European Journal of Endocrinology 10.1530/EJE-16-0888 adults withclassicCAHtoprovidethereaderanupdatedreviewonthisrapidlyevolvingfieldofknowledge. 5 years, concentratingonstudiesdealingwithcardiovascularrisk,fertility, treatmentandprenatalmanagementin been described,butremainasubjectofdebate.We focusedthepresent overviewonthedatapublishedinlast pregnancies atriskforcongenitaladrenalhyperplasiausingfetalsexdeterminationanddexamethasonehave also being developedandstudiedinanattempttoimprovepatientoutcomes.Newmanagementstrategiesthecareof due inparttothedrawbacksofcurrentlyavailableglucocorticoidtherapy. Consequently, noveltherapiesare CAH haveincreasedmortality, morbidity andriskforinfertilitymetabolicdisorders.Thesecomorbiditiesare allowing ustohaveabetterknowledgeoflong-termcomplicationsthediseaseanditstreatment.Patientswith cohorts ofadultswithCAHdueto21-hydroxylasedeficiencyfromEuropeandtheUnitedStateshavebeendescribed, and controlandrogenexcess,whileavoidingtheadverseeffects ofexogenousglucocorticoid.Overthelast5 years, cases aldosteronedeficiencyassociatedwithandrogenexcess.Goalsoftreatmentaretoreplacedeficienthormones Congenital adrenalhyperplasia(CAH)dueto21-hydroxylasedeficiencyischaracterizedbycortisolandinsome Abstract 1 Anne Bachelot prenatal treatment management ofadultpatientsand 21-hydroxylase deficiency:updateonthe Congenital adrenal hyperplasiadueto Management ofendocridisas Philippe Touraine Gynécologiques Rares,ICAN,Paris,Franceand de RéférencedesMaladiesEndocriniennesareslaCroissance,entrePathologies AP-HP, IE3M,HôpitalPitié-Salpêtrière,DepartmentofEndocrinologyandReproductiveMedicineCentre DOI: 10.1530/EJE-16-0888 www.eje-online.orgwww.eje-online.org treatment ofgrowthhormonedeficiency inadults. management ofpatientswithcongenital adrenalhyperplasiaduringtransitionandadulthood andfinallythe of prolactininhumanbreast diseases, thepathogenesisandgeneticsofprematureovarian failure,the Disorders. Hismajorresearch tumors,therole interestsincludethepathogenesisandtreatmentofpituitary disorders. Healsoleadsoneofthegroupsbelongingto European RareNetworkonSexDifferentiation Pierre et Marie Curie, Paris. He is the leader of two groups dedicated to rare endocrine and gynecological the HôpitauxUniversitairesPitiéSalpêtrière-CharlesFoix,Paris, FranceandafullprofessoratParisvi,Université Philippe Touraine MD,PhD,istheHeadofDepartmentEndocrinologyand ReproductiveMedicineat Invited author’s profile Review 1,2 , Virginie Grouthier 1,2 © 2017EuropeanSocietyofEndocrinology © 2017EuropeanSociety ofEndocrinology A Bachelotandothers 2 rance UPMCUniversitéPierreetMarieurie,UnivParis06,Paris,France 1,2 , Carine Courtillot Printed inGreatBritain 1 , Jérôme Dulon hyperplasia Update oncongenitaladrenal Published byBioscientifica Ltd. 1 and

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(2017) Endocrinology European Journal of [email protected] Email to PT should beaddressed Correspondence 176 176:4 : ouraine 4 176, R167–181

R 167– R 181 via freeaccess European Journal of Endocrinology www.eje-online.org (4, Cohorts ofadultswithCAH dueto21OHDfromEurope Cardiovascular (CV)risk publications concernthosetopics. treatment andprenatal management as mostofthe recent go further into four themes: cardiovascular risk, fertility, CAH inadultsorprenatalmanagement.We also choseto outcomes of CAH, to focus on studies dealing with classic that were dealing with non-classic CAH and childhood deficiency’. Forspaceconstraints,weexcludedallthedata ‘congenital adrenalhyperplasia’and‘21-hydroxylase PubMed research hasbeen performedwiththeterms years.Anexhaustive published onCAHoverthelast5 needed forsubstitution(1 to suppresstheandrogensareusuallyhigherthanthose cannot bemimickedwithoralGC,andthedosesneeded use. Thephysiologicalcircadian rhythmofcortisol the long-term consequences ofglucocorticoid(GC) adrenal gland,toensurenormalfertility, andtoavoid consequently the increased androgen production by the Its roleistoreducetheexcessiveACTHproductionand cortisol and,whennecessary, aldosteronesubstitution. aldosterone deficiency. Hormonaltreatmentisbasedon virilizing (SV)forms,dependingonthedegreeof Classic CAH encompasses salt-wasting (SW) or simple classified asclassicforthesevereform,ornon-classic(NC). phenotype, related to theless-severe mutated allele, is Most patientsarecompoundheterozygotes.Theclinical degrees ofimpairment21-hydroxylaseactivity(2 gene identifiedsofar, whicharethecausesofvarying CYP21A2 ( deletions ordeleteriousmutationsintheactivegene 21-hydroxylase deficiency (21OHD) is the result of known autosomal recessive disorders. CAH due to 95% of the cases and is one of the most commonly most commonformofCAH,accountingformorethan of cortisolbiosynthesis. results fromadeficiencyinoneorseveraloftheenzymes disorders thatarisefromdefectivesteroidogenesisand corresponds toagroupofinheritedautosomalrecessive Congenital adrenalhyperplasia(CAH,MI201910) Introduction for metabolicdisordersinadults (1, in therecentyears.Theyhave shownanincreasedrisk Review 5, In thisreview, wedecidedtofocusonthenewfindings Deficiency ofthe21-hydroxylaseenzymeis 6) andthe United States(7)havebeendescribed 1 ). TherearemanymutationsoftheCYP21A2 , 2 , 3 ). A Bachelotandothers 3, 8, ). Overweight 9). Overweight ). ).

