Cushing syndrome

(Hypercortisolism)
Summary
Cushing syndrome, or hypercortisolism, is an endocrine disorder that is most often
caused iatrogenically by the exogenous administration of glucocorticoids. Less commonly,
Cushing syndrome can result from endogenous overproduction of cortisol. Primary
hypercortisolism is the result of autonomous overproduction of cortisol by the adrenal
gland (e.g., adrenal adenoma, adrenal carcinoma). Secondary hypercortisolism, on the other hand,
is the result of increased production of adrenocorticotropic hormone (ACTH), either by pituitary
microadenomas (Cushing disease) or by ectopic, paraneoplastic foci (e.g., small cell lung cancer).
Typical clinical features include central obesity, thin, easily bruisable skin,
abdominal striae, secondary hypertension, hyperglycemia, and proximal muscle weakness. Since
serum cortisol levels vary diurnally, 24-hour urine cortisol measurement, midnight
saliva cortisol levels, and/or dexamethasone suppression test are used to diagnose
hypercortisolism. Serum ACTH levels and CRH stimulation test are used to identify the cause of
hypercortisolism, imaging is then employed to localize the tumor. Treatment of endogenous
hypercortisolism primarily involves surgical removal of the source of
excessive cortisol (e.g., adrenalectomy) or ACTH (e.g., transsphenoidal hypophysectomy). If
surgery is contraindicated, drugs that suppress cortisol synthesis (e.g., metyrapone) may be used
instead.
Etiology

Exogenous (iatrogenic) Cushing syndrome

• Prolonged glucocorticoid therapy → hypercortisolism
→ decreased ACTH → bilateral adrenal atrophy
• Most common cause of hypercortisolism

While adrenal adenomas occur more commonly among adults, adrenal carcinomas occur more
commonly among children.

Most pituitary adenomas that produce ACTH are microadenomas (< 10 mm in size). Therefore,
clinical features associated with macroadenomas (e.g., hypopituitarism, visual field defects) are
usually absent.
Clinical features
• Skin [2]

o Thin, easily bruisable skin with ecchymoses

o Stretch marks (classically purple abdominal striae)

o Hirsutism

o Acne

o If secondary hypercortisolism: often hyperpigmentation (darkening of the skin due to an overproduction

of melanin), especially in areas that are not normally exposed to the sun (e.g., palm creases, oral cavity)

▪ Caused by excessive ACTH production because melanocyte-stimulating hormone (MSH) is

cleaved from the same precursor as ACTH called proopiomelanocortin (POMC)

▪ Not a feature of primary hypercortisolism

o Delayed wound healing

o Flushing of the face

• Neuropsychological: lethargy, depression, sleep disturbance, psychosis

• Musculoskeletal [2]

o Osteopenia, osteoporosis, pathological fractures, avascular necrosis of the femoral head

o Muscle atrophy/weakness

• Endocrine and metabolic [3]

o Insulin resistance → hyperglycemia (see “Diabetes mellitus”) → mild polyuria in the case of

severe hyperglycemia

o Dyslipidemia

o Weight gain characterized by central obesity, moon facies, and a buffalo hump
o ♂: Decreased libido

o ♀: Decreased libido, virilization, and/or irregular menstrual cycles (e.g., amenorrhea)

o Growth delay (in children)

• Other features [1]

o Secondary hypertension (∼ 90% of cases)

o Increased susceptibility to infections (due to immunosuppression)

o Peptic ulcer disease

o Cataracts
Diagnostics

General laboratory findings [4]

• Hypernatremia, hypokalemia, metabolic alkalosis

• Hyperglycemia: due to stimulation of gluconeogenesis enzymes (e.g., glucose-6-phosphatase) and inhibition
of glucose uptake in peripheral tissue

• Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia)

• Leukocytosis (predominantly neutrophilic), eosinopenia [5][6]

Screening for hypercortisolism [7]

Any of the following can be used as a screening test for hypercortisolism :

• ↑ 24-hour urine cortisol (> 3 times the normal value i.e. > 300 μg/24 h) [2]

• ↑ Early morning serum cortisol levels (> 50 nmol/L) following a low-dose dexamethasone suppression test [8]

• ↑ Midnight salivary cortisol (> 4 nmol/L) [9]

• ↑ Midnight serum cortisol (> 7.5 μg/dL) [10]

