Cushing’s Syndrome

Cushing’s syndrome or hypercortisolism is a disorder characterized by features resulting from chronic exposure to excess glucocorticoids. Cushing’s syndrome may be exogenous, due to chronic glucocorticoid intake, or endogenous, due to increased adrenal secretion of cortisol or adrenocorticotropic hormone (ACTH) production from the pituitary gland or ectopic sources. Exogenous or iatrogenic hypercortisolism is the most common cause. Typical clinical features of hypercortisolism include central obesity, thin and bruisable skin, abdominal striae, secondary hypertension, hyperglycemia, and proximal muscle weakness. The initial diagnostic approach is to establish hypercortisolism via urinary and salivary cortisol tests along with low-dose dexamethasone suppression test. Once the elevated cortisol levels are confirmed, the etiology is determined based on ACTH levels, confirmatory biochemical tests, and subsequent imaging studies. Treatment options depend on the cause, and include surgery and medical therapy.

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Cushing’s syndrome or hypercortisolism is a disorder characterized by features resulting from chronic exposure to excess glucocorticoids.

Types of Cushing’s syndrome

  • Primary hypercortisolism:
    • ↑ Production of glucocorticoids by adrenal glands
    • Adrenocorticotropic hormone (ACTH)-independent condition
  • Secondary hypercortisolism:
    • Cushing’s disease: 
      • ↑ Pituitary ACTH production leading to adrenal gland hyperplasia
      •  ACTH-dependent condition
    • Ectopic ACTH syndrome: ↑ ACTH production outside the pituitary and adrenal glands (such as in lung cancer)
  • Exogenous/iatrogenic Cushing’s syndrome: medical use of glucocorticoids causing hypercortisolism


  • Iatrogenic Cushing’s syndrome is the most common form. 
  • Primary hypercortisolism:
    • More common in women
    • Adrenal tumors affect 2 age groups the most: peaks in the 1st 10 years, and again around 40 years of age (carcinomas) and 50 years of age (adenomas).
  • Secondary hypercortisolism:
    • Cushing’s disease: 
      • 5–6 times more common than primary hypercortisolism
      • More common in women
      • Age group most affected: 25–45 years of age
    • Ectopic ACTH:
      • More common after 50 years of age
      • Follows incidence of small-cell lung carcinoma
  • Increased risk of cardiovascular mortality compared to the general population


  • ACTH-dependent causes:
    • Cushing’s disease:
      • Pituitary microadenoma: 90% 
      • Pituitary macroadenoma
    • Ectopic ACTH syndrome:
      • Carcinoid tumors
      • Small-cell lung carcinoma
      • Pancreatic tumors
      • Thymus tumors
    • Ectopic corticotropin-releasing hormone (CRH) syndrome leads to ↑ ACTH and subsequent adrenal hyperplasia
    • Iatrogenic (treatment with exogenous ACTH)
  • ACTH-independent causes:
    • Iatrogenic (treatment with glucocorticoids)
    • Adrenal adenoma and carcinoma
    • Primary pigmented nodular adrenocortical disease
    • Bilateral macronodular adrenal hyperplasia
    • McCune-Albright syndrome
  • Pseudo-Cushing’s syndrome (physiological hypercortisolism):
    • Pregnancy
    • Obstructive sleep apnea
    • Uncontrolled diabetes mellitus
    • Obesity (women with polycystic ovarian syndrome)
    • Severe depression
    • Stress
    • Intense exercise


Hormonal regulation

  • Hypothalamic-pituitary-adrenal (HPA) axis
    • Hypothalamus secretes CRH → release of ACTH from the anterior pituitary gland
    • ACTH release:
      • Like CRH, the release of ACTH is pulsatile, following the circadian rhythm.
      • ↑ In the early morning hours (before awakening), with peak levels in the morning (approximately 8:30 a.m.) and ↓ in the evening
    • Adrenal gland (cortex):
      • ACTH mainly stimulates the zona fasciculata (cortisol) and zona reticularis (androgens).
      • Zona glomerulosa (aldosterone) is primarily regulated by the renin-angiotensin system and potassium levels.
  • Cortisol:
    • Metabolic effects:
      • ↓ Glucose uptake by cells and ↑ gluconeogenesis
      • ↑ Lipolysis → release of fatty acids into the circulation
      • ↓ Protein storage → myopathy, bone resorption
    • ↑ Smooth muscle (vasculature) sensitivity to catecholamines and angiotensin II (leading to ↑ blood pressure)
    • Anti-inflammatory actions: 
      • Apoptosis of T cells
      • ↓ Antibody production
      • ↓ Neutrophil migration
  • Androgens:
    • Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are the androgens secreted in excess. 
    • DHEA:
      • Weak androgenic activity
      • Precursor can be peripherally converted to more potent androgens (e.g., testosterone) and estrogens (e.g., estradiol).
      • Testes are the main source of androgens in men. 
  • Mineralocorticoids:
    • Regulation of renal sodium and water reabsorption 
    • Regulation of potassium excretion


