Photo: Colorized transmission electron micrograph of an endocrine cell from the anterior pituitary gland.

The secretory vesicles (brown) contain hormones.

From: Seeleys Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010.

Learning Objectives
4. Adrenocorticosteroids
1. The role of ACTH and the HPA axis in the regulation of corticosteroid
synthesis
2. The principal physiological responses to both glucocorticoids and
mineralocorticoids, especially the role of cortisol and exogenous
glucocorticoids in the negative feedback suppression of the HPA axis.
3. The use of synthetic glucocorticoids and mineralocorticoids drugs in the
treatment of adrenal deficiency diseases such as Adrenal insufficiency and
Congenital Adrenal Hyperplasia
4. The mechanism of action of glucocorticoid drugs and their pharmacological
use in the treatment of non-endocrine diseases e.g. Rheumatoid Arthritis,
Asthma, Inflammation and Cancer.

Marc Imhotep Cray, MD

Learning Objectives
Adrenocorticosteroids cont.
5. The major adverse effects associated with the clinical use of glucocorticoids
6. The concept that abrupt withdrawal of chronic glucocorticoid therapy can
lead to acute adrenal crisis due to atrophy of the adrenal cortex and
subsequent deficiency in endogenous cortisol production
7.The use of cortical synthesis inhibitors such as ketoconazole, metyrapone,
aminoglutethimide and mitotane in the treatment of Cushings disease.

Marc Imhotep Cray, MD

Summary of adrenal corticosteroids

CORTICOSTEROIDS

Betamethasone
Cortisone
Dexamethasone
Fludrocortisone
Hydrocortisone
Methylprednisolone
Prednisolone
Prednisone
Triamcinolone
INHIBITORS OF ADRENOCORTICOID BIOSYNTHESIS OR FUNCTION

Eplerenone
Ketoconazole
Spironolactone
Marc Imhotep Cray, MD

Corticosteroids &
Adrenocortical Dysfunction

Marc Imhotep Cray, MD

Marc Imhotep Cray, MD

Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009

Case 41
Adrenal Cortex
A 45-year-old man presents for the evaluation of weight gain. He has noticed a
20-lb weight gain in the past few months without any change in his diet or activity level. He has
started developing stretch marks on his abdomen as well. His wife has noted that even his face
seems to be growing fatter. Review of systems is significant for complaints of fatigue, multiple
recent upper respiratory infections, and the development of facial acne. He has no significant
medical history and takes no medications. There is a family history of diabetes and hypertension.
On examination, his blood pressure is elevated at 165/95 mm Hg, but his other vital signs are
normal. His face is plethoric, and he has a small fatty hump developing on his upper back. His
abdomen is obese but soft and nontender without masses or fluid. Skin examination is notable
for moderate facial acne and multiple violaceous striae on the abdomen. Blood tests show an
elevated glucose level of 150 mg/dL, normal electrolytes, and renal function. His thyroid function
tests are normal. You suspect idiopathic Cushing disease and order a dexamethasone suppression
test to assist with confirming the diagnosis.
_ Which pituitary hormone stimulates the release of adrenocortical steroids?
_ What is the major glucocorticoid produced in the adrenal glands?
_ What is the major mineralocorticoid produced in the adrenal glands?
_ What is the major effect of mineralocorticoids?
Marc Imhotep Cray, MD

Regulation of Adrenal Hormones

The 2 adrenal glands in human body are responsible for producing
mineralocorticoids (eg, aldosterone) regulate fluid and electrolyte
balance
glucocorticoids (eg, cortisol) which are essential for carbohydrate
metabolism
Aldosterone production is mediated primarily by renin-angiotensin
system
Cortisol production is regulated by a feedback mechanism involving
hypothalamic-pituitary-adrenal (HPA) axis

Marc Imhotep Cray, MD

Regulation of Adrenal Hormones

Cortisol production cont.

First, hypothalamus releases CRH in response to various

stimuli including neurotransmitters, vasopressin, and
catecholamines CRH stimulates anterior pituitary to release
ACTH which then stimulates adrenal cortex to produce
cortisol as serum cortisol levels increase, synthesis and
secretion of CRH and ACTH decrease via a negative feedback
loop

Marc Imhotep Cray, MD

Mineralocorticoids and Glucocorticoids

Mineralocorticoids enhance reabsorption of sodium and water from distal
tubule of kidney and increase urinary potassium and hydrogen ion
excretion

Principal function of glucocorticoids involves regulation of carbohydrate

metabolism
They are also involved in other physiologic actions, including:
o gluconeogenesis
o glucose utilization
o lipid and bone metabolism
o fluid and electrolyte homeostasis
o alteration of levels of various immune cells
o alleviation of inflammatory response, and
o participation in neuropsychiatric functions
Marc Imhotep Cray, MD

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Glucocorticoid functions cont.

