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 The adrenal gland is a multifunctional organ that produces the
steroid hormones and neuropeptides which are essential for life.
 Despite the complex effects of adrenal hormones, most
pathologic conditions of the adrenal gland are linked by their impact
on blood pressure and electrolyte balance.
 In clinical practice, patients often present with states of
diminished production or overproduction of one or more adrenal
hormones. Hypofunction is generally treated with exogenous
hormone replacement, and hyperfunction is generally treated with
pharmacologic suppression or surgery.
Anatomy of adrenal gland
 The two adrenal glands (also called the suprarenal glands) are
situated in the abdomen, above the kidneys and below the
They have a high cholesterol content giving them a yellowish color.
 They are contained within the same membrane as the kidney but
separated from them by a fibrous layer of tissue.
 The right gland is tetrahedral in shape and lies lower than the left,
which is semilunar in shape and usually the larger of the two.
 When cut in half each gland consists of an outer cortex, yellow in
color and an inner medulla, which is dark red, or grey.
The cortex consists of three distinct zones. They are:
- Zona glomerulosa
- Zona fasciculata
- Zona reticularis
Each zone has a characteristic histology and secretes different types
of hormones.
Blood supply
 Adrenal arterial supply is symmetric.
 Small arterioles branch to form a dense subcapsular plexus that
drains into the sinusoidal plexus of the cortex.
 There is no direct supply to middle and inner zones.
 Venous drainage from the central vein displays laterality.
After crossing the medulla, the right adrenal vein empties into the
inferior vena cava, and the left adrenal vein drains into the left renal
Adrenal cortex
The function of the cortex is to produce adrenocorticoid
Androgens )Sex steroids)
Mineralocorticoids: Zona
mineralocorticoids, the most important hormone is aldosterone,
which account for 90% of mineralocorticoids activity.
 It helps in maintaining the balance of water and salt in the body.
 Aldosterone helps in regulating the amount of sodium that is
excreted into the urine. The production of aldosterone is regulated
by the renin angiotensin. Whenever the blood pressure fluctuates
or the balance of salt and water is disturbed.
Glucocorticoids:• Zona fasciculata cells (middle 75%) synthesize glucocorticoids,
such as cortisol.
• The adrenal cortex releases corticosteroids that help the body to
deal with stressful situations.
• Cortisol is regulated by the brain's hypothalamus and the pituitary
gland. First, the hypothalamus releases hormone called
corticotropin-releasing hormone (CRH) that signals the pituitary
gland to respond by sending out ACTH, which in turn stimulates the
adrenal glands to respond by producing cortisol.
Cortisol released to raise blood sugar, blood pressure levels, and
strengthens the immune system.
If the cortisol level is low, the person has:1. Fatigue
2. low blood pressure
3. Hypoglycemia
4. Poor immune function
5. Increased tendency to allergies and environmental sensitivity
6. Inability to deal with stress.
Excess Cortisol result in:1. Diminished cellular utilization of glucose, thus increases blood
sugar levels.
2. Decreases protein synthesis.
3. Increases protein breakdown that can lead to muscle wasting.
4. Causes demineralization of bone that can lead to osteoporosis.
5. Diminishes lymphocyte numbers and function.
Androgens (Sex steroids):The fasciculata also generate androgen precursors such as
dehydroepiandrosterone (DHEA), which is sulfated in the innermost
zona reticularis to dehydroepiandrosterone sulfate (DHEAS)
Functions of DHEA:1. Is a precursor that is converted to testosterone (a male hormone).
2. Is a precursor to estrogen (a female anabolic hormone).
3. Reverses immune suppression caused by excess cortisol levels,
thereby improving resistance against viruses, bacteria and Candida
albicans, parasites, allergies, and cancer.
4. Stimulates bone deposition and remodeling to prevent
5. Increases muscle mass.
6. Decreases percentage of body fat.
7. Involved in the thyroid gland's conversion of the less active T4 to
the more active T3.
8. Improves cardiovascular status by lowering total cholesterol and
LDL levels, thereby lessening incidences of heart attack.
9. Accelerates recovery from any kind of acute stress (e.g.,
insufficient sleep, excessive exercise, mental strain, etc.).
Adrenal Steroidogenesis
• synthesis of the steroid hormones produced by the adrenal cortex .
• All steroid hormones are derived from cholesterol, which taken up by
the cell in the form of low density lipoprotein (LDL).
• LDL is taken into cells via LDL receptors, and broken down into
esterified cholesterol, and then free cholesterol.
• A series of enzymatic steps in the mitochondria and ER of
steroidogenic tissues convert cholesterol into all of the other steroid
hormones and intermediates.
• The first enzymatic step is the conversion of cholesterol to
pregnenolone, by enzyme cytochrome P450.
• This step occurs in the mitochondria, in the adrenal, ovary, and
• Next, pregnenolone can be converted into three different
pathways, depending upon whether you want to make
mineralcorticoids, glucocorticoids, or androgens.
