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The term "Cushing's syndrome" is used to describe a condition that results from long-term exposure to excessive glucocorticoids (a steroid hormone that is naturally produced by the adrenal cortex). The syndrome is most commonly caused by the therapeutic administration of exogenous glucocorticoids e.g. prednisone/prednisolone. The term "Cushing's disease" is reserved for Cushing's syndrome that is caused by excessive secretion of adrenocorticotropic hormone (ACTH) by a pituitary tumor, usually an adenoma; ACTH, in turn, signals the adrenal gland to produce high amounts of steroid hormones, a state known as "hypercortisolism."


Cushing's disease is responsible for approximately 60-80% of the cases of endogenous Cushing's syndrome. The remainder of cases are caused by ectopic ACTH-secreting tumors and primary adrenal neoplasms. Depression, alcoholism, medications, eating disorders and other conditions can also cause excess cortisol leading to a syndrome similar to Cushing's syndrome, termed "pseudo-Cushing's" syndrome. In the latter, the laboratory and clinical findings of hypercortisolism disappear if the primary cause is successfully treated.

Cushing's disease is significantly more common in females than in males with a ratio of approximately 5:1. It occurs most frequently in women of the reproductive age, but it can occur at any age.

In Cushing's disease the pituitary tumor is usually a microadenoma, which, by definition, is 10 mm or less in diameter. Microadenomas usually do not cause symptoms by local mass effect and these tumors are usually discovered when clinical manifestations of hypercortisolism become apparent. Occasionally, completely asymptomatic microadenomas are found incidentally during imaging performed for other reasons.

Macroadenomas are uncommon in patients with Cushing's disease, when they occur they can cause mass effect especially when their size exceeds 15 mm. Suprasellar extension with optic nerve(s) compression, local bone erosion, cavernous sinus compression and panhypopituitarism may occur at a later stage if the macroadenoma enlarges.

Cushing's disease results from continuous exposure of the body to high levels of the adrenal hormone cortisol as a result of an increased production of ACTH from a tumor of the anterior lobe of the pituitary gland. ACTH signals the adrenal glands to secrete excess of the hormone (cortisol), a hormone which is normally released by the human body during stressful situations, resulting in all its sequelae on the human body.

Symptoms vary, but most often involve upper body obesity, round full face, increased fat around the neck, and thinning of arms and legs. Other symptoms occurring in Cushing's disease are best described as an accelerated aging of the body: skin becomes fragile, thin, bruises easily and heals poorly, along with purplish pink stretch marks appearing on the abdomen, thighs, buttocks, arms and breasts; the bones are weakened (osteoporosis); severe fatigue, muscle weakness, irritability, anxiety and depression are common; high blood pressure (hypertension) and high blood sugar (diabetes) often occur.

Direct pressure by an enlarging pituitary adenoma in Cushing's disease can affect the surrounding critical neurovascular structures. Cranial nerve II (optic) may be affected as a result of direct pressure by the tumor leading to visual field defects (mainly in peripheral vision); cranial nerves III (occulomotor), IV (trochlear) and VI (abducens), may also be affected. Panhypopituitarism may result from direct pressure by the tumor on the pituitary gland.

There are many other symptoms of Cushing's disease and each patient's symptoms vary. Children, tend to be obese with slowed growth rates. Women usually have excess hair growth on their faces, necks, chests, abdomens, thighs and their menstrual periods may become irregular or stop. Men, have decreased fertility with diminished or absent sexual desire.

Cushing's disease is suspected when findings from the medical history and the physical examination of the patient suggest hypercortisolism and an iatrogenic cause (i.e., corticosteroid use) is not apparent. Further laboratory evaluation for suspected Cushing's disease is then obtained and is usually directed at confirming excessive glucocorticoid production.

The evaluation of a patient with suspected Cushing's disease is complex and requires a number of tests which are necessary to diagnose and confirm Cushing's disease. An important screening test for Cushing's disease is the 24-hour urine collection with analysis for urinary free cortisol excretion. Low-dose and high-dose dexamethasone (an exogenous glucocorticoid) suppression tests, corticotropin assays, and a corticotropin-releasing hormone (CRH) stimulation test may also be used. Inferior Petrosal Sinus Sampling, or IPSS (catheterization of the inferior petrosal sinus, which is a small vein that drains the pituitary gland, and a blood sample is obtained and measured for ACTH) may be required for a definitive diagnosis as it provides invaluable information in distinguishing ectopic ACTH production from pituitary Cushing's disease and in localizing the tumor in patients who are known to have Cushing's disease. Ultrasound examination can be performed to exclude or to determine if the primary cause of Cushing's syndrome is an adrenal gland tumor.

Radiological evaluation of the pituitary by magnetic resonanace imaging (MRI), with and without intravenous contrast, is useful in localizing the lesion and determining its size and invasiveness, but may fail alone to visualize extremely small microadenomas which can be the cause of Cushing's disease. Computed tomography (CT) scanning, is superior to MRI in showing the bony anatomy surrounding the pituitary region and in determining if the tumor has invaded any bone, but CT can miss small microadenomas. Dynamic MRI of the pituitary gland is a technically improved tool, which has gained importance in the evaluation and detection of very small microadenomas in Cushing's disease. The more accurate delineation of these small microadenomas is based on the principles of very slow infusion and differential diffusion of gadolinium (a contrast agent used in MRI).

Treatment options for Cushing's disease include medical, surgical and pituitary irradiation.

For the patient with Cushing's disease who is not considered a candidate for surgical intervention, or who has an unresectable, or incompletely treated tumor, medical therapy may be an option. In Cushing's disease medical therapy is only palliative, and should be reserved for use in preparation for surgery, in conjunction with pituitary irradiation to speed up recovery, or after both these treatment modalities have not achieved a cure. Medications for Cushing's disease act by inhibiting adrenal steroid biosynthesis, the most commonly used medications include ketoconazole (Nizoral), aminoglutethimide (Cytadren), and mitotane (Lysodren); each has its own side effects that should be considered when prescribing therapy for individual patients.

Rosiglitazone (Avandia), a potent oral antidabetic agent that has been extensively and safely used to treat diabetes in humans, appears to have a promising role in the management of human pituitary ACTH secreting tumors, as in addition to exerting inhibitory effects on pituitary tumor growth; it also inhibits tumor ACTH synthesis and secretion in patients with Cushing's disease. Further research will help to define its

potential role. Radiotherapy (Conventional "external beam" or Gamma Knife), as a primary treatment, is rarely used and is typically reserved for recurrent or residual cases or for patients that cannot tolerate surgery due to other medical conditions. Pituitary irradiation is effective in producing remission of the disease in up to 80% of the patients, the efficacy, however, is qualified by the delay in hormonal response and by the risk of radiation damage to the normal pituitary gland.

Surgical excision of the pituitary adenoma is the treatment of choice for Cushing's disease due to the high cure rates and low risk especially with the advent of minimally invasive techniques in pituitary surgery. After surgery, pituitary function may gradually return to normal. In the past, surgical removal of both adrenal glands (bilateral adrenalectomy) was common for treating Cushing's disease, but this always produced adrenal insufficiency and nowadays is rarely required and reserved for patients where all other modalities of treatment where unsuccessful.

Untreated Cushing's disease can lead to severe complications such as excessive fatigue, intolerable headaches, nausea and vomiting, pathological bone fractures, diabetes, hypertension, and premature death.

Surgical removal has a guardedly favorable prognosis, but long-term follow-up is required. After surgery, pituitary functions may gradually return to normal and by normalizing, or even markedly lowering cortisol levels, noticeable improvements in signs and symptoms of Cushing's disease could be achieved.

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