ENDOCRINOLOGIE

CURS 2
Prof Dana Stoian 0
TUMORI SECRETANTE

Prof Dana Stoian 1

 TUMORI HIPOFIZARE
Incidentaloame = 16.6% populatia generala

Celule Cromofobe = NESECRETANTE

Celule Cromofile (acidofile/bazofile) = SECRETANTE

PRL = GH = hiper- ACTH = boala

prolactinom somatotropie Cushing FSH
/LH TSH
• 440/1 mil • 84-130/1mil • 7/1 mil
PATOLOGIA HIPOFIZARA ANTERIOARA

Compresiune mecanica = Sd tumoral

Exces/ deficit productie = Sd hormonal

• Hiperproductie tropi = semne exces hormonal periferic
• Hiposecretie tropi = semne de deficit hormonali periferici

Modificari somatice = sd morfologic

Urmari metabolice

Combinatie intre ele

• sd. tumoral izolat
• sd. Tumoral + hipersecretie 1-2 hormon
• sd. Tumoral +hipersecretie 1 hormon+ insuficienta 1-4 hormoni
Prof Dana Stoian 3
 Prolactinom

Secretant de Secretant de
ACTH TSH

Tumori
secretante

Secretant de Secretant
GH FSH/LH

Prof Dana Stoian 4

Suspiciune
clinica

Confirmare • RMN/CT
localizare

Evaluare • Hipersecretie
hormonala • Hiposecretie

CONFIRMARE
HIPERsecretie

Prof Dana Stoian 5

 PRL
CE • 198 AA

• celulele lactotrope, acidofile, dispuse

CINE difuz

• Dezvoltare glandulara mamara in sarcina

CUM • Stimuleaza lactatia in postpartum

Efect asupra
• DOAR IN HIPERSECRETIE PRL
gonadostatului

Prof Dana Stoian 6

REGLARE PRL
Control
TRH – trop VIP – cale
predominant
hipotalamic serotoninica
inhibitor DOPAMINA

Reflex neurogen
Neural = somn = in Stres (fizic, psihic, ç stimulare
orice moment al zilei metabolic) mamelonara
(TORACIC)

+ alaptare + sexual + Traumatism

+ Leziuni
tegumentare: Hormonal:
+ Arsura
Herpes Zoster E2, TRH, T3,T4
toracic

Prof Dana Stoian 7

 CRESTEREA PRL SCADEREA PRL

Sarcina, alaptare, neonatal

Stimulare mamelonara
Efort fizic
Somn
Hipoglicemie

TRH Agonisti Dopaminergici

Estradiol Levodopa
VIP Apomorfina
Modificarea Antagonisti Dopaminergici
Haloperidol, Risperidona, Rezerpina,
Bromocriptina
Pergolid

PRL Methyl Dopa, opioide,

Metoclopramid
Cabergolid

IN AFARA Inhibitori moaminoxidazei

Cimetiidna

patologiei Verapamil

Leziuni perete toracic Pseudohipoparatiroidism

Leziuni medulare

Hipotiroidism

BCR stadiul IV, V

Insuficienta hepatca
 HiperPRL de = HIPOGONADISM
Infertilitate
orice cauza Disfunctii sexuale

LEGATURA
PRL –
GONADOSTAT
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Prof Dana Stoian 11
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Prof Dana Stoian 13
 SOMATIC

• galactoree (tardiv) Inhiba pulsatii secretorii

HORMONAL = sd endocrin

• RAPID Insuficienta FSH + LH

• TARDIV insuficienta celorlalti tropi

TUMORAL = sd functional

• sd tumoral hipofizar Compresiune tumorala

Extrem de rar in copilarie

Frecvent adult:

• F:B = 10:1
• tipic 20-50 de ani

Prof Dana Stoian 14

Sd endocrin
FEMEI BARBATI

• Anovulatie 90% • Hipogonadism

• - hipo-, oligo-, • Scadere libidou
amenoree • DE
• frecvent postpill • Infertilitate
• Inhiba secretia • Demineralizare osoasa
PULSATILA • Diagnostic tardiv
• Hipoestrogenie • Frecvent sd tumoral
• Uscaciune vaginala hipofizar
• Crestere ponderala • PRL ééé + LH, FSH ê
• Iritabilitate
• Retentie hidrica
• Galactoree 20%
• Demineralizare osoasa
• PRL é + LH, FSH n/ê

