ADRENOCORTICAL

HORMONES AND
ATAGONISTS

RSU MBBS Class

May 2023

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 Outline
• The Adrenocortical hormones
– Mineralocorticoids
– Adrenocorticoids
– Adrenal androgens

• Antagonists of Adrenal Agents

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Adrenal Glands

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Adrenal Glands

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 Adrenal Glands
Adrenal cortex:
• Does not receive
neural innervation.
• Must be stimulated
hormonally (ACTH).
• Consists of 3 zones:
– Zona
glomerulosa.
– Zona fasciculata.
– Zona reticularis.
• Secretes
corticosteroids.

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 The adrenocortical hormones
• The adrenocortical hormones are steroid
molecules produced and released by the
adrenal cortex.
• The adrenal cortex releases a large number of
steroids into the circulation.
• Some have minimal biologic activity and function
primarily as precursors, and there are some for
which no function has been established.

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Hormones of the Adrenal Cortex:Synthesis

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 Functions of the Adrenal Cortex
• Zona glomerulosa:
• Mineralcorticoids (aldosterone):
• Stimulate kidneys to reabsorb Na+ and
secrete K+.
• Zona fasciculata:
• Glucocorticoids (cortisol):
• Inhibit glucose utilization and stimulate
gluconeogenesis.
• Zona reticularis (DHEA):
• Sex steroids:
• Supplement sex steroids.

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 Functions of Mineralocorticoids
• Mineralocorticoids: Zona glomerulosa
• Aldosterone produced in greatest amounts.
Increases rate of sodium re-absorption by
kidneys increasing sodium blood levels
• Low blood pressure is the stimulus for production
• Increases water re-absorption and therefore
blood volume
 Functions of Glucocorticoids

• Glucocorticoids: Zona fasciculata

• Cortisol is the major hormone. Increases fat and
protein breakdown, increases glucose synthesis
(gluconeogenesis), promotes the increased use of
fats and proteins by muscles, decreases
inflammatory response
 Functions of Androgens

• Androgens: Zona reticularis

• Weak androgens secreted then converted to
testosterone by peripheral tissues. Stimulate
pubic and axillary hair growth and sexual drive in
females
• Dehydroepiandrosterone (DHEA) in its sulfated
form (DHEAS) is the major adrenal androgen
• DHEA and two other adrenal androgens,
androstenedione and androstenediol, are weak
androgens and, androstenediol is a potent
estrogen
 1. Mineralocorticoids
• Aldosterone, Deoxycorticosterone (DOC),
Fludrocortisone
• The most important mineralocorticoid in humans is
aldosterone
• But small amounts of deoxycorticosterone (DOC) are
also formed and released
• Fludrocortisone, is a synthetic adrenal steroid with
high mineralocorticoid activity that is commonly used
to treat adrenocortical insufficiency
• It is the commonly prescribed salt-retaining hormone
 Mechanism of Action of
Mineralocorticoids
 Mineralocorticoids act by binding to the
mineralocorticoid receptor in the cytoplasm of
target cells, principally, cells of the distal convoluted
and collecting tubules of the kidney
 The drug-receptor complex activates a series of
events similar to those described for the
glucocorticoids
 The major effect of activation of the aldosterone
receptor is increased expression of Na+/K+-ATPase at
the epithelial sodium channel (ENaC)
 1a. Aldosterone
• Aldosterone is synthesized mainly in the Zona
glomerulosa of the adrenal cortex.
• Without ACTH, aldosterone secretion falls to about
half the normal rate
• This indicates that other factors, eg, angiotensin, are
able to maintain and perhaps regulate aldosterone
secretion. Aldosterone and other mineralocorticoids
promote the reabsorption of sodium
• from the distal part of the distal convoluted renal
tubule and from the cortical collecting tubules
• This process is loosely coupled to the excretion of
potassium and hydrogen ion
 Physiologic and Pharmacologic
Effects of Aldosterone
 Aldosterone increases sodium reabsorption in the
sweat and salivary glands
gastrointestinal mucosa and
across cell membranes
 Excessive levels or over-dosage of aldosterone or the
synthetic mineralocorticoids will lead to
 hypokalemia and metabolic alkalosis,
increased plasma volume
hypertension.
 Metabolism of Aldosterone