controls (4, both diurnalandnocturnalSBP, comparedtomatched others reportingaslightincreaseofeitherdiurnalor resting (13, independent groups,withsomestudiesreportingnormal adult CAHpatientshasbeeninvestigatedbyseveral androgen exposure,BMIandvisceralfat. to performanassociationanalysisofglucocorticoid, interesting to follow-up the patients longitudinally (12). Asthesestudieswerecross-sectional,itwouldbe ofmetabolicsyndrome was associatedtofamilyhistory was ahigherprevalenceofmetabolicsyndrome,which (7). InaBraziliancohortofyoungCAHpatients,there no associationwasfoundwithandrogens,GCtypeordose NIH cohort(7).twasassociatedwitholderage,whereas innearly20%ofadultsthe patients andwasobserved controls. MetabolicsyndromewasalsoevaluatedinCAH CAH patientscomparedtoage-,sex-andBMI-matched compared tosubcutaneousadiposetissuewaspresentin visceraladiposetissue proportion ofproinflammatory (11). Increasedabdominaladiposity, withahigher precisely studied in CAH adolescents and young adults (5, the generalpopulationinlatestnationwidesurvey inCAHpatientswassimilartothatfound overweight 108 and219patients,theprevalenceofobesity rate of 36% (7). across phenotypes)wassimilartotheadultU.S.obesity patients, prevalenceofobesity(one-thirdpatients (4). IntheAmericancross-sectionalstudyof244CAH forEnglanddata general populationoftheHealthSurvey was foundtobehigherinCAHpatientsthanthatthe in theUnitedKingdom(UK)among199patients,BMI CAH. Intheprospectivecross-sectionalstudyconducted and obesityhavebeenreportedinadultpatientswith (10). Dyslipidemiainindividuals withCAHhasbeen CAH havearatherlowBP compared withhealthymen with arecentstudyshowing thatadultmaleswithclassic phenotypes andgenotypes (6).Thiswasinaccordance whereas thiswasrareornonexistentinthemoresevere subgroups, onlySVfemaleshadincreasedbloodpressure, CAH has been shown, but when analyzing the different increased frequencyofhypertensioninindividualswith study,(24). InarecentepidemiologicalSwedishregistry prevalence of hypertension in adult patients with CAH pressure. Thereareminimaldataavailableonthe may beinfluencedbythemethodsforrecordingblood hyperplasia Update oncongenitaladrenal 10). Morerecently, repartitionofadiposetissuewas Blood pressure(BP)controlinchildrenand 14, 18, 15, 19, In two Frenchcohorts of respectively 16) and24-hourBPprofile(17 20, Downloaded fromBioscientifica.com at09/24/202105:08:30PM 21, 22, 23). Thesedifferences 176:4 R168 via freeaccess European Journal of Endocrinology in CAHpatientswerestudied usingtheSwedishnational beginning tobecharacterized (6).Thelong-termoutcomes figure outinthisat-riskcohort. treatment ofCAHandCVevents,willbeimportantto dysfunction, cIMTprogression,hormonalimbalance, further examined.Theassociationbetweenendothelial These findingsandtheirclinicalimpacthaveto be in womenwithCAHthanthatcontrol(30 ). We durationwasshorter foundthatCAHQTinterval hormones onthedurationofventricularrepolarization. complex interactionsbetweengonadotropinsandsteroid performance wereshown.Recently, we reported the but milddiastolicdysfunction and impairedexercise left ventricularmorphologyhasbeenreported(13, obesity (12).InadolescentandadultCAHpatients,normal a levelcomparabletothesubjectswithmild-to-moderate vascular endothelialandsmoothmuscledysfunctions,at Children withCAHhavebeenshowntosignificant of endothelialorcardiacdysfunctionhavebeenstudied. measures andinstudydesign.Othersurrogatemarkers variations betweenstudiesmaybeduetodifferencesin and unfavorablemetabolicparameters(27, compared tocontrols,butfounditlinkedhigherBMI to aBMI-matchedcohort(12, adolescent CAHpatientsshowednormalcIMTcompared doses orandrogenlevels.Furtherstudiesinchildren was nocorrelationbetweencIMTandcumulativeGC found tohaveincreasedcIMTinonestudy(15).There (12, inexistingstudiesofindividualswithCAH results vary diseaseandstroke(25).However, artery coronary c IMT atherosclerotic change,thatiscorrelatedtotheriskfor (cIMT) isawell-establishedmarkerofearly, subclinical Carotidintima-mediathickness aged olderthan50 years. few of the studied patients are this population, as very morbidity andmortalityarenoteasytobringoutin never beensystematicallyascertained.Cardiovascular impact oftheseriskfactorsonthevascularsystemhas a high CV risk profile in CAHpatients. However, the had decreasedHDL(7). elevated totalcholesterol,whereasapproximately15% NC adultpatientshaddecreasedHDL.Inadults,6% the NIHcohort,approximately10%ofbothclassicand found, especiallyinmaleswithanullgenotype(6).In study,registry anincreasedrateofdyslipidemiawas reported insomestudies.IntheepidemiologicalSwedish Review The rateofCVeventsamongadultswith CAHis In thisintricatescenario,itisreasonabletoexpect 14, 26, 27, 28, 29). AdultswithCAHhavebeen A Bachelotandothers 26) orincreasedcIMT 28, 29). These 16), ). profile (32). been showntobeassociated withanadversemetabolic receptor genepolymorphisms, which have recently as welltheimpactofnewfindings,such GC respective rolesofandrogenandlifelongGCtreatment, to metabolicandCVabnormalitiesprecisethe tobetterclarifythemechanisms leadingare necessary doses isimportant.Furtherstudiesonlargercohorts disorders andCVriskfactors.ClosemonitoringofGC and obesity, toscreenfordiabetes,other metabolic tolimittheonset ofweightgainlifestyle interventions, more affected.Regularfollow-upisneeded,alongwith morbidity. Somesubgroupsofpatients