ENDOCRINE DISORDERS OF
THE ADRENAL GLAND
BMLS DEC 2009
1

The Adrenal Gland: Introduction
• The adrenal glands produce three major
classes of hormones
• The hormones aid in dealing with the
multitude of small and large stresses
• At least two of these groups -
glucocorticoids and mineralocorticoids -
are necessary for life
2

Functional Anatomy of the Adrenal Gland
• The two adrenal glands are located immediately anterior to the
kidneys
• Encased in a connective tissue capsule
• Usually partially buried in an island of fat.
• Adrenal glands are retroperitoneal.
An inner medulla
• , A source of the catecholamines epinephrine and
norepinephrine (The chromaffin cell is the principle cell type)
• Medulla is richly innervated by preganglionic sympathetic
fibers (In essence, an extension of the sympathetic nervous
system.
An outer cortex,
• Secretes several classes of steroid hormones (glucocorticoids
and mineralocorticoids, plus a few others).
• Histologic examination of the cortex reveals three concentric
zones of cells that differ in the major steroid hormones they
3

Adrenal Medullary Hormones
• Adrenal medulla synthesize and secrete
epinephrine and norepinephrine.
• In humans roughly 80% of the
catecholamine output is epinephrine
• Following release into blood, these
hormones bind adrenergic receptors on
target cells
• They induce essentially the same effects
as direct sympathetic nervous stimulation
4

Synthesis and Secretion of Catecholamines
In Chromaffin cells
5

• Norepinephine and epinephrine are stored in
electron-dense granules (which also contain
ATP and several neuropeptides)
• Secretion of these hormones is stimulated by
acetylcholine release from preganglionic
sympathetic fibers innervating the medulla.
• Many types of "stresses" stimulate secretion,
including exercise, hypoglycemia and trauma
• Catecholamines bind loosely to and are
carried in the circulation by albumin and
perhaps other serum proteins
6

Adrenergic Receptors and Mechanism of
Action
• The physiologic effects of epinephrine and
norepinephrine are initiated by their binding to
adrenergic receptors on the surface of target
cells.
• Complex physiologic responses result from adrenal
medullary stimulation because there are multiple
receptor types which are differentially expressed in
different tissues and cells.
• The alpha and beta adrenergic receptors are
defined by differential binding of various agonists
and antagnonists and, more recently, by analysis of
molecular clones
7

• In general, catecholamines have the same
effects on target organs as direct stimulation
by sympathetic nerves
• However their effect is longer lasting.
• Additionally, of course, circulating hormones can
cause effects in cells and tissues that are not
directly innervated.
• The physiologic consequences are responses
which aid in dealing with stress.
• Common stimuli include exercise, hypoglycemia,
hemorrhage and emotional distress
Physiologic Effects of Medullary Hormones
8

Major effects mediated by Catecholamines
• Increased rate and force of contraction of the heart muscle: this is
predominantly an effect of epinephrine acting through beta
receptors.
• Constriction of blood vessels: norepinephrine, in particular, causes
widespread vasoconstriction, resulting in increased resistance and
hence arterial blood pressure.
• Dilation of bronchioles: assists in pulmonary ventilation.
• Stimulation of lipolysis in fat cells: this provides fatty acids for
energy production in many tissues and aids in conservation of
dwindling reserves of blood glucose.
• Increased metabolic rate: oxygen consumption and heat production
increase throughout the body in response to epinephrine. Medullary
hormones also promote breakdown of glycogen in skeletal muscle
to provide glucose for energy production.
• Dilation of the pupils: particularly important in conditions of low
ambient light.
• Inhibition of certain "non-essential" processes: an example is
inhibition of gastrointestinal secretion and motor activity
9

Adrenal Steroids
• In total, at least two to three dozen different
steroids are synthesized
• Two classes are of particular importance:
Class of Steroid Major
Representative
Physiologic
Effects
Mineralocorticoids Aldosterone Na+, K+ and
water
homeostasis
Glucocorticoids Cortisol Glucose
homeostasis and
many others
10

