dr. gabler tamás se Áok iii. belgy ógy ászati klinika 2011 ... · acromegaly gh hypersecretion...

DisordersDisorders ofof thethe anterioranterior

pituitarypituitary andand

hypothalamushypothalamusDr. Dr. GablerGabler TamTamááss

SE SE ÁÁOK III. BelgyOK III. Belgyóógygyáászati Klinikaszati Klinika2011.02.15.2011.02.15.

LectureLectureLectureLectureLectureLectureLectureLecture sketchsketchsketchsketchsketchsketchsketchsketch

1.1. IntroductionIntroduction

2.2. PituitaryPituitary anatomy/developementanatomy/developement

3.3. PhysiologyPhysiology ofof adenohypophysealadenohypophyseal hormonshormons

4.4. HypopituitarismHypopituitarism ((inherited/aquiredinherited/aquired))

5.5. PituitaryPituitary tumorstumors, , otherother sellarsellar massesmasses

6.6. SpecificSpecific hormon hormon producingproducing tumorstumors::

�� ProlactinomaProlactinoma

�� AcromegalyAcromegaly

�� CushingCushing diseasedisease

IntroductionIntroductionIntroductionIntroductionIntroductionIntroductionIntroductionIntroduction

�� The The pituitarypituitary oftenoften referredreferred toto asas „„mastermaster

glandgland”” becausebecause togethertogether withwith thethe

hypothalamushypothalamus, , itit orchestratesorchestrates thethe

complexcomplex regulatoryregulatory functionsfunctions ofof multiplemultiple

endocrineendocrine glandsglands..

�� ~~ consistsconsists ofof anterioranterior andand posteriorposterior lobelobe..

�� AnteriorAnterior ~~ producesproduces sixsix major major hormonshormons::

PRL, GH, ACTH, LH, FSH, TSHPRL, GH, ACTH, LH, FSH, TSH

�� PituitaryPituitary hormonshormons areare producedproduced inin

pulsatilepulsatile mannermanner..

IntroductionIntroductionIntroductionIntroductionIntroductionIntroductionIntroductionIntroduction�� EachEach pituitarypituitary

hormonshormons elicitselicits

spesificspesific responsesresponses

inin periferialperiferial targettarget

tissuestissues..

�� The The periferialperiferial

glandsglands hormonshormons, , inin

turnturn, , exertexert feedbackfeedback

controlcontrol atat thethe levellevel

ofof thethe hypothalamushypothalamus

andand pituitarypituitary toto

modulatemodulate pituitarypituitary

functionfunction..

IntroductionIntroductionIntroductionIntroductionIntroductionIntroductionIntroductionIntroduction

�� PituitaryPituitary tumorstumors causecause characteristiccharacteristichormonehormone excessexcess syndromessyndromes..

�� HormoneHormone deficiencydeficiency maymay be be inheritedinheritedoror aquiredaquired..

�� EfficaciousEfficacious treatmentstreatments existexist forfor thethevariousvarious pituitarypituitary hormonehormone excessexcess andanddeficiencydeficiency syndromessyndromes..

�� NonethelessNonetheless, , thesethese diagnosesdiagnoses areareoftenoften elusiveelusive..

AnatomyAnatomyAnatomyAnatomyAnatomyAnatomyAnatomyAnatomy

�� The The pituitarypituitary glandgland

locatedlocated withinwithin thethe sellasella

turcicaturcica ventralventral toto thethe

diaphragmadiaphragma sellaesellae..

�� The The sellasella is is contigouscontigous toto

vascularvascular andand neurologicneurologic

structuresstructures::

�� CavernousCavernous sinussinus

�� CranialCranial nervesnerves

�� OpticOptic chiasmchiasm

AnatomyAnatomyAnatomyAnatomyAnatomyAnatomyAnatomyAnatomy

�� ExpandingExpanding intrasellarintrasellar pathologicpathologic processesprocesses

maymay havehave significantsignificant centralcentral massmass effectseffects inin

additionaddition toto theirtheir endocrinologicendocrinologic impactimpact..

AnatomyAnatomyAnatomyAnatomyAnatomyAnatomyAnatomyAnatomy�� HypothalamicHypothalamic neuralneural cellscells synthesizesynthesize specificspecific releasingreleasing

andand inhibitinginhibiting hormoneshormones thatthat areare secretedsecreted direrctlydirerctly intointo

thethe portalportal vesselsvessels ofof thethe pituitarypituitary stalkstalk..

�� ThisThis portalportal plexusplexus allowsallows reliablereliable transmissiontransmission ofof

hypothalamichypothalamic peptidepeptide pulsespulses, , withoutwithout systemicsystemic dilutiondilution..

PituitaryPituitaryPituitaryPituitaryPituitaryPituitaryPituitaryPituitary developmentdevelopmentdevelopmentdevelopmentdevelopmentdevelopmentdevelopmentdevelopment

�� AdenohypophysisAdenohypophysis is is formedformed

fromfrom anan evaginationevagination ofof thethe

primitiveprimitive roofroof ofof foregutforegut

((RathkeRathke’’ss pouchpouch))

�� NeurohypophysisNeurohypophysis anan

evaginationevagination fromfrom thethe floorfloor

ofof thethe diencephalondiencephalon

�� AdenohypophysisAdenohypophysis ––

endocrinendocrin glandgland

�� NeurohypophysisNeurohypophysis is part is part ofof

thethe brainbrain

HypothalamicHypothalamicHypothalamicHypothalamicHypothalamicHypothalamicHypothalamicHypothalamic –––––––– pituitarypituitarypituitarypituitarypituitarypituitarypituitarypituitary

functionfunctionfunctionfunctionfunctionfunctionfunctionfunction

�� HypothalamicHypothalamic peptidespeptides areare producedproduced ininpulsatilepulsatile mannermanner →→ consequentlyconsequently pituitarypituitarycellscells areare exposedexposed toto sharpsharp spikesspikes ofofreleasingreleasing factorsfactors andand inin turnturn releaserelease theirtheirhormoneshormones asas discreteddiscreted pulsespulses..

