USP8 is frequently mutated in adenomas causing Cushing's disease, especially in those from female adult patients diagnosed at a younger age.

Adrenal insufficiency occurs in about half of the patients with SH if defined only by the pathological dexamethasone test. However, prevalence of adrenal insufficiency and time to recovery are tightly related to the degree of hypercortisolism and diagnostic criteria to define SH, which might help to better define SH for future studies.

Objective: Our aim was to review short-and long-term outcomes of patients treated with bilateral adrenalectomy (BADx) in ACTH-dependent Cushing's syndrome. Methods: We reviewed the literature and analysed our experience with 53 patients treated with BADx since 1990 in our institution. Results: BADx is considered if ACTH-dependent Cushing's syndrome is refractory to other treatment modalities. In Cushing's disease (CD), BADx is mainly used as an ultima ratio after transsphenoidal surgery and medical therapies have failed. In these cases, the time span between the first diagnosis of CD and treatment with BADx is relatively long (median 44 months). In ectopic Cushing's syndrome, the time from diagnosis to BADx is shorter (median 2 months), and BADx is often performed as an emergency procedure because of life-threatening complications of severe hypercortisolism. In both situations, BADx is relatively safe (median surgical morbidity 15%; median surgical mortality 3%) and provides excellent control of hypercortisolism; Cushing's-associated signs and symptoms are rapidly corrected, and co-morbidities are stabilised. In CD, the quality of life following BADx is rapidly improving, and long-term mortality is low. Specific long-term complications include the development of adrenal crisis and Nelson's syndrome. In ectopic Cushing's syndrome, long-term mortality is high but is mostly dependent on the prognosis of the underlying malignant neuroendocrine tumour. Conclusion: BADx is a relatively safe and highly effective treatment, and it provides adequate control of long-term co-morbidities associated with hypercortisolism.European Journal of Endocrinology (2015) 173, M23-M32 Invited Author's profile Prof. Martin Heinrich Reincke is Director of the Medizinische Klinik and Poliklinik IV, Ludwig-MaximiliansUniversität München, and Chair of the Department of Endocrinology and Diabetology. His research specialities include adrenal physiology and pathophysiology, endocrine hypertension, pituitary disease, mineralocorticoid and glucocorticoid action and stress research. Professor Reincke heads a research team that specifically explores the prevalence and relevance of Cushing's syndrome at the epidemiological, clinical, genetic and molecular levels. The research teams of his clinic have particular expertise in assay development and validation for endocrine disease and in the development of genetically manipulated animals as models for human adrenal disease.

Time to recovery of adrenal function is dependent on the underlying etiology of CS.

CS affects muscle strength in the acute phase, but functional impairment remains detectable also during long-term follow-up despite biochemical remission.

Analysis of cortisol in a single scalp hair sample offers diagnostic accuracy for CS similar to currently used first-line tests, and can be used to investigate cortisol exposure in CS patients months to years back in time, enabling the estimation of disease onset.

Objective: The aim of the present study was to validate criteria of corticotropin-releasing hormone (CRH) stimulation and 8 mg dexamethasone suppression (high-dose dexamethasone suppression, HDDS) to distinguish the etiology of ACTH-dependent Cushing's syndrome. Subjects and methods: We retrospectively analyzed cortisol and ACTH after the injection of 100 mg human CRH in confirmed Cushing's disease (CD, nZ78) and confirmed ectopic Cushing's syndrome (ECS, nZ18). Cortisol and ACTH increase (in percentage above basal (% B )) at each time point, maximal increase (Dmax % B ), and area under the curve (AUC % B ) were analyzed using receiver operator characteristics (ROC) curve analyses. Cortisol suppression (% B ) after 8 mg of dexamethasone was evaluated as a supplementary criterion. Results: An increase in ACTH of R43% B at 15 min after CRH was the strongest predictor of CD, with a positive likelihood ratio of 14.0, a sensitivity of 83%, a specificity of 94%, a positive predictive value of 98% and a negative predictive value of 58%. All of the other criteria of stimulated ACTH and cortisol levels were not superior in predicting CD in response to CRH injection. The addition of cortisol suppression by dexamethasone did not increase the discriminatory power. However, the combination of a positive ACTH response at 15 min and a positive HDDS test excluded ECS in all cases. Conclusion: The present findings support the use of plasma ACTH levels 15 min after the injection of human CRH as a response criterion for distinguishing between CD and ECS. The addition of the HDDS test is helpful for excluding ECS when both tests are positive.

Our data support the concept that time of exposure to glucocorticoid excess appears to be a better predictor than peak serum cortisol levels at the time of diagnosis regarding long-term psychiatric morbidity and QoL.