BIO 5406 Notes, 2/20/12
ADRENAL CORTEX
I. History. [Hadley, pp. 337-338]
A. 1855 ‑‑ Thomas Addison described syndrome resulting from
destruction of adrenals.
1. Weakness, feebleness of the heart, irritability of the stomach and a
peculiar change in skin color.
2. Patients died.
B. 1856 ‑‑ Charles‑Edouard Brown‑Sequard -- adrenal glands are
essential for life.
1. Adrenalectomy resulted in death of experimental animals.
C. Discovery of epinephrine in late 1890's shifted emphasis away from the
cortex for 40 years.
D. 1924 -- Proposed that adrenal cortex is essential for life.
E. 1927 ‑‑ NaCl prolongs life of adrenalectomized dogs.
F. 1932 ‑‑ NaCl prolongs life of patients with Addison's disease.
G. 1932 ‑‑ Harvey Cushing described hyperplasia of the adrenal gland
associated with pituitary adenoma.
1. Pituitary basophilism.
H. 1936 -- Hans Selye introduced the general adaptation syndrome.
I. 1936 -- Cortisol isolated independently by Edward Kendall and
1. Led to ability to administer corticosteroids to patients with Addison's
disease.
J. 1949 ‑‑ Philip Hench, Edward Kendall, and coworkers described
the effectiveness of cortisone in relieving the symptoms of rheumatoid
arthritis.
K. 1954 ‑‑ Aldosterone was identified as the compound responsible for
mineralocorticoid activity.
L. 1955 ‑‑ Corticotropin (ACTH) was isolated from pituitary and its role
in regulating cortisol secretion was established.
M. 1981 -- Pro-opiomelanocortin discovered.
N. 1981 ‑‑ Identification of corticotropin‑releasing hormone (CRH)
by Wylie Vale.
II. Embryologic Origins. [pg. 338]
A. Epithelial cells from mesodermal tissues near gonadal ridge (figure).
1. Migrate to suprarenal position.
III. Aldosterone. [pp. 345-347, 354-357]
A. Review.
1. Mineralocorticoid (structure).
2. Produced in zona glomerulosa.
3. Key enzymes.
a. 21-hydroxylase required for mineralocorticoid activity.
b. 18‑hydroxylase enhances mineralocorticoid activity.
B. Review anatomy and physiology of the nephron.
1. Amount excreted = amt filtered + amt secreted - amt reabsorbed
C. Na+ reabsorption in the nephron.
1. 92% of filtered Na+ is reabsorbed from proximal tubule and ascending
limb of the loop of Henle.
2. Na+ reabsorption from distal tubule and collecting duct is under the
influence of aldosterone.
D. Effects of aldosterone on tubular Na+ reabsorption.
1. Promotes reabsorption of Na+ and simultaneous secretion of K+
through the walls of renal tubules (fig. 15.18).
2. Na+ is actively transported out of tubular cell into ECF on the blood
side.
a. K+ is exchanged for Na+ on blood side (Na-K pump).
b. Na+ concentration inside tubular cell is kept low.
3. Na+ enters tubular cell from lumen by diffusion and by facilitated
diffusion.
4. K+ leaves cell and enters lumen by diffusion.
D. Mechanism of action (fig. 15.19).
1. Aldosterone binds to cytoplasmic receptors on the blood side.
2. Stimulates synthesis of membrane proteins and mitochondrial
enzymes.
3. Three hypotheses.
a. Sodium pump hypothesis -- aldosterone promotes active
transport of Na+ and K+ on blood side.
b. Metabolic hypothesis -- aldosterone acts on mitochondria to
increase supply of ATP to Na-K pump.
c. Permease hypothesis -- aldosterone increases permeability
of luminal membrane to Na+.
E. Consequences of aldosterone deficiency.
1. Normal subject on ordinary diet reabsorbs 99.5% of filtered Na+.
2. Addison's disease patient may reabsorb 98.5%.
3. In complete absence of aldosterone ───> excrete up to 20 g Na+
per day.
4. Net loss is almost 2 liters of extracellular fluid/day.
5. Loss of fluid leads to decreased cardiac output, hypotension,
shock, and death within a few weeks.
F. Control of aldosterone secretion.
1. Outside of pituitary control.
2. Stimuli to aldosterone secretion.
a. Angiotensin II.
b. High plasma K+.
3. Renin‑angiotensin‑aldosterone system.
a. Juxtaglomerular apparatus -- where the afferent arteriole comes
into contact with the distal tubule (fig. 15.9).
b. Juxtaglomerular cells.
1. Located in walls of afferent arteriole at this site (figure).
2. Secrete renin into circulation.
c. Renin causes cleavage of circulating protein, angiotensinogen,
to produce a decapeptide, angiotensin I (fig. 15.8).
d. Angiotensin I is cleaved by angiotensin converting enzyme (ACE)
to produce an octapeptide, angiotensin II.
