1 184

A B Hansen and others Sex steroids in adolescencel 184:1 R17–R28 Review

DIAGNOSIS OF ENDOCRINE DISEASE Sex steroid action in adolescence: too much, too little; too early, too late

A B Hansen 1, D Wøjdemann1, C H Renault1, A T Pedersen 2, K M Main1, L L Raket3,4, R B Jensen1 and A Juul 1 Correspondence 1Department of Growth and Reproduction, 2Department of Gynecology and Fertility Clinic, Rigshospitalet, University should be addressed of Copenhagen, Copenhagen, Denmark, 3H. Lundbeck A/S, Valby, Hovedstaden, Denmark, and 4Clinical Memory to A Juul Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden Email [email protected]

Abstract

This review aims to cover the subject of sex steroid action in adolescence. It will include situations with too little sex steroid action, as seen in for example, Turners syndrome and androgen insensitivity issues, too much sex steroid action as seen in adolescent PCOS, CAH and gynecomastia, too late sex steroid action as seen in constitutional delay of growth and puberty and too early sex steroid action as seen in precocious puberty. This review will cover the etiology, the signs and symptoms which the clinician should be attentive to, important differential diagnoses to know and be able to distinguish, long-term health and social consequences of these hormonal disorders and the course of action with regards to medical treatment in the pediatric endocrinological department and for the general practitioner. This review also covers situations with exogenous sex steroid application for therapeutic purposes in the adolescent and young adult. This includes gender-affirming therapy in the transgender child and hormone treatment of tall statured children. It gives some background information of the cause of treatment, the patient’s motivation for medicating (or self-medicating), long-term consequences of exogenous sex steroid treatment and clinical outcome of this treatment.

European Journal of European Journal of Endocrinology Endocrinology (2021) 184, R17–R28

Introduction predominant sex steroids, testosterone (T) and its potent derivative dihydrotestosterone (DHT), stimulate androgen In females, the production of estradiol (E2) stimulates receptors (AR) in androgen-sensitive tissues and organs estrogen-receptors (ER) in estrogen-sensitive tissues and like penis, scrotum, skin, prostate and muscle. Both E2 organs like breast, uterus, fat and bone. In males the and T circulate and exert physiological action in males as

Invited Author’s profile Anders Juul is a pediatric endocrinologist and EAA certified andrologist. He is the head of the department of growth and reproduction at Rigs hospitalet, and clinical professor at the University of Copenhagen, Denmark. His research has focused on puberty and growth and their disorders, including the role of IGF-I and its binding proteins in the diagnosis and monitoring of GH deficiency. He initiated the North European Small for Gestational Age Study (NESGAS) a European multicenter study to unravel the role of IGF-I titrated GH dosing. The timing and regulation of puberty have been a central research theme, which led to the initiation of the Copenhagen minipuberty study. A recent research interest has been the evaluation of novel biomarkers in DSD conditions, such as Klinefelter syndrome, CAH and PAIS.

