ENDOKRINOLOGI

Dono Indarto, dr., M.Biotech.St., PhD

 ADRENAL (SUPRARENAL) GLANDS
1. Adrenal glands – paired, pyramid-shaped organs atop the
kidneys
2. Weigh 6-10 g
3. Structurally and functionally, they are two glands in one
• Adrenal cortex (80-90%)– glandular tissue derived from
embryonic mesoderm
• Adrenal medulla (10-20%)– formed from neural ectoderm, can
be considered a modified sympathetic ganglion
ADRENAL HISTOLOGY
ADRENAL
CORTEX
 STRUKTUR KELENJAR ADRENAL

1. Zona glomerulosa(outermost region)

• 15% of adrenal cortex
• produces mineralocorticoids,which are responsible for regulating
• salt and water metabolism
• Major mineralocorticoid: aldosterone
 STRUKTUR KELENJAR ADRENAL
(CONT)
2. Zona fasiculata(middle region)
• 78% of adrenal cortex
• produces glucocorticoids,which are concerned with normal
• metablism and resistance stress.
• Major glucocorticoid: cortisol
 STRUKTUR KELENJAR ADRENAL
(CONT)
3. Zona reticularis (innermost region )
• 7% of adrenal cortex
• produces adrenal androgens
• Major androgen: dehydroepiandrosterone (DHEA)
Regulasi sekresi
hormon kelenjar
adrenal (HPA
Axis)
STRUCTURE OF STEROID HORMONES
 BIOSYNTHESIS OF STEROID
HORMONES
1. Peptide hormones are encoded by specific genes; steroid hormones are
synthesized from the enzymaticaly modified cholesterol.

2. Thus, there is no gene which encodes individual hormone.

3. The regulation of steroidogenesis involves control of the enzymes which

modify cholesterol into the steroid hormone of interest.
 BIOSYNTHESIS OF STEROID
HORMONES
1. Steroids are derivatives of cholesterol

2. Cholesterol is from the lipid droplets in cortical cells (cholesterol

esters in LDL)

3. Removed cholesterol is replenished by cholesterol in LDL in blood

or synthesized from acetate
Peran Liver X Receptor dalam sintesis hormon
steroid dari Cummins et.al. (2006), J Cin Invest 116:
20
22
• Mitochondrial side chain cleavage enzyme
cholesteroldesmolase initiates the synthesis of
the progestins.
Isocaproic aldehyde

• It hydroxylates C 20 and 22 and involves the

cleavage of a 6-carbon group from cholesterol
(isocaproic aldehyde).

• This reaction require cytochrom P- 450 as an

intermediate electron carrier (integral part of the
inner mitochondrial membrane, a flavoprotein
containing both FAD and FMN).

• Electron pass from the reduced NADPH to FAD,

then to FMN and finally to an O2
Hormonal Stimulation Of Steroid Hormone
Biosynthesis
• Hormone stimulation depends
on the cell type and receptor
(ACTH for cortisol synthesis,
FSH for estradiol synthesis, LH
for testosterone synthesis etc.)

• Hormone binds to cell

membrane receptor and activates
adenylate cyclase mediated by a
stimulatory G protein.

• Receptor, activated by
hormone, may directly stimulate
a calcium channel or indirectly
stimulate it by activating the
phosphatidylinositol (PI) cycle.
 BIOSYNTHESIS OF STEROID
1. HORMONES(CONT)
Steroid hormones are synthesized and secreted on
demand (not stored)
2. The first and rate-limiting step in the synthesis of all steroid
hormones is conversion of cholesterol to pregnenolone by
the enzyme cholesterol desmolase (aka cholesterol side
chain cleavage (SCC) enzyme/P450scc/CYP11A1)
3. Newly synthesized steroid hormones are rapidly secreted
from the cell
4. Following secretion, all steroids bind to some extent to
plasma proteins: CBG and albumin
 BIOSYNTHESIS OF STEROID
HORMONES (CONT)
5. Critical step is the cell activity in mobilizing
cholesterol
stored in a droplets, transport of cholesterol to
mitochondrion.
6. The rate-limiting step is the rate of cholesterol side
chain
cleavage in mitochondrion by enzymes known as
the
cytochrome P450 side chain cleavage enzyme
complex.
Hormonal Stimulation Of Steroid Hormone
Biosynthesis
• The increase in cAMP
activates protein kinase
whose phosphorylations
cause increased hydrolysis of
cholesteryl esters from droplet
to free cholesterol and
increase cholesterol transport
into the mitochodrion.

• Elevated Ca 2+ levels and

protein phophorylation bring
about induced levels of the
side chain cleavage reaction.