Prof Dana Stoian 15

 Prolactinomul
Cel mai frecvent adenom hipofizar secretant

? Screening activ
1. Galactoree
2. Incidentalom hipofizar
3. Suspiciune tumora hipofizara
4. Amenoree/oligomenoree/scadere flux menstrual
5. Hipogonadism masculin
6. Infertilitate (feminina, masculina)

Majoritatea microadenoame (> 90 %)

Prof Dana Stoian 16

 PRL • Minim 2 dozari

• sarcina
Excludere • Iatrogenie
• PCOS, BCR, deviatie tija, hipoT

Localizare • RMN

Evaluare • Efect de masa

completa • Hormoni

Prof Dana Stoian 17

Diagnostic ≠ 1. Tumora secretanta de PRL
• !!!! Proportionalitate nivel
PRL – volum prolactinom
• Tipic > 100 ng/mL

f i z i o l o gice de
4. Cauze e PRL
al 2. Tum
cretsere ora ne
• COC depla secretant
seaza a ce
• sarcina 3 – 4 luni) tija
e(
• alaptar

3. Cauze functionale
de crestere a PRL

Prof Dana Stoian 18

Prof Dana Stoian 19
 Tratament

Medical Chirurgical Radioterapie

Transsfenoidal Conventionala
Dopaminergice craniotomie radiochirurgie

Prof Dana Stoian 20

 üControl hipersecretie
üScadere volum tumoral
Tratament üReluare gonadostat/fertilitate
Linia I = MEDICAMENTOS
BROMOCRIPTINA 1.25-2.5x2/zi
= stimuleaza receptorii DOPA din hipotalamus
= T1/2 scurt zilnic
= toleranta relativa

CABERGOLINA 0.5 x2/saptamana

= stimuleaza receptorii DOPA din hipotalamus
= T1/2 lung saptamanal
= toleranta excelenta
= ? Creste incidenta b.Parkinson
(regimuri zilnice)
= leziuni valvulare cardiace ........ Monitorizare
ecografica cardiaca periodica

Prof Dana Stoian 21

Tratament
Linia II = Chirurgie
Microprolactinoame
• PRL < 200 ng/mL
• Amenoree< 5 ani
• Vincedare 85-90%
• Recurenta 15%
Prof Dana Stoian
Macroprolactinoame
• PRL > 200 ng/ml
• Tumora > 2 cm
• Vindecare 80%
• PRL > 200 ng/mL
• Extensie extraselara
• Vindecare 25-50%
• In forme avansate se prefera medicatia
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 Alegere terapie
MICROADENOAME MACROADENOAME
Tratament universal

Dopaminergice Dopaminergice - 1st line therapy

• Cabergolin cp 0.5 mg • PRL > 200 ng/dL

• 0.2-1 mgx2/sapt • tumora > 2 cm
• Raspuns bun: êPRL + tumora
• 2-3 ani = renuntare Abord transfenoidal
• Verificare PRL+ RMN
• tumori mari +resturi/HPRL
Transsfenoidal
Radioterapie
• Recurenta
• Macroadenom (2 cm) • pacienti postchirurgical, cu reziduri
• Remisiune pe termen lung adenomatoase+ control partial cu
• Risc minimal dopaminergice

Radioterapie

• Nu este indicata
23
Prof Dana Stoian
● M.M., 30.04.2007
● Prima prezentare in clinica: noiembrie 2022
● Motivul adresarii: amenoree primara
● APF: debut pubertar la varsta de 12 ani
● APP: tulburare de alimentatie intre 12-14 ani (IMC=15,9 KG/M2)

Amenoreea primara= lipsa menarhei pana la varsta de 15 ani

Examen clinic
● G= 53 kg, T= 173 cm, IMC= 17,7 KG/2
● OGE: Stadiul Tanner IV

- axilarha prezenta
- pubarha P4
- telarha B4
● fara alte modificari patologice.
Evaluarea biologica initiala (noiembrie 2022)
Parametru biologic Interval de referinta