AnteriorAnterior pituitarypituitary hormonshormons

�� ProlactinProlactin (PRL)(PRL)

�� GrowthGrowth hormon (GH)hormon (GH)

�� AdrenocorticotropinAdrenocorticotropin (ACTH)(ACTH)

�� GonadotropinsGonadotropins (FSH,LH)(FSH,LH)

�� ThyreotropThyreotrop hormon (TSH)hormon (TSH)

ProlactinProlactinProlactinProlactinProlactinProlactinProlactinProlactin

�� ConsistConsist ofof 198 198 aminoacidaminoacid

�� WeeklyWeekly homologoushomologous toto GH GH andand hPLhPL

�� ProlactinProlactin is is synthetisedsynthetised inin lactotropeslactotropes (20% (20% ofofanterioranterior pituitarypituitary cellscells))

�� LactotropesLactotropes andand somatotropessomatotropes areare derivedderived fromfrom a a commoncommon precursorprecursor cellcell..

�� MarkedMarked lactotropelactotrope cellcell hyperplasiahyperplasia developsdevelopsduringduring thethe lastlast twotwo trimestertrimester ofof pregnancypregnancy andand thethefirstfirst fewfew monthsmonths ofof lactationlactation..

�� NormalNormal serumserum levellevel 1010--20 20 µµg/l, g/l, pulsatilepulsatile →→ peakpeakserumserum levellevel :: 4 4 –– 6 6 a.m.a.m.

ProlactinProlactinProlactinProlactinProlactinProlactinProlactinProlactin�� UniqueUnique→→ centralcentral controlcontrol mechanismmechanism is is inhibitoryinhibitory!!

�� DopamineDopamine supresssupress PRL PRL releaserelease

�� PRL PRL hypersecretionhypersecretion occursoccurs afterafter pituitarypituitary stalkstalk

sectionsection

�� DD22 receptor receptor mediatemediate PRL PRL inhibitioninhibition

�� TRH TRH →→ PRL PRL ↑↑ withinwithin 1515--30 min 30 min ofof iviv. . injinj..

�� VIP VIP →→ PRL PRL ↑↑

�� TSH, TSH, glucocorticoidsglucocorticoids →→ PRL PRL ↓↓

�� PRL PRL ↑↑: : exerciseexercise, , mealsmeals, , sexualsexual icic, , acuteacute stressstress, ,

minorminor surgicalsurgical proceduresprocedures, AMI, AMI……

ProlactinProlactinProlactinProlactinProlactinProlactinProlactinProlactin

�� DuringDuring pregnancypregnancy ~~ 1100x x ↑↑�� InIn breastbreast, , lobuloalveolarlobuloalveolar epitheliumepithelium↑↑

�� InduceInduce andand maintainmaintain lactationlactation

�� DecreaseDecrease reproductivereproductive functionfunction→→hypothalamichypothalamic GnRHGnRH ↓↓

�� SupressSupress sexualsexual drivedrive

GrowthGrowthGrowthGrowthGrowthGrowthGrowthGrowth hormonehormonehormonehormonehormonehormonehormonehormone

�� The most The most abundantabundant pituitarypituitary hormonhormon

�� SomatotropeSomatotrope cellscells constituteconstitute 50% 50% ofofant.pituitaryant.pituitary cellcell populationpopulation

�� ControlledControlled byby complexcomplex hypothalamichypothalamic andandperiferialperiferial factorsfactors::�� GHRH GHRH →→ GH GH ↑↑�� GhrelinGhrelin →→ GH GH ↑↑�� SomatostatinSomatostatin →→ GH GH ↓↓

�� IGFIGF--1 1 →→ GH GH ↓↓

�� GlucocorticoidsGlucocorticoids →→ GH GH ↓↓

GrowthGrowthGrowthGrowthGrowthGrowthGrowthGrowth hormonehormonehormonehormonehormonehormonehormonehormone

�� SecretionSecretion is is pulsatilepulsatile, , greatestgreatest levellevel atat nightnight

�� GH GH ↑↑: : deepdeep sleepsleep onsetonset, , afterafter exerciseexercise, , physicalphysical

stressstress, trauma, , trauma, sepsissepsis

�� GH GH ↑↑: : chronicchronic malnutritionmalnutrition, , prolongedprolonged fastingfasting, ,

highhigh protein protein mealsmeals ((LL--argininearginine))

�� Protein Protein synthesissynthesis ↑↑ ((musclemuscle massmass ↑↑))

�� ImpairesImpaires glucoseglucose tolerancetolerance ((gluconeogenesisgluconeogenesis ↑↑))

�� LipolysisLipolysis ↑↑

�� Na, K, Na, K, CaCa, P , P andand waterwater retentionretention

�� LinearLinear bonebone growthgrowth

�� StimulatesStimulates IGFIGF--1 1 secretionsecretion ((growthgrowth int. int. organsorgans ↑↑))

AdrenocorticotropinAdrenocorticotropinAdrenocorticotropinAdrenocorticotropinAdrenocorticotropinAdrenocorticotropinAdrenocorticotropinAdrenocorticotropin hormonehormonehormonehormonehormonehormonehormonehormone

�� CorticotropeCorticotrope cellscells constitueconstitue 20% 20% ofof pituitarypituitary cellscells

�� DerivedDerived fromfrom POMC POMC precursorprecursor proteinprotein

�� ACTHACTH↑↑: : CRH, CRH, argininarginin vasopressinvasopressin, , proinflamatoryproinflamatory

cytokinescytokines (IL(IL--6)6)

�� ACTHACTH↓↓: : glucocorticoidsglucocorticoids

�� ACTH ACTH secretionsecretion is is pulsatilepulsatile→→ circadiancircadian rythmrythm

�� PeakPeak: 6 : 6 amam, , nadirnadir: : midnightmidnight

�� GlucocorticoidsGlucocorticoids followsfollows paralellparalell diurnaldiurnal rythmrythm

GonadotropinGonadotropinGonadotropinGonadotropinGonadotropinGonadotropinGonadotropinGonadotropin hormonshormonshormonshormonshormonshormonshormonshormons

