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Neuroendocrinologie

Hipotalamusul Patologia vasopresinei Diabetul insipid

Corin Badiu, 2012

NeuroEndocrinologie
Sistem nervos

Sistem imun

citokine

Sistem endocrin

Proprietati
Comune
Potentiale de actiune Secretie Mediatori (Peptide) Receptori

Specifice
Amploarea raspunsului Latenta Durata Reglaj

Neurosecretie

Neurohormoni

Neuromodulatori

Sistemul port hipotalamo-hipofizar

Gr. Popa and U. Fielding, Lancet, 238, 1930

Hipotalamus
= sub talamus

Localizat inferior de talamus, portiunea majora a diencefalului ventral


Regleaza procese metabolice si activitati ale SNV Leaga sistemul nervos de sistemul endocrin via glanda pituitara, prin sinteza si secretia neurohormonilor, (liberine si statine). Neuronii care secreta GnRH sunt conectati cu sistemul limbic, care este implicat primar in controlul emotiilor si activitatii sexuale. Hipotalamusul controleaza temperatura, foamea, setea si ritmul circadian. Hipotalamusul este conectat cu SNC, formatiunea reticulata, sistemul limbic (amigdala, septum, banda diagonala Broca, bulbul olfactiv) si cortexul cerebral).

Martin, Reichlin, 1987

Functii
Responsiv la: Lumina: lungimea zilei si fotoperioada pentru a genera ritmurile circadian si sezonier Olfactie: stimuli, inclusiv feromoni (parfumuri) Steroizi: gonadali si corticosteroizi Informatii vegetative periferice : cardiovascular, stomac, tract reproductiv
SN Autonom Stimuli hormonali: leptina, ghrelin, angiotensina, insulina, hormoni adenohipofizari, citokine, glicemie, osmolaritate etc.

Stress Microrganisme: prin cresterea temperaturii, resetand termostatul.

Nuclei hipotalamici

Lateral Area Medial Area Anterior Anterior Lateral preoptic nucleus Medial preoptic nucleus Supraoptic nucleus Lateral nucleus Paraventricular nucleus Part of supraoptic nucleus Anterior nucleus Suprachiasmatic nucleus Tuberal Lateral nucleus Tuberal Lateral tuberal nuclei Dorsomedial nucleus Posterior Ventromedial nucleus Arcuate nucleus Lateral nucleus Posterior Mammillary nuclei (part of mammillary bodies) Posterior nucleus

Neurohormonii
Corticotropin-releasing hormone (CRH) Dopamina Gonadotropin-releasing hormone (GnRH) Growth hormone releasing hormone (GHRH) Somatostatin Thyrotropin-releasing hormone (TRH) Oxytocin Antidiuretic Hormone (Vasopresina, ADH)

Median Eminence
Organ circumventricular

Ependimal: tight J. Tanicitele (T4T3) Intermediar: VP&OT axons


Extern: capilare fenestrate

INTRACRINE
AUTOCRINE PARACRINE

Semnalizare chimica / Hormonala

ENDOCRINE

NEUROENDOCRINE

Control genetic Biosinteza

Transport axonal

Slide Source: www.obesityonline.org

Neuroendocrinologia aportului alimentar


Trunchiul cerebral - tinta pentru semnale de satietate periferice
Area Postrema:

part of dorsal vagal complex chemoreceptive (no BBB) site of neural integration bi-directional projections to the GI tract (via vagal afferents and efferents)

Hypothalamus

ARC

bi-directional projections to the hypothalamus, amygdala and other regions

NTS/AP

Vag CCK GhrelinPYY Leptin


Insulin

Spinal nerves

GI tract

Amylin+ peptide intestinale

Modified from Marx, Science 2003 February 7; 299: 846-849. (in News)

Slide Source: www.obesityonline.org

Obezitatea endocrina

Lenard and Berthoud, Obesity, 16, S3 (2008), S11-S22

Slide Source: www.obesityonline.org

Neuroimagistica setei
Zece subiecti au efectuat PET-CT si o evaluare psihologica a setei (Denton, PNAS, 96, 5304-5309, 1999)

Cai neurale implicate in homeostazia osmotica

Sete

Antidiureza

Osmoreceptori

Setea si balanta apei


2%Crestere Osmolaritatea LEC 10% Scadere Volum circulant

Osmoreceptori CNS
Descarca ADH Antidiureza Conservarea apei Sete Apetit de Na

Baroreceptori Angiotensina II

Stimuli Aport de apa

Volum circulant ANP&BNP Osmolaritate LEC ANP&BNP


Reeves et al, 1998

Structura hormonilor neurohipofizari


Oxytocin-like peptides
1 2 3 4 5 6 7 8 9 Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (NH2)

Vasopressin-like peptides
1 2 3 4 5 6 7 8 9 Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly (NH2)

