Last edited: 3/31/2023

CUSHING'S SYNDROME
Cushing's Syndrome Medical Editor: Jude Loyola

OUTLINE
I) PATHOPHYSIOLOGY III) DIAGNOSTIC APPROACH
(A) CORTISOL PATHWAY (A) SCREENING TESTS
(B) EFFECTS IN DIFFERENT ORGAN SYSTEMS (B) ACTH LEVEL
(C) EXCEPTIONS TO CUSHING’S SYNDROME (C) HIGH DOSE DEXAMETHASONE SUPPRESSION TEST
II) CUSHING’S SYNDROME & (D) CRH STIMULATION TEST
(E) IMAGING STUDIES
CUSHING’S DISEASE
(A) CUSHING’S SYNDROME IV) TREATMENT
(B) CUSHING’S DISEASE V) APPENDIX
VI) REVIEW QUESTIONS
VII) REFERENCES

I) PATHOPHYSIOLOGY
(A) CORTISOL PATHWAY (B) EFFECTS ON DIFFERENT ORGAN SYSTEMS
(1) Sympathetic Nervous System and the
Cardiovascular System

Figure 2. Effects of increased cortisol in the SNS and CVS.

Lateral gray horns innervate the viscera
↑↑cortisol

↑↑SNS stimulation → ↑↑NE release from the lateral gray

horns to the viscera
Figure 1. Cortisol pathway.
(i) Effects of SNS stimulation:
Hypothalamus produces CRH → ↑ACTH production from
the anterior pituitary (+) β-1 adrenergic receptors of the conducting system
ACTH → ↑cortisol production from the zona fasciculata and contractile muscles of the heart

(1) Cushing’s Syndrome vs Cushing’s Disease

(+) ⍺-1 receptors of the vessels → ↑↑SVR
Cushing’s Syndrome
o ↑↑cortisol from tumors or hyperplasia o Hypertension that does NOT respond to >3
Cushing’s Disease hypertension
o ↑↑ACTH from pituitary causes
Therefore,
↑↑ Cortisol upregulates both β1 and ⍺1 receptors of
the heart and vasculature → amplifies the response

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(2) Immune System
Figure 3. Effects of increased cortisol in the immune system.
(3) Endocrine/Metabolic
(i) Liver
Figure 4. Diabetogenic effect of increased
cortisol in the liver and pancreas.
(+) gluconeogenesis and
glycogenolysis → ↑↑glucose =
hyperglycemia
o Called the diabetogenic effect of
cortisol
o Gluconeogenesis: taking non-
carbohydrates (amino acids,
glycerol, odd-chain FA) and
converting them to glucose
o Glycogenolysis: break down
glycogen into glucose
(ii) Pancreas
(-) insulin production (see Figure 4)
(4) Reproductive
Figure 9. Reproductive effects of increased cortisol.
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↑↑cortisol suppress the margination response →
neutrophils cannot stick to the vessel wall → ↑↑WBC in
the bloodstream
o Margination: neutrophils slide along the vessel wall
and squeeze through the wall (called diapedesis) to
fight off pathogens
↑↑cortisol suppress T-cell response → (-) T-cell proliferation
↑↑cortisol inhibits Ab production of plasma cells
Therefore,
↑↑Cortisol increases the risk for infection,
especially fungal infection
(iii) Adipose Tissue (iv) Proteins
(+) proteolysis and (-) collagen
synthesis (see Figure 5)
o Break down proteins in muscles,
connective tissues, and bone
tissues to convert them to glucose
Results in:
o Muscle atrophy (especially in proximal muscles)
o Osteopenia → osteoporosis → fractures
 Due to the breakdown of collagen in bones
o Thin skin = abdominal striae (Fig 8),
ecchymoses, slow wound healing
 Collagen is heavy in the dermis to
provide tensile strength →
thickness, and integrity of the skin
Figure 5. Effects of increased cortisol in the
adipose tissue and proteins.
(+) lipolysis = break down
triglycerides in the fat tissue to free FA Fig 6. Moon facies in Cushing's syndrome.
and glycerol
(+) fat redistribution
o Cortisol only has an intracellular
receptor
o Takes adipose from the extremities
and redistributes them to the
central portion of the body →
moon facies (Figure 6), buffalo
hump (Figure 7), abdominal
obesity Fig 7. Buffalo hump in Cushing's syndrome.
Fig 8. Abdominal striae from Cushing's syndrome.
↑↑cortisol → (-) GnRH production in the pituitary
Cushing's Syndrome
 (C) EXCEPTIONS TO CUSHING’S SYNDROME

Recall the two reasons for ↑↑cortisol in Cushing’s:

o From ↑↑ACTH → Cushing’s disease
o From ↑↑cortisol production by the adrenal
regardless of ACTH → Cushing’s syndrome