1. ACE is found in the walls of blood vessels in lungs.
e. Angiotensin II is a potent stimulator of aldosterone secretion
and a vasoconstrictor.
f. Angiotensin II is broken down within minutes by angiotensinase.
1. Forms angiotensin III (heptapeptide).
a. Angiotensin III also stimulates aldosterone secretion, but is
not a vasoconstrictor.
2. Further broken down by angiotensinases to inactive fragments.
4. Stimuli to renin secretion.
a. Decreased renal arteriolar blood pressure.
1. Detected by juxtaglomerular cells.
2. Reflects drop in arterial BP.
b. Decreased distal tubular Na+ conc.
1. Detected by macula densa cells in walls of distal tubule.
2. Reflects diminished plasma Na+.
3. Signal JG cells to secrete renin.
c. Activation of renal sympathetic nerves.
1. Occurs as part of baroreceptor reflex (when BP is low).
G. Control system diagram: Loss of blood volume.
H. Control system diagram: Na+ deficiency (fig. 15.10).
IV. Comparative Aspects of Mineralocorticoids.
A. Structures of steroid hormones are remarkably uniform among
vertebrates.
1. Ex. corticosterone is produced by all vertebrates.
2. For new steroids to evolve, new enzymes must be produced.
3. Most prominent evolutionary change appears to be in the function of
corticosteroids.
B. Mineralocorticoids act on any epithelial surface capable of Na+ transport
(ex. skin, bladder, gills).
C. Cortisol is major salt‑regulating hormone in fish.
1. Stimulates Na+ excretion through the gills.
2. Salmon show increased adrenal steroidogenic activity before
migrating from fresh water to the sea (figure).
D. Aldosterone first appears in amphibians.
1. Stimulates Na+ influx across skin and Na+ retention by bladder.
E. Marine reptiles and birds have salt‑excreting glands.
1. Birds and iguanas ‑‑ nasal (figure, video).
2. Marine turtles ‑‑ lacrimal.
3. Marine birds have larger adrenal glands than freshwater or terrestrial
birds.
4. Experiment: Force ducks to drink salt water.
a. Adrenals hypertrophy.
b. Concentrated salt solution drips from nares.
c. Adrenalectomize ───>
d. Inject corticosterone ───>
e. Conclusion:
V. Cortisol. [pp. 351-356]
A. Review.
1. Glucocorticoid (structure).
2. Produced by zona fasciculata and zona reticularis.
3. Key enzymes.
a. 17‑hydroxylase to enter glucocorticoid pathway.
b. 11‑hydroxylase required for glucocorticoid activity.
B. Primary functions.
1. Regulation of glucose metabolism.
2. Response to stress.
C. Physiological actions of glucocorticoids.
1. Permissive effects.
a. Baseline secretion of glucocorticoids is required for many
physiological functions.
1. Maintenance of blood pressure.
2. Retention of sodium by kidneys.
3. Maintenance of normal blood glucose levels.
2. Protective effects.
a. Increased glucocorticoid secretion required to maintain
homeostasis during stress.
1. Trauma, infection, intense heat or cold, surgery, debilitating
diseases.
2. Patient undergoing surgery will become hypotensive unless
cortisol levels are at least tripled.
3. Pernicious effects.
a. Secretion or administration of glucocorticoids in large amounts
produces general catabolic effects.
1. Muscle atrophy.
2. Poor wound healing.
3. Increased susceptibility to infections.
4. Osteoporosis.
D. General adaptation syndrome -- introduced by Hans Selye in 1936
(figure).
1. Alarm reaction.
a. Activation of sympathetic n.s. and secretion of epinephrine.
2. Stage of resistance.
a. Hypertrophy of ZF and ZR.
b. Increased secretion of glucocorticoids.
3. Stage of exhaustion.
a. Continued secretion of glucocorticoids over long periods of time.
b. Pernicious effects appear ‑‑ muscle wasting, hyperglycemia,
ulceration, etc.
c. Leads to death.
E. Antiinflammatory effects of the glucocorticoids.
1. Key discoveries.
a. Edward Kendall ‑‑ discovery of cortisone (figure).
b. Philip Hench.
1. Treatment of Addison's patients.
2. Noted dramatic relief of rheumatoid arthritis.
3. First reported in 1949.
c. 1950 Nobel Prize awarded to Hench, Kendall, and Reichstein.
2. Requires pharmacological doses.
3. Preparations ‑‑ cortisone, prednisone.
4. Relieves a variety of inflammatory disorders.
a. Arthritis.
b. Bronchial asthma.
c. Inflammatory skin diseases.
d. Collagen disease.
e. Joint injuries.
5. Mechanism.
a. Does not cure underlying disease.
b. Suppresses many aspects of inflammatory response
(ex. lymphocyte production).