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-20-0545 European Journal of Endocrinology https://eje.bioscientifica.com may presentinfetalorinfant life(likeCHH,45,X/46,XY, phenotype. Disorders with altered testosterone secretion postnatal lifeandvirilization oftheboytoensureadultmale involved in testicular descent in lategestation or early important forandrogenization of themalefetus,are reproductive period. Inmales,testosterone levels are climacteric andpostmenopausalperiods,followthe into adulthood.Inadultwomenadditionalphases, 3rdtrimester), inminipubertyandagainpuberty males withthreedistinctperiods;infetallife(2ndand The HPGaxisisactivethroughoutlifeinfemalesand and disease Steroid actionthroughoutlifeinhealth estrogen responsivetargettissues. cells toestradiolthatbindsestrogenreceptorsin converted by theFSH-inducedaromatase in granulosa ovarian thecacellstoproducetestosterone,whichis androgen -sensitive target organs. In girls, LH stimulates to themorepotentandrogenDHTby5-alfareductasein to estradiol by aromatase in fatty tissue and converted through theandrogenreceptor(AR),butisalsoconverted cells toreleaseTasintocirculation. Texertsitsactions gonads. Inthemalechild,LHstimulatestesticularLeydig systemic circulation stimulates sexsteroidproductionin and folliclestimulatinghormone(FSH)releaseintothe luteinizinghormone(LH) HPG axis.Thepulsatilepituitary both boysandgirlsisinitiatedbythereactivationof lower levelsthaninpuberty( In prepubertalchildren,thereissexsteroidaction,butat approximately 3monthsandstaylowuntilpuberty( level correspondingtopubertallevels,onlyfallafter during whichgonadotropinsandsexhormonesrisetoa neonatal developmentandearlyinfancy(minipuberty) (HPG) axis.TheHPGaxisistransientlyactivatedin (GnRH) activatesthehypothalamic–pituitary–gonadal pulsatile release of gonadotropin releasing hormone Physiological pubertyisinitiated,whentheenhanced Endocrinology ofnormalpuberty altered pubertaltimingondiseaselaterinlife. sex steroidactioninpuberty, aswelltheimpactof diagnostic, clinicalandtherapeuticaspectsofdisordered concentrations andtheirratios. well asfemales,butwithsex-differencesintheirabsolute Review In thisreview, wewilldiscussupdatedknowledgeon 2 ). Theonsetofpubertyin A BHansenandothers 1 ). panel: serumlevelvariationinfemalefetusesandinfants. serum levelvariationinmalefetusesandinfants.Bottom birth, andthenchronologicalageoftheinfant.Toppanel: healthy fetusandinfant.X-axis:gestationalageofthefetus, Y-axis: serumlevelofgonadotropinsandsexsteroidinthe Figure 1 factors involvedinpubertal timing. environmental andnutritional factorsareallimportant declining globallyduringthe last4decades( nomogram forgenitalorbreast development( development fallsbelow2 classify boysandgirlswithdelayedpubertyifthepubertal diagnostic criteriahaverecentlybeenintroducedand age 8–13for girls and 9–14 for boys ( normal, ifpubertaldevelopmentisinitiatedbetween spurt. Traditionally, timingofpubertyisconsidered sexcharacteristicsand agrowth development ofsecondary onset ofpubertalchangesinthebody. This stimulates the The reactivationoftheHPGaxisiskeyfactorto The initiationofpuberty activity ( during minipuberty may be anindicator of adult gonadal pubertal onset.TheactivityoftheHPGaxisinearlylife or 47,XXY)inconditionswithprecociousdelayed Sex steroidsinadolescencel Age atonsetofpuberty seemstohavebeen Fig. 1 ) ( 3 ). Downloaded fromBioscientifica.com at09/25/202106:32:18PM s . d . onastandardpuberty 184 :1 4 , 5 ). Additional 8 6 ). Genetic, , 7 ). R18 via freeaccess European Journal of Endocrinology pubertal development is categorized into five distinct menarche is a late pubertal marker. This continuous to havegrowthspurtatanearlypubertystage,while breast buddingandpubichairdevelopment.Girlstend and sixstagesforpubichairdevelopment(PH1toPH6). in five distinct stages for genital development (G1 toG5), break, andspermarche occur. Thiscontinuumisdescribed years afterpubertyinitiation,peakheightvelocity, voice growth ofscrotumandpenispubichair. Two tothree for clinicalpubertyassessmentworldwide( for pubic hair, genital and breast development is still used first evaluatedby Tanner in1968,andthe Tanner staging The timingofphysicalsignspubertyinchildrenwas sex characteristics Development ofsecondary disrupting chemicalsarelikelytobeinvolved( in Denmark,whereastudyhassuggestedthatendocrine did notexplainthemarkedearlierbreastdevelopment at asamajorfactorforearly puberty. However, obesity increasing obesityratearoundtheworldhasbeenpointed environmental andnutritionalfactors.Especiallythe sexual maturationwhichmustbeduetochangesin timing, itcannotexplaintherapiddeclineinageat puberty ( most frequent known cause of familial central precocious inhibits puberty. MutationsintheMKRN3geneare the proteinmakorinringfinger3(MKRN3) effectonthetimingofpuberty,with astimulatory whereas puberty. KisspeptinandneurokininBareneuropeptides Review In girls, the physical landmarks of puberty include In boys, puberty is initiated by testicular growth, Although geneticsplayanimportantroleforpubertal Hypothalamic neuropeptidesinfluencethetimingof 9 ). A BHansenandothers 4 ). 10 ). like growthfactor-I(IGF-I)release. (GH) secretionwhichinturnstimulateshepaticinsulin- growthhormone indirectly via stimulationofpituitary by directeffectsonepiphysealgrowthplates,butalso some yearsafterpubertalonset,dependingonthesex. pubertal growthspurtwithamaximalvelocityoccurring Sex steroidactionstimulateslineargrowthandresultsina Sex steroidsandlineargrowth (pubarche pathway)( often withpubarche asthefirstpubertallandmark American girlstendstoenterpubertyearlierandmore in mostCaucasiangirls(thelarche pathway),whileAfro- development (PH1 toPH5).Thelarche precedes pubarche stages forbreastdevelopment(B1toB5)andpubichair (estrogens and/or androgens), the level ofsteroid and the normal adultphenotype,dependingontypeofexposure body results in the marked changes that lead to the epiphyseal closure( grow andcanendupwithgigantismduetothelackof or aromatasedeficiency (CYP19mutation) continueto target height. precocious pubertyendupconsiderablyshorterthantheir normal range,whereassubjectswithrapidlyprogressing influenced byearlyorlatepubertaltimingwithinthe early epiphysealclosure.Thus,adultheightisnotmuch in ahighpeakheightvelocity(PHV)( cessation athighconcentrations.Anearlypubertyresults but arealsoresponsibleforepiphysealclosureandgrowth linear growthatlowconcentrations(forreviewsee( Sex steroidsinadolescencel Thus, sexsteroids(primarilyestradiol)stimulate Increasing sexsteroidlevelsstimulatelineargrowth The pubertalsexsteroidexposureoftheadolescent Subjects lackingestrogenactionduetoERmutation ( previously beenpresentedasraw data regarding heightvelocitycurves have according toageinboysandgirls. Data Longitudinal heightvelocities(cm/year) Figure 2 7 13 , 56 11 ). ). ). Downloaded fromBioscientifica.com at09/25/202106:32:18PM https://eje.bioscientifica.com 184 Fig. 2 :1 ), butalsoan R19 12 via freeaccess )) European Journal of Endocrinology https://eje.bioscientifica.com types. dependent (central)orGnRH-independent (peripheral) although thisfieldremains to befurtherelucidated( obesity, metabolic andcardiovascularrisksinsomestudies, (and not PP 19 levels andrisk-takingbehaviorssuchasalcoholabuse( associated withpsychologicaldistress,loweducational since PPuntreatedcancauseshorterfinalheightand is of theincreaseddiagnosing. but also,increasedattentionandawarenesscanbeacause may havecausedanactualdeclineinpubertalonsetage, may be caused by several factors. Nutritional alterations rising incidenceinSouthKorea( have shownaten-foldlowerincidenceinSpainand not withotherstudiesfromSpainandSouthKoreawhich year ( and correspondedto0.9–1.3newcasesper100000 period of8years(1993to2001)inastudyfromDenmark frequent ingirlsthanboysratio10:1( 9 yearsofageinboys( signs ofpubertybefore8yearsageingirls,and Precocious puberty(PP)istraditionallydefinedasclinical Too earlypuberty gender dysphoria. affirming crosshormonetherapyinadolescentswith final heightintallstatureorbepartofdeliberategender- appearance andcanbeusedasatoolinreductionof Klinefelter syndromeinboys. due toTurner syndromeingirls,aswellanorchia or gonadalinsufficiencyforexample, defects orprimary hypogonadotropic hypogonadism, sexsteroidsynthesis Too little boys duetoestrogenexcess(e.g.hCGproducingtumors). syndrome (PCOS))orfeminizaton(gynecomastia)in congenital adrenalhyperplasia(CAH),polycysticovary result invirilizationgirlsduetoandrogenexcess(e.g. of growthandpuberty(CDGP). Too late in precociouspuberty and its variants. action is observed well asinrareendocrinedisorders. and itstimingareseenincommonpubertaldisorders,as timing ofit.Pathologicalchangesinsexsteroidexposure Review , 20 Attention shouldbepaidtoprecociouspuberty, The incidenceofPPwasfoundtobestableovera Exogenous sexsteroidtreatmentaltersphysical Precocious puberty can be divided into GnRH- 14 ). Earlyonsetofpubertyinthegeneralpopulation ). ThisalignswithastudyfromFrance( sex steroidactionisseeninconstitutionaldelay sexsteroidactionisseeninchildrenwith per se ) has been found to be associated with 4 ). Precociouspubertyismore Too much 16 A BHansenandothers , 17 Too early ). Thisdiscrepancy sex steroidcan 14 sexsteroid ). 15 ), but 21 18 ). , or McCuneAlbrightsyndrome(MAS)( adrenal hyperplasia,granulosacelltumors,testotoxicosis benign ormalignantbraintumors. caused by underlying brain pathologies like hamartoma, cause. ThisisknownasidiopathicCPP. CPPcanalsobe suppressed gonadotropinsandnocentralactivation. blood samplespresentwithhighlevelsofsexsteroidsbut hormone inendocrineglandsortumors.Thepatient’s caused byproductionofsupraphysiologicalsexsteroid so-called peripheral sex steroidserumlevels. increase inLHandFSHlevelswiththat, glandandisrecognizedby hypothalamus andpituitary puberty (CPP), which is caused by an activation of the spots or a familial history with neurofibromatosis-1 (NF-1), withneurofibromatosis-1(NF-1), spots orafamilialhistory should paycertainattention topatientswithcafé-au-lait in boystotalaKorean study ( abnormal cerebralMRIhas been foundtobeup70% and boys,sincethepercentage ofboyswithPPwho have gland),patientswithrapidlyprogressing puberty pituitary suspicion ofatumorintheareaopticchiasmaand symptoms likebitemporalhemianopsiawhichraise patients withneurologicalsymptoms(especiallyfocal certain high-riskgroups. findings islow, andMRIofthebrainisonly indicatedin intracranial pathology, buttheincidenceof pathological range. necessary, ifbasalgonadotropinlevelsareinpubertal to confirm aCPP diagnosis ( following aGnRHstimulationtestinchildrenthisage of the minipuberty, and peak LH should be above 9 IU/L years willhavehighersexhormoneserumlevelsbecause diagnosis ofCPPisconfirmed.Childrenattheage1–3 (or LH/FSHratio stimulation test.IfpeakLHconcentrationisabove5IU/L steroids andgonadotropins( growth, boneagedeterminationandmeasurementofsex examination focusingontannerstaging,evaluationof family history, personalmedicalhistory, aphysical rapid growth. hairand/or development, growthofpubicandaxillary Sex steroidsinadolescencel The reasonforreferraltoPPevaluationisoftenbreast Groups at risk include patients under the age of 6, Groups atriskincludepatientsundertheageof6, MRI ofthebraincanbeindicatedbecauserisk The goldstandarddiagnostictestforPPistheGnRH The diagnosticevaluationforPPincludesathorough PPP is observed indiseaseslikelate-onsetcongenital PPP isobserved Central PPismostoftenbenignandwithnoorganic More rarely, thecauseisindependentofGnRH, The mostcommoncauseiscentralprecocious > 0.6)followingGnRHstimulation,the

