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The most frequent cause of Cushing's syndrome is iatrogenic, as Cushing's syndrome is the unavoidable consequence of long-term glucocorticoid treatment using more than 7.5 mg prednisone per day. The most frequent cause of endogenous Cushing's syndrome is Cushing's disease (CD), which is an ACTH dependent hypercortisolism linked to a pituitary corticotroph adenoma. This adenoma is often very small, its diagnosis may require bilateral inferior petrosal sinus sampling and the first line treatment of CD is transsphenoidal surgery by an expert neurosurgeon. The second line treatments include drugs that can act either on the pituitary adenoma or on adrenal steroidogenesis, pituitary radiotherapy or bilateral adrenalectomy. Ectopic ACTH dependent Cushing's syndrome is linked either to poorly differentiated endocrine tumors with a very poor prognosis, such as small cell lung cancer, or to well differentiated endocrine tumors, such as bronchial carcinoid tumors, which have a good prognosis when treated by surgery, but may be very difficult to localize. Adrenal Cushing's syndromes, which are independent of pituitary ACTH secretion, include adrenal cortex carcinoma, which requires abdominal surgery with extended adrenalectomy by an expert surgeon, adrenal adenoma which is treated by laparoscopic unilateral adrenalectomy and bilateral macronodular hyperplasia, whose surgical treatment may require unilateral or bilateral adrenalectomy. Treatment of Cushing's syndrome generally leads to spectacular clinical results, which must not hide the fact that the reversibility of some signs is actually incomplete. This underlines the need for a timely multidisciplinary management of the patients by an expert team.

Transsphenoidal surgery, possibly through the endoscopic approach, remains the first line treatment. Opposing cortisol action with mifepristone proved efficacious in some individual cases but but with major monitoring difficulties. Combined treatment with three anticortisolic drugs (metyrapone, ketokonazole, O,p'DDD) is particularly attractive in severe cases. The Nelson's syndrome has been revisited, and the corticotroph tumor progression should rather be cautiously assessed after bilateral adrenalectomy. Two molecules potentially act directly to suppress the ACTH secretion by the corticotroph adenoma: agonists of the D2 Dopamine receptor and of the somatostatin receptor type 5. Their efficacy remains modest (20 to 30% of the patients actually normalize urinary cortisol). Pituitary radiotherapy can be efficiently performed by stereotaxic approach.

Recent discoveries in molecular biology offer new perspectives in the treatment of endocrine tumors. There is currently no medical therapy for Cushing's disease that targets the pituitary adenoma. Pasireotide, a new somatostatin analog, demonstrates a strong affinity for somatostatin receptors expressed by corticotroph adenomas. Some recent clinical trials showed a decrease of urinary free cortisol with pasireotide. This new treatment could be useful in case of pituitary surgery failure. Thyroid tumorigenesis involves kinase signaling cascade. Tyrosine-kinase inhibitors have now been tested in the treatment of progressive differentiated iodine refractory thyroid carcinomas or medullary carcinomas and showed modestly encouraging results.

Corticotroph adenomas cause ACTH oversecretion responsible for Cushing's disease. This represents the most frequent cause of Cushing's syndrome, or chronic excess of endogenous glucocorticoids. Ninety percent of corticotroph adenomas are microadenomas, sometime not visible on MRI. Corticotroph macroadenomas are rare, but can be responsible for an aggressive tumor. Cushing's disease diagnosis requires careful hormonal and imaging investigations, aiming first at the diagnosis of Cushing's syndrome and in a second step at the diagnosis of its pituitary origin. The treatment of corticotroph adenoma is mainly based on pituitary surgery. In case of failure of pituitary surgery, or in patients in whom surgery is not appropriate as a first line treatment, medical therapy (mainly anticortisolic drugs), pituitary radiotherapy or surgical bilateral adrenalectomy can be discussed.

Pituitary gland tumors that became aggressive, implying adjacent bone structure and the brain as metastases outside of the cranial box, are referred to as pituitary carcinomas.We reviewed 67 cases reported in the literature [44 corticotropic pituitary tumors, 11 PRL tumors, 3 GH tumors, 1 TSH tumor, 3 gonadotropic cell tumors and 5 non-functioning tumors].The corticotropic tumors occurred in 23 female and 15 males. Signs of hypercorticism were characteristic: generalized melanosis before adrenalectomy (N=1); headache (N=1); altered visual (N=1); diabetes insipidus (N=1); amenorrhea (N=1); Cushing syndrome (N=2); weight loss (N=1); refractory hypokaliemic alkalosis (N=1); diabetes mellitus (N=1); hypertension (N=1). ACTH, beta-lipotrophin, betaendorphin, alphamelano-stimulating hormone, CRH, and beta-gamma MSH were contributive while ultrastructural microscopy provided little information, as did an equimolar Lph/ACTH ratio. The possible association of prolactin tumors with corticotrophin forms has been underlined. The characteristic feature is a time interval from the initial diagnosis of adenoma to that of cancer, which has ranged from 0.3 to 18 years (mean: 6.6 years; median: 5.0 years).Corticotropic tumors resistance to high-dose medical treatment are usually aggressive tumors with a risk of recurrence after surgical treatment or even radiotherapy with the risk of metastases. GH tumors appear to predominate although it is known that these cancers can develop in association with corticotrophin cancers or with prolactin cell tumors.