An important question is whether CS from excessive ACTH-producing pituitary glands develops by a defect in the pituitary gland or through secondary factors that stimulate the pituitary corticotrophs. Although some past observations suggested that hypothalamic stimulation of the corticotrophs might be responsible for pituitary adenoma formation (34-37), it is now clear that CD arises in the pituitary gland by corticotroph hyperplasia, an adenoma, or extremely rarely a carcinoma (38-41). Transgenic mice with overproduction of CRH show features of CS without concomitant corticotroph proliferation (42). More importantly, most patients (depending on the neurosurgeon; in our institution approx 95%) with CD are in complete remission after adenomectomy (if the adenoma does not infiltrate the cavernous sinus or other structures).
The molecular pathogenesis of pituitary adenomas, including ACTH-producing ones, is the subject of intense investigation (43) (Chapter 2). Cortico-tropinomas are monoclonal, but the exact pathways of tumor formation remain unknown, although some genes, such as c-myc, c-erbB2, and ras, have been associated with more aggressive tumor behavior (44-48). Abnormalities in many other tumor-suppressor genes and oncogenes are found in cortico-tropinomas, although their exact role in tumorigenesis is not understood (43, 49). Also, abnormalities of the glucocorticoid receptor and its gene have been described in these tumors (50, 51).
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