precocious puberty(PPP)andis Downloaded fromBioscientifica.com at09/25/202106:32:18PM 4 23 ). , 24 25 ). A GnRH test is not 184 ). Also, the clinician ). Also,theclinician 22 :1 ). R20 via freeaccess European Journal of Endocrinology inhibitors ( been foundtorespond treatmentwitharomatase Testotoxicosis andMcCune–Albrightsyndromehave and requiresexogenous hydrocortisone treatment. while late-onset CAH is a steroid synthesis defect cause. Granulosacelltumorsrequiresurgicalremoval, adequate suppression( subcutaneous implantswithGnRHahavealsoshown but 6-monthlyinjections are alsobeingused.One-year been administered as 1- or 3-monthly depot injections, Bailey–Pinneau) thatarenotvalidatedinCPP. GnRHahas prediction based on various prediction models (e.g. accuracy of theinitialpre-treatmentfinal height patient, butthisconcernisnotverified( ( though treatmentinitiationisnotuncommonatthisage of psychosocialhealthasaresultthetreatment,even of theincreasedheightpotentialandimprovement limited effect on final height ( girls aged6–8yearsremainuncertainandmayhavenoor girls early maturationofthebone( with CPPtendtoendupashorterfinalheightdue maximum heightpotentialatthegivenpoint,sincegirls to delayfurther pubertal developmentand to ensure the the HPGaxis.ThegoalsofGnRHagonisttreatmentare agonist (GnRHa)tohaltmaturationviasuppressionof steroid contamination( investigations toruleoutpathologyorexogenoussex simultaneous growthaccelerationshouldpromptfurther development ofthelarche inthe3–5yearsoldgirlwith or PA haveahigherriskofdevelopingCPPlater. Sudden important forthispatientgroup,sincepatientswithPT treatment isindicated.However, clinicalfollow-upis (PT) due toself-limitingvariantslikeprematurethelarche intracranial pathology( factors aremorelikelytopresentwithICPPandno internationally adoptedchildren,aspatientswithsuch have atendencytowardearlynormalpubertyincluding over theageof6yearsandsomeethnicgroupswho CPP ( since NF-1canbeacauseofintracranialtumorsrelatedto 32 Review ). GnRHatreatmentmightinduceaweightgaininthe The treatment of PPP depends very much onthe The treatmentofPPPdependsvery The estimated height gain is dependent on the GnRHa is effective for final height improvement in Central precociouspubertycanbetreatedwithGnRH Premature breastorpubichairdevelopmentisoften Factors arguingagainstbrainMRareonsetofPP

