Suprarenala fiziologie

Monica Gheorghiu, 2014

Anatomie
2 glande situate retroperitoneal, ntre a 11-a vertebr toracic i
prima lombar, pe faa post-medial si superior de rinichi

Embriologie: deriv din

mezodermul primitiv,
din partea medial a
anului urogenital
Aspect piramidal, Y
inversat. 4-6 / 2-3 cm

Histologie
Capsula
Zona glomerulosa
Zona fasciculata
Zona reticularis
Medulosuprarenala

Vena central

Histologie

17HOlaza

CGA

Histologie

Electromicrograph of rat adrenal gland. Chromafine cell with

characteristic granules (G) in direct contact with adrenal
cortical cell with characteristic mitochondria (M)

Steroidogeneza specific
Mineralocorticoizi (C21)
Glucocorticoizi (C21)
Androgeni (C19)
Medulosuprarenala

Vena central

Structura hormonilor steroizi

Nucleu ciclopentano-perhidro-fenantrenic

Structura

Structura

Substratul steroidogenezei
22 CH

21 CH 3

20 CH

18 CH 3
12

19CH 3

HO

A
4

1
2

11

10

13
14

24 CH

23CH 2

25 CH
27 CH 3

17

16

15

8
7

26 CH

colesterol

Steroidogeneza

Enzime Steroidogene
Doar 2 familii
Citocrom P450:
- Hidroxilaze ( liase)
- Introduc O atomic (C-O-H)

Hidroxisteroid Dehidrogenaze (HSD)

- Oxideaz alcool / reduc cetone
- 3HSD acioneaz ca 4, 5 isomeraz

CYP17, 17a-hydroxylase/17,20-lyase; 3b-HSD, 3b-hydroxysteroid dehydrogenase;

CYP21A2, 21-hydroxylase; CYP11B1, 11b-hydroxylase; CYP11

Cholesterol
P450CSCC
Pregnenolone

P450C17

3HSD
Progesterone

17-hydroxypregnenolone

P450C17

Dehydroepiandrosterone

(DHEA)

ZR

3HSD
P450C17

17-hydroxyprogesterone

P450C21
Deoxycorticosterone
(DOC)
P450C11B1
Corticosterone
P450C11B2

Aldosterone ZG

P450C21

ZG

11-Deoxycortisol
P450C11B1

Cortisol

ZF

ZF
ZR

P450C11B1 & P450C11B2

P450C11B2 duplicaie genic a P450C11B1
P450C11B1 = 11-hidroxilaz
- Hidroxileaz 11-deoxicortisol n ZF
P450C11B2 = aldosteron sintetase
- Nou 18-hidroxilase + aldehid sintetaz
- Pstreaz rol de 11-hydroxylase in ZG

Reglarea steroidogenezei
A B C D + E
EDV (etapa determinanta a vitezei sintezei
pentru toti steroizii = conversia colesterol (C27)
la pregnenolon (C21)
Catalizat de P450CSCC (enzima de clivare a catenei lat)
Reacie catalizat n:
(A) Reticulul endoplasmic
(B) Aparatul Golgi
(C) Mitocondrie

Cum limiteaz
localizarea P450CSCC
steroidogeneza?
P450CSCC n membrana mitocondrial intern
MMI i MME separate prin spaiu apos
Necesit transport proteic(s) - StAR (steroidogenic acute regulatory
protein)

Steroidogeneza

Colesterol plasmatic LDL (80%) importat prin mec. mediat de receptor

Sintetizat de novo din acetat

Steroidogeneza

Reglarea cortizol si DHEA

Stress
CRH

Corticotrophin
releasing hormone

(+)
ACTH
(-)

(+)

Adrenocorticotrophic
hormone (from POMC*)

Cortisol
+ DHEA(S)

Ritmul circadian al cortizolului

600

Stress

Plasma
[ cortisol ]
(nmol/L)

100
00:00 06:00 12:00
Time

18:00

00:00

Reglarea aldosteronului

K+

Cortisol
OH

OH

HO

90% - CBG: 3Keto

5% - albumina
5% -liber

H
O

cortisol

T1/2 70-120 min

H

C% plasm. 8 a.m. = 5-22

g/dl
Productie/24 h = 8-25
mg/zi
Elim nemetabolizata 0.1%

Metabolismul cortizolului

11B HSD1 (E F) ficat, t adipos, gonade , os sd metabolic?

