**7.2 Evaluation**

Early recognition of CD is vital for mitigation of long-term consequences from high cortisol exposure. The first step in diagnosis relies on clinical suspicion. Exogenous corticosteroid source should be first ruled-out by a detailed history. The diagnostic work-up is summarized by 3 broad steps: detection of high cortisol level, ACTH level status, and localization of the disease origin (**Figure 6**). After biochemical confirmation of Cushing syndrome, ACTH level should be measured.

Low-ACTH levels mean that pituitary cells are suppressed and there is no extra-pituitary ACTH secretion. In this setting, it is prudent to rule-out adrenal adenomas. If ACTH level is high, CD is confirmed and the localization of the source of ACTH secretion should be evaluated. Unlike cancer cells that secret ACTH, adenomas affecting corticotrophic pituitary cells are usually suppressed by exogenous high corticosteroids doses. High-dose dexamethasone test (e.g. 8 mg given at 9 p.m. and cortisol levels measured at 8 a.m. the next morning) will suppress ACTH secreted from pituitary adenoma but not from ectopic sources. MRI pituitary need to be ordered if high-dose dexamethasone test localize the source to pituitary gland. As mentioned earlier, 70–75% of ACTH-secreting adenomas are microadenomas. However, up to 60% of these adenomas are not detected on MRI [43, 45, 46]. To increase detection rate of the adenoma, volumetric interpolated breath-hold examination (VIBE) sequences should be added [47]. If the brain MRI is negative or high-dose dexamethasone test is unequivocal and a pituitary source is still highly suspected, inferior petrosal sinus (IPS) sampling would confirm the pituitary source and also localize the tumor within the pituitary gland to the left or right side. IPS sampling has an accuracy rate of up to 95%, however, it is an invasive procedure and requires highly experienced operators. To enhance the detection rate, bilateral simultaneous IPS sampling after CRH *or* desmopressin stimulation is highly recommended (**Figure 7**) [48, 49].
