Corticosteroids

Question 1

Zona glomerulosa secretes:

Answer 1

Aldosterone.

Question 2

Zona fasiculata secretes:

Answer 2

Cortisol (glucocorticoid).

Question 3

Zona reticularis secretes:

Answer 3

DHEA and androstenedione.

Question 4

Corticosteroid MOA:

Answer 4

Bind to cytoplasmic receptor, which is a ligand activated transcription factor.
- Takes time, not a rescue drug.

Question 5

Glucocorticoid effects on metabolism:

Answer 5

Glucose regulation, induce hyperglycemia:
- Liver increases glucose synthesis and glycogen storage.
- Peripheral tissues: protein breakdown, decreased utilization of glucose, lipolysis, decreased uptake of glucose.
Fats, redistribution of body fats:
- Round face and back fat.
- Marked central obesity, reduced peripheral fats.

Question 6

Glucocorticoid effects on calcium balance:

Answer 6

Induces a negative calcium balance, decreases calcium uptake in the gut, increase calcium secretion by the kidney.

Question 7

Glucocorticoid effects on cardiovascular and blood:

Answer 7

Most glucocorticoids have some mineralocorticoid activity, sodium excretion can promote HTN.

Question 8

Glucocorticoid effects on inflammation:

Answer 8

Reduces NF-kappa-B levels - inhibits:
- Proteolytic enzymes, vasoactive and chemoatractant factors.
- Pro-inflammatory enzymes such as COX-2 and NOS.
Stimulates the synthesis of lipocortin, inhibits phospholipase A2 activity, decreases arachidonic acid release and subsequent production of ecosanoids.
(Main non-endocrine use.)

Question 9

Glucocorticoid effects on endocrine:

Answer 9

• Inhibits TSH release, can lead to misinterpretation of TSH assays for hyperthyroidism.
• Decrease serum levels of TBG.
• Decreased T3 levels.
• Inhibit growth via inhibition of IGF-1
• Prolonged –> inhibits FSH and LH surges

Question 10

Glucocorticoid effects on bone/connective tissue/skin:

Answer 10

• Inhibits osteoblast function.
• Decreases collagen and osteocalin synthesis.
• Increased bone reabsorption (promotes osteoporosis).
• Inhibits fibroblast function.
• Decreased synthesis of collagen, fibronectin etc. (promotes stria and bruising).

Question 11

Mineralocorticoid effects:

Answer 11

Water and ion balance:
- Increased Na/K ATpase expression on distal tubules and collecting duct to enhance Na+ and water reabsorption and K+ secretion.

Question 12

Pseudo Cushing’s:

Answer 12

Physiological hypercortisolism associated with disorders other than Cushing’s syndrome:

• Significant physical inflammatory stress.
• Severe obesity.
• Malnutrition, anorexia nervosa, intense chronic exercise.
• Psychological stress, severe MDD
• Chronic alcoholism.

Question 13

Cushing syndrome - ACTH dependent:

Answer 13

Associated with excessive ACTH secretion leading to adrenocortical hyperplasia:

• Cushing’s disease (pituitary hypersecretion of ACTH).
• Ectopic secretion of ACTH by nonpituitary tumors.
• Ectopic secretion of CRH by nonhypothalamic tumors.
• Iatrogenic or factitious Cushing’s syndrome due to administration of exogenous ACTH.

Question 14

Cushing syndrome - ACTH independent:

Answer 14

Iatrogenic or factitious Cushing’s syndrome.

• Most commonly due to long term glucocorticoid use.
• Adrenocortical adenomas and carcinomas.
• Primary pigmented nodular adrenocortical disease (PPNAD).
• Bilateral macronodular adrenal hyperplasia (BMAH).

Question 15

Cushing’s syndrome - symptoms:

Answer 15

• Central obesity, round “moon face”, “buffalo hump”.
• Excessive sweating.
• Muscle wastage.
• Skin striae
• Neurological complaints:
  
  • Euphoria.
  • Psychosis.
  • Depression.

Question 16

Cushing’s syndrome - diagnosis:

Answer 16

• Rule out exogenous glucocorticoids/pharmacological reasons.
• 24 hour urine cortisol.
• Late night salivary cortisol.
• Dexamethasone test.
• Metyrapone test.

Question 17

Dexamethasone test - low dose:

Answer 17

Differentiates if Cushing’s or not:

- If Cushing’s no suppression of cortisol.

Question 18

Dexamethasone test - high dose:

Answer 18

Differentiates type of Cushing’s:

• ACTH undetectable but no suppression of cortisol: adrenal tumor.
• ACTH elevated and no suppression of cortisol: ectopic ACTH syndrome.
• ACTH normal to elevated and suppression of cortisol: Cushing’s disease.

Question 19

Cushing’s syndrome - pharmacological approach (2):

Answer 19

1. Block and replace.
   - Patients with erratic cortisol secretion.
2. Normalization.
   - Patients with invariant hypercortisolism.

Question 20

Ketoconazole:

Answer 20

• Antifungal
• At higher doses than antifungal therapy: inhibits CYP17.
  
  • Inhibits glucocorticoid and androgen synthesis.
• Even higher doses: inhibits CYP11A1.
  