�� GonadotropGonadotrop cellscells

comprisecomprise ofof 10 % 10 % ofof

anterioranterior pituitarypituitary cellscells

�� ProduceProduce: FSH, LH: FSH, LH

�� DynamicallyDynamically regulatedregulated

�� HypothalamicHypothalamic GnRHGnRH

regulatesregulates thethe

synthesissynthesis andand

secretionsecretion

ThyreotropThyreotropThyreotropThyreotropThyreotropThyreotropThyreotropThyreotrop hormonehormonehormonehormonehormonehormonehormonehormone

�� ThyreotropThyreotrop cellscells comprisecomprise ~~ 5 % 5 % ofof AP AP cellcell

populationpopulation

�� StructurallyStructurally relatedrelated toto FSH, LHFSH, LH

�� TRH (TRH (hypothalamichypothalamic tripeptidetripeptide) ) →→ TSH TSH ↑↑

�� ThyreoidThyreoid hormonshormons, , dopaminedopamine, , glucocorticoidsglucocorticoids →→TSH TSH ↓↓

�� LongLong standing standing hypothyreoidismhypothyreoidism →→ TSH TSH ↑↑

�� TSH :TSH :

�� ThyroidThyroid folliculefollicule ↑↑

�� T3, T4 T3, T4 ↑↑

HypothalamicHypothalamicHypothalamicHypothalamicHypothalamicHypothalamicHypothalamicHypothalamic andandandandandandandand anterioranterioranterioranterioranterioranterioranterioranterior

pituitarypituitarypituitarypituitarypituitarypituitarypituitarypituitary insufficiencyinsufficiencyinsufficiencyinsufficiencyinsufficiencyinsufficiencyinsufficiencyinsufficiency

�� HypopituitarismHypopituitarism resultsresults fromfrom impairedimpaired

productionproduction ofof oneone oror more more anterioranterior

pituitarypituitary tropictropic hormon.hormon.

�� InheritedInherited disordersdisorders

�� AquiredAquired

InheritedInheritedInheritedInheritedInheritedInheritedInheritedInherited pituitarypituitarypituitarypituitarypituitarypituitarypituitarypituitary dysfunctiondysfunctiondysfunctiondysfunctiondysfunctiondysfunctiondysfunctiondysfunction

�� KallmannKallmann syndromesyndrome ––GnRHGnRH defectdefect, , anosmiaanosmia ––olfactoryolfactory agenesiaagenesia

�� LaurenceLaurence--MoonMoon--BiedlBiedlobesityobesity, , centralcentral DI DI hexadactily,blindnesshexadactily,blindness

�� FrFröölichlich syndromesyndrome ––hyperphagia,obesityhyperphagia,obesity

�� PraderPrader--WilliWilli syndromesyndrome ––extremextrem obesityobesity + + musclemusclehypotoniahypotonia

AquiredAquiredAquiredAquiredAquiredAquiredAquiredAquired pituitarypituitarypituitarypituitarypituitarypituitarypituitarypituitary dysfunctiondysfunctiondysfunctiondysfunctiondysfunctiondysfunctiondysfunctiondysfunction

1.1. HypothalamicHypothalamic infiltrationinfiltration disordersdisorders

2.2. InflammatoryInflammatory lesionslesions

3.3. CranialCranial irradiationirradiation

4.4. LymphocyticLymphocytic hypophysitishypophysitis

5.5. PituitaryPituitary apoplexyapoplexy

6.6. EmptyEmpty sellasella

7.7. PituitaryPituitary tumorstumors

HypothalamicHypothalamicHypothalamicHypothalamicHypothalamicHypothalamicHypothalamicHypothalamic infiltrationinfiltrationinfiltrationinfiltrationinfiltrationinfiltrationinfiltrationinfiltration

disordersdisordersdisordersdisordersdisordersdisordersdisordersdisorders

�� SarcoidosisSarcoidosis

�� HistiocytosisHistiocytosis XX

�� AmyloidosisAmyloidosis

�� HaemochromatosisHaemochromatosis

InflammatoryInflammatoryInflammatoryInflammatoryInflammatoryInflammatoryInflammatoryInflammatory lesionslesionslesionslesionslesionslesionslesionslesions

�� TBCTBC

�� OpportunisticOpportunistic fungalfungal ((HistoplasmosisHistoplasmosis, ,

PneumocystisPneumocystis jirovecijiroveci) ) oror parasiticparasitic

((ToxoplasmosisToxoplasmosis) ) infectionsinfections associatedassociated

withwith AIDS AIDS

�� TertiaryTertiary syphilissyphilis

�� BacterialBacterial meningitismeningitis

�� AbscessAbscess

CranialCranialCranialCranialCranialCranialCranialCranial irradiationirradiationirradiationirradiationirradiationirradiationirradiationirradiation

�� HeadHead andand neckneck tumorstumors

�� PituitaryPituitary oror sellasella massesmasses treatmenttreatment

LymphocyticLymphocyticLymphocyticLymphocyticLymphocyticLymphocyticLymphocyticLymphocytic hypophysitishypophysitishypophysitishypophysitishypophysitishypophysitishypophysitishypophysitis

�� PregnantPregnant oror postpost--partumpartum womenwomen

�� MRI MRI showsshows prominentprominent pituitarypituitary massmass

resemblingresembling anan adenomaadenoma

�� PituitaryPituitary failurefailure –– diffusediffuse lymphocytelymphocyte

infiltrationinfiltration

�� AutoimmunAutoimmun? (? (AssociatedAssociated withwith

HashimotoHashimoto--thyreoiditisthyreoiditis, , perniciouspernicious

anaemiaanaemia etcetc.).)

�� RespondRespond toto glucocorticoidglucocorticoid treatmenttreatment

PituitaryPituitaryPituitaryPituitaryPituitaryPituitaryPituitaryPituitary apoplexyapoplexyapoplexyapoplexyapoplexyapoplexyapoplexyapoplexy�� SpontaneouslySpontaneously inin preexistingpreexisting adenomaadenoma

�� PostpartumPostpartum –– SheehanSheehanSheehanSheehanSheehanSheehanSheehanSheehan’’’’’’’’ssssssss sysysysysysysysy........