seem tobe factors andprobablywithexcessCVmetabolic of thrombosisprophylaxisinthispopulation. hypercoagulability that should leadtomorefrequentuse a higherriskofvenousthromboembolismduetostate reported inbothCushing’s syndromeandGCuse,thereis reported. This should be furtherstudied to determine if, as frequency of venous thromboembolic events was also with SV(I172Ngenotype)orNCphenotype.ncreased frequency ofdiabeteswasincreased,especiallyinfemales of obstructivesleepapneainthisCAHcohort.Similarly, the entire CAH cohort. There was also an increased frequency obese patientswithCAHweresimilarlyaffectedasthe consistently increasedinallsubgroups.However, thenon- and atrialfibrillationinCAHpatients(6 showed higherfrequenciesofhypertension,dyslipidemia group). Separateanalysesoftheindividualdiseases specifically I172NandNCmalesinthenullgenotype subgroups beingmoreaffectedthanothers(females, 5.0) andCVdisease(OR:2.7;95%I:1.9–3.9),withsome 3.1– (OR (oddsratio):3.9;95%CI(confidenceinterval): showed anincreaseinbothCVandmetabolicdisorders metabolic morbidityinCAHpatients(6 cancer (16%)andsuicide(10%). were adrenalcrisis(42%),cardiovasculardiseases(32%), in malesand3.5(2.0–6.0)females.Thecausesofdeath (P lower inCAHpatients(41.2 population-based registers.Themeanageofdeathwas and mortalitywasderivedthroughlinkageofnational Information onmortality, causeofdeath,morbidity per patient, matched for sex, year and place of birth (31). females and253males)werecomparedwith100 controls CAH registry. Five hundred eighty-eight patients (335 hyperplasia Update oncongenitaladrenal < 0.001)). Thehazardratioofdeathwas2.3(1.2–4.3) CAH is therefore associated with higher CV risk Interestingly, thesameteamanalyzedCVand Downloaded fromBioscientifica.com at09/24/202105:08:30PM ± 26.9 vs47.7 176:4 www.eje-online.org ). Obesity was ). Obesitywas ). This study ). Thisstudy 77 years ± 27.7 R169 via freeaccess European Journal of Endocrinology www.eje-online.org despite controversyregarding the optimal timing and appearstobeprimarily restrictedtothisagerange procedure performedininfancy andearlychildhood vaginoplasty and clitoroplasty is the most common the procedure (37). the caseitincludesavaginoplastyasportion of to beperformedandthatapproximatelyin90% of feminizing genitoplasty in infants with CAH continues 4-years, a recent American study has shown that the practice,duringa limited periodofof currentsurgery and labiaplasty(36).Thankstoadetailedassessment canincludeclitoroplasty,women. Surgery vaginoplasty factor implicatedinthereducedfertilityofCAH follicular phaseofthemenstrualcycle. responsible forreducedLHpulsatilityduringthe of serumprogesteroneconcentrations,thatareprobably concern in CAHwomen,andparticular, suppression during fertilitymonitoringshouldthusbeanimportant Optimized GCandmineralocorticoid(MC)regimens and secretion and that hormonal control is a key factor. CAH adultwomenmayhaveanormalLHpulsatility of adisruptedgonadotropicaxisandhasshownthat has suggestedtheabsenceofaneonatalprogramming androstenedione levelsandlowerFSHlevels.Thisstudy progesterone (17OHP),testosterone,and with menstrualcycle disturbances, higher17OH amplitude andfrequencypresentedmorefrequently to the controls. The other one hadlower LH pulses group ofpatientshadLHpulsatilitypatternssimilar different profilesofLHpulsatilitywererecorded.One pulse amplitude or LH frequency. patients andcontrolsintermsofmeanLHlevels, between CAH (35).Nodifferenceshavebeenobserved study hasdescribedLHpulsatilityinwomenwithclassic disturb thereproductiveaxisinCAHfemales.Arecent prenatal exposuretosexualsteroid)aresuspected factors (androgenandprogesteroneoverproduction important therapeutictargetinthesepatients.Several form (4 with theSWformand 30–75% ofthosewiththeSV in CAHwomen,affectingfrom30%to68%ofwomen sexual factors(33,34). mechanical (relatedtosurgeries),psychologicaland issues suchasbiological(poorhormonalbalance), for thepatientswithSWform,asaresultofseveral Fertility inwomenwithclassicCAHisreduced,especially Female fertility Review The consequences of the genital surgery are another are another The consequences of the genital surgery Menstrual irregularitiesandanovulationarefrequent ). Menstrualcyclecontrolrepresentsthereforean It was also found that combined A Bachelotandothers In CAH patients, 2

and whenassessingwomen withtheSWandSVforms, have biologicalchildrenthan controls(OR:0.3(0.2–0.3)) compared withcontrols.CAH patientswerelesslikelyto married (OR:0.5(0.2–1.1)) andhadfewerpartnerships population (44).Women withthe SWformwerelessoften including 253womenwerecomparedtothegeneral in Sweden.Fivehundredandeighty-eightCAHpatients psychosocial outcomesinCAHpatientswasconducted a largepopulation-basedepidemiologicalstudyon control withoptimizedGCandMCregimens.Recently, most oftenspontaneous, obtained after a good hormonal the pregnancyestimatewas54%(4).Pregnancieswere 103 CAHwomenamongwhom25% wanted toconceive, toconceive(43). In aUKcohortof patients activelytrying are moreencouragingwhenexaminedonlyinthe population (42).Ontheotherhand,pregnancyestimates lower inCAHwomenthanthegeneralfemale results(36). 