  • Inhibits corticotroph adenylate cyclase activation.
  • Reduces ACTH secretion at therapeutic doses.
• Drug interactions: inhibits CYP1A2, CYP2C9, CYP3A4.
• Co-administration with ergot derivatives, cisapride or triazolam is contraindicated –> fatal cardiac arrhythmias.

Question 21

Metyrapone:

Answer 21

• MOA: selective inhibitor of CYP11B1 reducing the biosynthesis of cortisol.
• Use: hypercorticism resulting from adrenal neoplasms or tumors producing ACTH; diagnostic test for Cushing’s syndrome.
• Side effects: Hirsutism, nausea, headache, sedation and rash.
  
  • Hirsutism due to increased synthesis of adrenal androgens upstream from the enzymatic block.

Question 22

Mitotane:

Answer 22

• Acts on CYP11B1 and CYLP11A1 enzymes.
• Causes mitochondrial destruction and necrosis of adrenocortical cells.
• Has long term effect.
• Not used in pregnancy.
• Need to supplement with exogenous glucocorticoids.

Question 23

Mifepristone (RU-486):

Answer 23

• MOA: inhibits the release of the glucocorticoid receptor from the HSP chaperone proteins.
  
  • Reduces transcriptional effects of glucocorticoids.
  • Progesterone antagonist (abortion pill).
• Use: controlling hypercortisolism in patients with Cushing’s syndrome caused by inoperable ACTH tumors, adrenal carcinomas unresponsive to other therapies.
• Side effects: vaginal bleeding, headache, dizziness, abdominal pain, nausea, vomiting, diarrhea and abdominal cramps.
• Drug interactions: increased metabolism of some drugs.

Question 24

Adrenal insufficiency - Primary:

Answer 24

• Structural or functional deficiency of the adrenal cortex (Addison’s disease). High ACTH levels and low glucocorticoids and mineralocorticoids.

Question 25

Primary adrenal insufficiency treatment:

Answer 25

Combination of glucocorticoids and mineralocorticoids required. - Hydrocortisone or cortisone preferred. - Supplementation with fludrocortisone for mineralocorticoid effect.

Question 26

Cosyntropin test:

Answer 26

Used to determine between primary and secondary adrenal insufficiency. - Primary = ACTH levels high but low cortisol levels. - Symptoms: weakness, wt loss, anorexia, HTN, *dark skin pigmentation*, hyponatremia. - Secondary = baseline ACTH low and cortisol levels low - Symptoms: malaise, anorexia, *no hyperpigmentation*.

Question 27

Secondary adrenal insufficiency:

Answer 27

Pituitary or hypothalamic deficiency. | - Low ACTH and low-normal glucocorticoids/androgens, normal mineralocorticoids.

Question 28

Secondary adrenal insufficiency treatment:

Answer 28

Hydrocortisone, cortisone or prednisone. | - Mineralocorticoid not needed.

Question 29

Acute adrenal insufficiency:

Answer 29

Life threatening, should also consider isotonic NaCl and glucose therapy in conjunction with steroids.

Question 30

Congenital adrenal hyperplasia (CAH):

Answer 30

- Deficiency in CYP21 most common. - Reduced levels of corticosteroids. - Increased 17-hydroxyprogesterone (clinical test), DHEA and androgens due to lack of feedback inhibition and excess ACTH. - Classic-severe deficit: - Females - pseudohermaphroditism. - Males - normal at birth, precocious puberty. - Non-classic: post puberty presentation. - Treat with corticosteroids, females with classic can be treated in utero.

Question 31

Aldosteronism:

Answer 31

Excessive production of aldosterone leading to HTN and hypokalemia. - Most common: aldosterone producing adenomas and bilateral idiopathic hyperaldosteronism. - Less common: Unilateral hyperplasia, adrenal hyperplasia, familial or pure aldosterone producing carcinomas and tumors. - Tx: Surgery, aldosterone antagonist.

Question 32

Spironolactone (aldactone) side effects:

Answer 32

- Breast tenderness and menstrual irregularities in women. | - Impotence, decreased libido and gynecomastia in men.

Question 33

Most anti-inflammatory potent glucocorticoids (2):

Answer 33

1. Betamethasone. | 2. Dexamethasone.

Question 34

Glucocorticoid with the highest relative mineralocorticoid potency:

Answer 34

Fludrocortisone.

Question 35

Longest lasting (half-life) glucocorticoid:

Answer 35

Betamethasone. | Dexamethasone.

Question 36

Cortisol-cortisone shuttle:

Answer 36

- HSD1 activates (cortisone --> cortisol). | - HSD2 deactivates (cortisol --> cortisone).

Question 37

Cushing's syndrome common signs:

Answer 37

- Cardio: HTN, edema, Na and water retention, hypokalemia. - CNS: euphoria, depression, psychosis, insomnia. Immune: increased susceptibility esp viral and fungal. - GI: peptic ulcer. - Metabolic: hyperglycemia, muscle catabolism, hyperlipidemia, altered fat deposition, striae. - Eye: cataracts, glaucoma. - Osteoporosis: negative Ca balance; inhibition of osteoblasts.