Cushing’s Syndrome

Gatot Sugiharto, dr. SpPD

MiniLecture Cushing- GSH 2020

EMBRYOLOGY OF ADRENAL GLAND
ANATOMY OF ADRENAL GLAND
HISTOLOGY OF ADRENAL GLAND
STEROIDOGENESIS : biosynthesis of cortisol & adrenal androgen
MECHANISM OF ACTION OF ADRENAL STEROID HORMONE → SIGNAL TRANSDUCTION
BIOLOGIC EFFECTS OF GLUCOCORTICOID
PHARMACOLOGY OF STEROID: CORTICOSTEROID
THERAPEUTIC CORTICOSTEROIDS
ADRENOCORTICAL DISEASES : CUSHING’S SYNDROME

Outline topics
MiniLecture Cushing- GSH 2020
Anatomy & histology

MiniLecture Cushing- GSH 2020

HORMONAL
STIMULATION OF
ADRENAL STEROID
BIOSYNTHESIS

MiniLecture Cushing- GSH 2020

 MECHANISM OF ACTION OF
ADRENAL STEROID HORMONE

MiniLecture Cushing- GSH 2020

 EFFECTS OF CORTICOSTEROID

MiniLecture Cushing- GSH 2020

PHARMACOLOGY OF STEROID
• CS : caused by prolonged exposure to elevated levels of either
endogenous or exogenous glucocorticoids.
• exogenous glucocorticoids, in an emergency situation, the most
common cause of Cushing
• Exogenous steroids causing suppression of the hypothalamic-pituitary-
adrenal (HPA) axis that can last for as long as a year after exogenous
steroid administration has ended.
• HPA axis suppression  decrease steroid production, especially during
a medical illness or other stress  need to receive stress doses of
steroids to avoid adrenal crisis.

Introduction : Cushing's syndrome

MiniLecture Cushing- GSH 2020
 Caused by excess levels of either :
• Exogenously administrated glucocorticoids
• Endogenous overproduction of cortisol
• ACTH Independent :
• Primary adrenocortical neoplasm (usually adenoma, rarely carcinoma)
• Bilateral micronodular hyperplasia
• Macronodular hyperplasia (rare)
• ACTH-dependent / ACTH-secreting neoplasms :
• Anterior pituitary tumor, ie, classic Cushing disease (80%).
• Ectopic sources or non-pituitary ectopic sources of ACTH (oat cell, small-cell lung carcinoma, or
carcinoid tumor)
• Some rare cases : ectopic corticotropin-releasing hormone (CRH)

Classification
MiniLecture Cushing- GSH 2020
• US: majority of cases due to exogenous glucocorticoids.
• Annual incidence endogenous hypercortisolism : 13 cases per million individuals.
• 70% are due to Cushing disease, with a pituitary ACTH-producing tumor; 15% to ectopic
ACTH; and 15% to a primary adrenal tumor.
• Mortality/Morbidity : adrenocortical carcinomas are associated with a 5-year survival rate
of 30%
• Medical problem result from exposure to excess glucocorticoids : hypertension,
obesity, osteoporosis, fractures, impaired immune function, impaired wound
healing, glucose intolerance, and psychosis.
• Female to male incidence ratio 5:1 with peak incidence between ages 25-40 yo

Epidemiology:
MiniLecture Cushing- GSH 2020
Patients with CS may complain :
• Weight gain, especially in the face, supraclavicular region, upper back, and torso.
• Changes in their skin, including purple stretch marks, easy bruising, and other signs of skin thinning.
• Irregular menses and hirsutism, decreased libido, infertility, and impotence in men
• Progressive proximal muscle weakness : difficulty climbing stairs, getting out of a low chair, and
raising their arms.
• Psychological problems : depression, cognitive dysfunction, and emotional lability
• New onset or worsening of HT & DM, difficulty with wound healing, increased infections, osteopenia,
and osteoporotic fractures
• ACTH-producing pituitary tumor (Cushing disease) : headaches, polyuria and nocturia, visual
problems, or galactorrhea.
• Mass effect from the tumor : hyposomatotropism, hypothyroidism, and hypogonadism may develop.

Anamnesis/History:
MiniLecture Cushing- GSH 2020
 Increased adipose tissue in the face Facial plethora (mainly over the cheeks),

Head & truncal :

(moon facies), upper back at the base of
neck (buffalo hump), & supraclavicular
fat pads.
Central obesity w/ increased adipose
tissue in the mediastinum and
peritoneum; increased waist-to-hip ratio
greater than 1 in men and 0.8 in
Skin
Violaceous striae (most commonly at
abdomen, buttocks, lower back, upper
thighs, upper arms, and breasts)
Ecchymoses , telangiectasias , purpura,
cutaneous atrophy with exposure of
subcutaneous vasculature tissue and tenting
of skin.
Hirsutism and male pattern baldingin
women, increased lanugo facial hair.
Steroid acne, consisting of papular or
pustular lesions over the face, chest or back
Acanthosis nigricans at common sites : axilla,
elbows, around the neck, and under the
breasts  associated with insulin resistance
and hyperinsulinism.

