Lecture 1.2: CUSHINGS SYNDROME 2.

Inhibits WBC adhesion >

neutrophilia
3. Blocks histamine release from
mast cells
4. Reduces eosinophils
5. Blocks IL-2 production
f. Decrease Bone formation
(decreased osteoblast activity)

**** Cortisol is BIG FIB

Exogenous corticosteroids can cause

reactivation of Tuberculosis and
Candidiasis (Blocks IL-2 production)
Regulation:
a. CRH (Hypothalamus) stimulates
ACTH release (pituitary) > Increase
cortisol production in adrenal
fasciculate
b. Excess cortisol > Decreased CRH,
CORTISOL ACTH > Decreased cortisol
secretion
Source: Adrenal zona Fasicculata. c. Chronic stress induces prolonged
Bound to corticosteroid-binding secretion
globulin
a. Increases Blood Pressure: EPIDEMIOLOGY
1. Upregulates 1- receptors on
arterioles > Increased sensitivity Considered a rare disease
to norepinephrine and Incidence of 1-2 per 100,00 population
epinephrine /year
2. At high concentrations, can bind Caused by an ACTH- producing
to mineralocorticoid corticotrope adenoma of the pituitary
(aldosterone) receptors Affects women, exception of
b. Increased Insulin resistance prepubertal cases that is commonly with
(diabetogenic) boys
c. Increased Gluconeogenesis, Ectopic ACTH syndrome frequently
Lipolysis and Proteolysis identified in men
d. Decreased Fibroblast activity
(causes striae)
e. Decrease Inflammatory and
Immune responses:
1. Inhibits production of
leukotrienes and prostaglandins

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ETIOLOGY : CLINICAL MANIFESTATIONS:

Excess glucocorticoid secretion

overcomes the ability of 11-HSD2 to
rapidly inactivate cortisol to cortisone in
the kidney
a. Exerting mineralocorticoid actions:
1. Diastolic Hypertension
2. Hypokalemia
3. Edema
Excess glucocorticoids interfere with
A combination of germline and somatic central regulatory systems
mutation in the suppressor gene a. Leading to suppression of
ARMC5 has been a prevalent cause of subsequent hypogonadism and
Cushings syndrome due to amenorrhea
macronodular adrenal hyperplasia b. Suppression of the hypothalamic-
CARNEYs COMPLEX pituitary-thyroid axis
a. A mutation in one of the regulatory 1. Resulting in decreased thyroid-
subunits of PKA, PKKAR1A stimulating hormone secretion
b. Found in patients with primary Majority of clinical signs and symptoms
pigmented nodular adrenal disease observed in Cushings syndrome are
(PPNAD) non-specific
c. Autosomal dominant multiple a. Obesity
neoplasia associated with cardiac b. Diabetes
myxomas, hyperlentiginosis, Sertoli c. Diastolic hypertension
cell tumors and PPNAD d. Hirsutism
d. PPNAD can present as e. Depression
macro/micronodular or both
Specific features:
Mc CUNE-ALBRIGHT SYNDROME a. Fragility of skin
a. Associated with polyostotic fibrous b. Easy bruising
dysplasia c. Broad (>1cm) purplish striae
b. Unilateral caf-au-lait spots
c. Precocious puberty
d. Caused by activating mutations in
the stimulating G protein alpha
subunit 1, GNAS1 (Guanine
nucleotide binding protein alpha
stimulating polypeptide-1)

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 In ectopic ACTH syndrome
a. Hyperpigmentation of the knuckles,
skin areas exposed to friction
1. Caused by stimulatory effects of
excess ACTH
2. The POMC cleavage on
melanocyte production employing any tests used for the
Patients with ectopic ACTH syndrome differential diagnosis
and with Adrenocortical CA as the After exceeding exogenous
cause of Cushings may have more brisk glucocorticoid use as the cause of
onset and rapid progression of clinical clinical s/s
signs and symptoms a. Suspected cases should be tested if
Patients with Cushings syndrome can there are multiple and progressive
acutely be: features of Cushings--- Particular
a. Endangered by deep vein features with a potentially higher
thrombosis discriminatory value
b. Subsequent pulmonary embolism Exclusion of Cushings is abnormally
** both due to hypercoagulable indicated in patients with incidentally
states discerned adrenal masses.
c. Experience psychiatric symptoms TESTS:
1. Anxiety or depression a. Increased 24-h urinary free cortisol
2. Acute paranoia or depressive excretion in 3 separate collections
psychosis 1. Failure to appropriately
suppress morning cortisol after
DIAGNOSIS: overnight exposure to
dexamethasone
The most important step in the 2. Evidence of loss of diurnal
management of patients with suspected cortisol secretion with high
Cushings syndrome is to establish the levels at midnighttime of the
correct diagnosis physiologically lowest secretion
The protocol requires establishing the Factors potentially affecting the
diagnosis beyond doubt prior to outcome of these diagnostic tests have

