Beda Lec- Adrenals

8/14/2019 Beda Lec- Adrenals

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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



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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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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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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ACTH+


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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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Long-loop reflexes and

short-loop reflexes


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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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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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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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Ang II+


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Lecture Points



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



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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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



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Secondary insufficiency

Caused by primary deficiency of ACTH

hypopituitarism, suppression from exogenous

steroids

No hyperpigmentation, hypovolemia,

hyperkalemia and metabolic acidosis



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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



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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