LH 1,98 UI/L 0,9-32,8 UI/L

FSH 5,97 UI/L 1,3-10,0 UI/L

Estradiol 42 pg/mL <70 pg/mL

Prolactina 174 ng/mL 4,3-23,3 ng/mL

Testosteron 0,2 ng/mL <0,28 ng/mL

DHEA-S 216,4 ug/dL 33,4-245,0 ug/dL

17-OH Progesteron 1,18 ng/mL 0,42-2,26 ng/mL

TSH 1,7 mUI/L 0,48-4,17 mUI/L

FT4 14,03 pmol/l 10,68-18,40 pmol/l

IGF-1 257 ng/mL 191-496 ng/mL

Cortizol seric h 8 323 nmol/L 133-537 nmol/L

RMN HIPOFIZA CU SDC (DECEMBRIE 2022)
Ultima prezentare: august 2023
Menarha: iulie 2023
G= 59 kg, T= 173 cm, IMC= 19,7 KG/2

Parametru biologic Interval de referinta

LH 5,98 UI/L 1,9-12,5 UI/L
FSH 6,23 UI/L 2,5-10,2 UI/L
Estradiol 73 pg/mL 21-251 pg/mL
Prolactina 65,8 ng/mL 4,3-23,3 ng/mL
CAUZE DE HIPERPROLACTINEMIE
● Sarcina
● Lactatie
1 FIZIOLOGICE ●
●
Stimularea peretelui toracic
Somn
● Stres

● TUMORI
GRANULOAME
2 AFECTAREA TIJEI HIPOTALAMO- ●
HIPOFIZARE ● RADIOTERAPIE
● TRAUMATISME

PROLACTINOM
3
●
HIPERSECRETIE HIPOFIZARA
● ACROMEGALIE

● INSUFICIENTA RENALA CRONICA

CIROZA
4
●
AFECTIUNI SISTEMICE
● HIPOTIROIDISM
● CRIZE EPILEPTICE

● BlocantI aI receptorilor dopaminergici

● Inhibitori ai sintezei de dopamina
5 MEDICAMENTOASE ●
●
Opiacee
Blocanti receptor H2
● Blocanti ai canalelor de calciu
 Caz
• Barbat 56 de ani, IMC = 32.25
Medicatie
• Alterarea libido erectii stimulate
• Hipertensiv
• Cefalee intermitenta
• Minim simptome urinare joase
?

• Testosteron 1.5 mg/mL (> 2.3)

• LH, FSH < 2 mUI/L ( 5-15)
• PRL 7500 ng/ml (< 25) RMN

Prof Dana Stoian 32

Prof Dana Stoian 33
• Cabergolin 0.5 mg la 3 zile

moment L0 L1 L2 L3 L4

PRL 7500 4500 1000 250 25

Prof Dana Stoian 34

 Efecte
URMARIRE Efecte adverse
hipofizare
• PRL • IGF1 • Eco cardiac
• RMN • TSH, FT4
↓PRL = ↓adenom
• ACTH, cortisol
• LH, E2/TT

Prof Dana Stoian 35

 HIPERSOMATOTROPIA = Exces de GH

• Adenom hipofizar
• Proliferare celule acidofile mutante (GH±PRL)
= Mutatie somatica prot G – avantaj proliferativ
• HIPERSECRETIE de GH èIGF1

• 100% macroadenoame (diametru de> 1 cm)

• 86-130/1 milion persoane

Prof Dana Stoian 36

 GH
DE CE
CINE
CE Baza activitatii pulsatile =
= Celule somatotrope, necunoscuta
acidofile posterolateral Grevata de mai multi factori:
191 AA
Descarcari pulsatile, • factori nutritionali
nocturne • factori metabolici
h.Polipeptidic
Eliberarea PULSATORIE • steroixi sexuali – efect dependent de
= OBLIGATORIE varsta,
• glucocorticoizii adrenali,
• hormoni tiroidieni,
• functia hepatica si renala

