Hormones are the chemicals produced within the body by some

specialized cells and have specific effects on the activity of target organs
through specific receptors. There are 2 types of hormones:
a) Lipid soluble:
1. Can pass through cell membrane
2. Act via intracellular and intranuclear receptors
3. Mechanism: Protein synthesis
4. eg. Steroid hormones and thyroid hormones
b) Water soluble:
1. Cannot pass through cell membrane
2. Act via membrane receptors
3. Mechanism: cAMP, cGMP, IP3, Calcium-calmodulin, Tyrosine kinase

4. eg. All other hormones except steroid and thyroid hormones

Before Moving on to the mechanism of action, we will list the major
steroid and thyroid hormones.
Steroid hormones (Cholesterol derivatives):
1. Glucocorticoid (Cortisol)
2. Estrogen
3. Testosterone
4. Progesterone
5. Aldosterone
6. Vitamin D (Calcitriol)
Thyroid hormones (Amine derivatives):
1. Tri-iodothyronine (T3)
2. Thyroxine (T4)
Mechanism of Action of Steroid Hormones:

1. Simple Diffusion: The lipid soluble hormones diffuses through the

cell membrane to enter the cell.
2. Hormone binds to the intracellular receptor composed of a
"Hormone binding" domain, a "DNA binding" domain and a
"amino terminal" which interacts with other transcription factors.
Binding of the hormone leads to exposure of DNA binding zone.
3. Hormone-receptor complex enters nucleus and dimerizes.
4. Binding to HREs: Hormone-recpetor dimers bind to Hormone
(Steroid) Receptor Elements (SREs or HREs) of DNA.
5. Transcription: DNA transcription leads to formation of mRNA.
6. Translation: mRNA undergoes translation to produce new proteins.
e.g. Calbindin for Vitamin D
7. Physiologic action of hormones.

What is the difference in the mechanism of action of thyroid and

steroid hormones?
After passing through the cell membrane, steroid hormones except
calcitriol bind to the intracellular receptor in the cytosol before entering
the nucleus while the thyroid hormones and calcitriol directly enter
the nucleus to bind to the intranuclear receptor. Beside, this difference all
other steps are similar for both the hormone

Glucocorticoid Pharmacology
Definitions

Corticosteroid: Any of a class of steroids (aldosterone, cortisone &

hydrocortisone) related to steroids naturally synthesized by the adrenal cortex.
Includes both glucocorticoids (e.g. cortisol, prednisone) & mineralocorticoids
(e.g. aldosterone) that have selectivities for different intracellular receptors
affecting gene transcription.

Glucocorticoid: a word used to describe a class of steroid compounds that

was derived from glucose + cortex + steroid to reflect their: a) role in
regulating glucose metabolism, b) adrenal cortex origin, and c) steroidal
structure. Naturally occurring glucocorticoids are part of the feedback
mechanism the body utilizes to reduce immune activity (inflammation).
Exogenous glucocorticoids (synthetic or natural) are used to treat diseases
caused by an overactive immune system (e.g. allergies, asthma, autoimmune
diseases & sepsis). Glucocorticoids are distinguished from mineralcorticoid
and sex steroids that have different receptors, target cells and effects.

Hypercorticism: a condition of chronically elevated cortisol levels observed

in patients suffering from Cushing's syndrome or who have been under the
influence of chronic administration of systemic corticosteroids.

Mineralocorticoid: a class of steroid hormones that cause retention of sodium

(and water) (Chrousos 2015, Wikipedia:Mineralocorticoid). Aldosterone is the
most important endogenous mineralocorticoid. Aldosterone is produced in the
zona glomerulosa region of the adrenal cortex. Because of it comes from a
zone of the adrenal cortex, it is also considered a type of corticosteroid.
Aldosterone's physiological role is essential in maintenance of adequate fluid
volume needed for normal cardiac output and arterial blood pressure. Without
adequate levels of mineralocorticoids, diminished cardiac output can result in
fatal shock. In contrast, elevated levels of aldosterone associated with long
term stimulation of the Renin-Angiotensin-Aldosterone-System (RAAS) is
involved in the development of vascular remodeling and systolic heart failure.
For more information see the section on mineralocorticoid pharmacology.

Mechanism of Action:
Glucocorticoids exert a majority of their effects by altering gene expression (Figure
1).

Figure 1. Mechanism of action of glucocorticoids. The majority of effects produced

by glucocorticoids result from initial steroid binding to intracellular glucocorticoid
receptors followed by translocation to the nucleus and changes in gene transcription.
In their steroid-free (unbound) state, intracellular glucocorticoid receptors (GR) are
bound to stabilizing proteins that include heat-shock protein 90 (Hsp90) and
immunophilin. The unbound form of the receptor is not capable of affecting gene
transcription. Binding of steroid initiates a conformational change that results in an
exchange of chaperone proteins, which permits attachment of the steroid-GR complex
to the dynein protein trafficking pathway. This results in translocation of the steroidGR complex from the cytoplasm into the nucleus (Wikipedia:Hsp90). Once in the
nucleus, the steroid-GR complex dimerizes and binds to glucocorticoid response
elements (GRE) associated with the regulatory region of glucocorticoid-sensitive
genes. Binding of the glucocorticoid-GR dimer either represses, or stimulates the
transcription of sensitive genes, resulting in changes in synthesis of mRNA, followed
by changes in protein synthesis. These steps are necessary for producing most cellular
responses to glucocorticoids, and typically take hours to days to develop. Both a
reduction in the synthesis of inflammatory cytokines, as well as upregulation in
the synthesis of annexin A1 are known to play important roles in mediating the
antiinflammatory and immunomodulatory effects of glucocorticoids. As illustrated at
the top left, in some situations glucocorticoids are able to produce more rapid
responses by binding to membrane associated receptors and exerting effects that do
not involve changes in gene regulation. These non-genomic mechanisms remain
poorly understood.

