Term
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Definition
• Steroid molecules produced and released by the adrenal cortex
Adrenal Cortex:
-Glucocorticoids
Effect intermediary metabolism and immune function
-Mineralocorticoids
Salt-retaining activity
-Androgenic/Estrogenic Hormones |
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Term
| Hypothalamic-Pituitary-Adrenal (HPA) Axis |
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Definition
• Interactionsbetweenthe hypothalamus, pituitary, and adrenal cortex that regulate release of endocrine hormones
• Corticotropin-Releasing Hormone (CRH)
- Hypothalamic peptide that stimulates release of ACTH and AVP from the anterior pituitary
• Adrenocorticotropic Hormone (ACTH)
- Stimulates the adrenal cortex to synthesize and release adrenocortical hormones
- t1/2 = 15 minutes in the plasma |
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Term
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Definition
• Comprised of three anatomically and functionally distinct compartments
Zona glomerulosa- • Angiotensin II • K+ are regulators, Aldosterone synthase (CYP11B2) is a key enzyme, Aldosterone is secreted
Zona fasciculata- ACTH is regulator, • 17α-hydroxylase (CYP17) • 11β-hydroxylase (CYP11B1) are key enzymes, cortisol is secreted
Zona reticularis- unknown regulator, key enzyme: 17α-hydroxylase (CYP17) + C17 - 20 lyase reaction. DHEA Dehydroepiandr- osterone is secreted |
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Term
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Definition
• Cortisol (hydrocortisone): main glucocorticoid in humans
Rate of secretion under optimal conditions
10 mg/day
Concentration in peripheral plasma:
4:00 a.m.
4 mcg/100 mL
8:00 a.m.
16 mcg/100 mL
• Majorityofcortisolisboundtocirculatingprotein
in the plasma
- Corticosteroid-binding globulin (CBG, transcortin)
binds 90% of circulating hormone
- Albumin binds ~5% of steroid |
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Term
Cortisol t1/2 = 60–90 minutes in the blood
• Prolonged when: |
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Definition
• Administered in large amounts
• During states of stress or hypothyroidism • Liver disease |
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Term
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Definition
• 1% excreted unchanged in the urine as free cortisol
• Majority metabolized in the liver via conjugation and sulfation |
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Term
| Mechanisms of Corticosteroid Effects |
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Definition
| Corticosteroids bind to specific receptors in target tissues -> Regulate expression of corticosteroid-responsive genes -> Change the levels of proteins synthesized by target tissues |
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Term
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Definition
1. CBG-boundcortisol(S)enterscellasfreesteroid molecule
2. Cortisolbindstoglucocorticoid-receptorcomplex(R), creating an unstable complex
3. Newsteroid-receptorcomplexactivatesandisable to dimerize
4. Steroid-complex enters nucleus
5. Binds to a glucocorticoid response element (GRE)
6. Regulates transcription by RNA polymerase II and transcription factors
• Steroid-receptor complex can complex with and influence other
transcription factors (AP1) |
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Term
| The Glucocorticoid Receptor |
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Definition
• Comprised of three regions:
Glucocorticoid (ligand)
Region where steroid molecule binds
DNA
• Folds into two “zinc fingers” • Binds to the glucocorticoid
response element (GRE) on DNA
Transcription- activating
Involved in receptor transactivation activity and increases its specificity |
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Term
| Mechanisms for Corticoid Specificity |
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Definition
• Cortisol binds with equal affinity to the mineralocorticoid (MR) and glucocorticoid receptors (GR)
• Aldosterone synthase (CYP11B2) in the kidneys, colon, and salivary glands converts cortisol to cortisone
• Aldosterone is resistant to inactivation via CYP11B2 |
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Term
| Glucocorticoid Physiologic Effects |
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Definition
Widespread: glucocorticoids influence the function of most cells in the body
• Direct effects
- Metabolic, catabolic/antianabolic, anti-inflammatory, immunosuppressive, cardiovascular, etc.