�� DM, HT, DM, HT, sicklesickle cellcell anaemiaanaemia, , acuteacute shockshock

�� EndocrineEndocrine emergencyemergency::�� SevereSevere hypoglycemiahypoglycemia

�� HypotensionHypotension

�� CNS CNS hemorrhagehemorrhage

�� DeathDeath

�� PituitaryPituitary CTCT

�� TherapyTherapy: : highhigh--dosedose glucocorticoidglucocorticoid

�� SurgicalSurgical decompressiondecompression

AcuteAcute symptomssymptoms::

•• SevereSevere headacheheadache

•• MeningealMeningeal

irritationirritation

•• BilateralBilateral visualvisual

changeschanges

•• OphathalmoplegiaOphathalmoplegia

•• CardiovascularCardiovascular

collapsecollapse

EmptyEmptyEmptyEmptyEmptyEmptyEmptyEmpty sellasellasellasellasellasellasellasella

�� OftenOften incidentalincidental MRI MRI findingfinding

�� TheseThese patientpatient oftenoften has has normalnormal

pituitarypituitary functionfunction

�� HypopituitarismHypopituitarism cancan developedevelope

incidiouslyincidiously

�� PituitaryPituitary massmass cancan undergoundergo clinicallyclinically

silentsilent infarctioninfarction

ClinicalClinicalClinicalClinicalClinicalClinicalClinicalClinical presentationpresentationpresentationpresentationpresentationpresentationpresentationpresentation ofofofofofofofof

hypopituitarismhypopituitarismhypopituitarismhypopituitarismhypopituitarismhypopituitarismhypopituitarismhypopituitarism

FailureFailure ofof lactationlactationPRLPRL

„„WhiteWhite AddisonAddison diseasedisease””ACTHACTH

HypothyreodismHypothyreodismTSHTSH

MenstrualMenstrual disordersdisorders, ,

infertilityinfertility, , lossloss ofof

secundarysecundary sexualsexual

characteristiccharacteristic

FSH,LHFSH,LH

GrowthGrowth disordersdisorders, ,

abnormalabnormal bodybody

compositioncomposition, , energyenergy ↓↓, , mentalmental functionfunction ↓↓, CVD , CVD ↑↑

GHGH

SignSign andand symptomssymptomsDeficiencyDeficiency

LabLabLabLabLabLabLabLab investigationinvestigationinvestigationinvestigationinvestigationinvestigationinvestigationinvestigation –––––––– stimulationstimulationstimulationstimulationstimulationstimulationstimulationstimulation teststeststeststeststeststeststeststests

��LH,FSH,testosterone,estrogenLH,FSH,testosterone,estrogen

��GnRHGnRH testtestLH, FSHLH, FSH

��TRHTRH

��BasalBasal thyroidthyroid functionfunction testtestTSHTSH

��InsulinInsulin tolerancetolerance testtest

��CRHCRH

��SyntheticSynthetic ACTH (ACTH (CortrosynCortrosyn))

ACTHACTH

��TRHTRHProlactineProlactine

��InsulinInsulin tolerancetolerance testtest

��GHRH testGHRH test

��LL--ArginineArginine testtest

��LL--dopadopa testtest

GHGH

TestTestHormoneHormone

TreatmentTreatmentTreatmentTreatmentTreatmentTreatmentTreatmentTreatment ofofofofofofofof hypopituitarismhypopituitarismhypopituitarismhypopituitarismhypopituitarismhypopituitarismhypopituitarismhypopituitarism

�� HormoneHormone replacementreplacement therapytherapy

�� GlucocorticoidsGlucocorticoids

�� ThyroidThyroid hormonehormone

�� Sex Sex steroidssteroids

�� GHGH

�� vasopressinvasopressin

PituitaryPituitaryPituitaryPituitaryPituitaryPituitaryPituitaryPituitary tumorstumorstumorstumorstumorstumorstumorstumors andandandandandandandand otherotherotherotherotherotherotherother

sellularsellularsellularsellularsellularsellularsellularsellular massesmassesmassesmassesmassesmassesmassesmasses

�� PituitaryPituitary tumorstumors

�� ClassificationClassification ofof pituitarypituitary tumorstumors

�� OtherOther sellarsellar massesmasses

�� ClinicalClinical presentationpresentation

�� LocalLocal compressioncompression symptomssymptoms

�� Hormon Hormon overproductionoverproduction

PituitaryPituitaryPituitaryPituitaryPituitaryPituitaryPituitaryPituitary tumorstumorstumorstumorstumorstumorstumorstumors

�� PituitaryPituitary adenomasadenomas areare thethe most most commoncommon causecause

ofof pituitarypituitary hormonehormone hypersecretionhypersecretion andand

hyposecretionhyposecretion..

�� ~~ 15% 15% ofof allall intracranialintracranial neoplasmsneoplasms

�� ~~ 25% 25% ofof normalnormal individualsindividuals has has smallsmall pituitarypituitary

leasionsleasions

�� BenignBenign adenomasadenomas –– monoclonalmonoclonal originorigin

�� HormonallyHormonally activeactive tumorstumors →→ autonomousautonomous hormon hormon

secretionsecretion ((diminisheddiminished responsivenessresponsiveness toto

inhibitioninhibition))

�� HormoneHormone productionproduction maymay notnot correlatecorrelate withwith

tumor tumor sizesize

ClassificationClassificationClassificationClassificationClassificationClassificationClassificationClassification ofofofofofofofof pituitarypituitarypituitarypituitarypituitarypituitarypituitarypituitary tumorstumorstumorstumorstumorstumorstumorstumors

�� SizeSize: : microdenomasmicrodenomas (<1cm), (<1cm),

macroadenomasmacroadenomas (>1 cm)(>1 cm)

�� StainingStaining: : acidophilacidophil, , basophilbasophil, , chromophobechromophobe

�� FunctionalFunctional

�� HormonallyHormonally activeactive

�� HormonallyHormonally inactiveinactive (0 (0 cellscells, , oncocytomasoncocytomas))

