Pathophysiology of the Adrenal Cortex

Question 1

What enzymes does the zona glomerulosa lack as well as contain that allow it to synthesize aldosterone?

Answer 1

Lacks: 17-alpha hydroxylase -> cannot convert progesterones to 17-OH-progesterone precursors of cortisol and androgens

Contains: Aldosterone synthase

Question 2

Is DHEA an active hormone?

Answer 2

No receptor is found for it, it has very little intrinsic activity (weak androgen)

However, it can be converted to more potent androgens via peripheral aromatase

Question 3

How are cortisol and aldosterone transported in the blood?

Answer 3

Cortisool - 90% is bound to cortisol binding globulin / transcortin

Aldosterone - 50% bound to albumin, 20% to transcortin

Question 4

What are two tests for daily cortisol secretion? What is the control which must be done with one of them?

Answer 4

1. 24 hour urine free cortisol - creatinine is also measured to ensure adequate sample
2. Salivary free cortisol - better / easier to get in children

Question 5

When are stimulation vs suppression tests used and what drug is used for the stimulation test of the adrenal cortex?

Answer 5

Stimulation - used if hormone deficiency is suspected

Suppression - used if hormone excess is suspected (see if it’s suppressable)

Cosyntropin - ACTH analog which can be used for adrenal stimulation test (especially for Addison’s disease)

Question 6

Tell me if cosyntropin will stimulate adrenal cortex in the following situations:

1. Primary adrenal insufficiency
2. Secondary adrenal insufficiency - recent onset
3. Secondary adrenal insufficiency - longstanding

Answer 6

1. Primary adrenal insufficiency
   - > no, cortex is not responsive to ACTH
2. Secondary adrenal insufficiency - recent onset
   - > yes, cortex is ready to receive ACTH stimulation
3. Secondary adrenal insufficiency - longstanding
   - > no, cortical atrophy is likely to have occurred

Question 7

What is the insulin-induced hypoglycemia test used for? How does it work?

Answer 7

Used for testing for secondary adrenal insufficiency
-> insulin dropping your blood sugar to below 40 mg/dL should naturally trigger release of growth hormone and ACTH (so cortisol can raise your blood sugar)

Question 8

How do you differentiate between secondary and tertiary adrenal insufficiency?

Answer 8

CRH stimulation test
Tertiary -> ACTH release will be stimulated
Secondary -> ACTH release will not be stimulated

Question 9

What is considered the “screening” test for Cushing’s syndrome or states of hypercortisolemia?

Answer 9

Overnight dexamethasone suppression test

-> levels at 8am the next morning should be low

Question 10

What is the utility of low vs high dose dexamethasone suppression test in diagnosis of Cushing’s syndromes?

Answer 10

Low dose -> can make definitive diagnosis of Cushing’s syndrome of any time, as cortisol will not be suppressed.

High dose -> cortisol WILL be suppressed in Cushing’s disease (pituitary adenoma) but will NOT be suppressed in ectopic ACTH secretion

Question 11

What is the most common cause of ectopic ACTH secreting tumor?

Answer 11

Small cell lung cancers

Can also occur in other neuroendocrine tumors, i.e. medullary thyroid carcinoma, pancreatic carcinoid tumors

Question 12

What is the most common electrolyte imbalance seen in Cushing’s syndrome? Why? What other metabolic disease commonly occurs?

Answer 12

Hypokalemic metabolic alkalosis

• > high cortisol levels stimulate aldosterone receptor (11B hydroxy steroid DH can’t keep up)
• > aldosterone stimulates H+/K+ ATPase on alpha-intercalated cells

Diabetes mellitus Type 2 also occurs
-> hyperglycemia from cortisol

Question 13

What is Nelson syndrome?

Answer 13

As background, refractory Cushing’s disease (ACTH-secreting pituitary adenoma) often has to be treated via bilateral adrenalectomy.

Nelson syndrome is when the Cushing’s disease adenoma enlarges and causes increased ACTH secretion (loss of negative feedback).
-> causes hyperpigmentation, bitemporal hemianopsia, and headaches

Question 14

What are the most specific symptoms of Cushing’s syndromes?