 The half-life of aldosterone injected in small quantities

is 15–20 minutes
 metabolism of aldosterone is similar to that of cortisol
 About 50 mcg/24h appears in the urine as conjugated
tetrahydroaldosterone
 Approximately 5–15 mcg/24h is excreted free or as
the 3-oxo glucuronide
 Role of Aldosterone
• It is essential for sodium conservation in the
kidney, salivary glands, sweat glands and
colon.
• It plays a central role in the homeostatic
regulation of blood pressure, plasma
sodium, and potassium levels
• Regulates the body’s stress response

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 1b. Deoxycorticosterone (DOC)
• DOC serves as a precursor of aldosterone. It is an agonist om
m-receptors and an antagonist glucocorticoid receptors
• It is secreted in amounts of about 200 mcg/d and its half-life
when injected into the human circulation is about 70 minutes
• The secretion of DOC is primarily under the control of ACTH
• The secretion of DOC is increased in adrenocortical
carcinoma and congenital adrenal hyperplasia with reduced
P450c11 or P450c17 activity
• Plays a role in stress-related changes in seizure control
 1c. Fludrocortisone
• This compound, is a steroid with both glucocorticoid and
mineralocorticoid activities
• It is the most widely used mineralocorticoid
• Oral doses of 0.1 mg 2 to 7 times weekly have potent salt-
retaining activity
• It is used in the treatment of adrenocortical insufficiency
associated with mineralocorticoid deficiency
• These dosages are too small to have important anti-
inflammatory or antigrowth effects
• 2. The Glucocorticoids

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2.1 Natural Occurring Glucocorticoids
Cortisol (Hydrocortisone)
Pharmacokinetics
• Cortisol (Hydrocortisone, Compound F) causes regulation of
• Intermediary metabolism
• Cardiovascular function
• Growth and Immunity
• Corticosteroid-binding globulin (CBG) is an α2 globulin which binds to
about 90% of the circulating cortisol hormone
• CBG is increased in
• Pregnancy, with estrogen administration and in hyperthyroidism
• It is decreased by
• Hypothyroidism, genetic defects in synthesis and in
protein deficiency states
Cortisol contd.
• Mechanism of Action

• This binding induces conformational changes that allow cortisol to dissociate

from the heat shock proteins and to dimerize

• the dimeric ligand-bound receptor complex then is actively transported into

the nucleus, where it interacts with DNA and nuclear proteins which bind to
glucocorticoid receptor elements (GREs) in the promoters of responsive
genes
• ligand-bound receptor influences the function of other transcription factors,
such as nuclear factor kappa-B (NF-κB)
• These regulate transcription of their responsive genes. These transcription
factors cause the regulation of growth factors and proinflammatory
cytokines, etc, which
• mediate the anti-growth, anti-inflammatory, and immunosuppressive
effects of glucocorticoids
Mechanism of action of Cortisol (contd.)
Cortisol contd.
• Half-life of cortisol in the circulation is about 60–90 mins. This may
increase during stress or on administration of large doses of cortisol
• Cortisol is
• converted to cortisone by 11-hydroxysteroid dehydrogenase in the
kidney and other tissues
• excreted in the urine as dihydroxy ketone metabolites
• cortisol metabolites are conjugated with glucuronic acid or sulfate
• Free cortisol from the plasma and interstitial fluid enters the cell and
binds to the glucocorticoid receptor
• Synthetic corticosteroids such as dexamethasone are largely bound to
albumin rather than CBG
Effects of Glucocorticoids
• Physiological effects
• Glucocorticoids affect some physiological properties e.g.
• The response of vascular and bronchial smooth muscle to
catecholamines is diminished in the absence of cortisol
and restored by physiologic amounts of this
glucocorticoids
• Similarly, the lipolytic responses of fat cells to
catecholamines, ACTH, and growth hormone are
attenuated in the absence of glucocorticoids

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Effects of Glucocorticoids
• Metabolic Effects

• cause dose-related effects on carbohydrate, protein, and fat metabolism

• stimulate gluconeogenesis – the breakdown of protein and fat to provide

metabolites that can be converted to glucose in the liver and glycogen
synthesis in the fasting state

• activate antistress and anti-inflammatory pathways

• increase serum glucose levels and thus stimulate insulin release

• They stimulate hormone-sensitive lipase and thus lipolysis

 Effects of Glucocorticoids
• Catabolic Effects
• Supraphysiologic amounts of glucocorticoids lead to