Congenital adrenal hyperplasia
 Congenital adrenal hyperplasia (CAH) encompasses a group of
autosomal recessive disorders, each of which involves a deficiency
of an enzyme involved in the synthesis of cortisol, aldosterone, or
 The clinical presentation depends on the affected enzyme, with
95% result of a 21-hydroxylase deficiency
 Deficiency in 21-hydroxylase cause 17-OH progesterone and
androgen buildup while cortisol decreases.
 This deficiency inherited in severe or mild forms.
 The severe form, called Classical CAH, is usually detected in the
newborn period or in early childhood.
 The milder form, called Non-classical CAH (NCAH), may cause
symptoms at anytime from infancy through adulthood.
 NCAH is a much more common disorder than Classical CAH.
 When the pituitary gland senses that there is not enough
cortisol present in the bloodstream, it releases a hormone ACTH to
stimulates the adrenals to produce more cortisol.
Patient with CAH have insufficient amounts of the enzyme 21hydroxylase, needed to convert 17-hydroxyprogesterone (17OHP) into cortisol.
As a result, the pituitary gland continues to sense the need for
cortisol and pumps out more ACTH. This leads to an
overabundance of 17-OHP, which is converted in the adrenals
into excess androgens.
 Lack of adequate cortisol also prevents the body from
properly metabolizing sugar and responding to stress. The lack
of this stress response can lead to an adrenal crisis.
 In addition, over 75% of all individuals with classical CAH also
lack another adrenal hormone called aldosterone.
 When this deficiency occurs it is called “Salt-Wasting CAH”
The remaining 25% of those with Classical CAH who produce
sufficient aldosterone are referred to as “Simple Virilizers” (SVCAH).
 Insufficient aldosterone secretion is seen with:-
Adrenal gland destruction.
Chronic heparin therapy.
Following unilateral adrenalectomy (transient).
In G-layer enzyme deficiencies.
 Most hypoaldosteronism occurs in patients with mild renal
insufficiency such as persons with diabetes who present with mild
metabolic acidosis, high serum potassium, low urinary potassium
excretion (urine K urine Na), and low reninemia.
 Patients with excess aldosterone production may develop
metabolic alkalosis, HTN, and hypokalemia.
 Causes of HTN and unprovoked hypokalemia include:
- Primary aldosteronism (low renin)—autonomous oversecretion of
- Secondary aldosteronism (elevated renin)—RAS activated
aldosterone secretion
- Pseudoaldosteronism (variable renin and aldosterone levels)
Primary adrenal insufficiency
 Primary adrenal insufficiency, also known as Addison's disease,
occurs when the adrenal glands cannot produce an adequate
amount of hormones despite a normal or increased ACTH level.
Causes of primary adrenal insufficiency:1- autoimmune adrenalitis (slow destruction of the adrenal cortex
by cytotoxic lymphocytes).
2- autoimmune thyroid disease and other autoimmune endocrine
deficiencies ( that develop antibodies against the steroidogenic
enzyme 21-hydroxylase).
3- Acquired immunodeficiency syndrome (AIDS), in which the
adrenal gland may be destroyed by a variety of opportunistic
infectious agents.
All causes of primary adrenal insufficiency involve the adrenal
cortex as a whole, resulting in a deficiency of cortisol and
aldosterone (plus adrenal androgen).
Secondary and tertiary adrenal insufficiency
In secondary adrenal insufficiency, an insufficient amount of ACTH
is produced by the pituitary gland.
 In tertiary adrenal insufficiency, an insufficient amount of CRH is
produced by the hypothalamus.
Causes of secondary adrenal insufficiency:- Glucocorticoid therapy
- Tumors
- Hemorrhage
- Infiltrative processes
- Malignancies
Low Cortisol (baseline)
None to minimal
cortisol stimulation
Primary adrenal insufficiency
High ACTH (baseline)
Low aldo (or no stimulation?)
Normal cortisol stimulation(can be
blunted with chronic insufficiency)
Secondary adrenal insufficiency
Low ACTH (baseline)
Aldo normal (stimulation? >4 ng/dL)
Subtle symptoms
Electrolytes OK (Aldo preserved)
Differential diagnosis of low cortisol states
Cushing syndrome
 Cushing’s syndrome result from excess glucocorticoid production
or prolonged exogenous steroid use.
 The most common causes of Cushing’s syndrome are:• ACTH-secreting pituitary adenoma (68%).
• Autonomous cortisol production from an adrenal tumor (17%, ACTH
is suppressed).
• Excess ectopic ACTH or CRH production (15%, usually malignant).
Causes of Cushing’s Syndrome (High Cortisol) by ACTH
Cushing’s with hyperpigmentation
ACTH Dependent
- Primary ACTH (pituitary disease)
- Ectopic ACTH
- Ectopic CRF
ACTH Independent
- Adrenal adenoma
- Adrenal carcinoma
- Nodular adrenal hyperplasia
- Exogenous glucorticoids
Differentiating source of ACTH secretion
 In women, androgen overproduction can cause infertility, with
masculinizing effects (e.g., hirsutism, acne, male pattern baldness,
menstrual irregularities, and virility).
