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Cauze de nanismMalnutriia si deprivarea emoionalStatura mic familialntrzierea constituional a creterii si pubertiiDeficitul de GH (8%)Retardul de cretere intrauterin (7,5%)Displazii scheletice (acondroplazia, hipocondroplazia)Sdr. genetice dismorfice (Turner, Down)Boli cronice:IRC, boala celiac, malformaii cardiace, Boli endocrine: hipotiroidismhipoparatiroidismSdr. CushingRahitismul carenial comun sau vit. D rezistentSdr. de rezisten la GH nanism Laron: GH crescut, IGF-I sczut40%Deficitul de GH al adultului Scderea energiei vitale i a strii de bine

Izolare social Dispozitie depresiv Anxietate crescut

Creterea adipozitaii centrale i scderea masei musculare Scderea sensibilitii la insulin cu alterarea toleranei la glucoz Creterea LDL colesterolului si a apoB; scderea HDL

Scderea densitaii minerale osoase cu risc crescut de fractura patologic

Scderea masei miocadice Creterea fibrinogenului plasmatic i a inhibitorului tisular de plasminogen Ateroscleroza accelerat

ETIOLOGIETumori benigne: adenoame hipofizare craniofaringioame meningioameHiperplazie hipofizara lactotrofe (sarcina) tireotrofe, gonadotrofe somatotrofe (GHRH ectopicH)Tumori maligne primitive germinoame (pineloame ectopice), sarcoame, cordoame, carcinoame hipofizare) -secundare carcinom pulmoar, de sanChisturi: punga lui Rathke, arahnoide, dermoideAbceseHipofizita limfocitaraFistule arteriovenoase ale carotidei

CLASIFICAREmicroadenoame (< 1 cm)macroadenoame (> 1 cm)

Clasificarea Hardy modificata

0 - microadenom; sa turca normala I - microadenom intrahipofizar; invazia focala a peretelui sellar II - macroadenom intrasellar; sa turca difuz largita, fara invazie III - macroadenom; invazie sellara i/sau destructie localizata IV - macroadenom; invazie i/sau destructie sellara difuza

CLASIFICARESecretante GH (15 %)acromegalie / gigantismPRL (30 %)amenoree - galactoreeACTH (10 %)boala CushingTSH (0,9 %)tireotoxicozaClinic nefunctionalebFSH, bLH, a / GH, PRL, TSH (mute clinic)(30%)null cell adenoma

monohormonaleplurihormonale ex.GH-PRL (mammosomatotrofe)GH, PRL, TSH, a

PROPORTIA DIFERITELOR TIPURI SECRETORII

Hipofiza hipopituitarismChiasma optica pierderea perceptiei culorii rosii, hemianopsie bitemporala, cvadranopsie temporosuperioara, scotoame, cecitateHipotalamus - tulb. de termoreglare, de apetit, obezitate, ale setei, diabet insipid, ritm somn-veghe, tulb. de comport. , tulb. vegetativeSinus cavernos diplopie, oftalmoplegie, tulb de sensib. facialaLob frontal - tulb. de personalitate, anosmieCerebral cefalee, hidrocefalee, psihoza, dementa, crize gelasticeCLINICA TUMORILOR HIPOFIZARE EFECTUL DE COMPRESIE

SINDROMUL DE CHIASMA OPTICAPARACLINICHipersecretia tumoralaGH in OGTT PRLCortizol dupa inhibitie cu DXMfT4, TSHestradiol /testosteron, FSH, LH

HipopituitarismTeste bazale: cortizol, fT4, estradiol /testosteron, FSH, LHTeste in dinamica stimulare GH ITT, Arg -cortizol - ITTIMAGISTIC - RMN

IMAGISTIC - CT

CG 24 years

Macro PRMSSEPRL=3,100 ng/ml NFA

Bors Ion, M, 37 ani, SCHO, NFA IV SSE

LH - ICC FSH ICC

ANATOMIE PATOLOGICA - IMUNOHISTOCHIMIEDIAGNOSTIC POZITIVClinicaImagisticHormonii hipofizari nesupresibili (teste de inhibiie)Hormonii hipofizari deficitari (teste de stimulare)Complicaii: (oftalmologice, metabolice)DIAGNOSTIC DIFERENTIALRx- sindromul de sa turca goala-malformatii arteriovenoase (anevrism carotidian), - chisturi arahnoidiene sau dermoide- tumori (craniofaringiom/ meningiom / gliom nerv optic/ germinom / metastaze)- incidentaloame hipofizare- infiltrat hipofizar hipofizite, sarcoidozaAl sindroamelor clinice specifice hipersecreiilor hormonale adenohipofizare (ex: galactoreea, acromegaloidia, melanodermia, hipercortizolismul, tireotoxicoza) Al insuficienei secreiei hipofizare se face cu insuficienele glandulare primareSindromul de sa turceasca gola

