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European Journal of Endocrinology -17-1025 thelarche ( of adrenalandrogensfor andestrogens for to andthentosexualmaturity. Criticallevels the paceatwhichgirlsprogress fromtheonsetofpuberty construct thatdescribes pubertal tempoisanauxiliary characteristics andtheageatmenarche. Incontrast, and expressedbyTanner sexual stagesofsecondary inter-individual differencesinneuroendocrinematuration their same-sexandsame-agepeers,itisdeterminedby Timing describesthematurationofchildrenrelativeto described intermsoftiming(theageatonset)andtempo. Individual differencesinpubertalmaturationcanbe expected milestonesofpuberty. and duration.Theseresultsarereassuringinthiscontextwilladdtoclinicians’parentalunderstanding ofthe Conclusions ( heights atB5werecomparable.Therewasasignificantrelationshipbetweenthethelarcheageandpubertytempo B5. InEOs,pubertywas1 year(average)longerthaninLOs.AlthoughEOsgrew7 in theageatmainpubertalmilestoneslessenedaspubertyprogressed:2 yearsforB2; Results intermediate (IO;9.4–10.5 years),lateonset(LO; pubertal progression(timefromB2toM).We clusteredthegirlsaccording toB2ageintoearlyonset(EO; (B5)andpubichair(P5)becamefullymature,pubertalgrowth,duration(timefromB2toB5) the followingindicators:thelarcheage(Tanner stageB2),pubarcheage(P2),menarche(M),thewhen (SECCYD) whowererecruitedintheUSAfrom1991to2006andfollowedbirthage15.5 years.We used Methods hypothesized thattheageatonsetofgirls’pubertypredictspubertaltempoandrateprogression. Background Abstract of Technology, Haifa,Israel Human Ecology, UniversityofCalifornia,Davis,USA,and Center forLifeSciencesandEngineering,Technion –IsraelInstituteofTechnology, Haifa,Israel, 1 A German a functionofpubertalonsetage Outcomes ofpubertaldevelopmentingirlsas Pediatric Endocrinology, ClalitHMOandBnaiZionMedicalCenter, Haifa,Israel, r https://doi.org/ https://eje.bioscientifica.com =0.23, Clinical Study : AllindicatorsofpubertalonsetandconclusionoccurredearlierintheEOsthanLOs;yet,differences : We analyzedthedataof380girlsfromprospectiveStudyEarly ChildCareandYouth Development P

< 1 1 10.1530/EJE , M Shmoish : Thestudyhighlightsthepredictivenatureofvariationinonsetagepubertyonitsprogression 0.0001). : Therelationshipbetweenpubertalonsetandtempogrowthiscontroversial.We ) determinetheonsetofpuberty ingirls.At -17-1025 2 , J Belsky 5 © 2018EuropeanSociety ofEndocrinology A Germanandothers 3 and Z Hochberg Printed inGreatBritain > 10.5 years). 4 4 Faculty ofMedicine,Technion –IsraelInstitute than thatofaverageorlatematuring girls( peak heightvelocitywaslonger forearlymaturinggirls rapidly ( girls who started early tended to reach menarche of thisreport,issmall.Someinvestigatorsfoundthat timing and tempo of puberty in girls, which is the topic number ofpublishedreportsontheassociationbetween ( puberty and its relationship to adult height ( and reproductivematurityisdefined. the conclusion of puberty, agirl’s ultimate adult height Puberty duration 4 2 Published byBioscientifica Ltd. Lorry I.LokeyInterdisciplinary , 5 Numerous publicationshaveaddressedthetimingof ), BMI( 9 , 10 1 3 Department of ), but the interval fromTanner), buttheinterval stageB2to , 6 , 7 ) andtheadiposityrebound( cm (average)morethanLOs,their Downloaded fromBioscientifica.com at10/01/202104:02:57AM − 1.4 years forM; (2018) Endocrinology European Journal of [email protected] Email to ZHochberg should beaddressed Correspondence 179 179 :5 , 279–285 10 − ). Incontrast, 1 year for

