Lecture 1.2: CUSHINGS SYNDROME
Inhibits WBC adhesion >
CORTISOL
Source: Adrenal zona Fasicculata.
Bound to corticosteroid-binding
globulin
a. Increases Blood Pressure:
1. Upregulates 1- receptors on
arterioles > Increased sensitivity
to norepinephrine and
epinephrine
2. At high concentrations, can bind
to mineralocorticoid
(aldosterone) receptors
b. Increased Insulin resistance
(diabetogenic)
c. Increased Gluconeogenesis,
Lipolysis and Proteolysis
d. Decreased Fibroblast activity
(causes striae)
e. Decrease Inflammatory and
Immune responses:
1. Inhibits production of
leukotrienes and prostaglandins
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2.
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,
ACTH > Decreased cortisol
secretion
c. Chronic stress induces prolonged
secretion
EPIDEMIOLOGY
Considered a rare disease
Incidence of 1-2 per 100,00 population
/year
Caused by an ACTH- producing
corticotrope adenoma of the pituitary
Affects women, exception of
prepubertal cases that is commonly with
boys
Ectopic ACTH syndrome frequently
identified in men
ETIOLOGY :
A combination of germline and somatic
mutation in the suppressor gene
ARMC5 has been a prevalent cause of
Cushings syndrome due to
macronodular adrenal hyperplasia
CARNEYs COMPLEX
a. A mutation in one of the regulatory
subunits of PKA, PKKAR1A
b. Found in patients with primary
pigmented nodular adrenal disease
(PPNAD)
c. Autosomal dominant multiple
neoplasia associated with cardiac
myxomas, hyperlentiginosis, Sertoli
cell tumors and PPNAD
d. PPNAD can present as
macro/micronodular or both
Mc CUNE-ALBRIGHT SYNDROME
a. Associated with polyostotic fibrous
dysplasia
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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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
central regulatory systems
a. Leading to suppression of
subsequent hypogonadism and
amenorrhea
b. Suppression of the hypothalamic-
pituitary-thyroid axis
1. Resulting in decreased thyroid-
stimulating hormone secretion
Majority of clinical signs and symptoms
observed in Cushings syndrome are
non-specific
a. Obesity
b. Diabetes
c. Diastolic hypertension
d. Hirsutism
e. Depression
Specific features:
a. Fragility of skin
b. Easy bruising
c. Broad (>1cm) purplish striae
 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
Patients with ectopic ACTH syndrome
and with Adrenocortical CA as the
cause of Cushings may have more brisk
onset and rapid progression of clinical
signs and symptoms
Patients with Cushings syndrome can
acutely be:
a. Endangered by deep vein
thrombosis
b. Subsequent pulmonary embolism
** both due to hypercoagulable
states
c. Experience psychiatric symptoms
1. Anxiety or depression
2. Acute paranoia or depressive
psychosis
DIAGNOSIS:
The most important step in the
management of patients with suspected
Cushings syndrome is to establish the
correct diagnosis
The protocol requires establishing the
diagnosis beyond doubt prior to
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employing any tests used for the
differential diagnosis
After exceeding exogenous
glucocorticoid use as the cause of
clinical s/s
a. Suspected cases should be tested if
there are multiple and progressive
features of Cushings--- Particular
features with a potentially higher
discriminatory value
Exclusion of Cushings is abnormally
indicated in patients with incidentally
discerned adrenal masses.
TESTS:
a. Increased 24-h urinary free cortisol
excretion in 3 separate collections
1. Failure to appropriately
suppress morning cortisol after
overnight exposure to
dexamethasone
2. Evidence of loss of diurnal
cortisol secretion with high
levels at midnighttime of the
physiologically lowest secretion
Factors potentially affecting the
outcome of these diagnostic tests have
 to be excluded such as 24-h urine
collection or rapid inactivation of
dexamethasone due to concurrent intake
of CYP-3A4- inducing drugs (e.g.
antiepileptics, rifampicin)
Concurrent intake of oral contraceptives
that raise CBG and thus total cortisol
can cause failure to suppress after
dexamethasone
If in doubttesting should be repeated
after 4-6 weeks off estrogen
Patients with pseudo-Cushing states:
a. Alcohol-related
b. Cyclic cushings
** should require further testing to
safely confirm or exclude diagnosis
of Cushings.
Additionals (From Kaplan USMLE 2017):
The diagnostic tests used to establish the
syndrome of cortisol excess:
a. 1-mg overnight dexamethasone
suppression test
b. 24-hour urine free cortisol
** these tests are used to establish a
precise etiology of the cortisol
excess are the ACTH level, high
dose dexamethasone-suppression
test, CT and MRI scanning and
occasional sampling of the petrosal
venous sinus which drains out of the
pituitary
The 1-mg overnight dexamethasone
suppression test:
a. Used to rule out the diagnosis of
Cushings syndrome or
glucocorticoid excess
b. If you give a milligram of
dexamethasone at 11pm, the cortisol
level at 8am should be normal if
there is normal ability to suppress
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ACTH production over several
hours
c. The problem with this test is that
there can be falsely abnormal or
positive results
d. Any drug that increases the
metabolic breakdown of
dexamethasone will prevent the
ability to suppress cortisol levels---
phenytoin, carbamazepine,
rifampicin (increases the
metabolism of dexamethasone)
e. Stress increases glucocorticoid
levels
f. Can be falsely positive thru:
starvation, bulimia, alcohol
withdrawal, depression
g. An abnormality on the 1mg
overnight test should be confirmed
with a 24-hour urine free cortisol
24-hour urine free cortisol is MORE
ACCURATE and GOLD STANDARD
for confirming or excluding Cushings
syndrome
Third screening test is the MIDNIGHT
SALIVARY CORTISOL.