< or prematureadrenarche (PA) 26 6years,buttheeffectoftreatmentinitiationin ). 22 ). 22 26 30 ). , ). 27 22 , 12 28 , ). A BHansenandothers 31 ). ). There is uncertainty

( 29 31 ) forwhichno ). evaluation includes a family history, medical history, pathological conditioncomparedtoboys( certain attention,astheymoreoftenhaveanunderlying girls who present with delayed puberty should be paid but underlyingsyndromesmustbeexcluded.Incontrast, experience lowfertility, butnormalsexsteroidlevels( who haveundergoneiatrogenic gonadotoxictherapy radiotherapy orchemotherapyinfemales,whilemales togonadotoxic hypogonadism canalsobesecondary to theunderlyingdiagnosis( present withdelayedorlackofpuberty, which maylead Klinefelter syndromeoranorchia. Theseconditionscan commonly caused by Turner syndrome, and in boys with gonadal insufficiencyisseeningirlswithPOI,most ( cortisol, buttheimpactofthismechanismisunknown could trigger FHA through increased levels of and worry (FHA). Ithasbeenhypothesized,thatpsychosocialstress frequent causesoffunctionalhypothalamicamenorrhea eating/training disorders(orthorexia)orelitesportsare female adolescents,eatingdisorders(anorexia,bulimia), reduced caloric availability as well excessive exercise. In insufficiency, restrictiveeatinghabits,malabsorptionor is a reversible condition and can be caused by nutritional the firstsymptomsinupto19%ofcases( this slow-growingtumorpresentswithdelayedpubertyas shouldbeconsidered,since risk ofacraniopharyngioma areaarerarecausesofCHHbutthe hypothalamic–pituitary mutations ( or withoutassociatedanosmiahyposmia,duetogenetic is causedbyfullorpartialmalfunctionoftheHPGaxiswith (CDGP) isabenigncommonformofdelayedpuberty( adult life( related tolowereducationallevelandaBMIin problems andlowself-esteem( problems inadulthoodandcanleadtopsychosocial may cause lack of virilization/feminization and fertility more ofteninboysthangirls( in thefollowingchapter. action oftenoverlapandtheywillbementionedtogether The disorderscausingtoolateandlittlesexsteroid Too latesexsteroidaction Sex steroidsinadolescencel 35 ). Diagnostic evaluationofdelayed puberty: Hypergonadotropic hypogonadismduetoprimary Congenital hypogonadotropichypogonadism(CHH) In boys,constitutionaldelayingrowthandpuberty Functional hypogonadotropichypogonadism(FHH) Too latesexsteroidaction/productionpresents 18 5 , , 34 21 ). Intracerebral tumors and disorders in the ). Intracerebraltumorsanddisordersinthe ). Downloaded fromBioscientifica.com at09/25/202106:32:18PM 37 https://eje.bioscientifica.com , 5 38 , 34 33 ). Hypergonadotropic 184 ). Late menarche is ). Delayedpuberty :1 36 35 ). ). ).

