Adrenal

Question 1

What are primary causes of adrenal insufficiency?

Answer 1

Addison’s disease (most common)
CAH
Infection
1. TB
2. Histoplasmosis
3. HIV
Hemorrhagic infarction
Metastatic disease
1. Breast
2. Lung
Drugs (inhibit cortisol synthesis)
1. Etomidate
2. Ketoconazole/fluconazole

Question 2

What are secondary causes of adrenal insufficiency?

Answer 2

Exogenous steroid exposure (most common, decreased ACTH w/ adrenal atrophy)
Sheehan’s syndrome
Pituitary tumor s/p resection

Question 3

How do you diagnose Addison’s disease?

Answer 3

• Morning serum cortisol concentration (< 3 mcg/dL) & ACTH
• Short ACTH stimulation test (high vs low dose) - cortisol will fail to rise in primary adrenal insufficency; will be >2x in 30min if 2º

Question 4

What is Addison’s disease and what is the prevalence of concomitant autoimmune disease? POI?

Answer 4

Autoimmune process that destroys adrenal cortex

• 53% have another autoimmune disease
• 20% have pOI

Question 5

How do you diagnose CAH?

Answer 5

-17-OHP (8am in follicular phase) >800 ng/dL (neonates > 3500 ng/dL)
< 200 ng/dL excludes diagnosis (<100 in neonates)
200-800 ng/dL indeterminate (per UTD >200 is virtually diagnostic)
-If indeterminate, perform High-dose ACTH stimulation test:
Phlebotomy ~ 1 hour post 1 ug/m2 (or 250 mcg) ACTH; >1500 ng/dL = diagnostic

Question 6

Describe pattern of 17-OHP secretion?

Answer 6

17-OH P has diurnal pattern – peak in AM and nadir late in day

Question 7

How do you treat CAH initially?

Answer 7

-Classical: Glucocorticoids (hydrocortisone) + mineralocorticoids (fludrocortisone)
-Potential for GnRH agonist to avoid/delay precocious puberty
-Monitoring:
*17-OHP between 400 and 1200 ng/dL
Bone density, serum 17 OHP, androstendione, testosterone
*Plasma-renin levels for MC treatment

Question 8

How do you manage CAH long term in adults?

Answer 8

Transition to PM long-acting glucocorticoids (dex – most potent, prednisone – mid potent)

Question 9

How do you treat NCCAH

Answer 9

• Children: Glucocorticoids if premature puberty/accelerated growth (hydrocortisone 10-15 mg/m2)
• Women: OCPs for hirsutism/acne +/- anti-androgens

Question 10

Describe presentation of Sheehan’s syndrome?

Answer 10

Failed lactation, secondary amenorrhea, loss of sexual hair

Question 11

Common chronic s/sx of adrenal insufficiency?

acute?

Answer 11

Acute: shock, abd pain, fever

Nausea/vomiting, weakness, hypoglycemia, hypotension (rare in 2’ & 3’)

If PRIMARY - buccal hyperpigmentation (95%) (from increased ACTH and increase MSH as byproduct of POMC)

Question 12

How do you diagnose Cushing’s Syndrome?

Answer 12

(One of three tests)
1. 24-hour urine free cortisol excretion (measured twice)
2. Late night salivary cortisol level (measured twice)
3. 1mg (high dose) overnight dexamethasone suppression test (best test in patient with hirsutism)
*Take dexamethasone between 11pm-12am, measure serum cortisol at 8am
*False positive in women on OCPs (E2 leads to increased CBG) and obesity

Question 13

What are the different etiologies of Cushing’s Syndrome?

Answer 13

Iatrogenic / glucocorticoid therapy (most common)
Cushing’s Disease (pituitary ACTH-secreting adenoma)
Ectopic CRH or ACTH by bronchial carcinoids / small cell lung ca
Cortisol-secreting adrenal tumors

Question 14

How do you determine if the cause of Cushing’s Syndrome is ACTH independent or dependent?

Answer 14

-Measure serum ACTH (normal circadian rhythm is lost so can be measured anytime)
<5 pg/mL (low) = ACTH independent (adrenal tumor) -> CT A/P
>20pg/mL (high) = ACTH dependent (ACTH adenoma, ectopic ACTH secretion)

Question 15

What is the most common cause of secondary Cushing’’s Syndrome?

Answer 15

Cushing’s Disease

Question 16

What is the most common cause of primary Cushing’’s Syndrome?

Answer 16

Iatrogenic

(*only one without hyperandrogenism)

Question 17

Describe the role of CRH stim test in identifying the cause of Cushing’s Syndrome?

Answer 17

• Pituitary (responds to CRH)
• Ectopic (does not response to CRH) ACTH secretion

Question 18

Describe the role of high dose dexamethasone suppression test in identifying the cause of Cushing’s Syndrome?

Answer 18

High dose dexamethasone suppresses pituitary ACTH (i.e. CRH bronchiole tumor)
High dose dexamethasone does not suppress ectopic ACTH (i.e. small cell lung tumor)

Question 19

Describe the role of petrosal venous sinus catheterization in identifying the cause of Cushing’s Syndrome?

risks?

Answer 19

Measure differential in ACTH concentration b/w petrosal venous sinus & peripheral vein w/ 10 min of CRH administration
Higher in the petrosal venous sinus (brain) if pituitary tumor, lower in the brain if ectopic ACTH secreting tumor

Risks of CVA, PE/DVT, cranial nerve palsy

Question 20

Describe treatment approach for Cushing’s syndrome?

