Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

Nuclear medicine improves the sensitivity of conventional radiology when tumor site identification is problematic. OCT offers a good availability/reliability ratio, and FDG-PET was proven useful. 68Gallium-SSTR-PET/CT use was infrequent, despite offering the highest sensitivity.

Cushing’s syndrome is commonly complicated with an impairment of glucose metabolism, which is often clinically manifested as diabetes mellitus. The development of diabetes mellitus in Cushing’s syndrome is both a direct and indirect consequence of glucocorticoid excess. Indeed, glucocorticoid excess induces a stimulation of gluconeogenesis in the liver as well as an inhibition of insulin sensitivity both in the liver and in the skeletal muscles, which represent the most important sites responsible for glucose metabolism. In particular, glucocorticoid excess stimulates the expression of several key enzymes involved in the process of gluconeogenesis, with a consequent increase of glucose production, and induces an impairment of insulin sensitivity either directly by interfering with the insulin receptor signaling pathway or indirectly, through the stimulation of lipolysis and proteolysis and the consequent increase of fatty acids and amino acids, which contribute to the development of insulin resistance. Moreover, the peculiar distribution of adipose tissue throughout the body, with the predominance of visceral adipose tissue, significantly contributes to the worsening of insulin resistance and the development of a metabolic syndrome, which participates in the occurrence and maintenance of the impairment of glucose tolerance. Finally, glucocorticoid excess is able to impair insulin secretion as well as act at the level of the pancreatic beta cells, where it inhibits different steps of the insulin secretion process. This phenomenon is probably responsible for the passage from an impairment of glucose tolerance to an overt diabetes mellitus in susceptible patients with Cushing’s syndrome.

Endogenous Cushing's syndrome (CS), a rare endocrine disorder characterized by cortisol hypersecretion, is associated with psychiatric and neurocognitive disorders. Major depression, mania, anxiety, and neurocognitive impairment are the most important clinical abnormalities. Moreover, patients most often complain of impairment in quality of life, interference with family life, social, and work performance. Surprisingly, after hypercortisolism resolution, despite the improvement of the overall prevalence of psychiatric and neurocognitive disorders, the brain volume loss at least partially persists and it should be noted that some patients may still display depression, anxiety, panic disorders, and neurocognitive impairment. This brief review aimed at describing the prevalence of psychiatric and neurocognitive disorders and their characterization both during the active and remission phases of CS. The last section of this review is dedicated to quality of life, impaired during active CS and only partially resolved after resolution of hypercortisolism.

Cushing's syndrome is associated with increased mortality, mainly due to cardiovascular complications, which are sustained by the common development of systemic arterial hypertension and metabolic syndrome, which partially persist after the disease remission. Cardiovascular diseases and hypertension associated with endogenous hypercortisolism reveal underexplored peculiarities. The use of exogenous corticosteroids also impacts on hypertension and cardiovascular system, especially after prolonged treatment. The mechanisms involved in the development of hypertension differ, whether glucocorticoid excess is acute or chronic, and the source endogenous or exogenous, introducing inconsistencies among published studies. The pleiotropic effects of glucocorticoids and the overlap of the several regulatory mechanisms controlling blood pressure suggest that a rigorous comparison of in-vivo and in-vitro studies is necessary to draw reliable conclusions. This review, developed during the first ‘Altogether to Beat Cushing's syndrome’ workshop held in Capri in 2012, evaluates the most important peculiarities of hypertension associated with CS, with a particular focus on its pathophysiology. A critical appraisal of most significant animal and human studies is compared with a systematic review of the few available clinical trials. A special attention is dedicated to the description of the clinical features and cardiovascular damage secondary to glucocorticoid excess. On the basis of the consensus reached during the workshop, a pathophysiology-oriented therapeutic algorithm has been developed and it could serve as a first attempt to rationalize the treatment of hypertension in Cushing's syndrome.

Objective: Diabetes mellitus (DM) is one of the most frequent complications of Cushing's syndrome (CS). The aim of this study was to define the changes in insulin sensitivity and/or secretion in relation to glucose tolerance categories in newly diagnosed CS patients. Design: Cross-sectional study on 140 patients with CS. Methods: A total of 113 women (80 with pituitary disease and 33 with adrenal disease, aged 41.7G15.7 years) and 27 men (19 with pituitary disease and eight with adrenal disease, aged 38.1G20.01 years) at diagnosis were divided according to glucose tolerance into normal glucose tolerance (CS/NGT), impaired fasting glucose and/or impaired glucose tolerance (CS/prediabetes), and diabetes (CS/DM) groups. Results: Seventy-one patients had CS/NGT (49.3%), 26 (18.5%) had CS/prediabetes and 43 (30.8%) had CS/DM. Significant increasing trends in the prevalence of family history of diabetes (P!0.001), metabolic syndrome (P!0.001), age (P!0.001) and waist circumference (PZ0.043) and decreasing trends in HOMA-b (P!0.001) and oral disposition index (DIo) (P!0.002) were observed among the groups. No significant trends in fasting insulin levels, area under the curve for insulin (AUC INS ), Matsuda index of insulin sensitivity (ISI-Matsuda) and visceral adiposity index were detected. Conclusions: Impairment of glucose tolerance is characterized by the inability of b-cells to adequately compensate for insulin resistance through increased insulin secretion. Age, genetic predisposition and lifestyle, in combination with the duration and degree of hypercortisolism, strongly contribute to the impairment of glucose tolerance in patients with a natural history of CS. A careful phenotypic evaluation of glucose tolerance defects in patients with CS proves useful for the identification of those at a high risk of metabolic complications.

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SSA treatment in acromegaly patients-while improving disease control- reduces insulin levels, increases after load glucose and, ultimately, increases HbA1c levels without affecting FPG. The findings suggest that clinicians treating acromegaly with SSAs should consider targeting post-prandial glucose.