Cushings - HYPERfunction of the adrenal glands, excess secretion of cortisol.  Another example of HYPERfunctioning is primary and secondary aldosteronism

Addison's - HYPOfunction by primary or secondary means.  The adrenal glands do not produce enough cortisol or, in some cases, aldosterone

ACTH-dependent - Overproduction of ACTH by the pituitary gland, causing too much release of cortisol (80% of the time caused by pituitary adenomas, 20% of time by ectopic ACTH secreting tumors and other causes

Ectopic ACTH syndrome - Excessive ACTH producting resulting from an endocrine or nonendrocrine tumor, usually of pancreas lung or thyroid origin

ACTH independent - Usually by adrenal adenoma or carcinoma

- Central obesity and facial rounding (90%)

- Moon faces and buffalo hump (50%)

- Myopathies (65%) or muscle weakness (85%)

- Red or purple striae on lower abdromen

- HTN in almost 85% of patients, diastolic pressure >119mmhg in 20%

- Glucose intolerance in 60%

- Psychiatric changes in 55%

- Cushing-induced osteoporosis, 40% present with back pain and 20% will progress to fractures

- Amenorrhea (sx of gonadal dysfunction) present in 75% of women

- Excess androgen production (and subsequent hirsutism) in 80% of women

Tests: Midnight plasma cortisol, 11pm salivary cortisol, 24-hour urine free cortisol and/or low dose dexamethasone suppression test

Other tests: high dose dexamethasone suppression test, plasma ACTH test, metyrapone stimulation test, corticotropin releasing hormone stimulation test or inferior petrosal sinus sampling

Abnormal adrenal anatomy can be identified using high res computed tomography scanning and perhaps MRI

- Treatment of choice for both ACTH dependent AND independent cushing's is surgical resection of offending tumors

- Pituitary irradiation provides clinical improvement in about 50% of patients, but this improvement may not be seen for 6-12 months and pituitary-dependent hormone deficiencies can occur

- For ectopic ACTH syndrome

- 0.5-1g/day, divided every 4-6 hours

- Inhibits 11-hydroxylase activity, resulting in inhibition of cortisol synthesis

- Initial increase in ACTH because of decreased cortisol

- Rxns include n/v, vertigo, rash, and abdominal discomfort

- For ectopic ACTH syndrome

- 0.5-1g/day, either bid or qid

- Inhibits cortisol synthesis by blocking conversion of cholesterol to pregnenolone early in the pathway

- Rxns are severe sedation, ataxia, nausea, and skin rashes

- Effects seem to be dose dependent

- Limited efficacy, relapse after d/c

Note: Combo therapy of Aminoglutethemide and Metyrapone are more effective than either agent alone when used for various etiologies of cushings and with fewer side effects, useful for inoperable patients

- Adrenal adenoma --> surgery, postoperative replacement

- Also called Nizoral

- 200mg qd or bid

- Inhibits variety of P450 enzymes, including 11 and 17-hydroxylase.  Highly effective in lowering cortisol, patient can use for months to years

- Adverse effects are reversible elevation of hepatic transaminases and  GI upset

- Can cause gynecomastia and lower plasma testosterone

- Adrenal carcinoma --> Surgery

- Imidazole derivative similar to ketoconazole, inhibits 11-hydroxylase

- Available only in parenteral, use limited to those waiting for surgery

- Adrenolytic agent

- Inhibits the 11-hydroxylation of 11-desoxycortisol and 11-desoxycorticosterone in the adrenal cortex

- Reduced cortisol and corticosterone

- Decreases cortisol secretion rate, plasma cortisol concentrations, urinary free cortisol, and plasma concentrations of 17-substituted steroids

- Degeneration of cells within zona fasciculata and reticularis occurs with resultant atrophy of adrenal cortex

- zona glomerulosa is minimally affected initally but can become damaged with long term treatment

- Severely reduces cortisol, so hospitalize patients before therapy and continue as long as clinical benefits occur

- N/D at >2g/day, lessen by slowly titrating up or taking with food.  Other common effects are lethargy, , somnolence, and other CNS effects, reversible hypercholesteremia

Note: None of the neuromodulators of ACTH release as demonstrated consistent clinical efficacy, combo therapy may work better than only one agent