Answer 20

• Address underlying cause (transsphenoidal surgery (70% success), lung tumor resection, adrenalectomy)
• If surgery contraindicated or persistent/recurrent following surgery:
• Adrenal enzyme inhibitors = 1st line (i.e. ketoconazole -> metyrapone)
• Inhibits the first step in cortisol biosynthesis (side-chain cleavage) and, to a lesser extent, the conversion of 11-deoxycortisol to cortisol
• Even more potent inhibitor of C17-20 desmolase, decreasing androstenedione and testosterone production
• Also inhibits ACTH secretion in vitro at therapeutic doses by impairing corticotroph adenylate cyclase activation
• Adrenolytic agents (i.e. mitotane)
• If pituitary tumor, consider cabergoline or somatostatin-analog

Question 21

Describe clinical presentation of iatrogenic Cushing’s Syndrome?

Answer 21

Glaucoma
Cataracts
Osteonecrosis
Pseudotumor cerebri
Pancreatitis
Panniculitis

Question 22

Describe clinical presentation shared by Cushing’s Syndrome?

Answer 22

Central obesity
Psychiatric
Poor wound healing
Osteoporosis
Glucose intolerance
HPA supp.

Question 23

Describe clinical presentation of endogenous Cushing’s Syndrome?

Answer 23

HTN
Hirsutism / acne
Striae
Menstrual abn
Impotence

Cervical fat pad / buffalo hum

Round face

Question 24

Androgens in women – Serum concentration (highest to lowest)

Answer 24

i. DHEAS
ii. DHEA
iii. Androstenedione
iv. Testosterone
v. DHT

Question 25

Enzyme deficiencies associated w/ salt-wasting (and the 2 not)

Answer 25

i. 21-hydroxylase (low aldosterone/cortisol, high androgens)
ii. 11β-hydroxylase (low aldosterone/cortisol, high androgens)
iii. 3β-hydroxysteroid dehydrogenase (low aldosterone/cortisol/androgens) (Some masculinization of 46XX fetus (High DHEA can convert to Test); Amb genitalia of 46XY (Low test, Low DHT) )
iv. Aldosterone synthase (low aldosterone, high cortisol/androgens)
v. StAR (steroid acute-regulatory protein)
vi. Lipoid

NOT

i. 17α-hydroxylase (high deoxycorticosterone – low aldosterone)
ii. 17,20-lyase (normal deoxycorticosterone – normal aldosterone, normal cortisol

Question 26

How is 11B-hydroxylase deficiency different from the others?

Answer 26

HTN / HYPERnatremia / HYPOkalemia

Since some mineralcorticoid action, but can rarely still get salt-wasting

Question 27

17α- hydroxylase and its effect on ACTH, mineralcorticoids, renin, aldosterone

Answer 27

Increased ACTH & mineralcorticoids

Decreased renin & aldosterone (due to volume expansion/HTN form increased mineralcorticoids)

Question 28

Ovulation induction in a patient with 17α-hydroxylase deficiency?

Answer 28

(Will only work if the patient has some residual 17α-hydroxylase activity)

• Glucocorticoid replacement to decrease P4 levels & improve BP
• Continuous transdermal E3 and then add P4 on days 15-25
• Then stimulate w/ FSH, add incremental E2 for EMS (follicle will develop on its own mostly)

Question 29

RAAS system mechanism

Answer 29

1. Low blood pressure → kidneys secrete renin
2. Renin then converts angiotensinogen (from the liver) → angiotensin I
3. Angiotensin I → angiotensin II by the enzyme angiotensin converting enzyme from the lungs

Question 30

Effects of Angiotensin II

Answer 30

1. Blood vessel constriction
2. Stimulates the synthesis of aldosterone from the adrenal cortex
3. Aldosterone causes reabsorption of sodium/water from the kidneys
4. Stimulates vasopressin secretion from posterior pituitary
5. Vasopressin increases water reabsorption from kidney
6. Moderate peripheral vasoconstriction

Question 31

Treatment of prenatal CAH (for mom & fetus)

Answer 31

Mom: Hydrocortisone (not metabolized by placenta, no risk of fetal HPA suppression)

Fetus: If high risk, start Dex asap (before 9w) to decrease androgen production in fetus. If male (or unaffected female), can stop when CVS results

Question 32

Inheritance of CAH

Answer 32

AR

Question 33

CAH most common / least common in what population?

Answer 33

Most: Eskimo/French/Mediterranean

Least: AA’s/Chinese

Question 34

Autoimmune disorder with a deficit of thyroid/adrenal hormones – which hormone would you replace 1^st and 2^nd

Answer 34

MC → GC → Thyroid (otherwise can precipitate adrenal insuff.)

Question 35

How does metyrapone work?

If using to dx, what hormone are you checking?

What can it treat?

Answer 35

inhibits 11B-hydroxylase blocker - blocks cortisol synthesis

Checking ACTH to determine primary/secondary adrenal insuff.

Can treat Cushing’s syndrome

Question 36

Most potent GC receptor inhibitor

Answer 36

RU-486 (mifepristone)

Question 37

What causes a false positive dexamethasone suppression test?

Answer 37

Estrogen (i.e. OCP)

Question 38

Difference b/w low and high dose dex suppression test

Answer 38

LDDST used for initial cushing’s syndrome as a screening or a confirmatory test

HDDST - is used in ACTH-dependent Cushing syndrome, to help distinguish pituitary (i.e., Cushing disease) from an ectopic source of ACTH overproduction.

principle behind the high-dose test is that overproduction of ACTH in Cushing disease (but not ectopic tumors) can undergo partial or full suppression by high doses of dexamethasone