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PHYSIOLOGY of thePHYSIOLOGY of the
ADRENAL GlandADRENAL Gland
Melvin Valera, M.D.
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Lecture Points
Adrenals Form and development
Control and regulation
Steroid hormones
Adrenal cortex
Adrenal medulla
Clinical correlates
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Adrenal Glands
2 adrenal glands lie at the superior poles of the twokidneys
weighs 4-5 grams each composed of two distinct parts
adrenal medulla and the
adrenal cortex.
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Adrenal Glands
Adrenal Medulla
the central 20% of the gland, is functionallyrelated to the sympathetic nervous system
secretes the catecholamines, epinephrineand norepinephrine in response tosympathetic stimulation
cause almost the same effects as directstimulation of the sympathetic nerves in allparts of the body
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Adrenal Glands
Adrenal Cortex
secretes an entirely different group ofhormones, called corticosteroids
all synthesized from the steroid cholesterol,
and they all have similar chemical formulas differences in their molecular structures
give them crucial functional differences
.
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Adrenal Glands
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Adrenal Glands
Embryologically,
Cortex forms first Gonadal Ridge
mesodermal
Medulla forms after Neural Crest Origin
ectodermal
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Adrenal Glands
The cortical portion differentiates by 8weeks AOG
Initially larger than the kidney
2 zones
Peripheral neocortex, 15%, inactive
Fetal neocortex, 85%, active
Produces fetal steroids throughout intrauterine life
Fetal cortex degenerates 3-12 mos. after birth Steroidogenic factor-1 stimulates growth
and development of the mature adrenalcortex
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Adrenal Glands
The medullary portion is formed in parallelwith the peripheral sympathetic nervoussytem.
Starts at 7 weeks AOG
From neuroectodermal cells of the neuralcrest
Starts secreting catecholamines upon
development At birth the adrenal medulla is fully
developed and functional
Stimulated by nerve growth factor
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Adrenal Glands
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Adrenal Glands
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Adrenal Glands
Histological difference between the cortexand the medulla
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Adrenal Glands
Histologically,
Zona glomerulosa Very thin
consisting of small cells that have numerousmitochondria with lamellar cristae
Zona fasciculata Widest, consisting ofcolumnar cells forming long cords
Has highly vacuolated cytoplasm and contains lipiddroplets
Zona reticularis Contains network of interconnecting cells
Has fewer lipid droplets
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Adrenal Glands
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Adrenal Glands
Separation between cortex andmedulla not absolute
One has clusters of cells interspersedwith the other
Paracrine influence
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Adrenal Glands
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Lecture Points
Adrenals Form and development
Control and regulation
Steroid hormones
Adrenal cortex
Adrenal medulla
Clinical correlates
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Control andregulation of the
ADRENAL GLAND
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Regulation of secretion
Glucocorticoid secretion
ACTH is a key regulatorof the stress response Oscillates with 24-hr periodicity, or circadian rhythm
For those who sleep at night (diurnal), cortisol levelspeak just before waking up and are lowest in theevening.
Depends on sleep-wake cycle, jet-lag can result inalteration of pattern
Pattern can be abolished by blindness, loss ofconsciousness and constant exposure to dark or light
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Regulation of secretion
Hypothalamic control via CRH
CRH-containing neurons are located in the
paraventricular nuclei of the hypothalamus
When they are stimulated, CRH is released
and delivered to the ant. pituitary. CRH binds to receptors on corticotrophs and
directs them to synthesize POMC and secrete
ACTH.
Uses cAMP as the 2nd messenger
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Regulation of secretion
Pituitary control via ACTH ACTH stimulates desmolase, which convertcholesterol to pregnenolone, in all zones of the
adrenal cortex
ACTH up-regulates its own receptorso that thesensitivity of the adrenal cortex to ACTH is
increased
Chronic elevation of ACTH causes hypertrophy of
adrenal cortex
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Regulation of secretion
ACTH+
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Regulation of secretion
Glucocorticoid secretion
Negative feedback control
Cortisol inhibits the secretion of CRH from the
hypothalamus and ACTH from the pituitary.
When cortisol levels are chronically elevated,
CRH and ACTH levels in the blood are expected
to be low due to decreased secretion.