(1) Acne and Hirsutism

↑↑ACTH → ↑androgens in females = acne and hirsutism
o Not due to ↑cortisol
o Seen likely in patients with a pituitary tumor
Either of the following is ONLY seen in Cushing’s
Disease (d/t a pituitary tumor), NOT in Cushing’s
syndrome
o Acne and hirsutism due to ↑androgens
o Hyperpigmentation due to ↑MSH

Figure 10. Acne and hirsutism seen in patients with Cushing’s

disease. Fig 11. Exceptions to signs and symptoms of Cushing's syndrome.
(2) Hyperpigmentation
↑↑ACTH → ↑melanocyte-stimulating hormone (MSH) →
(+) melanocytes in the skin → ↑melanin production →
hyperpigmentation
II) CUSHING’S SYNDROME & CUSHING’S DISEASE
(A) CUSHING’S SYNDROME (B) CUSHING’S DISEASE

Figure 12. Cushing's syndrome.

Primary Hypercortisolism Figure 13. Cushing's disease.

(1) Causes: (1) Cause:

Tumor of the adrenal gland Pituitary adenoma or small cell lung cancer →
o Adenoma or carcinoma ↑↑ACTH → acts on the adrenal cortex (zona fasciculata)
→ ↑↑cortisol
Iatrogenic
o Small cell lung CA is the most common ectopic
Chronic corticosteroid use
ACTH-producing cancer
o From autoimmune diseases such as rheumatoid arthritis
o Other ectopic locations:
o Corticosteroids > cortisol
 Renal cell CA
 Recall that corticosteroids act like cortisol
 Pancreatic islet tumor
 Eventually, the adrenal gland can atrophy →
↓cortisol production The problem is NOT on the adrenal cortex
o No negative feedback with pituitary adenoma
↑↑cortisol → negative feedback to the pituitary gland →
(-) ACTH production = ↓↓ACTH

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 III) DIAGNOSTIC APPROACH
(A) SCREENING TESTS
Needs 2 out of 3 of the following tests to be positive = Cushing’s
It does not differentiate Cushing’s disease and Cushing’s syndrome
(1) Low Dose Dexamethasone (2) Urinary Cortisol (24-hour) (3) Late Night Salivary Cortisol
Suppression Test

Figure 15. 24-hr urinary cortisol.

Figure 14. Low-dose dexamethasone
suppression test.
Giving the patient 1 mg
dexamethasone should suppress
ACTH production → (-) cortisol
production = ↓cortisol level
Patients with (+) pituitary or
adrenal tumor (Cushing’s) will
NOT respond to this test →
↑↑cortisol after 1-mg
dexamethasone
Collect urine over 24 hours → Figure 16. Late-night salivary cortisol
test.
measure cortisol levels, whether
high or low Measuring cortisol levels in the
(+) Cushing’s: ↑↑cortisol → runs saliva
through the blood and is filtered (+) Cushing’s: ↑↑cortisol in the
by the kidneys → ↑↑cortisol in saliva
the urine
It does NOT differentiate
Cushing’s disease and Cushing’s
syndrome

(B) ACTH LEVEL (C) HIGH-DOSE DEXAMETHASONE SUPPRESSION

TEST

Figure 18. High-dose dexamethasone suppression test.

Determines which secondary cause of hypercortisolism:
pituitary vs ectopic
Measurement of cortisol after 8 mg of dexamethasone
(+) Pituitary tumor = can suppress ACTH → ↓↓ACTH →
Figure 17. Measurement of ACTH levels. ↓↓cortisol
(+) Ectopic site = continues to produce ACTH →
Done if there is ↑↑cortisol
↑↑ACTH → ↑↑cortisol
Can differentiate between Cushing’s disease and
Cushing’s syndrome
↑↑ACTH = Cushing’s Disease due to a pituitary or
ectopic problem
↓↓ACTH = Cushing’s Syndrome due to adrenal tumor or
iatrogenic

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 (D) CRH STIMULATION TEST

Figure 19. CRH stimulation test.

Alternative to high-dose dexamethasone test
CRH → (+) ACTH production
(+) Pituitary tumor = hyperresponsive to CRH due to
upregulated CRH receptors → ↑↑↑ACTH → ↑↑↑cortisol
(+) Ectopic site = low to no response to CRH → ↑ACTH
→ ↑cortisol
o ACTH is not low due to its ACTH production capability

(E) IMAGING STUDIES

Pituitary CT/MRI = shows pituitary adenoma

Figure 23. Algorithm for the management of suspected

Cushing's syndrome [Jameson et al, 2018].

IV) TREATMENT
Table 1. The treatment approach to Cushing's is according to
etiology.
Figure 20. Pituitary adenoma in MRI. ETIOLOGY TREATMENT
Adrenal CT/MRI
Pituitary adenoma Transsphenoidal resection

Adrenal adenoma Ketoconazole OR adrenalectomy

Ectopic etiology Chemoradiation OR ketoconazole

Iatrogenic Taper steroid dose

*Ketoconazole can suppress cortisol production

Figure 21. Adrenal adenoma in CT scan.