Signal Transduction:

Diffusion of glucocorticoids across cell membranes where they bind to

cytoplasmic glucocorticoid receptors (GRs).
o Inactive forms of GRs form complexes with other chaperone proteins
that maintain the conformation of the receptor. Two of the major
chaperone proteins are heat-shock protein 90, and immunophilin.

Steroid binding to GRs results in a conformational change in the GR receptor,

an exchange of chaperone proteins (immunophilin is exchanged for HSp52),
and attachment of the activated receptor to a dynein motor protein and
cytoskeleton, that results in translocation of the activated GR to the
nucleus.

Activated GRs dimerize and bind to specific DNA sequences within the
regulatory regions of affected genes.

The short DNA sequences that are recognized by activated GRs are called
glucocorticoid responsive elements (GREs). GREs provide specificity to the
effects of glucocorticoids on gene transcription.

Between 10 to 20% of expressed genes are regulated by glucocorticoids

(Chrousos, 2015).

Metabolic effects of glucocorticoids generally are mediated primarily by

transcriptional activation.

Antiinflammatory effects are largely mediated by transcriptional

inhibition (trans-repression), with a few exceptions including the upregulation
of Annexin A1 (lipocortin 1) (Schimmer & Funder, 2011).

Rapid non-genomic effects of glucocorticoids have been identified, but the

mechanisms responsible remain poorly understood (Boldizsar et al, 2010; Lee
et al, 2012). Non-genomic effects of glucocorticoids appear to be mediated by
a combination of hormone sensitive membrane-bound and cytoplasmic
receptors (Lee et al, 2012).

Anti-inflammatory Effects & Mechanisms

Glucocorticoids INHIBIT genes regulating expression of:

o COX-2 (Parente & Solito, 2004)
o inducible NOS (Parente & Solito, 2004)
o most inflammatory cytokines (IL-1 thru IL-6, IL-8, IL-10, IL-13,
GM-CSF, TNF-, Interferon-)(Chatham, 2014)

Glucocorticoids also UPREGULATE the expression of Annexin A1, which

in turn:
o directly inhibits PLA2 (reduces prostaglandin & leukotriene
production) (Perretti & D'Acquisto, 2009; Chatham, 2014)
o inhibits COX-2 (post-transcriptional activity) (Girol et al, 2013)
o promotes neutrophil detachment and apoptosis (Perretti &
D'Acquisto, 2009)
o reduces neutrophil penetration through the endothelium of blood
vessels (Perretti & D'Acquisto, 2009)

ANNEXIN A1 (Lipocortin-1) - A Glucocorticoid Signaling Peptide

Annexins are a superfamily of ~160 structurally related proteins that share the
common property of binding to (or annexing) to phospholipid membranes in
a calcium-dependent manner. As a family they serve a variety of biological
functions ranging from anchoring cytoplasmic proteins to the cell membrane,
assisting in vesicular trafficking, to influencing events involved in
coagulation, inflammation and apoptosis (Lim & Pervaiz, 2007;
Wikipedia:Annexin).

Annexin A1 (previously named lipocortin-1) was the first characterized

member of the annexin superfamily. It is a 37 kDa cytoplasmic protein that
exerts multiple antiinflammatory effects when its expression is upregulated by
glucocorticoids (Perretti & D'Acquisto, 2009; Wikipedia - Annexin A1). Its
major effects are summarized in Figure 1.

The role of annexin A1 in the pathogenesis of numerous disease states ranging

from rheumatoid arthritis to cancer is under investigation (Lim & Pervaiz,
2007; Guo et al, 2013).

Metabolic Effects & Mechanisms

Carbohydrate & Protein Metabolism

Cortisol (the naturally occurring corticosteroid) is released during times of stress

to supply glucose as an energy substrate to organs facing stressful conditions.
Stress responses that increase cortisol release include vigorous exercise, psychological
stress or fear, acute trauma, surgery, pain, severe infection and hypoglycemia.
Cortisol's effects to elevate blood glucose are important in maintaining energy
homeostasis during the stress response, and ensure that critical organs (such as the
brain) continue to receive nutrients at a time when they are most needed for survival.
The mechanisms involved in elevating blood glucose include:

Increased gluconeogeneis (glucose formation)

o the enzymes involved in amino acid metabolism & gluconeogenesis

are upregulated
o the liver forms glucose from amino acids & fatty acids

Reduce glucose uptake & utilization by peripheral tissues

o cortisol antagonizes the effect of insulin on peripheral tissues in order
to increase blood glucose
o cortisol stimulates the translocation of glucose transporters away from
the plasma membrane into the cell interior

Increase protein breakdown (to provide amino acids for gluconeogenesis)

o protein breakdown affects multiple tissues including muscle & skin
(Schoepe et al, 2006; Miller 2014)

Activate lipolysis (to provide fatty acids for gluconeogenesis)

o the effects of growth hormone on hormone-sensitive lipase in
adipocytes are stimulated, resulting in the release of free fatty acids.
o increased free fatty acids further increase insulin resistance.

