Cortisol Conditions

Question 1

hypothalamic-pituitary-adrenal (HPA) axis

Answer 1

1. cortisol release starts with pulsatile release of CRH from hypothalamus
2. CRH triggers release of ACTH from pituitary
3. ACTH triggers cortisol production and release in zona fasciculata of adrenal cortex
4. negative feedback loop prevents physiologic excess cortisol production

*time of day and stress influence the amount of cortisol being produced, but there should always be a baseline amount

Question 2

regulation of HPA axis

Answer 2

1. cortisol (negative feedback)
2. circadian rhythm
3. stress

Question 3

influence of stress on HPA axis / cortisol release

Answer 3

*stress (either physiologic or psychological) triggers release of CRH from paraventricular nucleus of hypothalamus → increased release of cortisol

*examples of physiologic stressors: hypoglycemia, hypotension, surgery, fever, injury

Question 4

cortisol synthesis

Answer 4

*steroid hormone produced in the zona fasciculata of the adrenal gland
*ACTH stimulates StAR protein to move cholesterol into mitochondria, where cholesterol desmolase converts cholesterol → pregnenolone → various steps → cortisol

Question 5

cortisol - overview

Answer 5

*steroid hormone (lipophilic, hydrophobic; needs to be bound to a binding protein to travel in bloodstream)
*binding proteins of cortisol:
1. corticosteroid binding globulin (GBG) = transcortin (90% of cortisol bound to this)
2. albumin (7% of cortisol bound to this)
3. free in plasma (3% of cortisol)

*permeates the cell membrane and binds to intracellular receptors → modulation of gene transcription

Question 6

effects of pregnancy on cortisol

Answer 6

*both total cortisol and CBG levels increase during pregnancy
*however, FREE (active) cortisol is usually normal, and pts do not have symptoms of high cortisol

Question 7

cortisol - functions

Answer 7

*increased appetite
*increased blood pressure (and brain)
*increased insulin resistance
*increased gluconeogenesis / decreased glucose utilizaiton
*decreased fibroblast activity (poor wound healing, decreased collagen, increased striae)
*decreased inflammatory and immune response
*decreased bone formation

Question 8

cortisol - functions in fetal development

Answer 8

*important in maturation of fetal lungs & surfactant production
*women in premature labor are treated with glucocorticoids to hasten fetal lung development

Question 9

Cushing’s Syndrome - overview

Answer 9

*a cluster of features (mnemonic: MOON FACIES) resulting from glucocorticoid excess:
Metabolic syndrome (HTN, insulin resistance, HLD)
Obesity (truncal weight gain w/ extremity wasting, moon facies, dorsocervical fat pad / buffalo hump)
Osteoporosis
Neuropsychiatric (depression, anxiety)_
Facial plethora
Androgen excess (acne, hirsutism)
Cataract
Immunosuppression
Ecchymoses
Skin changes (striae, hyperpigmentation)

also: increased risk for DVT, amenorrhea, polyuria

Question 10

Cushing’s Syndrome - etiologies

Answer 10

1. exogenous - from glucocorticoid drugs (most common)
2. endogenous - from:
   a. adrenal gland abnormality
   -adrenal adenoma
   -adrenocortical carcinoma
   -adrenal hyperplasia
   b. elevated ACTH level, which stimulates adrenal gland to make cortisol:
   -pituitary adenoma (Cushing disease)
   -paraneoplastic / ectopic ACTH production

Question 11

testing options for Cushing’s Syndrome

Answer 11

1. always ask about exogenous glucocorticoids (oral, inhaled, topical, injected)
2. screening tests:
   a. 1mg dexamethasone suppression test (DST)
   b. late night salivary cortisol
   c. 24h urine cortisol collection

note - may need to adjust timing if pt works night shift

Question 12

testing for Cushing’s Syndrome: dexamethasone suppression test

Answer 12

*under normal conditions, dexamethasone (a synthetic steroid) should suppress ACTH via negative feedback → low cortisol levels
*normal response: low cortisol levels
*Cushing’s Syndrome response: cortisol levels REMAIN HIGH despite dexamethasone administration

Question 13

testing for Cushing’s Syndrome: late night salivary cortisol level

Answer 13

*normal: low cortisol at night in saliva
*Cushing’s Syndrome: high cortisol at night in saliva

Question 14

testing for Cushing’s Syndrome: 24h urine free cortisol

Answer 14

*Cushing’s Syndrome will have elevated cortisol in urine
*does not affect night shift workers

Question 15

once screening test confirms excess cortisol / Cushing’s Syndrome, what is the next step to identify the source?