• Permissive effects
- Example: catecholamine response of vascular/bronchial smooth muscle ↓ with cortisol absence |
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Term
Metabolic Effects
• Carbohydrate and protein metabolism |
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Definition
-Liver
• Stimulates gluconeogenesis and glucose storage as glycogen
-Periphery
• ↓ glucose utilization, ↑ protein breakdown, glutamine synthesis, lipolysis
- Net effect = ↑↑ blood glucose levels
• Especially with pharmacologic administration of glucocorticoids |
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Term
Metabolic Effects
• Lipid metabolism |
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Definition
- Body fat redistribution
• ↑ neck, face, and supraclavicular area
• ↓ in the extremities
• Occurs during endogenous or pharmacologic induced hypercorticalism
- Facilitation of permissive lipolytic effects of other agents
• ↑ free fatty acids post-glucocorticoid administration |
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Term
Catabolic and Antianabolic Effects
• Effects observed in: |
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Definition
• Lymphoid, connective tissue, muscle, peripheral fat, skin
- Result:
• ↓ muscle mass, lymphoid tissue • Weakness/thinning of the skin
- Theory: glucocorticoids translocate glucose transporters from plasma membranes to intracellular locations |
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Term
| Anti-Inflammatory and Immunosuppressive Effects |
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Definition
Inflammation: extravasation/infiltration of leukocytes into affected tissue
-Glucocorticoids cause:
• ↓ concentration, distribution, and function of peripheral leukocytes
• Suppress inflammatory cytokines, chemokines, and other inflammatory mediators
- Post-administration:
• ↑ concentration of circulatory neutrophils
• ↓ concentration of circulatory lymphocytes (T/B cells), monocytes, eosinophils, basophils |
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Term
| Macrophages monocytes anti inflammatory effects |
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Definition
inhibit:
• Arachidonic acid, Prostaglandins, Leukotrienes
• Cytokines: Interleukin (IL)-1, 6 and Tumor Necrosis Factor (TNF)-α
• Acute phase reactants
• Mediated via inhibition of COX-2 and PLA2
• Production/release ↓; cytokines: ↑ T cells, ↑ fibroblast proliferation
• Includes third component of complement |
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Term
| Endothelial cells anti inflammatory effects |
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Definition
inhibit:• ELAM-1, ICAM-1
• Acute phase reactants
• Critical for leukocyte localization |
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Term
| Basophils and anti inflammatory effects |
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Definition
inhibits:
• Cytokines
• Arachidonic acid derivatives • Histamine, LTC4
• Production/release ↓
• ↓ IgE dependent release |
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Term
| Fibroblasts anti inflammatory effects |
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Definition
inhibit:
• Arachidonic acid metabolites
• ↓ growth-factor induced DNA synthesis and fibroblast proliferation |
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Term
| lymphocytes anti inflammatory effects |
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Definition
inhibit: • Cytokines (IL-1,-2,-3,-6, TNF-α, GM-CSF, interferon-γ)
• Blocked production and release |
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Term
| Synthetic Glucocorticoids Short Acting (t1/2 = 8–12 hours) |
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Definition
| Cortisol (Hydrocortisone) and Cortisone |
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Term
| Synthetic Glucocorticoids Intermediate Acting (t1/2 = 12–36 hours) |
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Definition
| Prednisone, Prednisolone, Methylprednisolone, Triamcinolone |
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Term
| Synthetic Glucocorticoids Long Acting (t1/2 = 36–72 hours) |
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Definition
| Betamethasone Dexamethasone |
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Term
| Adrenocortical Steroid Toxicities |
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Definition
Withdrawal of therapy (adrenal suppression)
• Corticosteroid administration ≥2–4 weeks results in HPA axis suppression
• Abrupt discontinuation may result in:
1. Acute adrenal insufficiency (anorexia, nausea/vomiting, fever, myalgia, arthralgia, malaise)
2. Reappearance or increased intensity of symptoms of underlying disorder
• Patients vary with degree and duration of adrenal suppression post-glucocorticoid therapy
- Prolonged tapers from several weeks to months may be required
• Continued supraphysiologic glucocorticoid doses
Metabolic system:
• Hyperglycemia and glycosuria
• Fat redistribution (neck, face, trunk)
Immune system:
• Increased susceptibility to infections • Reactivation latent tuberculosis
Fluids and electrolytes:
• Hypokalemic, hypochloremic alkalosis • Hypertension
Growth and development:
• Growth retardation in children
• Antenatal administration and ? subtle fetal
deformations
Gastric:
• Peptic ulcer formation (especially with NSAIDs use)
Muscular:
• Myopathy, especially proximal limb weakness
Central nervous:
• Nervousness, insomnia
• Mood changes, hypomania, acute psychosis
Ocular:
• Cataracts
Bones:
• Osteoporosis • Osteonecrosis
Skin:
• Dermal thinning
• Acne formation
• Increased fine hair growth on the face, thighs, trunk |
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Term
| Glucocorticosteroid Indications |
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Definition
Adrenal
• Chronic adrenocortical insufficiency (Addison’s disease)
• Acute adrenocortical insufficiency
• Congenital adrenal hyperplasia
• Cushing’s syndrome |
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Term
Addison’s Disease
• Causes |
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Definition
Primary
• Structuralorfunctional lesions of the adrenal cortex
• Adrenalectomy
• Bilateraladrenal hemorrhage
• AIDS
• Inheriteddisorders
Secondary
• Structural/function llesions of the anterior pituitary or hypothalamus |
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Term
| Addison’s Disease Symptoms |
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Definition
• Weakness
• Fatigue
• Weight loss
• Hypoglycemia during fasting
• Hypotension
• Hyperpigmentation |
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Term
Addison’s Disease
• Treatment |
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Definition
• Hydrocortisone 20–30 mg daily in divided doses - Two-thirds in the a.m. and one-third in the afternoon
• Most patients require mineralocorticoid supplementation
- Fludrocortisone 0.05–0.2 mg/day
• Dose adjustments warranted during minor illness and major stress
• Overtreatment may cause manifestations of Cushing’s syndrome |
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Term
| Congential Adrenal Hyperplasia |
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Definition
Groupofgeneticdisorderscharacterizedby defects of cortisol synthesis
- 90% caused by mutations in CYP21 resulting in:
• Decreased cortisol synthesis
• Compensatory increase in ACTH
• Hyperplastic adrenals, ↑ 17-hydroxyprogesterone precursor
• Diversion to the androgen pathwayàvirilization, ambiguous genitals in female fetuses, precocious puberty
- Treatment requires replacement with hydrocortisone and fludrocortisone |
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Term
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Definition
• Primary cause: bilateral adrenal hyperplasia resulting from an ACTH- secreting pituitary adenoma
• Symptoms: same as chronic presence of excessive glucocorticoids
• Treatment: surgical removal of the ACTH secreting tumor or adrenal gland(s) |
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Term
| Non-Adrenal Glucocorticoid Indications |
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Definition
Collagen- vascular
• Lupus erythematosus
• Polymyositis
• Polymyalgia rheumatica
• Rheumatoid arthritis
• Temporal arteritis
Gastrointestin al diseases
• Inflammatory bowel disease
Hematologic
• Acquired/autoimmune hemolytic anemia
• Leukemia • Lymphoma
• Idiopathic thrombocytopenic purpura
• Multiple myeloma
Pulmonary
• Asthma
• Sarcoidosis
• Chronic obstructive pulmonary disease
Skin
• Atopic dermatitis • Dermatoses
• Seborrheic dermatitis
Bone and joint
• Bursitis
• Gout |
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Term
Rheumatic Disorders
• Systemic lupus erythematosus (SLE) |
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Definition
• Chronic autoimmune disease characterized by flares of inflammation in multiple organs
• Pathogenesis:
- Adaptive immune system • Formation of autoantibodies directed against nuclear structures in the cell
- Innate immune system • Dysfunction in innate immune system’s (phagocytes/complement) ability to remove apoptotic debris |
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Term
Systemic Lupus Erythematosus
• Glucocorticoid mechanisms of action:
Genomic pathway |
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Definition
- Gene transactivation
• Increasing transcription of anti-inflammatory genes via GRE on DNA
- Gene transrepression
• Interaction and inhibition of proinflammatory transcription factors (i.e. cytokines, chemokines, proinflammatory enzymes) |
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Term
Systemic Lupus Erythematosus
• Glucocorticoid mechanisms of action:
• Non-genomic pathway |
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Definition
• Glucocorticoid-receptor complex binds intracellular proteins causing rapid ↓ in inflammatory mediators (i.e., arachidonic acid)
• Glucocorticoid interactions with cellular and mitochondrial membranes
- Reduce essential ATP for immune cells to maintain function
• Interaction with membrane-bound glucocorticoid receptors
- Leads to rapid T-cell immunosuppressive action |
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Term
Rheumatic Disorders
• Rheumatoid arthritis |