Prof Dana Stoian 37

 lipoliza

transport AA intratisular
DIRECTE
gluconeogeneza
CUM ?
crestere cartilaje

formare osoasa

sinteza proteica

uptake glucoza muscular

mediate IGF1
supravietuire neuronala

sinteza mielina

Prof Dana Stoian inhiba degradarea proteica

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 Efecte somatice ale GH
Tesut Efect
OS Crestere longitudinala – formare de os/cartilaj nou
Stiuleaza condrogeneza
Largire placile epifizare
Depunere de matrice osoasa
Sustine turnoverul osos la adult (formarea osoasa)
MUSCULAR Efect anabolic: Uptake AA in celule, incorporarea in proteine cu
proliferare celulara
FICAT Stimuleaza sinteza si eliberarea IGF 1
Sistem imun Raspuns celule B + Productia de Ac
Activitatea celulelor NK+ macrofage +limfocite T
SNC Modularea dispozitiei generale
Sinteza de mielina
Influenteaza supravietuirea neuronala
Sange Fibrinogen, Hb, HT, FAL
Rinichi Rata filtrare glomerulara
Viscere crestere
Piele Cretser pilozitate, derm, stimuleaza glande sudoripare
Prof Dana Stoian 39
Efecte metabolice ale GH

Metabolism Efect
Glucidic Scade Uptake ul glucozei in tesuturile extrahepatice
Creste depozite hepatice de glicogen
Crestre productia hepatoca de glucoza
Hiperglicemiant
Scade sensibilitarea la insulina
Lipidic Eliberarea/oxidarea AGL
Creste cetogeneza plasmatica
Proteic Uptake de AA intracelular
Sinteza proteica
Scade excretie de nitrogen

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 Evaluare GH

Productie zilnica Dozare din sange Nivel seric adult

• adult 400 mcg/zi • ( T1/2 = 10-12’) • < 2ng/mL
• copil 700 mcg/zi

IGF1 Teste de stimulare Teste de inhibitie

• = activitatea • = Arginina, • = Glucoza
biologica a GH Glucagon, GHRH

Prof Dana Stoian 47

 EXCES DE GH
Secretie crescuta de GH

Cresterea amplitudinii + pulsurilor GH

ALEATORII

Alterarea controlului dinamic

Raspuns anormal la teste de INHIBITIE

...... Sinteza anormala éééééé de IGF

Prof Dana Stoian 48

Prof Dana Stoian 49
 SOMATIC METABOLIC
sd morfologic sd metabolic

• = cresterea organelor • = urmari metabolice

• = crestere osoasa

HORMONAL TUMORAL
? sd endocrine sd functional

• = insuficienta celorlalti tropi • = sd tumoral hipofizar

Frecvent adult: F=B, > 40 ani,

Rar in copilarie vechime minim 5 - 10 ani

Prof Dana Stoian 50

Sd
Morfologic
? PANA LA finele
INAINTE pubertatii
inchidere
Predomina cresterea in
cartilaje lungime a oaselor lungi
crestere

Prof Dana Stoian 51

Prof Dana Stoian 52
 Simptome
Sd • Trasaturi dure
Morfologic • Secundare metabolice
Semne

INAINTE •
•
Talie peste media varstei
Viteza de crestere foarte mare
inchidere • Varsta osoasa accelerata

cartilaje • Crestere parti moi

• Palme
crestere • Plante
• Degete groase

Prof Dana Stoian 53

Prof Dana Stoian 54
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 Statura inalta constitutional
Statura inalta genetic

Dg ≠ Sd Marfan

clinic Gigantism cerebral

gigantism Sd Klinefeter
XYY, XYYY
Pubertati precoce BAREM CHIMIC
NORMAL

Prof Dana Stoian 56

Sd
Morfologic
DUPA FINELE pubertatii
DUPA
inchidere Predomina cresterea in
cartilaje grosime a oaselor late
crestere + viscere

Prof Dana Stoian 57

Prof Dana Stoian 58
Prof Dana Stoian 59
 Simptome Semne
• Proliferare parti moi 100%
• Dureri osteoarticulare
• buze,limba, urechi, nas
Sd • Parestezii
• Transpiratii excesive
• Crestere oase spongios 100%
• Palme
morfologic • Intoleranta la caldura
• Letargie/oboseala
• Plante

DUPA • Oligomenoree
• Facies = bose temporale
• Ingrosare calvarium
• Galactoree
inchidere • Disfunctie erectila
• prognatism
• Hiperhidroza 88%
cartilaje • Infertilitate
• Cefalee
• Crestere ponderala 87%
• Papiloame 45%
crestere • Fotofobie
• Hipertricoza
• Gusa 30%
• Acanthosis nigricans 30%
• HTA 24%
• Cardiomegalie 16%
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Sd metabolic