• Steroid is produced, secreted

into the extracellular space
and circulated to the target
tissue in the bloodstream
 STEROIDOGENIC ENZYMES

Common name „Old“ name Current name

Cholesteroldesmolase P450SCC CYP11A1

(Side-chain cleavage enzyme)
3b-hydroxysteroid dehydroge- 3 b-DH 3 b-DH
nase
17a-hydroxylase/17,20 lyase P450C17 CYP17

21-hydroxylase P450C21 CYP21A2

11b-hydroxylase P450C11 CYP11B1

Aldosterone synthase P450C11AS CYP11B2

Aromatase P450aro CYP19

Jalur klasik sintesis hormone korteks
Sintesis Gkukokortikoid Lokal (Ekstra Kelenjar Korteks Adrenal)
Fungsi Hormon Lokal Glukokortikoid dan Mineralokortikoid
 TRANSPORT OF HORMONES IN THE
BLOODSTREAM
Steroids are lipophilic molecules  they are bound
to protein carriers in the blood
Carrier-
bound

•
hormone
Albumin
• Corticosteroid binding globulin
Endocrine Free Hormone
(CBG) or transcortin cell hormone Receptor
• Sex hormone binding globulin
(SHBG) Hormone
• Androgen binding protein (ABP) degradation Biological
effects

Only the free fraction is biologically active usually less than

10%
Hormone half life
1. Steroids and thyroid hormone, which are bound to plasma
proteins,
have a long half life (~ hours)

2. Peptides and catecholamines are water-soluble, they are

transported
dissolved in plasma, generally have a very short half life (~
seconds to
minutes)
TRANSPORT OF ADRENAL STEROID HORMONES IN
THE BLOODSTREAM

CORTISOL ALDOSTERONE
70% is bound to corticosteroid 60% of aldosterone is bound
binding globulin to albumin
(transcortin) 10 % is bound to transcortin
22% of cortisol is bound to A small amount of
albumin aldosterone is bound to
8% free cortisol other plasma proteins

Transcortin is produced in the liver and its synthesis is increased by

estrogens.
Hormone bound to transport proteins are protect from metabolism and
inactivation.
Transport proteins assist in maintaining a level of hormones in circulation.
 MECHANISM OF STEROID HORMONE
ACTION

• Steroid hormones are

soluble in the plasma
membrane and readily
enter the cytosol.

• Steroids bind to intracellular

receptor either in the
cytosol or in the nucleus.

• The hormone-receptor
complex acts as a
transcription factor which
turns on / turns off the
genes.

Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations

 MECHANISM OF STEROID HORMONE
ACTION
• Messenger RNA is transcribed,
leaves the nucleus, and is
translated into a specific
protein by ribosome.

• The specific proteins then carry

out function in the target cell.

• Because steroid hormones

initiate protein synthesis their
effects are produced more
slowly, but are more long-
lasting than those produced
by other hormones.
 INTRACELLULAR RECEPTORS
Model of typical steroid hormone receptor

H2N- 1 2 3 4 - COOH

1. Variable domain – interacts with other transcription

factors
2. DNA-binding domain – „zinc finger“
3. Domain for dimerization – a site of dimerization of two
receptor-hormone complexes
4. Hormone- binding domain

„zinc finger structure“

MECHANISM OF STEROID HORMONE
ACTION
 HORMONE CATABOLISM AND
EXCRETION
•Inactivation of steroids involves reductions
and conjugation to glucuronides or sulfate
to increase their water solubility.

•Most are catabolized by the liver and

kidneys.
3

•70% of the conjugated steroids are

excreted in the urine, 20 % leave in feces
and rest exit through the skin.
estron-3sulfate
Hormone Catabolism and
Excretion
Cortisol metabolism:
• 20% converted to cortisone (by renal/other tissues
with mineralocorticoid receptors)
• catalyzed by 11-hydroxysteroid dehydrogenase
• Cortisol and cortisone inactivated in the liver by
conversion (3-hydroxysteroid dehydrogenase
catalyzed)
 PHYSIOLOGICAL EFFECTS OF
GLUCOCORTICOIDS
Major metabolic effects: due to direct cellular action
Some effects: secondary to homeostatic insulin and glucagon responses
Physiological responses modulated by glucocorticoids ("permissive" effects)
catecholamine vascular/bronchial smooth muscle response
 METABOLIC EFFECTS OF
 Stimulate and are required for:
GLUCOCORTICOID
a. gluconeogenesis (fasted state, diabetes);
b. increasing hepatic and renal amino acid
uptake
c. increase gluconeogenic enzyme activity
 Hepatic effects:
a. stimulation of glycogen synthase
b. increase glucose production from protein
c. stimulate insulin release
Efek metabolik GC pada Otot Skelet
 METABOLIC EFFECTS OF
GLUCOCORTICOID (CONT)
 Adipocytes:
a. inhibit glucose uptake promoting increased lipolysis
b. counteracted by enhanced insulin secretion which
stimulates lipogenesis
 Glucocorticoid effects most prominent in the fasting state,
through:
a. stimulation:gluconeogenesis
b. stimulation: amino acid release from muscle (catabolism)
c. inhibition: peripheral glucose uptake
d. stimulation: lipolysis
 METABOLIC EFFECTS OF
 Promotion of catabolism:
GLUCOCORTICOID (CONT)
a. lymphoid tissue
b. connective tissue
c. muscle
d. fat
e. skin
 High (supraphysiologic) glucocorticoid levels cause:
decreased muscle mass, weakness
 Reduced growth in children (not prevented by growth
hormone)
 MINERALOCORTICOIDS
• Synthesized exclusively in zona glomerulosa

