnRHaadministration(16,26,50).Patients sed before (10,16,28,29,50). LevelsofE2orTshouldbesuppres by IFMA, ICMA,orECL) below 4 IU/L (determined after monthlyortrimonthlyGnRHa,aimingatlevels ofLHvalues parameter ofchoiceisthemeasurement Thelaboratory cases suggestinginadequatecontrol. orsemiannuallyin control, te clinicalandhormonal annuallyincaseswithadequa BA mustbemonitored velocity, infinalheightprediction. andimprovement inheight sexualcharacteristics,decrease of secondary includestabilizationorregression good clinicalcontrol evaluations(10,15).Parametersof nical andlaboratory by cli ofCPPwithGnRHaismonitored The treatment Treatment monitoringincentralprecociouspuberty andglioma(55). astrocytoma nosis mustbeestablishedwithotherlesions,suchas 1-month depotGnRHa3.75mg 1-month depotGnRHa7.5mg Inadequate control Inadequate control Guideline ofcentral precocious puberty 169 - - - - -

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 170 GnRHa therapyaftertheageof6yr, started indicating adultheight most ofthegirlswhoachieved normal significantly andnegatively associated withfinalheight, ageattheonsetoftherapywas Although cronological (42). lineargrowth oftherapyandposttreatment start ageatthe nificant associationbetween chronological In a Brazilian study involving 45 girls, we found no sig Lazarandcols. plateaccording in thegrowth intrinsic changes treatment due to pre height, probably final heightgainandcompromised ced posttreatment versely, CPPdiagnosedaftertheageof6yrhadredu 6yearsofage(42,44,46,47).Con before treatement tential geneticheight,mainlyinthosegirlswhostarted the po is beneficial in preserving the GnRHa treatment withGnRHa.Evidenceshowsthat of patientstreated follow-up inthelong-term parametersofinterest are function,andpsychologicalcharacteristics reproductive Final height,bodycomposition,bonemineraldensity, Long-term follow-up tential (10,15,44,46). finalheightwithinthegeneticpo anormal at reaching cate thebestmomenttowithdrawtherapyaiming 12.5yearsingirlsand13.5 inboysindi around ABA and hisorherpsychosocialadequacydesire. age ofthepatient take intoaccountthechronological sofar(44,58).Treatmenttermined withdrawalshould take someadvantagewithrGHadditionwasnotde andthesubsetofCPP patients whose recommended association ofrGHtoGnRHcannotsistematicallybe the height (58).Allinall,basedonavailableliterature, resulted ina higherfinal was significantly higher and velocityintherGH/GnRHa group the meangrowth a combinationofrGHandGnRHa.Duringtreatment, for2-4ywithGnRHa,or domized fortreatment ran developingcountries were adoptedfrom puberty (56,57). Inaddition,46girlswithearlyorprecocious height predicted thanthepretreatment 7.5 cmgreater randomized studies,themeanfinalheightwasaround duringGnRHatherapy. growth creased Inthesenon withde adding rGHtoGnRHatherapyinchildren from CPP (56-58).Two studiesshowedabenefiteffect of rGHadministrationonfinalheightinpatientswith subcutaneously. Fewstudieshaveassessedtheimpact is0.15IU/kg/dayadministered in thiscircumstance rGHdose heightgain.Therecommended promoting theheightvelocityand aimsatincreasing This measure (56). (rGH)maybeaddedto thetreatment hormone Guideline ofcentral precocious puberty (24,47). (24,47). ------that GnRHa therapy is effective in preserving thepo inpreserving that GnRHatherapyiseffective although the findings are controversial (44,60). In ma controversial although the findings are hasbeenreported, syndrome valence ofpolycysticovary pre (44,59).Infemales,anincreased not beenreported has occur in60%to96%ofthepatients,andinfertility a variationof2to61months).Regularovariancycles ofCPPiswithdrawn(with months afterthetreatment occursonaverage16 dies indicatethatmenstruation function,stu toreproductive regard (44,47,59). With mass mayoccurwithoutconsequencesinadulthood (24,44,47). shouldbeconsidered in delaymenarche puberty, and althoughbenefitsonpsychosocialprofile height wasdemonstratedinthosegirlswithearlyorfast rapy, andtarget height(42).Finally, nobenefitsonfinal therapy, higher height SDS at the onset and end of the andonsetof betweentheonsetofpuberty ter interval shor withdepotGnRHawere in girlswithCPPtreated finalheight normal fact, themainfactorsdetermining tential geneticheightingirlsolderthan6yr(42).In and safe dosages in the short- andlong-term. and safedosages intheshort- convenient,effective, years,withmore advances inrecent nadal axis.Treatment withGnRHa hasshownsignificant theactivation ofthego valuestoconfirm cutoff ferent indif basal andGnRH-stimulated LH. Thisfactresults tomeasure availability ofseveralmethods andprotocols duetothe isstillrequired immunoassays, standardization sensitive and specific with more significant improvement ment. Althoughthebiochemicaldiagnosishasshown CPPtreat follow-up do notrecommend at short-term and bone age advance. Sometimes these data obtained data, in girls,isbasedonclinicalandanthropometric CPP,thological conditions.Thedecisiontotreat mainly pa andnonprogressive acceleration) withprogressive and puberty and constitutional growth thelarche mature development(pre females andamongvariantsofnormal isnotalwayseasy, puberty of precocious in particularly Theclinicaldiagnosis isamultifactorialprocess. Puberty CONCLUSIONS tion withGnRHaonpsychosocialcharacteristics. of thetherapeuticinterven effects andlong-term short- However, studiesevaluatingthe nocontrolled are there inpsychosocialadjustment(44). nodifferences are there antisocial behaviorislimitedtoadolescenceandthat evaluated thepsychosocialimpactofCPPsuggestthat gonadalfunction(43).Thefewstudiesthathave normal outhaveshown les, afewstudiesthathavebeencarried Transitional changesinbodycompositionandbone Arch Metab. Endocrinol 2016;60/2 ------Arch Metab. Endocrinol 2016;60/2 18. 7. 1 16. 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES reported. was relevant tothisarticle tential conflictofinterest Abbvie.Nopo feesfrom lecture allauthorsreceived Disclosure:

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Endocrinol 2016;60/4 INTRODUCTION diagnosis andtherapeutic management Central precocious revisiting puberty: the This process is named gonadarche (1-3). isnamedgonadarche This process gland. inhibit bothhypothalamusandanteriorpituitary bytheovaries) the testis,andE2=estradiol,produced by produced (T=testosterone, gonadalsteroids whereas onthehypothalamus, anegativefeedbackeffect exert stimulatethegonadsand Gonadotropins hormone). andFSH=follicle-stimulating luteinizing hormone gland(LH= bytheanteriorpituitary gonadotropins of ofGnRHstimulatingthesecretion secretion pulsatile hypothalamic onsetrequires pubertal effective (HPG) axis. An hypothalamic-pituitary-gonadal of the inreactivation economic factorsandresults ethnic,geographic,and metabolic, environmental, that includes genetic, and multifactorial process function.Itisacomplex achievement ofreproductive and adulthood, with accelerated linear growth DOI: 10.1590/2359-3997000000198 DOI: 10.1590/2359-3997000000144 Where youread: Where P psychological transition from childhoodto psychological transitionfrom and isaperiodofphysical,hormonal, uberty INTRODUCTION Should read: process is named gonadarche (1-3). isnamedgonadarche process gland.This both hypothalamusandanteriorpituitary bythe ovaries) inhibit and E2 =estradiol,produced bythetestis, produced (T=testosterone, steroids gonadal stimulate the gonads, whereas Gonadotropins andFSH=follicle-stimulatinghormone). hormone gland (LH = luteinizing by the anterior pituitary of gonadotropins GnRH stimulating thesecretion of pulsatile hypothalamic secretion onset requires pubertal (HPG)axis.Aneffective pituitary-gonadal ofthehypothalamic- inreactivation factors andresults ethnic,geographic,andeconomic environmental, that includes genetic, metabolic, multifactorial process function.Itisacomplexand achievement ofreproductive and adulthood, with accelerated linear growth P psychological transition from childhoodto psychological transitionfrom and isaperiodofphysical,hormonal, uberty erratum

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