GLUCOCORTICOI

DS

And metabolism

YUNIADI

SUTOWO
 Adrenal Cortex Hormones
The adrenal cortex comprises
three zones, or layers:
1- Zona glomerulosa: The outermost layer, main
site for production of mineralocorticoids ,
mainly aldosterone, which is largely
responsible for the long-term
regulation of blood pressure .

2- Zona fasciculata : middle layer,

responsible for producing glucocorticoids,
chiefly cortisol in humans. It secretes a basal
level of cortisol but can also produce bursts
of the hormone in response to
adrenocorticotropic hormone (ACTH) from
the anterior pituitary.

3- Zona reticularis : The inner most cortical

layer, It produces androgens, mainly
dehydroepiandrosterone (DHEA) and
androstenedione in humans.
3
 21 C

22
20 C 26
23
12 24 25
18 17
11 16
27
KOLESTEROL 13

C D
1 19 9
14 15
2
10 8

A B
3
7
5
OH 4 6

SIKLO PENTANO PERHIDRO FENANTREN

 STEROID  HASIL DARI   
      KORTEKS ADRENAL   
1. STEROID C21 :  GLUKOKORTIKOID, 
                                MINERALOKORTIKOID,    
                                PROGESTERON 

2. STEROID C19 :  ANDROGEN

3. STEROID C18 :  ESTROGEN ( TRACE               
                                HORMONE )
 STEROID HORMONE MODE OF ACTION

Steroid

+
Target cell

Steroid transporter nucleus

protein

Hsp90

SRC

Activated
SRC = Steroid
Hsp90
receptor

complex

DNA

Hsp90

mRNA
New Protein
Biological
protein synthesis
response

Steroid receptor complex in cytoplasm binding steroid activates and moves to nucleus
HORMONE OR EFFECTOR HRE DNA
SEQUENCE

GLUCOCORTICOID GRE
PROGESTINS PRE GGTACA NNN
TGTTCT
MINERALOCORTICOIDS MRE
ANDROGENS ARE

ESTROGENS ERE AGGTCA ---

TGA/TCTT

THYROID HORMONE TRE

RETINOIC ACID RARE AGGTCA
N3,4,5 AGGTCA
VITAMIN D VDRE

cAMP CRE TGACGTCA

NOTES : 1. IMPERFECT INVERTED PALINDROMES / HALF

BINDING
SITES
 CIRI   HORMON   GRUP I
1. LOKASI RESEPTOR DI INTRASEL
 2. BERSIFAT LIPOFILIK / HIDROFOBIK
 3. TERIKAT PADA  PROTEIN  
     PENGANGKUT HORMON
 4. WAKTU PARUH : PANJANG
 5. FUNGSI : SINTESIS PROTEIN
 6. MEDIATOR : KOMPLEKS                     
     H O R M O N  ­  R E S E P T O R 
 7. STEROID,  ASAM RETINOAT  DAN 
     TIROID
KOLESTEROL
17α0H ASE 17,20 LYASE
P450 SCC P450C17 P450 C17
DESMOLASE

