Revisão ABSTRACT Precocious Puberty Is Deﬁned As the Development of Secondary Sexual Charac- Teristics Before the Age of 8 Years in Girls and 9 Years in Boys

Home , Hyperestrogenism, Hypoestrogenism, Nafarelin, Premature thelarche

Update on the Etiology, Diagnosis and Therapeutic Management of Sexual Precocity

revisão ABSTRACT Precocious puberty is deﬁned as the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Gonadotropin- dependent precocious puberty (GDPP) results from the premature activation of the hypothalamic-pituitary-gonadal axis and mimics the physiological pubertal development, although at an inadequate chronological age. Hormonal evalua- VINICIUS NAHIME BRITO tion, mainly through basal and GnRH-stimulated LH levels shows activation of ANA CLAUDIA LATRONICO the gonadotropic axis. Gonadotropin-independent precocious puberty (GIPP) IVO J. P. ARNHOLD is the result of the secretion of sex steroids, independently from the activation of the gonadotropic axis. Several genetic causes, including constitutive activat- BERENICE BILHARINHO MENDONÇA ing mutations in the human LH-receptor gene and activating mutations in the Gs protein D-subunit gene are described as the etiology of testotoxicosis and McCune-Albright syndrome, respectively. The differential diagnosis between Unidade de Endocrinologia do GDPP and GIPP has direct implications on the therapeutic option. Long-acting Desenvolvimento, Disciplina de gonadotropin-releasing hormone (GnRH) analogs are the treatment of choice Endocrinologia da Faculdade in GDPP. The treatment monitoring is carried out by clinical examination, hor- de Medicina da Universidade monal evaluation measurements and image studies. For treatment of GIPP, de São Paulo e Laboratório de drugs that act by blocking the action of sex steroids on their speciﬁc receptors Hormônios de Genética (cyproterone, tamoxifen) or through their synthesis (ketoconazole, medroxy- Molecular LIM/42, São Paulo, SP, progesterone, aromatase inhibitors) are used. In addition, variants of the nor- Brazil mal pubertal development include isolated forms of precocious thelarche, precocious pubarche and precocious menarche. Here, we provide an update on the etiology, diagnosis and management of sexual precocity. (Arq Bras Endocrinol Metab 2008;52/1:18-31)

Keywords: Precocious puberty, GnRH analogs, Precocious thelarche, Preco- cious pu-barche, Testotoxicosis, McCune Albright syndrome.

RESUMO

Atualização em etiologia, diagnóstico e manejo da precocidade sexual. A puberdade precoce é definida como o desenvolvimento dos caracteres sexuais secundários antes dos 8 anos nas meninas e dos 9 anos nos meninos. A puberdade precoce dependente de gonadotrofinas (PPDG) resulta da ativação prematura do eixo hipotálamo-hipófise-gonadal e mimetiza o desenvolvimen- to puberal fisiológico, embora em idade cronológica inadequada. A avaliação hormonal, principalmente os valores de LH basal e após estímulo com GnRH exógeno confirmam a ativação do eixo gonadotrófico. A puberdade precoce independente de gonadotrofinas (PPIG) é o resultado da secreção de esteróides sexuais independentemente da ativação do eixo gonadotrófico. Diversas cau- sas genéticas, incluindo mutações ativadoras constitutivas no gene do recep-

ABE&M todos os direitos reservados tor do LH humano e mutações ativadoras no gene da subunidade da proteína © D G representam as etiologias da testotoxicose e da síndrome de McCune Al- Recebido em 31/07/2007 bright, respectivamente. O diagnóstico diferencial entre PPDG e PPIG tem im-

18 Arq Bras Endrocrinol Metab 2008;52/1 hypothalamic-pituitary-gonadal axisand gonadotro- hypothalamic-pituitary-gonadal activationofthe sexual characteristicsbythe premature developmentofsecondary is definedasthepremature (GDPP) puberty precocious Gonadotropin-dependent Classification ofprecociouspuberty cations onthetherapeuticoption. impli- hasdirect puberty these twotypesofprecocious diagnosisbetween dent orindependent.Thedifferential secretion-depen- asgonadotropin terization ofpuberty thefirststepconsistsofcharac- puberty, precocious investigationandfollow-up(3). and warrants teristics between6and8yearsisnotnecessarilybenign of thecases,indicatingthatfindingsexualcharac- in12% ofsexualprecocity found anon-idiopathicform between 6and8yearsofageinAfrican-Americangirls between7and8yearsofageinwhitegirls occurring However, of223patientswithsexualprecocity areview girls andin6.7%ofthewhiteat7yearsage(2). in27.3%oftheAfrican-American velopment waspresent and/orpubichairde- andphotographs,breast reports the UnitedStates(2).Inthisstudy, basedonmothers’ in an adjustmentinthemeanageofonsetpuberty sive discussion.Astudyincluding17,000girlssuggested wasobjectofexten- cal agethatdefinesexualprecocity (1). However, thedefinitionoflimitschronologi- outinthe60’s longitudinalstudiescarried European 8 yearsinthegirlsand9boys,basedon Arq Bras2008;52/1 EndrocrinolMetab P When evaluating a child with a clinical picture of When evaluatingachildwithclinicalpicture of secondary sexual characteristics before theageof sexualcharacteristicsbefore of secondary EOIU UET SDEFINED IS PUBERTY RECOCIOUS INTRODUCTION asthedevelopment apeoe ettxcs;SíndromedeMcCuneAlbright. ca precoce;Testotoxicose; Descritores: Metab 2008;52/1:18-31) o diagnóstico etratamentodaprecocidadesexual. telarca, pubarcaemenarcaprecoces.Nestarevisão,atualizamosaetiologia, Variantes dodesenvolvimentopuberalnormalincluem asformasisoladasde a sua síntese(cetoconazol,medroxiprogesteronaeinibidoresdaaromatase). sexuais nosseusreceptoresespecíficos(ciproterona,tamoxifeno)oubloqueiam tratamento daPPIG,sãousadasdrogasquebloqueiamaaçãodosesteróides realizada peloexameclínico,avaliaçãohormonale