OtherOtherOtherOtherOtherOtherOtherOther sellarsellarsellarsellarsellarsellarsellarsellar massesmassesmassesmassesmassesmassesmassesmasses

�� CraniopharingeomaCraniopharingeoma

�� RathkeRathke’’ss cystscysts

�� SellaSella chordomaschordomas

�� MeningeomasMeningeomas

�� PituitaryPituitary metastasesmetastases ~~ 3% 3% cancercancer patientspatients (50% (50%

breastbreast cancercancer) ) →→ DiabetesDiabetes insipidusinsipidus

�� HypothalamicHypothalamic hamartomashamartomas, , gangliocytomasgangliocytomas

�� BrainBrain germgerm--cellcell tumorstumors

LocalLocalLocalLocalLocalLocalLocalLocal compressioncompressioncompressioncompressioncompressioncompressioncompressioncompression symptomssymptomssymptomssymptomssymptomssymptomssymptomssymptoms

�� ClinicalClinical manifestationmanifestation

dependsdepends onon anatomicanatomic

localisationlocalisation ofof thethe massmass andand

directiondirection ofof itsits extensionextension..

�� HeadacheHeadache –– strechstrech thethe duraldural

plateplate

�� VisualVisual lossloss –– bitemporalbitemporal

homonim homonim hemianopiahemianopia

�� DiplopiaDiplopia, , ptosisptosis, ,

ophtalmoplegiaophtalmoplegia, , facialfacial

sensationsensation ↓↓

�� ErosionErosion throughthrough sellarsellar floorfloor

→→ liquororrhoealiquororrhoea

�� TemporalTemporal andand frontalfrontal lobelobe

disordersdisorders

�� HypothalamicHypothalamic syndromessyndromes

TreatmentTreatmentTreatmentTreatmentTreatmentTreatmentTreatmentTreatment

�� TransphenoidalTransphenoidal surgerysurgery�� DI, DI, hypopituitarismhypopituitarism ~~ 20%20%

�� RadiationRadiation

�� MedicalMedical�� PRL PRL –– dopamindopamin agonistsagonists

�� GH,TSH GH,TSH –– somatostatinsomatostatin

�� ACTH, ACTH, nonnon--funtioningfuntioning -- ØØ

HyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemia

�� HyperprolactinamiaHyperprolactinamia is is thethe statestate ofof

increasedincreased serumserum prolactinprolactin..

�� CausedCaused byby::

�� DopaminDopamin secretionsecretion ↓↓ inin hypothalamushypothalamus

�� PituitaryPituitary stalkstalk damagedamage

�� LactotropLactotrop cellcell functionfunction ↑↑

�� „„AutonomicAutonomic”” prolactinprolactin producingproducing

adenomaadenoma

HyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemia –––––––– ClinicalClinicalClinicalClinicalClinicalClinicalClinicalClinical

presentationpresentationpresentationpresentationpresentationpresentationpresentationpresentation

♀♀

�� Oligo/amenorrhoeaOligo/amenorrhoea –– 9090--

95%95%

�� GalactorrhoeaGalactorrhoea –– 80%80%

�� InfertilityInfertility

♂♂

�� ImpotencyImpotency

�� InfertilityInfertility

The clinical symptoms does not correlate with serum

prolactin level!

HyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemia –––––––– ClinicalClinicalClinicalClinicalClinicalClinicalClinicalClinical

presentationpresentationpresentationpresentationpresentationpresentationpresentationpresentation

IfIf thethe disorderdisorder is is longstandinglongstanding

�� OsteoporosisOsteoporosis

�� LossLoss ofof libidolibido

�� weightweight ↑↑�� hirsutismhirsutism

�� GynecomastiaGynecomastia

�� ReducedReduced musclemuscle massmass

�� DecreasedDecreased beardbeard growthgrowth

♀

♂

HyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemia --------

etiologyetiologyetiologyetiologyetiologyetiologyetiologyetiology

1.) 1.) PituitaryPituitary adenomaadenoma



�� CushingCushing diseasedisease, , NelsonNelson--syndromesyndrome


etiologyetiologyetiologyetiologyetiologyetiologyetiologyetiology

2.) 2.) PhysiologicPhysiologic hypersecretionhypersecretion

�� PregnancyPregnancy

�� LactationLactation

�� NippleNipple stimulationstimulation andand sexualsexual orgasmorgasm

�� ChestChest wallwall stimulationstimulation ((surgerysurgery, , herpesherpes

zoosterzooster))

�� SleepSleep

�� StressStress


etiologyetiologyetiologyetiologyetiologyetiologyetiologyetiology3.) 3.) HypothalamicHypothalamic –– pituitarypituitary stalkstalkdamagedamage

�� TumorsTumors

�� EmptyEmpty cellacella

�� LymphocyticLymphocytic hypophysitishypophysitis

�� AdenomaAdenoma withwith stalkstalk compressioncompression

�� GranulomasGranulomas

�� RathkeRathke’’ss cystcyst

�� IrradiationIrradiation

�� TraumaTrauma

HyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemia -------- etiologyetiologyetiologyetiologyetiologyetiologyetiologyetiology

4.) 4.) SystemicSystemic disordersdisorders

�� ChronicChronic renalrenal failurefailure

�� PrimaryPrimary hypothyreodismhypothyreodism

�� PCO PCO syndromesyndrome

�� CirrhosisCirrhosis


etiologyetiologyetiologyetiologyetiologyetiologyetiologyetiology5.) 5.) DrugDrug--inducedinduced hypersecretionhypersecretion

�� DopamineDopamine receptor receptor blockersblockers ((PhenothiazinesPhenothiazines, ,

butyrophenonesbutyrophenones, , metoclopramidemetoclopramide))

�� DopamineDopamine synthesissynthesis inhibitorsinhibitors ((αα--methyldopamethyldopa))

�� CatecholaminCatecholamin depletorsdepletors ((reserpinereserpine))

�� OpiatesOpiates ((cocainecocaine, , morphinemorphine, , methadonemethadone, heroin), heroin)