2 < , 9.4 years), 3 279 ), weight 8 –285 ). The via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com and pubertalstageassessments weremadebythestudy’s reported. Height,weightmeasurements, BMIcalculation total 380girls,whohadthe information onmenarche age (13%) blackparticipantsand 38(10%)otherminorities,in included inourreport293 (77%) whiteparticipants,49 was performedbyanursepractitionerorphysician.We sexual characteristics (2000–2006), stagingofsecondary study protocol.Annuallyfromages91 birth toage151 supported/seccyd study’s website in previousstudypublications( their recruitmentandselectionaredescribedindetail were recruitedfrom24hospitalsintheUnitedStates; Participants inthelongitudinalNICHDSECCYD( Subjects tempo andgrowth. age asindicesofpubertalprogression(B2tomenarche), puberty (Tanner stage B2 (thelarche)) and menarche our analysisusedreporteddatafromtheonsetageof was collectedfrom1991to2006( We analyzed data of 380 girls from the SECCYD, which Patients andmethods the largecohortSECCYD( adult height. We tested these hypotheses using data from pubertal progressandthegrowthtempo,butnotfinal hypothesized that the onset age of puberty will predict associated inawaythatbenefitsreproductivestrategy, we of plasticityforpubertyonset( a given genome to approach the extremes of their range quality ofmodernenvironmentsandallowsfemaleswith that theseculartrendforearlypubertyreflectsoverall in agivenenvironment.We andothershavesuggested andreproductivefitness strategies thatyieldhighsurvival schedulesandbehavioral controlling fecundity-survival maturational traitsrespondtoenvironmentalcuesfor theory,According toevolutionary developmentaland stageinitsdevelopmental context ( life-history biology, wepreviouslyexaminedpubertyasanevolutionary but notingirls( suggested thattimingandtempowereassociatedinboys, timing andtempoinChinesegirls( Li Clinical Study t al et Assuming thatthetimingandtempoofpubertyare anddevelopmental Using principlesfromevolutionary . foundnoevidenceforanassociationbetween 12 ⁄ 2 years(1991–2006)withacommon . Children were followed up from ). https://www.nichd.nih.gov/research/ 16 ). 13 A Germanandothers 16 , 12 14 11 , , , 18 16 ), andMarceau 15 , , ⁄ 2 to151 ). 17 19 ). Specifically, ) andonthe ⁄ years 2 et al 13 16 ). ) . function ofthelarcheage(B2). Pubertal progression(B2-M;years) forallfourquartilesasa Figure 1 the pubertalstagecontinueduntiltheirbreastandpubic characteristics werebetweentwostages.Theassessmentof examiners gaveagirllowerstageratingwhenhersexual used whenthedaughter’s self-reportwasmissing( their ageatfirstmenses.Theannualmaternalreportwas reported annually whether had begun and thegirls hair werefullydeveloped. From age10.5 years, assessment ofsexualmaturitystagesingirls( guidelines oftheAmericanAcademyPediatricson was assessedannuallyusingTanner criteriaandthe used beforetheage9.5assessments.Thepubertalstage breast budpalpation( of eachTanner stagewasdeterminedusingphotosand examination and anthropometry. The age of occurrence 15.5 assessments was determined annually by a physical The pubertaldevelopmentofeachgirlfortheage10.5– Pubertal development was obtainedfromallparticipants. previously reported ( approved attheinstitutionalreviewboardsofeachsite,as network ofinvestigators.Allstudyprocedureswere i. 1 Fig. Tanner stagesP2(pubarche) andB2(thelarche). Basedon Here, weinvestigatedtheageatonsetofpuberty– Retrospective dataanalysis Puberty duration r =0.23, , allparticipantsweredividedintothreeclusters: P

< 0.0001. 16 20 ), andparental informed consent Downloaded fromBioscientifica.com at10/01/202104:02:57AM , 21 n 8, (B2-M) =5.5–0.3 =380, ). Breastpalpationwasnot 179 :5 22 n × =117). B2age, ). The 280 via freeaccess