o tratamentodeescolhadaPPDG.AmonitorizaçãodoPPDGé Pbraepeoe nlgsd nH Telarca precoce;Pubar- Puberdadeprecoce;AnálogosdeGnRH; Etiology, diagnosisandtreatmentofsexual precocity guishing isolated premature thelarche from early-stage from thelarche guishing isolatedpremature ultrasound, anoninvasivetool,maybehelpfulindistin- inthiscondition(4).Pelvic hibin Bcanbeincreased range,althoughFSHlevelsandin- prepubertal normal within levelsare andsteroid gonadotropin line serum isnotcompletelyclarified.Base- thelarche precocious age.Thephysiopathologyof quate forchronological ade- velocityremain boneageandgrowth thelarche, months orpersistingtopuberty. Inisolatedprecocious within aspontaneousregression of age,presenting to3years birth from nign clinicalcondition,occurring signs.Thisisgenerallyabe- secretion other estrogen developmentwithno ed unilateralorbilateralbreast theisolat- represents thelarche” “precocious The term Isolated precociousthelarche menarche. andprecocious pubarche precocious thelarche, development canoccur:isolatedprecocious ual precocity, pubertal variantsofthepremature three (Table ofsex- 1).Inadditionto thesetwodistinctforms production steroid sexualdevelopmentisdependenton when premature (GIPP) occurs puberty pin-independent precocious Table 1. Isolated precocious menarche Isolated precocious pubarche Isolated precocious thelarche Variants development pubertal ofthenormal (GIPP) Gonadotropin-independent precocious puberty (GDPP) Gonadotropin-dependent precocious puberty Classification oftheprecociouspuberty. regardless ofgonadotr exames deimagem. (Arq BrasEndocrinol opin secretion Brito etal. Brito Para o Para o 19

copyright© ABE&M todos os direitos reservados copyright© ABE&M todos os direitos reservados gain in childhood may predispose to precocious pubarche pubarche toprecocious gain inchildhoodmaypredispose Brito etal. Brito Etiology, diagnosisandtreatmentofsexual precocity with precocious andobesityhavebeenassociated as welloverweight andsmallforthegestationalagestatus, Both prematurity outbyanACTH-stimulationtest. sia shouldberuled hyperpla- ofcongenitalvirilizingadrenal nonclassical form notseen.The were andfinalheightimpairment puberty of years inabout16%ofthecases,althoughprogression ofuptotwo mainly inthefirsttwoyears,withadifference slight advancementofboneagecanalsobeobserved, hair, velocityand growth increased velopment ofaxillary 8yearsofageingirlsand9boys.Thede- before This conditionconsistsoftheappearancepubichair Isolated precociouspubarche intocompletepuberty.detect apossibleprogression andbiannualevaluationofpatientsto advice toparents consistsof thelarche ofisolatedprecocious treatment should beperiodicallyevaluatedinthiscondition.The velocityandboneage and estradiollevels,growth (6).Baselinegonadotropin complete sexualprecocity mayevolvewith thelarche the girlswithprecocious ismandatory, thelarche with precocious since14%of ingirls(5).Thefollow-up ofgirls puberty precocious other hand, gonadotropin-independent precocious pu- precocious other hand,gonadotropin-independent theinitialevents. Onthe are velocity andthelarche isosexual GDPP. growth Inthefemale,increased thefirstclinicalmanifestationof > 2.5cm)represents testicularvolume>4mL(orlength male, theincresead age.Inthe though ataninadequatechronological development,al- mimics thephysiologicalpubertal (GDPP) puberty precocious Gonadotropin-dependent out possiblegenitaltraumaticinjuriesormanipulations. genitaliaisessentialtorule examination oftheexternal aswell range.Adetailedclinicalhistory bertal prepu- atthenormal andestradiollevelsare nadotropin acyclicalcharacter.the winteranddonotpresent Go- during frequent more advancement. Suchepisodesare signsorboneage age of8yearswithoutotherpubertal the It ischaracterizedbyisolatedvaginalbleedingbefore Isolated precociousmenarche in susceptibleindividuals(9). 20 GONADOTROPIN-DEPENDENT PRECOCIOUS PUBERTY pubarche (7,8). In addition, excess weight (7,8).Inaddition,excessweight pubarche TGF but TGF cocity, noGnRHimmunoreactivity contrast, GnRHpulse-generator(14).In function asaheterotopic ofGnRH-positive thepresence revealing studies bodies (13).Immunohistochemistry mamillary ventricle,nexttothe of thethird lamic tissue,locatedinthebaseofbrain,floor massofhypotha- consistingofaheterotopic formation, anon-neoplasiccongenitalmal- represent Hamartomas Hypothalamic hamartomas tients withsexualprecocity, inboys(1). particularly investigationinpa- need foranefficientneurological 50%ofthecases.Thesedataindicate proximately of precocious puberty, ap- andCNStumorsrepresent for2/3ofthecases responsible abnomalitiesare rological sexualprecocity.trauma, candetermine Inthemale,neu- tumors, braindevelopmentdefects,inflammationand system(CNS) centralnervous pothalamic hamartomas, tion (Table causes,including hy- 2).Severalneurological causes ofGDPPandshouldbeaddedtoclassifica- thefirstgenetic GDPP (10,12).Thesefindingsrepresent ligand, kisspeptin,wasidentifiedinaBrazilianboywith ing mutation(P74S)inthe can, andHispanicorigin(10,11).Additionally, anactivat- functionhavingCaucasian,African-Ameri- reproductive this changeisnotidentifiedinindividualswithnormal was identifiedinanadoptedBrazilianfemalewithGDPP; mutationin An activatingheterozygous was demonstrated. duringpuberty mone (GnRH)neurons tem inthe ofthekisspeptin-GPR54sys- few years,thepivotalrole (1).Inthelast form pathic gonadotropin-dependent ten seeninthefemale(3to23-fold),mainlyidio- of- ismore puberty ofprecocious (1). Theoccurrence es. TheestimatedGDPPincidenceis1:5.000-1:10.000 cas- byadultageinnon-treated stature lowed byshort overchildhoodfol- inexcessivestature This results fusion. maturation, culminatinginepiphysispremature