Diagnostic R21 39 6 via freeaccess ). ),

European Journal of Endocrinology https://eje.bioscientifica.com some arefoundinadolescence becauseofadelayedor are foundinchildhoodbecause ofdevelopmentalissues, phenotypes.Somepatients 45,X/46,XY canhavevarying disorders oftenpresentas46,XY females( local, androgen-sensitivetissueandindividualswiththis the conversionofTtomuchmorepotentDHT in 5-alpha reductasedeficiency. Thisdeficiencywill prevent Defects insteroidactionarealsoseenpatientswith T andE2serumlevelsareinatypicalmalerange( sex characteristics, although their female secondary identifies as females, are reared as females and develop imbalance ( and developgynecomastia due to high E2 andT/E2 males typicallypresentwithmicropenis,hypospadias syndrome (PAIS orCAIS)).PatientswithPAIS raisedas (AR) defects(partialorcompleteandrogeninsensitivity rare steroidsynthesisdefectsorwithandrogen receptor action areatsubnormallevels. puberty attheexpectedtime,butsexhormonelevelsand In casesoftoolittlesexsteroidproduction,subjectsenter Too littlesexsteroidactioninadolescence in alaterchapterunder‘pubertyinductionbysexsteroids’. chromosome defects( shouldbeperformedtodetermineanypossible karyotype and afinaldiagnosisrequireswatchfulwaiting( impossible becauseoftheoverlappingbiochemicalmarkers and CHH(especiallyinpartial forms) are difficult and often intracranial pathology ( hormonalaxesmustbeperformedtoruleout pituitary If CHHisfound,MRIofthebrainandtestingother hCG test,buttheefficiencyofthisisstilldiscussed( the LeydigcellmarkerINSL3)canreplacemorecostly some cases,basalmeasuresofAMHandInhB(oreven stimulation testtodeterminepeaktestosteronelevels.In line evaluationmayincludeaGnRHtestand/orhCG and CDGP. Iflowgonadotropinlevelsarefound,second- as thecauseandthenseektodistinguishbetweenCHH hormone (TSH)levels. steroid quantification,IGF-Iandthyroid-stimulating concentrations determined by ultrasensitive assays, sex biochemical assaysincludingINSL3,basalFSHandLH physical examination,boneagedetermination, Review Too little sex steroid action is seen in patients with The treatment of delayed puberty will be mentioned If hypergonadotropic hypogonadism is found, The clinicianshouldfirstruleoutchronicdisease Boys with chromosome disorders like 47,XXY or 41 ). Patients with CAIS virtually always 37 34 ). ). Distinguishing between CDGP ). Distinguishing between CDGP A BHansenandothers 43 ). 40 ). 42 33 ). ). ). of firstpassmetabolism are avoidedwhenusingTD Estrogen ismetabolizedin the liverandnegativeeffects (TD) route.TDtreatmentis preferredtooraltreatment. natural 17 Mimicking normal puberty requires accurate dosage Puberty inductionbysexsteroids compromise finalheightinboyswithCDGP( Treatment withoraltestosterone doesnotappearto age, andreproductivehormones(forreviewsee( increasing gradually) monitored by clinical signs, bone second day hereafter day or every mg transdermally every twice daily),ortransdermaltestosterone(initialdose10 dose 40 mg orally daily, increased gradually to 80 mg increasing doses), oral testosterone undecanoate (initial dose 50mgintramuscularlymonthlyfollowedbygradual include intramusculartestosteroneenanthate(initial exist andhavebeenusedtointhistreatment. These for CDGPwithtestosteroneandestradiol,respectively. of puberty. Thus,maleandfemalepatientscanbetreated when there are no imminent clinical or biochemical signs significantly retarded,theboneageispast10years,and with exogenoussexsteroidincases,where the growthis growth andpubertaldevelopmentcanbestimulated normal butdelayedpubertalgrowthspurt.The is acondition,inwhichthepatient(inretrospect)has etiology, sex,ageandthepreferenceofpatient.CDGP consequences. Treatment fordelayed puberty dependson timing ofinitiationcanminimizenegativepsychosocial minimize adverseeffectsatthesametime( to ensureprogression,maximizegrowthpotentialand and timing. The challenge of sex steroid treatment is present in occur in1/3TSpatients,butmenstrualcyclesareonly throughout adulthood. Signs of puberty spontaneously sex characteristics puberty and maintain secondary with TSneedhormonalreplacementtherapytoinduce of pubertyandfertilityproblemsinadulthood.Mostgirls short stature,hypergonadotropic hypogonadism, absence partial (mosaic) lack of one X chromosomes, causing Turner (TS)syndromearecharacterizedbycompleteor under masculinizationinadolescence( diagnosed. Otherpatientswill,however, experience of themneverseekmedicalattentionandare condition beforetheyvisitthefertilityclinic,andmost absent puberty, butmostpatientsarenotawareoftheir Sex steroidsinadolescencel In hypogonadalgirls,puberty inductionisdoneusing For malepatients,severaltestosteroneformulations β − -estradiol preferablythrough thetransdermal 6%, mostofthesewithTSmosaicism( Downloaded fromBioscientifica.com at09/25/202106:32:18PM 184 44 :1 , 45 37 ). Girlswith 5 ). Optimal , 6 ). 37 R22 , 47 46 via freeaccess )). ). European Journal of Endocrinology management of symptoms in PCOS, the combined oral management of symptoms in PCOS, the combined oral Disorders thatmimic PCOS shouldbeexcluded( for thediagnosisofPCOSwithin 8yearspostmenarche. müllerian hormone(AMH) levels arenotrecommended high-quality assays. However, pelvic ultrasound and anti- and/or hyperandrogenemiaconfirmedusingvalidated and (ii)hyperandrogenismdefinedashirsutism,acne irregular cyclesdefinedaccordingtoyearssincemenarche accuracy andavoidover-diagnosisinadolescentsinclude(i) with diagnosticcriteria.Criteriatoimprove because features of normal pubertal development overlap in 2001( Gallwayscore –publishedin1961andfurthermodified of distributionhirsutismisevaluatedbyFerriman- due to cultural stigmas. The degree, severity and area often causepsychologicaldistressandsocialdifficulties development of virilization. Hirsutism in adolescent girls (Sertoli–Leydig cells)orintheadrenalgland,causingrapid excessive androgenproductionaretumorsintheovary gland causesexcessandrogenproduction.Rareof feedback andtheresultingoverstimulationofadrenal deficiency resultsin highACTH