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 steroid-GR 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-α, Interferon-γ)(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 upregulatedo the liver forms glucose from amino acids & fatty acids

Reduce glucose uptake & utilization by peripheral tissueso cortisol antagonizes the effect of insulin on peripheral tissues in order

to increase blood glucoseo 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 tissueo 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 glucocorticoid-

induced 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 anti-inflammatory, 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 (11β-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-β hydroxysteroid dehydrogenase 1 (11β-HSD 1) in the liver (Figure 2).

FLUDROCORTISONE - has a structure identical to cortisol except for addition of a fluorine atom at the 9α position. This structural change produces a high mineralocorticoid/glucocorticoid potency ratio, and prevents its renal inactivation by 11β-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

AgentRelative

Glucocorticoid Potency

Relative Mineralocorticoid

Potency

Duration of Action

Hydrocortisone (Cortisol) 1 1 Short

Prednisolone 4-5 0.25 ShortMethylprednisolone 5-6 0.25 ShortDexamethasone 18 <0.01 LongFludrocortisone 10 125 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 11β-hydroxysteroid dehydrogenase (11β-HSD). 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

Anti-inflammatoryInhibit inflammation by blocking the expression & synthesis of inflammatory mediators, and by inducing the expression of anti-inlammatory mediators (e.g. Annexin A1)

Immunosuppressive Directly inhibit T lymphocyte function which suppresses delayed

Therapeutic Effect Mechanismhypersensitivity reactions

Antiproliferative Inhibition of DNA synthesis & epidermal cell turnover

Table 3: Common Clinical Indications for Systemic Glucocorticoids

Field of Medicine Disorders

Allergy & Pulmonology Asthma (moderate/severe), allergic rhinitis, anaphylaxis, urticaria, food/drug allergies

Dermatology Acute severe dermatitisEndocrinology Adrenal insufficiencyGI Diseases Crohn's Disease (IBD), ulcerative colitisHematologic Diseases Leukemia/lymphomaOpthalmology Uveitis (eye inflammation)

Rheumatology/Immunology Rheumatoid arthritis, systemic lupus erythematosus, vasculitis

Other Multiple sclerosis, organ transplant, nephrotic syndrome, 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 MechanismHyperglycemia & Diabetes

Increased hepatic glucose output & decreased peripheral glucose utilization (insulin-resistant diabetes mellitus)

Central Obesity, Moon Increases effect of lipolytic signals, leading to elevated

Side Effect Mechanism

Face, Buffalo HumpFFA to fuel gluconeogenesis. Redistribution of fat from extremities to the trunk, back of neck & supraclavicular fossae

Muscle Weakness & Wasting

Breakdown of protein & diversion of amino acids to glucose production

Weight Gain Increased appetite (CNS effect) and increased need for insulin over time results in weight gain

Osteoporosis

Decreased reabsorption of calcium by the kidney leading to secondary hyperparathyroidism; retardation of bone growth by direct action & decreasing GH. Inhibition of bone deposition.

Avascular Necrosis of Femur Head

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).

Thin Skin that Bruises Easily & Poor Wound Healing

Antiproliferative GC effect on fibroblasts & keratinocytes, resulting in dermal atrophy

Hirsuitism & Acne due to ACTH-mediated increase of adrenal androgensHyperpigmentation direct effect of ACTH on melanocortin 1 receptorsIncreased Infections Immunosuppression related to thymic atrophy, decreased

production (number) of neutrophils & monocytes, decreased production of cytokines

Hypertension Increased cardiac contractility, increased vascular reactivity to vasoconstrictors (catecholamines, Ang II)

Hypomania, Depression, Psychosis

Normal cortisol levels (eucortisolemia) maintains emotional balance

Cataract formation & Glaucoma 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 Häggström, 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). Longer-acting 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, Anti-

inflammatory steroid Mechanism of Action:

o a prodrug of prednisolone. Prednisone itself is inactive, and must first be converted to prednisolone by hepatic 11-β 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):

1. Endocrine disorders primary or secondary adrenocortical insufficiency (e.g.

Addison's syndrome) hypercalcemia associated with cancer

2. Rheumatic disorders acute gout

osteoarthritis rheumatoid arthritis

3. Collagen disorders systemic lupus erythematosus

4. Dermatologic diseases psoriasis severe seborrheic dermatitis Stevens-Johnson syndrome

5. Allergic states allergic rhinitis asthma contact dermatitis

6. Ophthalmic diseases allergic conjunctivitis herpes zoster ophthalmicus

7. Respiratory diseases aspiration pneumonitis sarcoidosis

8. Hematologic disorders idiopathic thrombocytopenic purpura (adults) thrombocytopenia acquired hemolytic anemia

9. Neoplastic diseases leukemias & lymphomas

10. GI diseases ulcerative colitis

11. 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 Contraindications:

o Systemic fungal infectionso 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. 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.

Side Effects: o see Glucocorticoid pharmacology

Notes:o Corticosteroids may mask some signs of infection, and new

infections may appear during their use Pharmwiki Groups:

o Immunosuppressants ; Glucocorticoids & Pulmonary Pharm Pronunciation:

pred-NI-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 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-β-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 formso 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 degreeso 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 therapyo 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 formulationso The inhaled route makes it possible to provide effective local anti-

inflammatory activity with reduced systemic corticosteroid effectso Though highly effective for asthma, glucocorticoids do not affect

asthma symptoms immediatelyo 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

MineralocorticoidsFludrocortisone

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 InhibitorsMifepristone [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:

1. 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.

2. Approved for the control of hyperglycemia associated with Cushing's (in patients who have failed surgical treatment, or cannot have surgery).

Contraindications:

o presence of an ectopic pregnancyo an intrauterine device (IUD) in place (The IUD must be removed

before taking mifepristone)o chronic adrenal failureo long term therapy with steroid medicationso hemorrhagic disorders, or are taking an anticoagulanto 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-β-hydroxylase, interfering with cortisol & corticosterone synthesis

o In the normal pituitary gland, there is a compensatory increase in 11-dexoycortisol 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 functiono May be useful for reducing cortisol production to normal levels in

Cushing's syndromeo A normal response (reduction in cortisol or its metabolites in urine)

indicates that the elevated cortisol levels are not due to a cortisol-secreting 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