velocityandthebone growth mine theincreasing cious puberty, concentrationsdeter- ,thehigh steroid preco- Inbothisosexualandheterosexual production). orvirilizationingirlsduetohighandrogen cretion (feminization inboysduetohighestradiolse- puberty precocious (GIPP) mightleadtoheterosexual berty hamartomas ledtothehypothesisthattheseneurons hamartomas tected (14). Approximately 2-28% of the patients with 2-28%ofthepatientswith tected (14).Approximately D , the epidermal growth factorreceptor, growth were , theepidermal D in other hamartomas associatedwithsexualpre- in otherhamartomas mRNA and protein, as well as the receptor for for aswellthereceptor mRNAandprotein, stimulation of gonadotropin-releasing hor-stimulation ofgonadotropin-releasing Arq Bras2008;52/1 EndrocrinolMetab KiSS1 gene tuber cinerium was demonstrated, was demonstrated, encoding GPR54’s encoding GPR54’s GPR54 neurons in some insome neurons (R386P) (R386P) or the orthe de- Arq Bras2008;52/1 EndrocrinolMetab size,exceptinboysbelowthe ageof2years, pubertal testicular stimulation.InGDPP, testicularvolumeisat ticular volume>4mLorlength2.5cmindicates toMarshallandTannercording criteria(15,16).Tes- hair developmentinbothsexes,classifyingthemac- developmentingirls,aswellpubic boys andbreast in ual characteristics,alongwithtestismeasurement sex- examination includesthedescriptionofsecondary Thephysical valuableinformation. are onset ofpuberty of intake, CNStraumaorinfectionsandfamilyhistory sexualcharacteristics,steroid velopment ofsecondary diagnosis.Theageofonsetandtherhythmde- rect toattainthecor- isimportant clinicalhistory Careful Clinical evaluation (nãoseria“regrowth”?). casesoftumorgrowth the rare orin difficulttocontrol symptomsthatare neurological with forlarge hamartomas isreserved Surgical treatment medicalusingdepotGnRHanalogs(13). ma ispreferably (1).The therapyofGDPPduetohypothalamichamarto- hypothalamusisdetected similar intensitytothenormal imaging(MRI),anon-enhancedmassof netic resonance Onmag- followedbyfocalandtonic-clonicseizures. ture, beingthemostcommonfea- (typical laughingseizures) puberty,sociated withprecocious withgelasticepilepsy manifestationscanbeas- acteristics (1,13).Neurological sexualchar- characterized bytheearlyonsetofsecondary 80%ofthecasesandis occursinapproximately precocity when symptomatic,theclinicalmanifestationofsexual canbeasymptomatic,and hypothalamic hamartomas (1).Clinically, hypothalamichamartomas GDPP present Table 2. No CNS abnormalities No CNSabnormalities CNS abnormalities Tumors: astrocytoma, craniopharingeoma, ependymoma, opticalorhypothalamic glyoma, LH-secretingadenoma, Acquired diseases:infectionsprocesses andinflammatory oftheCNS(encephalitismeningitis, tuberculosis and disrupters After exposuretoendocrine Genetic causes( Idiopathic sarcoidosis granulomas, abscesses, radiation, chemotherapy, headtrauma, asphyxia) perinatal myelomeningocele, vascular malformations Congenital malformations: arachnoid cyst, supraselar cyst, hydrocephaly, spinabifida, septum-opticaldysplasia, pinealoma, neurofibroma, dysgerminoma Hypothalamic hamartoma hyperplasia, afterresectionofsexsteroid-secreting tumors, testotoxicosis, syndrome) McCune-Albright totheprevious chronic forms exposuretosexsteroids:Secondary ofcongenitaladrenal (Latetreatmentofvirilizing Etiology ofgonadotropin-dependent precociouspuberty. GPR54 and KiSS-1 mutations) Etiology, diagnosisandtreatmentofsexual precocity U/L for boys and girls are considered enoughtoestab- considered U/L forboysandgirlsare individuals(17). Basal LHconcentrations>0.6 normal apopulationof (IFMA) havebeenestablishedfrom method valuesfortheimmunofluorometric The cut-off valuesshouldbeestablishedforeachmethod. normal and measurements available methodsforgonadotropin several are (17).There puberty diagnosis ofprecocious usefulinthediagnosisanddifferential GnRH, i.v)are after stimulationwithexogenousGnRH(100mcgof inbasalconditionsand measurements The hormonal Hormonal evaluation sions andCNSglyoma). (GDPP, dysplasia)orneurofibromatosis fibrous skinle- mous ovariancysts,café-au-laitspotsandpolyostotic duetoautono- puberty pin- independentprecocious (gonadotro- diagnosis ofMcCuneAlbrightsyndrome of skinlesions(café-au-laitspots)canbeusefulinthe nal andpelvicmassesmustbeevaluated.Thepresence odor, ofabdomi- musculardevelopmentandpresence hairand ofacne,oilyskinandhair,presence axillary tables.Otherphysicalaspectssuchasthe appropriate ageby (SDS)forchronological deviationscore dard andcalculatingheightweightstan- curves growth be evaluated,aswellthestaturalage,usingadequate and rests testicular tumors,adrenal toxicosis, hCG-producing size(testo- increased both testeshaveanintermediately somesituationsinwhich are volume isexpected,there size. Incontrast,inGIPP, testicular althoughareduced in whomtesticularvolumecanbestillatprepubertal DAX-1 mutation).Weight andheightmust Brito etal. Brito 21