6. Safety.
a. Single dose or short course of therapy is very safe.
b. Prolonged use has many side effects.
1. Pernicious effects listed above.
2. Suppression of adrenal function.
c. Patient must weigh risks vs. benefits.
VI. Control of Cortisol Secretion. [pp. 344-345]
A. Controlled variable is the cortisol concentration in blood.
B. Feedback loop (fig. 15.6).
C. Adrenocorticotropic hormone (ACTH, corticotropin).
1. 39 amino acids (fig. 5.8).
2. Synthesized and secreted by corticotrophs (basophils) in anterior
pituitary.
3. Stimulates hypertrophy of ZF and ZR.
4. Stimulates glucocorticoid secretion.
5. Similarity in amino acid sequences of ACTH and various MSH=s.
a. First 13 aa of ACTH are identical to those of α‑MSH (fig. 8.1).
b. Explains hyperpigmentation in some adrenal diseases.
c. Common prohormone -- pro-opiomelanocortin (POMC) (fig. 8.2).
D. Corticotropin‑releasing hormone (CRH).
1. Structure identified in 1981 by Wylie Vale.
2. 41 amino acids.
3. Stimulates secretion of ACTH, b-endorphin, a-MSH.
E. Intervening variables.
1. Daily rhythm -- higher in morning, lower in evening (figure).
2. Stress -- stimulates CRH secretion.
VII. Disorders of the Adrenal Cortex. [pp. 357-361]
A. Hypocortisolism ‑‑ cortisol deficiency (fig. 15.21).
1. Primary adrenal insufficiency (figure).
a. Causes.
1. Adrenalectomy.
2. Addison's disease -- progressive destruction of adrenal cortex.
b. Decreased cortisol, decreased aldosterone, increased ACTH.
c. Symptoms do not appear until 80 ‑ 90% of the cortex is destroyed.
1. Muscle weakness \
2. Weight loss \
3. Hypotension \ Due to lack of
4. Increased appetite for salt / aldosterone
5. Decreased plasma Na+, /
increased plasma K+ /
6. Hypoglycemia \ Due to lack
7. Inability to tolerate stress / of cortisol
8. Hyperpigmentation ───> due to excessive ACTH.
2. Secondary adrenal insufficiency -- inadequate stimulation of the
adrenal cortex.
a. Causes.
1. Hypopituitarism.
2. Withdrawal of glucocorticoid therapy.
b. Decreased cortisol, normal aldosterone, decreased ACTH.
c. Symptoms are limited to hypoglycemia and inability to tolerate stress.
3. Treatment -- replacement therapy with glucocorticoids.
B. Hypercortisolism ‑‑ excess cortisol secretion (fig. 15.21).
1. Causes.
a. Adrenal tumor.
1. Increased cortisol, normal or increased aldosterone,
decreasedACTH.
b. ACTH-secreting tumor (ex. pituitary tumor or lung cancer).
1. Increased cortisol, normal aldosterone, increased ACTH.
c. High dose glucocorticoid therapy ‑‑ most common cause.
1. Feedback inhibition of ACTH secretion ───> adrenal atrophy.
2. Symptoms -- Cushing's syndrome.
a. Muscular weakness and wasting \
b. Osteoporosis \
c. Thin skin, bruising, striae (figure) \ Pernicious effects
d. Redistribution of fat -- central obesity, / of glucocorticoids
moon face, buffalo hump (figure) /
e. Hyperglycemia /
f. Sodium retention, decreased plasma K+ \ Due to excess
g. Hypertension / aldosterone
h. Virilization of female ‑‑ due to excess adrenal androgens.
i. Hyperpigmentation -- if ACTH is increased.
j. Drug‑induced hypercortisolism does not show last four (f - i).
3. Treatment -- identify and eliminate source of the problem
(ex. surgical removal of tumor).
C. Congenital adrenal hyperplasia.
1. Congenital deficiency in adrenal 21‑hydroxylase.
2. Decreased cortisol ───> increased ACTH ───>
increased adrenal androgens.
3. Adrenal cells are large with high lipid content (figure).
4. Precocious puberty in male.
5. Virilization of female.
6. Treatment -- replacement therapy with glucocorticoids and aldosterone.
D. Review of ACTH secretion.
Condition
Plasma ACTH (mU/dl)
Normal (8 am)
Normal (10 pm)
Moderate stress
Hypopituitarism
Addison's disease
Cushing's disease
(pituitary tumor)
E. A Case of Abruptly Elevated Blood Glucose (Kocher, R., and Sackey, J.
Cortlandt Forum 15(2): 14-19, Feb. 2002).
1. A 62-year-old woman presenting with complaints of polyuria, nocturia,
polydipsia, dry mouth, and increasing emotional stress.
2. Lab tests.
3. Evidence of Cushing's syndrome.
4. Further testing.
5. Diagnosis.
6. Treatment.
