PHYSIOLOGY of the

ADRENAL Gland
Melvin Valera, M.D.
Lecture Points

• Adrenals
• Form and development
• Control and regulation
• Steroid hormones
• Adrenal cortex
• Adrenal medulla
• Clinical correlates
Adrenal Glands
• 2 adrenal glands
• lie at the superior poles of the two
kidneys
• weighs 4-5 grams each
• composed of two distinct parts
• adrenal medulla and the
• adrenal cortex.
Adrenal Glands
Adrenal Medulla
• the central 20% of the gland, is functionally
related to the sympathetic nervous system

• secretes the catecholamines, epinephrine

and norepinephrine in response to
sympathetic stimulation
• cause almost the same effects as direct
stimulation of the sympathetic nerves in all
parts of the body
Adrenal Glands
Adrenal Cortex
• secretes an entirely different group of
hormones, 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
.
Adrenal Glands
Adrenal Glands
Embryologically,
• Cortex forms first
• Gonadal Ridge
• mesodermal
• Medulla forms after
• Neural Crest Origin
• ectodermal
Adrenal Glands
• The cortical portion differentiates by 8
weeks 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 adrenal
cortex
Adrenal Glands
• The medullary portion is formed in parallel
with the peripheral sympathetic nervous
sytem.
• Starts at 7 weeks AOG
• From neuroectodermal cells of the neural
crest
• Starts secreting catecholamines upon
development
• At birth the adrenal medulla is fully
developed and functional
• Stimulated by nerve growth factor
Adrenal Glands
Adrenal Glands
Adrenal Glands
• Histological difference between the cortex
and the medulla
Adrenal Glands
Histologically,
• Zona glomerulosa
– Very thin
– consisting of small cells that have numerous
mitochondria with lamellar cristae
• Zona fasciculata
– Widest, consisting of columnar cells forming long cords
– Has highly vacuolated cytoplasm and contains lipid
droplets
• Zona reticularis
– Contains network of interconnecting cells
– Has fewer lipid droplets
Adrenal Glands
Adrenal Glands
• Separation between cortex and
medulla not absolute
• One has clusters of cells interspersed
with the other

• Paracrine influence
Adrenal Glands
Lecture Points

• Adrenals
• Form and development
• Control and regulation
• Steroid hormones
• Adrenal cortex
• Adrenal medulla
• Clinical correlates
Control and
regulation of the
ADRENAL GLAND
Regulation of secretion
Glucocorticoid secretion
• ACTH is a key regulator of the stress response
• Oscillates with 24-hr periodicity, or circadian rhythm
• For those who sleep at night (diurnal), cortisol levels
peak just before waking up and are lowest in the
evening.
• Depends on sleep-wake cycle, jet-lag can result in
alteration of pattern
• Pattern can be abolished by blindness, loss of
consciousness and constant exposure to dark or light
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
Regulation of secretion

Pituitary control via ACTH

• ACTH stimulates desmolase, which convert
cholesterol to pregnenolone, in all zones of the
adrenal cortex
• ACTH up-regulates its own receptor so that the
sensitivity of the adrenal cortex to ACTH is
increased
• Chronic elevation of ACTH causes hypertrophy of
adrenal cortex
Regulation of secretion

+ ACTH
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.
Regulation of secretion

Long-loop reflexes and

short-loop reflexes
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
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 the
plasma.
Regulation of secretion

• RAAS
• Angiotensin I is converted to
angiotensin II by ACE in the lungs.
• Angiotensin II acts on the zona
glomerulosa to increase the conversion
of corticosterone to aldosterone via
the enzyme aldosterone synthase.
Regulation of secretion
Regulation of secretion

+ Ang II
Lecture Points

• Adrenals
• Form and development
• Control and regulation
• Steroid hormones
• Adrenal cortex
• Adrenal medulla
• Clinical correlates
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.
Steroid hormones
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 yield
the 19-carbon steroids dehydroepiandrosterone
(DHEAS) or androstenedione in the adrenal cortex.
• In the testes, androstenedione is converted to
testosterone.
Steroid hormones
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
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 the
nucleus and dimerizes
• STEP 3: The hormone-receptor dimers are
transcription factors that bid to steroid-responsive
elements(SREs) of DNA
• STEP 4: DNA transcription is initiated.
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 their
specific 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
Lecture Points