copyright© ABE&M todos os direitos reservados copyright© ABE&M todos os direitos reservados entiation between pubertal andprepubertal entiation betweenpubertal allowingthediffer- sensitivethanIFMA,thereby more subjects demonstratedthatthismethodseemstobe immunochemiluminometric assays(ICMA)innormal by baseline andGnRH-stimulatedLHlevelsmeasured axis(18).Recently,of activationthegonadotropin alsoindicative acetateinjectionare first depotleuprolide strated thatLHlevels>10U/L(byIFMA)2hrafterthe concentrations(19).We gonadotropin serum demon- Brito etal. Brito Etiology, diagnosisandtreatmentofsexual precocity Table 3. leuprolide contains enoughfree test, h analog cansubstitutetheclassicGnRH-stimulation utes afterthefirstadministrationoflong-actingGnRH (17). Alternatively, 30 to 120min- LHmeasurement GnRH stimulationindicatethediagnosisofGDPP peak >9.6U/Linboysand6.9girlsafter levelsofLH GnRH stimulationtestisindicated.Serum the of77children), and 29%oftheboysinourcohort range(in37%ofthegirls withGDPP at prepubertal GnRH stimulationtest(17).WhenbasalLHlevelsare lish thediagnosisofGDPP, whichdispenseswith However, in thatstudy, 2 SD abovetheprepubertal withearlypuberty.constitute about90%ofchildren atleastinfemalesubjects,who secretion, gonadotropin than5U/Lwasindicativeofmaturing ICMA greater by thataGnRH-stimulatedLHpeakmeasured ported LH ICMAassaywas0.1U/L(20).Neely in boysunderbaselineconditions,sincethesensitivityof *Only normal subjectswere*Only normal included. RIA: radioimmunoassay; ICMA:immunochemiluminometricassay; IFMA:immunofluorometric assay;NA:notavailable 22 uhrProtocol Author Cavallo A Neely EK KE Oerter Resende Brito Brito Eckert et al et al owever atahighercost(18).Depotleuprolide LH cut-off values thatindicate et al et al 04(8 H2h fe .5m fdptlurld 10IM >10 U/L(girls) IFMA IFMA 30–45 120 LH2hsafter3.75mgofdepotleuprolide LHpeakafterGnRH(100µg) , 2004(18) , 1999(17) et al et al et al 96(4 L ekatrGR 10µ)4 CA>8.0U/L ICMA 40 LHpeakafterGnRH(100µg) , 1996(24) 95(1* Hpa fe nH(0 g 0ICMA 30 LHpeakafterGnRH(100µg) , 1995(21)* 07(0*LHpeakafterGnRH(100µg) , 2007(20)* 90(2 Hpa fe nH(0 g N RIA NA LHpeakafterGnRH(100µg) , 1990(22) 95(3 Hpa fe nH(0 g 3,4 r6 RA>15U/L IRMA 30, 45or60 LHpeakafterGnRH(100µg) , 1995(23) to cause a rapid rise in to causearapidrisein gonadotropic axismaturation. et al stage mainly stage mainly . (21)re- free T4 and adrenal androgen precursors. androgen T4andadrenal free includeTSH, measurements tumors. Otherimportant gonadalandextragonadal diagnosing hCG-producing outwiththeobjectiveof (hCG) levelsmustbecarried ofthehumanchorionicgonadotropin measurement (17).Inboys,the puberty pin-independent precocious suggestthediagnosisofgonadotro- pin levelsstrongly gonadotro- ofloworsuppressed levels inthepresence range(17).Highestradiol levels withintheprepubertal hadestradiol (41%inourcohort) with sexualprecocity puberty,of precocious asasignificantnumberofgirls outthediagnosis estradiol concentrationsdonotrule inthemale.Incontrast,female,low ual precocity isanexcellentmarkerofsex- testosterone (17). Serum puberty precocious cate gonadotropin-independent for thediagnosisofGDPP, levelsindi- butsuppressed notuseful line andGnRH-stimulatedFSHlevelsare inTable methodsispresented 3.Base- for thedifferent secretion values indicativeofmaturinggonadotropin oftheGnRH-stimulatedLHcut-off mation. Areview confir- hormonal clinical factors,aswelltherequired ofGDPPshouldbeasynthesisseveral treatment Obviously, thecriteriafordiagnosisandmainly sibly preferable,threshold stringent,andpos- LH peakinfemalesubjectsisamore of8U/LforGnRH-stimulated that adiagnosticcut-off bined mean ofLHpeakformaleandfemalesubjectscom- was 7.9U/L(21).Finally, thisstudysuggested ie(i) ehdCut-off value Method time (min) LH peak 0-4 IFMA ICMA 30 -45 30 –45 Arq Bras2008;52/1 EndrocrinolMetab for diagnosisof >9.6 U/L(boys) >6.9 U/L(girls) (both genders) > 5U/L >25 U/L(boys) >15 U/L(girls) >3.3 U/L(boys) >4.2 U/L(girls) >4.1 U/L(boys) >3.3 U/L(girls) GDPP (21). Arq Bras2008;52/1 EndrocrinolMetab sexual activity, pregnancy, preventing therisk reducing anxiety,alleviating theparents’ of delayingthestart thechild’semotionalproblems, maturation, preventing theaccelerationofskeletal characteristics, suppressing orstabilizingsexual onset,regressing age forpuberty sexualmaturationuntilthenormal mors, interrupting intracranialexpandingtu- as detectingandtreating which includeclinicalandpsychologicalaspects,such objectives, hasbroad treatment puberty Precocious Treatment those girls(25). ofGnRHin release inanincreased tinued, resulting toDDTisdiscon- to developedcountriestheexposure thehypothalamus;aftermigration andmature suppress activitymay mechanismisthatestrogen The proposed puberty. developingcountrieswithprecocious from levelsofDDThavebeenfoundinadoptedgirls creased hypothalamicmaturation.In- inpremature may result stillusedindevelopingcountries, ticides, whichare (DDT)-derivedpes- Dichlorodiphenyltrichloroethane Previous exposuretoendocrinedisrupters drome. (testotoxicosis)andMcCune-Albrightsyn- puberty hyperplasia,familialmale-limitedprecocious adrenal patientswithvirilizingcongenital sion inlate-treated suppres- condition isGDPPthatfollowssexualsteroid bone ageis10-13years.Themainexamplesofthis Thisconditiongenerallyoccurswhenthe treatment. disease and hypothalamicmaturationaftertheprimary boneage intheaccelerationoflineargrowth, resulting tosexsteroids, exposure bythechronic It istriggered precocious puberty Secondary gonadotropin-dependent identify CNStumors,butnotthesmallerhamartomas. byMRI,sinceCTisableto ried outpreferentially tomical evaluationoftheCNSinGDPPcasesiscar- Theana- the detectionofcystsandneoplasicprocesses. sound allowstheassessmentofovariandimensionsand Ingirls,pelvicultra- cal age,exceptinhypothyroidism. etiology, tochronologi- boneageisadvancedinrelation tion. Inthecasesofsexualprecocity, ofthe regardless low-up oftherapeuticefficacyandfinalheightpredic- toolindiagnosis,fol- amandatory methods represents &PyleorTannerBone ageassessmentbyGreulich Image studies Etiology, diagnosisandtreatmentofsexual precocity weight gain (1,26,33). The treatment monitoringis weight gain(1,26,33).The treatment in been demonstratedthatGnRH analogsdonotresult acetate.Ithas orcyproterone medroxyprogesterone optionsmustbeinstituted,suchas and othertreatment (32). Inthesesituations,theusemustbediscontinued canbefoundinupto10%ofthepatients reactions Localallergic tor