Treatment for Cushing's syndrome depends on the cause.

For Cushing's syndrome caused by long-term corticosteroid medicine use Never stop taking corticosteroid medicine on your own because it might lead to a life-threatening adrenal crisis. When you take steroids, your adrenal glands stop making cortisol. If you suddenly stop taking your medicine, your adrenal glands may not be able to start making cortisol quickly enough. This can lead to an adrenal crisis and a severe drop in blood pressure. To avoid this, your doctor will want to gradually reduce and then stop your medicine. Your doctor may change your corticosteroid medicine from a longer-acting steroid (such as prednisone) to a shorter-acting one (such as hydrocortisone). Sometimes corticosteroid medicines can be taken every other day. Either way, the body's normal production of cortisol returns gradually. If you must continue taking corticosteroid medicine to control another condition, the dosage can sometimes be lowered to reduce symptoms and the risk of complications. If your doctor and you are trying to reduce the dosage of your medicine and you become ill, contact your doctor immediately. If reducing the dosage does not make Cushing's syndrome go away, your doctor will perform more tests to look for another cause of your condition. For Cushing's syndrome caused by pituitary tumors (Cushing's disease) If you are well enough to have surgery, surgical removal of the pituitary tumor offers the best chance for recovery. The surgery (transsphenoidal adenomectomy) requires great skill and should be performed at a major medical center where teams of doctors specialize in pituitary surgery. Transsphenoidal adenomectomy is successful:1

About 85% of the time if the tumor is less than 0.4in. in diameter. About 25% of the time if the tumor is 0.4in. in diameter or larger.

Cushing's disease returns in about 2% of adults and up to 40% of children who have the operation.2 Surgery can be repeated, often with good results. Gamma knife radiosurgery has recently been introduced in the United States. In this technique, many small beams of radiation are focused on the tumor to shrink and destroy it. It does not involve a surgical incision (there is no "knife" involved), and there is minimal damage to surrounding tissue. It can be done as an outpatient and with local anesthesia. Few centers in the United States have gamma knife facilities. Medicine therapies may be tried if surgery is not possible or has failed.

For Cushing's syndrome caused by adrenal tumors Doctors almost always recommend surgery to remove benign adrenal tumors that are producing hormones. If a tumor is cancerous, the affected adrenal gland is removed. Although chemotherapy is usually advised, there is no proven long-term treatment for adrenal cancer. On rare occasions, both adrenal glands must be removed. In this case, you would take daily longterm hormone replacement. PENGOBATAN/ TERAPI Pengobatan sindrom cushing tergantung ACTH tidak seragam, bergantung pada apakah sumber ACTH adalah hiposis atau ektopik. Beberapa pendekatan terapi dugunakan pada kasus dengan hipersekresi ACTH hipofisis. Jika dijumpai tumor hipofisis sebaiknya sdiusahakan reseksi tumor transfenoidal. Tetapi jika terdapat bukti hiperfungsi hipofisis namun tumor tidak dapat ditemukan maka sebagai gantinya dapat dilakukan radiasi kobalt pada kelenjar hipofise. Kelebihan kortisol juga dapat ditanggulangi dengan adrenalektomi total dan diikuti pemberian kortisol dosis fisiologik atau dengan kimia yang mampu mrnghambat atau merusal sel-sel korteks adrenal yang mensekresi kortisol. Pengobatan sindrom ACTH ektopik adalah dengan reseksi neoplasma yang mensekresi ACTH atau adrenalektomi atau supresi kimia fungsi adrenal seperti dianjurkan pada penderita sindrom cushing jenis tergantung ACTH hipofisis. (Silvia A. Price; Patofisiologi, Hal. 1093) What is the prognosis? The prognosis for individuals with Cushing's syndrome varies depending on the cause of overproduction of cortisol. With treatment, most individuals with Cushing's syndrome show significant improvement, while improvement for others may be complicated by various aspects of the causative illness. Some kinds of tumors may recur. Most cases of Cushing's can be cured.