59–94% reportedsatisfactory was thepersonwhoassessedcosmeticoutcomes, good or excellent outcomes (36).Whenthephysician majority ofpatients(between60and94%)reported assessments ofcosmeticresultshaveshownthatthe recent reviewincluding151patientswithgenitoplasty, stated beingunhappyabouttheirsexuallife.Inamore during adulthood(4 and23%43% ofwhomhadmorethanonesurgery that 92womenhadundergonegenitalreconstruction, cohort studyof138CAHpatients,Arlt of thecurrenttechniqueswilltaketimetoemerge.Ina intermsofsexualfunction,andtheoutcomessurgery are fewdataintheliteratureaboutoutcomesofthis therefore amatterofdebate(41).Unfortunately, there remains (earlyorlatesurgery) timing ofthesurgery techniques (40).Moreover, todate,thechoiceof to theclitoroplasty(39)andimprovedvaginoplasty erotic sensitivityand orgasmic capacity secondary and clitoral sensation to conserve innervation preserve are nowadaysnewsurgicalproceduresthat,forinstance, CAH patientshaveevolvedsignificantlyovertime.There Surgical techniquesforgenitalfeminizationinfemale mayresultinsexualdissatisfaction.genital surgery between sexualactivityandvaginalfunction;thus, ( have beenreportedandcurrentlyremainrelevantissues poor cosmetics,anorgasmiaandpainfulintercourse incontinence, vaginalstenosisandinadequateintroitus, 2/3 were performed by experimented surgeons. Urinary performed laterinchildhoodoradolescenceandabout of vaginoplasty. Second and third procedures were hyperplasia Update oncongenitaladrenal 36, Fertility rate,i.e.livebirthsperwoman,issignificantly 38). Itiswellestablishedthattherearelationship ). Amongthesepatients,46%have Downloaded fromBioscientifica.com at09/24/202105:08:30PM 176:4 et al. haveshown R170 via freeaccess European Journal of Endocrinology in the SV form(46, higher inpatientswithSWformcomparedthose puberty (47, prevalence ofTARTs increaseswithage,afteronsetof of diagnosis,i.e.palpationorultrasound(10, a prevalenceof30–95%dependingonageandmodality testicular functions(45).TARTs havebeenidentifiedwith stimulation andinfluencebothendocrineexocrine (TARTs) maybecomehypertrophicunderchronicACTH deficiency. Inaddition,testicularadrenalresttumors with FSHandLHproduction,resultingingonadotropic especially androgenandprogesterone,mightinterfere CAH faceadualproblem.Adrenalsteroidoverproduction, function andinfertility. Itappearsthatadultmaleswith Male patientswithCAHmaypresentimpairedgonadic Male fertility sexual well-being. specialist care,procurationofmenstrualcyclecontroland support, organizationoftransitionfrompediatrictoadult compliance totherapy, availabilityofpsychological in genitalreconstruction,earliertreatment,optimized women willbelargelydependentonsurgicaladvances SV OR:0.4(0.2–0.7)).BetterfertilityandfecundityinCAH it wasstillsignificantlydecreased(SWOR:0.05(0.0–0.1); profile ofthe gonadotropic–testicular axis inthese patients also candestroyandreplace healthytesticulartissue.The damage of the surrounding testicular tissue (49). They finally leadtoobstructive azoospermiaandirreversible lead tocompressionoftheseminiferoustubulesthatmay of theircentrallocalizationneartheretetestis,TARTs can found versusonly3.6%whentheywerenot(10).Because had severeoligospermiaorazoospermiawhenTARTs were 71 hadaspermanalysis.Seventypercent ofthepatients testicular assessment with ultrasound, who underwent TARTs (10).Inalarge cohort of164 male CAHpatients total spermcountsandconcentrationinpatientswithout inhibin B levels differ significantly and there are higher spermatogenesis. InpatientswithandwithoutTARTs, markers (53). the expressionofadrenalcortexandtypicalLeydigcell tumors havemultiplesteroidogenicproperties,including molecular characterizationofTARTs hasshownthatthese for theirgrowth(51, suggesting thatundertreatmentisnottheonlycause development ofTARTs despitegoodhormonalcontrol, Review TARTs aremostoftenresponsibleforimpaired 48). TARTs volumeandprevalenceseem 52). Indeed,arecentstudyabout 49, 50). Some studiesreport the A Bachelotandothers 46). The given tothepatients. assess thesepsychosocialoutcomes, toimprovethecare (0.2–0.6)) (44).Furtherstudiesareneeded toproperly they hadlessbiologicalchildren thancontrols(OR0.4 than controls(OR1.6(1.0–2.5))but,astheCAHwomen, the reasonisunknown,menweremoreoftenmarried Swedish follow-upstudydescribedpreviously, although with areducedsexual drive. However, intherecent and ejaculations (59). Poor control disease was associated males hasrevealedimpairmentsinsexualdrive,erections Dudzinska et al. (59).Asexualwell-beingstudyof20CAH these patients(58) as was described in the study from males, erectiledysfunction was foundinabouthalfof lifetime partners(57, controls had an active sexual lifeand that theyhad fewer recent studieshave shown thatfewerCAHpatientsthan been reportedonsexualsatisfactioninCAHmales.Two adaptation andsexualwell-being.V in CAHmales,theremightbeaspectsofpsychosocial enabling thecoupletohaveahealthygirl. low spermconcentrationwithgoodmotility, astable replacement permittedtoobtainafter21 months due tountreatedSVform.Atreatmentwithgonadotropin The patienthadhypogonadotropicazoospermiaandTARTs fertility bygonadotropinreplacementinaCAHman(56). A recentcasereporthasdemonstratedtherestorationof leading to an increase in estrogen levels by aromatization. control withincreasedadrenalandrogensandprogesterone, hypogonadotropic hypogonadismdue to poorhormonal seemsfullyjustified(55). cryopreservation soon aspossible,andthequestionofsystematicsperm early stage. A semenanalysis should also be realized as is recommendedatpubertytodetectlesionsan of