• Additionally, the adrenal cortex produces some sex steroids (e.g.
androgens -related congenital adrenal hyperplasia)
• Some enzymes reside in endoplasmic reticulum and others inside
mitochondria.
• Hence, synthesis involves shuttling of the steroids between these two
organelles.
• Synthesis of the different steroids is not uniformly distributed through
the cortex.
• For example, the outermost group of cells (zona glomerulosa)
synthesizes aldosterone, but essentially no cortisol or androgens (cells
do not express the enzyme 17-alpha-hydroxylase which is necessary for
synthesis of 17-hydroxypregnenolone and 17-hydroxyprogesterone).
• 17-alpha-hydroxylase is present in cells of the inner zones of the cortex
(zonae fasiculata and reticularis), which are the major sites of cortisol
production
11

Major
Pathways
in
Steroid
Biosynthesis
12

Mineralocorticoids
• The principal steroid with mineralocorticoid
activity is aldosterone.
• Cortisol, is said to have "weak mineralocorticoid
activity"
• Mineralocorticoids play a critical role in
regulating concentrations of minerals -
particularly sodium and potassium - in
extracellular fluids
13

Physiologic Effects of Mineralocorticoids
• The major target of aldosterone is the distal
tubule of the kidney, where it stimulates
exchange of sodium and potassium.
• Three primary physiologic effects of aldosterone
result:
- Increased resorption of sodium: sodium loss in
urine is decreased under aldosterone stimulation.
- Increased resorption of water, with consequent
expansion of extracellular fluid volume. This is an
osmotic effect directly related to increased
resorption of sodium.
• Increased renal excretion of potassium. 14

Control of Aldosterone Secretion
• Control over aldosterone secretion is multifactorial.
• The two most significant regulators of aldosterone secretion
are:
- Concentration of potassium ions in extracellular fluid: Small
increases in blood levels of potassium strongly stimulate
aldosterone secretion.
- Angiotensin II: Activation of the renin-angiotensin system as a
result of decreased renal blood flow (usually due to decreased
vascular volume) results in release of angiotensin II, which
stimulates aldosterone secretion.
• Other factors which stimulate aldosterone secretion include
- adrenocorticotropic hormone (short-term stimulation only)
- sodium deficiency.
• Factors which suppress aldosterone secretion include
- atrial naturetic hormone
- high sodium concentration
- potassium deficiency. 15

Disease States
• A deficiency in aldosterone can occur by
itself
• More commonly, in conjunction with a
glucocorticoid deficiency (known as
Addison's disease).
• Without treatment by mineralocorticoid
replacement therapy, a lack of aldosterone is
lethal - due to:
- electrolyte imbalances
- hypotension and cardiac failure
16

Addison’s disease
Adrenocortical insufficiency usually as the result of
idiopathic atrophy or destruction of both adrenal glands
by tuberculosis, an autoimmune process, or other
diseases; characterized by decreased serum
electrolytes and cortisol , fatigue, decreased blood
pressure, weight loss, increased melanin pigmentation of
the skin and mucous membranes, anorexia, and nausea
or vomiting; without appropriate replacement therapy, it
can progress to acute adrenocortical insufficiency.
17

Glucocorticoids (cortisol )
• Failure to produce glucocorticoids is not acutely
life-threatening.
• Loss or profound diminishment of glucocorticoid
secretion leads to a state of
- deranged metabolism
- inability to deal with stressors
- if untreated, is fatal.
• In addition glucocorticoids frequently used
drugs
- prescribed for their anti-inflammatory and
- immunosuppressive properties. 18

Physiologic Effects of Glucocorticoids
• No cells that lack glucocorticoid receptors
• These steroid hormones have a huge
number of effects on physiologic systems.
• Best known and studied effects of
glucocorticoids are on carbohydrate
metabolism and immune function
19

Effects on Metabolism
• Glucose metabolism (hence the name glucocorticoid).
• In the fasted state, cortisol stimulates several
processes that collectively serve to increase and
maintain normal concentrations of glucose in blood.
These effects include:
• Stimulation of gluconeogenesis, particularly in the liver:
This pathway results in the synthesis of glucose from
non-hexose substrates such as amino acids and lipids
• Mobilization of amino acids from extrahepatic tissues:
These serve as substrates for gluconeogenesis.
• Inhibition of glucose uptake in muscle and adipose
tissue: A mechanism to conserve glucose.
• Stimulation of fat breakdown in adipose tissue: The
fatty acids released by lipolysis are used for production
of energy in tissues like muscle, and the released
glycerol provide another substrate for gluconeogenesis.
20