Identifying the cause of hypercortisolism

Hormone analysis

Once glucocorticoid therapy has been ruled out, the following tests are used to identify the cause of hypercortisolism:

1. Serum ACTH levels

o Low (< 5 pg/mL): suspect primary hypercortisolism (adrenal adenoma, carcinoma)

o Normal or elevated (> 20 pg/mL): suspect secondary hypercortisolism

2. If secondary hypercortisolism is suspected: one of the following tests may be used to differentiate

between Cushing disease and ectopic ACTH production

o High-dose dexamethasone suppression test

▪ Adequate suppression of cortisol levels to less than 50% of baseline: Cushing

disease

▪ No suppression: ectopic ACTH production

o CRH stimulation test

▪ ACTH and cortisol levels increase further: Cushing disease

▪ No increase in ACTH or cortisol levels: ectopic ACTH production

Imaging to localize the tumor

• CT and/or MRI of the abdomen: for adrenal tumors (if primary hypercortisolism is suspected)
o The adrenal cortex contralateral to the tumor shows atrophy due to

reduced ACTH stimulation.

o In Cushing disease, CT and/or MRI of the abdomen shows bilateral hyperplasia of both

the zona fasciculata and zona reticularis.

• CT and/or MRI of the skull: if Cushing disease is suspected
 o If no findings are present on neuroimaging, perform bilateral sampling of the inferior petrosal

sinus in order to measure ACTH levels.

o See also “Diagnostics” in “Pituitary adenoma”.

• Other tests: if ectopic ACTH production is suspected

o Chest x-ray and/or CT

o Abdominal CT

o Pelvic CT

o Thyroid ultrasound

Exogenous Cushing syndrome

• Consider lowering the dose of glucocorticoids

• Consider the use of alternatives to glucocorticoids (e.g., azathioprine)

Endogenous Cushing syndrome [2]

• Inoperable disease (e.g., inoperable adrenal carcinomas, advanced small cell carcinoma of the
lung): drugs to suppress cortisol synthesis (e.g., metyrapone, mitotane, ketoconazole)

• Operable disease: Surgical therapy is the treatment of choice.

o Adrenocortical tumor: laparoscopic or open adrenalectomy (a surgical procedure to remove

one or both adrenal glands)

o Pituitary adenoma: transsphenoidal resection of the pituitary adenoma (see “Therapy” in

“Pituitary adenoma”)

o ACTH-secreting ectopic tumor: resection of the ectopic foci (e.g., bronchial carcinoid)

Nelson syndrome (post adrenalectomy syndrome)

• Etiology: bilateral adrenalectomy in patients with a previously undiscovered pituitary adenoma

 • Pathophysiology: bilateral adrenalectomy → no endogenous cortisol production → no negative feedback
from cortisol on hypothalamus → increased CRH production → uncontrolled enlargement of

preexisting ACTH-secreting pituitary adenoma → increased secretion of ACTH and MSH → symptoms

of pituitary adenoma and ↑ MSH

• Clinical features: headaches, bitemporal hemianopia (mass effect), cutaneous hyperpigmentation

• Diagnostics
o High levels of beta-MSH and ACTH

o Pituitary adenoma on MRI confirms the diagnosis.

• Treatment: surgery (e.g., transsphenoidal resection) and/or pituitary radiation therapy (e.g, in the case of tumor residues
after surgery)

Molecular effects of glucocorticoids

– Metabolic: mobilization of energy

reserves through increased
gluconeogenesis, lipolysis, and protein
catabolism; also increased bone
resorption.

– Immunosuppressive and
antiinflammatory: direct and indirect
regulation of nuclear factor κ-B (NF-κB),
which is a central proinflammatory
transcription factor. Glucocorticoids bind
to glucocorticoid receptors (1), resulting in
increased transcription of the IκB gene, which codes for the antiinflammatory protein IκB. Indirect
regulation thus occurs through IκB-binding of NF-κB (2), preventing its translocation to the nucleus.
The glucocorticoid/GR complex can also directly inhibit the action of NF-κB within the nucleus. Both
direct and indirect pathways result in decreased production of proinflammatory factors, e.g., IL-1, IL-
2, TNFα.

– Catecholamine sensitivity: Glucocorticoids potentiate the effects of catecholamines such as

epinephrine and norepinephrine by upregulating their receptors.