Anda di halaman 1dari 34

GLUCOCORTICOIDS

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
KOLESTEROL 13 27

C D
1 19 9
14 15
2
10 8

A B
3
7
5
OH 4 6

SIKLO PENTANO PERHIDRO FENANTREN

A,B,C,D
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
receptor Hsp90
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
2. VDRE ( N=3 ) , TRE ( N=4 ) AND RARE ( N=5 )
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
HORMON - RESEPTOR
7. STEROID, ASAM RETINOAT DAN
TIROID
KOLESTEROL
170H ASE 17,20 LYASE
P450 SCC P450C17 P450 C17
DESMOLASE

PREGNENOLON 17 0H PREGNENOLON DHEA

3 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
ALDOSTERON
CH2
H
CH2H
C0
C0 CH3
0 0H
CH3 0H
0H H3C

0
kortison
kortisol
(hidrokortison)
CH2H

C0
CH3
CH2
H

CH3 C0 CH3
0H

CH3 0

0 11 deoksikortikosteron
kortikosteron
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 onset of sleep.

In the circulation, glucocorticoids are mainly protein-bound


(~90%), chiefly to cortisol-binding globulin (CBG or transcortin)
and to albumin. Plasma CBG is increased in pregnancy and with
oestrogen treatment. The biologically active fraction of cortisol in The hypothalamic-
plasma18isDecember
the free (unbound) form, though most assays measure Pituitary-
2017 Dr. Mohamed Z Gad 20
the total (bound + free) conc. Adrenocortical
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
and normal blood pressure.
Cortisone, sometimes used therapeutically, is not secreted in
human body in significant amounts. It is biologically inactive until it
has been converted in vivo to cortisol.
22
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 another substrate for gluconeogenesis.
Lipolysis in extremities and lipogenesis in face and trunk
Dr. Ma 23
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 leukotrienes
Prevent edema; Reduce capillary permeability.
Dr. Manal Basyouni 24
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
4. STEROID INAKTIF
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 exposure to
excessive glucocorticoids (cortisol)
hypercortisolism
intake of exogenous glucocorticoids /
overproduction of cortisol
10-15 in 1 million people are affected

Cushing disease
caused by excessive secretion of ACTH by
pituitary tumor ( pituitary adenomas )
The most common symptom of Cushing's
syndrome is sudden weight gain, usually
manifested by central obesity.
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

Post-surgery
Untreated Cushings 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