The following signs and symptoms are common:

• Weight gain
• Skin changes
• Hirsutism
• Menstrual disorders
• Progressive proximal muscle weakness
• Infertility
• Impotence
• Moodiness, irritability, or depression
• New-onset or worsening of hypertension and diabetes mellitus
• Immune suppression
• Osteoporosis
• Growth retardation

Workup for a suspected case of Cushing's disease is done to confirm or exclude the diagnosis of Cushing syndrome and to differentiate ACTH-independent disease from ACTH-dependent disease followed by imaging of pituitary or adrenal to localize the anatomic source [5] [6].

Urinary free cortisol

Urinary free cortisol (UFC) in a 24-hour urine specimen is the most sensitive screening test for the diagnosis of Cushing syndrome and can be done on an outpatient basis. UFC levels are almost never normal in Cushing syndrome. If the UFC is more than three times the upper limit of normal, the patient is presumed to have Cushing syndrome. However, if the results are equivocal, the patient may either be retested later or subjected to further tests [7] [8].

Overnight dexamethasone suppression test

1 mg dexamethasone is administered at 11 p.m. and plasma cortisol is measured at 8 a.m. In normal individuals dexamethasone suppresses the early morning surge of cortisol while in Cushing syndrome cortisol levels remain high. If both of the above tests are normal, Cushing syndrome is unlikely and is excluded. The above two tests may be falsely positive in conditions causing pseudo-Cushing syndrome such as obesity, acute or chronic illness, alcoholism, depression, drugs and high estrogen states.

Low dose dexamethasone suppression test

0.5 mg dexamethasone is administered every 06 hourly for 48 hours. Plasma cortisol and urinary free cortisol samples are obtained. This test distinguishes between pseudo-Cushing syndrome and Cushing syndrome.

High dose dexamethasone suppression test and ACTH levels

These tests help to localize the cause of Cushing syndrome. ACTH levels are non-detectable in adrenal tumors but high in cases of ectopic or pituitary tumors. Ectopic production of ACTH shows no suppression with high dose dexamethasone suppression test while in Cushing's disease decrease in more than 50% in urinary free cortisol is suggestive of an anterior pituitary adenoma.

Imaging

The above mentioned biochemical tests are followed by imaging studies. MRI pituitary is done if pituitary adenoma is suspected. CT scan chest and abdomen are done if ectopic ACTH production is suspected to localize the tumor. Inferior petrosal sinus sampling (IPSS) can be performed by experienced interventional radiologist to differentiate pituitary oversecretion of ACTH from ectopic ACTH production in difficult cases.

Treatment modalities are aimed at normalizing the cortisol levels and prevent the deleterious effects of hypercortisolism. Treatment options include surgical options and pharmacotherapy. In Cushing's disease the procedure of choice is transsphenoidal surgery to remove the pituitary adenoma. Pituitary irradiation is done in unsuccessful cases. Medical therapy is employed for the treatment of Cushing's disease when surgery is contraindicated or for control of hypercortisolism in patients waiting or surgery or reappearance of symptoms after surgery.

Various drugs used to treat Cushing's disease [9] are:

• Adrenal enzyme inhibitors: Aminoglutethimide, metyrapone, ketoconazole, fluconazole, etomidate and trilostane inhibit the enzymes involved in steroidogenesis. Ketoconazole is started and if hypercortisolism is not controlled, metyrapone is added.
• Adrenocorticolytic drugs: Mitotane is used for the treatment of adrenal carcinoma. It is also used in cases of Cushing's disease during or after pituitary irradiation.
• Drugs that target pituitary and reduce ACTH levels: These include cabergoline (a dopamine agonist) and pasireotide (a somatostatin analog).

If Cushing's disease remains untreated it may be fatal. Most deaths are due to cardiovascular and thromboembolic complications like myocardial infarction, pulmonary edema, hypertensive crisis and deep venous thrombosis. There is an increased incidence of opportunistic bacterial and fungal infections in such patients. With the development of surgical options and medical therapy, the prognosis improved, but advanced disease and unresectable tumors at the time of diagnosis may be present.

In Cushing's disease pituitary hypersecretion of ACTH occurs. In 90% of cases this is caused by a microadenoma while in other cases it is caused by a macroadenoma (tumors more than 1 cm in size). Rarely Cushing's disease is diagnosed as a part of multiple endocrine neoplasia type 1 (MEN 1).