�� HH22 antagonistsantagonists ((cimetidinecimetidine, , ranitidineranitidine))

�� ImipraminesImipramines ((amitryptilineamitryptiline, , amoxapineamoxapine))

�� SerotoninSerotonin--reuptakereuptake inhibitorsinhibitors ((fluoxetinfluoxetin))

�� CalciumCalcium channelchannel blockersblockers ((verapamilverapamil))

�� HormonesHormones ((EstrogensEstrogens, , AntiandrogensAntiandrogens, TRH), TRH)

DiagnosisDiagnosisDiagnosisDiagnosisDiagnosisDiagnosisDiagnosisDiagnosis –––––––– LaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratory

investigationinvestigationinvestigationinvestigationinvestigationinvestigationinvestigationinvestigation

�� BasalBasal, , fastingfasting morningmorning PRL PRL levelslevels ((normallynormally

< 20< 20µµg/L)g/L)

�� PulsatiliePulsatilie –– severalseveral differentdifferent occasionoccasion

<300<300III.dIII.d trimestertrimester

<50<50SleepingSleeping

1010--2020BasalBasal

µµg/lg/lPhysologicPhysologic statesstates


DiagnosisDiagnosisDiagnosisDiagnosisDiagnosisDiagnosisDiagnosisDiagnosis

1.st 1.st stepstep: : exclusionexclusionexclusionexclusionexclusionexclusionexclusionexclusion ofof thethe followingfollowing::

�� PhysiologicPhysiologic hypersecretionhypersecretion

�� DrugDrug--inducedinduced hypersecreionhypersecreion

�� PrimaryPrimary hypothyreodismhypothyreodism –– TSH, T3, T4TSH, T3, T4


DiagnosisDiagnosisDiagnosisDiagnosisDiagnosisDiagnosisDiagnosisDiagnosis

2.nd 2.nd stepstep

�� CT, MRICT, MRI

�� OphtalomolgistOphtalomolgist

�� PituitaryPituitary functionfunction teststests


TreatmentTreatmentTreatmentTreatmentTreatmentTreatmentTreatmentTreatment

�� DrugDrug –– withrawnwithrawn

�� HypothyreosisHypothyreosis –– LL--thyroxinthyroxin

�� Tumor Tumor –– resectionresection ofof hypothalamichypothalamic oror

sellarsellar massmass

�� GranulomatosusGranulomatosus –– glucocorticoidglucocorticoid

treatmenttreatment

�� 30% 30% ofof patientpatient –– withwith oror withoutwithout visiblevisible

pituitarypituitary adenomaadenoma resolvesresolves

spontenouslyspontenously..

ProlactinomaProlactinomaProlactinomaProlactinomaProlactinomaProlactinomaProlactinomaProlactinoma

ProlactinomaProlactinomaProlactinomaProlactinomaProlactinomaProlactinomaProlactinomaProlactinoma

�� 5500% % ofof pituitarypituitary tumorstumors

�� IncidenceIncidence ~~ 3/100.0003/100.000

�� PrevalencePrevalence ~~ 1.5 %1.5 %

�� MixedMixed tumorstumors: PRL/GH, PRL/ACTH, PRL/TSH: PRL/GH, PRL/ACTH, PRL/TSH

�� MicroadenomasMicroadenomas < 1 cm< 1 cm

�� MacroadenomasMacroadenomas > 1 cm> 1 cm –– locallylocally invasiveinvasive

�� MicroadenomasMicroadenomas ♀♀::♂♂ ~~ 20:120:1

�� MacroadenomasMacroadenomas ♀♀::♂♂ ~~ 1:11:1

�� 5% 5% microadenomamicroadenoma→→ macroadenomamacroadenoma

Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor sizesizesizesizesizesizesizesize ~~~~~~~~ PRL PRL PRL PRL PRL PRL PRL PRL

concentrationsconcentrationsconcentrationsconcentrationsconcentrationsconcentrationsconcentrationsconcentrations

<100<100IdiopathicIdiopathic

<100<100DrugsDrugs

<100<100StalkStalk compressioncompression

>100>100MacroprolactinomaMacroprolactinoma

<100<100MicroprolacinomaMicroprolacinoma

µµg/lg/lPathologicPathologicPathologicPathologicPathologicPathologicPathologicPathologic statestatestatestatestatestatestatestate

TreatmentTreatmentTreatmentTreatmentTreatmentTreatmentTreatmentTreatment ofofofofofofofof prolactinomaprolactinomaprolactinomaprolactinomaprolactinomaprolactinomaprolactinomaprolactinoma

�� MedicalMedical –– dopaminedopamine agonistagonist –– supresssupress PRL PRL secretionsecretion, , synthesissynthesis andand lactotropelactotrope cellcellproliferationproliferation

�� ErgotErgot alkaloid alkaloid –– bromocriptinebromocriptine –– shortshort actingacting ~~ 2.5mg 2.5mg tidtid

�� ErgolineErgoline derivatederivate –– carbegolinecarbegoline –– longlong actingacting ~~ 11--2/week2/week

�� SideSide effectseffects: : constipation,nausea,vomiting,insomnia,nightmares,verconstipation,nausea,vomiting,insomnia,nightmares,vertigotigo

�� SurgerySurgery -- indicationsindications: :

�� DopamineDopamine resistanceresistance oror intoleranceintolerance

�� InvasiveInvasive macroadenomamacroadenoma

�� PatientPatient requestrequest

AcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegaly

AcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegaly�� GH GH hypersecretionhypersecretion is is usuallyusually thethe resultresult ofof somatotropesomatotropeadenomaadenoma..

�� OtherOther rarerare reasonsreasons (<1%): GHRH (<1%): GHRH productingproducting tumorstumors((smallsmall cellcell lunglung cancercancer, , medullarymedullary thyroidthyroid carcinomacarcinoma, , pancreaticpancreatic isletislet cellcell tumor tumor etcetc.).)

�� IncidenceIncidence ~~ 33--4/1.000.000/year4/1.000.000/year

�� PrevalencePrevalence 5050--70/1.000.00070/1.000.000/year/year�� FemalesFemales > > MalesMales

�� AnyAny ageage cancan occuroccur, , meanmean ageage: 40: 40--50 50 yearsyears..