ETIOPATOGENIE

Heaney & Melmed, Endocrine related cancer, 7, 2000 ETIOLOGIEtumori monoclonalemutatii genetice -activarea unor oncogene -inactivarea unor supresori tumorali

Sd. MEN1 mutatia meninei

HPTHTumora enteropancreatica - insulinom, gastrinomCarcinoid bronsic, intestinalAngiofibroame cutanate TRATAMENTObiective: distrugerea celulelor tumorale cu blocarea secreiei tumorale si prezervarea hipofizei normale.Metode:chirurgia hipofizeiradioterapiachimioterapiacombinat TRATAMENTUL CHIRURGICAL

Tipuri transfenoidala /transfrontalaIndicatiiContraindicatiiEficientaEfecte adverseTRATAMENTUL CHIRURGICAL

Indicatii:Acuitatii vizualeCresterea tumoriiAdenoame functionale, cu exceptia PRMTranscranial tumori mari, asimetriceTransfenoidal -endoscopic -RMN intraoperator -microchirurgie -neuronavigatieM. Buchfelder, S. Schlaffer / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 677692RADIOTERAPIAnormovoltat (raze X cu energii de keV) convenional supravoltat (accelerator liniar, betatron, cobaltron cu energii de ordinul MeV)radiochirurgia (Gamma Knife) in care 200 surse independente de cobalt incluse intr-o casc sunt focalizate selectiv in funcie de volumul tumorii. interstiial: Au198, Ytriu90 risc de nevrit optic; RADIOTERAPIA HIPOFIZARA

Radioterapia fractionata conventionala 50 GyRadioterapia fractionata stereotactica 20 GyRadiochirurgia Gamma knife 10-15 Gy

ACROMEGALIA -DEFINITIEBoal determinat de hipersecreia de GH, ce duce la creterea accentuat a scheletului i viscerelor. determinata in peste 95% din cazuri de un adenom hipofizar, rareori fiind o secreie paraneoplazica de GHRH (tumori pancreatice). ACROMEGALIA DATE EPIDEMIOLOGICEIncidena: 3-4 cazuri/ 1 000 000 /anPrevalena: 69 / 1 000 000Rata mortalitii: 2-3 X populaia general 1.16Cauza de decesn=56 (66+12 ani)Frecvena % (n) n acromegalieFrecvena % n populaia generalBoala coronariana23.2 (15)25.6Boli cerebrovasculare14.3 (8)10Alte boli cardiovasculare16.1 (9)7.2Neoplasme21.4 (12)21.3Tumori hipofizare5.4 (3)Accidente8.9 (5)8.4Altele10.7 (6)27.5Kauppinen-Makelin et al. J Clin Endocrinol Metab, July 2005, 90(7):4081408629Acromegalia netratat a fost asociat cu o cretere a mortalitii de 2-3 ori comparativ cu populaia generala, doar 20% din pacienii netratai supravieuind peste vrsta de 60 ani. Analiznd difereniat cauzele de mortalitate, se cunoate c 60% din pacieni mor de cauze cardiovasculare, 20% de complicaii respiratorii si 15% de neoplazii (7). Criteriile de vindecare a acromegaliei s-au modificat de-a lungul timpului, tocmai pentru c mortalitatea (n principal de cauze cardiovasculare) a rmas crescut i dup ce pacienii erau declarai vindecai.Intr-o populaie de 334 pacieni diagnosticai cu acromegalie ntre 1980-1999 si urmrii pn la sfritul anului 2002 (in medie 12 ani), 16,8% (56 pacieni) au decedat in intervalul de urmrire, avnd o vrsta medie la deces de 66,6 + 12,9 ani (8). 55,4 % au avut in final GH bazal 1 ng/ml media GH bazale 500 ng/mlmacroprolactinomPRL > 250ng/mlPRMPRL > 200 ng/mlPRM / medicamente / sarcina PRM < 200 ng/ml PRM/alte cauzeETIOLOGIA HIPERPROLACTINEMIEI

