ACTH(Adrenocorticotropichormone)orcorticotropinisa39-aminoacidpeptidehormone(MW=4500)secretedbythepituitarytoregulatetheproductionofsteroidhormonesbytheadrenalcortex.ACTHsecretionfromtheanteriorpituitaryiscontrolledbybothaclassicalnegativefeedbackcontrolmechanismandCNS-stressmediatedcontrolsystem.1Varioustypesofstressorpainperceivedinhigherlevelsofthebrainmodulatesecretionofthehypothalamicneurosecretoryhormone,corticotropinreleasinghormone(CRH),a41-aminoacidpeptide.CRHstimulatespituitaryACTHsecretion.ThesecondpeptidethatmodulatesACTHsecretionisvasopressin(AVP).AVPsecretionisalsostimulatedbystressandactssynergisticallywithCRHtoincreaseACTHsecretioninthepituitaryportalcirculation.ACTHincreasesthesynthesisandreleaseofalladrenalsterioids,aldosterone,cortisolandadrenalandrogens.Itistheprincipalmodulatorofcortisol,themostimportantglucocorticoidinman.Asthecortisollevelinbloodincreases,releaseofACTHisinhibiteddirectlyatthepituitarylevel.Throughthissamemechanism,decreasingcortisollevelsleadtoelevatedACTHlevels.2,3,4,5BIOLOGicallyactiveACTHresultsfromenzymaticcleavageofalargeprecursormolecule,pro-opiomelanocortin(POMC).ThismoleculecontainswithinitsstructuretheaminoacidsequencesofACTH,Pro-ACTH,ß-melanocytestimulatinghormone,lipotropin,aswellasendorphinandtheenkephalins.Becausethereactioninimmuno-assaysisdeterminedbyantigenicstructure,notbiologicalfunction,theusualACTHRIAreactswithPOMC,Pro-ACTH,ACTHandsomefragmentsoftheACTH.5Likeotherpituitaryhormones,ACTHissecretedinapulsatilemanner.Thesesmallpulsesaresuperimposedonacharacteristicdiurnalfluctuationofgreateramplitude.Inhealthyindividuals,ACTHreachesapeakintheearlymorning(6:00-8:00hour)andlevelsbecomelowestlateinthedayandnearthebeginningofthesleepperiod.BecauseofthisdiurnalrhythmitiscustomarytodrawplasmaACTHsamplesbetween8:00and10:00hour.However,differentiationofpatientswithCushing’sdiseasefromnormalindividualsmaybebestachievedonsamplesobtainedintheevening(16:00-18:00hour).InCushing’sdiseaseandinectopicACTHsyndromes,thediurnalpatternofACTHsecretionisgenerallyabsent.Stressmayalsooverridethediurnalvariation.PlasmaACTHassaysareusefulinthedifferentialdiagnosisofpituitaryCushing’sdisease,Addison’sdisease,autonomousACTHproducingpituitarytumors(e.g.Nelson’ssyndrome),hypopituitarismwithACTHdeficiencyandectopicACTHsyndrome.5,6,7,8,9,10Cushing’ssyndromeiscausedbytheeffectsofexcessglucocorticoidactions.AllcausesofCushing’ssyndrome,withtheexceptionofglucocorticoidmedication,areassociatedwithincreased24-hoururinarycortisol.ThemostcommoncauseofCushing’ssyndromeisbilateraladrenalhyperplasia,duetopituitaryACTHhypersecretion(Cushing’sdisease)fromapituitaryadenomaorcorticotrophhyperplasia.5,6,7,8,9,10LaboratorydiagnosisofCushing’sdiseaseissupportedbythefollowing:(1)suppressionofplasmaACTHandcortisolconcentrations,byhigh-dose(2.0mgq6hx8)dexamethasoneadmiNISTration,(2)absenceofACTHandcortisolsuppressionwithlow-dose(0.5mgq6hx8or1mggivenat23:30hour)dexamethasone,(3)largerthannormalresponsetometyrapone(Metopirone)stimulationandnormalorelevatedplasmaACTHlevels.4WhenCushing’ssyndromeiscausedbyprimaryadrenalabnormality(adenomaorcarcinoma),theadrenalglandactsindependentlyofACTHandpituitaryACTHsecretionissuppressed.5,6,7,8,9,10Hence,thereisnoresponsetodexamethasonesuppressionormetyraponestimulation.ThistypeofCushing’ssyndromeischaracterizedbyveryloworundetectablelevelsofACTH.Therefore,measurementofplasmaACTHishelpfulindifferentialdiagnosisofpituitaryCushing’ssyndrome.Inpatientswithadrenaltumors,ACTHlevelsarelow.HighlevelsofACTHareseeninpatientswithectopicACTHsyndrome.PatientswithbilateraladrenalhyperplasiawillhaveACTHlevelsinappropriatelyelevatedfortheirdegreeofhypercortisolism,whichshouldsuppressACTH.However,inmostcasestheACTHconcentrationwillbewithinthenormalrange.Adrenocorticalinsufficiencyorinadequatecortisolproductioncanbeduetodestructionoftheadrenalcortexortoabnormalitiesofthepituitaryorhypothalamus,whichresultininadequateACTHproductionofrelease.5,6,7,8,9,10Primaryadrenocorticalinsufficiency,Addison’sdisease,ischaracterizedbymarkedlyelevatedplasmaACTHlevelsandadrenalunresponsivenesstostimulationwithexogenousACTH.HypopituitarismwithACTHdeficiency,whichissecondaryadrenocorticalinsufficiency,ischaracterizedbylowplasmaACTHandcortisolconcentrations,andasubnormal,butusuallydistinctadrenalresponsetostimulationwithsyntheticACTH(Cortrosyn®).Ifhypoglycemicstressormetyraponestimulationisrequiredfordiagnosis,ACTHandcortisolresponsesarelessthannormal.AggressiveandinvasiveACTHproducingpituitarytumorsoccurringbeforeorfollowingbilateraladrenalectomyforCushing’sdisease(Nelson’ssyndrome)arecharacterizedbythedevelopmentofAddisonianpigmentation,ofteninanadrenalectomizedpatientwhoistakingadequateglucocorticoidreplacementtherapy.Inthesepatients,plasmaACTHlevelsaremarkedlyelevatedanddonotrespondwelltodexamethasonesuppression.