maleCAHfertility. Asystematicultrasoundevaluation Prevention has a real importantplaceinthemanagement improved, andontheotherhand,sizeofTARTs hasshrunk. gonadotropins levels,inhibinBandspermcountshave months of treatment, patients with TARTs (54). After 8 have shown that mitotanecouldrestorefertilityinCAH Recently,data onfertilitypreservation. Bry-Gaillard canbeproposedbutthereareno disappointing. Surgery treatment ispoorlytolerated,andthemedicalresponse control with GC (50). However, in some patients, are stilllimitedandmainlybasedonagoodhormonal endocrine andexocrinetesticulardysfunctions(54). will primarilyshowtesticularfailureandeventuallyreveal hyperplasia Update oncongenitaladrenal Besides thesesomaticcausesofimpairedfertility to Reduced fertility in CAHmen can also besecondary Treatment optionsformalepatientswithTARTs 58). InaSwedishcohortof30CAH Downloaded fromBioscientifica.com at09/24/202105:08:30PM 176:4 ery fewdatahave ery www.eje-online.org R171 . et al via freeaccess European Journal of Endocrinology www.eje-online.org lyase; GC,glucocorticoids. side chaincleavageenzyme;CYP17 A1, 17αhydroxylase/17,20 subcutaneous hydrocortisoneinfusion; CYP11A1,cholesterol CRH, corticotropin-releasinghormone; CSHI,continuous ACTH, adrenocorticotropinhormone; AR,androgenreceptor; hyperplasia. 3βHSD2,3-hydroxysteroiddehydrogenasetype2; Potential therapeutictargetsincongenitaladrenal Figure 1 morning. Upuntilnow, whateverregimenwasused,the proposed with at least half or 2/3 of the global dose in the between 06:00and08:00 is secretedmainlyinthemorningand,reachesapeak major driverofadrenalandrogenproduction.Ascortisol to bluntthenocturnalACTHsecretion,whichis only tocompensateforthedeficienthormonebutalso adrenal insufficiency, theaimofGCtreatmentisnot the needsforpatient.Indeed,contrarilytoprimary solution forthelastdecadesandhasfailedtomeetall children withCAH,ithasremainedtheonlymedical this treatment has notablychangedtheprognosis of mortality arereportedinpatientswithCAH. not reacheduptonowasincreasedcomorbiditiesand enable a goodquality of life (60). However, thisgoalis monitored toavoidiatrogenic comorbidities andto androgen excess.Ideally, thetreatmentshouldbe for GCandMCdeficiencies andalsotocorrectadrenal Treatment tocompensate inclassic21OHDisnecessary Treatment ofclassicCAHinadults Review GC substitutionisavailablesincethe50s.Although h, mostoralGCregimensare A Bachelotandothers cortisol concentrationsby dosingatmorningand profile. Chronocortaims atreplacingphysiological profile ratherthananimmediate- andsustained-release Plenadren by having a delayed andsustainedabsorption molecule isamodified-releaseHC,butitdiffersfrom current developmentbyDiurnal(Cardiff,UK)(65).This during thenight. Plenadren wouldexposepatientstohighlevelsofcortisol in cortisolisnotreplicated,andeveningadministration of unlikely tocontrolexcessandrogens as theovernight rise with CAH. However, in the latter case, this molecule is currently availableregardinghormonalcontrolinpatients adrenal insufficiency. Unfortunately, therearenodata based serumcortisolprofileinpatientswithprimary (63, and diastolicbloodpressureglucosemetabolism with HCregimen,improvesbodyweight,systolic CAH havedemonstratedthatthisnewformulacompared adrenalinsufficiencyand studies inpatientswithprimary daily regimenofimmediate-releaseHC.Preliminary of Plenadrengivessimilarcortisolexposuretoathrice- immediate-release HC. In adults, a single morning dose more extendedserumprofileofcortisolcomparedwith of the drug and an extended-release core. an outercoatinglayerthatprovidesimmediaterelease V selective adrenalsteroidogenesisblockade(61)Fig. 1). molecules interferingwithCRHfunctionandnon- are undercurrentdevelopment,suchastheuseof addition, besidestheGCapproach,non-GCapproaches one (Chronocort)iscurrentlyunderinvestigation.In formula (Plenadren)hasbecomeavailableandanother to hypercorticism. Recently, anewslow-releaseHC dose ofGC,thereforeleadingtosideeffectsinrelation androgen secretionisdifficulttoachievewithoutahigh a higherriskofsideeffects.Unfortunately, anadequate prednisone, prednisolone or dexamethasone(DEX),with control ofandrogensecretionorthelong-acting hydrocortisone (HC),welltoleratedbutwithapoor dilemma haspersistedbetweenusingthephysiological Treatment ofclassicCAHadults New glucocorticoidapproaches patients with primary adrenalinsufficiency(Plenadren patients withprimary developed foronce-dailymorningadministrationin The firstmoleculeisadual-releaseHC,whichwas hyperplasia Update oncongenitaladrenal iroPharma-Shire) (62).Itisamodified-releaseHCwith The secondmolecule,Chronocort 64). Thismoleculealso provides amorecircadian- Downloaded fromBioscientifica.com at09/24/202105:08:30PM 176:4 (R) It provides a , isunder R172 (R) via freeaccess ,