PREGNENOLON 17 0H PREGNENOLON DHEA

3 β OHSD DAN  5-4 ISOMERASE

PROGESTERON 17 OH PROGESTERON
ANDROSTENEDION

21 OH ASE
11 DEOKSIKORTIKOSTERON 11 DEOKSIKORTISOL
TESTOSTERON
11 OH ASE
KORTIKOSTERON KORTISOL

18 OH ASE
18 0H KORTIKOSTERON KORTISON

18 OH DEHIDROGENASE
 CH2H

CH2H
C0
CH3

C0 0
CH3 0H
0H 0H H3C
CH 3
0

0
kortison
kortisol
(hidrokortison)
CH2H

CH3
CH2H C0

CH3 C0 CH3
0H

CH3 0

0
11 deoksikortikosteron
kortikostero
 THE BIOLOGIC ACTIVITY OF A
STEROID DEPENDS ON:
1. Its ability to bind to a receptor
2. Concentration of free hormone in the
plasma
• Cortisol, corticosterone, and aldosterone
all bind with high affinity to the
glucocorticoid receptor
• However, cortisol is dominant because of
its high plasma concentration
 RESEPTOR 
MINERALOKORTIKOID
TIPE I DAN II DIGUNAKAN MENGIKAT 
MINERALOKORTIKOID, 
TIPE II JUGA MENGIKAT  HORMON  
GLUKOKORTIKOID. 
      AFINITAS MINERALOKORTIKOID PADA TIPE III  
SANGAT  RENDAH. 
 AFINITAS ALDOSTERON
TERHADAP RESEPTOR NYA
KADAR ALDOSTERON DARAH LEBIH KECIL DPD KADAR  
  DOC,   KORTISOL DAN KORTIKOSTERON. NAMUN
  IKATAN ALDOSTERON TERHADAP RESEPTOR   
  MINERALOKORTIKOID TIPE I   LEBIH KUAT DPD IKATAN 
  TERHADAP DOC, KORTISOL DAN KORTIKOSTERON
  OLEH KARENA:

1. KADAR ALDOSTERON EFEKTIF LEBIH BESAR DPD KADAR  
    DOC, KORTIKOSTERON ( BENTUK BEBAS ).
2. RESEPTOR ALDOSTERON MENGANDUNG ENZIM 11 BETA 
    OHSD YANG MAMPU MENGUBAH KORTIKOSTERON DAN 
    KORTISOL  MENJADI SENYAWA YANG TIDAK AKTIF  ( me –
    tabolit 11 beta ) .
 KORTISOL LEBIH POTEN (
AKTIF ) DARIPADA KORTIKOSTERON

meskipun ikatan kortisol lebih

kuat
terhadap CBG ( corticosteroid binding
globulin ) oleh karena
T1/2 kortisol lebih lama daripada
kortikosteron .

T1/2 kortisol = 1,5 - 2 jam

T1/2 kortikosteron : kurang dari 1 jam
 Storage & Secretion
Steroid hormones are secreted into circulation when they
are produced (little storage).
NB: In contrast to the direct innervation of the medulla, the
cortex is regulated by neuroendocrine hormones secreted
by the pituitary gland and hypothalamus, as well as by the
renin-angiotensin system.
The hypothalamus produces corticotropin-releasing
hormones, which stimulate the pituitary gland. the
pituitary gland, in turn, produces corticotropin hormones,
which stimulate the adrenal glands to produce
corticosteroid hormones.
• Cortisol release follows the diurnal rhythm of ACTH
release. Highest level in the morning, lowest in the
evening. 18
 Cortisol: Regulation & Transport
Cortisol secretion is under control of the hypothalamic-Pituitary-

Adrenocortical axis as in figure.

Three factors regulate adrenocorticotrophic hormone ACTH (and

therefore cortisol) secretion:

1. Negative feedback control: ACTH release from the anterior

pituitary is stimulated by hypothalamic secretion of

corticotrophin-releasing hormone (CRH). Increased plasma

cortisol or synthetic glucocorticoids suppress secretion of CRH.

2. Stress (e.g. major surgery, emotional stress): leads to a sudden

large increase in CRH (and ACTH) secretion.

3. The diurnal rhythm of plasma cortisol: cortisol levels are

highest at the start of the working day, falling to lowest levels at The hypothalamic-
March 4, 2013 Dr. Mohamed Z Gad 20
the onset of sleep. Pituitary-
Degradation & Excretion
Glucocorticoids: Half life of
glucocorticoids is about 60 min; They
are reduced by NADPH dependent
enzymes to form biologically inactive
compounds; that conjugated with
either glucuronide or sulfate which
render them water soluble. About 70%
excreted in urine, 20% in feces & rest
in the skin. 21
 Cortisol: Action
Glucocorticoids have widespread metabolic effects on carbohydrate,

fat and protein metabolism.

In the liver cortisol stimulates gluconeogenesis , amino acid uptake

and degradation, and ketogenesis . Lipolysis is increased in adipose

tissue. Therefore, they oppose some of the actions of insulin.