• Adrenals
• Form and development
• Control and regulation
• Steroid hormones
• Adrenal cortex
• Adrenal medulla
• Clinical correlates
Adrenal Cortex
• Inner: Zona Reticularis
• Anabolic and Sex Steroids
• Creates a pre-hormone called DHEA for
production 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
Adrenal Cortex
• Middle: Zona Fascicularis
• constitutes about 75% of the cortex
• Glucocorticoids- Cortisol, corticosterone
and 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
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
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
Glucocorticoids
Actions
• Anti-inflammatory effects and suppression
of immune response thru:
• Synthesis of lipocortin, an inhibitor of
phospholipase A, the enzyme that liberates
arachidonic acid from membrane phospholipids
• Arachidonic acid is the precursor of prostaglandins
and leukotrienes, the chemicals involved in the
inflammatory response
Glucocorticoids
Actions
• Anti-inflammatory effects and suppression
of immune response thru:
• Inhibition of production of interleukin-2(IL-2) and
inhibition of proliferation of T lymphocytes
• Both are critical for cellular immunity
• Glucocorticoids are used to prevent rejection of
transplanted organs
• Inhibition of release of histamine and serotonin
from mast cells and platelets
Glucocorticoids
Glucocorticoids
Actions
• Maintenance of vascular responsiveness to
catecholamines thru:
• Up-regulation of α1 receptors on arterioles,
increasing their sensitivity to the vasoconstrictor
effect of norepinephrine
• Cortisol excess causes increase in arterial pressure
• Cortisol deficiency causes decrease in arterial
pressure
Mineralocorticoids
Actions
• Na+ reabsorption
• Aldosterone induces synthesis of channels in
the principal cells in the late distal tubule and
collecting duct for increased Na+
reabsorption
• Affects 2% of overall reabsorption of Na+.
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
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
Primary insufficiency (Addison’s 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
Secondary insufficiency
• Caused by primary deficiency of ACTH
• hypopituitarism, suppression from exogenous
steroids
• No hyperpigmentation, hypovolemia,
hyperkalemia and metabolic acidosis
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
Adrenocortical excess

Cushing’s syndrome
• 3rd - 6th decade, 4 to1 females
• causes
– pharmocologic
– pituitary adenoma 75-90%
– adrenal adenoma, carcinoma
– ectopic ACTH
Dexamethasone Suppression Test

• Based on the ability of dexamethasone to inhibit

ACTH secretion

Effect on cortisol secretion

Low-dose High-dose
DEXA DEXA
normal Inhibits Inhibits

ACTH-secreting tumors No change Inhibits

Adrenal cortical tumors No change No change

(cortisol-secreting)
Adrenocortical excess – Treatment
Hyperaldosteronism
• primary causes (Conn’s 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
Lecture Points

• Adrenals
• Form and development
• Control and regulation
• Steroid hormones
• Adrenal cortex
• Adrenal medulla
• Clinical correlates
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 not
have the typical structure of a neuron.
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 the
same type of receptor.

• Chromaffin cells lack axons, and they secrete

epinephrine and norepinephrine into the blood,
instead of interneural transmission.
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 neurotransmitter produced by some neurons in the brain
and the periphery
– dopamine has its own receptors.
Catecholamines
• 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
• β-receptors activate Gs and uses cAMP as the
second messenger
• Receptors of the type α1 activate Gq and use
DAG and Ca as second messengers
• Receptors of the type α2 activate Gi, and thus
inhibit adenylyl cyclase.
•
Epinephrine
• 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

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 β 1 adrenergic receptors.
Epinephrine

Actions on cardiovascular system

• relaxes blood vessels which have β 2 receptors in
their smooth muscle (e.g., arterial vessels of
skeletal muscle and of the liver).
• contracts blood vessels which have α-adrenergic
receptors in their smooth muscle (e.g., vessels in
skin, kidney, and some other abdominal organs)
Epinephrine

Actions on cardiovascular system

∀ β 1 adrenergic receptors
– norepinephrine = epinephrine.
∀ β 2 receptors
– epinephrine >> NE
• α receptors
– Epinephrine > NE
Epinephrine

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
Epinephrine

Effects on metaboilsm
• In adipose tissue, epinephrine stimulates
the hydrolysis of stored triglycerides to free
fatty acids and glycerol, both of which
can be utilized by some tissues.

• In pancreatic beta (β) cells, epinephrine

inhibits the production of insulin, which
has opposite metabolic effects.
Epinephrine

Effects on metaboilsm
• In skeletal muscles, epinephrine stimulates
the breakdown of glycogen stores and
inhibit glycogen synthesis.

• Lactate is utilized by the liver for

gluconeogenesis.
Adrenal Medulla
Pheochromocytoma
• a tumor of 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
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 (α1-blocker)