NeuroendocrinologieHipotalamusul Patologia vasopresinei Diabetul insipid

Corin Badiu, 2012

NeuroEndocrinologieSistem nervos

Sistem imun

citokine

Sistem endocrin

ProprietatiComune Potentiale de actiune Secretie Mediatori (Peptide) Receptori

SpecificeAmploarea 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 EminenceOrgan circumventricular

Ependimal: tight J. Tanicitele (T4T3) Intermediar: VP&OT axonsExtern: capilare fenestrate

INTRACRINE AUTOCRINE PARACRINE

Semnalizare chimica / Hormonala

ENDOCRINE

NEUROENDOCRINE

Control genetic Biosinteza

Transport axonal

Slide Source: www.obesityonline.org

Neuroendocrinologia aportului alimentarTrunchiul cerebral - tinta pentru semnale de satietate perifericeArea 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 LeptinInsulin

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 seteiZece 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 apei2%Crestere Osmolaritatea LEC 10% Scadere Volum circulant

Osmoreceptori CNSDescarca ADH Antidiureza Conservarea apei Sete Apetit de Na

Baroreceptori Angiotensina II

Stimuli Aport de apa

Volum circulant ANP&BNP Osmolaritate LEC ANP&BNPReeves et al, 1998

Structura hormonilor neurohipofizariOxytocin-like peptides1 2 3 4 5 6 7 8 9 Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (NH2)

Vasopressin-like peptides1 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 V1aTM IV TM III TM II

TM V TM VI

TM VII

TM I

Noyau paraventriculaire

Noyau supraoptique

Neurohypophyse de rat -ME

Hipotalamus

Vasopresina RinichiMuschi neted

OxitocinaUter

SinGonade ? AH ?Adipocite Creier

AH FicatSuprarenale

Creier

Sindroame poliuro-polidipsiceHipotalamusSete

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 InsipidCaracteristici clinice sunt rezultatul deficientei de AVP Excreia unor volume mari de urin (poliurie) Excreia de urin diluat (OSM 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 distalisCell Type Secretory Products Cell Population %

SomatotrophLactotroph Corticotroph Thyrotroph Gonadotroph

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

5015 15 10 10

SubstancesPeptides: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 TypesF, 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 Test0.1/0.15 UI/Kgc, i.v. Obese: 0,3 UI/Kgc

ContraindicateEpileptic seizures Severe heart ischemia

Oral Glucose Tolerance TestAcromegaly: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 Test250 mg ACTH i.v.

Screening in Cushing Syndrome

Diagnosis in Cushing Syndrome

Inferior Petrosal Sinus SamplingV. femurala ... IPS CRH 100 ug i.v.

Control - VCIIPS: -5, 0, 2, 5, 10 min

Reglarea Axei Tiroidiene TRH TSH

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

TRH test400 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).