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. While it is known that up to 20% or so of patients with CD recur after apparently successful transsphenoidal tumor resection, little is known about what factors may predict recurrence. Perioperative increases in adrenocorticotropic hormone (ACTH) and cortisol mimic corticotropin releasing hormone (CRH) stimulation testing. This phenomenon may help identify patients with residual adenoma after transsphenoidal surgery (TSS) for Cushing's disease (CD). We retrospectively evaluated whether early post-operative measurements of ACTH and cortisol would be helpful in this regard. This was a case control study of 291 consecutive patients treated at NIH from December 2003 till July 2016. Early and medium-term remission were assessed at 10 days and 11 months. 257 patients had biochemical evidence of CD. Normalized early post-operative values (NEPV) for cortisol and ACTH were calculated as immediate post-operative cortisol or ACTH minus preoperative post-CRH stimulation test levels. The NEPV for cortisol and ACTH predicted early non-remission (adjusted OR 1.1, 95% CI 1.0 - 1.1, P = 0.016; and adjusted OR 1.0, 95% CI 1.0 - 1.0, P = 0.048 respectively). ROC for NEPV cortisol was 0.78, 95% CI 0.61 - 0.95; and for NEPV ACTH was 0.80, 95% CI 0.61 - 0.98. NEPV for both cortisol and ACTH predicted medium-term non-remission (hazard ratios (HR) 1.1, 95% CI 1.0 - 1.1, P = 0.023; and HR 1.0, 95% CI 1.0 - 1.0, P = 0.025 respectively). Thus, NEPV for cortisol and ACTH may help predict non-remission after TSS for CD. 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. We found that diverticular perforation is an uncommon associated finding in the setting of hypercortisolism. Importantly, its presentation is quite variable, and may not include typical abdominal findings, fever or increased white blood cell count. Hence, this possibility should be considered in unwell patients, particularly in those with very high cortisol production.

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Feelders, Richard A; Newell-Price, John; Pivonello, Rosario et al. (2018) Advances in the medical treatment of Cushing's syndrome. Lancet Diabetes Endocrinol :
Nieman, Lynnette Kaye (2018) Diagnosis of Cushing's Syndrome in the Modern Era. Endocrinol Metab Clin North Am 47:259-273
Chatain, Grégoire P; Patronas, Nicholas; Smirniotopoulos, James G et al. (2018) Potential utility of FLAIR in MRI-negative Cushing's disease. J Neurosurg 129:620-628
Ironside, Natasha; Chatain, Gregoire; Asuzu, David et al. (2018) Earlier post-operative hypocortisolemia may predict durable remission from Cushing's disease. Eur J Endocrinol 178:255-263
Nieman, Lynnette K (2018) Recent Updates on the Diagnosis and Management of Cushing's Syndrome. Endocrinol Metab (Seoul) 33:139-146
Asuzu, David; Chatain, Grégoire P; Hayes, Christina et al. (2017) Normalized Early Postoperative Cortisol and ACTH Values Predict Nonremission After Surgery for Cushing Disease. J Clin Endocrinol Metab 102:2179-2187
Del Rivero, Jaydira; Kim, Chul; Eid, Mary et al. (2017) Thymic Hyperplasia after Treatment of ACTH-Dependent Cushing's Syndrome Can Be Mistaken for a Thymic Epithelial Tumor. J Thorac Oncol 12:e29-e32
Lonser, Russell R; Nieman, Lynnette; Oldfield, Edward H (2016) Cushing's disease: pathobiology, diagnosis, and management. J Neurosurg :1-14
Sharma, S T; Nieman, L K; Feelders, R A (2015) Comorbidities in Cushing's disease. Pituitary 18:188-94
Nieman, Lynnette K; Biller, Beverly M K; Findling, James W et al. (2015) Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 100:2807-31

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