levelsbecause ofnegative gene. Impairmentofcortisolbiosynthesisduetoenzyme cortex usuallycausedbymutationsintheCYP21A2 CAH –anautosomalrecessivediseaseoftheadrenal adrenal androgenproductionisalsoseeninlate-onset cause is PCOS (polycystic ovarian syndrome). Excess endocrine imbalance,adrenalorovarian,andacommon and deepeningofvoice.Hirsutismistheresultan testosterone, virilizationoccurswithclitorisenlargement cases with a morepronounced and rapid production of hirsutism with ‘male’ pattern hair growth and acne. In and gynecomastia. This chapterwillcoverthetopicsPCOS,late-onsetCAH Too muchsexsteroidactioninadolescence therapy) cyclicprogestinisadded( bleeding occurs(ormaximally2yearsafterinitiationof appropriate circulating E2levels.Whenbreak-through approximately 2yearsreachingadultE2doseandage- application) withanincreasingdoseoveraperiodof transdermal treatment (initial dose 6.25 µg nocturnal start at11–12yearsofage,beginningwithlowdose side effectsinthishigh-riskgroup( estradiol shouldbeavoidedbecauseofthehypertensive treatment ( Review Diagnosing PCOS during adolescence is challenging Diagnosing PCOSduringadolescenceischallenging Androgen excessdisorderscan,ingirls,result 50 ). 48 ). ForTSpatients,thealternativeethinyl A BHansenandothers 49 37 ). ). Initiationshould 51 ). For ). For does –incontrasttoclassicalCAHnothaveclinical caused by androgen production in theadrenal gland but should berecommended( topreventweightgainand healthy lifestyleinterventions during thetreatment.Available dataendorsethebenefitsof the youngfemalepatient,whoshouldavoidpregnancy teratogenic effectofthisdrugshouldbediscussedwith effective thaninsulinsensitizersonhirsutism.Thepossible possibly combined with OCP, have been found to be more patient ( Metformin caninduceasmallweightlossintheoverweight considered tobepartofthemechanismaction. are beneficialandatreatmentofthemetabolicdisorder free T. In adolescents insulinsensitizers such as metformin binding globulin(SHBG)andtherebyreducesthelevelsof as wellitincreasestheliversecretionofsexhormone effective andlowerstheovarianproductionoftestosterone contraceptive pillthatcontainsestrogenandprogestin,is is aphysiologicalphenomenon inmid-pubertalboys enhance proliferationviaER ( inhibit breasttissueproliferation viaARandestrogens levels orbyelevatedestrogen levels,sinceandrogens estrogen ratio.Thiscanbe caused byloweredandrogen Gynecomastiais caused by an imbalance in the androgen/ called pseudo-gynecomastia)bythoroughpalpation. ( boys withCarneysyndromeorPeutz–Jeghers andisoftenasymptominSertoli celltumorsin observed in pubertalboys,butprepubertalgynecomastiaisrarely glandular breasttissue.Gynecomastiaisnormallyobserved surgery. virilization. Androgenproducingtumorsaretreatedwith or adrenalgland,oftencausingrapiddevelopmentof (Sertoli–Leydigcells) producing tumorsintheovary these patientsshouldbefollowedclosely( formation andadversepsychologicaleffects,whichiswhy can leadtoearlypuberty, virilization,adrenalresttumor In contrast,absenceofadequateandrogensuppression growth suppressionanddecreasedbonemineraldensity. should be paid, because excess levels can result in obesity, insufficiency ( of severehyperandrogenism,physicalstressoradrenal onset CAH,glucocorticoidsareonlyindicatedincases supplementation, butfortheadolescentpersonwithlate- and doesusuallynotinduceadrenalinsufficiency. manifestations untilafterinfancyuptoearlyadulthood Sex steroidsinadolescencel 54 ). Thisshouldbedistinguishedfromlipomastia(also Gynecomastia is the inappropriate appearance of Rare causesofhyperandrogenismareandrogen In thecaseoflate-onsetCAH,hyperandrogenismis The treatmentforCAHisglucocorticoid 51 ). Antiandrogens (finasteride or spironolactone) ). Antiandrogens(finasterideorspironolactone) 53 ). Attentiontoglucocorticoidtreatment Downloaded fromBioscientifica.com at09/25/202106:32:18PM 52 ). 55 https://eje.bioscientifica.com ). Transient gynecomastia 184 :1 53 ). R23 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com girls and14yearsinboys. The otheroption,sexsteroid for patients with a bone age less than 12.5 years in treatment withpercutaneous epiphysiodesisispreferred be counselledonpotential options.Today, surgical final heightpredictions andtheirfamiliesshould need hormonaltreatment.Adolescentswithextreme stature is not a pathological condition and does not does not need treatment. Idiopathic (familial) tall tall statureisnotapathologicalcondition which needtoberuledoutfirst.Idiopathic(familial) sex chromosomeanomalies(47,XXY, 47,XYY, 47,XXX) Beckwith–Wiedemann syndrome,homocystinuriaor Marfansyndrome, Sotossyndrome,FragileXsyndrome, Tall staturemaybecausedbyseveralsyndromes like statured children of high-dosesexsteroidsintall Treatment withexogenousadministration the actualcause categories, although chronic disease maysometimesbe gastrointestinal, musculoskeletal,andneuro-cognitive of cancers, cardio-metabolic, gynecological/obstetric, with higherrisksofadverseoutcomes,acrossarange puberty timing in both women and men are associated ( (bipolar diseases,chronicfatiguesyndrome,depression) boweldiseaseandpsychiatriccomorbidities inflammatory puberty is associated with increased risk of asthma, eczema, addition, recentepidemiologicalevidencefindthatlate delayed pubertyhaveincreasedriskofosteopenia( Finkelstein has long-lasting consequences for bonehealth.Thus, this review( has long-termhealthconsequencesaswehavecoveredin Early sexsteroidactionresultinginprecociouspuberty Timing iseverything oil, whichislinkedtoprepubertalgynecomastia( might wanttoaskthepatientaboutuseoflavender PAIS ( defective androgenreceptorsignalingasseeninboyswith of androgensasseen in Klinefeltersyndrome,ordueto pubertal gynecomastiacanbeasignofdecreasedlevels but willdisappearwithin6–24months( (genital stages3–4)andisseeninupto50%ofboys 61 Review ). Timing ofsexsteroidactioniskey. Earlyandlate Late sexsteroidactionresultingindelayedpuberty 41 ). If the patient is otherwise healthy,). Ifthepatientisotherwise theclinician et al. 58 ,