• decreased muscle mass

• weakness and

• thinning of the skin

• They cause osteoporosis in Cushing’s syndrome and

• reduce growth in children

• Cushing syndrome (hypercorticolism) occurs from exposure to high

cortisol levels for along time. May be caused by use of steroid drugs
or by overproduction of cortisol by the adrenal glands
 Effects of Glucocorticoids
• Anti-Inflammatory and Immunosuppressive Effects

• Glucocorticoids reduce inflammation by

• increasing concentration, distribution, and function of peripheral
leukocytes (neutrophils)
• leading to reduced number of cells at the site of inflammation
• reducing circulating lymphocytes, monocytes, eosinophils, and
basophils
• suppression of inflammatory cytokines, chemokines and other
mediators of inflammation

• inhibition of the functions of tissue macrophages and other antigen-

presenting cells
 Effects of Glucocorticoids
• Other effects
• On the CNS: adrenal insufficiency causes slowing of the alpha
rhythm of the electroencephalogram and causes depression
• Increased amounts of glucocorticoids causes insomnia and
euphoria initially and subsequently depression
• Chronic administration suppress the pituitary release of ACTH,
growth hormone, thyroid-stimulating hormone, and luteinizing
hormone
• Large doses is associated with the development of peptic ulcer,
by suppressing the local immune response against
Helicobacter pylori etc.
 2.2 Synthetic Glucocorticoids
 Glucocorticoids are used in the treatment of many
inflammatory, immunologic and hematologic disorders
 This has lead to the development of synthetic steroids with anti-
inflammatory and immunosuppressive activity
 The synthetic glucocorticoids are divided into short-acting,
intermediate-acting and long-acting
 Short-acting include Hydrocortisone (synthetic cortisol),
Cortisone, Prednisolone etc
 Intermediate-acting include Triamcinolone, Fluprednisolone
 Long-acting include Betamethasone and Dexamethasone
 Synthetic Glucocorticoids
• Pharmacokinetics
• Synthetic corticosteroids are rapidly and completely
absorbed when given orally
• They have similar metabolic pathways as the endogenous
steroids, though with important differences because of
halogenation, methylation etc.
• Most have the half-life prolonged by more than 50%
• Most are excreted in the free form
 Synthetic Glucocorticoids (Sg)
• Pharmacodynamics
• In some cases, the Sg given is a prodrug; for example,
prednisone is rapidly converted to the active product
prednisolone in the body
• The actions of the synthetic steroids are similar to those of
cortisol
• Sgs bind to the specific intracellular receptor proteins and
produce the same effects
• But they have different ratios of glucocorticoid to
mineralocorticoid potency
Glucocorticoids:Clinical Pharmacology
• Adrenocortical insufficiency
• Chronic (Addison’s disease) - Chronic adrenocortical insufficiency.
A disorder that occurs when the adrenal glands don’t make
enough of certain hormones eg cortisol (stress homones)
essential for life
• Causes weakness, weight loss, hypotension, inability to
maintain the blood glucose level during fasting etc
• Treatment is with hydrocortisone
• Acute (Addison’s disease) – Acute adrenocortical insufficiency
• Therapy consists of large amounts of parenteral
hydrocortisone in addition to correction of fluid and electrolyte
abnormalities
 Clinical Pharmacology contd.
 Adrenocortical hypo-function

• Congenital adrenal hyperplasia – this is characterized by specific defects

in the synthesis of cortisol and in some cases aldosterone

• The most common defect is a decrease in or lack of P450c21 (21α-

hydroxylase) activity

• Fetuses can be protected from genital abnormalities by administration of

dexamethasone to the mother

• Primary generalized glucocorticoid resistance (Chrousos syndrome) –

This is a rare genetic condition due to inactivating mutations of the
glucocorticoid receptor gene
• This leads to production of ACTH and a high circulating levels of
cortisol and cortisol precursors with mineralocorticoid activity
• Therapy is high doses of synthetic glucocorticoids (dexamethasone) with
no inherent mineralocorticoid activity
 Clinical Pharmacology
• Adrenocortical hyperfunction
• Cushing’s syndrome – this is due to ACTH secreting
pituitary adenoma (Cushing’s disease)
• It can also be due to tumors or nodular hyperplasia of
the adrenal gland or ectopic production of ACTH by
other tumors
• It leads to chronic presence of excessive
glucocorticoids
• Treatment is by
• surgical removal of the tumor producing ACTH or
cortisol
• irradiation of the pituitary tumor, or
• resection of one or both adrenals
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 Clinical Pharmacology
 Adrenocortical hyper-function