In excess, they impair glucose tolerance and alter the distribution of

adipose tissue. Also cortisol helps maintain the extracellular fluids

22
and normal blood pressure.
 Metabolic functions of
Glucocorticoid
• Glucocorticoid Hormones (cortisone, cortisol &
corticosterone).
A- Effect on Carbohydrate metabolism:
• gluconeogenesis, particularly in the liver (the synthesis of
glucose from non-hexose substrates such as AA and glycerol
from triglyceride breakdown).
• AA from extrahepatic tissues: These serve as substrates for
gluconeogenesis.
• glucose uptake in muscle and adipose tissue: A mechanism to
conserve glucose.
• glycogen storage (liver).

B- Effect on fate metabolism:

• fat breakdown : The fatty acids released by lipolysis in
adipose tissue For production of energy in tissues like
muscle, and the released glycerol provide
Dr. Ma another substrate 23
for gluconeogenesis.
C- Effect on Protein metabolism:
• Protein degradation to release AA for
gluconeogenesis.
• Protein synthesis in the liver.
• Muscle catabolism .

D- Other Effects:
It has potent anti-inflammatory and
immunosuppressive
properties.
• Impair phagocytic activity and migration of white
blood cells; Reducing production of PG and 24
Dr. Manal Basyouni
 EFFECTS OF GLUCOCORTICOIDS

• Increase protein and RNA metabolism

( PHYSIOLOGIC EFFECT )
• Suppress immune response (lysis of lymphocytes)
• Suppress inflammation by :
- Decreased leukocyte activity
- Decreased fibroblast
- Increased lipocortins which inhibit phospholipase
A2
 KLASIFIKASI HORMON 
STEROID
DIDASARI KEMAMPUAN
MENGINDUKSI ENZIM TAT
( TIROSIN
AMINOTRANSFERASE ) DI HATI
1. AGONIS
2. AGONIS PARSIAL
3. ANTAGONIS DAN ANTAGONIS
PARSIAL
 GANGGUAN FUNGSI KORTEKS 
ADRENAL
I. INSUFISIENSI ADRENAL PRIMER 
              (   PENYAKIT ADDISON )
   TJD PENURUNAN GLUKOKORTIKOID, SEHINGGA TJD 
   PENINGKATAN ACTH DAN POMC ­­­ 
                     HIPERPIGMENTASI .
   MINERALOKORTIKOID, ANDROGEN JUGA MENURUN.
 II.  INSUFISIENSI ADRENAL SEKUNDER
    TJD PENURUNAN GLUKOKORTIKOID DAN ANDROGEN
    DARAH AKIBAT PENURUNAN ACTH­­­­­ TIDAK TERJADI 
    HIPERPIGMENTASII
 GANGGUAN FUNGSI KORTEKS 
ADRENAL

III. SINDROMA CUSHING (     GLUKOKORTIKOID )
       PENYAKIT CUSHING (      ACTH ­­­­­­ BISA  TERJADI
      HIPERPIGMENTASI ). TJD EFEK MINERALOKORTIKOID 
      DARI GLUKOKORTIKOID,   GLUKOKORTIKOID DAN 
      ANDROGEN    , ALDOSTERON NORMAL 
 Cushing
syndrome
•condition resulting from long term exposur
to
excessive glucocorticoids (cortisol)
• ‘hypercortisolism’
• intake of exogenous glucocorticoids /
overproduction of cortisol
Cushing
• 10-15 in 1 million people are affected
disease
caused by excessive secretion of ACTH
by
 The most common symptom of
Cushing's
syndrome is sudden weight gain,
usually
Multiple wide striae
on the abdomen of a
patient with
Cushing's disease.
http://www-clinpharm.medschl.cam.ac.uk/images/addisons.jpg
 Hyper­
adrenocorticism

Post­surgery
Untreated Cushing’s Syndrome
 Laboratory studies of

adrenocorticol functions
1. ACTH stimulation test
2. Dexamethasone suppression test
3. Metyrapone/Metopirone stimulation
test
4. Insulin hypoglycemia test
5. Plasma total cortisol