European Journal of Endocrinology (10 evaluate theefficiencyofadoubledoseChronocort Another phase 2 study on 16 patients was designedto that anadditional morning dose of GC is needed (66). in the afternoon with once-daily dosing, suggesting the 08:00 label study, Chronocorthasshownitsabilitytodecrease pre-waking riseincortisollevels.InafirstphaseII,open- HC intheearlyhoursofmorningprovidinga night such that the night dose provides release of will requirefurtherstudies. term effect,toleranceandacceptation ofthistreatment may alsobeconsideredas limitingfactors.Thelong- pumps, thepotentialdysfunction andlocalirritation, in managingthepatientsdaily(71).Thecostofthese promising; however, theyalsounderlinethedifficulty studies maybeconsideredasinterestingorevenmore and hadpositiveeffectsonqualityoflife.Allthese treatment resultedinimprovedadrenalsteroidcontrol approximated physiologiccortisolsecretion.Six-month In thisstudy, subcutaneoushydrocortisone pump patients withpoorcontrolhasbeenpublished(72 ). use of subcutaneous hydrocortisone pump in8 CAH circadian rhythmicity. Arecentphase2trialonthe leadingtothereplicationof 10and60 min, every subcutaneously (71).CortisolandACTHweremeasured by DEX,whereasHCwaspermanentlyinfused volunteers, intrinsicadrenalfunctionwasblocked improve thedynamicsofHCinfusions.Inhealthy ( treatment onqualityofliferemainsamatterdebate conventional GC therapy. However, the impact of this underand morephysiologicalthanthoseobserved levels andcortisolprofileswererespectivelylower cortisol.Inthisstudy,depending onsalivary ACTH adrenal insufficiency. DosesofHCwereadjusted in a randomized trial on 33 patients with primary found tobemoreefficientthanconventionalGC recently, acontinuoussubcutaneousHCinfusionwas values comparedtoconventionaltherapies(68).More bring 17OHPandACTHlevelsclosertophysiological reproduction ofcortisolcircadian rhythmpermittedto the useofparenteralGChadbeendiscussed.The parameters andinlargerpopulations. dataneedtobeconfirmedalsoonclinical preliminary underclassicalGCtherapies(67).These those observed and 17OHPlevelswerediminishedcomparedwith oftreatment,the meanandrostenedione after 6 months 69, Review mg at 07:00 Before the development of these new molecules, 70). Anotherapproachhasbeenproposedto h 17OHPlevel;however, androgenlevelsrise h and 20 mg at 23:00 A Bachelotandothers h). It showed that

an investigationaltool.Different experimentalmodels,in could provideausefultherapeutic approachandatleast ligand specificitysuggeststhat antagonismofitsreceptor occurring agonistforitsreceptor. Thehigh degreeof axis hasbeenproposed.ACTHistheonlyknownnaturally function, theopportunityofinterferingwithcorticotroph used inmalepatients,asitblocksallandrogensynthesis. patients, MCtreatment(78).Thiscannotbe therefore, requires the adjunction of a GC, and in some not compensatefortheadrenalinsufficiency, and daysoftreatment.However, thisapproachdoes after 6 day theandrostenedionelevelwascompletelynormalized 100 androstenedione levelwhentheadministereddosewas after6daysoftreatment,adecreaseby2/3the observe, ( proven itsefficiencyindecreasingtestosteronelevels men treatedforprostatecancer, abirateroneacetatehas 1).In forandrogensynthesis(Fig. enzyme necessary blockade. AbirateroneisaninhibitorofCYP17A1, most oftheGCtreatmentsareunabletoinducesuch action ofandrogenssince,aspreviouslymentioned, is basedonthenecessityofdecreasingsecretionand the developmentofACTHandCRHreceptorantagonists. the development of androgen biosynthesis inhibitors and lines throughactivatedapoptosis(75). byreducingtheviabilityofgonadotrophcell the pituitary mitotane mayhaveatoxiceffectonthetestesandalso increase afterthedecrease in free testosterone suggeststhat hormone biosynthesis(76).Inaddition,thelackofLH the expressionofseveralgenesinvolvedinsteroid programmed celldeath(75, and inducingmitochondrialfragmentation,leadingto chaincomplex reducing theactivityofrespiratory focuses onapoptoticeffectsatadrenocortical level of actionremainpoorlyunderstood.Recentevidence mitotane, anadrenolyticagentforwhichthemechanisms (73, frequently retroperitonealadrenalresttumorsinwomen as it can induce the development of TARTs in men and less adrenal glands. This approach must be carefully discussed The mostradicaltreatmentisthesurgical removal ofboth Treatment ofclassicCAHadults Non-glucocorticoid approaches hyperplasia Update oncongenitaladrenal 77). ArecentphaseIstudyinCAHwomenpermittedto mg/day. Whenthedosewasincreasedupto250 As ACTHisakeyfactorincontrollingadrenal The developmentofandrogenbiosynthesisinhibitors Two novelapproachesareundercurrentinvestigation: 74). Chemicaladrenalectomymaybeobtainedusing Downloaded fromBioscientifica.com at09/24/202105:08:30PM 76). Mitotanealsomodulates 176:4 www.eje-online.org R173 mg/ via freeaccess European Journal of Endocrinology www.eje-online.org of genitalsensitivitytoandrogens, atthelatest7th (89, probably bereducedwhenpoorly toleratedinthemother performed, butsomedatashow thattheDEXdosecould the fetus’(87, physiologic GCneedsofthemother(85, day (83, divided in2or3dailydoses,withoutexceeding1.5 is 20 external genitaliainfemalefetuses.ThedoseofDEXused of androgenexcess,whichblocksthevirilization CAH fetus,DEXleadstoACTHsuppressionandreduction the placentaandbecomesbioavailabletofetus.In 11-hydroxysteroid dehydrogenasetype2andthatcrosses with alonghalf-life, not deactivatedbytheplacental early 80s(81, be causedbyanexternalgenitaliaanomalyintheirchild. the emotionaldistressandanxietyofparentsthatmay inthelittlegirlandtorelieve is toavoidtheneedforsurgery a separateurethraandvagina.Theaimofprenataltreatment folds andformationofacommonurogenitalsinusinplace development ofclitoromegaly, fusionofthelabioscrotal their increasedexposuretoandrogens.Thisresultsinthe In CAH,46XXfemalefetusesarevirilizedinuterodueto Prenatal managementofCAH not compensateforcortisolandaldosteronedeficiencies. antagonist, withoutforgettingthatthisapproachdoes