symptomsduetohypoestrogenism. inal bleedingafterthefirstdoses,nauseaandvasomo- oflong-actingGnRH analogsinclude:vag- side effects withGDPP(30,31).The levelsfor1yrinchildren roid ofpeakLHandsexste- maintains excellentsuppression implantachievesand GnRHanalog(histrelin) dermal (27-29). Recently, itwasdemonstratedthatthesub- optionforthepatientwithGDPP comfortable a more represent acetateor10.8mgofgoserelin) of leuprolide higher dosethanthemonthlyusedanalogs(11.25mg witha3-fold quarterly GnRH analogsadministered of cade, theevidenceonsafetyandeffectiveness (17,18).Overthelastde- puberty precocious control dose(7.5mg/month)to logs neededanincreased withGnRHana- treated children puberty precocious outcomes(26).Only4%ofour used, withsatisfactory 28dayshasbeenwidely every intramuscular route) acetateatadoseof3.75mg(subcutaneousor prolide Theuseofleu- suppression. complete gonadotropin levels,preventing valuestoprepubertal nadotropin Ouraimistolowergo- blocking isstillcontroversial. pubertal asatisfactory The adequatedosetoreach implantsornasaladministration. taneous, transdermal forintramuscular, formulations are subcu- used. There dependonthetypeofanalogtobe process the pubertal blockingof andthedoseusedforeffective route tion ofboneageadvancement.Theadministration velocityandreduc- ofgrowth teristics, normalization sexualcharac- orstabilizationofsecondary regression inthe administrationofGnRHanalogsresults Chronic (17). production ofthesexsteroid quent suppression withconse- production ofgonadotropin suppression chronically,tion, andwhenadministered itleadstothe synthesisandsecre- initial stimulationofgonadotropin isan amongothers.There andnafarelin, tryptorelin acetate,goserelin, available,suchasleuprolide logs are inthehypophysis.SeveralGnRHana- GnRH receptors numberof gland,leadingtoareduced the pituitary GnRH decapeptide.Thesiteofactionsuchagentsis syntheticanalogsofthenatural GDPP (1).Theyare ofchoicein thetreatment GnRH agonistanalogsare Long-acting menarche. associated withprecocious cancer theriskofbreast of sexualabuseanddecreasing Brito etal. Brito 23

copyright© ABE&M todos os direitos reservados copyright© ABE&M todos os direitos reservados treatment doseofdepotleuprolide treatment itant ovarian processes are suspected. are itant ovarianprocesses blockingorconcom- except whenincompletepubertal withGnRHanalogs, indicated duringGDPPtreatment be evaluatedyearly. USassessmentisnot Theroutine displayedinTable are ent protocols, 4.Boneagemust valuesforGDPPmonitoring,aswelldiffer- cut-off LH (18).Different control suggest goodhormonal acetateinjection hours aftera3.75mgdepotleuprolide well-blocked GDPPgirls,thatLHvalues<6.6U/L2 (18,19). We of18clinically demonstrated,inagroup comparablewithGnRH-stimulationtest directly Brito etal. Brito Etiology, diagnosisandtreatmentofsexual precocity Table 4. efficacy tooltoevaluatetreatment reliable sampleforLHdrawn serum monitoringcanbeused(18).Asingle the treatment for IFMA method(18).Somesimplifiedalternatives criterion,usingthe control gests agoodhormonal GnRH-stimulation test,avalueofLH<2.3U/Lsug- 6months(18).After with exogenousGnRHevery 3months,aswellastimulationtest ommended every (18). Evaluationatbaselineconditionsisrec- puberty of (<14 ng/dL)inboys,indicateadequatesuppression elevatedestradiollevels,andtestosterone with previous estradiol(<10pg/mL)ingirls IFMA) andsexsteroids, ranges(<0.6U/L, LHlevelsatprepubertal line serum (1,18).Base- line andGnRH-stimulatedmeasurements withGnRHanalogs includesbase- puberty precocious of evaluationduringthetreatment site. Thehormonal velocityandtheexaminationofinjection of growth sexualcharacteristics,theanalysis sion ofthesecondary tion mustaimatverifyingthestabilizationorregres- evaluation andimageassessment.Theclinicalexamina- clinicalexamination,hormonal outthrough carried NA: notavailable RIA: radioimmunoassay; ICMA:immunochemiluminometricassay;IFMA:immunofluorometric assay 24 uhrProtocol Author Parker KL Lawson ML SF Witchel Cook JS Bhatia Brito Brito Brito Brito Badaru Badaru et al et al LH cut-off values ofdifferent methodsfor ofGDPP treatmentwithdepotGnRHanalogs. themonitoring et al et al et al 04(8 Hatrdptlurld .5m 2 FA<6.6U/L IFMA 120 LHafter depotleuprolide 3.75mg , 2004(18) 04(8 HatrGR 10µ) 0–4 IM <2.3U/L IFMA 30–45 LHafter GnRH(100µg) , 2004(18) et al et al 02(9 Hatrdptlurld . g4 0 CA<3.0 U/L ICMA 40–60 LHafterdepotleuprolide 7.5mg , 2002(19) et al 06(8 Hatrdptlurld . g4 CA<4.5U/L ICMA 40 LHafterdepotleuprolide 7.5 mg , 2006(38) 92(5 otra admL esrmn ARA<4.0U/L RIA NA random LHmeasurement Nocturnal , 1992(35) 91(4 Hpa fe nH(0 g 0–4 RA<1.75U/L IRMA 20–40 LHpeakafterGnRH(100µg) , 1991(34) 96(6 Hpa fe nH(0 g ADLI <1.75U/L DELFIA NA LHpeakafterGnRH(100µg) , 1996(36) 99(7 L fe nH(0 g 4 CA<2.0U/L ICMA 40 LHafterGnRH(100µg) , 1999(37) 30 to120minutesaftera is anaccurateand in amanner they reach finalheight(26,42,43). they reach rangeforthefemaleswhen withinthenormal remains (26,42,43). However, follow-up,BMD atlong-term unchanged orremains ing theGnRHagonisttreatment dur-age atthemomentofdiagnosisanddecreases forchronological (BMD) is,inmostcases,increased (26).Bonemineraldensity treatment before narche me- presented inthegirlswhohadalready precocious withdrawal,beingmore (6-18 months)aftertreatment occursatvariabletimeperiods strated (42).Menarche ter GnRH-analogtherapywithdrawalhasbeendemon- af- axissuppression the hypothalamic-pituitary-gonadal of (26,39-41).Acompletereversibility same direction availableformales,buttheypointinthe are reports age(26).Fewer tween 8and10yearsofchronological onsetwasbe- GnRH analogsingirlswhosepuberty with obtainedaftertreatment heightwere predicted on earlier(26).However,treatment