Oxytocine
* * * * * * * Ile *

Vasopressine
* * * * * * * Lis *

Mesotocine
*
*

* * Ser * *
* * Ser * *

*
*

Ile *
Glu *

Lisine-vasopressine
* Phe * * * * * * *

Isotocine Glumitocine
*
*

Phenipressine
* * * * Ile * * * * * *

* * *

* *

* Val *
*

Valitocine
* * Asn * *

Vasotocine

Aspargtocine

Receptor V1a
TM IV TM III TM II

TM V TM VI

TM VII

TM I

Noyau paraventriculaire

Noyau supraoptique

Neurohypophyse de rat -ME

Hipotalamus

Vasopresina Rinichi
Muschi neted

Oxitocina
Uter

Sin
Gonade ? AH ?Adipocite Creier

AH Ficat
Suprarenale

Creier

Sindroame poliuro-polidipsice
Hipotalamus
Sete

Polidipsie psihogena Absenta AVP Vasopresinaza Rinichi: rezistenta la AVP insuficienta renala

AVP

IRM normal

Lechan RM. Neuroendocrinology of Pituitary Hormone Regulation. Endocrinology and Metabolism Clinics 16:475-501, 1987

Diabet insipid: Deficitul de AVP


Deteriorarea hipotalamusului (site-ul de sinteza AVP), tijei pituitare (transportul AVP) sau a retrohipofizei (site-ul de stocare AVP), va duce la o boala cunoscut sub numele de diabet insipid central. Muli dintre aceti pacieni nu au hipersemnal in T1 in lobul posterior al hipofizei pe imagistica RMN a creierului.

Diabet Insipid
Caracteristici clinice sunt rezultatul deficientei de AVP Excreia unor volume mari de urin (poliurie) Excreia de urin diluat (OSM <200 mOsm/L) Cresterea osmolaritatii plasmei (i Na+ seric) Stimularea setei (polidipsie)

Craniofaringiom

Infiltrat hipotalamic
Sarcoidoza Histiocitoza Metastaza Tumora de tija Germinom Agenti patogeni

Diabet Insipid
Cele mai multe cazuri de diabet insipid central sunt datorate unor leziuni care implica zona hipotalamusului i n jurul bazei ventriculului trei. Deoarece pacienii cu diabet insipid devin simptomatici numai la o reducere de 80-85% din celulele AVP, leziunea trebuie s fie suficient de mare.

Nivelurile AVP la pacienii cu DI Central

Pe msur ce crete osmolalitatea plasmatic, AVP se ridic la subiecii normali, dar rmne sczut la pacienii cu deficit de AVP complet sau parial.

Diagnosticul Diabetului Insipid


Determinai dac pacientul are un rspuns adecvat la deshidratare, care provoac att Hiperosmolalitate Hipovolemie Ambele ar trebui s stimuleze o cretere a AVP Testul de privare de ap permite diagnosticul Cnd pacientul a pierdut 2-3% din greutatea totala a corpului i dou urini consecutive difer n osmolalitate cu <10%, este obinut o proba de sange pentru sodiu si osmolalitate plasmatica (rar se dozeaza ADH).

Raspunsul la Deshidratare
Pacienii cu diabet insipid complet hipotalamic, in momentul de deshidratare maxim vor avea: o osmolalitatea urinar <200 mOsm o osmolalitatea serica crescuta (> 295) (au un nivel sczut de AVP) creterea osmolaritii in urin cu mai mult de 50% dac este administrat exogen AVP

Tratament Diabet Insipid


DDAVP (Desamino-D-Arginine Vasopressin)10-20 mg 1-3 /zi instilatii nazale Per os , DDAVP cp 0,2 mg , 1 cp la 8-12 ore SLG: 120- 240 mg 1-3/zi IM/SC la 1/10 din doza. Etiologie !!!

Hipernatremia
Na+> 145 mEq/L

Hipodipsie primara, DI (central sau nefrogen) Diureza osmotica (DZ dezechilibrat)

Neurologic: astenie, stare confuzionala, convulsii, deficit focal. Trat: Desmopresina 10 mg intranazal sau

0.12 mg x 3/zi slg (Minirin Melt) aport hidric po sau 5% glucoza: 1-2 L

Hiponatremia
Neurologic:

greata,

edem cerebral, cefalee, obnubilare, coma

Semnele afectiunii de baza (Addison, hipopituitarism, SIADH) Scadere Na+ hTa Rapiditatea instalarii hNa+ Na+ < 120 mEq/L: risc vital

Hiponatremia - tratament
Etiologic SIADH: Restrictie hidrica Antagonist Rec V2 AVP = Vaptan
Substitutie corticoida (HHC Fludrocortizon, 2 x 0.1 mg/zi)

Substitutie tiroidiana: LT4 in doze de la 25 la 100 mg/zi, sub protectie antiagreganta


Cresterea capitalului de Na: < 10-15 mEq / 24h

Solutii fiziologice sau saline hipertone 0.5 - 2 L/zi


Creste> 15mEq/zi Risc de mielinoza pontina (sdr de demielinizare osmotica), mai sever in hNa+ cronica

Reglarea i explorarea hipofizei


Hipofiza: anatomie funcional Tipuri celulare i implicaii funcionale Comunicarea hipotalamo hipofizar Axa de cretere: reglare i explorare funcional Axa tiroidian: reglare i explorare funcional Axa suprarenal: reglare i explorare funcional Axa gonadic: reglare i explorare funcional Explorarea: farmacologic / fiziologic ?