59 of delayedpuberty( have shown that men with a history of haveshownthatmenwithahistory ). A BHansenandothers 61 ) ( Fig. 3 56 ). Persistent ). per se 57 60 ). and ). In thelarche (PT),prematureadrenarche(PA),McCuneAlbright observed iscentralprecociouspuberty(CPP),premature rare endocrinedisorders.Tooearlysexsteroidactivityis Sex steroidactioninpubertychildrenandadolescentswith Figure 3 syndrome (47,XXY)andmixedgonadaldysgenesis(45,X/46,XY). insufficiency (POI)andTurnersyndrome(45,X),Klinefelter complete androgeninsensitivity(CAIS),prematureovarian patients withpartialandrogeninsensitivitysyndrome(PAIS), substances (doping).Toolittlesexsteroidactionisobservedin due totallstature,ormisuseofanabolicandrogenic ovary syndrome(PCOS),orpatientstreatedwithsexsteroids patients withcongenitaladrenalhyperplasia(CAH),polycystic hypogonadism. Toomuchsexsteroidactivityisobservedin puberty (CDGP)andcongenitalhypogonadotropic is observedinpatientswithconstitutionaldelaygrowthand syndrome (MAS)andtestotoxicosis.Toolatesexsteroidaction to ensureanearlyandrapidlyprogressingpuberty( high-dose ethinylestradiolornaturalisused 63 steroids inadolescentswithidiopathictallstature( melanomas argue height reduction,riskofimpairedfertility in womenand treatment, isseldomlyusednowadays.Themoderate studies, beenfoundnotbeaffected ( treated withtestosteronein adolescencehave,innewer By contrast,fatherhoodand semenqualityintallmen ovarian aging with concomitant follicle pool ( of subfertilityinlaterlifeand showsignsofaccelerated Thus, high-doseestrogen-treatedtallwomenareatrisk exist. consequences topharmacologicalintervention treatment isinitiatedearly. Importantly, severelong-term weeks ( 2 doses (testosteroneenanthate250–500mgevery Tall hightestosterone staturedboyshavebeengivenvery Sex steroidsinadolescencel , 64 ). Intheexceptionswheretreatmentisinitiated, 66 )) withsignificantreductioninfinalheight if against Downloaded fromBioscientifica.com at09/25/202106:32:18PM