• Hiperglicemie (70%) è ATG (50%) èDZ

Sd endocrinologic

• Insuficienta alti tropi hipofizari

• Hipogonadism 60%
• Hipotiroidism 13%
• Hipocorticotropism 4%

Sd functional
= sd tumoral hipofizar

• Compresiune structuri invecinate +

Prof Dana Stoian 65

 • I Evaluare
IGF1 • Dep de gen, varsta

• 5-500 ng/ml
GH
• Posibil “normal”

• Incarcare de glucoza 75 gr
INHIBITIE
• GH< 1 ng/ml la 1-2 ore

Localizare • RMN

Evaluare • Efect de masa

completa • Hormoni

Prof Dana Stoian 66

Prof Dana Stoian 67
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 DZ TTGO
FO
VCN
microalbuminurie
HTA FO
microalbuminurie
RFG
CMH EKG
disfunctie diastolica
Dg ECO

complicatiilor Gusa
nodulara
eco

Punctie ac fin

SASO Polisomnografie

Polipoza Colonoscopie

Prof Dana Stoian 69

 Alte cauze de hipersecretie GH/IGF1
• Anxietate
• Efort fizic excesiv ABSENTA
• Afectiune acuta tablou clinic
• BCR
INHIBITIE CORECTA
Diagnostic •
•
Infometare
Malnutritie protein calorica
≠ • Anorexie nervoasa
Secrectie ectopica de GH sau GHRH
• carcinom pulmonar
• tumori carcinoide Hipofiza
normala
• celule C pancreatice

Prof Dana Stoian 70

 Tratament

Medical
Chirurgical Radioterapie
SSTA
Transsfenoidal Conventionala
PEGVISOMAT
craniotomie radiochirurgie
DOPAminergic

Prof Dana Stoian 71

 Tratament

• adenomectomie selectiva
I linie = Chirurgical transsfenoidala
• craniotomie extensie supraselara

Rezultate
reducere GH = 60- • GH < 50 ng/mL
80% tumora < 2cm

Recurenta < 5%
• GH > 50 ng/mL
= 30-60%
extensie supras
Prof Dana Stoian 72
Prof Dana Stoian 73
 Tratament

Chirurgical Medical Radioterapie

Transsfenoidal analogi de Conventionala
craniotomie SST radiochirurgie

Prof Dana Stoian 74

Prof Dana Stoian 75
linia II = medicamentos ANALOGI SOMATOSTATINA

– Hipersecretie reziduala ( Rx, Ch)

OCTREOTID
– Contraindicatie pentru chirurgie LANREOTID
– Tumori mici, de preferat la varstnici
Actiune: activare receptor SST 2, SST5
Adminsitrare lunara (retard)
Rezultate
reducere GH = 75 % cazuri
reducere tumorala = cu circa 20% din initial

CABERGOLIN - asociere cu SSTI, efect aditional de 30% de reducere a GH

PEGVISOMANT

– Antagonist receptor GH
– Administrare zilnica, sc
– Normalizeaza IGHF1 la 90% din cazuri
– De rezerva: cost/adminsitrare zilnica

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Prof Dana Stoian 77
Linia III – Radioterapie

1. Conventionala
45 Gy succes in 60-80%
nerecomandata normalizare GH in 5-10 ani
hipopituitarism 100%

2. Gamma knife chirurgie radiologica

25-75 Gy remisiune 50-90% in 2 ani

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Prof Dana Stoian 79
 Tratamentul complicatiilor
• Insuficienta liniilor hipofizare
• GN
• Obezitate
In paralel • DZ
• Afectiuni cardiace
• HTA
• Cardiomegalie
• CMH

Prof Dana Stoian 80

RASPUNS bun RASPUNS partial REZISTENT
Clinic OK Clinic variabil Clinic activ
IGF1 N IGF é IGF é
Inhibitie GH < 1 mg/ml Inhibitie GH < 1 mg/ml Inhibitie GH > 1 mg/ml