Macroprolactinemia: Big-big + big > 50% Frequency: 19% (16/84)

1628178638

FIZIOPATOLOGIETRATAMENTMedicamentos!Agonisti dopaminergici bromocriptina 5-30 mg/zi - cabergolina 0,5-2 mg/saptEfect antisecretor si citonecroticChirurgicalRadioterapia

SarcinaPRLDiam. tumoral 1 cm, cu SCHO> 1 cm, fara SCHO2 anitemozolomidTRATAMENTUL HIPERPROLACTINEMIEIGhidul Endocrine Society, 2011COCPRM maligneBOALA CUSHINGDefiniie: hipersecreie relativ autonoma de ACTH de ctre un adenom hipofizar. De regul un microadenom, care secret ACTH i uneori peptide derivate din POMC, determinnd hiperplazie corticosuprarenal bilateral cu hipersecreie de cortizol.CLINIC

Vergeturi rosii-violaceePiele subtire, fragilitate capilaraScaderea fortei musculaturii proximale

Obezitate centralaHipertensiune arteriala secundaraIntoleranta la glucoza/diabet zaharat sceundarOsteoporozaAlterare afect (depresie), cognitie, somnPARACLINIC Cortizol pl. ora 8, ora 24, CLU, 17 OHCS crescutiDXM 1mg overnightDXM 2mg x 2DXM 8 mg x 2ACTH crescutTeste uzualeTest la CRHCateterizare sinus pietros inferior

Suspiciune clinic (3-5 semne clinice) Cortizol liber urinar DXM 1 mg p.o. overnight (ora 23)Hipercortizolism reactiv Sindrom pseudo-Cushing* Sindrom Cushing DXM 2 x 2 mg p.o.cortizol pl. ora 24,00 n somn Sindrom Cushing confirmat DXM 2 x 8 mg p.o.ACTH plasmatic DXM 2 x 8 (-)ACTH < 5 pg/ml DXM 8 x 2 (-) ACTH > 10 pg/ml DXM 8 x 2 (+) ACTH > 10 pg/ml Forme ACTH independenteTumora suprarenalaHiperplazie suprarenala nodulara bilaterala (autonoma) Forme ACTH dependenteBoala Cushing Secretie ectopica de ACTH/CRHExplorare imagistic + examen histopatologicTeste speciale ** Hiperplazie suprarenala bialterala difuza /macro/ micronodulara Adenom/ Carcinom de corticosuprarenalaBoala Cushing Tumora cu secretie ectopica de ACTH/CRH GHIDUL ENDOCRINE SOCIETY (2008) DE DIAGNOSTIC AL SINDROMULUI CUSHING

80%Boala Cushing

X. Bertagna et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009)TRATAMENTHipofizectomie selectivaSuprarenalectomie bilateralaComplicatii: sindrom NelsonIradiere hipofizara supravoltataMedicatie adjuvanta ketoconazol, aminoglutetimid, mitotanTRATAMENTUL BOLII CUSHING

X. Bertagna et al. J Clin Endocrinol Metab, April 2013, 98(4)COMPLICATIISindromul NelsonInsuficienta corticosuprarenalarecidiva

Feelders, J Clin Endocrinol Metab, February 2013

Barber T M et al. Eur J Endocrinol 2010;163:495-507 2010 European Society of EndocrinologySindrom Nelson Examples of hyperpigmentation-affected patients with Nelson's syndrome: (a) hyperpigmentation affecting skin flexures in a Caucasian patient with Nelson's syndrome; (b) hyperpigmentation in a Malawian patient with Nelson's syndrome (middle), sitting between her two normal siblings for comparison. Full colour version of this figure available via http://dx.doi.org/10.1530/EJE-10-0466.CONCLUZIITumorile hipofizare sunt tumori intracraniene cu frecventa crescuta, evolutie in general benignamortalitate crescutasecretie tumorala, efect compresiv tratament uneori excesivCOMPLICATIIHipogonadism pe termen scurt -pe termen lung - osteoporozaInfertilitateDate de tumoraDate de tratamentGONADOTROPINOMULAdenom hipofizar secretant de gonadotropi FSH, LH, a30-40% din tumorile hipofizareSecreia nepulsatil de gonadotropi tumorali blocheaz de regul funcia gonadic. Uneori se poate manifesta cu hiperstimulare ovariana/testicularaTratament chirurgical, radioterapieTIREOTROPINOMULTumora secretanta de TSH, este cea mai rar tumor hipofizar (10aniGlucagon7ng/ml) si cortizol (n>21g/dl)Test de stimulare cu glucagon, cand ITT este contraindicatTest de stimulare cu ACTH pentru aprecierea rezervei adrenale (dg. dif. cu b.Addison)

