Majority of cases

1. Cushing's Disease
2. Ectopic ACTH Syndrome

Functioning Adrenocorticoid Tumor

-primarily unilateral adrenal adenomas and/or adrenal carcinomas

• Pituitary overproduction of ACTH causing adrenal hyperplasia
• 85% are pituitary adenomas
• Women > men

• small cell carcinomas of the lung and bronchioles can release ACTH
• can have rapid onset and severe features
• Non-neoplastic corticotropin hypersecretion (increase CRH)

1. obesity
2. erythematous cheeks
3. rounded face
4. thin skin and easy bruising
5. HTN
6. osteopenia or fracture
7. menstrual irregularities
8. decreased libido

Which of the following is/are not a result of Cushing's?

1. increased cardiovascular risk
2. depression
3. impairment in short-term memory and cognition
4. all of the above are a result of Cushing's

4 is correct

impairment in short-term memory and cognition result from an apparent reduction in brain volume and can last for at least one year after treatment

1. 24 hr urine free cortisol
2. midnight plasma cortisol
3. low-dose dexamethasone suppression test (DST)

Which of the following is/are considered false-positive(s) in diagnosing Cushing's?

1. Addison's Disease
2. An infection
3. Hypercortisolemia
4. Secondary hyperaldosteronism
5. trauma
6. burns
7. hypotension

2,3,5,6,7

acute concurrent illness (burns, trauma, etc.) can increase ACTH secretion which results in an increase in cortisol by as much as a factor of six

Normal Level = 20-90 mcg/day

Cushing's = 2-3 x nl

Used to diagnose Cushing's

Stressors -- severe infection, burns, trauma, etc.

False positives -- digoxin, stressors, carbamazepine

Normal Level = 6 - 23 mcg/dl at 8am

Cushing's = midnight cortisol remains elevated

Used to diagnose Cushing's

False positives might occur with stressors

Premise: DEX is a synthetic steroid that suppresses ACTH secretion in normal individuals

DEX at 11 pm, take plasma level at 8 am

If AM cortisol < 1.8 mcg/dl -- NL

If AM cortisol elevated -- Cushing's

NL ACTH = 10-80 pg/ml

ACTH-Dependent = NL or elevated

Very high levels favor Ectopic production

Low levels favor ACTH-Independent

Premise: Patients with Cushing's not caused by adrenal tumors or ectopic production will suppress the HPA axis in the presence of glucocorticoids, but it takes much higher doses to suppress the HPA axis

DEX at 11pm, measure at 8am

If AM cortisol < 1.8 mcg/dl or NL = Cushing's

1. Steroidogenic Inhibitors (metyrapone, aminoglutethimide, ketoconazole)
2. Adrenolytic agents (Mitotane)
3. Neuromodulators of ACTH release (Cyproheptadine, bromocriptine, valproic acid, octroetide)
4. Glucocorticoid-Receptor Blocking Agents (Mifepristone)

1. metyrapone
2. aminoglutethimide
3. ketoconazole

1. cyproheptadine
2. bromocriptine
3. valproic acid
4. octroetide

Steroidogenic Inhibitor for Cushing's Disease

Inhibits 11beta-hydroxylase --> prevents conversion of 11-deoxycortisol to hydrocortisone

• Most frequently used as an adjunctive therapy to surgery and irradiation
• For compassionate use only

Steroidogenic Inhibitor for Cushing's Disease

Inhibits conversion of cholesterol to pregnenolone

Inhibits 11 beta hydroxylase (11-deoxycortisol to hydrocortisone)

Used short-term for inoperable patients

Can be combined in lower doses with metyrapone to reduce side effects

most are dose-dependent

nausea, ataxia, sedation, rash, profound adrenal insufficiency

Steroidogenic Inhibitor for Cushing's Disease

Inhibits 17 alpha hydroxylase (pregnenolone to 17 alpha hydroxypregnenolone)

Inhibits 11 beta hydroxylase (11-deoxycortisol to hydrocortisone)

Most effective inhibitor of steroid synthesis

May be used chronically

CYP2C19 Inhibitor -- significant drug interactions are common

increase LFTs, gynecomastia, GI upset, profound adrenal insufficiency

Andrenolytic for Cushing's Disease

Inhibits hydroxylation of 11-deoxycortisol (decreases cortisol) and 11-desoxycorticosterone (decreases corticosterone)

• Cytotoxic agent
• Requires hospitalization to initiate therapy due to intense reduction in cortisol (adrenal insufficiency)
• May continue as long as benefits are observed
• leads to degeneration of zona glomerulosa (alosterone) and zona fasciculata/reticularis (cortisol)

Neuromodulators of ACTH Release for Cushing's Disease

• Reserved for non-surgical candidate that fail most conventional therapy
• Patients need to be followed closely due to poor response rates and relapses
• Only effective in 30% of patients

Glucocorticoid-Receptor Blocking Agents for Cushing's Disease

• Glucocorticoid, androgen, and progesterone receptor antagonist
• Raises endogenous cortisol and ACTH values
• Limited clinical experience suggests efficacy in hypercortisol states
• Currently only recommended for inoperable conditions