Clinical outcomes:
o atrophy of lymphoid tissue
o decreased muscle mass
o thinning of the skin (cigarette-paper-like consistency, fragile, easy to
bruise)
o hyperglycemia, worsening of diabetes

Lipid Metabolism

Chronically elevated glucocorticoids can produce a dramatic redistribution of body

fat. The redistribution of fat is believed to result from different sensitivities of
peripheral vs truncal fat cells to:

the lipolytic effects of glucocorticoids themselves

lipolytic effects of insulin that is released in response to glucocorticoidinduced hyperglycemia

Clinical outcomes:

o increased fat in the back of the neck (buffalo hump)

o increased facial fat (moon face)
o loss of fat in body extremities
Central Nervous System

Glucocorticoids can cause diverse neurological effects & behavioral changes that
may reflect steroid effects on neuronal excitability. The mechanisms remain poorly
understood.
Formed Elements of Blood

Administration of glucocorticoids results in a decreased number of circulating

lymphocytes, eosinophils, monocytes & basophils within 4-6 hours that results from
a redistribution of cells away from the periphery. Certain lymphoid malignancies
are also destroyed by treatment with glucocorticoids, most likely due to activation of
programmed cell death (Schimmer & Funder, 2011).

Therapeutic Uses
Synthetic glucocorticoids are analogs of cortisol that are used for their antiinflammatory, immunosuppressive & antiproliferative effects (Tables 2 & 3).
Examples of commonly used synthetic compounds include:

PREDNISONE: perhaps the most widely used synthetic corticosteroid (with a

very long list of FDA-approved indications). Prednisone has a high ratio of
glucocorticoid vs mineralocorticoid activity, which is desirable for use as an
anti-inflammatory and immunosuppressant agent (where effects on sodium
and water balance are undesirable). Prednisone is a prodrug that has no
biologic activity until it is converted by hepatic metabolism to prednisolone
(the active metabolite). Metabolic conversion may be impaired with hepatic
dysfunction.

PREDNISOLONE: The active metabolite of prednisone. It has 4-5 times the

anti-inflammatory potency of cortisol, and ~1/4th the mineralocorticoid
potency than cortisol. Pregnancy: In pregnancy, the placenta expresses an
enzyme (11-hydroxysteroid dehydrogenase 2) that inactivates either cortisol
or prednisolone by converting them to inactive forms (cortisone or
prednisone). This protects the fetus from high levels of these glucocorticoids.
In contrast, this enzyme does not have the same inactivating effect on some
other synthetic glucocorticoids such as dexamethasone.

METHYLPREDNISOLONE - a methylated analog of prednisolone that has

5-6 times the anti-inflammatory potency of cortisol, and 1/4th cortisol's
potency as a mineralocorticoid.

DEXAMETHASONE - a potent, long-acting glucocorticoid that has

relatively little effect on mineralocorticoid receptors.

HYDROCORTISONE (Cortisol) - the naturally occurring stress hormone

that stimulates both glucocorticoid and mineralocorticoid receptors (see Table
1).

CORTISONE - a naturally occurring inactive form of cortisol. Cortisone is

converted to cortisol by 11- hydroxysteroid dehydrogenase 1 (11-HSD 1) in
the liver (Figure 2).

FLUDROCORTISONE - has a structure identical to cortisol except for

addition of a fluorine atom at the 9 position. This structural change produces
a high mineralocorticoid/glucocorticoid potency ratio, and prevents its renal
inactivation by 11-HSD 2. At recommended doses, it is essentially free of
glucocorticoid activity. Duration of action is 12-24 hrs. It is used in the
treatment of Addison's disease (in which cells of the zona glomerulosa region
of the adrenal cortex that produce aldosterone have been destroyed).

Table 1: Relative Potencies & Duration of Action of Therapeuic Glucocorticoids

Relative
Glucocorticoid
Potency

Agent
Hydrocortisone
(Cortisol)
Prednisolone
Methylprednisolone
Dexamethasone
Fludrocortisone

Relative
Mineralocorticoid
Potency

Duration of
Action

Short

4-5
5-6
18
10

0.25
0.25
<0.01
125

Short
Short
Long
Short

Therapeutically, glucocorticoids are usually given at doses that produce minimal

mineralocorticoid stimulation in order to avoid the side effects associated with
activation of this pathway (e.g. hypokalemia, volume expansion & hypertension).

Figure 2. Regulation of steroid activity by 11-hydroxysteroid dehydrogenase (11HSD). This enzyme exists in two isoforms that catalyze opposing conversions of
cortisone to cortisol. The type 1 isozyme, which is expressed in the liver, converts
inactive cortisone to cortisol. Cortisol can interact with both glucocorticoid (GR) and
mineralocorticoid (MR) receptors. In contrast, the type 2 isoform converts active
cortisol to inactive cortisone. This significantly reduces the effects of circulating
cortisol on the mineralocorticoid receptors expressed in the collecting duct of the
kidney, and minimizes the mineralocorticoid effect of normal levels of cortisol on the
cells of the distal collecting duct. However, enzymatic inactivation can become
saturated at extremely high levels of cortisol (such as in Cushing's disease), resulting
in the development of sodium retention, fluid retention and hypertension. Type 2 HSD
is also expressed by the placenta, which inactivates maternal cortisol before it reaches
the fetus. A similar inactivation process also occurs for predisolone. Hence both
maternal cortisol, and prednisone/prednisolone given to the mother have little effect
on fetal development. This is not true for some other synthetic glucocorticoids such as
dexamethasone, that are not similarly affected by this enzyme.
Table 2: Therapeutic Effects of Glucocorticoids
Therapeutic Effect