Physical Examination(1)
MiniLecture Cushing- GSH 2020
 Hypertension, Peptic Proximal muscle Emotional

Neuropsychological
Skeletal/muscular
Gastroenterologic
Cardiovascular/renal weakness, liability, fatigue,
volume ulceration,
expansion : particularly at osteoporosis lead and depression.
edema ec risk when given to incident Bitemporal
sodium and high doses of fractures and blindness &
water retention. glucocorticoids kyphosis, height blurred vision
(rare in loss, and axial (large ACTH-
ASHD caused by skeletal bone
lipid endogenous producing
hypercortisolism pain. pituitary tumors
abnormalities
). Avascular involve optic
necrosis of the chiasma)
hip

Physical Examination(2)
MiniLecture Cushing- GSH 2020
 Hypothyroidism, galactorrhea Hypotension, abdominal pain,

Adrenal crisis
Endocrine
/hyperprolactinemia (anterior pituitary vomiting, and mental confusion,
tumors compress the pituitary stalk, hypoglycemia, hyperkalemia,
leading to levels.
hyponatremia, and metabolic
Polyuria and nocturia from diabetes acidosis.
insipidus.
Menstrual irregularities, amenorrhea,
and infertility (Low estrogen levels)
Decreased testicular volume (Low
testosterone levels).
Increase HDL, LDL chol,
hypertriglycerides, hypokalemia &
metabolic alkalosis

Physical Examination(3)
MiniLecture Cushing- GSH 2020
 Exogenous steroid administration
• Common : oral steroids, occasionally injections of steroids
into joints and the use of steroid inhalers
• Risk : organ transplants, rheumatologic, pulmonary,
neurological, and nephrologic diseases.

Endogenous glucocorticoid overproduction

• Primary adrenal lesions
• Adrenal adenoma/carcinoma, or macro/micro nodular adrenal
hyperplasia, secrete both glucocorticoids and androgens but
generally do not secrete aldosterone
• ACTH-producing pituitary adenoma, if large  loss of
production of other hormone
• Ectopic ACTH (oat cell, small-cell lung tumors, carcinoid tumors)

Causes
MiniLecture Cushing- GSH 2020
 Diagnosis of excess
Lekositosis >
endogenous cortisol
11,000/mm3,
production requires the
Hypokalemic, metabolic
demonstration of
alkalosis (common at
inappropriately high
urinary free cortisol
serum cortisol levels or
(UFC) > 1500 mcg/24-h.
its urinary metabolites.
Acute illness activates
Histopathology :
• Diffuse adrenal cortical
the HPA axis, resulting in
hyperplasia (60-70%)
increases in ACTH and
• Nodular adrenal cortical
cortisol, the laboratory
hyperplasia(15-20% of
workup should not be
cases)
performed when
subjects are acutely ill.

Lab Studies
MiniLecture Cushing- GSH 2020
24-hour UFC test Excellent indicator of overall daily cortisol production
Values > 3- 4-times the upper limit of normal are very suggestive
Values 1-3-times : are consider either pseudo-Cushing or Cushing syndrome.
Over night 1-mg Ingestion of 1 mg dexamethasone at 11 PM, with measurement of an 8-AM serum
dexamethasone cortisol the next morning.
suppression test Normal < 2-3 mcg/dL, may be excluded if cortisol < 1.8 mcg/dL.

False-pos Obesity, alcoholism, CKD, affective disorders, anorexia, and bulimia (raises cortisol
secretion), medications (increase corticosteroid-binding globulin) : estrogen and
tamoxifen

False neg Medications that facilitate the metabolism of dexamethasone (phenobarbital,

phenytoin, rifampin)

Screening tests for Cushing syndrome

MiniLecture Cushing- GSH 2020
48-hour low-dose dexamethasone suppression test (0.5 mg dexamethasone
PO q6h for 8 doses)

24-hour urinary
CRH stimulation: Ovine CRH (1 mcg/kg IV) is given 2
17-hydroxyl
corticosteroids <
hours after the 8 dose of 0.5 mg dexamethasone.
4 mg during the 15 minutes after
second day of
dexamethasone
ovine CRH Late-evening serum cortisol > 7.5
administration :
ingestion. cortisol level > 1.4
mg/dL is very
mcg/dL is suggestive of Cushing
(sensitivity &
specificity 70%) suggestive of
Cushing syndrome
syndrome.