nopositiveeffects thoseobtainedinpatientswhoinitiated are best results the heightatthebeginningoftreatment, predicted withthe range (26).Whenfinalheightiscompared finalheightwithintarget height them havereached withGnRHanalogsshowedthat75%of girls treated than637GDPP (1,26). Ameta-analysisincludingmore age ingirlsandbetween1313.5yearsboys ment withdrawalbetween12and12.5yearsofbone obtainedwithGnRH-analogtreat- are The bestresults andthepatient’sfamily’swishes. logical profile togetherwiththeboneage,psycho- be considered withdrawalhasto agefortreatment The chronological Treatment withdrawal ie(i)Mto Cut-off value Method time (min) LH peak Arq Bras2008;52/1 EndrocrinolMetab with GnRH-a (growth velocitybelowthe25 with GnRH-a(growth results in marked growth deceleration inmarkedgrowth results greater than the adult height reached by thantheadultheightreached greater duringGnRHatherapy(44,45).In growth creased Arq Bras2008;52/1 EndrocrinolMetab Table 5. greater thanthe greater two studies,themeanfinalheightwas7.1and8.1cm studies encourage their use in GDPP treatment (47). (47). studies encouragetheiruseinGDPPtreatment butexperimental used inassistedreproduction, currently developedforclinicaluse.Theyhavebeen been recently ofGnRHandhave They immediatelyblocktheeffect GnRH receptorantagonists (46). 1.2 cm)ofalllarge GDPPcohorts thelowestfinalheight(151.9± GnRH-a alonereached with treated inotherstudiessincethegroup confirmed (46).However,group shouldbe thisexcellentresult adding GHtoGnRH-atherapy benefitfrom be associated.Two studiesshowedareal age),GH(0.15U/Kg/d)therapycan for chronological first and second report, respectively,first andsecondreport, cm greater thantheadult cm greater heightand4.5 predicted thanthepretreatment greater GDPP. Inthisstudy, themeanadultheightwas7.8cm wasdescribedingirlswith androgen, aromatizable (0.06mg/kg·dbymouth),anon- with oxandrolone (44,45). withGnRH-aalone,respectively treated group Genetic causes hypothyroidismSevere untreated primary long-term Autonomous ovarian cysts Tumors Exogenous useofsex steroids Activating andinactivating mutations inthearomatase gene Activating mutations inLH-receptorgene( Activating mutations inthe Inactivating mutations in Inactivating mutations in Congenital Adrenal hypoplasia ( Inactivating receptorgene(GR) mutations intheglucocorticoid v v v v v v When the suppression of the pituitary-gonadal axis axis ofthepituitary-gonadal When thesuppression More recently,More theassociationofGnRH-atherapy Granulosa andthecacelltumors Ovarian tumors Leydig cellhyperplasiaortumors Testicular tumors Adrenal tumors hCG-producing tumors:hepatomas,gonadalchorioepitheliomaorextragonadalteratomas. Etiology ofGonadotropin-Independent precociouspuberty. pretreatment predicted height in the heightinthe predicted pretreatment height reached by the control bythecontrol height reached CYP11 CYP21A2 B -subunit oftheGsproteinsyndrome) gene(McCune-Albright andHSD3B2genes DAX-1 in children withde- in children gene and 3.5 and 4.6 cm and 3.54.6cm during treatment during treatment mutation) LHR the control the control th percentile percentile ) (testotoxicosis) these these Etiology, diagnosisandtreatmentofsexual precocity clinically malignant. Abdominal pain is a frequent clini- clinically malignant.Abdominalpainisafrequent seldombilateralor andare rare Ovarian tumorsare Ovarian tumors ofchoice. isthetreatment removal fortumor ticular nodules.Thesurgical approach thediagnosisofGIPP.firm USisusefultodetecttes- levelscon- gonadotropin orsuppressed by prepubertal accompanied tumors (48).Highlevelsoftestosterone has beendescribedinseveralpatientswithLeydigcell gene(LHR),Asp578His, mutation oftheLHreceptor accompaniedornotbysolidmasses.Theactivating try withtesticularedema,testisasymme- cocious puberty The earlyclinicalmanifestationofthesetumorsispre- however, malignantbehavior. 10%ofthemcanpresent generallybenign; of allthetesticulartumors.Theyare Testicular Tumors: Tumor causes listedinTableof GIPPare 5. axis(17).Themaincauses vation ofthegonadotropic theacti- independentlyfrom ofsexsteroids, secretion of the precocious (GIPP)istheresult cious puberty puberty,precocious preco- gonadotropin-independent orperipheral pseudopuberty Also calledprecocious (CYP19) GONADOTROPIN-INDEPENDENT PRECOCIOUS PUBERTY Leydig cell tumors represent 1-3% Leydigcelltumorsrepresent Brito etal. Brito 25

copyright© ABE&M todos os direitos reservados copyright© ABE&M todos os direitos reservados tor, and human TSHactsonthewild-typeFSHrecep- multiple ovariancysts.The associatedwith hypothyroidism primary untreated andlong-term been describedformanyyearsinsevere has causingsexualprecocity hypothyroidism Primary Hypothyroidism notexclud although somaticmutationswere duetoovarian cysts(51), puberty in girlswithprecocious notfound gene(FSHR)were tations intheFSHreceptor mu- Germline surgical intervention. requiring infarction, torsionofthepedicleand er follicularcystscanpresent riseofestradiollevels.Larg- causingatransitory recurrent, velopment orevenacyclicvaginalbleeding.Theycanbe de- thatcausemammary estrogens cystssecrete Follicular Ovarian follicularcysts gene(FSHR)(50). mutations intheFSHreceptor been describedinsomeovariantumors(49),aswell Brito etal. Brito Etiology, diagnosisandtreatmentofsexual precocity Mutations inthe ThepelvicUSgenerallyallowsthediagnosis. tropin. levelsofgonado- elevated, accompaniedbysuppressed cal manifestation.Estradiollevelscanberemarkably cocious pubarche, boneageadvancement,signsofhy- cocious pubarche, the male.Infemale, manifestations includepre- andboneagein ciency causesadvancementofpuberty GIPP. defi- of21-hydroxylase Thenonclassicalform puberty, inthefemaleitcausesheterosexual