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Regulation of secretion
Long-loop reflexes and
short-loop reflexes
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Regulation of secretion
Aldosterone secretion Under tonic control by ACTH, but is also
separately regulated by the renin-
angiotensin system and potassium (RAAS)
Hyperkalemia
Increases aldosterone secretion because it
increases renal K+ secretion (in exchange for
Na+ absorption), restoring blood K+ to normal
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Regulation of secretion
RAAS Decreases in blood volume cause a
decrease in renal perfusion pressure,
which is detected by the macula densa. JG cells then secrete renin, which
catalyzes the conversion of
angiotensinogen to angiotensin I in theplasma.
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Regulation of secretion
RAAS Angiotensin I is converted to
angiotensin II by ACE in the lungs.
Angiotensin II acts on the zonaglomerulosa to increase the conversion
ofcorticosterone to aldosterone via
the enzyme aldosterone synthase.
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Regulation of secretion
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Regulation of secretion
Ang II+
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Lecture Points
Adrenals Form and development
Control and regulation
Steroid hormones
Adrenal cortex
Adrenal medulla
Clinical correlates
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Steroid hormones
21-carbon steroids
Include progesterone, deoxycorticosterone,
aldosterone and cortisol.
Progesterone is the precursor for the others in the
21-carbon series Hydroxylation at C-21leads to the production of
deoxycorticosterone, which has mineralocorticoid
(but not glucocorticoid) activity.
Hydroxylation at C-17 leads to the production of
cortisol.
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19-carbon steroids
Have androgenic activity and are precursors to
the estrogens
If the steroid has been previously hydroxylated at C-
17, the C20-21 side chain can be cleaved to yieldthe 19-carbon steroids dehydroepiandrosterone
(DHEAS) or androstenedione in the adrenal cortex.
In the testes, androstenedione is converted to
testosterone.
Steroid hormones
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18-carbon steroids
Have estrogenic activity
Oxidation of the A ring (aromatization) to produce
estrogens occurs in the ovaries and placenta, not
in the adrenals or testes.
Steroid hormones
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S
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Steroid hormones
Mechanism of action STEP 1: Steroid hormones (and thyroid) diffuse
across the cell membrane and binds to its
intracellular receptor.
STEP 2: The hormone-receptor complex enter thenucleus and dimerizes
STEP 3: The hormone-receptor dimers are
transcription factors that bid to steroid-responsiveelements(SREs) of DNA
STEP 4: DNA transcription is initiated.
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St id h
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Steroid hormones
Mechanism of action STEP 5: New mRNA is produced, leaves the
nucleus and is translated to synthesize new
proteins.
STEP 6: New proteins synthesized perform theirspecific physiologic actions.
aldosterone induces the synthesis of Na+ channels in the
renal principal cells.
1,25 dihydrocholecalciferol (Vit D) induces the synthesis
of calbindin D-28K, a Ca2+-binding protein in the intestine
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L t P i t
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Lecture Points
Adrenals Form and development
Control and regulation
Steroid hormones
Adrenal cortex
Adrenal medulla
Clinical correlates
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Adrenal Cortex
Inner: Zona Reticularis Anabolic and Sex Steroids
Creates a pre-hormone called DHEA forproduction of testosterone/estradiol
Changes muscle development/personality Most testosterone/estradiol are
produced in the gonads ACTH also regulates secretion of these
cells Also by cortical androgen-stimulating
hormone released from the pituitary
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Adrenal Cortex
Middle: Zona Fascicularis constitutes about 75% of the cortex
Glucocorticoids- Cortisol, corticosteroneand small amounts of adrenal androgens and
estrogens Controls carbohydrate metabolism
Catabolism of glycogen and protein Suppression of immune system and
inflammation controlled in large part by the H-P axis via
ACTH
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Adrenal Cortex
Outer: Zona Glomerulosa: 15%of the adrenal cortex Mineralocorticoids- Aldosterone Controls sodium reabsorption to adjust
blood pressure Largely and separately controlled by RAAS Angiotensin II and potassium both
stimulate aldosterone secretion. Contain mostly the enzyme aldosterone
synthase
Gl ti id
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Glucocorticoids
Actions
Generally, they are utilized in response to stress
Stimulation of gluconeogenesis thru:
Increased protein catabolism in muscle and
decreased protein synthesis, thereby providing
more amino acids to the liver for gluconeogenesis
Decreased glucose utilization and insulin
sensitivity of adipose tissue Increased lipolysis, providing more glycerol to the