Aldosteron
OH
CH2

HO

O
aldosterone

60% - albumina

O 30% -liber

C% plasm. 2-9 ng/dl

H
H

10% - CBG

Productie/24h = 10-30
mg/zi

Dehidroepiandrosteron (DHEA)
O

Slab legat de
proteine, cu
exceptia DHEAs

Variaza cu varsta
H
HO

Conversie periferica
in T si aromatizare
in E2

Neurosteroizi naturali i sintetici

TEM, 13, 1, 2002

Efecte ale Neurosteroizilor

Moduleaza excitabilitatea neuronilor centrali

TEM, 13, 1, 2002

Aciune celular a steroizilor

R nucleari + citosolici legati de complex inhibitor hsp

Aciune celular

Aciune celular

Translocation of the green fluorescence protein (GFP)-fused hGR into the

nucleus. HeLa cells were transfected with the GFP-hGR-expressing plasmid
and Translocation of GFP-hGR was sequentially detected by confocal
microscope after addition of 10-6 M of dexamethasone.

Efecte fiziologice - Cortizol

Metabolism glucidic : protejeaza de starvare
tesuturile dependente de glucoza
( cresc gluconeogeneza, sinteza de glicogen)
periferie : utilizarea glucozei
Metabolism proteic: proteoliza
efecte catabolice : masa musculara, atrofia tes.
limfoid, balanta negativa a azotului, subtierea pielii

Efecte fiziol (cont.):

Metabolism lipidic : redistributia grasimii corpului
(ceafa de bizon, fata luna plina, supraclavicular,
pierderea grasimii pe extremitati)
- induce lipoliza in adipocite ( FFA)
Balanta electroliti si apa: creste excretia renala de
apa libera, excretia Ca de catre rinichi

Efecte fiziol (cont.)

Cardiovasculare:
- creste reactivitatea vasculara la alte
substante vasoactive
Muschi scheletici: functie normala
(miopatie steroida)
SNC: neurosteroizi (regleaza excitabilitatea
neuronala)

Efecte fiziol (cont.)

Sange: afecteaza leucocitele circulante
(Addison: limfocitoza; Cushing; neutrofilie, eozinopenie )
Anti-inflammatorii si imunosupresive
altereaza raspunsul imun al limfocitelor,
scade extravazea leucocitelor la locul injuriei,
scade fibroza ,
afecteaza productia de citokine si de factori vasoactivi

Alte efecte:
Psihice: doze insomnie, euforia,
depressie, pseudomotor cerebri
depresie
Scade absorbtia vit. D
Scade actiunea GH
Inhiba actiunea gonadotropilor
Efecte asupra plamanului fetal

Efecte fiziol - Aldosteron

Cardiovasculare: creste TA

Retentie de Na, excretie de K si H+

Efecte fiziol - DHEA

Anabolizant proteic

Virilizant slab (pilozitatea axilo-pubiana la pubertate)

Well-being, +/- libido

Aplicaii farmacologice

Glucocorticoizi

Transport: liber 30%, legat de albumina 70%

Clasificarea
adrenocorticosteroizilor
I. Short to medium-acting glucocorticoids:
a. Hydrocortisone (cortisol)
b. Cortisone
c. Prednisone
d. Prednisolone
e. Methylprednisolone
f. Meprednisone

II. Intermediate-acting glucocorticoids

a. Triamcinolone
b. Paramethasone
c. Fluprednisolone

III. Long-acting glucocorticoids

a. Betamethasone
b. Dexamathasone

IV. Mineralocorticoids
a. Fludrocortisone
b. Desoxycorticosterone acetate

Comparaii farmacologice

Dozele echivalente de glucocorticoizi (puterea antiinflamatorie) sunt:

Hidrocortizon (cortizol)
20mg
Cortizon acetat
25mg
Prednison sau Prednisolon 5mg
Metilprednisolon sau Triamcinolon 4mg
Betametazona
2 mg
Dexametazona
0,5mg

Toxicitate:
Intreruperea terapiei:
febra, mialgii, artralgii, malaise, pseudomotor cerebri (
presiunea intracraniana, papilledema), rebound al bolii tratate
Corticoterapie cronica
anomalii fluide si electroliti, HTA, hiperglicemie,
suscceptibilitate la infectii, miopatie, tulb. comportament,
cataracta, oprirea cresterii, redistrib grasimii , acnee, hirsutism,
vergeturi, echimoze, osteonecroza, ulcer peptic
Supresie adrenal - >2 sapt de trat.
Contraindicatii: ulcer peptic, boli cardiace, HTA with ICC,
infectii, psihoza, diabet zaharat, osteoporoza, glaucom, inf cu
herpes simplex