 Aldosteronism- excessive production of aldosterone by

an adrenal adenoma

 It is associated with hypertension, weakness, and tetany

due to loss of potassium

 Treatment is with spironolactone, an aldosterone

receptor-blocking agent

the response to this agent is of diagnostic and

therapeutic value
 Clinical Pharmacology
• Use of glucocorticoids for diagnostic purposes
• Glucocorticoids are used to suppress the production of
ACTH
• This helps to identify source of a particular hormone
• A potent substance used for this purpose is
dexamethasone
• The dexamethasone suppression test is used for the
diagnosis of Cushing’s syndrome
• It has also been used in the differential diagnosis of
depressive psychiatric states
 Toxicity of Glucocorticoids
• The major undesirable effects of glucocorticoids lead to
iatrogenic Cushing’s syndrome
• Side effects include, insomnia, behavioral changes (primarily
hypomania), and acute peptic ulcers
• Acute pancreatitis is a rare but serious acute adverse effect
of high-dose glucocorticoids
• Iatrogenic Cushing’s syndrome is a metabolic effect
associated with rounding, puffiness, fat deposition, and
plethora usually appear (moon faces)
 Special Precautions
• Patients receiving • Glucocorticoids must be used
glucocorticoids must be with great caution in patients
monitored carefully for with
the development of • peptic ulcer
- hyperglycemia • heart disease or hypertension
- glycosuria with heart failure
• - sodium retention with • certain infectious illnesses
such as varicella and
edema or hypertension
tuberculosis
- hypokalemia
• psychoses
- peptic ulcer
- osteoporosis and • diabetes
- hidden infections • osteoporosis or
• glaucoma
Dosage forms
 3. Adrenal Androgens
• The adrenal cortex secretes large amounts of
Dehydroepiandrosterone (DHEA) and smaller amounts of
androstenedione and testosterone
• These hormones contribute to the normal maturation process.
• DHEA is converted to more potent androgens or to estrogens and
interacts with androgen and estrogen receptors. They peak about
age 25 and then go down steadily as you get older
• DHEA and its sulfate may have other important physiologic
actions
 4. Antagonists of Adrenal agents
• Synthesis inhibitors and adrenocortical
antagonists
• Inhibitors of steroid synthesis act at several
different steps
• The glucocorticoid antagonists act at the receptor
level
 Steroid Synthesis inhibitors
1. Aminoglutethimide
2. Ketoconazole
3. Etomidate
4. Metyrapone
5. Trilostane
6. Abiraterone

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 1. Aminoglutethimide
• Aminoglutethimide blocks the conversion of cholesterol to
pregnenolone
• It causes a reduction in the synthesis of all hormonally
active steroids
• It is used along with dexamethasone or hydrocortisone to
reduce or eliminate estrogen production in patients with
carcinoma of the breast.
• It is well tolerated at a dose of 1 g/d

• Higher doses cause lethargy and skin rash

 1. Aminoglutethimide contd.
• The use of Aminoglutethimide in breast cancer patients
has been supplanted by

• Tamoxifen or by the Aromatase inhibitors

• Aminoglutethimide is used with metyrapone or

ketoconazole to reduce steroid secretion

• It is used in patients with Cushing’s syndrome due to

adrenocortical cancer who do not respond to Mitotane
• It enhances the metabolism of dexamethasone, reducing
its half-life from 4–5 hours to 2 hours
 2. Ketoconazole
• Ketoconazole, is an antifungal imidazole derivative

• It is a potent and nonselective inhibitor of adrenal and gonadal steroid

synthesis

• This compound inhibits the cholesterol side-chain cleavage

• Its inhibitory effects are seen only at high doses greater than for fungal
infection
• It has been used in the treatment of patients with Cushing’s syndrome
• Dosages of 200–1200 mg/d have caused a reduction in hormone levels
and clinical improvement in patients
• This drug has hepatotoxicity
• It is started at 200 mg/d and slowly increased by 200 mg/d every 2–3
days up to a total daily dose of 1000 mg
 3. Etomidate
• Etomidate is used for induction of general anesthesia
and sedation
• At sub-hypnotic doses of 0.1 mg/kg per hour it inhibits
adrenal steroidogenesis at the level of 11β-hydroxylase
• It has been used as the only parenteral medication
available in the treatment of severe Cushing’s
syndrome
 4. Metyrapone
• Metyrapone is a selective inhibitor of steroid 11-hydroxylation
• It interferes with cortisol and corticosterone synthesis
• In doses of 0.25 g twice daily to 1 g four times daily, metyrapone
reduces cortisol production to normal levels in patients with
endogenous Cushing’s syndrome

