Cushing’s syndrome

Cushing`s syndrome is the name used for a myriad of clinical manifestations that occur due to high levels of glucocorticoids. It is more common among woman between 25-45 years of age. Cushing`s manifestations may increase mortality and morbidity and the identification of the condition and its management is very important. The terminology Cushing`s disease is used for Cushing`s syndrome caused by pituitary issues.


Primary hypercortisolism

Cortisol secreting adenoma on the adrenals

Secondary hypercortisolism

Pituitary adenoma

Tertiary hypercortisolism

Hypothalamic CRH hypersecretion


Ectopic ACTH production

All the cases mentioned may also be divided in ACTH dependent (Cushing`s disease, Ectopic ACTH or CRH syndrome) or ACTH independent (adrenal adenoma or carcinoma, micro or macronodular hyperplasia).


As a syndrome, usually many signs and symptoms may appear together and get worse over time. Such clinical features may be present in different organs and systems, including:

Neuropsychiatric: Depression, decreased libido.

Skin: Plethora, round face, hirsutism, acne, striae.

Cardiovascular: Hypertension.

Musculoskeletal: Muscle weakness, osteopenia or osteoporosis, edema.

Gastrointestinal: Abdominal pain, obesity and glucose intolerance.

Genitourinary: Menstrual irregularity.


If there is not an obvious cause of hypercortisolism (e.g. use of glucocorticoids) patients with Cushing`s syndrome features should be tested.

The presence of two positive tests will confirm Cushing`s syndrome. These tests may include any two of the following:

Late-night salivary cortisol

24h urinary free cortisol (UFC)

Overnight 1mg dexamethasone suppression test

After confirming the diagnosis of Cushing`s syndrome, the cause should be established.

The best initial approach is to differentiate between ACTH-dependent hypercortisolism and ACTH-independent hypercortisolism. For that, plasmatic ACTH should be measured in at least two separate days.

Values of ACTH <5pg/mL indicate ACTH-independent condition. ACTH >20pg/mL indicates ACTH-dependent conditions. Patients with intermediate values should receive a CRH or desmopression stimulation test. If these tests are negative negative (no ACTH response), an ACTH-independent condition is present. If they are positive (ACTH response) there is an ACTH-dependent condition.

If an ACTH-independent state is identified, adrenal CT or MRI should be obtained since the most probable cause is an adrenal condition.

If an ACTH-dependent state is identified, brain MRI should be obtained (evaluate the presence of adenoma). Inferior petrosal sinus sampling (IPSS) may help to confirm the diagnosis of Cushing`s disease, particularly in patients with adenomas <6mm, by registering the level of ACTH on the blood that leaves the pituitary. Normal MRI and IPSS indicates ectopic ACTH secretion. The diagnosis of Cushing`s disease without the use of IPSS is also possible if there is a pituitary tumor >6mm that responds to a high dose dexamethasone suppression test (8mg of dexamethasone PO at 11pm-12am) and CRH or desmopressin stimulation.


Treatment depends on the cause.

Iatrogenic Cushing`s should be managed with slow corticosteroid removal through tapering.

Pituitary adenomas (Cushing`s disease) may be treated surgically (transsphenoidal removal). If the individual cannot be treated with surgery for any reason, medications can be used, including ketoconazole, metyrapone (adrenal enzyme inhibitors), cabergoline, pasireotide (help reducing the cortisol), mitotane (chemotherapeutic) or mifepristone (improves hyperglycemia). For patients that need to preserve the fertility or for those that cannot receive surgery for whatever reason, pituitary radiation may be an option. A final option of definitive cure is bilateral adrenalectomy (which obviously will require daily replacement of glucocorticoids { hydrocortisone 15-25mg } and mineralocorticoids { fludrocortisone 0.05-0.2mg/day } ).

Ectopic ACTH secreting tumors can be cured with resection. In the meantime (or if surgery is not an option) they may respond to adrenal enzyme inhibitors (ketoconazole, metyrapone). Mifepristone (control hyperglycemia) or octreotide (may reduce ACTH secretion) can also be tried. If nothing works, chemotherapy with mitotane or bilateral adrenalectomy may be considered.

Bilateral adrenal causes may be treated with adrenalectomy (or managed with the medications mentioned above if surgery is not an option).

Unilateral adenomas are treated with unilateral adrenalectomy.

After the resolution of the hypercortisolism it may take up to 12 months for the signs and symptoms to improve.


  1. Nieman LK et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015 Aug; 100(8): 2807–2831.
  2. Castro MD, Moreira AC. Screening and diagnosis of Cushing’s syndrome. Arq Bras Endocrinol Metabol. 2007 Nov;51(8):1191-8.
  3. Giraldi FC et al. Specificity of First-Line Tests for the Diagnosis of Cushing’s Syndrome: Assessment in a Large Series. J Clin Endocrinol Metab (2007) 92 (11): 4123-4129.
  4. Nieman LK et al. The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab (2008) 93 (5): 1526-1540.