Effects on Inflammation and Immune Function
• Glucocorticoids have potent anti-
inflammatory and immunosuppressive
properties.
• This is particularly evident when they
administered at pharmacologic doses
• Glucocorticoids are widely used as drugs to
treat inflammatory conditions such as
arthritis or dermatitis
• Glucocorticoids are used as adjunction
therapy for conditions such as autoimmune
diseases.
21

Other Effects of Glucocorticoids
• Glucocorticoids have multiple effects on fetal
development.
- role in promoting maturation of the lung and
production of the surfactant necessary for
extrauterine lung function. .
• Several aspects of cognitive function are known to
both stimulate glucocorticoid secretion and be
influenced by glucocorticoids.
• Excessive glucocorticoid levels may cause:
- inhibition of bone formation
- suppression of calcium absorption
- and delayed wound healing.
• These observations suggest a multitide of less
dramatic physiologic roles for glucocorticoids
22

Cortisol Disease States
• Hyperadrenocorticism or Cushings disease. The most
prevalent disorder involving glucocorticoids in man
• Excessive levels of glucocorticoids are seen in two
situations:
- Excessive endogenous production of cortisol (can result
from a primary adrenal defect (ACTH-independent) or from
excessive secretion of ACTH (ACTH-dependent).
- Administration of glucocorticoids for theraputic purposes (
common side-effect of these widely-used drugs).
• Cushing's disease has widespread effects on
- metabolism and
- organ function,
• Clinical manifestations accompany this disorder
- Hypertension, obesity, muscle wasting, thin skin, metabolic
aberrations such as diabetes
23

Cushing's syndrome
• Also called hyperadrenocorticism or
hypercorticism)
• A disorder caused by high levels of cortisol
• Can be caused by:
- Taking glucocorticoid drugs
- Tumors that produce cortisol or ACTH
• Cushing's disease refers to one specific cause, a
non-cancerous tumor (adenoma) in the pituitary
gland that produces large amounts of ACTH
• It was described by American Dr. Harvey Cushing
in 1932
24

Exogenous vs. endogenous
• The most common is exogenous administration of
glucocorticoids
• Endogenous Cushing's syndrome:
- pituitary Cushing's, a benign pituitary adenoma
secretes ACTH.
- Also known as Cushing's disease
- Responsible for 65% of endogenous Cushing's
syndrome.
• In adrenal Cushing's
- excess cortisol is produced by adrenal gland tumors,
hyperplastic adrenal glands, or adrenal glands with
nodular adrenal hyperplasia.
• Paraneoplastic Cushing's syndrome
- Seen in diseases like small cell lung cancer. 25

ACTH-dependent vs. ACTH-independent
• Cushing's syndrome can also be sub-classified
according to whether or not the excess cortisol is
dependent on increased ACTH.
• ACTH-dependent Cushing's syndrome
- driven by increased ACTH (exogenous ACTH
administration, pituitary and ectopic Cushing's).
• ACTH-independent Cushing's syndrome
- increased cortisol,
- ACTH is decreased due to negative feedback.
- Can be caused by exogenous administration of
glucocorticoids or by adrenal adenoma,
carcinoma, or nodular hyperplasia.
26

Signs and symptoms
• Symptoms include:
- Rapid weight gain, particularly of the trunk and face with
sparing of the limbs (central obesity).
- Fat pads along the collar bone and on the back of the neck
(buffalo hump)
- Round face often referred to as a "moon face".
• Other symptoms include
- excess sweating, telangiectasia (dilation of capillaries)
- thinning of the skin (which causes easy bruising and
dryness, particularly the hands) and other mucous
membranes, purple or red
- hirsutism (facial male-pattern hair growth).
- effects other endocrine systems and cause (insomnia,
reduced libido, impotence, amenorrhoea and infertility.
- Various psychological disturbances, ranging from euphoria
to psychosis. Depression and anxiety
27

• Other features
- persistent hypertension (due to cortisol's
enhancement of epinephrine's
vasoconstrictive effect)
- insulin resistance (especially common in
ectopic ACTH production), leading to
diabetes mellitus.
- Cushing's syndrome due to excess ACTH
may also result in hyperpigmentation (due to
Melanocyte-Stimulating Hormone production
as a byproduct of ACTH synthesis from Pro-
opiomelanocortin (POMC).
28