• It produces transient dizziness and gastrointestinal disturbances

• It is the only adrenal-inhibiting drug used in pregnant women with

Cushing’s syndrome

• Its major adverse effects are salt and water retention and hirsutism (xs
male hormone in women)

• It is used in tests of adrenal function

 5. Trilostane
• Trilostane is a 3β-17 hydroxysteroid dehydrogenase
inhibitor
• It interferes with the synthesis of adrenal and gonadal
hormones
• It is comparable to aminoglutethimide
• It has mainly gastrointestinal adverse effects
 6. Abiraterone
• Abiraterone is the newest of the steroid
synthesis inhibitors to be approved
• It blocks 17α-hydroxylase and 17,20-lyase
• It reduces synthesis of cortisol in the adrenal
and gonadal steroids in the gonads
• It is an orally active steroid prodrug
• It is approved for the treatment of refractory
prostate cancer
 Adrenocortical antagonists
• Mifepristone (RU-486) and Mitotane
• Mifepristone (RU-486) is a glucocorticoid receptor
antagonist
• It is a pharmacologic antagonist at the steroid receptor
• It has strong antiprogestin activity
• High doses of mifepristone exert antiglucocorticoid
activity by blocking the glucocorticoid receptor
 Mifepristone (RU-486)
• The mean half-life of mifepristone is 20 hours

• Less than 1% of the daily dose is excreted in urine

• It binds strongly to plasma proteins

• It binds to albumin and α1-acid glycoprotein, but not corticosteroid-

binding globulin

• Given orally in Cushing’s syndrome due to ectopic ACTH

production or adrenal carcinoma

• it reverses the cushingoid phenotype

• eliminates carbohydrate intolerance

• normalizes blood pressure

• corrects thyroid and gonadal hormone suppression

 Mitotane
 Mitotane
• It is a drug related to the DDT class of insecticides
• It has a nonselective cytotoxic action on the adrenal cortex
• It is given orally in divided doses up to 12 g daily
• Its toxic effects include diarrhea, nausea, vomiting, depression,
somnolence, and skin rashes
 Mineralococortcoid Antagonists
• These are steroids that compete with aldosterone
for its receptor and decrease its effect peripherally
• They include
• Spironolactone
• Eplerenone
• Drospirenone
 Spironolactone
• Spironolactone is a 7α-acetyl-thiospirolactone

• It is also an androgen antagonist and is sometimes used in the treatment

of hirsutism and acne in women

• It has slow onset of action

• Dosages of 50–200 mg/d cause a reduction in the density, diameter, and

rate of growth of facial hair. The effect can usually be seen in 2 months
and becomes maximal in about 6 months

• Its effects last for 2–3 days after the drug is discontinued

• It is used in the treatment of primary aldosteronism

• This agent reverses many of the manifestations of aldosteronism

 Spironolactone
• Spironolactone is a diuretic

• It has benefits in heart failure greater than those

predicted from its diuretic effects alone
• Adverse effects reported for spironolactone include
• hyperkalemia, cardiac arrhythmia, menstrual
abnormalities, gynecomastia, sedation, headache,
gastrointestinal disturbances, and skin rashes
 Eplerenone
• Eplerenone, is aldosterone antagonist approved for the
treatment of hypertension and heart failure
• It reduces mortality in heart failure
• It is more selective than spironolactone
• It has no reported effects on androgen receptors
• The dosage in hypertension is 50–100 mg/d
• The common toxicity is mild hyperkalemia
 Drospirenone
• This is a progestin
• It is an oral contraceptive
• It also antagonizes the effects of aldosterone
 References: END
• Celso E. Gomez –Sanchez and Kiran K
Soma. Extra-adrenal glucocorticoids and
mineralocorticoids: evidence for local
synthesis, regulation, and function. Am J.
Physiol Endocrin. Metab. 2011, E11-E24
doi:10.1152/aipendo.00100,2011
• PMCID:PMC3275156| PMID21540450

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