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

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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 reninangiotensin 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 C17, 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 DEXA High-dose DEXA Inhibits Inhibits No change

normal
ACTH-secreting tumors Adrenal cortical tumors (cortisol-secreting)

Inhibits No change No change

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)

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