• Cortisol can also exhibit mineralcorticoid activity in
high concentrations, worsening the hypertension
and leading to hypokalemia (common in ectopic
ACTH secretion).
• Opportunistic infections and impaired wound
healing (cortisol is a stress hormone, so it
depresses the immune and inflammatory
responses).
• Osteoporosis is also an issue in Cushing's
syndrome since, as mentioned before, cortisol
evokes a stress-like response.
• oligomenorrhea (decreased frequency of
menstruation) due to elevations in androgens
(male sex hormones), normally at low levels in
women.
29

Lab Diagnosis
• Basal levels of Cortisol and ACTH
• Dexamethasone suppression test
- administration of dexamethasone and
- frequent determination of cortisol and ACTH level), or a
- 24-hour urinary measurement for cortisol
• Dexamethasone is a glucocorticoid and simulates the effects
of cortisol, including negative feedback on the pituitary gland.
• When dexamethasone is administered and a blood sample is
tested, high cortisol would be indicative of Cushing's
syndrome because there is an ectopic source of cortisol or
ACTH (eg: adrenal adenoma) that is not inhibited by the
dexamethasone.
• A novel approach, recently cleared by the US FDA, is
sampling cortisol in saliva over 24 hours, which may be
equally sensitive, as late night levels of salivary cortisol are
high in Cushingoid patients 30

Addison’s Disease
• Primary adrenocortical insufficiency
• Due to the destruction or dysfunction of the entire
adrenal cortex.
• It affects glucocorticoid and ineralocorticoid
function.
• The onset of disease usually occurs when 90% or
more of both adrenal cortices are dysfunctional or
destroyed.
• Patients may present with
- clinical features of chronic Addison disease or
- in acute addisonian crisis (precipitated by stress
factors such as infection, trauma, surgery)
31

Presentation of chronic Addison disease
• The onset of symptoms most often is insidious
and nonspecific.
• Hyperpigmentation
• Progressive weakness, fatigue, poor appetite, and
weight loss.
• Nausea, vomiting, and occasional diarrhea.
32

Presentation of acute Addison disease
• Prominent nausea, vomiting, and vascular
collapse.
• Shock
• cyanotic and confused.
• Abdominal symptoms may take on features of an
acute abdomen.
• In acute adrenal hemorrhage, the patient, usually
in an acute care setting, deteriorates with sudden
collapse, abdominal or flank pain, and nausea
with or without hyperpyrexia
33

Causes
• The most common cause of Addison disease is
idiopathic autoimmune adrenocortical
insufficiency
• Resulting from autoimmune atrophy, fibrosis,
and lymphocytic infiltration of the adrenal cortex
- Usually with sparing of the adrenal medulla
- This accounts for more than 80% of reported
cases.
- Idiopathic autoimmune adrenocortical atrophy
and tuberculosis (TB) account for nearly 90% of
cases of Addison disease.
34

• Antibodies against the adrenal tissue are present
in a significant number of these patients,
• Evidence of cell-mediated immunity against the
adrenal gland also may be present.
• The steroidogenic enzyme 21-hydroxylase
(21OH) is the main autoantigen
• Patients may have a hereditary predisposition to
autoimmune Addison disease.
• Idiopathic autoimmune Addison disease may
occur in isolation or in association with other
autoimmune phenomena (eg, polyglandular
autoimmune disease types 1 and 2).
35

Additional causes of chronic Addison
disease
• Chronic granulomatous diseases (TB of the adrenal glands
usually is a tertiary disease due to the hematogenous spread
of infection)
• Hematologic malignancies (Hodgkin and non-Hodgkin
lymphoma and leukemia)
• Metastatic malignant disease
• Infiltrative metabolic disorders - Amyloidosis and
hemochromatosis
• Acquired immunodeficiency syndrome
• Congenital adrenal hyperplasia
• Drug-related causes
• Abdominal irradiation
36

Causes of acute Addison disease
• Stress -
• Failure to increase steroids
• Bilateral adrenal hemorrhage
• Bilateral adrenal artery emboli and
bilateral vein thrombosis
• Bilateral adrenalectomy for any reason
37