As a result of these functionsmost notably immunosuppressive and
antiinflammatory actions (a direct result of immunosuppressive
effects) glucocorticoids are widely used in treatment of
cancer
autoimmune disorders
inflammatory disorders such as
asthma
inflammatory bowel disease
arthritis, and
allergies

Marc Imhotep Cray, MD

11

Corticosteroids
Therapeutic corticosteroids (eg, hydrocortisone, prednisone,
dexamethasone), with different mineralocorticoid and glucocorticoid
activities, are antiinflammatory and immunosuppressive via inhibiting
immune cells
This reduces formation, release, and activity of inflammation mediators (eg,
cytokines, histamine, prostaglandins, leukotrienes)

Short-term therapy adverse effects include

Insomnia
euphoria, and increased appetite
Long term therapy effects include
osteoporosis
hypertension
edema
hyperglycemia, and
cushing-like syndrome
Marc Imhotep Cray, MD

12

Corticosteroids cont.
Long-term drug use can suppress the HPA axis and abrupt
stopping of therapy can cause possibly fatal acute adrenal
insufficiency syndrome adrenal crisis
Slow dosage tapering allows HPA axis to begin functioning
To reduce systemic absorption and side effects, drugs can be
given topically or by inhalation or nasal spray, intraarticular
injection, or rectal suppository
Alternate-day and lowest effective dosing may limit side effects
and adrenal atrophy
Marc Imhotep Cray, MD

13

Question
A 37-year-old kidney transplant recipient presents to her primary care
physician for follow-up. Among other immunosuppressant drugs, she has been
taking daily prednisone for the past 2 months since her transplant. With only a
few doses of prednisone left, she gets snowed into her house and cannot refill
her prescription (but she has enough of the other medications to last a few
more weeks). If she runs out of prednisone and cannot get it refilled, what is
she most at risk for developing?
(A) Cardiovascular collapse
(B) Osteoporosis
(C) Increased risk of infection
(D) Insomnia (short-term oral/parenteral)
(E) Nausea/vomiting (short-term oral/parenteral)

Marc Imhotep Cray, MD

14

The answer is A: Cardiovascular collapse (adrenal crisis)

Chronic use of glucocorticoids (such as prednisone) will lead to adrenal atrophy
because the exogenous steroid suppresses the hypothalamic-pituitary-adrenal
(HPA) axis. If the exogenous steroid is abruptly withdrawn, the atrophied
adrenal gland is unable to compensate by producing endogenous steroids
quickly enough. The sudden loss of adrenal steroids is termed adrenal crisis
and can result in cardiovascular collapse and death.
(B) Osteoporosis is a possible result of continued chronic glucocorticoid
therapy, not abrupt cessation.
(C) Increased risk of infection is a result of continued chronic glucocorticoid
therapy, not abrupt cessation.
(D) Insomnia is a possible side effect from short-term oral or parenteral
glucocorticoid therapy.
(E) Nausea/vomiting are possible side effects from short-term oral or parenteral
glucocorticoid therapy.
Marc Imhotep Cray, MD

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Pathophysiology of acute adrenal crisis

Patients with acute adrenal crisis have symptoms of fever, weakness, apathy, and
confusion.
Anorexia, nausea, and vomiting may lead to volume depletion and dehydration.
Abdominal pain may mimic that of an acute abdominal process.
Evidence suggests that symptoms of acute glucocorticoid deficiency are mediated by
significantly elevated plasma levels of cytokines, particularly IL-6 and, to a lesser extent,
IL-1 and TNF.
Hyponatremia, hyperkalemia, lymphocytosis, eosinophilia, and hypoglycemia occur
frequently.
Acute adrenal crisis can occur in patients with undiagnosed ACTH deficiency, in patients
receiving corticosteroids and who are not given increased steroid dosage during periods
of stress Precipitants include infection, trauma, surgery, and dehydration.
o Gastrointestinal infections are particularly challenging because of the associated inability to ingest or
absorb oral hydrocortisone replacement, which can lead to adrenal crisis despite other treatments.

If unrecognized and untreated, coma, severe hypotension, or shock unresponsive to

vasopressors may rapidly lead to death.
Hammer GD, McPhee SJ, eds. Pathophysiology of Disease: An Introduction
to Clinical Medicine, 7th Edn. New York: McGraw-Hill, 2014

Adrenal steroids and congenital adrenal hyperplasia

Marc Imhotep Cray, MD

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

17

Adrenal steroids and congenital adrenal hyperplasia (2)

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Marc Imhotep Cray, MD

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Question
Regarding the release of ACTH from the anterior pituitary in a 24-year-old
man who is a marathon runner, which of the following is the next step in the
process?
(A) Activation of protein S
(B) Increase of cGMP
(C) Stimulation of conversion of cholesterol to pregnenolone
(D) Release of adrenocorticosteroids
(E) Synthesis of pulmonary ACTH

Marc Imhotep Cray, MD

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The answer is C: Stimulation of conversion of cholesterol to pregnenolone.