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Definition
Most common inflammatory arthritis
- Characterized by:
• Synovial inflammation and swelling
• Auto-antibody production
• Cartilage and bone destruction
• Systemic features (cardiovascular, pulmonary, psychological, and skeletal disorders) |
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Term
| Rheumatoid Arthritis Endothelial cells and cell migration effect of glucocorticoids |
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Definition
• Inhibition of Ia antigen, ICAM-1, COX-2 expression
• Inhibition of NO, arachidonic acid metabolites,
angiogenesis
• Block endothelin receptor expression
• Stabilize vascular permeability
• Upregulation of lipocortin 1 |
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Term
| Rheumatoid Arthritis Monocytes, macrophages, neutrophils Effect of Glucocorticoids |
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Definition
• Inhibition neutrophil functions of superoxide generation, chemotaxis, adhesion, apoptosis, phagocytosis
• Decrease migration to inflammatory sites
• Inhibit macrophage antigen presentation to T
lymphocytes
• Suppress NF-kB and COX2
• Inhibit production of cytokines
• Induce lipocortin 1, lipomodulin, macrocortin |
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Term
| Rheumatoid Arthritis Eosinophils lymphocytes Effect of Glucocorticoids |
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Definition
• Decrease migration to sites of inflammation
• Lymphopenia induction due to redistribution of
lymphocytes
• Inhibit T cell function and natural killer cell activity |
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Term
| Rheumatoid Arthritis Fibroblasts Effect of Glucocorticoids |
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Definition
• Decrease proliferation and protein synthesis
• Decrease synthesis of metalloproteinases
• Inhibit IL-6, IL-8, GM-CSF |
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Term
| Rheumatoid Arthritis Bone Effect of Glucocorticoids |
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Definition
• Inhibit bone formation, osteoblast function
• Increase osteoclast life span and function |
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Term
| Rheumatoid Arthritis Cartilage Effect of Glucocorticoids |
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Definition
| • Increase glycosaminoglycan and DNA synthesis |
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Term
| Rheumatoid Arthritis Muscle Effect of Glucocorticoids |
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Definition
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Term
| Rheumatoid Arthritis Synovium Effect of Glucocorticoids |
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Definition
| • Decrease expression of collagenase, TNF, IL-8, ICAM- 1, hyaluronate |
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Term
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Definition
• Glucocorticoids:stabilizingagentsfor progressive disease
• Providereliefuntil,slower-actingdrugs (methotrexate, etanercept) take effect
• Typicalstartingdose:prednisone5–10mg/day - 20–40 mg/day during acute exacerbation
• Intra-articularsteroidinjectionscanbeusedin localized disease
- Triamcinolone acetonide 5–20 mg/joint (dose dependent on joint size) |
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Term
| Gastrointestinal Diseases |
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Definition
• Glucocorticoidsusedduringacutemoderate- severe exacerbations or when conservative management fails
- Bowel rest, diet, sulfasalazine
• Mildulcerativecolitis:hydrocortisoneretention enema
• Acuteexacerbations:10–30mg/dayoforal prednisone
• Severelyill(fever,anorexia,anemia,impaired nutrition): 40–60 mg/day oral prednisone |
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Term
Gastrointestinal Disease
• Corticosteroid molecular effects: |
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Definition
- Inhibition of early inflammatory events:
• Vasodilation
• Leukocyte infiltration
• Increased vascular permeability
• Release of inflammatory mediators (cytokines, prostaglandins, leukotrienes, histamine)
- Inhibition of later inflammatory events: • Fibroblast activation
• Vascular proliferation |
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Term
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Definition
Pulmonary disease characterized by airway inflammation and constriction
- Treatment may involve administration of:
• IV glucocorticoids and transitioning to oral therapy (severe asthma attack)
• Short oral pulse steroids administered (i.e., 30–60 mg PO prednisone daily for five days) for a less severe acute asthma exacerbation
• Inhaled glucocorticoid therapy for asthma maintenance |
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Term
Asthma
• Molecular effects of inhaled glucocorticoid therapy: |
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Definition
• Anti-inflammatory gene activation (transactivation)
- Increasedproductionofannexin1,interleukin10,andinhibitorof factor kappa B (ikB)
• Inhibiting inflammatory gene synthesis (transrepression)
