Transcript Adrenocortical Hormones

Adrenocortical
Hormones
Prof. dr. Zoran Valić
Department of Physiology
University of Split School of Medicine
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two adrenal glands, at the superior poles of
the two kidneys (about 4g)
medulla – central 20% (functionally related
to the sympathetics – epinephrine &
norepinephrine)
cortex – 80% (corticosteroids – synthesized
from the steroid cholesterol; similar
chemical formulas)
Mineralocorticoids,
Glucocorticoids, and Androgens
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androgens of only slight importance,
although extreme quantities can be secreted
– masculinizing effects
MC – affect electrolytes (minerals) of the
extracellular fluids (Na+ and K+)
GC – increase BGC, but protein and fat also
more than 30 steroids have been isolated
two important: aldosterone and cortisol,
Synthesis and Secretion of
Adrenocortical Hormones
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adrenal cortex has three distinct layers:
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zona glomerulosa – thin layer underneath
capsule, 15% of cortex, aldosterone synthase
(angiotensin II and K+)
zona fasciculata – 75% of cortex, cortisol and
corticosterone, small amounts of adrenal
androgens and estrogens (ACTH)
zona reticularis – deep layer of cortex, DHEA
and androstenedione (ACTH, cortical
androgen-stimulating hormone, ?)
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all human steroid hormones are synthesized
from cholesterol
cells can synthesize de novo cholesterol
(from acetate), 80% comes from LDL
cells  coated pits – endocytosis
ACTH   receptors for LDL and 
activity of enzymes LDL degradation
cholesterol  pregnenolone (desmolase,
rate-limiting step, in mitochondria)
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90-95% of the cortisol in plasma binds to
cortisol-binding globulin or transcortin, less
to albumin – long half-life (60-90 min)
60% of circulating aldosterone combined
with plasma proteins (half-life 20 min)
degraded in liver – conjugation especially to
glucuronic acid and sulfates (25% excreted
in the bile, remaining by kidneys)
Functions of Mineralocorticoids
– Aldosterone
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total loss of MC – rapid  in NaCl and 
in K+ (death within 3 days without therapy),
 EC fluid volume and blood volume
acute "lifesaving" hormones
aldosterone – 90% MC activity
cortisol – 3000x less activity, but 2000x 
concentration
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aldosterone – reabsorption of Na+ and
secretion of K+ (principal cells of the
collecting tubules)
 aldosterone –  EC fluid volume & 
MAP, cNa + stays the same (osmotic
absorption of water, stimulation of thirst)
transient Na+ retention occurs – pressure
natriuresis and pressure diuresis (ECF  515%  MAP  15 to 25 mmHg)
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aldosterone escape
in the meantime hypertension develops
when aldosterone secretion becomes zero –
large amounts of salt are lost and ECF
severe extracellular fluid dehydration and
low blood volume – circulatory shock –
death
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excess aldosterone causes hypokalemia
(from 4,5 to 2 mmol/L; transport into cells)
and muscle weakness (alteration of the
electrical excitability); too little aldosterone
causes hyperkalemia and cardiac toxicity
(rise of 60-100%, arrhythmia – heart failure)
excess aldosterone –  secretion of H+
(intercalated cells of the cortical collecting
tubules, metabolic alkalosis)
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aldosterone  transport Na+ & K+ in sweat
glands and salivary glands
important in hot environments
greatly enhances Na+ absorption by the
intestines, especially in the colon; in the
absence – diarrhea
Cellular Mechanism of
Aldosterone Action
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still not fully understood
lipid soluble – diffuses readily to the interior of
the tubular epithelial cells
in cytoplasm combines with a highly specific
cytoplasmic mineralocorticoid receptor protein
aldosterone-receptor complex diffuses into the
nucleus  DNA  RNA
mRNA diffuses back into the cytoplasm –
ribosomes – protein formation
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one or more enzymes
membrane transport proteins for Na+, K+, H+
especially increases Na+/K+ -ATPaze which serves
as the principal part of the pump for Na+ & K+
exchange at the basolateral membranes of the renal
tubular cells
increases epithelial sodium channel (ENaC)
protein – inserted into the luminal membrane
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sequence of events (30-45 minimal, maximal
effect after several hours)
possible nongenomic actions – increase formation
of cAMP (fast – less than 2 minutes), but also
involves phosphatidylinositol second messenger
system
Regulation of Aldosterone
Secretion
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deeply intertwined with the regulation of