liver for gluconeogenesis
Gl ti id
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Glucocorticoids
Actions
Anti-inflammatory effects and suppression
of immune response thru:
Synthesis oflipocortin, an inhibitor of
phospholipase A, the enzyme that liberatesarachidonic acid from membrane phospholipids
Arachidonic acid is the precursor ofprostaglandins
and leukotrienes, the chemicals involved in the
inflammatory response
Gl ti id
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Glucocorticoids
Actions
Anti-inflammatory effects and suppression
of immune response thru:
Inhibition of production of interleukin-2(IL-2) and
inhibition of proliferation ofT lymphocytes
Both are critical for cellular immunity
Glucocorticoids are used to prevent rejection of
transplanted organs
Inhibition of release ofhistamine and serotonin
from mast cells and platelets
Gl ti id
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Glucocorticoids
Glucocorticoids
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Glucocorticoids
Actions
Maintenance ofvascular responsiveness to
catecholamines thru:
Up-regulation of 1receptors on arterioles,
increasing their sensitivity to the vasoconstrictor
effect of norepinephrine
Cortisol excess causes increase in arterial pressure
Cortisol deficiency causes decrease in arterialpressure
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Mineralocorticoids
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Mineralocorticoids
Actions
Na+ reabsorption
Aldosterone induces synthesis of channels in
the principal cells in the late distal tubule and
collecting duct forincreased Na+reabsorption
Affects 2% of overall reabsorption of Na+.
Mineralocorticoids
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Mineralocorticoids
Actions
H+ secretion
Increases the activity H+-ATPase in the
luminal membrane of intercalated cells in the
late distal tubule and collecting duct,increasing the secretion of H+ into the lumen
of the tubules and ducts
Mineralocorticoids
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Mineralocorticoids
Actions
K+ secretion Increased Na+ entry into the cells across the luminal
membrane also increases the activity of the Na+/K+pump driving Na+ out to the bloodstream.
Increased activity of the pump increases uptake of K+into the principal cells, increasing the intracellular K+concentration and the driving force for K+ secretion.
Aldosterone also increases the number of luminal
membrane K+
channels
Adrenocortical insufficiency
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Adrenocortical insufficiency
Primary insufficiency (Addisons disease) Most commonly due to autoimmune destruction of the
adrenal cortex
Causes acute adrenal crisis
Characterized by:
Decreased glucocorticoids, androgen, and minearlocorticoid,
increased ACTH
Hyperpigmentation
hypoglycemia, fatigability, weakness, anorexia, nausea,
weight loss
women loss of axillary and pubic hair
hypotension, hyperkalemia, hypovolemia, metabolic acidosis
Adrenocortical insufficiency
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Adrenocortical insufficiency
Secondary insufficiency
Caused by primary deficiency of ACTH
hypopituitarism, suppression from exogenous
steroids
No hyperpigmentation, hypovolemia,
hyperkalemia and metabolic acidosis
Adrenocortical insufficiency
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Adrenocortical insufficiency
symptoms, signs
fatigability, weakness, anorexia, nausea, weight
loss, hyperpigmentation, hypotension, women
loss of axillary and pubic hair
can lead to severe volume depletion and shock treatment
glucocorticoid replacement, mineralocorticoid
replacement
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Adrenocortical excess
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Cushings syndrome 3rd - 6th decade, 4 to1 females causes
pharmocologic
pituitary adenoma 75-90%
adrenal adenoma, carcinoma
ectopic ACTH
Adrenocortical excess
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Dexamethasone Suppression Test
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Dexamethasone Suppression Test
Based on the ability of dexamethasone to inhibit
ACTH secretion
Effect on cortisol secretion
Low-doseDEXA
High-doseDEXA
normal Inhibits Inhibits
ACTH-secreting tumors No change Inhibits
Adrenal cortical tumors(cortisol-secreting)
No change No change
Adrenocortical excess Treatment
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Adrenocortical excess Treatment
Hyperaldosteronism
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primary causes (Conns syndrome)
adenoma, nodular hyperplasia zona glomerulosa
secondary
cirrhosis, ascites, nephrotic syndrome, diuretic
use
Signs and Symptoms
Hypertension
hypokalemia causing muscle weakness,nocturnal polyuria, metabolic alkalosis
Decreased renin secretion
Hyperaldosteronism
Lecture Points
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Lecture Points
Adrenals Form and development
Control and regulation
Steroid hormones Adrenal cortex
Adrenal medulla
Clinical correlates
Adrenal Medulla
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Adrenal Medulla
Specialized ganglion of the sympathetic
nervous system Preganglionic fibers synapse directly on chromaffin
cells in the adrenal medulla
Adrenal medullar cells (chromaffin cells) do nothave the typical structure of a neuron.