European Journal of Endocrinology EO, early-onsetgroup;IO,intermediate-onsetLO,late-onsetgroup. Data aredisplayedasmean 4 3 2 1 B: B2–Mintervalquartiles A: B2age(years) thelarche totheageatmenarche(years,B2-M;B). (years; A)andquartilesoftheintervalfromageat Table 1 Pubarche age Thelarche age quartile) orlong(4thquartile).Dataaredisplayedasmean late ( Table 2 quartiles.Spearman’sinterval correlationcoefficients and thirdB2clustersthefirstfourthB2-M used tocomparethecontinuousvariablesoffirst samples the EOsandLOswerecomparedusinganindependent pubertal durationandtheratesofprogression The chronologicalages,growth,theagesatmenarche, (SPSS StatisticsforWindows, version 20.0, SPSSInc.). Data wereanalyzedusingstatisticalanalysissoftware Statistical analysis at allages. into quartiles.BMIforstudyparticipantswascalculated todividethestudy’sused theB2-Minterval participants elapsed fromTanner stageB2tomenarche (M)( mature breast),and‘pubertalprogression’asthetime at thelarche totheappearance ofTanner stagesB5(fully LO. We defined ‘pubertal duration’ as the time from age werelabeledas those withthelarche after age10.5 years yearswerelabeledintermediateonset(IO)and(c) 10.5 years were labeled EO, (b) from the age of 9.4– of 9.4 girls whoshowedsignsofthelarche (a)beforetheage * Age withfullymaturepubichair P5 Age withmaturebreastB5 Menarche age P

Clinical Study > 9.4–10.5 (IO) < < .5 ** 0.05, 10.5 (LO) 9.4 (EO) > 10.5 years) B2ageandforgirlswhoseintervalsfromthe atthelarchetotheagemenarche(B2-M)areshort(1st t The clustersaccordingtotheageatthelarche(B2) Age atpubertyonset(thelarcheB2andpubarcheP2) end(B5andP5)forgirlswithearly( P test.Anindependentsamples

<

0.001; diff., difference. ± tnad deviation. standard n 138 156 95 95 95 95 86 A Germanandothers 13.7 13.6 11.8 9.8 9.0 < ± ± 9.4 ± ± ± 11.0 Mean 3.9 2.8 2.1 1.3 9.9 9.0 t 0.6 0.1 1.1 1.0 1.1 testwasalso ± ± ± ± ± ± ± ± 0.7 0.2 0.2 0.5 0.5 0.2 0.1

14.5 14.6 13.2 10.9 11.0 s . d 17 B2 age . > 10.5 ± ± ± ± ± ). We 0.8 0.5 0.8 0.8 1.1 ±

s (years) . d . 0.8 (1.1,0.6)** 1.0 (1.3,0.8)** 1.4 (1.7,1.1)** 1.1 (1.3,0.9)** 2.0 (2.1,2.0)** Mean diff. (CI) cohort was12.3 11.0 earlierthanitsoccurrenceintheLOs 2 years LOs ( The numberofEOswastwiceasmanythe Average ageatB2intheentirecohortwas9.8 Results deviation ( Dataaredisplayedasmean by B2-Minterval. groups definedbyageatthelarche andthegroupsdefined statistics wereusedtotesttherelationshipbetween and thetempoofpubertyitsvariation.Chi-square done toexploretherelationshipbetweentiming pubertal development.Acrosstabulationanalysiswas anthropometrical parametersandtheageatstagesof were usedtodeterminethelinearassociationbetween at thelarche andtherateofpubertalprogression( comparable ( years,whenall participants reachedB5,were of 15.5 the timefromB2toB5,theirheightsatage the LOs(27.8 ( 1.0 years 3.6 longer intheEOsthanLOs(4.5 LOs ( of theLOs(0.1 the age at thelarche, and P2 coincided with the age at B2 EOs, theageatpubarche P2occurred0.8 ( and forB5,thedifferencewas1.0 years forM,thedifferencewas1.4 years difference was2 years, milestones diminishedaspubertyprogressed.ForB2,the the LOs.Thedifferencesinageofmainpubertal and menarche alsooccurred earlythanitsoccurrencein Puberty duration ± We foundasignificantrelationshipbetween the age Puberty progressed slower in the EOs than in the ± . yas ( years 0.8 al 1 Table al 3 Table