• Regulate the electrolyte concentrations of extracellular fluids

• Aldosterone – most important mineralocorticoid

• Maintains Na+ balance by reducing excretion of sodium from
the body

• Stimulates reabsorption of Na+ by the kidneys and K+ excretion

 MINERALOCORTICOIDS
• Aldosterone secretion is stimulated by:
• Decreasing blood volume or pressure (renin-angeotensin
system) is the major stimulant
• Low blood Na+
• Rising blood levels of K+
• ACTH
 THE FOUR MECHANISMS OF ALDOSTERONE
SECRETION
• Renin-angiotensin mechanism – kidneys release renin, which
is converted into angiotensin II that in turn stimulates
aldosterone release
• Plasma concentration of sodium and potassium – directly
influences the zona glomerulosa cells
• ACTH – causes small increases of aldosterone during stress
• Atrial natriuretic peptide (ANP) – inhibits activity of the zona
glomerulosa
THE FOUR MECHANISMS OF ALDOSTERON
SECRETIO
 ACTIONS OF ALDOSTERONE
Stimulates sodium reabsorption by distal tubule and
collecting duct of the nephron and promotes
potassium and hydrogen ion excretion
1. Increases transcription of Na/K pump
2. Increases the expression of apical Na
channels
and an Na/K/Cl cotransporter
3. Expands ECF volume
 ALDOSTERONE: ROLE IN DISEASES
• Complete failure to secrete aldosterone leads to death (dehydration, low
blood volume).

• Hyperalsdosterone states: Contribute to hypertension associated with

increased blood volume.
 55

ENDOCRINE PANCREAS
• The pancreas is both an endocrine and an exocrine gland
• Houses the islets of Langerhans
• Secretion of glucagon and insulin
• Cells
• Alpha—glucagon
• Beta—insulin
• Delta—somatostatin and gastrin
• F cells—pancreatic polypeptide
 56

ENDOCRINE PANCREAS
 60

ENDOCRINE PANCREAS
• Insulin
• Synthesized from proinsulin
• Secretion is promoted by increased blood glucose levels
• Facilitates the rate of glucose uptake into the cells of the body
• Anabolic hormone
• Synthesis of proteins, lipids, and nucleic acids
 62

ENDOCRINE PANCREAS
• Glucagon
• Secretion is promoted by decreased blood glucose levels
• Stimulates glycogenolysis, gluconeogenesis, and lipolysis
• Somatostatin
• Possible involvement in regulating alpha and beta cell secretions
 68

ENDOCRINE PANCREAS
It is now recognized that GLP-1(7–36)amide is the predominant
bioactive GLP-1 present in human serum. It has an MW of 3298 Da
and is composed of 30-amino-acid residues with the sequence
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2.
34 This truncated

and fully bioactive GLP-1 binds to the human GLP-1R35,36 expressed

on islet b-cells in order to potentiate glucose-stimulated insulin secretion
in vivo (GSIS).6–8 Importantly, the insulin secretagogue action of GLP-1
is accompanied by its ability to stimulate insulin gene transcription, insulin
mRNA translation, and proinsulin biosynthesis in b-cells.37–
 The dipeptidyl peptidase 4 (DP4) gene
family

Figure 1 Schematic structure of the DP4 family. Adapted from Gorrell

(2005) Clinical Science, 108: 277-292
Figure 2. Schematic localization of the DP4 gene family.
Adapted from Kirby (2010) Clinical science, 118: 31-41
DP8 (pink) |
DPIV/CD26 (blue)

β - propeller
domain

α/β hydrolase
domain
(35% aa identity,
51% aa similarity)

Image provided by Dr Melissa Pitman