  • ACTH-dependent causes:
    • Cushing’s disease:
      • Pituitary adenoma secreting ACTH
      • ↑ ACTH → bilateral adrenal hyperplasia and hyperfunction → ↑ cortisol
      • ACTH secretion is resistant to glucocorticoid feedback inhibition.
    • Ectopic ACTH syndrome:
      • Occurs in malignant and neuroendocrine tumors
      • ↑ Ectopic ACTH → ↑ cortisol 
    • Ectopic CRH syndrome:
      • Secretion of CRH by a tumor
      • ↑ CRH → pituitary hyperplasia → ACTH hypersecretion → ↑ cortisol
      • Generally with loss of glucocorticoid negative feedback
  • ACTH-independent causes:
    • Iatrogenic:
      • Synthetic glucocorticoids → ↓ CRH and ACTH → bilateral adrenocortical atrophy 
      • Most common: prednisone
    • Cortisol-secreting adrenal adenomas and carcinomas:
      • Tumors secrete cortisol, suppressing ACTH and leading to pituitary corticotroph atrophy.
      • Hyperaldosteronism can occur. 
      • Excessive glucocorticoids interfere with central regulation and result in gonadotropin suppression (resulting in hypogonadism and amenorrhea).
    • Macronodular adrenal hyperplasia:
      • Involves aberrant membrane receptors in the adrenal cortex stimulated by other hormones (e.g., vasopressin, gastric inhibitory peptide)
      • Adrenal glands are significantly enlarged with macronodules.
    • Primary pigmented nodular adrenocortical disease:
      • Also known as micronodular adrenal hyperplasia
      • Can be sporadic or familial (Carney’s syndrome)
      • Characterized by myxomas, multiple endocrine gland disorders, and lentigines
      • Bilateral adrenal gland disease with pigmented nodules that are autonomously functioning
      • Associated with PRKAR1A mutation
    • McCune-Albright syndrome:
      • Triad of polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and precocious puberty (autonomous endocrine hyperfunction)
      • Also associated with hyperthyroidism, acromegaly, and Cushing’s syndrome
      • Adrenal effect caused by a somatic mutation in the alpha subunit of Gs protein → constant activation mimicking ACTH stimulation

Clinical Presentation

Table: Signs and symptoms of Cushing’s syndrome
  • Acne, facial plethora, violaceous striae/stretch marks, easy bruising, hirsutism
  • Secondary hypercortisolism: hyperpigmentation (both ACTH and ɑ-melanin-stimulating hormone are derived from pro-opiomelanocortin → melanocyte stimulated)
Body fatMoon facies, central obesity, buffalo hump (dorsocervical fat pad)
BoneShort stature (decreased linear growth in children), osteopenia, osteoporosis, ↑ risk of avascular necrosis
MuscleProximal myopathy, weakness
MetabolismElevated glucose/diabetes, dyslipidemia
ReproductiveAmenorrhea in women, decreased libido
CardiovascularAtherosclerosis, hypertension, edema
NeuropsychiatricIrritability, depression, emotional lability, sleep disturbance, psychosis
OphthalmologicCataracts (steroids affect gene transcription of lens epithelial cells)
Immune systemIncreased WBC count, increased susceptibility to infection


To recall the most common clinical features of Cushing’s syndrome, remember CUSHINGOID”:

  • Cataracts
  • Ulcers
  • Skin: striae, thinning, bruising
  • Hypertension, hirsutism, hyperglycemia
  • Infections
  • Necrosis (avascular necrosis of the femoral head)
  • Glucose elevation
  • Osteoporosis, osteopenia, obesity
  • Immunosuppression
  • Diabetes, depression
Cushingoid symptoms

The common clinical manifestations of hypercortisolism

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Diagnosis of hypercortisolism

Clinical features increase suspicion of diagnosis:

  • Many signs and symptoms are nonspecific.
  • Biochemical tests are needed to establish the diagnosis.