Laboratory Diagnosis
• Rests on the assessment of the functional capacity
of the adrenal cortex to synthesize cortisol.
• This is accomplished primarily by use of the rapid
ACTH stimulation test (Cortrosyn, cosyntropin, or
Synacthen)
– ACTH, through complex mechanisms, activates
cholesterol esterase enzymes and leads to the release of
free cholesterol from cholesterol esters. It also activates
the 20,22-desmolase enzyme, which catalyzes the rate-
limiting step in adrenal steroidogenesis and increases the
NADPH (nicotinamide adenine dinucleotide phosphate)
levels necessary for the various hydroxylation steps in
steroidogenesis.
• Within 15-30 minutes of ACTH infusion, the normal
adrenal cortex releases 2-5 times its basal plasma
cortisol output
38

 In acute adrenal crisis, where treatment
should not be delayed in order to do the
tests, a blood sample for a random plasma
cortisol level should be drawn prior to
starting hydrocortisone replacement.
39

Other laboratory tests
• Comprehensive metabolic panel
• The most prominent findings are
- hyponatremia, hyperkalemia, and a mild non–
anion-gap metabolic acidosis due to the loss
of the sodium-retaining and potassium and
hydrogen ion-secreting action of aldosterone.
• The most consistent finding is elevated blood
urea nitrogen (BUN) and creatinine due to the
hypovolemia, a decreased glomerular filtration
rate, and a decreased renal plasma flow.
 Adrenal autoantibodies may be present.
40

Pheochromocytoma
• A rare catecholamine-secreting tumor derived
from chromaffin cells.
• Tumors that arise outside the adrenal gland are
termed extra-adrenal pheochromocytomas or
paragangliomas.
• Because of excessive catecholamine secretion,
pheochromocytomas may precipitate life-
threatening hypertension or cardiac arrhythmias.
• If the diagnosis of a pheochromocytoma is
overlooked, the consequences could be
disastrous, even fatal
• If a pheochromocytoma is found, it is potentially
curable.
41

The clinical Manifestations
• Result from excessive catecholamine
secretion by the tumor.
• Stimulation of alpha-adrenergic receptors
results in elevated blood pressure,
increased cardiac contractility,
glycogenolysis, gluconeogenesis, and
intestinal relaxation.
• Stimulation of beta-adrenergic receptors
results in an increase in heart rate and
contractility.
42

• Catecholamine secretion in pheochromocytomas is
not regulated in the same manner as in healthy
adrenal tissue.
• Unlike the healthy adrenal medulla,
pheochromocytomas are not innervated, and
catecholamine release is not precipitated by neural
stimulation.
• The trigger for catecholamine release is unclear, but
multiple mechanisms have been postulated,
including direct pressure, medications, and changes
in tumor blood flow.
• Relative catecholamine levels also differ in
pheochromocytomas.
- Normal adrenal medulla is composed of roughly 85%
epinephrine
- Most pheochromocytomas contain norepinephrine
predominantly (except in Familial
pheochromocytomas)
43

Clinics (Cardiovascular morbidity)
• Cardiovascular morbidity:
- Hypertension is the most common complication
- Cardiac arrhythmias, such as atrial and
ventricular fibrillation, may occur
- Myocarditis
- signs and symptoms of myocardial infarction
- dilated cardiomyopathy
- pulmonary edema, either of cardiac or
noncardiac origin.
44

Laboratory Studies
 Plasma metanephrine testing has the highest
sensitivity (96%) for detecting a
pheochromocytoma, but it has a lower specificity
(85%).
 In comparison, a 24-hour urinary collection for
catecholamines and metanephrines has a
sensitivity of 87.5% and a specificity of 99.7%.
• Chromogranin A levels are sometimes used to
detect recurrent pheochromocytomas.
• Plasma levels of chromogranin A reportedly are
83% sensitive and 96% specific for identifying a
pheochromocytoma. 45

• Chromogranin A is an acidic monomeric
protein that is stored with and secreted
with catecholamines
46

Neurologic complications
• A pheochromocytoma-induced
hypertensive crisis may precipitate
hypertensive encephalopathy
• Focal neurologic signs and symptoms, or
seizures.
• Other neurologic complications include
- stroke due to cerebral infarction or an
embolic event secondary to a mural
thrombus from a dilated cardiomyopathy.
- Intracerebral hemorrhage also may occur
because of uncontrolled hypertension 47