for ongoingexperimentalstudiesusingCRHreceptor treatments (80).Thesepromisingdataprovidearationale reduced byameanof0.7%and27%underthesame respectively comparedwithplacebo,whereas17OHPwas ACTH byameanof43%and41%,under300600 after treatmentadministration.Therewasareductionof and 17OHPweremeasuredsequentiallyduringtheday time; treatment was prescribed at 22:00 weekswashout of treatmentbeingseparatedbya3 have receivedafixeddoseof300or600 blind, placebo-controlledstudy, 8patientswithCAH CRH receptortype1antagonistNBI-77860.nasingle- approach hasbeenrecentlyexploredwithaselective receptor couldbeapotentialtherapeuticstrategy. This receptor type1,ACTHsecretion.Anyantagonismtothis the keyfactorinducing,afteraspecificbindingtoCRH approach (79). animals, mayprovidenewinsightsinthispotential Review Prenatal treatment was first introduced in the Besides ACTH,CRHisatthehypothalamiclevel, 90). DEXmustbeinitiatedbefore thepresumeddate µg/kg maternalbodyweight(pre-conception)/day, 84). Thisdosecorrespondstoabout6timesthe 88). Studieswithlowerdoseshave notbeen 82), usingDEX,whichisasyntheticGC A Bachelotandothers 86) and60times mg, eachperiod h, and ACTH mg/ mg (91, continued until birth in CAH females to ensure its efficacy week of gestation (WG) or 9th week of amenorrhea and A long-termfollow-upstudy inScandinaviashowed or length, compared to untreated affected siblings (109). significant difference in head circumference, birth weight infants were treated prenatally with DEX, reported no A largestudyon600CAH-affected pregnancieswhere that canbeclearlyattributedtothistreatment(84, children, butnoharmfuleffectshavebeendocumented debate. Rareadverseeventshavebeenreportedintreated offers thepossibilitytoonlytreataffectedfemalefetus. large-scale prospectivestudiesareneeded,thistechnique WG, hasrecentlybeen published (106, using cell-freefetalDNAinmaternalplasma,asearly 6 demonstration ofnon-invasiveprenataldiagnosisCAH of non-CAHfemales.V response delayhasallowedminimizingDEXexposure (approximately 14WGvs20WG)andwithashorter sampling (CVS)performedearlierthanamniocentesis WG (105).Inaddition,thedevelopmentofchorionicvilli male fetalDNAinfetusesatriskforCAHasearly5 an approachthatnoninvasivelyandcorrectlyidentifies wasrecentlyproventobe and isolationfromthecervix 4 WGin96%cases(90).Moreover, trophoblast retrieval the sensitivityofSRY testwasguaranteed justafter WG infemales(103, CAH malesandtoinitiatethetreatmentatlatest6 in CAHafewyearslatertopreventtheuseofDEX test). Itwasfirstdescribedinthelate90s(102)andused sex determinationbydetectingtheYchromosome(SRY Circulating cell-freeDNA inmaternalserumallowsfetal to postnataltreatment(100,101). ongoing antenataltreatment,butitisgenerallyresponsive tubercle continuestooccur inlatepregnancywithout easier surgicalcorrection(99).Enlargementofthegenital both reducetotalfetalexposuretoDEX,yetstillfacilitate during thetimeofurogenitalcleavage,whichwould be limitedtotheperiodofpartitioningwindow, suggested that prenatal DEX therapy could potentially 95, treatment wasstartedafter8WG(84, when in 80–85%cases,failurebeingusuallyobserved have resultedinnormalfemininegenitaliaCAHgirls at 6WG,anditsmaintenanceduringthewholegestation of CAHgirls(90,97). seems toplayanessentialroleinthegenitalmorphology hyperplasia Update oncongenitaladrenal 98). ArecentsmallstudyfromFrenchsurgeonshas Prenatal DEX,however, continuestobeasubjectof Prenatal DEX exposurehas decreased over the years. Early DEXinitiationbefore7WG,ideallyatthelatest 92, 93, 94, 95, 104). Ithasrecentlybeenshownthat 96). The timingof DEX initiation Downloaded fromBioscientifica.com at09/24/202105:08:30PM ery interestingly,ery thefirst 176:4 107). Eventhough 90, 92, 93, R174 108). 94, via freeaccess European Journal of Endocrinology children asmoresociable thanthecontrols’parents (118). Ontheotherhand,parents describedtheirtreated self-perceived social anxiety and scholastic competence children hadlowerquestionnaire scoresthancontrolsin on atestofverbalworking memory. Inaddition,treated for a short time had significantly poorer performance to controls,CAH-unaffectedchildrentreatedprenatally term memory. However, theyfoundthat,incomparison encoding orlong- intelligence, handedness,memory the authorsfromS.Lajic’s groupfoundnoeffectson with DEXinutero, comparedto35matchedcontrols, a small-sampleSwedishstudyof26childrentreated sexual function in adulthood (117). Conversely, in defects, disordersofgenderidentityandbehavioror no adverseeffectssuchasincreasedriskforcognitive DEX inaffectedandunaffectedCAHpatientsfound large studyevaluatingthelong-termeffectsofprenatal (116). Recently, thesameAmericangrouppublisheda effects ofprenatalDEXonmotorandcognitiveoutcome study fromthesamegroupwasunabletofindanyadverse shy, moreemotionalandlesssociable(115).Anotherlarge increase ininternalizingbehaviors,suchasbeingmore differences incognitiveabilitiesbutdemonstratedan from CAH at-riskpregnancies and showed no significant prenatally exposedtoDEXcompareduntreatedchildren CAH. AsmallstudyM.New’s groupdescribedchildren potentially holdinglittlerelevancetoprenatalDEXin later partofpregnancyortoanimals(111, higher dosesweregiventothehumansubjectsat treatment ofCAH.Theseincludestudieswheremuch other conditionsratherthandirectstudiesonprenatal effects onthefetalbrain,whicharisefromstudiesof the