Exclude use of exogenous glucocorticoids:

  • Review of oral, injected, inhaled, and topical glucocorticoid use and dosages
  • Review of drug interactions (e.g., ritonavir delays clearance of inhaled/injected steroids)

Initial tests for hypercortisolism:

  • Late-night salivary cortisol 
  • 24-hour urinary free cortisol (UFC) excretion 
  • 1 mg dexamethasone-suppression test ((DST) 1 mg of dexamethasone administered in the late evening suppresses endogenous cortisol production the next morning))
    • Normal cutoff for suppression of serum cortisol (post-dexamethasone): < 1.8 μg/dL (50 nmol/L)
    • If cortisol is not suppressed (i.e., cortisol > 1.8 μg/dL or 50 nmol/L) → hypercortisolism 
  • Longer low-dose DST (2 mg/day for 48 hours)

Abnormal results prompt additional evaluation:

  • Exclude physiological hypercortisolism.
  • Retest especially if high index of suspicion
  • Consult an endocrinologist regarding the identification of the cause of hypercortisolism.
Algorithm to confirm diagnosis of Cushing syndrome

Algorithm to diagnose hypercortisolism or Cushing’s syndrome (CS):
In patients clinically suspected with CS, the 1st step is to rule out the exogenous use of glucocorticoids. Once excluded, initial tests to check for elevated cortisol levels include late-night (LN) salivary cortisol, 24-hour urinary free cortisol (UFC), and 1 mg dexamethasone suppression test (DST). Once elevated cortisol levels are confirmed, evaluate whether the elevation is from physiological hypercortisolism. Once physiologic causes are excluded, proceed with additional testing to identify the etiology (which can be primary or secondary).

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Identification of the cause

After confirming elevated cortisol levels, determining the etiology starts with ACTH.

  • ACTH levels:
    • Identify ACTH-independent versus ACTH-dependent etiologies.
    • Results:
      • ↓ ACTH (< 5 pg/mL): primary hypercortisolism (ACTH-independent)
      • ↑ ACTH (> 20 pg/mL): secondary hypercortisolism (ACTH-dependent)
      • Intermediate ACTH (5–20 pg/mL): likely ACTH-dependent (further tests needed)
  • If with ↓ ACTH:
    • Etiology is ACTH-independent (adrenal gland).
    • Proceed with CT or MRI of the adrenal glands.
    • Possible adrenal mass, bilateral hyperplasia, or macronodular adrenal hyperplasia
  • If with ↑ or intermediate ACTH:
    • Etiology is likely ACTH-dependent.
    • Proceed with tests to identify Cushing’s syndrome versus ectopic Cushing’s syndrome.
    • CRH test: 
      • ACTH concentration is measured before and after administration of CRH. 
      • ↑ ACTH: Cushing’s disease (pituitary adenoma)
      • No ↑ ACTH: ectopic ACTH syndrome
    • High-dose DST: 
      • 8 mg dexamethasone is administered.
      • Cortisol is suppressed: Cushing’s disease (pituitary adenoma)
      • Cortisol is not suppressed: ectopic ACTH syndrome
    • If etiology is:
      • Cushing’s disease → proceed with pituitary MRI
      • Ectopic → search for tumor/malignancy 
  • Inferior petrosal sinus sampling (IPSS):
    • Directly determines ACTH secretion from the pituitary gland:
      • Determines central-to-peripheral ACTH gradient by measuring ACTH from the petrosal and peripheral veins after CRH administration
      • Gradient of ≥ 3 after CRH → Cushing’s disease (pituitary)
    • Disadvantages: invasive, expensive, and associated with possible risks
    • Complications: cerebrovascular accident, thromboembolism
    • Performed in certain situations:
      • Mixed responses in CRH and DSTs
      • No pituitary tumor or lesion is < 6 mm on MRI
Table: Summary of steps in identifying the etiology of Cushing’s syndrome
ACTH levelEtiology and additional testsIdentifying the cause
↓ ACTH: ACTH-independentAdrenal gland (possible adenoma, carcinoma, hyperplasia)Obtain CT scan/MRI of the adrenal gland.
↑ or intermediate ACTH: likely ACTH-dependentCushing’s disease:
  • ↑ ACTH in CRH test
  • Excess cortisol suppressed in high-dose dexamethasone suppression test
Obtain pituitary MRI.
Ectopic ACTH syndrome (such as lung cancer, carcinoid):
  • No ↑ ACTH in CRH test
  • Excess cortisol not suppressed in high-dose dexamethasone test
Workup for malignancy:
  • Chest X-ray
  • CT scan/MRI
ACTH: adrenocorticotropic hormone
CRH test: corticotropin-releasing hormone test

Management and Prognosis

Exogenous Cushing’s syndrome

  • Stop glucocorticoids.
  • Gradual withdrawal is necessary while switching to an alternative medication.
  • If unable to discontinue, consider lowering the dose.