CT Chest Abdomen and Pelvis = may show small cell
lung CA or renal cell CA

Figure 24. Treatment approaches to Cushing's syndrome.

Figure 22. Small cell lung CA in CT scan.

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 V) APPENDIX

Table 2. Effects of Hypercortisolism on Different Body Systems.

PATHOPHYSIOLOGY SIGNS AND SYMPTOMS

SNS and CVS ↑↑cortisol → ↑↑activity and sensitivity of SNS: Secondary hypertension
• (+) β-1 AR → ↑↑HR and SV → ↑CO Tachycardia
• (+) ⍺-1 AR → ↑↑SVR → ↑BP

Immune ↑ ↑ cortisol → Infections, especially fungal infections

• (-) margination response of PMNs
• (-) T-cell response
• (-) Ab production of plasma cells

Endocrine/ Liver: ↑ ↑ cortisol → (+) gluconeogenesis and Hyperglycemia → increased risk of

Metabolic glycogenesis diabetes
Pancreas: ↑ ↑ cortisol → (-) insulin production Moon facies, buffalo hump, abdominal
Fat: ↑ ↑ cortisol → (+) lipolysis and (+) fat obesity
redistribution Muscle atrophy, osteopenia
Proteins: ↑ ↑ cortisol → (+) proteolysis and (-) Abdominal striae, ecchymoses, slow
collagen synthesis wound healing

Reproductive ↑↑cortisol → (-) GnRH production in the pituitary → (- ↓libido in males

) FSH and LH Amenorrhea in females

Table 3. Cushing’s Syndrome vs Cushing’s Disease

CUSHING’S SYNDROME CUSHING’S DISEASE

Causes Adrenal adenoma or carcinoma Pituitary adenoma

Chronic exogenous steroid use Small cell lung CA
Renal cell CA, pancreatic islet tumor

Cortisol levels ↑↑ ↑↑

ACTH levels ↓↓ ↑↑

Additional S/Sx (-) Acne and hirsutism

Hyperpigmentation

Table 4. Summary of Diagnostics used in Cushing’s Syndrome.

TEST RESULTS AND INTERPRETATION

Screening Tests

Low Dose Dexamethasone Measure cortisol levels after 1 mg of ↑↑cortisol = Cushing’s

Suppression Test dexamethasone

Urinary Cortisol Measure urine cortisol over 24 hours ↑↑cortisol = Cushing’s

Late Night Salivary Cortisol Measure cortisol in the saliva ↑↑cortisol = Cushing’s

Other Tests

ACTH Measurement of ACTH ↑↑ACTH = Cushing’s disease

↓↓ACTH = Cushing’s syndrome

High Dose Dexamethasone Measure cortisol levels after 8 mg of ↑↑cortisol = Pituitary tumor
Suppression Test dexamethasone ↓↓cortisol = Ectopic tumor

CRH Stimulation Test Alternative to high-dose ↑↑↑cortisol = Pituitary tumor

dexamethasone test ↑cortisol = Ectopic tumor
Measures cortisol after CRH *cortisol from pituitary tumor >>> cortisol from
administration → stimulates ACTH ectopic tumor

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 VI) REVIEW QUESTIONS VII) REFERENCES
1) Which of the following causes Cushing’s disease? ● Loscalzo, J., Fauci, A. S., Kasper, D. L., Hauser, S. L., Longo, D. L.,
& Jameson, J. L. (2022). Harrison's Principles of Internal Medicine.
a) Exogenous steroid use McGraw Hill.
b) Adrenal adenoma
c) Renal cancer
d) Pituitary adenoma
2) Which manifestation can differentiate between
Cushing’s syndrome and Cushing’s disease in the
following patients with high cortisol?
a) Indented streaks on the abdomen
b) Hirsutism on a woman
c) Fat deposition on the central portion of the body
d) Bruising on the upper and lower extremities
3) The following are screening tests for Cushing
syndrome EXCEPT:
a) Low-dose dexamethasone test
b) High-dose dexamethasone test
c) Urinary cortisol
d) Salivary cortisol
4) What is the next step once hypercortisolism is
established?
a) Measure the patient’s ACTH
b) Order cranial and CAP CT scan
c) Give 1 mg of dexamethasone to see if ACTH can be
suppressed
d) Test whether CRH stimulates ACTH production
5) How much dexamethasone should be administered
to determine ACTH suppression in secondary
hypercortisolism?
a) 1 mg
b) 8 mg
c) 100 mcg
d) 800 mcg
6) Which of the following does NOT match their
treatment modality?
a) Pituitary adenoma: transsphenoidal resection
b) Adrenal adenoma : adrenalectomy
c) Exogenous steroids: ketoconazole administration
d) None of the above
7) What PE findings can suggest Cushing’s in a 30-
year-old man who complains of polyuria, polydipsia,
and symmetric joint pains on the elbow and hands?
a) Increased blood pressure
b) Increased fat on the sides of the face
c) Tachycardia
d) All of the above

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