a. Normal patients: cortisol is low at
midnight
b. Cushings: Abnormally high at
midnight
*** The precise etiology of the Cushings
syndrome is established by ACTH levels.
Sometimes in combination with high-dose
dexamethasone suppression testing:
a. ACTH levels= pituitary source of
ACTH (adenoma/ ectopic source)
b. dose dexamethasone suppression
testing --- suppressed in pituitary
adenoma, nothing happens with the
ectopic source
 c. If ACTH levels- etiology is from
adrenal tumor
d. When the adrenal gland is the source of
increased cortisol production--- there is
a feedback inhibition on the pituitary
and ACTH level is suppressed.
e. When low ACTH levelprecise etiology
can be confirmed thru CT scan
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=
pituitary or ectopic source
b. LOW PLASMA ACTH LEVELS=
adrenal tumors or hyperplasia
DIFFERENTIAL DIAGNOSIS
The evaluation of patients with
confirmed Cushings should be carried
out by an endocrinologist and begins
with differential diagnosis of ACTH-
dependent and ACTH-independent
cortisol excess
Generally, plasma ACTH levels are
SUPPRESSED in cases of autonomous
adrenal cortisol excess
a. As consequence of enhanced
negative feedback to the
hypothalamus and pituitary
Patients with ACTH- dependent
Cushings have normal or increased
plasma ACTH with very high levels
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being found in some patients with
ectopic ACTH syndrome
Imaging should be used ONLY after it
is established whether the cortisol
excess is ACTH-dependent or
independent.
a. Because nodules in the pituitary or
the adrenal are a common finding
in the general population
In patients with confirmed ACTH-
independent excess adrenal imaging (CT
scan) is indicated.
a. Helps distinguish between benign
and malignant adrenal lesions.
For ACTH- dependent cortisol excess
a. An MRI of the pituitary is the
investigation of choice
b. Pituitary corticotrope adenomas fail
to enhance following gadolinium
administration or T1-weighted MRI
images
In all cases of confirmed ACTH-
dependent Cushings, further tests are
required for the differential diagnosis of
pituitary Cushings disease and ectopic
ACTH syndrome
a. Ectopic sources of ACTH are
resistant to dexamethasone
suppression and unresponsive to
CRH
 ** should be noted that a small
minority of ectopic ACTH-
producing tumors exhibit dynamic
responses similar to pituitary
corticotrope tumors.
If 2 tests show conflicting results:
a. Perform Bilateral Inferior Petrosal
Sinus Sampling (IPSS) with
concurrent blood sampling for
ACTH in the Right and Left inferior
petrosal sinus and peripheral vein.
b. An increased central/ peripheral
plasma ACTH ratio >2 at baseline
and >3 at 2-5 minutes after CRH
is INDICATIVE of Cushings
disease--- very high sensitivity and
specificity.
*** IPSS cannot be reliably used for
lateralization (prediction of location
of the tumor within the pituitary) ---
Because there is broad
interindividual variability in the
venous drainage of the pituitary
region.
*** IMPORTANT: NO
CORTISOL-LOWERING
AGENTS should be used prior to
IPSS.
If the differential diagnostic testing
indicates ECTOPIC ACTH-
SYNDROME:
a. Further imaging should include
high-resolution, fine-out CT
scanning of the chest and abdomen
for evaluating the lung, thymus and
pancreas
b. If NO LESIONS IDENTIFIED:
1. MRI of the chest can be
considered because carcinoid
tumors usually show high signal
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intensity on T2-weighted
images
2. Octreotide scintigraphy can be
helpfulEctopic ACTH-
producing tumors express
somatostatin receptors
c. Undergo blood sampling for fasting
gut hormones, chromogramin A,
calcitonin, biochemical exclusion of
pheochromocytoma
TREATMENT:
In ACTH-independent disease:
a. Treatment consists of surgical
removal of the adrenal tumor
1. Smaller tumors: minimally
invasive approach
2. Large tumors and suspected of
malignancy: open approach
In cushings disease
a. Treatment of choice: selective
removal of the pituitary corticotrope
tumor--- via an endoscopic
transphenoidal approach--- cure rate
of 70-80%
b. Long term follow up is important:
may recur late.
c. If recurs:
1. 2nd surgery
2. Radiotherapy
3. Stereotactic radiosurgery
4. Bilateral adrenalectomy
Patients with very severe overt
Cushings (Difficult to control
hypokalemic Hypertension or acute
psychosis):
a. Introduce medical treatment to
rapidly control the cortisol excess
during the period leading up to
surgery
 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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