Mechanism
Inhibit inflammation by blocking the expression & synthesis of
Anti-inflammatory inflammatory mediators, and by inducing the expression of antiinlammatory mediators (e.g. Annexin A1)
Immunosuppressive Directly inhibit T lymphocyte function which suppresses delayed

Therapeutic Effect
Antiproliferative

Mechanism
hypersensitivity reactions
Inhibition of DNA synthesis & epidermal cell turnover

Table 3: Common Clinical Indications for Systemic Glucocorticoids

Field of Medicine

Disorders
Asthma (moderate/severe), allergic rhinitis, anaphylaxis,
Allergy & Pulmonology
urticaria, food/drug allergies
Dermatology
Acute severe dermatitis
Endocrinology
Adrenal insufficiency
GI Diseases
Crohn's Disease (IBD), ulcerative colitis
Hematologic Diseases
Leukemia/lymphoma
Opthalmology
Uveitis (eye inflammation)
Rheumatoid arthritis, systemic lupus erythematosus,
Rheumatology/Immunology
vasculitis
Multiple sclerosis, organ transplant, nephrotic syndrome,
Other
cerebral edema
(Adapted from Liu et al, 2013)

Figure 3. The major therapeutic effects (top) and side effects (bottom) produced by
glucocorticoids. Many of the side effects are reversible when glucocorticoid treatment
is discontinued. Aspetic necrosis of the femur & cataract formation is permanent, and
usually requires surgical intervention. (Adapted from Buttgereit et al, 2005).

Side Effects
High-dose, long-term glucocorticoid therapy can produce a constellation of severe
toxicities (Saag & Fust, 2014) which are summarized in Figures 3 & 4, and Table 4.
Table 4: Corticosteroid Side Effects & Mechanisms
Side Effect
Hyperglycemia &
Diabetes
Central Obesity, Moon

Mechanism
Increased hepatic glucose output & decreased peripheral
glucose utilization (insulin-resistant diabetes mellitus)
Increases effect of lipolytic signals, leading to elevated

Side Effect
Face, Buffalo Hump
Muscle Weakness &
Wasting
Weight Gain
Osteoporosis
Avascular Necrosis of
Femur Head
Thin Skin that Bruises
Easily & Poor Wound
Healing
Hirsuitism & Acne
Hyperpigmentation
Increased Infections

Hypertension
Hypomania, Depression,
Psychosis
Cataract formation &
Glaucoma

Mechanism
FFA to fuel gluconeogenesis. Redistribution of fat from
extremities to the trunk, back of neck & supraclavicular
fossae
Breakdown of protein & diversion of amino acids to
glucose production
Increased appetite (CNS effect) and increased need for
insulin over time results in weight gain
Decreased reabsorption of calcium by the kidney leading
to secondary hyperparathyroidism; retardation of bone
growth by direct action & decreasing GH. Inhibition of
bone deposition.
Mechanism is unclear. Animal studies have suggested
increased levels of serum lipids result in lipid deposition
in the femoral head, causing femoral hypertension &
ischemia (Wang et al, 1977).
Antiproliferative GC effect on fibroblasts & keratinocytes,
resulting in dermal atrophy
due to ACTH-mediated increase of adrenal androgens
direct effect of ACTH on melanocortin 1 receptors
Immunosuppression related to thymic atrophy, decreased
production (number) of neutrophils & monocytes,
decreased production of cytokines
Increased cardiac contractility, increased vascular
reactivity to vasoconstrictors (catecholamines, Ang II)
Normal cortisol levels (eucortisolemia) maintains
emotional balance
Increased intraocular pressure & hypoparathyroidism

Side Effects highlighted in red are irreversible. Abbreviations: GC

(glucocorticoid).

Figure 4. Symptoms of Cushing's Syndrome, or chronic systemic effects of elevated

glucocorticoids. (Figure by Mikael Hggstrm, reproduced from Wikimedia
Commons)
Cushingoid mnemonic
The Cushingoid mnemonic is a useful way to remember the signs & symptoms of
glucocorticoid excess:

Cataracts

Ulcers

Skin: striae, thinning, bruising

Hypertension/ hirsutism/ hyperglycemia

Infections

Necrosis, avascular necrosis of the femoral head

Glycosuria

Osteoporosis, obesity

Immunosuppression

Diabetes

Suppression of the HPA Axis by Glucocorticoids

Figure 5. Secondary adrenal insufficiency caused by chronic glucocorticoid (GC)

therapy. Chronic treatment with glucocorticoids will reduce pituitary release of
ACTH, which over a time period of weeks to months can result in progressive atrophy
of cortisol producing cells in the adrenal gland (top right). If glucocorticoid therapy is
suddenly discontinued (which is not recommended), adrenal atrophy can significantly
affect the ability of the adrenal glands to release normal levels of cortisol in response
to ACTH release, resulting in signs & symptoms of adrenal insufficiency.

