Download Cortisol and Aldosteron

Cortisol and Aldosteron
• Two hypothalamic peptides are the principal
regulators of pituitary ACTH release ,
corticotropin releasing hormone (CRH) and
arginine vasopressin. They act independently and
synergistically.
• CRH is a 41 A.A peptide secreted by the
paraventicular nucleus which acts via the cAMP
second messenger system .
• AVP is a 9 A.A peptide synthesized by both the
supraoptic and paraventicular nuclei , which acts
by altering intracellular calcium ion channels .
• Negative feedback by cortisol reduces the action
of both CRH and AVP .
• ACTH
• ACTH is part of the 241 A.A precursor
molecule proopiomelanocortin (POMC) .
• POMC is unusual as a hormone precursor in
that it is cleaved to release several hormonally
active peptides including the endorphins and
melanocyte stimulating hormones . POMC is
normally only produced by the pituitary gland
but it may also be produced in large quantities
by certain malignancies giving rise to ectopic
ACTH syndrome.
• ACTH itself is comprised of 39 A.A with the
biological activity residing in the N-terminal 24
moieties . ACTH . It transported unbound in
plasma. It has a half-life of about 10 minutes
and is unstable in plasma . ACTH stimulates
the synthesis and release of glucocorticoid
hormones by interacting with cell surface
receptors on the adrenal cortex that stimulate
the production of intracellular cAMP . Acute
increases in the adrenal synthesis of cortisol
occur with 3 minutes , principally by
stimulating the activity of cholesterol esterase.
• Chronic effects of ACTH include induction of
transcription of the genes that encode
steroidogenic enzymes and other factors
• Fast feedback alters the release of
hypothalamic CRH and CRH-mediated
secretion of ACTH . Slow feedback results from
reduced synthesis of CRH and AVP plus
suppression of POMC gene transcription ,
which results in reduced ACTH synthesis .
• Biosynthesis of cortisol
• Cortisol is the major glucocorticoid
synthesized in man in the inner two zones of
the adrenal cortex under the direct controle of
pituitary ACTH.
• Cholesterol is the precursors for all steroid
hormones synthesis. Cleavage of the
cholesterol side chain liberates the so-called
C-21 corticosteriods, further side chain
cleavage yields the C-19 androgens and
aromatization of the A ring result in the C-18
estrogens.
• The biosynthesis of cortisol depends on
stimulation by pituitary ACTH hormone which
binds to its plasma membrane receptor and
cause hydrolysis of cholesterol esters stored in
lipid droplets and activation the enzyme
desmolase (cytochrome P450 monoxygenase
system) which is the rate limiting enzyme.
• Approximately 95% of cortisol in plasma is bound
to protein, mainly CBG. As cortisol concentration
rises, the percentage of free cortisol also rise,
indicating that CBG binding is saturable. Cortisol
has a half-life in plasma of about 100 minutes.
Cortisol is metabolized in the liver and other
organs by a combination of reduction.
• Cortisol has a major influence on
gluconeogenesis by enhancing virtually every
step in the gluconeogenesis pathway. At the
same time, cortisol inhibits glucose uptake
and metabolism in peripheral tissues.
• Excess cortisol has a wide range of effects on
the immune system causing overall
suppression and providing a useful from of
therapy. It is likely that at least some of these
action are important in the control of the
immune response in normal physiology.
• Cortisol also influences the heart, vasculature,
blood pressure, water excretion and
electrolyte balance.
Clinical disorders of cortisol secretion:Hyposecretion of cortisol may occur as a result
of:
1- adrenal gland destruction was often due to
tuberculosis, auto immune disease is now the
main cause of primary adrenal failure. Both
cortisol and aldosterone production may be
affected.
2- Secondary due to long-standing suppression
and subsequent impairment of the
hypothalamic-pituitary axis.
• In the primary adrenal insufficiency, patients
become hyponatraemic, due to lack of
aldosterone which leads to pathological
sodium loss by the kidney which results in a
contraction of the extracellular fluid volume,
causing hypotension and pre-renal uremia.
• The hypovolaemia and hypotention stimulate
AVP secretion, thus causing water retention.
• In the secondary deficiencies of CRH and
ACTH are often accompanied by deficiencies
of other hypothalamic or pituitary hormones.
• Hypersecretion of cortisol results in
Cushing's syndrome.
•
ALDOSTERONE
Renin is released from juxtaglomerular cells in
response to decreased renal perfusion
pressure . It is protease that uses
angiotensinogen as its substrate .
Angiotensinogen, a glycoprotein of more than
400 a. a , is synthesized in the liver . The renin
liberates Angiotensin 1 from angiotensinogen .
Angiotensin 1 is a short, 10 a.a peptide. It is the
substrate for Angiotensin-converting enzyme
(ACE) .
• ACE is responsible for the removal of two
amino acids from Angiotensin ǀ to produce the
most potent known vasoconstrictor molecule ,
Angiotensin ǀǀ . In the kidney , Angiotensin ǀǀ
affects blood flow, glomerular function , and
by stimulation of aldosterone secretion which
in turn affects sodium, potassium and
hydrogen ion transport. These actions of
Angiotensin ǀǀ are mediated through two
different receptors: the AT 1 receptor is Gprotein-linked, whereas the AT2 receptor can
inhibit protein tyrosine phosphatase activity .
• Aldosterone is produced in the adrenal cortex,
and is the major mineralocorticosteroid
hormone in man . Its production is stimulated
by increases in the plasma concentration of
potassium . Aldosterone regulates electrolyte
balance in the kidney , salivary glands , sweat
glands and gastrointestinal tract . In the
kidney , it increases the activity of the Na/KATPase that causes renal sodium retention
and, in parallel, an increased excretion of
potassium .