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Localizarea hipofizei
B: Empty sella: Partea anterioara a şeii turceşti este ocupata progresiv de un diverticul al
spaţiului subarahnoidian, conţinând LCR
Sistemul port hipotalamo-hipofizar
• Imunohistochimie:
Adenom secretant de GH/ PRL/ ACTH/ TSH/ FSH/ LH/
subunitati alfa; sau mixte ex. GH+PRL
Adenoame cu celule nule
(SOMATOTROPINOAME)
Manifestari clinice datorate secretiei GH
Simptome
• Transpiratie excesiva (>80% din pacienti)
• Cefalee
• Oboseala, letargie
• Dureri articulare
• Cresterea nr. la picior, cresterea mainilor, extremitatilor
Semne
• Faciale: trasaturi ingrosate, bose frontale, nas marit, prognatism, piele grasa,
largirea spatiilor interdentale
• Ingrosarea vocii
• Marirea limbii
• Edeme ale tes. moi: sindrom tunel carpian
• Modif. musculoscheletale: cresterea nr. la picior, cresterea mainilor,
osteoartrita, miopatie generalizata
• Gusa si alte organomegalii (ingrosarea muc. bronsiolelor, hipertrofie
ventriculara)
COMPLICATII
1. HIPERTENSIUNE ARTERIALA (40%)
1-clinoide anterioare;
2-planseu selar;
3-sinus sfenoid
4-lama patrulatera;
5.clinoide
posterioare;
6. stanca temporala;
7. clivus.
• GH Receptor Antagonist
Pegvisomant
OCTREOTIDE AS PRIMARY MEDICAL
THERAPY FOR ACROMEGALY
GH serum levels:
N=27, octreotide 300-600 µg 24 wk
N=15 Oct-LAR 24 wk
GH
GH
Site 1
Binding
Pre-formed
GHR Dimer
Cell Surface
GH Site 2 GH
Binding
Signal Generation of
Functional GHR Dimerization Transduction IGF-l
Adapted from Kopchick JJ. Presented at: Global Endocrine Summit: Focus on Acromegaly; November 7-8, 2003; Barcelona, Spain.
GHRA (pegvisomant,SOMAVERT®)- structure
PEG
PEGMoiety
Moiety
Site 2: 2:
Site
GHRA 1 Amino
1 Amino Acid
AcidSubstitution
Substitution
Site 1:
8 Amino Acid
Substitutions
Pre-formed
GHR Dimer Cell Surface
Adapted from Kopchick JJ. Presented at: Global Endocrine Summit: Focus on Acromegaly; November 7-8, 2003; Barcelona, Spain.
GHRA - mechanism of action
Site 2
GHRA Binding
• Highly selective for GHR
Site 1 • Long half-life (6 days)
Binding Site 2
• Peak serum levels: 33-77
Binding
h
• Reduced immunogenicity
• Internalization not impaired
No No
Signal Generation
Transduction of IGF-l
Improper or Nonfunctional
GHR Dimerization
Adapted from Kopchick JJ. Presented at: Global Endocrine Summit: Focus on Acromegaly; November 7-8, 2003; Barcelona, Spain.
Radioterapia adenoamelor hipofizare
Conventionala fractionata, de inalt
voltaj (45 – 50 Gy, 1.8 –
2Gy/sedinta)
Tumor size
Treatment Safe GH (%) Normal IGF-I (%) reduction Comments
Transsphenoidal surgery 23–65 (Macro) — Yes Outcome dependent on
expertise of surgeon,
60–90 (Micro)
pretreatment GH, tumor
position
Conventional radiotherapy 90 60–80 Yes Efficacious but slow (up to 18
yr) reduction of GH and IGF-I
Dopamine agonists 10–20 10–43 May be seen More efficacious in PRL
in PRL cosecreting tumors
cosecreting
tumors
SMS analog 22–55 (sc) 45 (sc) Uncertain Tumor shrinkage in selected
patients, no randomized studies
60–70 (LA) 50–60 (LA)
normal PRL
60 600
IGF1
36.9
40 29.3 400
20 200
0 0
Baseline Postsurgery Post SSA 6 mth Post 2nd Post 2nd
surgery (1 mth) surgery (2 mth)
Time
Nadir GH (ng/ml) IGF1 (ng/ml)
“Aggressive” acromegaly
surgery (SS + FS), SSA (lanreotide), gamma knife, SSA
(octreotide 30 mg/month), pegvisomant
After
774 900
80 793 800
677 62.2
60 700
60 600
IGF1
500
36.9 35.3
40 29.3 400
300
20 200
100
0 0
eline g e ry N 6m (1 m) (2 m) OCT 5m 2m
Ba s
Post
su r
Post
L A
surg
er y
surg
er y Pegv
2n d 2 n d G K 8m +
Post Post Post
Time
Nadir GH (ng/ml) IGF1 (ng/ml)
PROLACTINOMUL
(TUMORA LACTOTROFA)
Cautati galactoreea!
