Cortisol Conditions Flashcards
hypothalamic-pituitary-adrenal (HPA) axis
- cortisol release starts with pulsatile release of CRH from hypothalamus
- CRH triggers release of ACTH from pituitary
- ACTH triggers cortisol production and release in zona fasciculata of adrenal cortex
- 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
regulation of HPA axis
- cortisol (negative feedback)
- circadian rhythm
- stress
influence of stress on HPA axis / cortisol release
*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
cortisol synthesis
*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
cortisol - overview
*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
effects of pregnancy on cortisol
*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
cortisol - functions
*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
cortisol - functions in fetal development
*important in maturation of fetal lungs & surfactant production
*women in premature labor are treated with glucocorticoids to hasten fetal lung development
Cushing’s Syndrome - overview
*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
Cushing’s Syndrome - etiologies
- exogenous - from glucocorticoid drugs (most common)
- 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
testing options for Cushing’s Syndrome
- always ask about exogenous glucocorticoids (oral, inhaled, topical, injected)
- 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
testing for Cushing’s Syndrome: dexamethasone suppression test
*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
testing for Cushing’s Syndrome: late night salivary cortisol level
*normal: low cortisol at night in saliva
*Cushing’s Syndrome: high cortisol at night in saliva
testing for Cushing’s Syndrome: 24h urine free cortisol
*Cushing’s Syndrome will have elevated cortisol in urine
*does not affect night shift workers
once screening test confirms excess cortisol / Cushing’s Syndrome, what is the next step to identify the source?
*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
ACTH-dependent Cushing’s Syndrome: determining pituitary vs. ectopic ACTH source
*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
management of Cushing’s Syndrome
*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
Cushing’s DISEASE complication: Nelson Syndrome
*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
adrenal insufficiency - defined
*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
primary adrenal insufficiency - defined
*a problem with the adrenal glandthat results in both glucocorticoid deficiency AND mineralocorticoid deficiency
primary adrenal insufficiency - clinical features
*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
mechanism of hyperpigmentation in primary adrenal insufficiency
*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
primary adrenal insufficiency - diagnosis
- 8am cortisol level; if LOW…
- 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
causes of primary adrenal insufficiency
- autoimmune destruction due to 21-hydroxylase antibodies (majority of cases) = Addison’s Disease
- tuberculosis
- other: adrenal hemorrhage, congenital adrenal hyperplasia, adrenoleukodystrophy (young males), sarcoidosis, amyloidosis, HIV/AIDS, metastatic cancer, fungal infections
primary adrenal insufficiency - treatment
*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
adrenal crisis
*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
secondary adrenal insufficiency - defined
*a problem with the pituitary gland that leads to glucocorticoid (cortisol) deficiency
secondary adrenal insufficiency - clinical features
*sx of glucocorticoid deficiency:
-nausea, vomiting, anorexia, weight loss
-fatigue, weakness
-hypoglycemia
note - there is NOT hyperpigmentation of skin in secondary adrenal insufficiency
secondary adrenal insufficiency - etiologies
- suppression of ACTH from chronic glucocorticoid therapy (most common)
- pituitary or hypothalamic issues:
-pituitary adenoma, craniopharyngioma, meningioma, CNS radiation, etc
secondary adrenal insufficiency - management
*diagnose and treat underlying cause if possible
*replace glucocorticoids (with education about sick day and stress day dosing)
*no need for mineralocorticoid replacement