• Inflammatory cell inhibition
- Decreasedmucosalinflammationcharacterizedbyfewer inflammatory cells (T lymphocytes, eosinophils, mast cells, and dendritic cells)
• Enhancement of beta-2 adrenergic signaling
- Increasebeta-2receptorexpressionandfunction |
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Term
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Definition
• Inflammatory dermal diseases treated with topical glucocorticoids
Treatment of choice for: Eczema
Contact dermatitis
Atopic dermatitis
Lichen planus
Lichen simplex chronicus
Chronic dermatitis Neurodermatitis
Insect and arthropod bites Burns and sunburns Keloids |
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Term
Dermatologic Conditions
• Mechanisms of anti-inflammatory action of topical glucocorticoids |
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Definition
Inhibition Phospholipase A2
• Decreased production of lipid mediators
• Prostaglandins, leukotrienes, platelet-activating
factor
Inhibition COX induction
• Decreased prostaglandin synthesis
Inhibition NO synthase
• Decreased nitric oxide production
Inhibition cytokine production
• Suppression cell-mediated inflammation
Inhibition mast cell activity and number
• Decreased levels of mast cell inflammatory mediators • Histamine, 5-HT
Vasoconstriction
• Decreased local blood flow |
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Term
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Definition
- Glucocorticoids used primarily in the management of:
• Acute lymphocytic leukemia • Lymphomas
- Mechanism of action:
• Induction of cellular apoptosis (programmed cell death)
• Antilymphocytic effects |
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Term
| primary mineralocorticoid in humans |
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Definition
Aldosterone:
• Synthesized in the zona glomerulosa of the adrenal cortex
- Secretion primarily regulated by angiotensin II and K+
• 100–200 mcg secreted daily
• t1/2 = 15–20 minutes
• Poor binding to serum proteins
• Metabolism: undergoes hepatic reduction and conjugation
- Metabolic products excreted renally |
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Term
| Mechanism of Mineralocorticoid Effect |
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Definition
Mineralocorticoid receptors expressed in tissues involved in electrolyte transport
• Epithelial
- Kidney, colon, salivary glands, sweat glands
• Nonepithelial
- Hippocampus, heart, vasculature, adipose tissues |
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Term
| Physiologic Effects: Water and Electrolyte Balance |
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Definition
• Aldosterone: potent effects on water/electrolyte balance
• Acts on the distal tubules and collecting ducts of the kidney
1. Enhances reabsorption of Na+ from tubular fluid
2. Increases urinary excretion of K+ and H+ |
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Term
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Definition
Here's a picture that's demonstrating how aldosterone works. Very similar to cortisol. As you'll see, on the outside of the cell, we have aldosterone and cortisol. Aldosterone is entering the cell, and it's able to work on the cellular nucleus. Cortisol tries to enter, but gets inactivated to cortisone by 11 beta HSD2.
Ultimately, when aldosterone enters, binds to that mineralocorticoid receptors, enters the cellular nucleus, binds to DNA response elements, and then it will up regulate release of sodium potassium ATPase pumps. What happens here, we see sodium entering back into the cell, potassium exiting the cell, and ultimately, again, water follows sodium and we'll have increased preservation of water in the body. |
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Term
Physiologic Effects: Water and Electrolyte Balance
Hyperaldosteronism |
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Definition
• Positive Na+ balance
• Increased extracellular fluid volume
• Normal/low K+
• Alkalosis
• Chronically leads to hypertension |
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Term
Physiologic Effects: Water and Electrolyte Balance
Hypoaldosteronism |
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Definition
• Na+ wasting, hyponatremia
• Decreased extracellular fluid volume
• Hyperkalemia
• Acidosis
• Leads to hypotension and vascular collapse |
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Term
| Physiologic Effects: Cardiovascular |
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Definition
Mineralocorticoid receptor activation in the heart and vessel walls leads to:
• Hypertension and interstitial cardiac fibrosis |
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Term
| Synthetic Mineralocorticoids |
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Definition
Short Acting (t1/2 = 8–12 hours): Cortisol (Hydrocortisone)
Intermediate Acting (t1/2 = 12–36 hours): Fludrocortisone |
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Term
| Select a common adverse effect of glucocorticoids. |
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Definition
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