Answer 14

1. Central obesity
2. Purpura, ecchymoses, striae -> connective tissue thinning
3. Muscle atrophy / proximal myopathy -> for gluconeogenesis
4. Hirsutism -> effect of ACTH on zona reticularis

Question 15

What is Cushing’s syndrome vs Cushing disease?

Answer 15

Cushing’s syndrome -> ANY cause of increased circulating glucocorticoids (includes exogenous)

Cushing disease -> Pituitary adenoma secreting ACTH

Question 16

How will the response to CRH stimulation test differ between Cushing’s disease and ectopic ACTH production?

Answer 16

Cushing’s disease - hyper-responds to exogenously administered CRH by increasing ACTH production massively

Ectopic ACTH (i.e. small cell carcinoma) -> minimal responds to CRH, they work autonomously

Question 17

What is the test should be done after diagnosis of a Cushing syndrome via a dexamethasone suppression test?

Answer 17

Plasma ACTH levels

If ACTH is low -> primary adrenal adenoma / hyperplasia / carcinoma

If ACTH is high -> Cushing’s disease or ectopic ACTH secretion

Question 18

What should be done if adrenal tumor or Cushing’s disease is diagnosed?

Answer 18

Adrenal tumor -> CT scan to visual adrenal glands, and surgical resection of tumor

Cushing’s disease -> MRI of theh pituitary, and transsphenoidal tumor resection

Question 19

What is Addison’s disease?

Answer 19

PRIMARY adrenal insufficiency

contrast this to Cushing’s disease which is secondary adrenal hyperplasia basically

Question 20

What is the definition of adrenal insufficiency? How do you differentiate primary for secondary clinically?

Answer 20

Deficiency in cortisol secretion (no other hormones matter, though they may be deficient)

Primary - ACTH levels will be high, and will not respond to cosyntropin or insulin-induced hypoglycemia

Secondary - ACTH levels will be low, cortex will respond to cosyntropin so long as the gland has not atrophied yetl

Question 21

What symptoms are specific to Addison’s disease vs secondary adrenal insufficiency?

Answer 21

1. Hyperpigmentation- Overproduction ACTH due to lack of negative feedback from primary issue
2. Salt craving and hyperkalemia - Addison’s disease only, as zona glomerulosa will also not be working. In secondary, zona glomerulosa is intact and functioning normal (does not require ACTH)

Question 22

Where are the top places to get hyperpigmentation in Addison disease, and why does this hyperpigmentation happen?

Answer 22

Buccal mucosa / lips, and gums

Can occur anywhere on body

Due to increased MSH, a byproduct of ACTH production from POMC

Question 23

What are other common symptoms of all adrenal insufficiency?

Answer 23

Fatigue, weakness, hypotension, weight loss (lack of cortisol), GI disturbances

Question 24

What are the top two causes of Addison’s disease?

Answer 24

1. Autoimmune destruction (of adrenal gland)-> most common in Western world
2. Tuberculosis -> most common in developing world

Question 25

What are some other causes of Addison’s disease?

Answer 25

1. Adrenal hemorrhage -> Waterhouse-Friderichsen syndrome
2. Congenital adrenal hyperplasias
3. X-linked adrenoleukodystrophy (look for in males, peroxisomal problem of VLCFA buildup)

Others are low yield or intuitive

Question 26

What is the treatment of primary vs secondary adrenal insufficiency? What will renin levels be in each condition pretreatment (this is really a hint).

Answer 26

Primary - administration of a glucocorticoid + mineralocorticoid. Renin levels high pre-treatment.

Secondary - administration of a glucocorticoid only (aldosterone okay). Renin levels normal.

Question 27

How does cortisol cause hypertension?

Answer 27

1. Activation of aldosterone receptor

2. High cortisol increases sensitivity of peripheral vessels to catecholamines via upregulation of alpha1 receptors

Question 28

What is functional / relative adrenal insufficiency?

Answer 28

Subnormal cortisol production / secretion during acute, severe illness (should lose diurnal pattern and increase 5-10 fold).

Question 29

What hormone is the chief regulator of ACTH biofeedback? How does this explain congenital adrenal hyperplasia?

Answer 29

Cortisol. In situations where cortisol is low, ACTH levels will be increased, causing massive overproduction of mineralocorticoids and androgens.