Masuri suplimentare in
corticoterapia cronica :
Reducere progresiva a dozei sau
Administrare in zile alternative
Dimineata (mimarea ritmului circadian)

Dieta bogata in potasiu si saraca in sodiu

Restrictie calorica pt prevenirea obezitatii
Aport proteic crescut
Terapie antacida
Calcium and vit D, therapie fizica
Bifosfonati pt cei cu terapie cr si risc de osteoporoza

Antagonisti ai sintezei
corticosuprarenalei
Synthetic inhibitors and glucocorticoid antagonists
Metyrapone inhiba 11-hydroxylation, interfering with cortisol
and corticosterone synthesis
Aminoglutethimide blocks the conversion of cholesterol to
pregnanelolone and causes a reduction in the synthesis
Ketoconazole an antifungal imidazole derivative; potent, nonselective inhibitor of adrenal and gonadal steroid synthesis;
Mitotane adrenolytic; adrenal Ca;
Mifepristone (RU 486) 19-norsteroid; has strong antiprogestin activity; blocks glucocorticoid receptor

Insuficienta suprarenaliana
Insuficienta suprarenala primara
a. Boala Addison (> 90% din tes. CSR este distrus)
75% Auto-imuna
20% Tuberculoza
5% Rare procese distructive
Waterhouse-Friederichson syndrome (hemoragie SR bilat prin
infectie cu Meningococcus sau Pseudomonas

b.Deficite enzimatice SR (hiperplazia congenitala SR) deficit

de 21 OH-laza
Insuficienta suprarenala secundara: Boala hipofizara
Iatrogenica

Insuficienta suprarenala primara

Clinica
Precoce:
Anorexie, letargie &
slabiciune.

Piele :
Hiperpigmentare (dg dif
cu I.SR sec paloare)
Ariile expuse la soare
Cavitatea bucala
Cicatrici

Cardiovascular:
Hipotensiune ortostatica

Gastrointestinal:
Greata & voma

Acut:
Criza Addisoniana :
Post chirurgie/trauma
Infectie

Hipotensiune, greata,
varsatura, astenie,
Soc hipovolemic
Alte boli autoimune:
tiroida, ovar, pancreas

Sindromul poliglandular autoimun

Asocierea mai multor anomalii endocrine de cauza autoimuna,
avand in comun boala Addison la care se adauga :
- sindrom PGA I: hipoparatiroidism i candidoz
mucocutanat, displazii ectodermale
- sindrom PGA II : boal autoimun tiroidian (mai frecvent
tiroidit) i diabet zaharat tip 1.
Ambele tipuri pot asocia si alte boli autoimmune endocrine
sau non- endocrine, de exemplu: insuficien ovarian sau
testicular primar (mai frecvent in PGA tip 1), vitiligo,
anemie Biermer

Adrenal Failure
Laboratory Findings: Non-Endocrine
Haematology:
Lymphocytosis & eosinophilia

Biochemistry:
hyperkalaemia & hyponatraemia
Hypoglycaemia

Immunology:
Adrenal autoantibodies (70% case autoimmune).

Microbiology:
Blood culture & adrenal biobsy
Tuberculosis or fungal infection

Insuficienta SR
Investigatii Endocrine
Cortizol seric ora 8 9 am < 5 ug/dl.
Cortisol urinar nu e util pt dg
Testarea rezervei adrenale

Insuficienta SR
Investigatii Endocrine
Pacientul primeste substitutie steroida?
Prednisone/prednisolone cross-reactioneaza partial
in testele pt cortisol.
Hydrocortisone = Cortisol.

