It was assumed that resolution of hypercortisolism in Cushing syndrome (CS) was followed by normalization of morbidity; however, in the last decade evidence is accumulating that patients with cured CS still have increased morbidity and mortality after the biochemical control of hypercortisolism. Patients with CS have an increased cardiovascular and metabolic risk and persistent accumulation of central fat, with an unfavorable adipokine profile, not only during the active phase of the disease but also long after biochemical remission. Clinical management should be particularly careful in identifying global cardiovascular risk, as a primary goal during the followup of these patients, aimed at improving global vascular morbidity. Moreover bone mass is reduced not only due to the endogenous hypercortisolism but also due to duration and dose of exogenous glucocorticoid (GC) replacement therapy after surgery. Thus, therapy in operated patients with inhibition of the hypothalamic-pituitary-adrenal axis should be reduced to the lowest dose and duration possible. Specific treatments should be considered in patients with decreased bone mass, aimed at reducing the increased fracture incidence. Finally, cognitive and health related quality of life impairments, described in active disease, are still abnormal after endocrine cure. Thus, residual morbidity persists in cured CS, suggesting irreversibility of GC-induced phenomena, typical of chronic hypercortisolism. 1. Introduction 1.1. Classification and Epidemiology of Cushing’s Syndrome Cushing’s syndrome (CS) results from chronic exposure to an excess of cortisol produced by the adrenal cortex. Cortisol (a glucocorticoid hormone) is naturally produced by the adrenal glands in response to stress, through the hypothalamic-pituitary-adrenal axis (HPA). Cortisol actions on each tissue are summarized in Figure 1. Figure 1: Cortisol actions on each tissue. CS is caused by excess ACTH production (80–85%), usually by a pituitary corticotroph adenoma (called Cushing’s disease (CD)), less frequently by an extrapituitary tumor (ectopic ACTH syndrome), or very rarely by a tumor secreting CRH (ectopic CRH syndrome). CS can also be ACTH-independent (15–20%) when it results from excess secretion of cortisol by unilateral adrenocortical tumors, either benign or malignant or by bilateral adrenal hyperplasia or dysplasia [1, 2]. The incidence of Cushing’s syndrome ranges from 0.7 to 2.4 per million-population per year [3]. New data however suggest that CS is more common than previously thought [4, 5]. It is 3–8 times more frequent
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