Concluzii

Cell types in pars distalis


Cell Type Secretory Products Cell Population %

Somatotroph
Lactotroph Corticotroph Thyrotroph Gonadotroph

Growth hormone
Prolactin Adrenocorticotropic hormone Thyroid stimulating hormone Luteinizing hormoneFollicle-stimulating hormone

50
15 15 10 10

Substances
Peptides:
Activin B, inhibin, follistatin Aldosterone-stimulating factor Angiotensin II (angiotensinogen, angiotensin I-converting enzyme, cathepsin B, renin) Atrial naturetic peptide Corticotropin-releasing hormone-binding protein Dynorphin Galanin GAWK (chromogranin B) Growth hormone-releasing hormone Histidyl proline diketopiperazine Motilin Neuromedin B Neuromedin U Neuropeptide Y Neurotensin Protein 7B2 Somatostatin 28 Substance P (Substance K) Thyrotropin-releasing hormone Vasoactive intestinal poltpeptide Basic fibroblast growth factor Chondrocyte growth factor Epidermal growth factor Insulin-like growth factor I Nerve growth factor Pituitary cytotropic factor Transforming growth factor alpha Vascular endothelial growth factor Interleukin-I beta Interleukin-6 Leukemia inhibitory factor Acetylcholine Nitric oxide

Cell Types
F, G UN C,G,L, S G C G L, S,T G UN UN S T C T UN G, T UN G,L,T G, L,S,T G,L,T C,F UN G,T S,F UN UN L,S,G F T F C,F C,L F

Growth factors:

Cytokines:

Neurotransmitters:

C-corticotroph: F -Folliculostellate cell; G-gonadotroph; L-Lactotroph; S-somatotroph, T -thyrotroph; UN-unknown.

Disorders of the Endocrine System


Excess or deficiency Impaired synthesis Transport and metabolism of hormones Resistance to hormone action

Reglarea Axei GH
GHRH (44) SMS (14) GH

IGF1
GHRP Ghrelin

Insulin Tolerance Test


0.1/0.15 UI/Kgc, i.v. Obese: 0,3 UI/Kgc

Contraindicate
Epileptic seizures Severe heart ischemia

Oral Glucose Tolerance Test


Acromegaly:
positive & differential diagnosis Diabetes Mellitus

Oral glucose 75g GH peak level > 1 mg/L

IGF-1 : variation with age & sex

Reglarea Axei CSR


CRH / VP ACTH

Cortisol
Leptina Citokine GR, CRHR, V1b, ACTH R,

Short ACTH Stimulation Test


250 mg ACTH i.v.

Screening in Cushing Syndrome

Diagnosis in Cushing Syndrome

Inferior Petrosal Sinus Sampling


V. femurala ... IPS CRH 100 ug i.v.

Control - VCI
IPS: -5, 0, 2, 5, 10 min

Reglarea Axei Tiroidiene


TRH TSH

T4 / T3
Type II deiodinase Leptina TR, TRH R, TSH R

TRH test
400 mg i.v. TRH TSH is measured each 30 mins, for 3 h

Reglarea Axei Gonadice


GnRH LH & FSH

Prolactina
Testosteron /E2, Pg Inhibina /activina

Controlul sintezei LH i FSH de ctre GnRh

GnRH este eliberat in sistemul port hipotalamo- hipofizar, pornind din eminena median i legnd vascular adeno-hipofiza. Eliberarea este pulsatil tonic, iniial nocturn, apoi i diurn, ulterior apare o descrcare major, pre-ovulatorie. Eliberarea tonic provine din MBA, cea pre-ovulatorie din AHPO

Hypothalamic Hypophyseal Portal System Gonadotrophs

Stadiile dezvoltarii pubertare (Tanner)


Stage 1 Stage 1: Prepubertal, no pubic hair growth Stage 2: Testes grow; scrotal skin becomes redder and coarser; sparse and fine hair develops at base of penis Stage 3: Penis lengthens with small increase in diameter; scrotal skin reddens, thickens and crinkles, pubic hair thicker and coarser Stage 4: Penis and testes continue to grow; pubic hair coarser, darker and more curly Stage 5: Penis at adult size; pubic hair covers symphysis pubis and extends to inner thighs

Stage 2

Stage 3

Stage 4

Stage 5

Pulsatile LH Pattern in Human

Pulsatility in gonadal axis

Pulsatile hormones: Mix & Measure

CONCLUZII
Evaluarea bazala pentru hormonii cu secreie cvasiconstanta. Evaluare dinamica pentru hormoni cu ritm, sau secretie pulsatila. Teste de inhibiie pentru sindroame de hipersecretie. Teste de stimulare pentru deficit hormonal. Integrarea rezultatelor clinice, biochimice, imagistice.

Tineti cont de : hormoni, transport, metaboliozare,


receptori, interferente de reglare (feed-back nespecific).

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