CAUZE DE HIPERPROLACTINEMIE
1. Fiziologice: sarcina, actul sexual, stimularea mamelonului/suptul, stresul
2. Tumora hipofizara: prolactinom/ macroadenom care comprima tija
3. Boala hipotalamica: craniofaringiom, meningiom, sarcoidoza
4. Sectionarea tijei: traumatism cranian, chirurgie
5. Iradiere craniana
6. Medicamente:
• Antagonist de receptor de dopamina (metoclopramide, domperidome)
• Estrogeni
• Neuroleptice (exceptie: clozapine, quetiapine, olanzapine)
• Antidepresive (MAOI, SSRI, tricyclics)
• Opioide
• Cardiovasculare (verapamil, methyldopa)
• Inhibitori proteaza (zidovudine, ritonavir, indinavir)
• Altele ( benzafibrate, omeprazole, H2 blockers)
7. Hipotiroidism
8. PCOS
9. Boala renala/hepatica cronica
10. Leziuni de perete toracic (inclusiv zona zoster)
11. Macroprolactinemia
TRATAMENT
Obiective: MicroPRL: restabilirea functiei gonadale
MacroPRL: - reducerea dimensiunii tumorii
- prevenirea expansiunii tumorii
- restabilirea functiei gonadale
Medicamentos: Agonisti dopamina
• Bromocriptina 7,5 mg – 15 mg/day
• Cabergolina 0,5 – 3 mg /week
Chirurgical:
• rezistenta/intoleranta la agonisti dopaminergici
• MacroPRL cu fistula LCR (prolactinom invaziv )
1. HIPERTENSIUNE (>50%)
2. DIABET ZAHARAT(30%)/ TOLERANTA
ALTERATA LA GLUCOZA (40%)
3. OSTEOPENIE/OSTEOPOROZA
4. BOALA VASCULARA
5. COAGULOPATII
6. SINDROM METABOLIC
5. SUSCEPTIBILITATE LA INFECTII
INVESTIGATII
1. Cortisol liber urinar /24h crescut
2. Pierderea ritmului circadian
• Ora 23- 24 cortizol >50nmol/l (sau de 5ug/dl)
3. Teste de supresie la Dexametazona
• Overnight 1mg;
• DXM 2mg x 2 zile
• DXM 8mg x 2 zile
4. ACTH
5. Cateterism de sinus pietros inferior
masoara ACTH si cortisol dupa CRH (100mcg i.v.)
raport central:periferic >2 inainte de CRH
raport central:periferic >3 dupa CRH
6. K seric <3.2 mmol/l caract in sd Cushing ectopic
7. Imagistica hipofizara: MRI (80% microadenoame)
Cauzele sindromului Cushing
ACTH-dependente (80%):
• adenom hipofizar 68% (Boala Cushing)
• ACTH ectopic 12%
• CRH ectopic <1%
ACTH-independente (20%):
• adenom adrenal
• carcinom adrenal
• hiperplazia adrenala nodulara
Sindrom pseudo-Cushing :
• alcooolism
•depresie severa
Tratamentul bolii Cushing
1. Chirurgie hipof. trans-sfenoidala
2. Radioterapie hipofizara
3. Suprarenalectomie bilaterala
4. Tratament medicamentos:
Preop.: metyrapone/ ketoconazole/aminogluthetimide
Postop. daca cortisol scazut: substitutie cu glucocorticoizi
• hiperpigmentare +
tumora hipofizara in evolutie
dimensionala +
ACTH foarte crescut
Investigatii
- MRI hipofizar
- evaluare camp vizual
- PRL (dg diferential cu prolactinomul!)
- evaluarea functiei hipofizare.
- imunohistochimie:
negative (null cell tumors/ oncocytoma)
ACTH (silent corticotroph)
gonadotropi/ alpha subunits
Managementul NFPA
1. Chirurgie
2. Radioterapie