Cushing's syndrome

C U S H I N G ’ S S Y N D R O M E
B Y - D R S A B U A U G U S T I N E
A S S I S T A N T P R O F E S S O R
D E P A R T M E N T O F G E N E R A L M E D I C I N E

H Y P O T H A L M U S - P I T U I T A R Y -
A D R E N A L A X I S

ACTH (+) (-) Cortisol
CRH
(+)
(-)

C U S H I N G ’ S D I S E A S E
• Introduction
• Clinical Features
• Diagnosis
• Treatment

D E F I N I T I O N
• Cushing’s syndrome is a symptom complex associated
with prolonged exposure to inappropriately elevated
levels of free plasma glucocorticoids.
• “Glucocorticoid” covers excess from both endogenous
(cortisol) & exogenous
(eg:Prednisolone,Dexamethasone)
• Cushing syndrome caused by hypersecretion of ACTH
by a pituitary corticotroph adenoma is called Cushing’s
disease

Pituitary ACTH over secretion induces bilateral adrenocortical
hyperplasia
h production of cortisol, adrenal androgens and 11-
deoxycorticosterone
Together provoke the clinical and biologic features of the
disease

E P I D E M I O L O G Y
• Female preponderance. F:M - 3:1 to 10:1
• Common age of presentation : 25-45 yrs
Bertagna et al , Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 607–623

Causes of Endogenous Cushing Syndrome

C L I N I C A L F E A T U R E S

Neiman et al The American Journal of Medicine (2005) 118, 1340-1346
Frequency of clinical signs and symptoms

F A T D I S T R I B U T I O N
• Centripetal fat deposition - most common manifestation
• Most sensitive symptom of the patient
• Although weight gain is classic, it may be minimal.
• Fat accumulates in face and the supraclavicular and
dorsocervical fat pads : Moon face , Buffalo hump
• Fat also accumulates over the thorax and the abdomen,
which becomes protruding

Before After 6 months, with Cushings

P R O T E I N - W A S T I N G F E A T U R E S
• Absent in simple obesity, they have a high diagnostic
value
• Mainly seen in :
• Skin and connective tissue
• Muscle
• Bone
• Immunoglobulins

SKIN AND CONNECTIVE TISSUE
• Atrophy of epidermis and underlying connective tissue
• Thinning - Papery Skin , Best seen over tibial crest
I N C R E A S E D T H I N N I N G + T E N S I O N O N U N D E R L Y I N G F A T
I N C R E A S E D V I S I B I L I T Y O F U N D E R L Y I N G C A P I L L A R I E S
P U R P L E S T R I A E , F A C I A L P L E T H O R A

Nature of striae in Cushings
• Most commonly located on
the abdomen and the flanks,
and also on the breasts, hips
and axillae.
• Typically purple to red
• Depressed surface
• More than 1 cm wide

Easy bruisability
• Minimal trauma generates multiple
ecchymotic/purpuric lesions
especially on forearm
• Blood collection often results in large
ecchymotic lesions
• Minor wounds heal slowly
• Superficial wounds, especially on
lower extremities - Indolent infection
and ulceration

Muscle
• Characteristically proximal wasting - particularly in
the lower limbs
• Preference of involvement of type 2b muscle fibres
• May prevent the patient from getting up from a chair
without help

Bone
• Osteoporosis - Multifactorial
• Vertebral body particularly vulnerable
• Compression fractures of the spine are not uncommon - half of
the patients complain of backache
• Kyphosis and loss of height frequently seen
• Pathological fractures can occur , particularly in the ribs and
pelvis

• Predominantly due to direct effect on Osteoblasts
• Reduced proliferation and matrix synthesis in mature
osteoblasts
• Reduction in intestinal calcium absorption
• Marked hypercalciuria - Direct effect on renal Ca
reabsorption. Renal calculi seen due to this effect.
• Osteoblast sensitivity to parathyroid hormone may be
increased in the presence of glucocorticoids
MECHANISMS OF OSTEOPOROSIS

• Contribute greatly to the morbidity and mortality rate
• Complications include coronary artery disease,
congestive heart failure
• Risk factors persist even after remission
C A R D I O V A S C U L A R
C O M P L I C A T I O N S
Pivonello et al Endocrinol Metab Clin N Am 2005 34;327–339

