The differential diagnosis and treatment of Cushing's syndrome

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Cushing's syndrome is caused by autonomous adrenal production of cortisol, or by excess secretion of adrenocorticotropic hormone (ACTH) by a benign monoclonal pituitary adenoma (termed Cushing's disease, CD) or by excessive ACTH secretion by a non-pituitary tumor (Ectopic ACTH secretion, EAS). The excessive secretion of ACTH stimulates secretion of cortisol by the adrenal glands, resulting in supraphysiological levels of circulating cortisol. The pathophysiological levels of cortisol are associated with hypertension, diabetes, obesity, and early death. Successful resection of the ACTH-secreting pituitary adenoma is the treatment of choice and results in immediate biochemical remission with preservation of pituitary function. Accurate and early identification of the source of ACTH is critical for effective surgical management and optimal prognosis. We recently reviewed the current pathophysiological principles, diagnostic methods, and management of these patients. Additionally, in view of the COVID19 epidemic, we provided advice on modifications for the evaluation and management of Cushing's syndrome patients at this time. Accurate presurgical localization of microadenomas in Cushing's disease (CD) leads to improved remission rates and decreased adverse events. While inferior petrosal sinus sampling can identify CD as the cause of Cushing syndrome, its utility in localizing a tumor to the right or left side of the gland is limited. MRI of the pituitary gland is unfortunately, also negative in about 50% of known cases of CD. Previous work suggested that fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) can detect some of these tumors, and in vitro studies showed that corticotropin-releasing hormone (CRH) stimulation leads to delayed, selective glucose uptake in corticotropinomas. Thus, we prospectively evaluated the utility of CRH stimulation in improving 18F-FDG-PET detection of adenomas in CD patients. 27 subjects underwent two FDG-PET scans, with or without pretreatment with CRH. Of the 54 scans, radiologists agreed on the presence of tumor on 21 and the absence of tumor on 26 (they disagreed on 7). CRH pretreatment enhanced the ability to see the tumor in 6 patients. In 5 patients with no tumor on routine MRI, 2 had tumors detected by FDG-PET. This suggests a potential role for CRH to enhance the detection of ACTH-secreting tumors. Hypertension associated with Cushing's syndrome (CS) increases cardiovascular risk. The time-course of improvement after cure is unclear. We retrospectively reviewed the medical records of 75 hypertensive adults cured of CS (72 with ACTH-dependent CS; 3 with adrenal adenoma) to describe the time-course and predictors of blood pressure (BP) normalization during one year after surgical cure of CS. Hypertension was defined as current use of antihypertensives, a systolic BP >130 mm Hg, or diastolic BP >80 mm Hg. At postoperative discharge, 17 (23%, P < .001), 51 (68%, P < .001) and 7 (9%) patients had remission, improvement in hypertension or no change. Twenty-nine had no follow-up. Others achieved remission at 3 (n = 5), 6 (n = 6), or 12-months (n = 5). At the last evaluation, 33/75 (44%) had remission, 36/75 (48%) had improved hypertension and 6 were unchanged. Patients with improvement discontinued a median of one medication (P < .001). At 12-months, 27/42 (64%) patients had normal BP (P < .002). Longer estimated duration of CS (P = .0106), younger age (P = .0022), and lower baseline body mass index (P = .0413) predicted hypertension remission. Thus, about 80% of CS patients experienced BP normalization or improvement within 10 days of cure, but about half failed to normalize BP by one year. BP should be monitored after cure, and antihypertensive medications adjusted to avoid unwanted cardiovascular effects.