Context: Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are conditions at high risk for the development of hypopituitarism. Objective: The objective of the study was to clarify whether pituitary deficiencies and normal pituitary function recorded at 3 months would improve or worsen at 12 months after the brain injury. Design and Patients: Pituitary function was tested at 3 and 12 months in patients who had TBI (n = 70) or SAH (n = 32). Results: In TBI, the 3-month evaluation had shown hypopituitarism (H) in 32.8%. Panhypopituitarism (PH), multiple (MH), and isolated (IH) hypopituitarism had been demonstrated in 5.7, 5.7, and 21.4%, respectively. The retesting demonstrated some degree of H in 22.7%. PH, MH, and IH were present in 5.7, 4.2, and 12.8%, respectively. PH was always confirmed at 12 months, whereas MH and IH were confirmed in 25% only. In 5.5% of TBI with no deficit at 3 months, IH was recorded at retesting. In 13.3% of TBI with IH at 3 months, MH was demonstrated at 12-month retesting. In SAH, the 3-month evaluation had shown H in 46.8%. MH and IH had been demonstrated in 6.2 and 40.6%, respectively. The retesting demonstrated H in 37.5%. MH and IH were present in 6.2 and 31.3%, respectively. Although no MH was confirmed at 12 months, two patients with IH at 3 months showed MH at retesting; 30.7% of SAH with IH at 3 months displayed normal pituitary function at retesting. In SAH, normal pituitary function was always confirmed. In TBI and SAH, the most common deficit was always severe GH deficiency. Conclusion: There is high risk for H in TBI and SAH patients. Early diagnosis of PH is always confirmed in the long term. Pituitary function in brain-injured patients may improve over time but, although rarely, may also worsen. Thus, brain-injured patients must undergo neuroendocrine follow-up over time.

Objective: To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients.Design: Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months.Results: A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 μg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87–1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34–2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality.Conclusions: Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.

An impaired glucose metabolism, which often leads to the onset of diabetes mellitus (DM), is a common complication of chronic exposure to exogenous and endogenous glucocorticoid (GC) excess and plays an important part in contributing to morbidity and mortality in patients with Cushing syndrome (CS). This article reviews the pathogenesis, epidemiology, diagnosis, and management of changes in glucose metabolism associated with hypercortisolism, addressing both the pathophysiological aspects and the clinical and therapeutic implications. Chronic hypercortisolism may have pleiotropic effects on all major peripheral tissues governing glucose homeostasis. Adding further complexity, both genomic and nongenomic mechanisms are directly induced by GCs in a context-specific and cell-/organ-dependent manner. In this paper, the discussion focuses on established and potential pathologic molecular mechanisms that are induced by chronically excessive circulating levels of GCs and affect glucose homeostasis in various tissues. The management of patients with CS and DM includes treating their hyperglycemia and correcting their GC excess. The effects on glycemic control of various medical therapies for CS are reviewed in this paper. The association between DM and subclinical CS and the role of screening for CS in diabetic patients are also discussed.

The CDKN1B gene encodes the cyclin-dependent kinase inhibitor p27^KIP1, an atypical tumor suppressor playing a key role in cell cycle regulation, cell proliferation, and differentiation. Impaired p27^KIP1 expression and/or localization are often observed in tumor cells, further confirming its central role in regulating the cell cycle. Recently, germline mutations in CDKN1B have been associated with the inherited multiple endocrine neoplasia syndrome type 4, an autosomal dominant syndrome characterized by varying combinations of tumors affecting at least two endocrine organs. In this study we identified a 4-bp deletion in a highly conserved regulatory upstream ORF (uORF) in the 5′UTR of the CDKN1B gene in a patient with a pituitary adenoma and a well-differentiated pancreatic neoplasm. This deletion causes the shift of the uORF termination codon with the consequent lengthening of the uORF–encoded peptide and the drastic shortening of the intercistronic space. Our data on the immunohistochemical analysis of the patient's pancreatic lesion, functional studies based on dual-luciferase assays, site-directed mutagenesis, and on polysome profiling show a negative influence of this deletion on the translation reinitiation at the CDKN1B starting site, with a consequent reduction in p27^KIP1 expression. Our findings demonstrate that, in addition to the previously described mechanisms leading to reduced p27^KIP1 activity, such as degradation via the ubiquitin/proteasome pathway or non-covalent sequestration, p27^KIP1 activity can also be modulated by an uORF and mutations affecting uORF could change p27^KIP1 expression. This study adds the CDKN1B gene to the short list of genes for which mutations that either create, delete, or severely modify their regulatory uORFs have been associated with human diseases. Gene expression can be modulated at different steps on the way from DNA to protein including control of transcription, translation, and post-translational modifications. An abnormality in the regulation of mRNA and protein expression is a hallmark of many human diseases, including cancer. In some eukaryotic genes translation can be influenced by small DNA sequences termed upstream open reading frames (uORFs). These elements located upstream to the gene start codon may either negatively influence the ability of the translational machinery to reinitiate translation of the main protein or, much less frequently, stimulate protein translation by enabling the ribosomes to bypass cis-acting inhibitory elements. CDKN1B, which encodes the cell cycle inhibitor p27^KIP1, includes an uORF in its 5′UTR sequence. p27^KIP1 expression is often reduced in cancer, and germline mutations have been identified in CDKN1B in patients affected with a syndrome (MEN4) characterized by varying combinations of tumors in endocrine glands. Here we show that a small deletion in the uORF upstream to CDKN1B reduces translation reinitiation efficiency, leading to underexpression of p27^KIP1 and coinciding with tumorigenesis. This study describes a novel mechanism by which p27^KIP1 could be underexpressed in human tumors. In addition, our data provide a new insight to the unique pathogenic potential of uORFs in human diseases.