• Variable in expression and severity and do not correlate with the
intensity of the hypercortisolism
• Most often mild : anxiety, increased emotional lability, irritability,
sleep disorders or unwarranted euphoria
• Severe psychotic symptoms may occur: Depression, maniac
disorders, delusions and hallucinations
• Short term memory may be impaired
• In many cases controlling the hypercortisolism results in dramatic
improvement with complete disappearance of manifestations
P S Y C H O L O G I C A L S Y M P T O M S
Bertagna et al , The pituitary 3rd edition

• Increase blood glucose concentrations through their action on
glucose, protein, and lipid metabolism
• Reduced glucose tolerance - 21- 64%
• Diabetes mellitus- 20- 47%
• Increased plasma Insulin levels reflect the state of insulin
resistance
• Functions of the pituitary-thyroid axis and the pituitary-gonadal
axis are suppressed in patients with Cushing’s syndrome
because of a direct effect of cortisol on TSH and gonadotropin
secretion
E N D O C R I N E F E A T U R E S

• Hirsutism is extremely frequent
• Excess adrenal androgens and cortisol - Suppress the
gonadotroph function
• Most female patients have oligomenorrhoea and
amenorrhoea, and infertility is frequent.
• In male patients: Dramatic fall in testosterone - Loss of
libido and diminished sexual performance
• Loss of pubic hair and reduced testis size are observed
E F F E C T O F E X C E S S A D R E N A L
A N D R O G E N S

• ACTH levels are only moderately elevated
• Hyperpigmentation is almost never observed in the
usual, uncomplicated forms
• More frequently seen in Ectopic ACTH secretion or in
CD with Nelson’s syndrome when treatment is directed
primarily at the adrenals
A C T H R E L A T E D F E A T U R E S

• Cyclic cortisol production is present in about 20–40% of patients
• Episodes of active hypercortisolism are separated by periods of
normal pituitary-adrenal activity of varying length
• Patients commonly complain of swelling from time to time
• 24 hour urinary cortisol studies / Midnight Salivary cortisol when
symptoms recur are recommended screening tests
C Y C L I C A L D I S E A S E
Meinardi, European Journal of Endocrinology (2007) 157 245–254

• Cushing’s disease almost invariably provokes
growth retardation
• A decrease in growth rate may be the sole symptom
in mild forms of the disease, where the final
diagnosis is often delayed.
• Weight gain with centripetal obesity, is present in
most cases however
C U S H I N G S D I S E A S E I N C H I L D R E N

• Pregnancy occurs rarely in a hypercortisolic woman
• Presence of exaggerated morphological changes, virilism and
especially catabolic features and hypokalemia, should raise
suspicion
• Associated with a high rate of maternal and fetal complications
• Maternal Complications: HTN , Impaired glucose tolerance , Pre-
eclampsia common
• Fetal complications : Prematurity (45%) , IUGR (20%) , Miscarriages
(5%) and stillbirths (6%)
C U S H I N G S D I S E A S E I N
P R E G N A N C Y

W H O S H O U L D B E T E S T E D ?
• Patients with unusual features for age (e.g. osteoporosis,
hypertension)
• Patients with multiple and progressive features, particularly
those that are more predictive of Cushing’s syndrome
• Children with decreasing height percentile and increasing
weight
Neiman et al J Clin Endocrinol Metab, May 2008, 93(5):1526–1540

Features which best discriminate Cushing’s Syndrome–
easy bruising
facial plethora
proximal myopathy
striae (reddish purple & > 1cm wide)

D O E S T H E P T H A V E C U S H I N G ’ S
• Exclude Exogenous Steroid Intake
• Perform one of the following initial tests based on suitability
for Patient:
1. Urinary Free Cortisol (at least two measurements) - h
Cortisol Production
2. Late-night salivary cortisol (two measurements) - Failure
to reach nadir of circadian Rhythm
3. 1-mg overnight DST / Longer low-dose DST (2 mg/d for
48 h) - Attenuated sensitivity to glucocorticoid feedback