Secondary Adrenal Insufficiency

When a patient takes a glucocorticoid for treatment of an illness, the presence of the
cortisol-like medication will suppress the release of ACTH by the pituitary (Figure 5,
top right). Because the cortisol-producing cells of the adrenal gland (zona fasciculata)
depend on ACTH stimulation for normal homeostasis, a reduction in ACTH release
for any significant time (e.g. several weeks or more) will result in a progressive
atrophy of this zone. Adrenal atrophy reduces the ability of the adrenal gland to
produce normal levels of cortisol when therapy with a glucocorticoid (such as
prednisone) is discontinued.
Several weeks of exogenous glucocorticoid therapy are typically required for
development of adrenal insufficiency (Salvatori, 2005; Chrousos, 2015). Longeracting glucocorticoids, and higher doses of systemic glucocorticoids (vs topical or
inhaled formulations) have been associated with a higher risk of developing adrenal
suppression. There are no current evidence-based guidelines regarding the optimal
method for discontinuing glucocorticoid therapy, although gradual tapering of
dosages over a period of weeks to months, prior to complete discontinuation, is
recommended to allow time for recovery of the hypothalamic-pituitary-adrenal
axis (Liu et al, 2013).
The signs and symptoms of secondary adrenal insufficiency that result from a sudden
withdrawal of glucocorticoids in the presence of HPA axis suppression are typically
similar to those seen with Addison's disease, but don't include changes in skin
pigmentation (because ACTH secretion is not increased), or significant electrolyte
disturbances (because aldosterone is regulated by the renin-angiotensin system rather
than ACTH)(Nieman 2013).
Hydrocortisone (given twice or three times per day) is commonly preferred for the
treatment of adrenal insufficiency because its short half-life allows it to more
closely mimic the normal circadian rhythm for cortisol.
References:

Boldizsar F et al (2010): Emerging pathways of non-genomic glucocorticoid

(GC) signalling in T cells. Immunobiology 215:521-526.

Buttgereit F et al (2005): Optimised glucocorticoid therapy: the sharpening of

an old spear. Lancet 365:801-803

Carroll B, Aron DC, Findline JW, Tyrrell JB (2011): Glucocorticoids &

adrenal androgens (Chapter 9). In: Greenspan's Basic and Clinical
Endocrinology. 9th Edition. Gardner DG, Shoback D (Editors). McGraw-Hill /
Lange. (Access-Medicine).

Chatham WW (2014): Glucocorticoid effects on the immune system. In:

UpToDate, Basow, DS (Ed), Waltham, MA. Cited 7/7/15

Chrousos GP (2015): Adrenocorticosteroids & Adrenocortical Antagonists

(Chapter 39). In: Basic and Clinical Pharmacology. 13th Edition. Katzung
BG, Trevor AJ (Editors). McGraw-Hill / Lange. (Access-Medicine).

Girol AP et al (2013): Anti-Inflammatory Mechanisms of the Annexin A1

Protein and Its Mimetic Peptide Ac2-26 in Models of Ocular Inflammation In
Vivo and In Vitro. J Immunology 190(11):5689-5701. doi:
10.4049/jimmunol.1202030

Guo C et al (2013): Potential role of Anxa1 in cancer. Future Oncol

9(11):1773-93. doi: 10.2217/fon.13.114

Lee SR et al (2012): Non-genomic effect of glucocorticoids on cardiovascular

system. Pflugers Archiv - Eur J Physiol. 464(6):549-559.

Lim LHK, Pervaiz S (2007): Annexin 1: the new face of an old molecule.
FASEB J 21: 968-975.

Liu D et al (2013): A practical guide to the monitoring and management of the

complications of systemic glucocorticoid therapy. Allergy, Asthma & Clinical
Immunology 9:30. doi:10.1186/1710-1492-9-30

Miller ML (2014): Glucocorticoid-induced myopathy. In: UpToDate, Basow,

DS (Ed), Waltham, MA. Cited 6/30/15

Nieman LK (2013): Clinical manifestations of adrenal insufficiency in adults.

In: UpToDate, Basow, DS (Ed), Waltham, MA. Cited 7/8/15.

Parente L, Solito E (2004): Annexin 1. More than an anti-phospholipase

protein. Inflamm res 53:125-132. DOI 10.1007/s00011-003-1235-z

Perretti M, D'Acquisto F (2009): Annexin A1 and glucocorticoids as effectors

of the resolution of inflammation. Nature Reviews Immunology 9:62-70.
doi:10.1038/nri2470

Schimmer BP, Funder JW (2011): ACTH, Adrenal Steroids, and Pharmacology

of the Adrenal Cortex (Chapter 42). In: Goodman & Gilman's The
Pharmacological Basis of Therapeutics. 12th Edition. Brunton LL (Editor).
McGraw Hill

Saag KG, Furst DE (2014): Major side effects of systemic glucocorticoids. In:
UpToDate, Basow, DS (Ed), Waltham, MA. Cited 6/30/15

Salvatori R (2005): Adrenal insufficiency. JAMA 294(19):2481-2488.

doi:10.1001/jama.294.19.2481

Schoepe S, et al (2006): Glucocorticoid therapy-induced skin atrophy. Exp

Derm 15:406-420.

Wang GJ, Sweet DE, Reger SI, et al. Fat-cell changes as a mechanism of
avascular necrosis of the femoral head in cortisone-treated rabbits. J Bone
Joint Surg Am. Sep 1977;59(6):729-35.

Yang YH et al (2013): Annexin A1: potential for glucocorticoid sparing in RA.

Nat Rev Rheumatol 9:595-603.