24-hour urine free cortisol levels and serum cortisol levels are essential to monitor for efficacy and adrenal insufficiency

If adrenal insufficiency occurs, steroid replacement should be given as needed

Physiological abnormality is within the adrenal cortex

Most common causes: solitary adrenal adenoma, idiopathic adrenocorticol hyperplasia

Stimulation of the zona glomerulosa by an extra-renal factor

Usually stimulation from the renin-angiotensin system

other stimulators: hyperkalemia, oral contraceptives, pregnancy, menses, CHF, cirrhosis, renal artery stenosis

Enhances uptake of Na

Increased oxidative stress and collagen remodeling on non-epithelial tissue --> LVH, Fibrosis in heart, kidney, blood vessels

Primary hyperaldosteronism is associated with increased number of cardiovascular events compared with essential HTN

Most patients are asymptomatic

1. HTN
2. Mild-moderate hypokalemia
3. metabolic alkalosis
4. reduced glucose tolerance
5. muscle weakness and fatigue
6. headache

1. HTN and spontaneous hypokalemia
2. severe HTN (Stage 2 or > 160/100)
3. Patient on 3+ antiHTN meds
4. HTN in age < 20 yrs
5. whenever evaluation for secondary HTN considered
6. HTN relatives of patients with primary aldosteronism

Lab Values:

1. hypokalemia
2. high plasma and urinary aldosterone and low plasma renin
3. hypernatremia (> 142 mEq/L)
4. hypomagnesemia (< 1.6 mEq/L)
5. Metabolic Alkalosis (HCO3 > 31 mEq/L)

CT scans can detect majority of APA

Patients with APA tend to have: more severe HTN, more profound hypokalemia, higher plasma and urinary aldosterone levels

Laproscopic resection of the adenoma

If surgery contraindicated, use medical management

Mineralocorticoid Receptor Antagonist

First line therapy for Primary Hyperaldosteronism

• Avoided in men due to gynecomastia and sexual dysfunction -- drug has high affinity for androgen and progesterone receptor at higher doses
• GI discomfort, impotence, menstrual irregularities

Mineralocorticoid Receptor Antagonists for Primary Hyperaldosteronism

gynecomastia and sexual dysfunction are less compared to spironolactone

K+ Sparing Diuretic for Primary Hyperaldosteronism

prevents aldosterone-induced endothelial edema

possible DOC in men and those intolerance to spironolactone

AKA Addison's Disease

Destruction of all regions of the adrenal cortex

Deficiences in:

glucocorticoid (cortisol)

mineralcorticoid (aldosterone)

adrenal androgens

Overall excess of ACTH

90% of adrenal cortex destroyed before symptoms occur

1. Idiopathic autoimmune -- present with one or more clinical disorders involving multiple endocrine organs (ovary, thyroid, pancreas, parathyroid)
2. Tuberculosis
3. Other adrenal functions
4. Infiltrative diseases/tumors
5. adrenal hemorrhage

• Suppression of hypothalamic-pituitary-adrenal (HPA)-axis and decreased released of ACTH --> deficiences in cortisol and androgens
• Deficiency in glucocorticoids only
• Aldosterone usually preserved
• Chronic suppression may cause atrophy of the ant. pit. and hypothalamus impairing recovery following discontinuation of exogenous agent

• Exogenous steroids (most common): oral, inhaled, intranasal, topic
• Other drugs: ketoconazole, phenytoin, phenobarbital, progestins (medroxyprogesterone, megestrol)

1. hypotension
2. hyperpigmentation
3. hyperkalemia
4. hyponatremia
5. fasting hypoglycemia

Establishing hypocortisolism when diagnosing Secondary AI can be done with which tests?

1. AM serum cortisol levels
2. 24 hr urine free cortisol
3. midnight plasma cortisol
4. ACTH stimulation test
5. Insulin tolerance test
6. Low or High dose DEX suppression test

1, 4, and 5

2 and 3 are for diagnosing hypercortisolism

low dose DEX supp is for diagnosing hypercortisolism and high dose DEX supp is for differentiating etiologies for hypercortisolism

Normal AM cortisol = 10-20 mcg/dl

levels < 3 mcg/dl= highly suggestive of AI

levels < 10 mcg/dl = further evaluation

measure baseline AM cortisol, give corticotropin injection, measure cortisol at 30 and 60 min post-injection

total cortisol > 18-20 = excludes primary AI but not secondary AI

total cortisol < 18-20 = AI

measure baseline AM cortisol, give insulin IV, measure cortisol at 30, 60, and 90 min post-injection

total cortisol < 18-20 = AI

• hyperpigmentation usually not seen in secondary AI
• aldosterone secretion is usually preserved in secondary AI
• weight loss, dehydration, hyponatremia, hyperkalemia, and elevated BUN are common in Primary AI

administer lowest dose possible

BID to try and mimic diurnal variation

In order to replace mineralocorticoid loss for the treatment of Addison's disease, which agent should be used?

1. Cortisone
2. Aldosterone
3. Pregnenolone
4. Fludrocortisone