U R I N A R Y F R E E C O R T I S O L ( U F C )
• Provides an integrated assessment of cortisol
secretion over a 24-h period
• It measures the cortisol that is not bound to Cortisol-
Binding Globulin (CBG), which is filtered by the kidney
unchanged

• Upper limit of normal for the particular assay is taken as the
criterion for a positive test
• High fluid intake (5 liters/d) significantly increases UFC
• Values are significantly lower in patients with moderate to
severe renal impairment
• False positive results seen with drugs like Carbamazepine
and fenofibrate

L A T E N I G H T S A L I V A R Y C O R T I S O L
• In healthy individuals with stable conventional sleep- wake
cycles:
• Serum cortisol begins to rise at 0300–0400 h
• Reaches a peak at 0700–0900 h
• Falls for the rest of the day to very low levels at midnight
 h in blood cortisol reflected by a change in the salivary
cortisol concentration within a few minutes

• Saliva collected either by passive drooling into a
plastic tube or by placing a cotton pledget (salivette) in
the mouth and chewing for 1–2 min
• Sample stable at room or refrigerator temperature for
several weeks
C U T O F F V A L U E : > 1 . 4 5 N G / M L

• The salivary glands express 11 B-HSD type 2— converts
the biologically active cortisol to inactive cortisone
• Licorice or chewing tobacco (contain the 11B-HSD2
inhibitor glycyrrhizic acid) - falsely elevated late-night
salivary cortisol
• Circadian rhythm blunted in many patients with depressive
illness and in shift workers and in the critically ill
• Timing of the collection adjusted to the time of sleeping for
those with bedtimes after midnight

D E X A M E T H A S O N E S U P R E S S I O N
T E S T S
Overnight Dexamethasone Supression Test (ODST)
• Dexamethasone is used for suppression testing because it
does not cross-react in radioimmunoassays for cortisol.
• Normal response : Serum cortisol < 1.8 μg/dl
• Sensitivity ~ 95% , Specificity - 80 %
1 M G D E X A M E T H A S O N E G I V E N A T 1 1 : 0 0 P M
S E R U M C O R T I S O L M E A S U R E D B E T W E E N 0 8 0 0 A N D 0 9 0 0 A M
T H E F O L L O W I N G M O R N I N G

Low dose Dexamethasone Suppression Test (LDDST)
• Normal response : Serum cortisol < 1.8 mcg/dl
• Sensitivity ~ 95 % , Specificity - 70 %
S E R U M C O R T I S O L M E A S U R E D A T 0 9 0 0 H
D E X A M E T H A S O N E I S G I V E N I N D O S E S O F 0 . 5 M G
F O R 4 8 H , B E G I N N I N G A T 0 9 0 0 H O N D 1 , A T 6 - H
I N T E R V A L S , I . E . A T 0 9 0 0 , 1 5 0 0 , 2 1 0 0 , A N D 0 3 0 0 H
S E R U M C O R T I S O L M E A S U R E D 6 H A F T E R T H E
L A S T D O S E O F D E X A M E T H A S O N E

• In both the supression tests the negative feedback
doesn’t happen. Hence high cortisol levels are
diagnostic of Cushing’s Syndrome.
• Once the presence of Cushing’s syndrome is
confirmed, measurement of plasma ACTH is the key to
establishing the differential diagnosis.
• In the presence of excess cortisol secretion, an
undetectable ACTH indicates an adrenal cause, while
ACTH levels greater than 3.3 pmol/L (15 pg/mL)
suggest a pituitary cause or ectopic ACTH.

I F R E S U L T S A R E E Q U I V O C A L
• Midnight Serum Cortisol
• Dexamethasone - CRH Test

M I D N I G H T S E R U M C O R T I S O L
• Blood sample must be drawn within 5–10 min of
waking the patient, or through an indwelling line
• Sensitivity - 100 % when 1.8 mcg/dl taken as cut off
• Value < 1.8 effectively eliminates Cushing’s in doubtful
cases
Sleeping midnight serum cortisol

• Sleeping midnight cortisol requires inpatient admission
for a period of 48 h or longer to avoid false-positive
responses due to the stress of hospitalisation
• Because the test is cumbersome to perform, not used
as initial testing for Cushing’s syndrome

