Endocrinology Internal Medicine

Cushing’s Syndrome

Cushing's Syndrome
Obesity, hirsutism in women, skin changes, and muscle weakness are common findings in patients with Cushing's Syndrome.

Introduction – Cushing’s Syndrome

The most common cause of clinical cortisol excess is treatment with cortisone containing medications. Endogenous hypercortisolism (Cushing’s syndrome) is usually caused by an ACTH- or cortisol-producing tumor in the pituitary, lung or adrenal cortex. Untreated, the disease leads to a greatly increased mortality in cardiovascular disease.

The incidence of Cushing’s syndrome is about 3-4 per one million individuals per year, but there is probably a significant underdiagnosing of above all ectopic ACTH production from lung cancer. Women are more often affected by the condition, especially due to a higher risk of benign tumors (adenomas) of the pituitary and adrenal glands.

Hypercortisolism in Cushing’s syndrome may be ACTH-dependent or ACTH-independent.

The most common of the ACTH-dependent variants is Cushing’s disease, which is caused by an ACTH-producing pituitary adenoma. The second most common cause is ectopic ACTH production from a carcinoid tumor most commonly located in the lung as well as ectopic ACTH production from small cell lung cancer. Otherwise, there is a large number of sites for ectopic ACTH production such as the thymus, pancreas, adrenal glands (pheochromocytoma), thyroid (medullary thyroid cancer), ovaries, prostate, breast, etc.

Non-ACTH-dependent Cushing syndrome is caused (except in exogenous cortisone supply) mainly by benign adenomas in the adrenal cortex, secondarily by adrenal cortex malignancy. Uncommon variants include bilateral macronodular hyperplasia as well as primary pigmented nodular adrenal disease.

Symptoms and Clinical Findings – Cushing’s Syndrome

  • Obesity with increased fat accumulation in the abdomen, supraclavicularly, retroorbitally (with exophthalmos as a result), dorsocervically (“buffalo hump”, unspecific and common in general obesity), and the cheeks (“moon facies”). In some adults, instead, general obesity is seen, in children accompanied by growth retardation.
  • Skin changes:
    – Facial pletora (pronounced facial erythema).
    – Hirsutism in women, especially in adrenal cancer (virilization in severe hypercortisolism) – in milder forms of Cushing’s disease.
    – Striae. Typical red-violet striae in the abdominal skin are seen in younger patients. These striae are usually wider than the white/pale red striae that can be seen in conjunction with pregnancy or rapid weight gain.
    – Acne.
    – Bruises associated with loss of subcutaneous tissue, often occur after minimal trauma. Skin atrophy is typically seen on the back of the hand.
  • Gonadal dysfunction: Menstrual disorders, lowered libido, impotence.
  • Muscle weakness: Typically located proximally in the arms and thighs. Can express itself by difficulties when walking up flights of stairs or trying to stand up from a chair. Associated with decreased muscle mass.
  • Mental disorders: Common and probably underestimated. Includes alterations in mood and cognitive disorders. Sleep disorders are very common. Deep depressions occur, as well as manic behavior with, in rare cases, psychotic episodes. Typically varied symptomatology.
  • Metabolic disorders: Glucose intolerance (possibly diabetes mellitus), hyperlipidemia.
  • Hypertension
  • Osteoporosis, often accompanied by vertebral compressions – sometimes pathological fractures of the ribs, long tubular bones and aseptic bone fractures in the hip/shoulder.
  • Increased susceptibility to infections
  • In Cushing’s syndrome with very high cortisol production caused by, for example, small cell lung cancer, rapid onset and pronounced symptoms are seen, including weight loss, palpable myopathy, hypokalemic alkalosis, hypertension that can be severe and peripheral edema.

Differential Diagnoses

Mild to moderate hypercortisolism can be seen in pronounced physiological stress (severe illness, surgery), intensive exercise over time, deep depression, chronic alcoholism (rare), poorly controlled diabetes mellitus, glucocorticoid resistance, elevated levels of corticosteroid-binding globulin (CBG; plasma cortisol is elevated but not urinary and salivary cortisol, for example in treatment with estrogen preparations) and eating disorders such as anorexia and bulimia nervosa.

Investigation – Cushing’s Syndrome

Exogenous administration of cortisone preparations should be excluded. Also, application of strong cortisone preparations to the skin, injections (for example, intra-articular depot preparations), and inhalation of high glucocorticoid doses (especially fluticasone) can cause systemic hypercortisolism.

As a screening test for Cushing’s syndrome, analysis of cortisol in 24h urinary measurements, overnight dexamethasone suppression test or salivary cortisol at 22:00-23:00 is recommended. When performing 24h urinary samples, at least two cycles should be analyzed. Sensitivity is limited for this test (70-75%). Clearly elevated levels, however, strongly suggest Cushing’s syndrome as the correct diagnosis. Impaired renal function or incomplete urine collection can cause falsely low levels.

In dexamethasone suppression testing, 1 mg of dexamethasone is given at 22:00-23:00. Serum cortisol levels above 50 nmol/l at 08.00 the following morning justify further investigation. Normal suppression occurs in 5-10% of patients with Cushing’s syndrome. False-positive or negative results can be seen in conditions with aberrant levels of corticosteroid-binding globulin (CBG) and in treatment with drugs that affect the metabolism of dexamethasone.

An elevated salivary cortisol measurement taken at 22:00-23:00 provides support for continued investigation (important to use locally developed reference levels with validated methods of analysis!).

In case of strong clinical suspicion, at least two of the tests should be performed. Cyclic activity in the ACTH / cortisol-forming tumors is not uncommon, which may contribute to variations in the outcome of different tests. Therefore, for progression / cyclic symptoms consistent with Cushing’s syndrome, the tests should be repeated.

In positive screening tests, definitive diagnostic tests should be performed. This includes determination of ACTH in plasma, and analysis of daily levels of plasma cortisol.

Radiological examinations are done at a later stage to locate eventual underlying tumors.

For ACTH-dependent Cushing’s syndrome, sampling of ACTH levels from collecting veins of the pituitary and the periphery is recommended (Petrosal Sinus Sampling) and is usually needed to determine whether ACTH is synthesized in the pituitary or other sites. Hypercortisolism must be present in order to do this test.

Treatment – Cushing’s Syndrome

When possible, the ACTH / cortisol producing tumor is removed. In pronounced hypercortisolism, medical treatment may be given preoperatively to reduce cortisol production, primarily ketoconazole and/or metopirone.

Bilateral adrenalectomy may be necessary, especially in ectopic Cushing’s syndrome, to avoid life-threatening complications before the underlying tumor is identified.


After removal of the ACTH or cortisol producing tumor, the patient needs postoperative glucocorticoid substitution, usually at least 6, often 12 months, sometimes several years.

Recurrence of normal cortisol axis function can be verified with the SynacthenT test.

Lifelong follow-up is recommended for pituitary-induced Cushing’s syndrome. Special attention should be paid to any remaining risk factors for cardiovascular morbidity, as well as mental health. Upon removal of a benign adrenal gland adenoma with typical radiological characteristics, follow-ups may be terminated when endogenous cortisol production is demonstrated without evidence of recurrence.

Further Reading