Treating Cushing's syndrome

Treatment of Cushing's syndrome depends on the cause of the high levels of cortisol. Treatment includes:

reducing the dose of steroid medication, cortisol-inhibiting drugs, surgery, radiotherapy, or chemotherapy.

If treated, the symptoms of Cushing's syndrome can be cured, but recovery is a slow process and can take between several weeks and a couple of years. However, you will begin to feel better and symptoms will gradually improve as time goes on. If Cushing's syndrome is left untreated, it can be fatal. Death is usually because of high blood pressure, infection, heart attack or heart failure. Reducing steroid medication If Cushing's syndrome is due to high doses of steroid hormones used to treat another illness, you will probably have to reduce the dose of steroid and explore alternative treatments for the illness. Your doctor will reduce your steroid medication to the lowest dose needed to control your illness and other medication may be prescribed instead. Steroids should not be stopped suddenly as this could lead to a cortisol deficiency which could make you ill. Cortisol-inhibiting drugs Medication to block the production and effects of cortisol (cortisol-inhibiting drugs) may be another option. These include ketoconazole, metyrapone, and occasionally mitotane. Surgery Surgery may be needed to remove or destroy a pituitary tumour or an adrenal gland tumour. These operations are described below. After pituitary and adrenal surgery, you may have to take a hormone called hydrocortisone for some time as your body will not produce enough adrenocorticotropin hormone (ACTH) on its own. There are possible complications associated with surgery (see the box, right).

Pituitary tumour Under general anaesthetic, the surgeon will remove your pituitary tumour through your nostril or an opening made behind the upper lip, just above the front teeth. This surgery means the surgeon can reach your pituitary gland without having to operate on the main part of your head. If it is not possible to remove all the cells that make the excess ACTH hormone or if the level of ACTH is still high after the operation, you may need medication, further surgery or radiotherapy. Adrenal gland tumour Adrenal gland tumours are either benign (non-cancerous) or malignant (cancerous). They can often be removed with surgery under general anaesthetic. In some cases it may be necessary to remove both adrenal glands. This is called an adrenalectomy. The adrenal glands are reached through a cut in the stomach or back. Radiotherapy Your doctor may decide to use radiotherapy to destroy the tumour instead of surgery or if surgery has failed. Radiation to the pituitary gland is given in hospital over a six-week period (see Useful links for more information on radiotherapy). Chemotherapy If the Cushing's syndrome is caused by a cancerous tumour, such as a lung tumour, it is best treated by chemotherapy, an injection of drugs that kill cancer cells (see Useful links for more information).

Treatment of Cushing syndrome is directed by the primary cause of the syndrome. In general, therapy should reduce the cortisol secretion to normal to reduce the risk of comorbidities associated with hypercortisolism. A culprit tumor should be removed if possible. The treatment of choice for endogenous Cushing syndrome is surgical resection of the causative tumor. The primary therapy for Cushing disease is transsphenoidal surgery, and the primary therapy for adrenal tumors is adrenalectomy. When surgery is not successful or cannot be used, as often occurs with ectopic ACTH or metastatic adrenal carcinoma, control of hypercortisolism may be attempted with medication. However, medication failures are common, and adrenalectomy may be indicated in ACTHmediated Cushing syndrome. Pituitary radiation may be useful if surgery fails for Cushing disease.[10] The treatment for exogenous Cushing syndrome is gradual withdrawal of glucocorticoid. Medical care for Cushing syndrome can be summarized as follows:

Agents that inhibit steroidogenesis, such as mitotane, ketoconazole, metyrapone, aminoglutethimide, trilostane, and etomidate, have been used to cause medical adrenalectomy. These medications are used rarely and often are toxic at the doses required to reduce cortisol secretion. Thus, medical treatment should be initiated cautiously and, ideally, in conjunction with a specialist. Efficacy of these medical interventions can be assessed with serial measurements of 24-hour urinary free cortisol. Patients receiving these medications may require glucocorticoid replacement to avoid adrenal insufficiency. Patients should be counseled on the signs and symptoms of adrenal insufficiency when starting these drugs. Metyrapone and trilostane are agents that competitively inhibit a single steroidogenic enzyme. Ketoconazole and aminoglutethimide act at several sites. In ACTH-dependent Cushing syndrome, ACTH secretion continues to stimulate steroidogenesis, which counters the actions of these medications. Because ACTH production may persist or increase in patients with Cushing disease, radiation therapy of the pituitary is often required after unsuccessful initial therapy, either surgical or medical. These agents have higher efficacy when used in combination because they may act synergistically. Ketoconazole is probably the most popular and effective of these agents for long-term use and usually is the agent of choice. It acts on several of the P450 enzymes, including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11deoxycortisol to cortisol. o A daily dose of 600-800 mg often decreases cortisol production. If this agent is ineffective at controlling hypercortisolism, the dose may be maintained while another steroid enzyme inhibitor, typically metyrapone, is initiated. o Adverse effects of ketoconazole include headache, sedation, nausea, irregular menses, decreased libido, impotence, gynecomastia, and elevated liver function tests. The drug is contraindicated during pregnancy. o Ketoconazole is less effective in patients on H2 blockers or proton-pump inhibitors because gastric acidity is required for metabolism.

Metyrapone blocks 11-beta-hydroxylase activity, the final step in cortisol synthesis. Therapy is begun at 1 g/d divided into 4 doses and increased to a maximum dose of 4.5 g/d. Adverse effects are from increases in androgen and mineralocorticoid precursors, including hypertension, acne, and hirsutism. Aminoglutethimide is an anticonvulsant agent that blocks cholesterol side-chain cleavage to pregnenolone. It is a relatively weak adrenal enzyme inhibitor at doses that patients can tolerate. Aminoglutethimide is typically initiated at 250 mg twice daily, and doses of 1-2 g daily are often used. o Adverse effects of aminoglutethimide include somnolence, headache, a generalized pruritic rash, hypothyroidism, and goiter. o In rare cases, it may cause bone marrow suppression. o Aminoglutethimide increases the metabolism of dexamethasone but not cortisol. Trilostane is not widely available and is not as well studied. Trilostane inhibits the conversion of pregnenolone to progesterone, which decreases the synthesis of cortisol, aldosterone, and androstenedione. It is not a first-choice agent because it is a weak inhibitor of steroidogenesis. In addition, trilostane interacts with some assays, causing a false elevation of cortisol measurements. Etomidate, an imidazole-derivative anesthetic agent, blocks 11-beta-hydroxylase. It is used intravenously at 0.3 mg/kg/h. Its use is limited by the requirement for chronic administration by the intravenous route. Mitotane is an adrenolytic agent that acts by inhibiting 11-beta hydroxylase and cholesterol side-chain cleavage enzymes. This drug also leads to mitochondrial destruction and necrosis of adrenocortical cells in the zona fasciculata and reticularis. For this reason, it is used in treatment of adrenal cancer at doses of 2-4 g daily. Its survival benefit is unclear. It can be used in addition to radiation therapy for treatment of Cushing disease and in combination with metyrapone or aminoglutethimide for treatment of ectopic ACTH secretion. o Unfortunately, mitotane is expensive, and its utility is limited by adverse gastrointestinal and neurologic effects, including nausea, diarrhea, dizziness, and ataxia. Other adverse effects include rash, arthralgias, and leukopenia. o It is taken up by adipose tissues and persists in the circulation long after discontinuation. o It is a potential teratogen and can cause abortion; therefore, it is relatively contraindicated in women interested in remaining fertile. Mifepristone (RU 486) is an antiprogestational agent, which, at high doses, competitively binds to the glucocorticoid and progesterone receptors. It currently is used only on an investigational basis for treatment of Cushing syndrome.[11] Agents that decrease CRH or ACTH release have been studied for the treatment of Cushing disease. Such agents include bromocriptine, cyproheptadine, valproic acid, and octreotide. Currently, use of these agents is investigational.

Treatment options for patients with persistent or recurrent Cushing disease have included pituitary irradiation and repeat surgery. A small study found that a percentage of such patients respond to cabergoline therapy.[12] Mechanism of action, longer-term follow-up, and a larger number of patients are needed to confirm these encouraging preliminary results.