Objective: Glucocorticoid receptor (GR) polymorphisms alter glucocorticoid (GC) sensitivity and have been associated with altered metabolic profiles. We evaluate the prevalence of the four GR (NR3C1) polymorphisms BclI, N363S, ER22/23EK, and A3669G in patients with Cushing's syndrome (CS) compared with healthy controls (HC) and we investigate their role in the development of metabolic abnormalities in patients with CS according to their hormonal profile. Patients and methods: Sixty-one patients with CS and 71 sex-and age-matched HC were genotyped. Results: BclI variant was markedly higher in patients with CS compared with HC (62 vs 41%, P!0.05) while no significant differences were found among other polymorphisms. A very low frequency of N363S and the ER22/23EK was observed. In CS patients, despite the significantly increased levels of morning serum cortisol in BclI carriers compared with wild type no clinical or metabolic differences were found. In contrast, A3669G GR carriers showed a significantly reduced prevalence of type 2 diabetes mellitus compared with wild type (19 vs 68%, PZ0.001) despite the higher levels of both serum morning (21.7G6 vs 27.3G8.6 mg/dl, PZ0.009) and midnight cortisol (18.8G5.8 vs 24.0G8.0 mg/dl, PZ0.01). The negative association between diabetes and A3669G GR polymorphism remained significant when data were adjusted for potential confounding factors. Conclusions: The A3669G polymorphism of the GR gene plays a protective role in patients with CS, attenuating the effects of GC excess on glucose metabolism as shown by their reduced risk of diabetes.

A 56-yr-old woman was referred with a diagnosis of Cushing's disease. Hypertension and severe hypokalemia were present and high urinary free cortisol/cortisone ratio was detected, raising a suspicion of an ectopic ACTH syndrome. Inferior petrosal sinus sampling, thoracic computed tomography, and octreotide scans were negative. Remission and relapse periods lasting 3-4 months were observed during the 3.5 yr of follow-up. Finally a thoracic computed tomography scan showed a basal paracardic nodule in the left lung. After surgery, a well-differentiated neuroendocrine tumor (typical bronchial carcinoid) was diagnosed, staining positively for ACTH. RT-PCR revealed expression of proopiomelanocortin, CRH receptor, and V3 vasopressin receptor. Somatostatin receptor type 1, 2, 3, and 5 mRNA was detected only in tumoral tissue. Interestingly, we observed the simultaneous presence of ghrelin and both GH secretagogue (GHS) receptors (1a and 1b) mRNA in tumoral tissue but not in the normal lung. This finding correlates with the in vivo ACTH hyperresponsiveness to hexarelin (a GHS). This is the first report of a cyclical ectopic ACTH-secreting tumor with an in vivo ACTH response to hexarelin coupled with the tumoral expression of ghrelin and GHS receptors. This finding might imply an autocrine/paracrine modulatory effect of ghrelin in bronchial ACTH-secreting tumors.

While GR gene variants as well as gender and disease etiology seem not to play a role, the degree and duration of hypercortisolism seem to be the major determinants of bone loss and fractures in this group of patients. More investigations are needed to understand the real impact of these determinants on the development of bone complications in patients with hypercortisolism.

Pasireotide is a multireceptor-targeted somatostatin analogue acting at pituitary level recently approved in both the EU and US for the treatment of adult patients with CD in whom surgery has failed or is declined. The Phase III study found that pasireotide treatment is effective in reducing biochemical markers as well as in improving signs and symptoms of hypercortisolism in about 30-50 % of CD patients with a safety profile similar to other somatostatin analogues with the exception of the increased risk of hyperglycemia [8, 9]. The 2-year extended Phase II and Phase III studies confirmed these results and the longterm benefit achieved during pasireotide treatment [10, 11]. In this study, we report our 10-year experience with pasireotide in CD by reviewing and analyzing data about all the patients treated with pasireotide at our referral center and regularly

This case presentation indicates that uncontrolled UFC levels during the first few months of pasireotide treatment as well as worsening of glycemic control in patients with CD and DM are not always predictive of the efficacy and tolerability and appears to support the long-term continuation of pasireotide.