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25 Cards in this Set

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Cushing's Syndrome:
Symptoms
Central obesity
Facial plethora (redness)
Dorsocervical fat deposits (buffalo hump)
Moon facies
HTN
Menstrual irregulatirites
Hirsutism
Glucose intolerance
Why "central" obesity in Cushing's Syndrome?
Glucocorticoid excess causes muscle atrophy (makes extremities look thin)

HSD1 (Cortisone-->Cortisol) is present in large quantities in abdominal fat
Why does hypertension arise in Cushing's Syndrome?
Inc'd sensitivity to catechols and AgII in vasc smooth muscle
Inc'd Angiotensinogen
Sodium retention from mineralocorticoid activity
How can cortisol act as a mineralocorticoid?
Mineralocorticoid = Aldosterone

Cortisol is an agonist of mineralocorticoid receptors in kidney but is deactivated by HSD2 (guardian)

In Cushing's there's so much cortisol that HSD2 is overwhelmed and interacts with mineralocorticoid receptor.
What features are specific to Cushing's Syndrome?
Central Obesity
Proximal muscle weakness
Wide purple striae
Spontaneous ecchymoses
Facial plethora
Hypokalemic ALKALOSIS
Cushing's Syndrome:
ACTH-dependent vs ACTH-independent
ACTH-dep: Pituitary adenoma, Ectopic ACTH or CRH

ACTH-ind: Adrenal tumors (or hyperplasia), or exogenous ACTH/Cortisol (most common cause of CS)
CS due to Cushing's Disease:
Lab values
Causes
ACTH-secreting pituitary adenoma (autonomously acting, no feedback inhibition despite high cortisol)

HIGH ACTH
HIGH Cortisol
CS due to Ectopic ACTH:
Lab values
Causes
Labs:
HIGH Cortisol
Suppressed Pituitary ACTH (but not ectopic ACTH)

Causes:
SCC
Bronchial carcinoid tumors
Neuroendocrine tumors
Medullary thyroid carcinoma
Pheochromocytoma
CS due to Adrenal Tumor:
Lab values
Causes
Labs:
LOW ACTH
HIGH Cortisol

Cause:
Benign (adenoma) or malignant (carcinoma) neoplasms of adrenal origin (ACTH-independent) produce cortisol
Describe ACTH-independent macronodular adrenal hyperplasia.
Receptors on glucocorticoid cells supposed to have ACTH receptors to drive cortisol production

In this disorder have aberrant receptors that bind other hormones (GIP, catechols, LH/hCG, vasopressin)--thus can develop with pregnancy, or with eating (GIP receptors)

THIS IS RARE RARE RARE
What is the most common cause of Cushing's Syndrome?
Exogenous corticosteroids

(can minimize effects with local routes, e.g., topical, nasal)
Megesterol is used to treat metastatic breast cancer, but can also act as an ____________ to ______.
Acts as an agonist at Glucocorticoid Receptor and cause CS

Promiscuous!
Describe Pseudo-Cushing's Syndrome.
Stress states activate HPA axis and cause cortisol excess (EtOH, depression, eating disorders, chronic pain)
Describe the overnight low dose dexamethasone suppression in screening CS.
Low dose dexamethasone (synthetic glucocorticoid) will suppress normal HPA, but NOT cortisol in a patient with CS (won't inhibit adenoma or ectopic tumor, but will inhibit normal pituitary)

So administer dexameth at night and measure cortisol the next morning
Describe Urine Free Cortisol Collection in screening CS.
Most useful test

Not effected by cortisol binding globulin levels (Oral Contraceptives)

Patients terrible at collecting urine.

Should find inc'd unbound (free) cortisol (inc'd cortisol filtered by kidney and excreted)
50% of women on oral contraceptives have a false-positive __________.
Dexameth suppression test
Describe bedtime salivary cortisol in screening CS.
Cortisol nadir at midnight

As develop CS, lose circadian rhythm, and don't get nadir at midnight

If saliva collected at midnight and cortisol NOT low, there's a problem.
What is the general recommendation for screening test(s) selected for CS?
Perform either multiple runs of the same test

OR

Perform multiple tests
If suspect someone has CS (positive screen), what test do you run?
Look into this

Measure ACTH:

If adrenal tumor--> LOW (suppressed)

If ectopic-->high

If CD-->inappropriately normal (SHOULD BE SUPPRESSED)

You may now run imaging tests!
When is imaging for CS NOT reliable?

What test compensates for this?
ACTH-dependent CS
(pit MRI normal in up to 50% pts w/ACTH secreting pituitary adenoma)

HIGH Dose Dex can suppress adenoma's production of ACTH by 50% or more

but will not suppress MOST (!) ECTOPIC ACTH-secreting tumors
Describe CRH test.
Give CRH:
ACTH-secreting pit adenoma will INCREASE

MOST ectopic ACTH-producing tumors will be unresponsive
What does inferior petrosal sinus sampling determine?
Whether pituitary is source of ACTH.

If pituitary is source, ratio of pituitary ACTH to peripheral ACTH will be HIGH

If ectopic is source, ratio will be 1 (pituitary ACTH is suppressed)
1st line treatment of CS due to Pituitary Adenoma.
Resect pituitary Tumor

If not curative:
Irradiate
B/L Adrenalectomy
Antiadrenal agents (ketoconazole)
Antiadrenal Drugs:
Examples
Metyrapone (inhibits last step of cortisol biosynthesis)
Ketoconazole (interferes with adrenal steroidogenesis)

Often used in combination.

Mitotane (tumoricidal, cousin of DDT, used for adrenal carcinoma; HORRIFIC AE's. Adrenal carcinoma is likely fatal)
What is Nelson's Syndrome?

When does this occur?
Growth of adenoma is being restrained by high levels of cortisols it's producing

If remove the cortisol but leave tumor, get unrestrained growth of adenoma

(Remember: adenoma is responsive to HIGH levels of hormone)

Occurs when b/l adrenalectomy is used as tx for CS