Prednisone (Prototype)

Trade Names: generic, Meticorten

Drug Class: Glucocorticoid (synthetic), Immunosuppressant, Antiinflammatory steroid

Mechanism of Action:
o a prodrug of prednisolone. Prednisone itself is inactive, and must first
be converted to prednisolone by hepatic 11- hydroxysteroid
dehydrogenase 1 before it can bind to glucocorticoid receptors.
o See glucocorticoid pharmacology.
o Major mechanisms include:

inhibits PLA2

downregulates COX-2

downregulates expression of inflammatory cytokines

reduces the activity of the immune system

alters the expression of numerous genes in many tissues

FDA Indications (major examples):

o Endocrine disorders

primary or secondary adrenocortical insufficiency (e.g.

Addison's syndrome)

hypercalcemia associated with cancer

o Rheumatic disorders

acute gout

osteoarthritis

rheumatoid arthritis

o Collagen disorders

systemic lupus erythematosus

o Dermatologic diseases

psoriasis

severe seborrheic dermatitis

Stevens-Johnson syndrome

o Allergic states

allergic rhinitis

asthma

contact dermatitis

o Ophthalmic diseases

allergic conjunctivitis

herpes zoster ophthalmicus

o Respiratory diseases

aspiration pneumonitis

sarcoidosis

o Hematologic disorders

idiopathic thrombocytopenic purpura (adults)

thrombocytopenia

acquired hemolytic anemia

o Neoplastic diseases

leukemias & lymphomas

o GI diseases

ulcerative colitis

o Prevent transplant rejection

prednisone is one of the most commonly used

immunosuppressants.

Used to minimize allergic reactions that may occur with the use
of monoclonal antibodies

2. Contraindications:
o Systemic fungal infections
o Hypersensitivity to components of the drug formulation.
o Patients on immunosuppressant doses of corticosteroids should be
warned to avoid exposure to chicken pox or measles.
o Pharmacokinetics:
o Prednisone is rapidly converted to the active product prednisolone by
the liver. Prednisone has an intermediate duration of action compared
to other glucocorticoids.
o Side Effects:
o see Glucocorticoid pharmacology
o Notes:
o Corticosteroids may mask some signs of infection, and new
infections may appear during their use
o Pharmwiki Groups:
o Immunosuppressants; Glucocorticoids & Pulmonary Pharm
o Pronunciation:
pred-NI-sone
o References:
o Carroll B, Aron DC, Findline JW, Tyrrell JB (2011): Glucocorticoids &
adrenal androgens (Chapter 9). In: Greenspan's Basic and Clinical

Endocrinology. 9th Edition. Gardner DG, Shoback D (Editors).

McGraw-Hill / Lange. (Access-Medicine).
o Boushey HA (2012): Drugs used in asthma (Chapter 20). In: Basic and
Clinical Pharmacology. 12th Edition. Katzung BG, Masters SB, Trevor
AJ (Editors). McGraw-Hill / Lange. (Access-Medicine).
o Lake DF, Briggs AD, Akporiaye ET (2012): Immunopharmacology
(Chapter 55). In: Basic and Clinical Pharmacology. 12th Edition.
Katzung BG, Masters SB, Trevor AJ (Editors). McGraw-Hill / Lange.
(Access-Medicine).
o rxlist.com - prednisone (Deltasone )
Keywords

Hydrocortisone [Cortisol]

Trade Names: generic, Cortef, Hydrocortone, Solu-Cortef

Drug Class: Glucocorticoid (Naturally occurring, Short-acting)

Mechanism of Action:
o See glucocorticoid pharmacology.
o Major mechanisms include:

inhibits PLA2

downregulates COX-2

downregulates expression of inflammatory cytokines

reduces the activity of the immune system

alters the expression of numerous genes in many tissues

Indications:
o replacement therapy in adrenocortical deficiency states such as
primary adrenocortical insufficiency (Addison's disease) or
secondary adrenocortical insufficiency.
o They are also used for their potent anti-inflammatory effects in
disorders of many organ systems (e.g. lupus, rheumatoid arthritis,
asthma).

Contraindications:
o Systemic fungal infections (because of cortisol's effect to depress the
immune system)
o Hypersensitivity to this product

Side Effects:
o see Glucocorticoid pharmacology

Pharmacokinetics:
o Cortisol is sometimes refered to as the stress hormone since it is
elevated under stress and produces an elevation in glood glucose
(amongst other effects)
o Cortisol synthesis & secretion is tightly regulated by the CNS
o Cortisol is synthesized from cholesterol, and its rate of secretion
follows a circadian rhythm governed by pulses of ACTH that peak in
the early morning & after meals
o Mostly (90%) bound to corticosteroid-binding globulin (CBG) in the
plasma at physiologic levels
o The half life in the circulation is normally 60-90 mins, but it's half life
may be increased when stress, hyperthyroidism or liver disease is
present
o Cortisol is inactivated by P450 enzymatic reduction in the liver, and is
converted to inactive cortisone by 11--hydroxysteroid dehydrogenase
2 in the kidney (and placenta). This reduces the effect of cortisol on the
fetus and on mineralocorticoid receptors in the cells of the renal
collecting duct.

