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Adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas give rise to a severe endocrinological disorder, comprising Cushing's disease, with multifaceted clinical presentation and treatment outcomes. Experimental studies suggest that the disease variability is inherent to the pituitary tumour, thus indicating the need for further studies into tumour biology. The present study evaluated transcriptome expression pattern in a large series of ACTH-secreting pituitary adenoma specimens in order to identify molecular signatures of these tumours. Gene expression profiling of formalin-fixed, paraffin-embedded specimens from 40 human ACTH-secreting pituitary adenomas revealed the significant expression of genes involved in protein biosynthesis and ribosomal function, in keeping with the neuroendocrine cell profile. Unsupervised cluster analysis identified 3 distinct gene profile clusters and several genes were uniquely overexpressed in a given cluster, accounting for different molecular signatures. Of note, gene expression profiles were associated with clinical features, such as the age and size of the tumour. Altogether, the findings of the present study show that corticotroph tumours are characterised by a neuroendocrine gene expression profile and present subgroup-specific molecular features.

Recurrence of Cushing’s disease after successful transsphenoidal surgery occurs in some 30% of the patients and the response to desmopressin shortly after surgery has been proposed as a marker for disease recurrence. The aim of the present study was to evaluate the response to desmopressin over time after surgery. We tested 56 patients with Cushing’s disease in remission after transsphenoidal surgery with desmopressin for up to 20 years after surgery. The ACTH and cortisol response to desmopressin over time was evaluated in patients on long-term remission or undergoing relapse; an increase by at least 27 pg/mL in ACTH levels identified responders. The vast majority of patients who underwent successful adenomectomy failed to respond to desmopressin after surgery and this response pattern was maintained over time in patients on long-term remission. Conversely, a response to desmopressin reappeared in patients who subsequently developed a recurrence of Cushing’s disease, even years prior to frank hypercortisolism. It appears therefore that a change in the response pattern to desmopressin proves predictive of recurrence of Cushing’s disease and may indicate which patients require close monitoring.

Objective Evidence is limited regarding outcome of patients with ectopic Cushing’s syndrome (ECS) due to neuroendocrine tumors (NETs). Design We assessed the prognostic factors affecting the survival of patients with NETs and ECS. Methods Retrospective analysis of clinicopathological features, severity of hormonal syndrome, treatments from a large cohort of patients with NETs and ECS collected from 17 Italian centers. Results Our series included 110 patients, 58.2% female, with mean (±s.d.) age at diagnosis of 49.5 ± 15.9 years. The main sources of ectopic ACTH were bronchial carcinoids (BC) (40.9%), occult tumors (22.7%) and pancreatic (p)NETs (15.5%). Curative surgery was performed in 56.7% (70.2% of BC, 11% of pNETs). Overall survival was significantly higher in BC compared with pNETs and occult tumors (P = 0.033) and in G1-NETs compared with G2 and G3 (P = 0.007). Negative predictive factors for survival were severity of hypercortisolism (P P = 0.001), diabetes mellitus (P = 0.0146) and distant metastases (P P Conclusions Multiple factors affect prognosis of ECS patients: type of NET, grading, distant metastases, severity of hypercortisolism, hypokalemia and diabetes mellitus. BCs have the highest curative surgical rate and better survival compared with occult tumors and pNETs. Hypercortisolism plays a primary role in affecting outcome and quality of life; therefore, prompt and vigorous treatment of hormonal excess by NET surgery and medical therapy should be a key therapeutic goal. In refractory cases, adrenalectomy should be considered as it affects outcome positively at least in the first 2 years.

Previous evidence supports a role for growth hormone (GH)-insulin-like growth factor (IGF)-I deficiency in the pathophysiology of osteopenia/osteoporosis in adult thalassemia. Moreover, serum IGF-II has never been studied in this clinical condition. Thus, we elected to study the GH secretory status and the levels of circulating somatomedins, correlating these parameters with bone mineral density (BMD) and biochemical markers of bone turnover. A hundred and thirty-nine normal weight adult thalassemic patients (72 men and 67 women) were studied. Lumbar and femoral neck BMD were measured in 106/139 patients. Sixty-eight patients underwent growth hormone releasing hormone plus arginine testing. Measurement of baseline IGF-I and IGF-II was performed in all patients, while osteocalcin, C-terminal telopeptide of type I collagen (CTx), and urinary cross-linked N-telopeptides of type I collagen (NTx) were assayed in 95 of them. Femoral and lumbar osteoporosis/Z score below the expected range for age were documented in 61.3 and in 56.6 % of patients, respectively. Severe GH deficiency (GHD) was demonstrated in 27.9 % of cases, whereas IGF-I SDS was low in 86.3 %. No thalassemic patients displayed circulating levels of IGF-II below the reference range. GH peaks were positively correlated with femoral, but not lumbar, Z score. No correlations were found between GH peaks and osteocalcin, CTx and NTx. GH peaks were positively correlated with IGF-I values, which in their turn displayed a positive correlation with osteocalcin, CTx, and NTx. No correlations emerged between IGF-I values and either femoral or lumbar Z scores. No correlations were found between IGF-II and any of the following parameters: GH peaks, osteocalcin, CTx, NTx, femoral Z score, and lumbar Z score. Our study, besides providing for the first time evidence of a normal IGF-II production in thalassemia, contributes to a better understanding of the involvement of the somatotropin-somatomedin axis in the pathophysiology of bone demineralization in this disease. In particular, the contribution of GHD to femoral osteoporosis appears to be likely mediated by locally produced rather than circulating IGF-I.

Cushing's disease, i.e. cortisol excess due to an ACTH-secreting pituitary adenoma, is a rare disorder with considerable morbidity and mortality but no satisfactory medical treatment as yet. Experimental data have recently shown that retinoic acid restrains ACTH secretion by tumoral corticotropes.Our objective was to evaluate the efficacy and safety profile of retinoic acid treatment in patients with Cushing's disease.This is a prospective, multicenter study. Seven patients with Cushing's disease (three men, four postmenopausal women) were started on 10 mg retinoic acid daily and dosage increased up to 80 mg daily for 6-12 months. ACTH, urinary free cortisol (UFC), and serum cortisol as well as clinical features of hypercortisolism and possible side effects of retinoic acid were evaluated at baseline, during retinoic acid administration, and after drug withdrawal.A marked decrease in UFC levels was observed in five patients; mean UFC levels on retinoic acid were 22-73% of baseline values and normalization in UFC was achieved in three patients. Plasma ACTH decreased in the first month of treatment and then returned to pretreatment levels in responsive patients whereas no clear-cut pattern could be detected for serum cortisol. Blood pressure, glycemia, and signs of hypercortisolism, e.g. body weight and facial plethora, were ameliorated to a variable extent on treatment. Patients reported only mild adverse effects, e.g. xerophthalmia and arthralgias.Long-term treatment with retinoic acid proved beneficial and well tolerated in five of seven patients with Cushing's disease. This represents a novel, promising approach to medical treatment in Cushing's disease.

Despite recent advances in the management of endogenous Cushing’s syndrome (CS), its treatment remains a challenge. When surgery has been unsuccessful or unfeasible as well in case of recurrence, the “old” pharmacological agents represent an important alternative for both ACTH-dependent and independent hypercortisolism. Especially in the latter, the advent of novel molecules directly targeting ACTH secretion has not outweighed the “old” drugs, which continue to be largely employed and have recently undergone a reappraisal. This review provides a survey of the “old” pharmacological agents in the treatment of CS.