Cushing’s disease, or pituitary ACTH dependent Cushing’s syndrome, is a rare disease responsible for increased morbidity and mortality. Signs and symptoms of hypercortisolism are usually nonspecific: obesity, signs of protein wasting, increased blood pressure, variable levels of hirsutism. Diagnosis is frequently difficult, and requires a strict algorithm. First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting microadenomas. The rate of remission is lower in macroadenomas. Other therapeutic modalities including anticortisolic drugs, radiation techniques or bilateral adrenalectomy will thus be necessary to avoid long-term risks (metabolic syndrome, osteoporosis, cardiovascular disease) of hypercortisolism. This review summarizes potential pathophysiological mechanisms, diagnostic approaches, and therapies.

Epidemiology

The incidence of Cushing’s syndrome is estimated to be equal to 1–3 cases per million inhabitants per year, whereas its prevalence is close to 40 cases per million inhabitants. Of note, prevalence of hypercortisolism is thought to be equal to 2-5% of patients with poorly controlled diabetes and hypertension. Female preponderance is generally assumed to be close to 3:1 [2]. Cushing’s disease is an extremely rare condition in children, with a peak in adults in the 3rd or 4th decade. Cushing’s disease leads to death if untreated; it is responsible for increased morbidity and mortality, due to cardiovascular complications, infections and psychiatric disturbances [3,4].

Etiopathogenesis

Characteristics of corticotroph adenomas

Cushing’s disease is frequently due to monoclonal benign and slow growing microadenomas (less than 10 mm) [9,10]. Plasma ACTH (and cortisol) classically lose their physiologic circadian periodicity. They are partially resistant to physiologic stimuli (i.e., glucocorticoids), and do not respond to the normal feedback negative loop. In contrast, corticotroph adenomas are inappropriately sensitive to CRH and AVP. Altered CRH secretion as well as POMC qualitative changes in gene expression were also reported to be involved in the pathogenesis of Cushing’s disease. Cushing’s disease can be more atypical: secretion profiles are sometimes cyclic, with hypersecretion preceding a long period of normal secretion [8,11]. Some corticotroph adenomas are called “silent” as they are clinically and biologically comparable to non-secreting pituitary adenomas: diagnosis is made by the pathologist [12]. Finally, rare cases of aggressive pituitary adenomas or carcinomas have been reported [13]. Whether hyperplasia of corticotroph cells is or not a required initial step before the genesis of corticotroph adenoma remains a matter of debate. The origin of the disease, primary pituitary condition or secondary to an abnormality in the hypothalamus (chronic stimulation by CRH [14]), remains a matter of debate.

Potentially involved molecular mechanisms

Triggering signals leading to Cushing’s disease remain unclear. Oncogenes do not appear to be involved, as somatic mutations are usually not present in corticotroph adenomas cells. Recent studies in mice identified a potential role of loss of function of Brg1 (brahma-related gene 1) and HDAC2 (Histone Deacetylase 2) in the pathogenesis of Cushing’s disease. Both proteins form a complex with the glucocorticoid receptor and the orphan nuclear receptor nuclear growth factor IB (NGFI-B) to repress POMC secretion. Interestingly, about 50% of corticotroph adenomas do not express these proteins anymore. The loss of Brg1 could lead to overexpression of cyclin E, leading to increased cell proliferation and sporadic hyperplasia or tumors. Interestingly, tumors with a loss of nuclear localization of Brg1 seem to be more responsive to anticortisolic drugs in vitro compared to the ones with a complete loss of Brg1 oncogene [16,17].

Diagnosis

Diagnosis of Cushing’s disease is difficult [20]. Clinical signs and symptoms are often non-specific; no single biological test combines optimal sensitivity and specificity for the diagnosis of hypercortisolism and for the determination of its etiology [21]. Moreover, pituitary and adrenal imaging can sometimes be confusing.

Several steps are needed to first confirm the diagnosis of hypercortisolism and then determine its origin: the first will be to confirm the lack of exposure to exogenous glucocorticoids that induces the same clinical characteristics as Cushing’s syndrome and makes hypercortisolism screening unavailable [22]. In normal subjects, cortisol levels reach a peak at early morning and a nadir < 50 nmol/l around midnight. Patients with Cushing’s syndrome lose this circadian rhythm. As a consequence, early morning ACTH and cortisol values are of poor diagnostic value in the screening methods of hypercortisolism. In contrast a midnight cortisol value > 200 nmol/l is strongly suggestive of Cushing’s syndrome [23]. Evaluation of the circardian rhythm of cortisol is however not recommended as a first line screening method for hypercortisolism.

CRH test (100 μg intra-venously): more than 50