. years).Average ageatmenarche intheentire 0.5 s Table 4 . d ). Thelarche intheEOshappenedamean ). The duration of the B2-B5 interval was). ThedurationoftheB2-B5interval . Table 2 ) andstatisticalsignificancewassetat5%. ± 1st quartile ± 13.6 13.7 11.3 10.2 10.0 m s 20.6 vs 4.7cm ± 0.8 years). P . er ( 1.2 years

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< ± < Table 1 0.6 ( 0.4 ( 2.1 ( − Mean diff. (CI) 9.4 years) or ± . er after 0.6 years 0.1 ( .0) during 0.001) . yas vs years 1.1 0.3 (0.1;0.4)* ± ( − − − 9.0 0.83 years. ± − 0.7; 0.5; 2.4; standard 0.2;0.0) ). Inthe ± r − − − =0.23, . vs 0.1 0.4)** 0.2)** 1.8)** 281 via freeaccess European Journal of Endocrinology correlate withtheBMIatanyage. years.Pubertalprogression and durationdidnot age 3 at onsetofpuberty, andmanyyearsbeforehand–asof age at B2 and M correlates significantly withthe BMI milestones andBMISDSasafunctionofage( we study the correlation coefficients at pubertyonsetandtherateofpubertalprogression, yet, wehavenogrowthdatabeyondage15.5. 2.2 vs 163.9 at B5wereindistinguishable:164.4 maximum of8 puberty, themeanheightdifferenceincreasedtoa (139.9 quartile) B2-Minterval. had short(1stquartileB2-M)and55.9%long(4th andamongLOgirls44.1% (4th quartile)B2-Minterval 25.4% hadshort(1stquartileB2-M)and74.6%long heterogeneity ofthesetwovariables.AmongEOgirls showsthe clusters againstshortandlongB2-Minterval not beignored.CrosstabulationofearlyandLOB2 the variationarounddepictedregressionlineshould thelarche shortenspubertalprogressionuntilmenarche, that anearlyageatthelarche prolongsandalateageat months.Despitethisclearevidence progression by4 year ofearlythelarche appearanceincreasedpubertal annually duringtheSECCYD( because theassessmentsofTanner stagesweredone of breastTanner stage 2 didnotdistribute continuously P https://eje.bioscientifica.com Count Total Expected Count Long Expected Count Short B2-M groups girls whoseB2-Mareshort(1stquartile)orlong(4thquartile). pubertal progressionforearlyandlatematuringgirls Table 3

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0.0001) girls( ± % withinB2groups % withinB2groups To evaluatethecontributionofadipositytoage At thelarche, theEOwere shorterthantheLOgirls The slopeoftheregressionlineindicatesthateach m n 4.0 and 2.5cm ± m s 144.7 vs 8.5cm Cross tabulation analysis on the age at thelarche and Cross tabulationanalysisontheageatthelarcheand ±

6.7 cm (LOs).Growthfromage14–15was cm at age 12 years. Nevertheless,heights cm atage12 years. i. 1 Fig. ±

2.9, respectively ( ). Dataontheageofappearance ± 100.0 125 Early 8.4cm, 74.6 86 93 25.4 40 32 Fig. 1 B2 groups A Germanandothers ). P R