TRATAMENTUL INSUFICIENTEI HIPOFIZARETratarea cauzeiInsuficienta CSR: Hidrocortizon 15-30 mg/zi in 2-3 prize sau prednison 5-10 mg/ziInsuficienta tiroidiana: levothyroxina, 1,6 ug/Kg/zi (100 ug/zi)Insuficienta gonadica: estrogeni+progesteron ciclic testosteron FSH+LH pentru restabilirea fertilitatiiDeficitul de GH

Deficitul de GH al adultuluiCriterii de selectie pt. tratamentDeficit sever de GH: ITT: GH26 en 2001sous Dostinexprimaireregle sousLuthenyl?sous ParlodelTSH=37 en ce momentfT3=8,3, fT4=13,1sous Duphaston

Sheet2NNomSexeAgeGPPRAdnomeIHCOPpriode de OPcause de hyperprolactinemiecause de simptomsATCD pers.ATCD familieux thyroideATCD familieux autresLatence diagnostiqueCirconstance du diagnostiquecdcyclecdgalcdinfertcdautrescyclesgalactorrheinfertilitbaisse libidoautres signes cliniquesIRM hypTDM hypPRL initialedatePRL TimonedatePRL Martindaterponse au TRHrponse au MCPbigbigbigmonomerFSHrponse au LHRHLHrponse au LHRHTSHATPOAc anti TGautres Acevolutiontraitementpriode de traitementgrosseses sous traitementPRL TimonePRL directePRL traitex2,3% macroprolactine7Verdier/Guillaume04611ndnd0macroprolactinemiephase luteale courtegoitre multinodulaire0nd0.750,1,3=mastodynies110100strilet au progestndmastodynies41351.09.200181.06.200222.506.20021066.2924.85.6116.111.600nd2Dostinex11/2001-05/2002087.12.35.325.510Muselli042221100macroprolactinemiendmnometrorrhagies sous strilet, papillom mamaire oper-19980HTA, D1, D2, mre avec mnopause precoce38 ans16.000.1110002ndndcephales, obesit androide0101.08.2002101.08.2002203.708.20021146.111.642.33.814.902.1ndndnd0Parlodel1997-200201067.233.273.0-8.73Faure/Isouard0405214nd0macroprolactinemiemnopausens0tante=mnopause 42 ans0.670, 3=bouffes de chaleur10002MP0ndndbouffes de chaleur4331.02.200110.51.12.200119.712.20011132.119.848.1120nd58nd1ndndndndsans10.58.23.58.11.816Gratereau/Corneau050441300macroprolactinemiesndHTA, Luthenyl il y a 2 ans0PR0100030ndndcephales3511.10.2000151.03.200231.71159.77.133.24.3nd5.75.71.6ndndnd2sans1512.73.58.136.615Bataille/Myard0512213011982-2001macroprolactinemiemnopausensndnd0.170, 3=cephales10012MP0ndndcephales614.51.06.2001161.05.200255.904.20021159.314.526.2105nd68nd0.8ndndndndsans1618.15.813.326.36Bleicher027001301en 1988 Diane 35 pour acnmacroprolactinemiehyperandrogenieamnorrhe rsposive aux progestatifs en 19970D2, HTA, IR0.25010002 MP0ndndhirsutisme, acn peribucale0421997191.02.20024402.20021166.118.115.85.7nd8.2nd1.2ndndnd0sans1914.34.710.824.412Contat04122nd01Androcur, Diane 35; arret 3 mois avant 09.2002macroprolactinemiendfibrom uterin0nd15.001010000ndnd0adnome hypophysaire en 1987211.09.2002211.09.200260.609.20020174.51312.5ndndndnd0.7ndndndndParlodel1987-199211 grossesse aprs Parlodel2118.23.88.752.02Judicone04822170124 ansmacroprolactinemiendhisterectomie totale pour endometriose avec preservation des ovaires, depression traite avec Floxybral, Tranxne, Seropram, anomalie genetique du FV1D20.173=asthenie, cephales000140ndndcephales frontales et occipitales3631.02.20022304.200233.803.20021155.318.825.98.9nd58.1nd3.2ndndTRAB