ECF electrolyte concentrations, volume of
ECF, blood volume and MAP
almost entirely independent of the
regulation of cortisol and androgens
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 K+ in ECF
 angiotensin II concentration in ECF
 Na+ in ECF very slightly decreases
ACTH necessary for secretion, not for control
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in turn, the aldosterone acts on the kidneys:
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help them excrete the excess K+
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increase the blood volume and MAP
effects of Na+ & ACTH usually minor (total
absence of ACTH can significantly reduce
aldosterone secretion – "permissive" role)
Functions of Glucocorticoids
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MC can save the life of an acutely
adrenalectomized animal, metabolic
systems remain considerably deranged
animal cannot resist physical or even
mental stress (infection = death)
on a long run GC equally important as MC
95% of activity – cortisol (hydrocortisone)
smaller effect – corticosterone
Effects of Cortisol on
Carbohydrate Metabolism
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stimulation of gluconeogenesis ( 6-10x)
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 enzymes required to convert amino acids
into glucose
mobilization of amino acids from the
extrahepatic tissues mainly from muscle
increase in glycogen storage in the liver cells
 glucose utilization by cells
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cause of this decrease is unknown
depress the oxidation of NADH to form NAD+
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 BGC & “adrenal diabetes”
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 rate of gluconeogenesis &  rate of glucose
utilization
high levels of GC reduce the sensitivity of
many tissues to insulin
unknown, high levels of fatty acids
 BGC greater of 50% – adrenal diabetes
(tissues are resistant to the effects of insulin)
Effects of Cortisol on Protein
Metabolism
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 of the protein stores in all body cells
except those of the liver
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 synthesis &  catabolism – decreased
amino acid transport into extrahepatic tissues;
 formation of RNA and subsequent protein
synthesis (muscle and lymphoid tissue)
 liver and plasma proteins (from liver)
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enhancement of amino acid transport into liver
cells the liver enzymes for protein synthesis
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 AA in blood, transport into extrahepatic
cells,  transport into hepatic cells
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 transport into muscle cells (isolated tissues)
 synthesis of protein in those cells
catabolism continues normally – mobilization
of AA from the nonhepatic tissues
increasing the liver enzymes required for the
hepatic effects
Effects of Cortisol on Fat
Metabolism
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mobilization of fatty acids
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from adipose tissue –  free fatty acids in the
plasma and their utilization for energy
enhance the oxidation of fatty acids in the cells
mechanism unknown, diminished transport of
glucose ( α-glycerophosphate)
in times of starvation or other stresses – shift to
utilization of fatty acids for energy (requires
several hours to develop)
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obesity caused by excess cortisol
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peculiar type of obesity (despite fatty acid
mobilization)
deposition of fat in the chest (buffalo-like
torso) and head regions (moon face)
obesity results from excess stimulation of food
intake – fat being generated more rapidly than
mobilized and oxidized
Cortisol Is Important in Resisting
Stress and Inflammation
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physical or neurogenic stress – marked  in
ACTH secretion by anterior pituitary gland
within minutes –  secretion of cortisol
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trauma of almost any type
infection
intense heat or cold
injection of norepinephrine
surgery
injection of necrotizing substances beneath skin
restraining an animal so that it cannot move
almost any debilitating disease
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unknown why cortisol secretion is of
significant benefit
GC cause rapid mobilization of amino acids
and fats from cellular stores – release of
energy and glucose synthesis
use of amino acids in damaged tissues
synthesis of purines, pyrimidines, and
creatine phosphate from amino acids
preferential mobilization of labile proteins
Anti-Inflammatory Effects of
High Levels of Cortisol
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trauma or infection – inflammation
inflammation can be more damaging than
trauma or disease itself (rheumatoid arth.)