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 to be excluded such as 24-h urine ACTH production over several
collection or rapid inactivation of hours
dexamethasone due to concurrent intake c. The problem with this test is that
of CYP-3A4- inducing drugs (e.g. there can be falsely abnormal or
antiepileptics, rifampicin) positive results
Concurrent intake of oral contraceptives d. Any drug that increases the
that raise CBG and thus total cortisol metabolic breakdown of
can cause failure to suppress after dexamethasone will prevent the
dexamethasone ability to suppress cortisol levels---
If in doubttesting should be repeated phenytoin, carbamazepine,
after 4-6 weeks off estrogen rifampicin (increases the
Patients with pseudo-Cushing states: metabolism of dexamethasone)
a. Alcohol-related e. Stress increases glucocorticoid
b. Cyclic cushings levels
** should require further testing to f. Can be falsely positive thru:
safely confirm or exclude diagnosis starvation, bulimia, alcohol
of Cushings. withdrawal, depression
g. An abnormality on the 1mg
Additionals (From Kaplan USMLE 2017): overnight test should be confirmed
with a 24-hour urine free cortisol
The diagnostic tests used to establish the
24-hour urine free cortisol is MORE
syndrome of cortisol excess:
ACCURATE and GOLD STANDARD
a. 1-mg overnight dexamethasone
for confirming or excluding Cushings
suppression test
syndrome
b. 24-hour urine free cortisol
Third screening test is the MIDNIGHT
** these tests are used to establish a
SALIVARY CORTISOL.
precise etiology of the cortisol
a. Normal patients: cortisol is low at
excess are the ACTH level, high
midnight
dose dexamethasone-suppression
b. Cushings: Abnormally high at
test, CT and MRI scanning and
midnight
occasional sampling of the petrosal
venous sinus which drains out of the *** The precise etiology of the Cushings
pituitary syndrome is established by ACTH levels.
The 1-mg overnight dexamethasone
suppression test: Sometimes in combination with high-dose
a. Used to rule out the diagnosis of dexamethasone suppression testing:
Cushings syndrome or
a. ACTH levels= pituitary source of
glucocorticoid excess
ACTH (adenoma/ ectopic source)
b. If you give a milligram of
b. dose dexamethasone suppression
dexamethasone at 11pm, the cortisol
testing --- suppressed in pituitary
level at 8am should be normal if
adenoma, nothing happens with the
there is normal ability to suppress
ectopic source

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 c. If ACTH levels- etiology is from being found in some patients with
adrenal tumor ectopic ACTH syndrome
d. When the adrenal gland is the source of Imaging should be used ONLY after it
increased cortisol production--- there is is established whether the cortisol
a feedback inhibition on the pituitary excess is ACTH-dependent or
and ACTH level is suppressed. independent.
e. When low ACTH levelprecise etiology a. Because nodules in the pituitary or
can be confirmed thru CT scan the adrenal are a common finding
f. When there is high ACTH--- precise
etiology is confirmed thru MRI of the
pituitary looking for an adenoma or a
CT scan of the chest looking for an
ectopic focus.
g. If neither--- Inferior petrosal sinus
sampling should be done if there is
increased ACTH coming out from the
brain
Single Random cortisol tests are not
reliable:
a. HIGH PLASMA ACTH LEVELS= in the general population
pituitary or ectopic source In patients with confirmed ACTH-
b. LOW PLASMA ACTH LEVELS= independent excess adrenal imaging (CT
adrenal tumors or hyperplasia scan) is indicated.
a. Helps distinguish between benign
DIFFERENTIAL DIAGNOSIS
and malignant adrenal lesions.
The evaluation of patients with For ACTH- dependent cortisol excess
confirmed Cushings should be carried a. An MRI of the pituitary is the
out by an endocrinologist and begins investigation of choice
with differential diagnosis of ACTH- b. Pituitary corticotrope adenomas fail
dependent and ACTH-independent to enhance following gadolinium
cortisol excess administration or T1-weighted MRI
Generally, plasma ACTH levels are images
SUPPRESSED in cases of autonomous In all cases of confirmed ACTH-
adrenal cortisol excess dependent Cushings, further tests are
a. As consequence of enhanced required for the differential diagnosis of
negative feedback to the pituitary Cushings disease and ectopic
hypothalamus and pituitary ACTH syndrome
Patients with ACTH- dependent a. Ectopic sources of ACTH are
Cushings have normal or increased resistant to dexamethasone
plasma ACTH with very high levels suppression and unresponsive to
CRH