whereas precocious mines isosexualgonadotropin-independent deficiencydeter- of21-hydroxylase the classicalform clinical manifestationsofthedisease(55).Inmale, ofthe spectrum forthebroad ment, beingresponsible ofenzymaticactivityimpair-cause variabledegrees Different disorders. recessive (CAH), whichisoneofthemostcommonautosomal hyperplasia 95% ofthecasescongenitaladrenal than formore deficiencyisresponsible 21-hydroxylase Mutations intheCYP21A2gene several geneticcauseshavebeenidentified(54). anetiologicalpointofview,From incontrastwithGDPP, Monogenic causesofsexualprecocity TSHlevels(52,53). increased companied byextremely ac- inhypothyroidism puberty explain theprecocious suggestsamechanismto isoform, human FSHreceptor 26 that the response isnotdependentuponthe theresponse that D -subunit of the Gs protein genehave -subunit oftheGsprotein in vitro CYP21A2 demonstrationthat ed. mutations and is usuallyoccurssporadically McCune-Albright syndrome nal hyperplasiaandhypophosphatemicosteomalacia. autonomousadre- adenomas,hyperthyroidism, tuitary pi- suchasGHand/orprolactin-secreting syndrome, crinopaties havebeendescribedinMcCune-Albright endo- histidine orcysteine.Otherhyperfunctional inposition201by substitution ofanarginine residue ic mutationisalmostalwayscharacterizedbythe tively activatedadenylcyclase(57).This D of post-zygoticactivatingmutationsintheGsprotein consists molecular basisofMcCune-Albrightsyndrome dysplasiaandcafé-au-laitspots.The totic fibrous puberty,pin-independent isosexualprecocious polyos- condition characterizedbyaclassictriad:gonadotro- clinical isaheterogeneous McCune-Albright syndrome Mutations intheGsprotein (56). cious pubarche bypreco- signs canoccurinbothsexes,represented toromegaly. Duringchildhood,hyperandrogenism genitaliaormildcli- external genetic femalehasnormal the as incompletemasculinizationinthemale,whereas mutationsinthe sults from hypokalemic alkalosis.Thedeficiencyof3- and ized byvirilizationwithorwithouthypertension tions inthe ofmuta- deficiencyistheresult The 11-hydroxylase gene HSD3B2( and Mutations in the CYP11B1 (11-hydroxylase) gene intheCYP11B1(11-hydroxylase)gene Mutations ovaries, acneandhirsutism(55). irregularity, menstrual perandrogenism, polycystic fected bymutationsinthe af- cellsare occurswhenthebonemarrow syndrome hyperactivation. ThebonediseaseinMcCune-Albright thefollicular from identifiedatultrasound,resulting are findings. Ovariancysts(asymmetricalandoftenbilateral) commonhormonal transitorily highestradiollevelsare levelsassociatedwith gonadotropin age. Suppressed stimu tropic phonates have been used in the prevention andtreat- phonates havebeenusedin theprevention multiple.Bisphos- elevated,mainlyiftheinjuriesare are andresorption bone disease.Markersofformation usefultoolstoevaluate gene. X-raysandbonescanare -subunit gene,leadingtomosaicismwithaconstitu- Precocious puberty is independent from gonado- isindependentfrom puberty Precocious more commoningirlsthanboys(54). more CYP11B1 lation, beingdiagnosedingirlsatanearly E -hydroxysteroid dehydrogenase 2) -hydroxysteroid dehydrogenase2) Arq Bras2008;52/1 EndrocrinolMetab geneanditisclinicallycharacter- D HSD3B2 -subunit of the Gs protein -subunit oftheGsprotein D -subunit gene gene and presents geneandpresents missense E HSD2 re- somat- Arq Bras2008;52/1 EndrocrinolMetab ment ofthebonedisease sic salt-retaining activity(54). sic salt-retaining suchasdexamethasone,without theintrin- corticoids, therapywithhighdosesyntheticgluco- replacement is inthefemale(54,63).Thisconditiontreatment form inthemaleandheterosexual puberty precocious leadtotheisosexualgonadotropin-independent rarely can androgens action.Theexcessiveadrenal corticoid uponmineralo- andsteroids androgens adrenal creased riseofACTHwithin- gene causeacompensatory receptor Inactivating mutationsoftheglucocorticoid receptor gene Inactivating mutationsoftheglucocorticoid advancement oftheboneage(62). acneand pubarche, sociated withprecocious as- andpost-natalvirilizationpicture ciency causespre- defi- (61).Aromatase inhyperestrogenism resulting intoestrogens non-gonadal conversionofandrogens females. Thepathophysiologyconsistsofexacerbated in and/ormacromastia puberty isosexual precocious and/orgynecomastiainmalesand puberty precocious cancauseheterosexual excesssyndrome The aromatase Mutations inthearomatasegene(CYP19) inhibitors. and aromatase blockers receptor acetate),estrogen age (cyproterone block- receptor gens (ketoconazol)and/orandrogenic andtesticularsynthesisofandro- that blocktheadrenal consistsofdrugs tion test.Thisconditiontreatment afterexogenousGnRH-stimula- response prepubertal and high despitethelowlevelsofbasalgonadotropins oftheepiphyses.Testosteronecious closure levelsare bytheadultagedue tothepreco- stature ing toshort velocitylead- accelerated virilization,excessivegrowth signs, 2-4yearsofagewithpuberty ataround presents gene(LHR)(59,60).Thediseasegenerally receptor by constitutiveactivatingmutationsinthehumanLH testotoxicosis, isanautosomal-dominantdiseasecaused puberty,Familial male-limitedprecocious alsocalled Familial male-limitedprecociouspuberty sions (58). ofthecysticle- thecontrol has nobenefitsregarding bonepain,butit dysplasia seemstobesafeandreduces fibrous withsevere inchildren treatment Pamidronate in McCune-Albrightsynd rome. rome. Etiology, diagnosisandtreatmentofsexual precocity development diatric conditioninpe- insufficiencyisarare adrenal Primary mutation the Xchromosome,gene-1,NR0B1/AHC) hypoplasia congenita(AHC),criticalregionon (dosage-sensitive sexreversal,adrenal Primary adrenalinsufficiencyduetoDAX-1 response. Side effects such as edema, chronic headache, suchasedema, chronic