Diagnostic
1. Stabilirea sindromului
test scurt la synacthen (250 g i.v.)
masurare cortizol 0 - 30 60 min. Normal > 20 ug/dl.
test lung la synacthen depot (1 mg i.m.)
masurare dupa 24 h cortizol - > 20 ug/dl
CLU, 17 OHCS, 17 KS N > 2 x valoarea
bazala (nu se mai folosesc)

Raspunsul cortisolului seric la ACTH sintetic (testul scurt) in

insuficienta adrenala

nmol/L

1100

825

550

275

Diagnostic

1. Stabilirea

sindromului (test la synacthen)

2. Stabilirea cauzei- ACTH = Boala Addison anticorpi antiSR
CT adrenal
Rx pulm

CT adrenals

Tratament
Principii
- tratament de substitutie, zilnic, toata viata;
- doza de glucocorticoizi se creste in stres, infectii
acute, interv. chirurgicale
- dieta normo/hipersodata, bogata in dulciuri (mai
ales initial)
Hydrocortisone 20 mg/zi sau Prednison 5-7.5 mg/zi p.o
Mineralocorticoid: fludrocortizon (Astonin) 0,1 mg/zi p.o
optional DHEAS 50 mg /zi la femei

Insuficienta SR acuta
Definiie = Urgen medical generat de scderea
brusc a produciei de cortizol datorat unei leziuni
suprarenale primare sau unui deficit sever de ACTH,
manifestat prin adinamie, vrsturi, colaps i semne
ale agentului etiologic.
decompensarea unei insuficiene suprarenale cronice
sau de "novo"

Tratamentul insuficientei SR acute

Obiective
-corectarea colapsului i a deshidratrii extracelulare
- echilibrarea cortizolemiei
-corectarea tulburrilor electrolitice i a hipoglicemiei
- corectarea factorilor declanatori

Principii: glucocort. i.v.

Tratamentul insuficientei SR acute

Soluie izoton NaCl 0, 9% + glucoz 5%: 3L foarte rapid apoi
70mL/kg lent n 24h p.e.v.

2. Hemisuccinat hidrocortizon 100mg iv bolus, apoi 100mg

perfuzie pn la 400-600mg/24h
sau dexametazon fosfat 4mg iv (timp de njumtire lung, nu
interfer cu testele)
3. Cldur, microclimat optim.
4. Supraveghere K+: in hiperkalemie se adm. gluconat de calciu
10% i.v. lent; se adaug insulin n perfuzie.
5. n infecii ca factor precipitant (febr): antibiotice
6. La scderea dozei de glucocorticoizi - fludrocortizon 0.1 mg/zi

Hiperplazia adrenala congenitala

Defecte enzimatice corticosuprarenale congenitale, urmate
de hiperplazia compensatorie a glandelor suprarenale

Etiologie (in ordinea frecventei):

Deficit de 21 hidroxilaza
Deficit de 11 beta-hidroxilaza
Deficit de 3 beta HSD, alte deficite

Cholesterol
P450CSCC
Pregnenolone

P450C17

3HSD
Progesterone

17-hydroxypregnenolone

P450C17

Dehydroepiandrosterone

(DHEA)

ZR

3HSD
P450C17

17-hydroxyprogesterone

P450C21
Deoxycorticosterone
(DOC)
P450C11B1
Corticosterone
P450C11B2

Aldosterone ZG

P450C21

ZG

11-Deoxycortisol
P450C11B1

Cortisol

ZF

ZF
ZR

Hiperplazia adrenala congenitala

Clinica
La nou-nascut si copil
- fete: intersexualitate, urmata de pubertate precoce heterosexuala (cu virilizare) def.
CYP 21, 11, 3bHSD
- baieti: macrogenitosomie, urmata de pubertate precoce (def CYP21, 11); rareori
dezvoltare sexuala insuficienta (def 3bHSD)

+/- sd pierderii de sare (forma completa def CYP 21)

+/- HTA (def CYP 11, CYP 17)

Hiperplazia adrenala congenitala

Clinica

Hiperplazia adrenala congenitala

Clinica
La adult
- fete:
Forme cu pierdere de sare (Insuf. SR acuta)
- virilizanta simpla (amenoree, hirsutism)
- cu debut tardiv (anovulatie, minim hirsutism)
- baieti: infertilitate (inhib gonadotropilor)
Ambele sexe: statura finala mica

Hiperplazia adrenala congenitala

Clinica

Hiperplazia adrenala congenitala

Diagnostic

Hormonul din aval fata de deficitul hormonal este crescut

- 17 OH Progesteron pt def CYP 21
- 11 deoxicortizol pt def CYP 11
DHEAs, 17 KS urinari crescuti

Hiperplazia adrenala congenitala

Tratament
Principii: blocarea sintezei excesive de androgeni printr-o doza substitutiva de
glucocorticoizi care sa scada ACTH
Prednison 5 mg/zi sau Dexametazona 0,5 mg/zi seara la culcare
sau Hidrocortizon 12 mg/mp in 2-3 prize
Corectia chirurgicala a tractului genital