E4: Adrenals Flashcards
Describe the structure of the Adrenal gland layers & their products from superficial to deep.
Superficial: Capsule
Adrenal Cortex;
- Zona Glomerulosa: Mineralocorticoids (Aldosterone)
- Zona Fasiculata: Glucocorticoids (Cortisol)
- Zona Reticularis: Weak Androgens (DHEA)
Adrenal Medulla: Catecholamines (Epinephrine & Norepinephrine)
Describe the basic regulation of Adrenal Cortex hormones
- Stimuli (i.e. Stress) triggers release of Corticotropin Releasing Hormone from the Hypothalamus
- CRH induces Prepro-Opiomelanocortin (POMC) release from the anterior pituitary
- POMC is converted to Adrenocorticotropin Hormone (ACTH)
- ACTH induces release of Aldosterone, Cortisol, & DHEA from the Adrenal Cortex
Negative Feedback:
- Cortisol inhibits;
- CRH release from Hypothalamus
- POMC/ACTH release from Anterior Pituitary
Explain Cortisol Signal transduction
Steroid signaling: Cortisol ex.
- Cortisol travels through bloodstream bound to Corticosteroid-binding Globulin (CBG)
- It enters the cell as a free molecule
- Intracellular receptor is bound to stabilizing proteins
- 2 Heat shock protein 90 (HSP90) & others
- Cortisol binds to the receptor, forcing the stabilizing proteins to dissociate
- This also allows the complex to dimerize with another Cortisol-receptor complex
- The Dimerized complex enters the nucleus & binds to a Glucocorticoid response Element (GRE) of the gene
- Facilitates transcription by RNA Polymerase II & ass. TF’s
How do Cortisol levels vary throughout the day?
How does that compare to glucocorticoid sensitivity variation in target tissues?
Plasma cortisol levels vary throughout the day, relative to the circadian rhythm
- Highs in the morning ~8am, & decreasing throughout the day
- Begins rising again during nighttime
Tissue sensitivity to Glucocorticoids (Cortisol) also varies based on Glucocorticoid Receptor (GR) acetylation via CLOCK (TF)
- Degree of GR acetylation mirrors the pattern of Cortisol level variation
- i.e. As Cortisol levels drop, so too does Acetylation of GR
- Thus, Tissue sensitivity is Inversely related to GR Acetylation & Cortisol levels.
Review Glucocorticoid principle & Adverse effects
How do Glucocorticoids affect the inflammatory response?
Antiinflammatory Actions:
Macrophages
- ↓ Activation
- ↓ Cytokine Synthesis & Release
Neutrophils
- Stabilize lysosomal membranes
- Prevent release of catabolic enzymes
Mast cells
- ↓ Release of Histamine, PG’s, & Leukotrienes
- ↑ Transcription of Annexin-1
Eosinophils
- ↓ Release of Histamine, PG’s, & Leukotrienes
- ↑ Transcription of Annexin-1
T-cells
- ↓ Activation
- ↓ Cytokine Synthesis & Release
How are the Corticosteroid drugs categorized?
Examples?
Categorized based on duration of action:
Short-Acting (8-12hr): Cortisone
Intermediate-acting (12-36hr): Prednisone
Long-acting (24-72hr): Dexamethasone
*Fludrocortisone is classified as a mineralocorticoid due to it’s salt-retaining potency.
Describe the diagnostic strategy for an individual with high Cortisol
- Measure ACTH Levels
- Low ACTH = Adrenal Adenoma; producing extra Cortisol
- High ACTH -> High Dose Dexamethasone Suppression Test
- High Dose Dexamethasone Suppression Test
- Suppress Cortisol >50% = Pituitary Adenoma
- No Suppression = Ectopic Origin
What are the characteristics of Cushing’s Disease?
Cushing’s Syndrome:
- Due to excess adrenal Steroids
Characteristics:
- Moon face; Red Cheeks
- Fat pads (buffalo hump)
- Thin skin; Bruisability (Ecchymoses); Red skin striations
- Pendulous abdomen
- Thin arms & legs
- High blood pressure
- Poor Wound healing
Describe the characteristics of Addisons’s disease
Addisons Disease:
- inadequate adrenal steroid production
Characteristics:
- Skin: Hyperpigmentation; Vitiligo
- GI: Nausea, Diarrhea, Vomiting, Constipation, abdominal pain
- Other: Low BP, Weakness, Weight loss
Adrenal Crisis:
- Fever
- Syncope
- Convulsions
- Hypoglycemia
- Hyponatremia
- Severe vomiting & diarrhea
Fludrocortisone
What is it?
Fludrocortisone:
a short-acting mineralocorticoid drug that is used to supplement hydrocortisone (cortisol) treatment in patients with adrenal insufficiency.
What are the actions of Glucocorticoids?
Actions:
- ↑ Gluconeogenesis
- ↑ Protein and lipid catabolism
- ↑ Body’s resistance to stress.
- ↓ Reduce inflammation by inhibiting the migration of leukocytes and the production and release of cytokines, prostaglandins, leukotrienes
- Stabilize lysosomal membranes
- Cause Vasoconstriction
What are the adverse effects of Glucocorticoids?
Adverse effects;
- Fat accumulation in the face and trunk
- Muscle wasting
- Skin changes
- Glucose intolerance
- Potassium depletion
- Osteoporosis
- Hypertension
- Cataracts
What are the clinical uses of Glucocorticoids?
Glucocorticoid Clinical Uses:
•Primarily used as antiinflammatory and immunosuppressive drugs in the treatment of a wide range of allergic, inflammatory, and autoimmune disorders.
In patients with Primary adrenal insufficiency (Addison disease) & congenital adrenal hyperplasia:
- Used as replacement therapy
In patients with acute allergic reactions;
- Glucocorticoids are initially given in large doses, then rapidly tapered & eventually discontinued
In patients with severe autoimmune and inflammatory diseases;
- Large doses of prednisone or other glucocorticoids may be required for several months
- Alternate-day therapy is preferred for their long-term administration
Generally administered topically to treat skin, mucous membrane, and ocular disorders and by inhalation to treat allergic rhinitis and asthma
•Topical steroids for treating dermatologic conditions include
- •Low Potency: Desonide
- •Medium Potency: Triamcinolone & fluticasone
- •High Potency: Desoximetasone
- •Very High Potency: Clobetasol
How do synthetic glucocorticoids compare to endogenous cortisol?
Synthetic Glucocorticoids:
•In comparison with cortisol, most have increased glucocorticoid potency & decreased mineralocorticoid potency.
