Adrenal Gland: Physiology, Pathology,

and Pharmacology (Mineralocorticoids

& Glucocorticoids)

Table of Contents

Adrenal Gland
Physiology of the Adrenal Gland
Pathology of the Adrenal Gland
Exogenous Agents
References

Adrenal Gland
The adrenal gland is located on the superior pole of the kidney and is covered by
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the Gerota fascia. The blood supply comes from three branches: inferior phrenic
artery, renal artery and aortic branches.
Venous drainage occurs through the inferior vena cava on the right side and into the
left renal vein on the left side. There are two distinct developmental origins of the
adrenal gland that divide it into two regions: the cortex and the medulla.

The cortex is derived from the mesoderm and it consists of three layers: zona
glomerulosa, zona fasciculata, and zona reticularis.

The medulla is derived from the neural crest and is made of chroma n cells.

Physiology of the Adrenal Gland

Cortex

Zona glomerulosa

This is the outermost layer of the cortex. It produces and secretes the
mineralocorticoid aldosterone. It is regulated by the renin-angiotensin system
(RAAS).

Aldosterone acts on the kidneys’ renal collecting ducts to promote sodium

reabsorption and potassium excretion. Absorption of water is followed by sodium
which will lead to an increase in extracellular uid volume.

A loss of aldosterone would result in excretion of sodium, followed by water, leading

to dehydration, and due to its e ects on potassium, it can lead to hyperkalemia and
result in cardiac toxicity. Excess aldosterone can lead to hypokalemia and result in
extreme fatigue and muscle weakness. Hydrogen can also be excreted and result in
metabolic alkalosis.

As a component of the RAAS system, angiotensin II induces the release of

aldosterone to increase uid retention and ultimately blood pressure. Give Feedback

Zona Glomerulosa cells also respond directly to high and low levels of sodium and
potassium in the extracellular uid to either stimulate aldosterone release in
hyperkalemic states or to inhibit aldosterone release in hypernatremia.
Adrenocorticotropic hormone (ACTH) from the anterior pituitary stimulates
aldosterone release.

Zona fasciculata

This is the middle layer of the cortex. It produces and secretes the glucocorticoid
cortisol. It is regulated by ACTH from the anterior pituitary. For cortisol release, it is
important to know that ACTH is regulated by a corticotropin-releasing hormone from
the hypothalamus. There is a circadian component to cortisol regulation with the
highest levels being in the morning and lowest being in the evening. Stress and other
factors can in uence how cortisol is regulated throughout the day.

Anti-in ammatory e ects come from the prevention of lysosomal protein release
through stabilization of membranes, decrease in capillary permeability and a
decrease in white blood cell chemotaxis. Often time with exogenous glucocorticoids
you can see an increase in white cell count because of this.

Thus, cortisol plays an important role in the increase in glycogen store in the liver,
reduction in protein stores, increase in in ammatory reactions and reduction in
immunity in an adverse manner.

Zona reticularis

The innermost layer of the cortex produces and secretes both male and female sex
hormones. The male sex hormones are Dehydroepiandrosterone (DHEA), DHEA
sulfate, androstenedione, and 11-hydroxy-androstenedione. The female sex hormones
are in much smaller quantities of progesterone and estrogen.

The e ect of the sex hormones mostly comes from their conversion of androgen
outside of the adrenal gland into testosterone. Their e ect is seen during male
gonadal development and in females during puberty. ACTH stimulates its release.

For the USMLE, it will be important to remember those sex hormones are produced in
this layer of the adrenal cortex and to be aware of the speci c names of the
hormones.

Medulla

The medulla is composed of one cell type, the chroma n cells. The chroma n cells
are derived from the neural crest and migrate to the adrenal medulla. Chroma n
cells secrete catecholamines: epinephrine, norepinephrine, and dopamine. The
medulla is responsible for the release of epinephrine (80 %) and norepinephrine (20)
with a very little secretion of dopamine into the blood under the in uence of
acetylcholine.

The sympathetic nervous system stimulates the secretion of the catecholamines Give Feedback
through acetylcholine release via preganglionic bers originating in the thoracic
spinal cord, from vertebrae T5–T11. Because it is innervated by preganglionic nerve
bers, the adrenal medulla can be considered as a specialized sympathetic
ganglion. The release of
catecholamines leads to
increased cardiac output
and increased vascular
resistance.

Pathology of the Adrenal Gland

Hyperplasia

Hyperplasia manifests itself through congenital adrenal hyperplasia, which is due

to an autosomal recessive disorder most commonly in the enzyme 21-hydroxylase. It
is an enzyme necessary for cortisol production, which leads to ACTH oversecretion.
Female patients will present at birth with ambiguous genitalia.

Hypoplasia

Hypoplasia manifests itself through a de ciency in ACTH. It is commonly diagnosed

in later childhood when the patient will present with dehydration, hyponatremia,
hyperkalemia, and hypotension.

The cortex has distinct pathology and expression depending upon each layer.

Zona glomerulosa

The zona glomerulosa can present with primary pathologies such as idiopathic
adrenal nodular hyperplasia, adrenocortical carcinoma, and adenoma. Secondarily, it
can present with renal artery stenosis and renin tumors.