routine use of high-dose sex 68 184 , :1 69 ). 64 , R24 67 65 62 via freeaccess ). ). ). , European Journal of Endocrinology ‘acromegalic state’withassociated insulinresistance. characteristics, psychomotor adjustments,andatransient sex growth acceleration,development ofsecondary vulnerability, immature decisionmaking, as well as recognized asaperiod of emotionalinstability, result inchangesbodyandmind.Puberty is Changes insexsteroidlevelsthepubertaltransition Concluding remarks are lacking( randomized clinical trialsofdifferent treatment regimens term dataareavailableonthesafetyoftreatmentand homogeneous clinicalguidelinesworld-wide,littlelong- of treatmentoptionsformorethan20yearsandrelatively all countries–orevenlegal( treatment is possible, but notroutinely established yet in priortohormone semen orovariancryopreservation with female andcontinuedlifelong.Fertilitypreservation testosterone infemale-to-maleandestradiolmale-to- treatment isofteninitiatedaroundage15–16years( stops testisgrowthandvirilizationinboys.Sexhormone development of breast tissue and menstruations in girls and hormone treatmentisinitiated.LongactingGnRHastops for genderclarificationbeforeirreversiblecrosssex and gender identity and thus creates a time window diminishes the discordance between body appearance hormones. PubertysuppressionfromTanner stage2 with GnRHaandgender-affirmingtreatmentsex ( endocrinologists intheassessmentandtreatmentofGD based onateamofpsychologists,psychiatristsand be multifaceted. societal factorsarediscussed,andtheoriginofGDmay natal girls. The etiology is unknown, but biological and to beincreasinginmostcountries,especiallyamongst group ( psychological distressandsocialmarginalizationinthis reviews haveshownahighprevalenceofmentaldisorders, sex characteristicsduringpuberty. Epidemiological Often, GD becomes more severe with onset of secondary adolescence oradulthoodbutdesistinthemajority( The onsetofGDmaybeinchildhoodandcanreachinto which inconsequencecanleadtogenderdysphoria(GD). the natal(assigned)sexandperceived genderidentity, A transgenderpersonexperiencesincongruencebetween Transgender youth 71 Review ). Endocrinetreatmentconsistsofpubertysuppression Standards ofcareforchildrenandadolescentsare 71 ). The prevalence is unknown but appears 75 ). 73 , 74 A BHansenandothers ). Despitetheexistence 70 72 ). ), The authors declare that there is no conflict of interest that could be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest endocrine disorders. transition throughpubertalforpatientswith There isafocuswithinENDO-ERNtoensureoptimal patients, pediatricaswelladult(www.endo-ern.eu). (ENDO_ERN) encompassesperspectivesfromendocrine European referencenetworkforrareendocrinedisorders manage chronic patients in the transitional period. The considerations, and expertise by health care providers who interfere withthepubertalchanges.Thisrequirescareful be additionallychallengedbytheirdiseasewhichmay face thesechangesofpubertylikeotherteenagersbutmay signs andsymptoms.Adolescentswithchronicdiseases Abnormal developmentortimingmayworsenallthese References the public,commercialornot-for-profitsector. 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Accepted 14October2020 Revised versionreceived30September2020 Received 21May2020

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