Primary adrenal disease

  • Functional adenoma: unilateral adrenalectomy
  • Primary pigmented nodular adrenocortical disease and macronodular adrenal hyperplasia: 
    • Bilateral adrenalectomy 
    • Adrenal enzyme inhibitors (metyrapone or ketoconazole) can be given prior to surgery.
  • Adrenal carcinoma:
    • Resectable tumor: adrenalectomy (+/- radiotherapy for incomplete resection)
    • Unresectable tumor/advanced disease: mitotane, metyrapone, or ketoconazole

Cushing’s disease (pituitary adenoma)

  • Transsphenoidal surgery to remove adenoma
  • Medical therapy (to prepare for the procedure, or if surgery is contraindicated or unsuccessful):
    • Adrenal enzyme inhibitors
    • Cabergoline (dopamine agonist) or pasireotide (somatostatin analog)
    • Mifepristone (for hyperglycemia in Cushing’s syndrome)
  • Radiotherapy: 
    • Used when surgical methods fail to achieve remission
    • Can be the primary treatment option in individuals < 18 years of age
  • Adrenalectomy: option in cases of persistent or recurrent Cushing’s disease

Ectopic ACTH syndrome

  • Resectable tumor: surgical excision
  • Unresectable tumor: Use adrenal enzyme inhibitors (metyrapone, ketoconazole, mitotane).

Outcomes and prognosis

  • With treatment: 
    • Signs and symptoms regress in months to a year.
    • Some complications (hypertension, diabetes) may persist but improve over time.
    • Patients at risk for adrenal insufficiency (e.g., bilateral adrenalectomy) would need glucocorticoid replacement.
  • Nelson syndrome can develop in up to 25% of patients who undergo bilateral adrenalectomy:
    • Enlarging pituitary tumor occurring after bilateral adrenalectomy
    • Presumed to be from growing ACTH-secreting cells in a previously undetected pituitary adenoma
    • With no adrenal glands, there is no glucocorticoid negative feedback; thus, pituitary growth is facilitated.
    • In Cushing’s disease, radiotherapy is performed before bilateral adrenalectomy to reduce the risk of Nelson syndrome.
  • Cushing’s syndrome is fatal without treatment, and mortality is related to:
    • Cardiovascular disease
    • Thromboembolic events
    • Infections
  • If hypercortisolism is associated with a tumor, the prognosis is related to the nature (e.g., malignancy) of the tumor and the severity of hypercortisolism.

Clinical Relevance

  • Pituitary adenoma: tumors that develop within the anterior lobe of the pituitary gland. Pituitary adenomas are classified based on size (micro- or macroadenomas) and their ability to secrete hormones. Non-functioning or non-secretory adenomas do not secrete hormones but compress the surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type they evolve from and lead to hyperpituitarism.
  • Paraneoplastic syndrome: a constellation of signs and symptoms that arise from substances produced by the tumor and not by a direct effect of the tumor. Conditions can range from immunological responses to the presence of a neoplasm in the body that leads to antibody production (Lambert-Eeaton syndrome). Hormones, peptides, or cytokines produced by the tumor also result in paraneoplastic syndrome (Cushing’s syndrome due to ectopic ACTH secretion).
  • Adrenal insufficiency: an inadequate production of the following adrenocortical hormones by the adrenal glands: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary adrenal insufficiency, also called Addison’s disease, is caused by afflictions in the gland itself. Secondary adrenal insufficiency occurs due to decreased production of ACTH either from prolonged glucocorticoid therapy, or pituitary or hypothalamic disease.
  • Small-cell lung carcinoma: highly aggressive lung cancer that is often metastatic at the time of diagnosis. About 15% of all lung cancers are secondary to small-cell lung carcinomas. Apart from the pulmonary manifestations of dyspnea, cough, and cachexia, small-cell lung carcinomas can present with Cushing’s syndrome due to ectopic production of ACTH. Diagnosis of the cancer is based on imaging studies and biopsy. Treatment depends on whether the disease is limited or extensive.


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