Ectopic ACTH secretion occurs from small cell carcinoma of the lung [1], carcinoid tumors, medullary carcinoma of the thyroid and pheochromocytoma. Overproduction of ACTH and iatrogenic administration of ACTH are rare causes of ACTH-dependent Cushing syndrome.

Cushing's disease is a rare condition, seen more frequently in women. It most often occurs between the second and fourth decade of life.

Glucocorticoid excess has deleterious effects on all systems on the body. There is redistribution of body fat manifesting in the form of moon facies, buffalo hump and central obesity. Abdominal striae and skin bruising result from atrophy of the skin and connective tissue. An increased incidence of osteoporosis, fractures in adults and growth retardation in children was reported. Steroid induced proximal myopathy leads to lethargy and poor mobility of patients. Hypertension, edema and hypokalemia result due to the increased mineralocorticoid effect of steroids [2].

Glucose intolerance or diabetes mellitus follows due to the antiinsulin effects of cortisol. Glucose intolerance occurs due to increased gluconeogenesis and glycogenesis by cortisol and may lead to overt diabetes mellitus which is present in 10-15% patients with Cushing syndrome [3]. Gonadal dysfunction causes hirsutism, acne, amenorrhea and infertility in women while decreased libido, loss of body hair, small testes and impotence occur in men. Patients also display psychiatric effects including irritability, psychosis or depression. Increased susceptibility to infections and poor wound healing are common [4]. Hyperpigmentation of the skin may occur due to the fact that circulating ACTH has some melanocyte stimulating hormone (MSH) like activity. Patients with ACTH-producing tumors may present with headaches, visual disturbances and other endocrine disorders.

There are no guidelines for prevention of Cushing' disease.

Cushing syndrome refers to the constellation of clinical features that result from chronic exposure to excess glucocorticoids. The high levels of glucocorticoids can come from exogenous (iatrogenic) or endogenous sources. Endogenous causes can be overproduction of cortisol by an adrenal tumor or increased adrenocorticotropic hormone (ACTH) production due to a pituitary tumor - a condition referred to as Cushing's disease.

Cushing's disease presents with a wide variety of signs and symptoms none of which are specific to this disorder. Laboratory investigations and imaging techniques are used to establish the diagnosis of Cushing's disease and localize the lesion. Treatment aims at normalizing the cortisol levels and includes pharmacotherapy and surgical options to remove the tumor.

Cushing's disease is caused by high levels of a hormone called cortisol in human body. Cortisol is produced by a small organ present on top of each kidney called adrenal gland and is required for normal functioning of human body. Cortisol is made in the adrenal glands as a result of a signal passed from a small organ present near brain called pituitary. Cushing's disease is caused by an abnormal growth in the pituitary. People with Cushing's disease may have one or more of these symptoms: Weight gain especially around neck and waist, easy bruising and poor wound healing of the skin, increased blood sugar levels, high blood pressure, feeling too weak to get up from sitting position and perform day to day activities, stretch marks on the abdomens that are purple colored, mood changes and irregularities in the monthly menstrual cycles. The disorder is diagnosed by blood tests, CT scan and MRI scans. Cushing's disease is treated by surgery and medicines. Surgery removes the abnormal growth in the pituitary. Medicines can be used to normalize the levels of cortisol to control the symptoms caused by an increased amount of cortisol.

1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006; 24:4539.
2. Pareira AM, Delgadov V, Romijn JA, et al. Cardiac dysfunction is reversed upon successful treatment of Cushing’s syndrome. Eur J Endocrinol. Feb 2010; 162(2):331-40.
3. Yanovski JA, Cutler GB Jr. Glucocorticoid action and the clinical features of Cushing’s syndrome. Endocrinol Metab Clin North Am. Sep 1994; 23(3):487-509.
4. Raff H, Findling JW. A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med. Jun 17 2003:138(12):980-91.
5. Elamin MB, Murad MH, Multan R, et al. Accuracy of diagnostic tests for Cushing’s syndrome: A systematic review and metaanalyses. J Clin Endocrinol Metab 2008; 93:1553.
6. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2003; 88:5593.
7. Kidambi S, Raff H, Findling JW. Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of Cushing syndrome. Eur J Endocrinol. Dec 2007; 157(6):725-31.
8. Flack MR, Oldfield EH, Cutler GB Jr, et al. Urine free cortisol in the high-dose dexamethasone suppression test for the differential diagnosis of the Cushing syndrome. Ann Internal Med. Feb 1 1992; 116(3):211-7.
9. Kamenický P, Droumaguet C, Salenave S, et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing's syndrome. J Clin Endocrinol Metab 2011; 96:2796.