Adrenal Medulla
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Adrenal Medulla
They have some characteristics of adrenergic
neurons of the peripheral autonomic system: ability to produce catecholamines, epinephrine
(80%) and norepinephrine (20%)
to respond to stimulation by acetylcholine via thesame type of receptor.
Chromaffin cells lack axons, and they secreteepinephrine and norepinephrine into the blood,
instead of interneural transmission.
Catecholamines
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Catecholamines
Catechol is 1,2-dihydroxy benzene.
catecholamines are synthesized from tyrosine.
Four enzymes are required for epinephrine production
only the first three are needed for norepinephrine synthesis.
The product of the second enzyme is dopamine. not secreted by the adrenal medulla
a neurotransmitterproduced by some neurons in the brain
and the periphery
dopamine has its own receptors.
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Catecholamines
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Epinephrine and norepinephrine act via the same
series of the so-called adrenergic receptors, although their relative effectiveness on the various
receptors is not the same
-receptors activate Gs and uses cAMP as the
second messenger
Receptors of the type 1 activate Gq and use
DAG and Ca as second messengers
Receptors of the type 2 activate Gi, and thusinhibit adenylyl cyclase.
Catecholamines
Epinephrine
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facilitates the ability of the animal to cope with
various stresses, including an acute stress.
the hormone of fight or flight, it is needed in
the encounter of predator and prey.
Both animals need to exert an intensive
physical effort, and to be capable of quick
responses.
Epinephrine
Epinephrine
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Actions on cardiovascular system increases the heart rate by acting on the pacemaker
(inotropicity)
increases the contractile force of the heart muscle,
increasing the cardiac output (chronotropicity)
mediated by 1 adrenergic receptors.
Epinephrine
Epinephrine
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Actions on cardiovascular system relaxes blood vessels which have 2 receptors in
their smooth muscle (e.g., arterial vessels of
skeletal muscle and of the liver).
contracts blood vessels which have -adrenergic
receptors in their smooth muscle (e.g., vessels in
skin, kidney, and some other abdominal organs)
Epinephrine
Epinephrine
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Actions on cardiovascular system 1 adrenergic receptors
norepinephrine = epinephrine.
2 receptors epinephrine >> NE
receptors
Epinephrine > NE
Epinephrine
Epinephrine
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Effects on metaboilsm Increase the release of glucose from the liver
to the blood by
increasing the breakdown of glycogen stores, inhibiting glycogen synthesis
stimulating gluconeogenesis
p ep e
Epinephrine
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Effects on metaboilsm In adipose tissue, epinephrine stimulates
the hydrolysis of stored triglycerides to freefatty acids and glycerol, both of whichcan be utilized by some tissues.
In pancreatic beta () cells, epinephrine
inhibits the production of insulin, whichhas opposite metabolic effects.
p p
Epinephrine
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Effects on metaboilsm In skeletal muscles, epinephrine stimulates
the breakdown of glycogen stores and
inhibit glycogen synthesis.
Lactate is utilized by the liver forgluconeogenesis.
p p
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Adrenal Medulla
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Pheochromocytoma
a tumorof the adrenal medulla that secretes
excessive amounts of catecholamines and is
asccociated with increased excretion of VMA.
90% are benign, 10% are malignant 10% Rule - Malignant, bilateral, extra-adrenal, multiple,
familial, children.
Adrenal Medulla
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Pheochromocytoma
Hypertension 50% sustained - Can have paroxysms of more severe hypertension
superimposed.
50% intermittent
Sweating, headaches, palpitations, tremor, nervousness,
weight loss, fatigue, abdominal or chest pains, polydipsia and
polyuria, convulsions
Treated with surgery and pre-operative administration of
phenoxybenzamine (1-blocker)
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