�� MacroadenomaMacroadenoma ~~ 7070--75%75%

�� MicoadenomasMicoadenomas ~~ 2525--30%30%

�� IncidiousIncidious onsetonset, 1st , 1st symptomsymptom→→ dg. dg. ~~ 77--12 12 yearsyears

�� ProgressiveProgressive formform –– more more commoncommon amoungamoung youngyoung adultsadults

AcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegaly –––––––– clinicalclinicalclinicalclinicalclinicalclinicalclinicalclinical

presentaionpresentaionpresentaionpresentaionpresentaionpresentaionpresentaionpresentaion�� AcralAcral bonybony overgrowthovergrowth

�� IncreasedIncreased footfoot andand handhand sizesize –– increasedincreased shoe/gloveshoe/glove sizesize, ring , ring tighteningtightening

�� ProximalProximal musclemuscle weeknessweekness

�� CarpalCarpal tuneltunel sysy..

�� FaceFace�� FrontalFrontal bossingbossing

�� LargeLarge fleshyfleshy nosenose

�� ThickerThicker mouthmouth

�� CourseCourse facialfacial featuresfeatures

�� MacroglossiaMacroglossia

�� WidenedWidened spacespace betweenbetween thethe lowerlower incisorincisor teethteeth

�� MandibularMandibular enlargementenlargement –– prognathismprognathism

�� OilyOily skinskin

�� HyperhydrosisHyperhydrosis

�� Deep,hollowDeep,hollow--soundingsounding voicevoice

�� GeneralizatedGeneralizated organomegalyorganomegaly�� CardiomegalyCardiomegaly, , liverliver andand spleen spleen enlargementenlargement..

AcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegaly –––––––– clinicalclinicalclinicalclinicalclinicalclinicalclinicalclinical

presentaionpresentaionpresentaionpresentaionpresentaionpresentaionpresentaionpresentaion

�� Overall Overall mortalitymortality ↑↑ ~~ survivalsurvival is is reducedreduced byby 10 10 yearsyears comparedcompared withwith anan ageage--matchmatch controlcontrolpopulationpopulation

�� CardiovascularCardiovascular systemsystem

�� CoronaryCoronary heartheart diseasedisease

�� CardiomyopathyCardiomyopathy withwith arrythmiasarrythmias

�� LeftLeft ventricularventricular hypertrophyhypertrophy

�� DiastolicDiastolic functionfunction ↓↓

�� HypertensionHypertension

�� GlucoseGlucose--intoleranceintolerance –– DiabetesDiabetes mellitusmellitus

�� IncreasedIncreased riskrisk forfor colon colon polypspolyps→→coloncolon tumorstumors!!!!!!

�� UpperUpper airwayairway obstructionobstruction––thyroidthyroid glandgland↑↑,tongue,tongue ↑↑�� SleepSleep apnoeapnoe

AcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegaly –––––––– LaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratory


�� RandomRandom GH GH levellevel uselessuseless ((pulsatilepulsatile secretionsecretion))

�� AgeAge andand gendergender--matchedmatched IGFIGF--1 1 levelslevels ↑↑

�� OGTT OGTT –– failurefailure ofof GH GH supressionsupression (<1(<1µµg)g)

�� Paradox GH Paradox GH ↑↑ afterafter glucoseglucose oror TRH TRH

administrationadministration

�� PRL PRL levelslevels shoudshoud meme measuredmeasured ((↑↑ inin 25%)25%)

�� PituitaryPituitary hormon hormon teststests

AcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegalyAcromegaly –––––––– treatmenttreatmenttreatmenttreatmenttreatmenttreatmenttreatmenttreatment

�� SurgicalSurgical resectionresection�� InitialInitial treatmenttreatment forfor most most patientspatients

�� TranssphenoidalTranssphenoidal surgicalsurgical resectionresection, , curecure raterate ~~70%70%

�� GH GH levelslevels returnreturn toto normalnormal withinwithin 1 1 hourhour

�� HypopituitarismHypopituitarism developsdevelops 15% 15% ofof patientspatients

�� MedicalMedical treatmenttreatment�� SomatostatinSomatostatin analoguesanalogues –– OctreotideOctreotideOctreotideOctreotideOctreotideOctreotideOctreotideOctreotidesubcutanouslysubcutanously�� LanreotideLanreotideLanreotideLanreotideLanreotideLanreotideLanreotideLanreotide –– depotdepot formulationformulation , 4 , 4 weeksweeks

�� DopamineDopamine agonistsagonists

�� RadiationRadiation therapytherapy�� NotNot respondrespond toto surgicalsurgical oror medicalmedical treatmenttreatment

�� StereotacticStereotactic ablationablation byby gammagamma--knifeknife is is promisingpromising

CushingCushingCushingCushingCushingCushingCushingCushing syndromesyndromesyndromesyndromesyndromesyndromesyndromesyndrome

CushingCushingCushingCushingCushingCushingCushingCushing syndromesyndromesyndromesyndromesyndromesyndromesyndromesyndrome -------- CushingCushingCushingCushingCushingCushingCushingCushing

diseasediseasediseasediseasediseasediseasediseasedisease

�� CushingCushing syndromesyndrome:: combinationcombination ofof

symptomssymptoms andand signssigns whichwhich resultsresults fromfrom

elevationelevation ofof circulatingcirculating glucococorticoidglucococorticoid

levelslevels..

�� CushingCushing diseasedisease:: excessiveexcessive ACTH ACTH

productionproduction byby thethe pituitarypituitary. . →→ Most Most

commoncommon causecause ofof endogenousendogenous CushingCushing’’ss

syndromesyndrome..

CushingCushingCushingCushingCushingCushingCushingCushing syndromesyndromesyndromesyndromesyndromesyndromesyndromesyndrome

�� 70% 70% CushingCushing diseasedisease

�� 30% 30% benignbenign oror malignantmalignant adrenaladrenal

tumortumor

�� EctopicEctopic ACTH ACTH productionproduction ((smallsmall cellcell

lunglung cancercancer))

�� IatrogenicIatrogenic hypercortisolismhypercortisolism is is thethe most most

commoncommon causecause ofof cushingoidcushingoid featuresfeatures!!