Pharmwiki Groups: Immunosuppressants & Glucocorticoids

Pronunciation:
hye droe CORE tih sone

References:
o Carroll B, Aron DC, Findline JW, Tyrrell JB (2011): Glucocorticoids &
adrenal androgens (Chapter 9). In: Greenspan's Basic and Clinical
Endocrinology. 9th Edition. Gardner DG, Shoback D (Editors).
McGraw-Hill / Lange. (Access-Medicine).

o Lake DF, Briggs AD, Akporiaye ET (2012e): Immunopharmacology

(Chapter 55). In: Basic and Clinical Pharmacology. 12th Edition.
Katzung BG, Masters SB, Trevor AJ (Editors). McGraw-Hill / Lange.
(Access-Medicine).
o rxlist.com (Cortef )
Keywords

Dexamethasone

Trade Names: generic, Decadron-LA

Drug Class: Glucocorticoid, Anti-Inflammatory

Mechanism of Action:
o See glucocorticoid pharmacology.
o Major mechanisms include:

inhibits PLA2

downregulates COX-2

downregulates expression of inflammatory cytokines

reduces the activity of the immune system

alters the expression of numerous genes in many tissues

Indications:
o used for its potent anti-inflammatory effects in disorders of many
organ systems.
o Examples of indications include: rheumatic disorders, arthritis, lupus
erythrematosus, bronchial asthma & ulcerative colitis.
o Glucocorticoids cause profound and varied metabolic effects. In
addition, they modify the body's immune responses to diverse stimuli.
o At equipotent anti-inflammatory doses, dexamethasone almost
completely lacks the sodium-retaining property of hydrocortisone and
closely related derivatives of hydrocortisone.

Dexamethasone Suppression Test:

o The dexamethasone suppression test is used for the diagnosis of

Cushing's syndrome (adrenocortical hyperfunction) & in the
differential diagnosis of depressive psychiatric states
o In normal patients, the administration of a supraphysiologic dose of
glucocorticoid results in suppression of ACTH and cortisol secretion
(due to negative feedback to the hypothalamus)
o In Cushing's syndrome of whatever cause, there is a failure of this
suppression when low doses of the synthetic glucocorticoid
dexamethasone are given
o In Cushing's disease there is typically a bilateral adrenal hyperplasia
secondary to an ACTH-secreting pituitary adenoma, resulting in
glucocorticoid hypersecretion, which can produce protein loss, poor
wound healing, mental depression, etc.
o In patients with Cushing's disease, an appropriate high dose of
dexamethasone will produce a >50% reduction in morning cortisol
levels
o Note: dexamethasone would not suppress glucocorticoid release from
adrenal tumors, hence it is a useful diagnostic test for distinguishing
between the two disorders

Contraindications:
o Systemic fungal infections (because of compromise to the immune
system)
o Hypersensitivity to this drug

Pharmacokinetics:
o Available in oral, aerosol and topical forms
o Topical corticosteroids can be absorbed from normal intact skin. Once
absorbed through the skin, topical corticosteroids are handled through
pharmacokinetic pathways similar to systemically administered
corticosteroids
o Corticosteroids are bound to plasma proteins in varying degrees
o Corticosteroids are metabolized primarily in the liver and are then
excreted by the kidneys.

Side Effects:
o see glucocorticoid pharmacology

Pharmwiki Groups:NSAIDs, DMARDs, Rx of Arthritis & Gout &

Glucocorticoids

Pronunciation:
DEX-uh-METH-uh-sone

References:
o Carroll B, Aron DC, Findline JW, Tyrrell JB (2011): Glucocorticoids &
adrenal androgens (Chapter 9). In: Greenspan's Basic and Clinical
Endocrinology. 9th Edition. Gardner DG, Shoback D (Editors).
McGraw-Hill / Lange. (Access-Medicine).
o Kronenberg HM (2008): Classification and Pathophysiology of
Cushing's Syndrome. Chapter 14. In: Williams Textbook of
Endocrinology. 11th Edition. (Accessed via MD Consult on 5/25/10).
o rxlist.com (Decadron )

Keywords

Methylprednisolone

Trade Names: generic, Medrol, Depo-Medrol, Solu-Medrol

Drug Class: Glucocorticoid (Medium - acting, 5-6 times as potent as

hydrocortisone)

Pharmwiki Group: Glucocorticoids

Pronunciation:
METH il pred NIS oh lone

References:
o rxlist.com (Medrol )

Keywords

Triamcinolone [Triamcinolone acetonide]

Trade Names: generic, Aristocort, Azmacort, Kenacort

Drug Class: Corticosteroid (lipid soluble, inhalational formulation)

Indications:
o Maintenance treatment of asthma as prophylactic therapy
o An inhalation aerosol formulation is also indicated for asthma patients
who require systemic corticosteroid administration, where adding
triamcinolone may reduce or eliminate the need for the systemic
corticosteroids

Pharmacokinetics:
o Available in oral, injectible, & topical/inhalational formulations
o The inhaled route makes it possible to provide effective local antiinflammatory activity with reduced systemic corticosteroid effects
o Though highly effective for asthma, glucocorticoids do not affect
asthma symptoms immediately
o While improvement in asthma may occur as soon as one week after
initiation of Inhalation aerosol therapy, maximum improvement may
not be achieved for 2 weeks or longer.