The target organ of ACTH is the adrenal cortex, where it binds to specific
receptors on the cell surfaces. The occupied receptors activate G protein
coupled processes to increase cyclic adenosine monophosphate (cAMP),
which in turn stimulates the rate-limiting step in the adrenocorticosteroid
synthetic pathway (cholesterol to pregnenolone). This pathway ends with the
synthesis and release of the adrenocorticosteroids and the adrenal androgens.
(A) The occupied receptors activate G proteincoupled processes.
(B) The activated G protein complex increases cyclic AMP.
(D) Release of adrenocorticosteroids occurs after they are synthesized.
(E) Pulmonary ACTH is produced in disease states such as oat cell carcinoma.

Marc Imhotep Cray, MD

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Cushing Syndrome
Cushing syndrome is a group of clinical symptoms that result from
prolonged exposure to excess glucocorticoids
May be caused by exogenous factors, such as long-term corticosteroid use,
or
May be of endogenous origin due to either
excess ACTH secretion (ACTH dependent) or
autonomous cortisol hypersecretion (ACTH independent)

Conditions such as adrenocortical adenomas and carcinomas as well as

ectopic ACTH and CRH syndromes are responsible for endogenous
syndrome
Marc Imhotep Cray, MD

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Increase cortisol due to a variety of causes:

1. Exogenous corticosteroidsresult in
(Most common cause)

ACTH, bilateral adrenal atrophy

2. Primary adrenal adenoma, hyperplasia, or carcinomaresult in

atrophy of uninvolved adrenal gland.

ACTH,

3. ACTH-secreting pituitary adenoma (Cushing disease); paraneoplastic

ACTH secretion (eg, small cell lung cancer, bronchial carcinoids)result in
ACTH, bilateral adrenal hyperplasia.
Note: Cushing disease is responsible for majority of
endogenous cases of Cushing syndrome.
Marc Imhotep Cray, MD

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Cushing Syndrome cont.

Clinical manifestations affect multiple organ systems and depend
on degree and duration of hypercortisolism
Most common sign is progressive obesity seen in face, neck,
trunk, and abdomen
Facial fat accumulation produces a moon-face appearance,
and an enlarged dorsocervical fat pad produces a buffalo
hump
Other symptoms include
o weakness
o muscle wasting
o reduced arm muscle mass
o osteoporosis,
o cardiovascular and
o metabolic complications

23

Ketoconazole
Therapy for exogenous Cushing syndrome consists of minimizing exposure
to glucocorticoids or ACTH
For the endogenous syndrome, therapy aims to reduce cortisol production
in preparing patients for surgery or to maintain normal plasma cortisol levels
until full effects of surgery or radiation are felt
Ketoconazole (an antifungal agent) is used to treat paraneoplastic Cushing
syndrome secondary to ectopic ACTH production
The agent is highly effective in decreasing cortisol by inhibiting
adrenocortical cytochrome P-450dependent enzymes
o These enzymes normally catalyze formation of cortisol precursors
such as pregnenolone as well as metabolizing drugs
(see NIP Figure 5-21 steroidogenesis schematic)
Marc Imhotep Cray, MD

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Ketoconazole cont.
Drug-Drug Interactions
Because ketoconazole is a cytochrome P-450enzyme inhibitor , it can
increase levels of many hepatically metabolized agents, such as

cyclosporine
warfarin
digoxin, and
phenytoin

Side effects of ketoconazole include

blood dyscrasias
headache
dizziness
fatigue
gynecomastia
GI symptoms, and
rash

Patients respond to therapy after 4 to 6 weeks

Marc Imhotep Cray, MD

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Metyrapone
Metyrapone is used to treat Cushing syndrome when dose limiting side
effects occur with ketoconazole
and it can be used in combination with other agents

Metyrapone is also used as a test for adrenal function

MOA It reduces cortisol production by inhibiting 11--hydroxylation
final step in glucocorticoid synthesis process leads to accumulation of
adrenal androgens and 11-deoxycorticosterone (the potent
mineralocorticoid)
Resultant adverse effects include
water retention
hirsutism
GI disturbances, and
dizziness

o Dose reduction can limit these adverse effects

Metyrapone may take up to 4 months to produce a response
Marc Imhotep Cray, MD

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Aminoglutethimide
Aminoglutethimide is used primarily for
Cushing syndrome secondary to adrenal hyperplasia
ectopic ACTH production, or
adrenal carcinoma
o most useful when given after pituitary irradiation or in combination
with metyrapone
MOA Aminoglutethimide partially inhibits conversion of cholesterol to
pregnenolone in adrenal glands and blocks conversion of androstenedione
(prehormone produced in adrenals) to estrone and estradiol in peripheral
tissues