cortisol:
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block the early stages of the inflammation
process before inflammation even begins
rapid resolution of the inflammation and
increased rapidity of healing
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stabilization of lysosomal membranes – 
proteolytic enzymes
decreased permeability of the capillaries –
secondary
decreased migration of white blood cells into the
inflamed area and phagocytosis of the damaged
cells –  prostaglandins and leukotrienes
suppression of immune system –  lymphocyte
reproduction
attenuation of fever –  release of interleukin-1
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reducing all aspects of inflammatory process
block most of the factors that promote the
inflammation
rate of healing is enhanced (mobilization of
amino acids, increased glucogenesis,
increased amounts of fatty acids)
useful in: rheumatoid arthritis, rheumatic
fever, and acute glomerulonephritis
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blocks the inflammatory response to allergic
reactions – anaphylaxis
decreases the number of eosinophils and
lymphocytes in the blood; decreases the
output of both T cells and antibodies
(fulminating tuberculosis / preventing
immunological rejection)
increases the production of red blood cells
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cortisol binds with its protein receptor in the
cytoplasm
easily diffuse through the cell membrane
hormone-receptor complex interacts with
glucocorticoid response elements at DNA –
transcription
rapid nongenomic effects
Regulation of Cortisol Secretion
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ACTH (corticotropin or
adrenocorticotropin) enhances secretion of
cortisol
ACTH is a large polypeptide of 39 amino
acids (24 has all effects of total molecule)
corticotropin-releasing factor (CRF, 41
amino acids, paraventricular nucleus)
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ACTH activate adenylyl cyclase – cAMP
(in 3 min), activation of the protein kinase A
– initial conversion of cholesterol to
pregnenolone (rate-limiting step)
ACTH – hypertrophy and proliferation of
the adrenocortical cells in the zona
fasciculata and zona reticularis
physical or mental stress   ACTH
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cortisol has direct negative feedback effects:
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hypothalamus   CRH
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anterior pituitary gland   ACTH
stress stimuli are the prepotent
circadian rhythm of glucocorticoid secretion
– measurements of blood cortisol levels
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when ACTH is secreted several other
hormones are secreted simultaneously
(preprohormone – POMC)
melanocyte-stimulating hormone (MSH), βlipotropin and β-endorphin
under normal conditions small secretion
MSH – stimulates formation of the black
pigment melanin (pars intermedia in some
lower animals, ACTH is normally more
important than MSH in determining the
amount of melanin in the skin in humans)
Adrenal Androgens
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especially during fetal life
most important – dehydroepiandrosterone
in female: growth of pubic and axillary hair
some of the adrenal androgens are
converted to testosterone in extra-adrenal
tissues
Abnormalities of Adrenocortical
Secretion
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hypoadrenalism (adrenal insufficiency) –
Addison's disease
hyperadrenalism – Cushing's syndrome
primary aldosteronism – Conn's syndrome
adrenogenital syndrome
Hypoadrenalism – Addison's
disease
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adrenal cortices do not produce hormones
most frequently caused by primary atrophy or
injury of the adrenal cortices – in 80%
autoimmunity, tuberculosis, or cancer
lack of MC –  ECF volume, hyponatremia,
hyperkalemia & mild acidosis   plasma
volume,  Ht,  CO – death (shock, 4 days)
lack of GC – disturbances in BGC, fats and
proteins – sluggishness of energy mobilization;
deteriorating effects of different types of stress
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melanin pigmentation of the mucous membranes
and skin
melanin is not always deposited evenly but
occasionally is deposited in blotches (thin skin
areas –lips and the thin skin of the nipples)
tremendous rates of ACTH & MSH secretion due
to normal negative feedback
treatment – daily administration of small
quantities of MC & GC
Hyperadrenalism – Cushing's
Syndrome
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hypersecretion by adrenal cortex (adenomas of
anterior pituitary, abnormal function of
hypothalamus, "ectopic secretion" of ACTH by a
tumor, adenomas of adrenal cortex)
adenomas of anterior pituitary – Cushing's disease
dexamethasone test (incorrect diagnosis)
iatrogenic Cushing's syndrome
fat deposition – buffalo torso, "moon face", acne
and hirsutism, 80% – hypertension
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increase in BGC after meals to 11 mmol/L
(enhanced gluconeogenesis and decreased glucose
utilization)
greatly decreased tissue proteins everywhere in
the body with the exception of liver and plasma –
severe weakness, suppressed immune system,
large purplish striae (collagen), osteoporosis
treatment – removal of a tumor (before – drugs
that block steroidogenesis)
Primary Aldosteronism – Conn's
Syndrome
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small tumor of the zona glomerulosa cells –
secretes large amounts of aldosterone
hypokalemia, mild metabolic alkalosis,  ECF
volume & blood volume, hypertension
occasional periods of muscle paralysis caused by
the hypokalemia (depressant effect of
hypokalemia on action potential transmission)
diagnostic criteria – decreased plasma renin
treatment – surgical removal of the tumor
Adrenogenital Syndrome
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tumor secretes excessive quantities of androgens –
intense masculinizing effects
in a female: growth of a beard, a much deeper
voice, occasionally baldness, masculine
distribution of hair on the body and the pubis,
growth of the clitoris
in prepubertal male: early masculinization
in adult male: difficult to make a diagnosis
excretion of 17-ketosteroids in the urine increase
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