Sideeffects response. totheclinical-laboratory es beingtitratedaccording twoweeks,withthedos- 100 mgintramuscularlyevery useddoseis10to50mgorallydailyor routinely byblockingseveralenzymaticsteps.The roidogenesis ongonadalste- effect andadirect release gonadotropin of includes suppression action ofmedroxyprogesterone inbothgenders.Themechanismof Albright syndrome intestotoxicosis aswellinMcCune a beneficialeffect acetate demonstrates The useofmedroxyprogesterone Progestational agents agents: andantiestrogen drogen antian- The therapeuticoptionsincludeprogestational, used. itssynthesisare orthrough its specificreceptors on thatactbyblockingtheactionofsexsteroids Drugs Medical treatment of tumorandtheclinicalindication. and chemotherapycanbeuseddependingonthetype Radiation process. ofthepubertal inregression results tumorsofwhichthesurgical removal hCG-producing ovarianortesticulartumors,aswell such asadrenal, diagnosedneoplasias, forthepreviously It isreserved Surgical treatment pic hypogonadisminadulthood(66). al DAX-1 one, leadingtoaGIPPinthisboy(66).Therefore, testoster-supposed tostimulateLeydigcellssecrete elevatedACTH levelswere (66). Theextremely berty ing infancy developmentcharacterizedbyGIPPdur- on pubertal isosexual gonadotropin-independent the oplasia congenitaduetoanewframeshiftmutationin . describedaBrazilianboywithX-linkedadrenal DAX-1, age, and its association with precocious sexual age, anditsassociationwithprecocious mutations in humans can promote adualeffect mutationsinhumanscanpromote and childhoodfollowedbyhypogonadotro- ofwhichthefirstclinicalmanifestationwas is very uncommon(64,65).Domenice is very GIPP TREATMENT precocious pu- precocious Brito etal. Brito hyp- 27 et

copyright© ABE&M todos os direitos reservados copyright© ABE&M todos os direitos reservados Brito etal. Brito Etiology, diagnosisandtreatmentofsexual precocity hibitors, such as anastrozole and letrozole, haveshown andletrozole, hibitors, suchasanastrozole in- Highly selective aromatase intoestrogens. drogens inhibitorsblocktheconversionofan- The aromatase Aromatase inhibitors out quarterly. follow-upmustbecarried andelectrolytic patic, renal hematological,he- Acareful toxicity andhypertricosis. includehepato- orally(68).Sideeffects administered 10to20mg/day,maturation. Thedoserangesfrom velocityanddeceleratedskeletal growth sodes, reduced ofvaginalbleedingepi- frequency showing adecreased inMcCune-Albrightsyndrome, puberty of precocious sents anattractivetherapeuticoptionforthetreatment I Tamoxifen synthesisblockers. modulators andtheestrogen receptor twotypesofagents,theestrogen are There Antiestrogen agents (67). drenalism hypoa- transaminaselevelsandlaboratory vated serum ele- includegastricintolerance,reversibly side effects ishepaticinjury. Other 200 mg.Itsmainside-effect Theaveragedailyoraldoseisusually androstenedione. into 17-hydroxyprogesterone zyme, whichconverts It isanimidazolederivativethatinhibitsP450c17en- Ketoconazol situations. attention instressful special use,deserving alism canoccurwithcyproterone hypoadren- and gynecomastiainthemale.Laboratory symptoms include:gastrointestinal tone. Sideeffects acetateand100mgforspironolac- m2 forcyproterone 50to100mg/ Theusualdailyoraldosesare cretion. se- gonadotropin suppressing level,partially pituitary actionatthe one hasanadditionalprogestational inperipheraltissuesandcyproter-one foritsreceptor activity,have antiandrogenic competingwithtestoster- acetate.Bothdrugs andcyproterone spironolactone synthesisinhibitors. androgen blockersand receptor twotypes:androgen are There Antiandrogen agents factorstotheclinicalapplication. restricting frequent insufficiencyare weight gain,purplestriaeandadrenal 28 t is a selective estrogen receptor modulatorandrepre- receptor t isaselectiveestrogen Androgen receptor blockers: this category includes blockers:thiscategory receptor Androgen always usedtomonitorGIPPtherapyefficacy. Clinicalparametersshouldbe peutic efficacycontrol. goodparametersforthethera- ments donotrepresent measure- andsexsteroid and tamoxifen,gonadotropin suchascyproterone that inhibittheactionofsexsteroids seems attractivedespitethehighcost.Whenusingdrugs inhibitor withanaromatase one orspironolactone) (71). McCune-Albright syndrome in5girlswith estradiolproduction did notprevent drome hassuggestedletrozole drome study includingninegirlswithMcCuneAlbrightsyn- (69,70).Recently,sexes, withfewsideeffects apilot oftheGIPPinboth inthetreatment to bepromising hne(0.However, inourexperiencethesedrugs change (70). months (70).Incontrast,uterinevolumesdidnot .Hra-idn E lr EJ,Wasserman RC,BourdonyCJ, Slora Herman-GiddensME, 2. SippellWG.Managementandoutcome CJ,HegerS, Partsch 1. for theEnglishreview. theirgratitudetoMs.SoniaStrong The authorsexpress and 300828/2005-5,respectively). numbers:300469/2005-5,200938/2006-3 (process Tecnológico (CNPq)GrantstoACL,IJPA andBBM Conselho NacionaldeDesenvolvimentoCientíficoe Fundação FaculdadedeMedicinaGranttoVNBand byUniversidadedeSãoPaulo, This studywassupport peutic options. actionmechanismsoftheavailablethera- different both sexeshastobeindividualizedandbasedonthe tion ofdepotaGnRH.Finally, in GIPPtreatment withtheaddi- GDPPiswellcontrolled Secondary GnRH agonistanalogues p o hscniin(0.Ma vra volume, apy forthiscondition(70).Meanovarian infiatyatr6monthsbuttendedtoriseby24–36 significantly after estradiol levels,andmarkersofbonemetabolismfell 1997; 99:505-12. h eiti eerhi fc Settingsnetwork.Pediatrics. the PediatricResearchinOffice and mensesinyounggirlsseenofficepractice:astudyfrom Bhapkar MV, KochGG,etal.Secondarysexualcharacteristics 56:129-48. 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