Question 30

What is the metyrapone stimulation test? What is normal / abnormal.

Answer 30

Test blocking the last step of cortisol synthesis -> 11-deoxycortisol to cortisol.

Normal: decreased cortisol and compensatory increase in ACTH + 11-deoxycortisol.

Primary adrenal insufficiency: ACTH is increased but 11-deoxycortisol is still low after test.

Secondary / Tertiary adrenal insufficiency: both ACTH / 11-deoxycortisol remain low after the test.

Question 31

Why should you taper steroids? Will aldosterone be affected in the resulting condition?

Answer 31

Primary adrenal insufficiency may occur to abrupt withdrawal of steroids, due to cortical atrophy. Need to taper.

Aldosterone will not be affected -> loss of ACTH stimulation does not cause atrophy.

Question 32

What is the most common cause of congenital adrenal hyperplasia? What accumulates / what is decreased in it?

Answer 32

21-hydroxylase deficiency, enzyme which catalyzes the conversion of 17-OH-progesterone and progesterone to aldosterone and cortisol precursors.

Accumulates: DHEA / androstenedione (androgens) + 17-OH progesterone

Decreased: Cortisol / aldosterone

Question 33

What are the symptoms of classical 21-hydroxylase deficiency?

Answer 33

Presents in infancy:
Lack of aldosterone: Hyponatremia, hyperkalemia

Lack of cortisol: Hypotension (salt-wasting type)

Excess androgen:
Females - clitoral enlargement / ambiguous genitalia = female pseudohermaphroditism

Question 34

What are the symptoms of non-classical 21-hydroxylase deficiency?

Answer 34

Less severe form, presents in childhood due to excess androgens:

Females - hirsutism with menstrual irregularities
Males - precocious puberty

Question 35

In the classical form of 21-hydroxylase deficiency, is salt-wasting always present? Why or why not?

Answer 35

Not always -> only minimal aldosterone needs to be produced (relative to cortisol) to have normal functioning.

Virilization at birth will always happen in the classical form, however.

Question 36

What is the second most common cause of CAH, and what accumulates / is underproduced?

Answer 36

11-beta-hydroxylase deficiency
-> similar to metyrapone testing

11-deoxycortisol accumulates -> decreased cortisol synthesis

11-deoxycorticosterone accumulates (precursor to aldosterone), but is actually a mineralocorticoid

Some level of excess androgen is also present due to shunting away from cortisol pathway

Question 37

What are the clinical features of 11-beta-hydroxylase deficiency? Will renin levels be up or down?

Answer 37

Androgen excess -> similar to 21 hydroxylase deficiency, females have virilization at birth

11-deoxycorticosterone -> actually potentially activates mineralocorticoid receptor -> causes hypertension with hypokalemia, low renin levels.

Question 38

What accumulates or is decreased in 17a-hydroxylase deficiency? Will aldosterone be increased?

Answer 38

Inability to make 17-OH-progesterones, so all is shunted into mineralocorticoid pathway

Accumulates: 11-deoxycorticosterone, mineralocorticoid. Aldosterone not increased because aldosterone synthase under control of angiotensin II

Decreased: cortisol / androgens

Question 39

What are the clinical features of 17a-hydroxylase deficiency in males and females?

Answer 39

Increased 11-DOC -> hypertension with hypokalemia

Females: Normal genitalia at birth, but primary amenorrhea (lack of sex hormones for puberty)

Males: Normal testes but undescended, ambiguous external genitalia (lack of androgens, but testes present due to SRY)

Question 40

What test is run at newborn screening to check for congenital adrenal hyperplasia? How will they be changed in the three major conditions?

Answer 40

17-hydroxyprogesterone levels

21-hydroxylase: increased
11beta-hydroxylase: increased
17alpha-hydroxylase: decreased

Question 41

What are the presenting symptoms of aldosterone synthase deficiency? Why is this different than the other conditions?

Answer 41

Failure to thrive, Na+ wasting, hypotension, hyponatremia, and hyperkalemia

In this cause, lack of aldosterone matters since there isn’t ACTH stimulating 17,20 desmolase since cortisol levels will be normal -> 11-DOC will not accumulate enough to compensate for loss of aldosterone.