Pharmwiki Group: Glucocorticoids

Pronunciation:
TRY-am-SIN-oh-lone

References:
o rxlist.com (Azmacort )

Keywords

Mineralocorticoids
Fludrocortisone

Trade Names: generic, Florinef Acetate

Drug Class: Mineralcorticoid (Synthetic)

Mechanism of Action:
o has salt & water retaining properties

Indications:
o In the treatment of adrenocortical insufficiency (e.g. Addison's dx.)
associated with mineralcorticoid deficiency
o The most widely used mineralcorticoid (also has some glucorcorticoid
activity)

Side Effects:
o Most adverse reactions are caused by the drug's mineralocorticoid
activity (retention of sodium and water) and include hypertension,
edema, cardiac enlargement, congestive heart failure, potassium loss,
and hypokalemic alkalosis

Pharmacokinetics:
o Oral administration

Pharmwiki Group: Glucocorticoids

Pronunciation:
FLOO droe KOR ti sone

References:
o rxlist.com (Florinef )

Keywords

Glucocorticoid Inhibitors
Mifepristone [RU-486]

Trade Name: Mifeprex , Korlym

Drug Class: Glucocorticoid & Progesterone Receptor Antagonist

Mechanism of Action:
o A potent progesterone receptor antagonist. Blocking the effects of
progesterone prevents pregnancy.
o Mifepristone, when used together with prostaglandin E1 (misoprostol),
is used to end an early pregnancy (49 days or less since the last
menstrual period began).

o Mifepristone also acts as a glucocorticoid receptor antagonist, and

has occasionally been used in refractory Cushing's syndrome
(marketed under the trade name Korlym )

Indications:
o Termination of Pregnancy (used in combination with misoprostol).

Indicated for the medical termination of intrauterine

pregnancy through 49 days (7 weeks) of pregnancy. The
combination of a single dose of mifepristone & a vaginal
suppository containing prostaglandin E1 (misoprostol) has been
found to terminate pregnancy in over 95% of patients treated
during the first 7 weeks after conception.

The FDA-approved regimen for medical abortion consists of

taking 600 mg (three 200 mg tablets) of oral mifepristone on
Day One and 400 mcg (two 200 mcg tablets) of oral
misoprostol on Day Three.

Mifeprex may be administered only under the supervision of a

physician, able to assess the gestational age of an embryo and
to diagnose ectopic pregnancies.

o Approved for the control of hyperglycemia associated with

Cushing's (in patients who have failed surgical treatment, or cannot
have surgery).
2. Contraindications:
o presence of an ectopic pregnancy
o an intrauterine device (IUD) in place (The IUD must be removed
before taking mifepristone)
o chronic adrenal failure
o long term therapy with steroid medications
o hemorrhagic disorders, or are taking an anticoagulant
o history of allergic reactions to mifepristone, misoprostol or similar
drugs

Side Effects: vaginal bleeding & infections

Black Box Warnings: FATAL INFECTIONS & BLEEDING

Serious and sometimes fatal infections & bleeding occur rarely following abortions
(either spontaneous, surgical or medical in origin), including following the use of
mifepristone (Mifeprex ). No causal relationship between these events and
mifepristone has been established. Patients should be informed about the risk of these
adverse events, as well as what to do should they occur. If provided contacts are not
available, the patient should go to an Emergency Department if she experiences a
sustained fever, severe abdominal pain, prolonged heavy bleeding, syncope or
abdominal discomfort or general malaise (including weakness, nausea, vomiting or
diarrhea) of more than 24 hours duration while taking mifepristone.

ATYPICAL INFECTIONS: Patients with serious bacterial infections (e.g.

Clostridium sordellii) or sepsis can present without fever, bacteremia or
significant findings on pelvic exam following an abortion. Very rarely deaths
have occurred in patients without fever, with or without abdominal pain, but
having leukocytosis with a marked left shift, tachycardia, hemoconcentration,
and a general malaise. A high index of suspicion is required to rule out sepsis
or serious infection (e.g from Clostridium sordellii).

BLEEDING: Prolonged heavy bleeding may be a sign of an incomplete

abortion or other complications, which may require prompt medical or
surgical intervention. Advise patients to seek immediate attention if they
experience prolonged heavy vaginal bleeding.

Pharmwiki Group: Glucocorticoids

Pronunciations:
miff-eh-PRIH-stone & mih feh PRIH stone

References:
o Chrousos GP (2012): The Gonadal Hormones & Inhibitors (Chapter
40). In: Basic & Clinical Pharmacology. 12e. BG Katzung, SB
Masters, AJ Trevor (Editors). Lange/McGraw-Hill.
o FDA Website on Mifeprex Questions & Answers (updated 2/24/2010)
o rxlist.com (Korlym )
o rxlist.com (Mifeprex )

Keywords

Metyrapone

Trade Name: Metopirone

Drug Class: Inhibitor of Glucocorticoid Synthesis

Mechanism of Action:
o Inhibits 11--hydroxylase, interfering with cortisol & corticosterone
synthesis
o In the normal pituitary gland, there is a compensatory increase in 11dexoycortisol secretion; this response is a measure of the capacity of
the anterior pituitary to produce ACTH and this has been adopted for
clinical use as a diagnostic test

Indications:
o Diagnostic test of pituitary function
o May be useful for reducing cortisol production to normal levels in
Cushing's syndrome
o A normal response (reduction in cortisol or its metabolites in urine)
indicates that the elevated cortisol levels are not due to a cortisolsecreting adrenal carcinoma or adenomal, since secretion by such
tumors produces suppression of ACTH & atrophy of normal adrenal
cortex

Side Effects:
o transient dizziness & GI disturbances

Steroid hormones are all made up of 4 joined carbon rings. This structure
is called a steran nucleus and consists of 3 cyclohexanes and 1
cyclopentane. They are all highly lipohilic and are extensively fat soluble.
Steroid hormones bind to steroid receptors which are located inside the
cell as opposed to on the surface of the cell.
Non steroid hormones are anything that is not structurally a steran
nucleus and are usually amines or proteins but can also be fatty acids.
Many non-steroid hormones bind to receptors on the surface of cells