D E X A M E T H A S O N E - C R H T E S T
• To improve the sensitivity of low-dose DST (LDDST)
• In pituitary-dependent Cushing’s disease, ACTH
secretion is suppressed by highdose dexamethasone.
• If given CRH, patients with Cushing’s disease should
respond with an increase in ACTH and cortisol
• Ideal test to differentiate from Pseudo-cushing states

A D M I N I S T E R A T I O N O F 4 8 - H 2 M G / D D S T
A D M I N I S T R A T I O N O F C R H ( 1 M C G / K G , I V ) 2 H A F T E R T H E
L A S T D O S E O F D E X A M E T H A S O N E
C O R T I S O L I S M E A S U R E D 1 5 M I N L A T E R
• Cut off : 1.4 mcg/dl
• Sensitivity : 98% with high negative predictive value
• Specificity : 60 %
• Complexity and costs make it unsuitable as a screening
procedure
• Low specificity points against its routine use as a confirmatory
procedure
Reimondo et al European Journal of Endocrinology 2008 159 569–576

Pseudo Cushing's
Alcohol
Obesity
Depression
Pregnancy

I S I T A C T H D E P E N D E N T O R
I N D E P E N D E N T ?
ACTH levels
Normal 9-52 pg/ml at
9:00 AM

W H A T I S T H E S O U R C E O F A C T H ?
• Dynamic studies
• CRH stimulation test
• High Dose Dexamethasone Supression Test
(HDDST)
• Desmopressin test
• MRI pituitary
• Inferior Petrosal Sinus Sampling

Pituitary MRI obtained with standard spin echo and SPGR techniques
Lonser et al J Clin Endocrinol Metab, March 2013, 98(3):892–901

G O A L S O F R X
• To correct adrenocortical oversecretion
• Ablate or destroy the primary tumoral lesion
• To conserve anterior pituitary functions and restore a
normal HPA axis
• To reverse the peripheral manifestations of chronic
steroid excess
Biller et al , J Clin Endocrinol Metab. July 2008, 93(7):2454 –2462

T R E A T M E N T M O D A L I T I E S
• Pituitary Directed Treatment
• Adrenal directed Treatment
• Glucocorticoid Antagonists

P I T U I T A R Y D I R E C T E D T H E R A P Y
• Surgery
• Radiotherapy
• Medical therapy

• Selective pituitary adenomectomy is the treatment of
choice
• Trans-sphenoidal approach
S U R G E R Y

• Trans-sphenoidal surgery carried out by an
experienced surgeon with selective removal of the
adenoma is the treatment of choice, with
approximately 70% of patients going into immediate
remission.
• Around 20% of patients suffer a recurrence, years
later, emphasising the need for life-long follow-up.

W H A T I F H Y P E R C O R T I S O L I S M P E R S I S T S ?
• Review Diagnosis
• If Cushing’s disease confirmed :
• Repeat surgery
• Bilateral Adrenalectomy
• Radiotherapy/Radiosurgery

• Laparoscopic bilateral adrenalectomy effectively cures
ACTH-dependent Cushing’s syndrome, but in patients
with pituitary dependent Cushing’s syndrome, this can
result in Nelson’s syndrome, (invasive pituitary
macroadenoma and very high ACTH levels causing
pigmentation)

R A D I O T H E R A P Y
• Indications:
• Adjunct therapy in Surgical Failures
• Primary therapy in patients who cannot
undergo/refuse surgery
• Patients who undergo bilateral adrenalectomy to
reduce the risk of Nelson’s syndrome

S T E R E O T A C T I C R A D I O S U R G E R Y
• Gamma knife most widely used
• Achieves high precision and can deliver a fixed dose
of radiation to smaller focussed areas
• Complete treatment is achieved in a single painless
session of 5-30 minutes
• However efficacy same as conventional

D I S A D V A N T A G E S O F R A D I O T H E R A P Y
• Slow onset of action
• High risk of hypopituitarism - Predominantly Growth
hormone deficiency
• Risk of damage to optic tract/chiasma - More with
conventional (in doses > 50 gy)

M E D I C A L T R E A T M E N T
• SST5 (somatostatin-receptor subtype 5) Receptor
Antagonists – 'Pasireotide'
• Dopamine agonists – 'Cabergoline'