CushingCushingCushingCushingCushingCushingCushingCushing diseasediseasediseasediseasediseasediseasediseasedisease

�� ACTH ACTH producingproducing pituitarypituitary tumortumor

�� IncidenceIncidence 2.4/1.000.000/year2.4/1.000.000/year

�� PrevalancePrevalance 39/1.000.000/year39/1.000.000/year

�� ♀♀::♂♂ = 5= 5--10: 110: 1

�� 1010--15 % 15 % ofof allall pituitarypituitary tumorstumors

�� MicroadenomasMicroadenomas

�� TheyThey retainretain partialpartial supressibilitysupressibility inin thethe

presencepresence ofof highhigh dosesdoses glucocorticoidsglucocorticoids

CushingCushingCushingCushingCushingCushingCushingCushing diseasediseasediseasediseasediseasediseasediseasedisease

CushingCushingCushingCushingCushingCushingCushingCushing diseasediseasediseasediseasediseasediseasediseasedisease –––––––– LaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratory


The The diagnosisdiagnosis ofof CushingCushing sysy. is . is basedbased onon

lablab documentationdocumentation ofof endogenousendogenous

hypercortisolismhypercortisolism::

�� MeasurementsMeasurements ofof 24 24 hourshours urineurine freefree

cortisolcortisol

�� SerumSerum cortisolcortisol levelslevels measurementsmeasurements

fewfew timestimes a a dayday ((midnightmidnight!)!)

�� SalivaSaliva cortisolcortisol concentrationconcentration

�� DexamethasoneDexamethasone supressionsupression testtest

CushingCushingCushingCushingCushingCushingCushingCushing diseasediseasediseasediseasediseasediseasediseasedisease –––––––– LaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratoryLaboratory


�� MeanMean basalbasal ACTH ACTH levelslevels

�� CRH testCRH test

�� MetopyronMetopyron testtest

�� Most Most effectiveeffective: : inferiorinferior petrosalpetrosal venousvenous

samplingsampling

�� BeforeBefore andand afterafter CRH CRH administrationadministration

CushingCushingCushingCushingCushingCushingCushingCushing diseasediseasediseasediseasediseasediseasediseasedisease –––––––– imagingimagingimagingimagingimagingimagingimagingimaging

technicstechnicstechnicstechnicstechnicstechnicstechnicstechnics

�� MRI MRI –– sensitivitysensitivity ~~ 5050--60%60%

�� ACTH ACTH secretingsecreting tumorstumors < 5mm< 5mm

CushingCushingCushingCushingCushingCushingCushingCushing diseasediseasediseasediseasediseasediseasediseasedisease –––––––– TreatmentTreatmentTreatmentTreatmentTreatmentTreatmentTreatmentTreatment

�� SurgicalSurgical:: SelectiveSelective transphenoidaltransphenoidal resectionresection is is thethe

treatmenttreatment ofof choicechoice!!

�� RemissionRemission: 80 % : 80 % ofof micromicro--, 50% , 50% ofof macroadenomamacroadenoma..

�� AfterAfter successfulsuccessful surgicalsurgical tumor tumor resectionresection ––

postoperativepostoperative adrenaladrenal insufficiencyinsufficiency willwill developedevelope! ! →→cortisolcortisol replacementreplacement

�� PituitaryPituitary irradiationirradiation

�� MedicalMedical: : SteroidSteroid inhibitorsinhibitors –– ketokonazoleketokonazole –– inhibitsinhibits P450P450

�� MetyraponeMetyrapone –– inhibitsinhibits 1111ββ--hydroxylasehydroxylase –– normalizenormalize plasmaplasma cortisolcortisol

�� BilateralBilateral adrenalectomyadrenalectomy –– predisposespredisposes thethe developmentdevelopment

ofof NelsonNelson’’ss syndromesyndrome = rapid = rapid pituitarypituitary tumor tumor

enlargementenlargement andand ↑↑ pigmentationpigmentation ((highhigh ACTH)ACTH)

TSHTSHTSHTSHTSHTSHTSHTSH--------secretingsecretingsecretingsecretingsecretingsecretingsecretingsecreting adenomasadenomasadenomasadenomasadenomasadenomasadenomasadenomas

�� <1% <1% ofof hypophysisadenomashypophysisadenomas

�� InvasiveInvasive macroadenomamacroadenoma

�� TSH TSH ↑↑ -- T3,T4 T3,T4 →→ GoiterGoiter andand

hyperthyreoidismhyperthyreoidism

�� AfterAfter administrationadministration TRH TRH →→ TSH TSH willwill notnot

elevateelevate

�� Tumor Tumor alsoalso cancan produceproduce GH GH oror prolactinprolactin

�� TreatmentTreatment -- surgicalsurgical

CaseCase historyhistory

A 40A 40--yearyear--old old womanwoman presentspresents toto herher doctordoctor withwith a a 12 12 monthmonth historyhistory ofof progressiveprogressive headachesheadaches, , weightweight lossloss, , poorpoor appetiteappetite, , lethargylethargy, , coldcoldintoleranceintolerance, , andand amenorrhoeaamenorrhoea. . SheShe has has difficultydifficultylookinglooking intointo thethe peripheryperiphery whenwhen sheshe is is drivingdrivingherher carcar. . SheShe has has notednoted a a breastbreast dischargedischarge andandherher lastlast menstrualmenstrual periodperiod waswas 12 12 monthsmonths agoago. . PhysicalPhysical examinationexamination is is remarkableremarkable forforbradycardiabradycardia, , weightweight lossloss, , delayeddelayed relaxationrelaxation ofofherher reflexes, reflexes, galactorrhoeagalactorrhoea, , andand bitemporalbitemporalhaemianopiahaemianopia..

ENDEND

dr. gabler tamás se Áok iii. belgy ógy ászati klinika 2011 ... · acromegaly gh hypersecretion...

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