< between puberty 100.0 P Late 68 55.9 46 38 44.1 22 30 .0) During 0.001). =0.024; ± m (EOs) 6.1cm Fig. 3 i. 2 Fig. Total 100.0 193 132 132 ). The 68 32 62 62 ), we call‘pubertyprogression’–thetempofromB2to constant, andwethereforedefinedanewfeaturethat frommenarcheour hands,theinterval toB5isfairly not ingirls( pubertal timingandtempowereassociatedinboys,but statistical modelsthattheydeveloped,reported Usingtwo and psychologicaloutcomesatage15.5 years. years related themtoBMI,height,weightatage12.5 Marceau sites intheUnitedStates( from alargesampleofCaucasiangirlstendifferent adult height.SECCYDcomprisesdatathatwerecollected of pubertalonset,progressionandtempo this reportconcernstherelationshipbetweenage its consequences.Theclinicalquestion at thecenterof is parentalconcernaboutearlypubertaldevelopmentand A common cause for referral to a pediatric endocrinologist Discussion their heightatTanner stage5forbreast.Theslowpuberty are greater than those of the LOs despite no difference in growth pattern:thetempoand pubertalheightoftheEOs the timingandtempoofpuberty substantially affect the number ofgirlsviolatedthis trend.We alsofoundthat large variationaroundthissignificanttrend,anda tocompletetheirpuberty. However,3.7 years wefound years to reach menarche and found that LOs took 2.3 to complete their puberty. In contrast, we and 4.7 years LOs; ittookalmost3 years forthesegirlstoreachmenarche We foundthatpubertyisslowerintheEOsas comparedto making itpossiblethattheywillenduptallerthangroup. final adult height. Threeof the girlswere stillgrowing, measurement atage15.5 years astheheightatB5andnot Therefore, wedefinedthelastheight until age15.5 years. is thatassessmentsofthesubjectsinSECCYDweredone sexual maturation in children ( that self-assessmentcanbevalidlyusedinevaluating Stages inGirls( Academy ofPediatricsAssessmentSexualMaturity development basedoninstructionsfromtheAmerican used ahighlyreliableprotocolforassessingpubertal at developmentalstage2.Nonetheless,thisresearch led toanunderestimationofthepercentage ofgirls consideration whenthestudybegan.Thismighthave used beforeage9.5becauseitwasnotamethodological for age10.5–15.5assessments,breastpalpationwasnot Tanner stage;theyusedphotosandbreastbudpalpation with B2age(timing). menarche, whichcorrelates negativelyandsignificantly Puberty duration A limitationofSECCYDistheassessmentabreast et al 12 . modeledpubertalgrowthandtempo ). We cometoadifferentconclusion.In 22 ). Moreover, itwasrecentlyconfirmed Downloaded fromBioscientifica.com at10/01/202104:02:57AM 12 ). Usingthesamedatabase, 23 ). A second limitation 179 :5 282 via freeaccess European Journal of Endocrinology interval. Test, * short (1stquartile,black)orlong (4thquartile,gray)B2-M with early(black)orlatethelarche (gray);(B)forgirlswitha Mean heightprogressionfrom age6–15.5 years.(A)forgirls Figure 2 the UnitedStates( years) ( 0.9 vs EOs wasalmosttwiceaslongofthatLOs(1.6 years in duration of the B2 to peak height velocity interval of 307prepubertalGreekschoolgirlsreportedthatthe of EOs has been previously reported. A longitudinal study Height gainfromB2toB5(cm) Height atB2(SDS) Height atB2(cm) M-B5 interval(years) B2-B5 interval(years) B2-M interval(years) B2-P2 interval(years) thelarche totheageatmenarche(B2-M);areshort(1stquartile)orlong(4thquartile).Datadisplayedasmean Table 4 * Height atB5(cm) P

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0.001, diff. difference P ). Similar results have been reported from