 In men, excess adrenal androgens can also cause infertility with
feminizing effects by inhibiting pituitary gonadotropins, which
effectively lowers testicular testosterone production.
Diagnosis of Excess Androgen
 <10% of DHEAS and DHEA are produced by the gonads,
therefore, high DHEAS and DHEA production strongly suggests
adrenal hyperandrogenism, whereas elevated testosterone values
are seen with either adrenal or gonadal hyperandrogenism.
 Plasma DHEAS, DHEA, or urine 17-ketosteroids can identify
patients with adrenal causes of pathologic masculinization
(females) and feminization (males).
 In response to stimulation, the medulla secretes catecholamines
directly into the circulation.
 Medullary catecholamine products serve as first responders to
stress by acting within seconds (cortisol takes 20 minutes) to
promote the fight-or-flight response, which increases cardiac output
and blood pressure, diverts blood toward muscle and brain, and
mobilizes fuel from storage.
 Catecholamines are hydrophilic, circulate in low levels (50%
albumin bound), have short half-lives (seconds to 2 minutes).
 The most abundant catecholamines are epinephrine
(adrenaline) and norepinephrine (noradrenaline) which
synthesized from phenylalanine and tyrosine.
 The ratio of NE to EPI in the serum is normally 9:1 (98% from
postganglionic neurons, 2% from the medulla).
lipid vesicles
80% of adrenal
Biosynthesis and storage of catecholamines
PNMT :- phenylethanolamine N-methyltransferase
VMAT:- vesicle monoamine transporters
Catecholamine Degradation:All catecholamines are rapidly eliminated from target cells and the
circulation by three mechanisms:
1. Reuptake into secretory vesicles
2. Uptake in nonneuronal cells (mostly liver)
3. Degradation
Degradation relies on two enzymes:- catechol methyltransferase (COMT) (in nonneuronal tissues)
- monoamine oxidase (MAO) (within neurons)
 Catecolamines
(metanephrines and VMA) from free catecholamines.
 Metabolites and free catecholamines are eliminated by direct
filtration into the urine and excreted as free NE (5%), conjugated
NE (8%), metanephrines (20%), and VMA (30%).
 Urine EPI (50%) is converted from NE by renal, not adrenal,
before excretion.
Methods of analysis:• Urine catecholamines (free NE and EPI) are assayed using liquid
chromatography, fluorometry, and liquid chromatography (LC)
tandem mass spectrometry.
• 24hr urine catecholamine and metabolite levels are more reliable
and are not altered by age or gender.
• Most antihypertensive drugs and many other medications
interfere with accurate catecholamine measurement by
fluorometric assays.
Substances causing autofluorescence (e.g., tetracyclines, ephedrine, methlyldopa) can produce erroneous results when measured by
fluorometric assays.
 Pheochromocytomas are rare catecholamine producing
tumors arising from chromaffin tissue, which causes HTN in
association with nonspecific clinical symptoms that mimic
 Mechanisms of catecholamine secretion by persons with
pheochromocytoma remain unclear (tumors are not innervated).
But characterized by:- Increased catecholamine synthesis
- limited degradation capacity
- limited storage for excess NE and metabolites likely cause spillover
into the blood, increasing circulating free NE and/or EPI along with
other active peptides that cause symptoms.
Diagnosis of Pheochromocytoma
• The best test for diagnosing pheochromocytoma is measurement
of Catecholamine
and their metabolites
which include
(metanephrine, normetanephrine, dopamine, and vanillylmandelic
acid (VMA)) in urine or blood.
• Plasma metanephrines, measured by high-performance liquid
chromatography or RIA, are touted as the most specific and
sensitive diagnostic test, although some investigators found that
plasma metanephrines lack specificity and do not recommend it as
a first-line test but reserve it for high-risk patients or patients who
cannot collect an accurate 24-hour urine specimen.
• Urine metanephrines may be the most sensitive urine test; it is less
likely to be altered by drugs or certain foods.
• 80% of pheochromocytoma patients have increased plasma
chromogranin A levels.
• Serum chromogranin A is is less sensitive and specific for
pheochromocytoma than are direct catecholamine and metabolite
• In combination, serum chromogranin A and plasma
catecholamines are specific (95%) but less sensitive (88%), likely
because of high dependence on renal function.
Adrenal Incidentaloma
 Asymptomatic adrenal tumor that is discovered on an imaging
test (CAT scan, MRI, etc) which was ordered to evaluate a problem
that is unrelated to adrenal disease.
 Many adrenal masses, typically greater than 1 cm in diameter, are
found incidentally.
 Autopsy studies report a frequency of adrenal adenomas at
about 6%, and the prevalence increases with age.
 Although most of these lesions are nonfunctioning and benign,
all should be assessed for malignancy or hypersecretion.