Prof Dana Stoian 81

 Acromegalie confirmata
Tratament
I= CHIRURGIE

MEDICAMENTOS SST analogi

I = Risc operator crescut
= Fara compresiune structuri neurologice/vizuale
II Linie = Rest postoperator
Algoritm in cazul
+ Analogi Somatostatina absentei vindecarii
Chiar si doza maxima biochimice

+ Cabergolin

Pegvisomant Abord individualizat Radioterapie

Chirurgie

Tratament combinat
Pegvisomat + Analogi somatostatina
Pegvisomant + CAbergolin
Prof Dana Stoian 82
 DA 34 de ani

Cefalee frontala
Caz
STRABISM/DIPLOPIE
recent instalata
 Tumora
orbitala

Boala Tumora
Graves hipofizara

?
Anevrism
Pareza
/tromboza
postvirala
de ACI

Tumora lob
temporal

Prof Dana Stoian 84

Preoperative MRI with contrast enhancement (A- sagittal, B-coronal, C- axial). Post operative MRI with
contrast enhancement showing resection of theProf
tumor
Dana (D- sagittal, E- coronal, F-axial)
Stoian 85
 HIPERFUNCTIE?
HIPOFUNCTIE? • IGF1
• CLU 24 h
? • PRL

Prof Dana Stoian 86

 05.2017
Prolactin 77.26 ng/ml (59-619)
IGF-1 498.8 ng/ml (96-301) x1.65 UNL
LH 3.6 mUI/ml (2.4-12.6)
FSH 4.5 mUI/ml (3.5-12.5)
Estradiol 221 pmol/L (FF: 114-332 )
TSH 2.35 µUI/ml (0.27-4.20)
FT4 14.6 pmol/l (12.6-21)
Salivary cortisol 0.082 µg/dl (<0.41)
Glicemia (mg/dl) 81 60-99
HbA1c (%) 5.2 4.8-5.6
 05.2017 V.N.
IGF-1 418.3 ng/ml (96-301)
GH basal 1.54 ng/ml (<10)
GH 60min 1.05 ng/ml (<1)
GH 120min 0.88ng/ml (<1)

“A nadir serum GH level < 1 μg/L within 2

hours after 75 g of oral glucose usually
L Katznelson. Acromegaly: An Endocrine Society Clinical Practice Guideline, JCEM, November 2014
excludes the diagnosis”
• Macroadenom DAR

+ diplopia = invazie de sinus cavernos (VI )

• Fara defect de camp vizual
• Fara hipopit + hipersecretie de GH
Macroadenom 15/12/9 mm, izosignal T1 / T2
Medial + parasagital drept
Bombare cort hipofizar
medioinferior contact cu ACI
Deviatie tija la stanga
Chiasma optica normala
 •09.2017
interventie chirurgicala transfenoidala
fara complicatii postop.

celule tumorale + pentru GH

Histopathology
KI 67 > 3% ??? Comportament potential agresiv
•Chromogranin A was positive in most tumoral cells.
•The Ki-67 nuclear labeling index was estimated at 3%.

•Reevaluare la 6 luni
RMN fara recidiva + IGF1 in limite
? IGF1 + TTGO cu masurate postinhibitie a GH

Prof Dana Stoian 92

“significant relationship between Ki-67 and higher postoperative hormonal recurrence rate”

Asian J Neurosurg. 2014

 LABORATOR POSTOPERATOR

06.11.2017 26.09.2018
GHI b 0.4
on25 ng/ml (0.05-8) 0.067ng/ml (0.05-8)
1 h GH 0.634 ng/ml (< 1) 0.075 ng/ml (< 1)
2 h GH 0.099 ng/ml (< 1) < 0.05 ng/ml (< 1)
IGF-1 341 ng/ml (88-537) 241 ng/ml (88-537)
Exam
PRL 163 ng/ml (59-619) 253 ng/ml (59-619)
LH 5.6 mUI/ml (1-11) 3.6 mUI/ml (2.4-12.6)
FSH 4.5 mUI/ml (1.7-7.7) 8.3 mUI/ml (3.5-12.5)
TSH 2.35 µaUreI/am
Treatment l (0.27-4.2 0)
ny signs of tumor reg 3.1 µUI/ml (0.27-4.20)
FT4 16.5 pmol/l (12.6-21) 12.9 pmol/l (12.6-21)
Cortizol 15.3 µg/dl (6-18) 17.9 µg/dl (6-18)

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