< 0.05. 24 ) andSpain( 139.9 164.4 27.8 0.6 1.8 4.5 2.8 0.8 A Germanandothers 25 < 9.4 ± ± ± ± ± ± ± ± ). 4.7 0.8 1.2 1.1 1.1 0.6 8.5 6.1 144.7 163.9 − − 20.6 0.1 1.4 3.6 2.2 0.1 > B2 age 10.5 ± ± ± ± ± ± ± ± 6.7 3.8 1.10 8.4 1.2 0.8 1.0 0.8 (years) − − 7.1 ( 0.8 ( 0.5 ( Mean diff. (CI) 4.8 (2.5,7.0)** 0.4 (0.1,0.7)* 1.0 (0.8,1.3)** 0.6 (0.3,0.9)** 0.9 (0.7,1.1)** − − maturers and(b)latetimingofpubertyiscompensated buffered byaslowrateofpubertalprogressioninearly daughters. We foundthat(a)earlytimingofpubertyis second concernisgrowthandadultheightoftheir with an early puberty is the time to menarche, their reciprocity betweenadiposityandpuberty( minimizes psychosocialproblems. puberty, whichallowsfordevelopmentalreadiness and slowingofsuggest theexistenceofacompensatory pubertal tempoandduration,butresultsofthisstudy did notinvestigatethecognitiveandsocialaspects of tempo predictedpsychologicalproblems( combination of early pubertal onset and fast pubertal a riskfactorforgirls’behavioraldifficulties( timing of puberty has consistently been shown to be is developmentalandpsychosocialreadiness.Early or late( 75 girlsirrespectiveofwhethertheymaturedearly, average in thepeakheightvelocityandadult ( slow tempoofpubertybutdoesnotaffectB5height’ yearsofageingirlsdeterminesa of pubertyat8 that an ‘onsetfinding confirms previous observations additional heightgainduringthisperiod( onset byalongdurationofpuberty, therebyenabling of pubertycompensatedtheirshortheightatpubertal Vinolas for byarapidprogressioninthelatematurers.Llop- pubertal tempo.Thus,the association ofadipositywith and menarche. However, adipositydidnotcorrelatewith significant atayoungageof 36 months forboththelarche menarche ( found anassociationbetween BMIandthelarche and Our resultsagreewiththoseofarecentstudywhich Puberty duration 25 − 8.6, 1.0, 1.7, 2.7) ). Pantsiotou Whereas the primary concernofparents daughtersWhereas the primary Much workhasbeendoneonthenatureof The thirdapprehensionofparentsanEOgirl − − 5.7)** 0.5)** 10 t al et ). 18 . reportedthatgirlswithanearlyonset ), andweshowthatthecorrelation becomes 139.9 162.5 28.3 0.40 1st quartile 2.4 3.7 t al et ± ± ± ± ± ± 11.1 1.1 1.0 6.7 5.8 1.00 . foundnosignificantdifference Downloaded fromBioscientifica.com at10/01/202104:02:57AM 139.0 165.6 4th quartile 30.7 0.31 0.8 4.4 ± ± ± ± ± ± B2-M 10.3 0.9 0.7 6.09 4.3 0.93 179 https://eje.bioscientifica.com :5 − − − 2.4) 0.7 ( 0.5 ( Mean diff. (CI) 0.9 ( 0.1 ( ± 1.6 (1.3;1.9)** 12

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22 23 24 Clinical Study Biro FM, Lucky AW, Simbartl LA, Barton BA,Daniels SR,Striegel- Chavarro JE, Watkins DJ, Afeiche MC,Zhang Z,Sánchez BN, Herman-Giddens ME, Slora EJ,Wasserman RC, Bourdony CJ, girls andtherelationshiptoanthropometricchanges:pathways Moore R, Kronsberg SS&Morrison JA.Pubertalmaturationin jpeds.2017.03.050) Pediatrics against physicianassessmentsandhormonelevels. & Téllez-Rojo MM. Validity ofself-assessedsexualmaturation Cantonwine D, Mercado-García A, Blank-Goldenberg C,Meeker JD peds.99.4.505) network. practice: astudyfromthePediatricResearch inOfficeSettings characteristics andmensesinyounggirlsseenoffice Bhapkar MV, sexual Koch GG&Hasemeier CM.Secondary 2017 Pediatrics 186 1997 172–178.e3. 99 505–512. (https://doi.org/10.1016/j. A Germanandothers (https://doi.org/10.1542/ Journal ofJournal Accepted 6August2018 Revised versionreceived1August2018 Received 13December2017

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