Marc Imhotep Cray, MD

27

Aminoglutethimide cont.
Inhibition interrupts production of cortisol, aldosterone, and estrogens
A reflex increase in ACTH results, which partly or completely overcomes blockade
this reflex can be prevented by replacement amounts of hydrocortisone (but not
dexamethasone) given concomitantly

Adverse effects include

headache
sedation
dizziness
nausea
anorexia
rash
blood dyscrasias
tachycardia, and
hypertension

This drug may take up to 4 months to produce a response

Marc Imhotep Cray, MD

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Addison Disease or Primary Adrenal Insufficiency

Addison disease is due to
autoimmune-mediated destruction of adrenal cortex
mycobacterial infection
adrenal metastases, or
use of certain drugs

Symptoms, caused by reduced production of

glucocorticoids
mineralocorticoids, and
sex hormones
range from vague feelings of illness to acute syncope and mental status
changes
Biochemical abnormalities (eg, hyponatremia, hyperkalemia) usually exist
Marc Imhotep Cray, MD

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Adrenal Insufficiency cont.

life-threatening adrenal crisis, which occurs in cases of undiagnosed
adrenal insufficiency & untreated stress, mimics septic shock presents with
severe anorexia
dehydration, and
hypotension
Treatment: IV fluids and high-dose IV glucocorticoids
Chronic disease is managed with a glucocorticoid (hydrocortisone) plus a
mineralocorticoid (fludrocortisone) with dosage tailored to avoid Cushing
syndrome or inadequate therapy
Patients should be monitored for fludrocortisone side effects (eg,
electrolyte changes, hypertension, edema, and hyperglycemia)
Marc Imhotep Cray, MD

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Case 41 Answers
Adrenal Cortex
Summary: A 45-year-old man has Cushing disease.
Pituitary hormonal stimulus of adrenocortical steroid production: ACTH.
Primary adrenal glucocorticoid: Cortisol.
Primary adrenal mineralocorticoid: Aldosterone.
Major mineralocorticoid effects: Regulation of salt and water balance in the
kidney, promote sodium retention, and potassium loss.
CLINICAL CORRELATION
Cushing disease is caused by ACTH-secreting tumors in the pituitary gland. The
continuous production of ACTH disrupts the normal circadian production of ACTH
and overrides the feedback of adrenal steroids on the hypothalamus and pituitary,
resulting in excessive adrenocortical steroid production. Glucocorticoids affect
most organs and tissues in the body.
Marc Imhotep Cray, MD

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Case 41 Answers
Adrenal Cortex cont.
Their effects are mediated by specific intracellular glucocorticoid receptors that
modulate the transcription rates of specific genes and results in increases or
decreases of specific proteins.
The major glucocorticoid produced in the adrenal glands is cortisol
(hydrocortisone). Glucocorticoids have numerous physiologic effects, including
the stimulation of gluconeogenesis, increasing lipolysis, decreasing glucose
uptake into fat cells, and redistributing body fat. These effects cause some of the
symptoms and signs of Cushing disease, which include glucose intolerance or
overt diabetes, weight gain, and increasing truncal obesity. Glucocorticoids also
have anti-immune effects, which include decreasing circulating lymphocytes,
monocytes, eosinophils, and basophils, increases in circulating neutrophils and
atrophy of lymphoid tissue. The excess production of glucocorticoids can
therefore lead to immune system suppression and recurrent infections.
Marc Imhotep Cray, MD

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Case 41 Answers
Adrenal Cortex cont.
Under normal physiologic conditions, adrenocortical steroids will exert a
negative feedback of ACTH release from the pituitary gland. ACTH release, and
subsequent cortisol production, can be suppressed even more by the
administration of synthetic steroids such as dexamethasone. ACTH, which is
continuously produced by a tumor, will not be suppressed by this feedback
mechanism. This formulates the basis for the dexamethasone suppression test,
in which a dose of dexamethasone is administered and subsequent cortisol
production is measured. Normally dexamethasone administration would cause
a reduction of circulating cortisol. In Cushing disease the measurement of
cortisol will remain at normal, or even elevated, levels.

Marc Imhotep Cray, MD

33

THE END

See next slide for further study.

Marc Imhotep Cray, MD

34

Sources and further study:

eLearning
Endocrine cloud folder tools and resources
MedPharm Guidebook:
Unit 5 Drugs Used In Disorders of Endocrine System
Endocrine and Reproductive System Pharmacology eNotes
Clinical Pharmacology Cases 39 to 44 (Learning Triggers)
Textbooks
Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilmans The Pharmacological
Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011
Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill,
2012
Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.
Philadelphia: Sanders, 2014
Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014.
Marc Imhotep Cray, MD

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