Answer 15

*check ACTH:
-low ACTH = ACTH-independent Cushing’s Syndrome (adrenal CT to evaluate for tumor, adenoma, or hyperplasia)
-high ACTH = ACTH-dependent Cushing’s Syndrome
-pituitary adenoma (Cushing disease), ectopic ACTH, paraneoplastic, carcinoid, medullary thyroid caner

Question 16

ACTH-dependent Cushing’s Syndrome: determining pituitary vs. ectopic ACTH source

Answer 16

*HIGH DOSE dexamethasone suppression test:
-if ACTH and cortisol levels are suppressed, suggests pituitary source
-if ACTH and cortisol are not suppressed, suggests ectopic ACTH (cancer)

*can confirm with CRH stimulation test:
-if ACTH / cortisol increased further: pituitary source
-if ACTH / cortisol don’t increase further: ectopic source

Question 17

management of Cushing’s Syndrome

Answer 17

*key point = find and treat the underlying cause
1. exogenous: lower/remove the glucocorticoid medication
2. adrenal adenomas & pituitary adenomas: surgical resection
3. ectopic cancers: locate & treat (surgery, chemo)
4. bilateral adrenal hyperplasia: drugs that inhibit synthesis of cortisol - ketoconazole, mitotane, metyrapone, osilodrostat

Question 18

Cushing’s DISEASE complication: Nelson Syndrome

Answer 18

*recall: Cushing DISEASE is high cortisol due to pituitary making excess ACTH
*Nelson Syndrome: removal of adrenal glands = no negative feedback; hypothalamus releases CRH → CRH stimulates pituitary cells to make ACTH → rapid tumor growth
*can lead to:
-hyperpigmentation from high ACTH levels
-mass effect: headaches, bitemporal hemianopsia
*treatment: transsphenoidal resection, postoperative pituitary irradiation for residual tumor

Question 19

adrenal insufficiency - defined

Answer 19

*inability of adrenal glands to make enough glucocorticoids (cortisol) +/- mineralocorticoids (aldosterone)
*classified as primary vs. secondary:
-primary = ADRENAL GLAND problem (Addison’s disease)
-secondary/tertiary = PITUITARY or hypothalamus problem

Question 20

primary adrenal insufficiency - defined

Answer 20

*a problem with the adrenal glandthat results in both glucocorticoid deficiency AND mineralocorticoid deficiency

Question 21

primary adrenal insufficiency - clinical features

Answer 21

*sx of glucocorticoid deficiency:
-nausea, vomiting, anorexia
-fatigue, weakness
-hyperpigmentation (diffuse tan, including areas not exposed to sun: mucosa, palmar creases)
-hypoglycemia
-hypotension

*sx of mineralocorticoid deficiency:
-sodium wasting (hyponatremia, hypovolemia, hypotension, elevated BUN)
-hyperkalemia
-metabolic acidosis

Question 22

mechanism of hyperpigmentation in primary adrenal insufficiency

Answer 22

*lack of cortisol production → loss of negative feedback to pituitary
*to compensate for low cortisol, pituitary produces excess amounts of ACTH to try to stimulate adrenal gland
*POMC (precursor for ACTH) is also precursor for melanocyte-stimulating hormone (MSH); POMC is increased → increased MSH → hyperpigmentation

note - hyperpigmentation only occurs in PRIMARY (not secondary) adrenal insufficiency

Question 23

primary adrenal insufficiency - diagnosis

Answer 23

1. 8am cortisol level; if LOW…
2. ACTH stimulation test; if cortisol levels remain low, confirms primary adrenal insufficiency

lab findings:
*HIGH ACTH levels
*+21-hydroxylase antibodies (most common cause)
*consider testing for non-autoimmune causes

Question 24

causes of primary adrenal insufficiency

Answer 24

1. autoimmune destruction due to 21-hydroxylase antibodies (majority of cases) = Addison’s Disease
2. tuberculosis
3. other: adrenal hemorrhage, congenital adrenal hyperplasia, adrenoleukodystrophy (young males), sarcoidosis, amyloidosis, HIV/AIDS, metastatic cancer, fungal infections

Question 25

primary adrenal insufficiency - treatment

Answer 25

*hormone replacement!
1. glucocorticoid replacement:
-prednisone, hydrocortisone most common
-sick day dosing: when ill, triple the glucocorticoid dose to mimic HPA axis
-stress dosing (surgery, infection, hospital): high dose IV glucocorticoids
2. mineralocorticoid replacement:
-fludrocortisone
-adequate salt intake

Question 26

adrenal crisis

Answer 26

*acute adrenal insufficiency (aka adrenal crisis or Addisonian crisis)
*often precipitated by an acute stressor (infection, surgery, blood loss, etc) in a person with adrenal insufficiency
*inability to make cortisol → hypovolemic shock
*sx: abdominal pain, N/V, altered mental status, fever, shock
*tx: high dose glucocorticoids

Question 27

secondary adrenal insufficiency - defined

Answer 27

*a problem with the pituitary gland that leads to glucocorticoid (cortisol) deficiency

Question 28

secondary adrenal insufficiency - clinical features

Answer 28

*sx of glucocorticoid deficiency:
-nausea, vomiting, anorexia, weight loss
-fatigue, weakness
-hypoglycemia

note - there is NOT hyperpigmentation of skin in secondary adrenal insufficiency

Question 29

secondary adrenal insufficiency - etiologies

Answer 29

1. suppression of ACTH from chronic glucocorticoid therapy (most common)
2. pituitary or hypothalamic issues:
   -pituitary adenoma, craniopharyngioma, meningioma, CNS radiation, etc

Question 30

secondary adrenal insufficiency - management

Answer 30

*diagnose and treat underlying cause if possible
*replace glucocorticoids (with education about sick day and stress day dosing)
*no need for mineralocorticoid replacement