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 ** should be noted that a small intensity on T2-weighted
minority of ectopic ACTH- images
producing tumors exhibit dynamic 2. Octreotide scintigraphy can be
responses similar to pituitary helpfulEctopic ACTH-
corticotrope tumors. producing tumors express
If 2 tests show conflicting results: somatostatin receptors
a. Perform Bilateral Inferior Petrosal c. Undergo blood sampling for fasting
Sinus Sampling (IPSS) with gut hormones, chromogramin A,
concurrent blood sampling for calcitonin, biochemical exclusion of
ACTH in the Right and Left inferior pheochromocytoma
petrosal sinus and peripheral vein.
b. An increased central/ peripheral TREATMENT:
plasma ACTH ratio >2 at baseline In ACTH-independent disease:
and >3 at 2-5 minutes after CRH a. Treatment consists of surgical
is INDICATIVE of Cushings removal of the adrenal tumor
disease--- very high sensitivity and 1. Smaller tumors: minimally
specificity.
invasive approach
*** IPSS cannot be reliably used for 2. Large tumors and suspected of
lateralization (prediction of location malignancy: open approach
of the tumor within the pituitary) ---
In cushings disease
Because there is broad
a. Treatment of choice: selective
interindividual variability in the
removal of the pituitary corticotrope
venous drainage of the pituitary
tumor--- via an endoscopic
region.
transphenoidal approach--- cure rate
of 70-80%
*** IMPORTANT: NO
b. Long term follow up is important:
CORTISOL-LOWERING
may recur late.
AGENTS should be used prior to
c. If recurs:
IPSS.
1. 2nd surgery
If the differential diagnostic testing
2. Radiotherapy
indicates ECTOPIC ACTH- 3. Stereotactic radiosurgery
SYNDROME: 4. Bilateral adrenalectomy
a. Further imaging should include
Patients with very severe overt
high-resolution, fine-out CT
Cushings (Difficult to control
scanning of the chest and abdomen
hypokalemic Hypertension or acute
for evaluating the lung, thymus and
psychosis):
pancreas
a. Introduce medical treatment to
b. If NO LESIONS IDENTIFIED:
rapidly control the cortisol excess
1. MRI of the chest can be
during the period leading up to
considered because carcinoid
surgery
tumors usually show high signal

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 Patients with metastasized, After the successful removal of an
glucocorticoid- producing carcinomas: ACTH- or Cortisol- producing tumor:
a. Require long term a. HPA axis will be suppressed
antiglucocorticoid drug treatment. b. Hydrocortisone replacement needs
Ectopic ACTH-syndrome (tumor cannot to be initiated at the time of surgery
be located): and slowly tapered following
a. Carefully weigh whether the drug recovery---- to allow physiologic
treatment or bilateral adrenalectomy adaptation to normal cortisol levels.
is the most appropriate choice.
b. Bilateral adrenalectomy---
immediate cure but requiring life-
long corticosteroid replacement
c. Paramount to ensure regular
imaging follow up for identification
of the ectopic ACTH source
ORAL AGENTS
a. Metyrapone
1. Inhibits cortisol synthesis at the
level of 11-hydroxylase
2. 500mg tid (maximum dose- 6g)
b. Ketoconazole
1. Inhibit the early steps of
steroidogenesis
2. 200mg tid (maximum dose-
1200gm)
c. Mitotane
1. Derivative of the insecticide
o,pDDD
2. Adrenolytic agent effective for
reducing cortisol
3. Most commonly used in the
context of adrenocortical CA
but low dose treatment (500-
1000mg /d)
4. Used in benign Cushings
d. Etomidate
1. In severe cases of cortisol
excess
2. Used to lower cortisol
3. Administered via continuous IV
infusion in low, non-anesthetic
doses

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