- Pituitary dependent --> surgery, radiation

- Dose 4mg bid

- Brand Periactin

- Decreases ACTH secretion, monitor plasma cortisol and 24 hour urine free cortisol

- Effects include sedation and hyperphagia

- reserve for nonsurgical candidates who fail convential therapy

- Response rate no more than 30%, so follow closely for relapses

- Reduce ACTH secretion through inhibition of transcriptional activities, limited to animal models

Other neuromodulatory agents: Bromocriptine, Cabergoline, valproic acid, octreotide, and rosiglitazone

- Progsterone, androgen, and glucocorticoid receptor antagonist

- Inhibits dexamethasone suppression and increases endogenous cortisol and ACTH in normal subjects.  

- Limited experience, but could be highly effective in reversing manifestations of hypercortisolism

- Commonly referred to as adrenal insufficiency

- Most often involves destruction of all regions of the adrenal cortex

- There are deficiencies of cortisol, aldosterone, and various androgens

- Medications that inhibit cortisol production, such as ketoconazole, or accelerate cortisol metabolism (phenytoin, rifampin, phenobarbital) can also cause adrenal insufficiency

- Secondary insuffiency is most commonly caused by exogenous corticosteroid consumption, which suppresses the hypo-pituitary-adrenal axis, which results in decreased ACTH.  Mirtazipine and progestins can cause this

- Weight loss, dehydration, hyponatremia, hyperkalemia, and elevated BUN

- hyperpigmentation is common and may affect exposed and nonexposed parts of body

- Much more common in primary, higher amounts of melanocyte-stimulating hormone

- Short cosyntropin-stimulation test can be used to assess patients with suspected hypocortisolism.  Cortisol increase to > 18mcg/dL rules out adrenal insufficiency

- Patients with Addison's have an abnormal response to the short cosyntropin-stimulation test; plasma ACTH levels are 400-2000 pg/ml in primary insuffiency vs normal to low 0-50pg/ml in secondary deficiency.  In short, a false test does not rule out secondary insuffiency

Other tests: Insulin hypoglycemia test, metyrapone test, and corticotrophin releasing hormone test

What is the pharmacotherapy of adrenal insuffiency?

Drug-> anti-inflam-> equiv pot -> half-life -> sodium ret

Cortisone               0.8       25mg     30m           2

Hydrocortisone        1         20mg      90m          2

Prednisone             3.5       5mg       60m          1

Prednisolone           4         5mg       200m         1

Triamcinolone          5         4mg      300m          0

Methylprednisolone  5         4mg      180m          0

Betamethasone       25       0.6mg    100-300m    0

Dexamethasone      30        0.75mg   100-300m   0

- Hydrocortisone, Cortisone, and prednisone are glucocorticoids of choice, administered twice daily at lowest effective dose while mimicking  the normal diurnal rhythm of cortisol production

- Starting doses: hydrocortisone 15mg, cortisone acetate 20mg, prednisone 2.5mg; give two-thirds dose in the morning and one-third at night

- Monitor patient symptoms every 6-8 weeks

- Use fludrocorticoid acetate (0.05mg - 0.2mg) orally once daily for mineralcorticoid replacement.  If parenteral, 2-5mg of deoxycorticosterone trimethylacetate  in oil IM, every 3-4 weeks.  The major reason for giving a mineralcorticoid is to minimize hyperkalemia

- Add 5-10mg of hydrocortisone shortly before exercise

- During times of physical stress (febrile illness, accidents) patients should double their dose until recovery

- Treatment of secondary adrenal insufficiency is identical to primary, except that mineralcorticoid replacement is usually not necessary

- Adrenal crisis is a true emergency

- Caused by extreme stress to body that increases adrenal requirements

- Most common cause is abrupt withdrawal of glucocorticoid therapy

- Hydrocortisone given because of combined gluco/mineralcorticoid activity, 100mg by rapid infusion then 100-200mg/24 hours, continue for 24-48 hours, if stable can give PO HC 50mg tid for 48 hours, slowly taper dose

- Fluid replacement with 5% dextrose in normal saline is often required to maintain blood pressure

- If hyperkalemia is present after hydrocortisone phase add fludrocortisone 0.1mg qd

- End point of therapy is difficult to assess, but look for signs of cushings (excess therapy) and a reduction in pigmentation caused by Addison's