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
Functional Anatomy of the Adrenal Gland
• The two adrenal glands are located immediately anterior to the
• 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
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
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
• They induce essentially the same effects
as direct sympathetic nervous stimulation
• 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
Adrenergic Receptors and Mechanism of
• The physiologic effects of epinephrine and
norepinephrine are initiated by their binding to
adrenergic receptors on the surface of target
• 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
• 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
• 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
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
• 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
• Inhibition of certain "non-essential" processes: an example is
inhibition of gastrointestinal secretion and motor activity
• In total, at least two to three dozen different
steroids are synthesized
• Two classes are of particular importance:
Class of Steroid Major
Mineralocorticoids Aldosterone Na+, K+ and
Glucocorticoids Cortisol Glucose
• Additionally, the adrenal cortex produces some sex steroids (e.g.
androgens -related congenital adrenal hyperplasia)
• Some enzymes reside in endoplasmic reticulum and others inside
• Hence, synthesis involves shuttling of the steroids between these two
• Synthesis of the different steroids is not uniformly distributed through
• 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
• The principal steroid with mineralocorticoid
activity is aldosterone.
• Cortisol, is said to have "weak mineralocorticoid
• Mineralocorticoids play a critical role in
regulating concentrations of minerals -
particularly sodium and potassium - in
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
- 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
- Concentration of potassium ions in extracellular fluid: Small
increases in blood levels of potassium strongly stimulate
- 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
• A deficiency in aldosterone can occur by
• More commonly, in conjunction with a
glucocorticoid deficiency (known as
• Without treatment by mineralocorticoid
replacement therapy, a lack of aldosterone is
lethal - due to:
- electrolyte imbalances
- hypotension and cardiac failure
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.
Glucocorticoids (cortisol )
• Failure to produce glucocorticoids is not acutely
• 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
- 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
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.
Effects on Inflammation and Immune Function
• Glucocorticoids have potent anti-
inflammatory and immunosuppressive
• 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
Other Effects of Glucocorticoids
• Glucocorticoids have multiple effects on fetal
- 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
Cortisol Disease States
• Hyperadrenocorticism or Cushings disease. The most
prevalent disorder involving glucocorticoids in man
• Excessive levels of glucocorticoids are seen in two
- 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
• Also called hyperadrenocorticism or
• 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
Exogenous vs. endogenous
• The most common is exogenous administration of
• Endogenous Cushing's syndrome:
- pituitary Cushing's, a benign pituitary adenoma
- Also known as Cushing's disease
- Responsible for 65% of endogenous Cushing's
• 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.
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
- 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
• Other features
- persistent hypertension (due to cortisol's
enhancement of epinephrine's
- insulin resistance (especially common in
ectopic ACTH production), leading to
- 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-
• Cortisol can also exhibit mineralcorticoid activity in
high concentrations, worsening the hypertension
and leading to hypokalemia (common in ectopic
• Opportunistic infections and impaired wound
healing (cortisol is a stress hormone, so it
depresses the immune and inflammatory
• 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
• 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
• 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
• Primary adrenocortical insufficiency
• Due to the destruction or dysfunction of the entire
• It affects glucocorticoid and ineralocorticoid
• The onset of disease usually occurs when 90% or
more of both adrenal cortices are dysfunctional or
• Patients may present with
- clinical features of chronic Addison disease or
- in acute addisonian crisis (precipitated by stress
factors such as infection, trauma, surgery)
Presentation of chronic Addison disease
• The onset of symptoms most often is insidious
• Progressive weakness, fatigue, poor appetite, and
• Nausea, vomiting, and occasional diarrhea.
Presentation of acute Addison disease
• Prominent nausea, vomiting, and vascular
• cyanotic and confused.
• Abdominal symptoms may take on features of an
• 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
• The most common cause of Addison disease is
idiopathic autoimmune adrenocortical
• 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
- Idiopathic autoimmune adrenocortical atrophy
and tuberculosis (TB) account for nearly 90% of
cases of Addison disease.
• 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).
Additional causes of chronic Addison
• Chronic granulomatous diseases (TB of the adrenal glands
usually is a tertiary disease due to the hematogenous spread
• Hematologic malignancies (Hodgkin and non-Hodgkin
lymphoma and leukemia)
• Metastatic malignant disease
• Infiltrative metabolic disorders - Amyloidosis and
• Acquired immunodeficiency syndrome
• Congenital adrenal hyperplasia
• Drug-related causes
• Abdominal irradiation
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
• 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
– 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
• Within 15-30 minutes of ACTH infusion, the normal
adrenal cortex releases 2-5 times its basal plasma
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.
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.
• A rare catecholamine-secreting tumor derived
from chromaffin cells.
• Tumors that arise outside the adrenal gland are
termed extra-adrenal pheochromocytomas or
• 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
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
• Stimulation of beta-adrenergic receptors
results in an increase in heart rate and
• Catecholamine secretion in pheochromocytomas is
not regulated in the same manner as in healthy
• Unlike the healthy adrenal medulla,
pheochromocytomas are not innervated, and
catecholamine release is not precipitated by neural
• 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
- Normal adrenal medulla is composed of roughly 85%
- Most pheochromocytomas contain norepinephrine
predominantly (except in Familial
Clinics (Cardiovascular morbidity)
• Cardiovascular morbidity:
- Hypertension is the most common complication
- Cardiac arrhythmias, such as atrial and
ventricular fibrillation, may occur
- signs and symptoms of myocardial infarction
- dilated cardiomyopathy
- pulmonary edema, either of cardiac or
Plasma metanephrine testing has the highest
sensitivity (96%) for detecting a
pheochromocytoma, but it has a lower specificity
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
• Chromogranin A is an acidic monomeric
protein that is stored with and secreted
• A pheochromocytoma-induced
hypertensive crisis may precipitate
• Focal neurologic signs and symptoms, or
• 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