Other tests that may be useful

MiniLecture Cushing- GSH 2020
 Plasma ACTH (measured by an immunoradiometric assay)
• < 5 pg/mL is suggestive of a primary adrenal tumor.
• > 10-20 pg/mL is consistent with Cushing disease (ACTH dependent)

Over night 8-mg dexamethasone suppression test

• Ingest 8 mg dexamethasone orally at 11 PM, measurement of an 8-AM cortisol the next day.
• Suppression of serum cortisol < 50% of baseline is suggestive of a pituitary source of ACTH
rather than ectopic ACTH or primary adrenal disease.

48-hour high-dose dexamethasone suppression test

• Ingest 2 mg dexamethasone every 6 hours for 8 doses.
• UFC < 50% of baseline is suggestive of an anterior pituitary adenoma rather than ectopic
ACTH or a primary adrenal tumor.

Determination of etiology of excess glucocorticoid

secretion
MiniLecture Cushing- GSH 2020
Abd-CT scan
• Recommended for primary adrenal problem/ectopic ACTH
• Adrenal mass > 4-6 cm raises is possible  CT-guided FNAB.

Contrast-enhanced MRI : study of the pituitary

Inferior petrosal sinus (IPS) sampling study : lateralizing occult lesion & for guiding for
surgical therapy.
Chest-CT scan : for suspected ectopic ACTH production.

Octreotide/somatostatin scintigraphy : detecting ectopic ACTH from neuroendocrine

Imaging Studies:
MiniLecture Cushing- GSH 2020
• Directed to primary cause of the syndrome.
• In general : reduce the cortisol secretion to normal
• Surgical resection of the causative tumor (transsphenoidal surgery, adrenalectomy)
• When surgery is not successful or cannot be used : medication or pituitary radiation
• Exogenous Cushing syndrome : gradual withdrawal of glucocorticoid.
• Agents that inhibit steroidogenesis : mitotane, ketoconazole, metyrapone,
aminoglutethimide, trilostane, and etomidate.
• Hormone replacement
• Indicated for endogenous Cushing syndrome who undergo surgical resection during intraoperative &
immediate postoperative period.
• Hydrocortisone at 200-300 iv, either continuously or in boluses (60-100 mg every 8 h) starting prior to
surgery and for the first 24 hours afterwards.
• In the event of pituitary destruction or bilateral adrenalectomy, lifelong steroid replacement is
necessary.

Management :
MiniLecture Cushing- GSH 2020
• Treat pre-existing comorbid conditions that may increase risk of GC-associated AEs
• Prescribe lowest effective GC dose for minimum period of timerequired to achieve treatment goals
• Administer as single daily dose (given in the morning), if possible
• Consider intermittent or alternate-day dosing, if possible
• Use GC-sparing agents whenever possible (e.g., omalizumab in severe asthma, azathioprine/ cyclophosphamide in
vasculitis, methotrexate in rheumatoid arthritis)
• Advise patients to:
- Carry a steroid treatment card
- Seek medical attention if they experience mood or behavioural changes
- Avoid contact with persons that have infections, such as shingles, chickenpox, or measles (unless they are immune)
- Not discontinue GC therapy abruptly unless advised to do so by their physician

▪ Adopt lifestyle recommendations to minimize the risk of weight gain or other AEs:
- Eat a healthy balanced diet, including adequate calcium intake, Smoking cessation, Reduction in alcohol
consumption, Regular physical activity
• Regularly monitor for signs/symptoms of AEs

General strategies for the prevention

MiniLecture Cushing- GSH 2020
 Increased Diabetes
Osteoporosis susceptibility to Hirsutism mellitus
infections /insipidus

Risk for adrenal Panhypopituitari

Hypertension
crisis sm

Complications of Cushing syndrome

MiniLecture Cushing- GSH 2020
 Effective diagnosis and management of Cushing disease
often is facilitated by multiple disciplines
Internist/endocrinologist
Pediatrist/endocrinologist
General/neurosurgeon, urologist, Oncologist
Radiologist intervention
Clinical pathology

Consultations and Referral

MiniLecture Cushing- GSH 2020
General sign of
Chusing’s syndrome

https://doctorlib.info/physiology/pathophysiology/123.html
Moo
n
face
 MiniLecture Cushing- GSH 2020
Facies Plethoric
Buffalo hump (bull neck,
dorso-cervical fat pad)
Supraclavicular fat pad
Purple/pinkish striae
Skin bruises
Truncal obesity
Facial hirsutism + acne
Pituitary adenoma on CT scanning
Thank You
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MiniLecture Cushing- GSH 2020

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MiniLecture Cushing- GSH 2020