adverseeffectsinmother(110). ofthemedicationtofetuswhileminimizing delivery to thefetalcompartmentmorethan10-fold,allowing enhances thepermeabilityofdrugfrommaternal recently beenshownthatnanoencapsulationofDEX stillbirth orspontaneousabortions(98, complications suchashypertension,gestationaldiabetes, been aconfirmedassociationwithmajorpregnancy acne andstriae(84, weight gain,edema,moodchange, sleep disturbance, birth (90).MaternalsideeffectsofprenatalDEXinclude the absenceofmalformationsandgrowthrestrictionat (95). ArecentlargeFrenchretrospectivestudyconfirmed increaseinfetalabnormalitiesordeath no observed compared tomatchedcontrols.Furthermore,therewas demonstrated normal prenatal and postnatal growth that 44childrenwhowerevariablytreatedprenatally Review Concerns havebeenraisedinregardtotheGC 98, 109). However, therehasnot A Bachelotandothers 112, 109). Ithas 113, 114), Monitoring oftheefficacy ofglucocorticoidreplacement Table 1 Psychological support assessed bytheirparents,and evenscoredlowerthanthe without majorbehavioral or emotionalproblems,as DEX duringearlyfetallife seemedtobewelladjusted concluded thatnon-CAHchildren whoweretreatedwith quality (98).Moreover, recent Scandinavianstudy avery identified, whichinadditionhadlowmethodological studieswere although only4eligibleobservational outcomes ofchildrentreatedprenatallywithDEX, found nosignificantdifferenceinneuropsychological processing (117). girls treatedwithDEXinthelong-termhadslowermental performance; however,mental processingandmemory actually performedbetterthancontrolsinmostareas of found thatsubjectstreatedwithshort-termprenatalDEX (120). AlargeneuropsychologicalAmericanstudyalso behavior inboysexposedtoshort-termprenatalDEX same patients, the authors suggest effects on gender role adaptive functioning or behavioral fields (119).In the difference inpsychopathology, schoolperformance, did, andtreatedchildrendidnotdisplayanysignificant hyperplasia Update oncongenitaladrenal closemonitoragebyagynecologistandanendocrinologist Pregnancy management Genetic counseling clinicalandbiologicalhyperandrogenism Sexuality gynecological,obstetricalandendocrinologicalcare Assessment offemalegonadicfunctionandfertility fertilitypreservation spermanalysis t Assessment ofmalegonadicfunctionandfertility Glycemia Weight Periodic measurementsand/ormonitoringofthefollowing: Monitoring oftheefficacy ofmineralocorticoidreplacement excess therapy Hormonal measurements:progesterone,estradiol,FSH Menstrual cycle Hormonal measurements:totaltestosterone,LH,FSH Bone mineraldensity Blood pressure Lipid profile Early-morning plasmareninactivityconcentration Plasma electrolytes Blood pressure Weight gain andclinicalsignsofcortisolandrogen Diurnal 17OHPcurvewithdriedbloodspotsifavailable Early-morning serumconcentrationsof17-OHP, esticular adrenalrestbyultrasonography Despite theseinconsistencies,ameta-analysishas approximately everysixto12 months Δ4-androstenedione, totaltestosterone,SHBG Management ofadultpatientswithclassicCAH. Downloaded fromBioscientifica.com at09/24/202105:08:30PM 176:4 www.eje-online.org R175 via freeaccess European Journal of Endocrinology www.eje-online.org References such moleculesonbrainfunctionormetabolism. discussed takingaccountthepotentiallong-termuse of diminish theriskofvirilizationyounggirlhastobe remains anothermatterofdebate.Itsusetopreventor well asinchildren.TheuseofDEXduringpregnancy outcomes andsafetyprofilesareneeded,inadults as pros andcons.Inallcases,largertrialstodeterminethe receptor antagonists.Alltheseapproaches may have as inhibitorsofandrogenbiosyntheticenzymesorCRH new GCapproachesareundercurrentelevationsuch systems,oralorparenteral, Besides improvedGCdelivery of relatively stagnant progress, advances are now noted. the needfornewtherapeuticapproaches.Afterdecades 1). areas (Table of CAHcomorbiditiesespeciallyintheCVandfertility Recent yearshave brought newinsightsinthedescription Conclusion 123, is inappropriate for use in community practice (122, with writteninformedconsent,andthatthistreatment Review Board-approvedprospectiveresearch protocols, experimental andshouldonlybedoneinInstitutional based ondatapresentedpreviouslyandagreedthatitis issued opinionsconcerningprenataltreatmentofCAH situations (121). control subjects on items assessing anxiety in new, social follow-up oftheprenatallytreatedpatients. with informedconsentoftheparentsandlong-term referencecenters, only beproposedinmultidisciplinary at-risk pregnancies.Itisobviousthattreatmentshould routine yet,isamajorimprovementinthecareofthese devices,eventhoughthetechniquesarenot delivery of onlytreatingaffectedgirlswithspecifictransplacental overall efficacyofprenatalDEX.Theactualperspective assessed. However, thereviewofliteratureshowsan in uteroremainscontroversialandneedstobebetter Stockholm (128). DEX andnotifiedtheRegionalEthicsCommitteein behavioral developmentinchildrenexposedtoprenatal recruiting patientsduetoconcernsregardingabnormal 1 Review EP14474) hyperplasias. EndocrinePractice2015 21 383–389.(doi:10.4158/ Auchus RJ. Theclassicandnonclassic concenitaladrenal Since theearly2000,severalmedicalsocietieshave It iscertainthatDEXsafetyinchildrentreated 124, 125, 126, In both cases, this description suggests 127). TheSwedishgrouphasstopped A Bachelotandothers

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