AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Objective: The European Registry on Cushing's syndrome (ERCUSYN) is designed to collect prospective and follow-up data at EU level on Cushing's syndrome (CS). Design and methods: Baseline data on 481 CS patients (390 females, 91 males; mean age (GS.D.): 44 G14 years) collected from 36 centres in 23 countries, including new patients from 2008 and retrospective cases since 2000. Patients were divided into four major aetiologic groups: pituitarydependent CS (PIT-CS) (66%), adrenal-dependent CS (ADR-CS) (27%), CS from an ectopic source (ECT-CS) (5%) and CS from other aetiologies (2%). Results: Proportion of men in the ECT-CS group was higher than in the other groups (P!0.05). The ADR-CS group was older than the PIT-CS (P!0.05). Prevalence of hirsutism (92%) and diabetes (74%) in ECT-CS was higher than in the other groups (P!0.05 and P!0.01 respectively). PIT-CS had more skin alterations, menstrual irregularities and hirsutism than ADR-CS (P!0.01). Reduced libido was more prevalent in men than women (P!0.01). Prevalence of spine osteoporosis was higher in men than women (P!0.05), and males had more vertebral and rib fractures than females (52 vs 18% for vertebrae; P!0.001 and 34 vs 23% for ribs; P!0.05). ECT-CS consulted a diabetologist more frequently than ADR-CS (P!0.05), while a gynaecologist was consulted more often by women with PIT-CS or ADR-CS than with ECT-CS (P!0.05). Overall, weight gain was more common in women than men (P!0.01). CushingQoL and EuroQoL visual analogue scale scores did not differ between the groups. Conclusions: The ERCUSYN project demonstrates a heterogeneous clinical presentation of CS at a European level, depending on gender and aetiology.

Background: Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments. Methods: We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at !30 years of age. Results: Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas. Conclusion: Germline AIPmut occur in 11.7% of patients !30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

We assessed the value of midnight salivary cortisol for the initial diagnosis of Cushing's syndrome. Sixty-three patients with various causes of Cushing's syndrome (37 with Cushing's disease, 17 with adrenal Cushing's syndrome, and nine with ectopic ACTH syndrome) and 54 control subjects with simple obesity were studied. All patients with Cushing's syndrome excreted more than 90 microg urinary free cortisol (UFC)/d (248 nmol/d), and all controls excreted less than 90 microg/d UFC. All patients with Cushing's syndrome had a midnight salivary cortisol concentration above 2.0 ng/ml (5.52 nmol/liter), whereas only three controls did so [2.0 ng/ml (5.52 nmol/liter); 2.05 ng/ml (5.66 nmol/liter); and 3.6 ng/ml (9.96 nmol/liter)]. This cut-off provides a sensitivity of 100% and a specificity of 96%. In patients with Cushing's syndrome, midnight salivary cortisol concentrations were correlated with UFC collected over the same period of time (0800-0800 h). Salivary cortisol measurements taken every 4 h showed a typical lack of circadian variation. The daily measurement of midnight salivary cortisol concentrations for 2 wk or more in five other out-patients (with obvious Cushing's disease, subclinical adrenal Cushing's syndrome, suspected Cushing's syndrome, pituitary incidentaloma, and prolactinoma) demonstrated the clinical utility of this factor. Measuring midnight salivary cortisol is an easy and noninvasive means of diagnosing hypercortisolism. Its diagnostic accuracy is identical to, if not better than, that of previously described gold standards.

Summary Objective Hypercortisolism in Cushing's syndrome (CS) is associated with impaired health‐related quality of life (HRQoL), which may persist despite remission. We used the data entered into the European Registry on Cushing's syndrome (ERCUSYN) to evaluate if patients with CS of pituitary origin (PIT‐CS) have worse HRQoL, both before and after treatment than patients with adrenal causes (ADR‐CS). Methods Data from 595 patients (492 women; 83%) who completed the CushingQoL and/or EQ‐5D questionnaires at baseline and/or following treatment were analysed. Results At baseline, HRQoL did not differ between PIT‐CS (n = 293) and ADR‐CS (n = 120) on both EuroQoL and CushingQoL. Total CushingQoL score in PIT‐CS and ADR‐CS was 41 ± 18 and 44 ± 20, respectively (P = .7). At long‐time follow‐up (>1 year after treatment) total CushingQoL score was however lower in PIT‐CS than ADR‐CS (56 ± 20 vs 62 ± 23; P = .045). In a regression analysis, after adjustment for baseline age, gender, remission status, duration of active CS, glucocorticoid dependency and follow‐up time, no association was observed between aetiology and HRQoL. Remission was associated with better total CushingQoL score (P < .001), and older age at diagnosis with worse total score (P = .01). Depression at diagnosis was associated with worse total CushingQoL score at the last follow‐up (P < .001). Conclusion PIT‐CS patients had poorer HRQoL than ADR‐CS at long‐term follow‐up, despite similar baseline scoring. After adjusting for remission status, no interaetiology differences in HRQoL scoring were found. Age and presence of depression at diagnosis of CS may be potential predictors of worse HRQoL regardless of CS aetiology.