PASIREOTIDE
• Corticotroph adenomas express somatostatin receptors,
predominantly somatostatin-receptor subtype 5
• Activation of this receptor inhibits corticotropin secretion
• targets four of the five somatostatin receptors, with
highest affinity for subtype 5
• Adverse effects : Transient GI discomfort,
Hyperglycemia

CABERGOLINE
• D2receptor is expressed in more than 75% of
corticotroph pituitary adenomas
• 30- 40% of patients with Cushing’s disease respond to
the dopamine agonist cabergoline with a normalisation
of cortisol production
• Side effects include dizziness, nausea, postural
hypotension
Pivonello et al J Clin Endocrinol Metab, January 2009, 94(1):223–230

A D R E N A L D I R E C T E D T H E R A P Y
• Surgery
• Medical Treatment
• Adrenolytic drugs
• Inhibitors of cortisol synthesis
• Antiglucocorticoid Drugs

S U R G E R Y
Total Bilateral Adrenalectomy
• Advantages:
• Constant and immediate control of hypercortisolic state
• No risk of Hypopituitarism
• Disadvantages:
• High mortality and morbidity of procedure
• Lifelong supplementation of steroids
• Nelson’s syndrome

N E L S O N ’ S S Y N D R O M E
• Association of an expanding pituitary tumor and a high ACTH
concentration after adrenalectomy in patients with Cushing’s
disease
• Prevalence : 8 - 29 %
• Pituitary MRI and ACTH plasma level measurements are
advised 3– 6 months after bilateral adrenalectomy and then at
regular intervals thereafter
• High plasma ACTH level in the year after bilateral adrenalectomy
may be a predictive factor for corticotroph tumour progression
Assie et al J Clin Endocrinol Metab, January 2007, 92(1):172–179

M E D I C A L T R E A T M E N T
• Used for preoperative preparation of patients to correct
severe complications of the disease
• Also suitable for patients awaiting a response to
radiation therapy and whenever a palliative treatment
is needed
• Effective in the majority of patients in a dose-
dependent manner

A D R E N O L Y T I C D R U G S
• Mitotane - specifically targets the adrenal cortex

I N H I B I T O R S O F C O R T I S O L S Y N T H E S I S
Ketoconazole
Metyrapone
Etomidate
• All of those compounds exert an almost immediate
effect on cortisol production
• Long-term benefit in patients with Cushing’s disease is
countered by the inevitable increase in ACTH, which
may overcome their partial blocking effect

G L U C O C O R T I C O I D A N T A G O N I S T S
• Mifepristone is an antagonist to both the progesterone and
glucocorticoid receptors
• FDA approved for management of Diabetes to control
hyperglycemia secondary to hypercortisolism in adults with
endogenous Cushing’s syndrome who have failed surgery or
are not candidates for surgery
• Dosage: 300 - 1200 mg OD
• Side effects include GI symptoms, hypokalaemia,
hypertension, irregular menses, endometrial hyperplasia, rash
Nieman Curr Opin Endocrinol Diabetes Obes. 2013 August ; 20(4): 330–334

S U M M A R Y
• Cushing syndrome caused by hypersecretion of
ACTH by a pituitary corticotroph adenoma is
called Cushing’s disease.
• Clinical suspicion is based on a combination of
sensitive (central obesity) and specific (related to
protein wasting) signs.
• Initial work up consists of measuring
ODST/Midnight cortisol levels/24 hr UFC.

S U M M A R Y
• The final diagnosis requires sophisticated
hormonal testing and imaging procedures .
• Pituitary surgery by the trans-sphenoidal route is
the first-line therapeutic option.
• Bilateral adrenalectomy gives upto 100%
remission.

A Checklist for Use Prior to the Administration of
Glucocorticoids in Pharmacologic Doses
• -Presence of tuberculosis or other chronic infection (chest x-
ray, tuberculin test)
• -Evidence of glucose intolerance or history of gestational
diabetes mellitus
• -Evidence of preexisting osteoporosis (bone density
assessment)
• -History of peptic ulcer, gastritis, or esophagitis
• -Evidence of hypertension or cardiovascular disease
• -History of psychological disorders

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