Zona fasciculata

The zona fasciculata can present with Cushing syndrome. Cushing syndrome is
caused by excess exogenous steroid or glucocorticoid secreting tumors. It is a very
common USMLE question topic, and you should be very familiar with the material.
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Excess glucocorticoid production leads to the classic signs and symptoms of the
moon-like facies, acne, obesity, hypertension, easy bruising, abdominal striae, and
osteoporosis. It is important to remember that there is also Cushing’s disease, which
is di erent from Cushing’s syndrome. Cushing’s disease is usually caused by a
pituitary adenoma.

Zona reticularis

The zona reticularis can present with ambiguous genitalia in females and can present
in older children with pseudo precocious puberty and increased bone age. These
signs are most commonly seen in congenital adrenal hyperplasia and adrenal
adenomas and carcinomas.

Pheochromocytoma

The most common pathology in the medulla is pheochromocytoma. The tumors will
secrete catecholamines resulting in symptoms of hypertension, headache,
hyperhidrosis, palpitations, and pallor. There are several genetic conditions that can
predispose to pheochromocytoma: Von Hippel-Lindau (autosomal dominant defect in
repair gene on Chr. 3) and MEN2A and 2B.

Investigative tests are to check urine for vanillylmandelic acid (VMA) from the
breakdown of epinephrine and norepinephrine. Treatment with α-blockers and β-
blockers is for symptom relief and a safe anesthetic induction, followed by surgical
resection of the tumor.

The condition follows the ’10 % rule’, where 10% will be malignant, 10 % will be
bilateral, 10 % outside the adrenal gland, 10 % calcify, and 10 % pediatrics.

In pediatric patients, neuroblastoma is the third most common pediatric cancer (ALL
being the rst). Neuroblastoma accounts for 15 % of all pediatric cancer deaths. It
also originates from the neural crest and can be found in the adrenal medulla and
sympathetic chain.

Exogenous Agents

Zona glomerulosa

The zona glomerulosa secretes aldosterone. When there is a loss of aldosterone, as

seen in adrenal hypoplasia, the mineralocorticoid udrocortisone can be used to
replace the aldosterone e ects. This treatment is often combined with salt tablets or
free restriction of salt in the patient’s diet.

Zona fasciculata

The zona fasciculata secretes glucocorticoids. They can be used in many di erentGive Feedback
clinical settings, for instance, to treat asthma and decrease systemic in ammation.
Direct replacement as seen in adrenal hypoplasia can be treated with long-term
dexamethasone replacement.
Zona reticularis

The zona reticularis produces androgens that are converted in the periphery to
testosterone. Exogenous testosterone can be used as a replacement.

Epinephrine

In the medulla, the

catecholamines epinephrine,
norepinephrine and dopamine
are released. It is secreted in
response to stress, also known
as adrenaline. Epinephrine acts
to increase cardiac output
through β1 adrenergic receptors
in the heart increasing cardiac
output. It also acts to increase
vasoconstriction through the ɑ-
adrenergic receptors. It can be used to treat anaphylaxis, cardiac arrest, glaucoma,
and hypotension.

Norepinephrine

Norepinephrine acts on both ɑ1,2 and β1adrenergic receptors, and it has a much
greater e ect on the ɑ receptors for vasoconstriction. It is also released in the
medulla in response to stress, also referred to as stress hormone. It is used to treat
shock and hypotension.

Dopamine

Dopamine is often presented as a neurotransmitter but is commonly used in the

acute setting. It acts on both ɑ and β receptors, it has a greater e ect on cardiac
function. It can be used to treat shock and heart failure.

Mineralocorticoids

Aldosterone agonists

Part of the RAAS

Very strong salt-retaining activity

Fludrocortisone (Florinef)
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→ structurally similar to cortisol

Moderate glucocorticoid activity

 Strong mineralocorticoid activity
Cerebral salt wasting syndrome
Addison’s disease
POTS (Paroxysmal Orthostatic Tachycardia Syndrome)
Geriatric orthostatic hypotensive syncope

Spironolactone, eplerenone

Discusses in combination with diuretics

Also used to treat hirsutism (mild anti-androgen activity)

Glucocorticoid

Glucocorticoid enters the cell as a free molecule.

Binds to an intracellular receptor or other proteins

Enters nucleus
Binds to the glucocorticoid response element (GRE) which is a portion of DNA
GRE regulates gene expression and transcription.

Side E ects

Metabolic: gluconeogenesis, lipolysis, reduced subdermal fat

Morphologic: lipid deposit in certain spots (Face, neck, shoulder)
Catabolic: protein catabolism, tissue wasting, osteoporotic e ects
Immunosuppressive: cell-mediated immunity (i.e. lymphocyte dependent)
Renal: cortisol is normally required for water excretion
Anti-in ammatory: dramatic suppression of multiple markers
Neuropsychiatric: excess cortisol causes giddiness, euphoria

Prednisone, active metabolite prednisolone

Longer half-life, better membrane penetration

Used in acute in ammation, and steroid replacement

Dexamethasone

Longer half-life, better membrane penetration

Potent; often used in cancer therapies

Triamcinolone

Beclomethasone, budesonide Give Feedback

Readily penetrate the airway mucosa; used in inhalers

 Synthesis inhibitors

Ketoconazole Metyrapone Aminoglutethimide

Antifungal drug Inhibits synthesis of Blocks conversion of

cortisol but not cortisol cholesterol to
producers pregnenolone

Used in adrenal Used in diagnostic Used in steroid-

adenoma, breast cancer, tests of adrenal producing
prostate cancer function adrenocortical
cancers

Used in hirsutism

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