Cushing's syndrome (CS) is characterized by pathologically elevated free glucocorticoid levels. Endogenous hypercortisolism is usually due to ACTH-secreting pituitary corticotropic adenomas and less often due to ectopic ACTH-secreting neuroendocrine neoplasms or ACTH-independent adrenal cortisol hypersecretion. CS is a serious chronic disease leading to a several-fold increase in cardiovascular morbidity and mortality. Multiple genetic alterations have been described in the setting of sporadic corticotropinoma formation. Changes in the expression profiles have been demonstrated in growth factors and their receptors, cell-cycle regulators and in various genes related to hormonal gene transcription, synthesis and secretion. Sporadic adrenal adenomas and carcinomas may demonstrate dysfunction in genes such as TP53 among others. Cushing's disease can be an inherited condition also. Multiple endocrine neoplasia type 1 (MEN1) and familial isolated pituitary adenomas (FIPA) together account for 5% of pituitary adenomas. Cushing's disease occurs infrequently in an inherited setting in both of these conditions. To date only 2 cases of Cushing's disease have been described in association with mutations in AIP. One case of Cushing's disease has been reported as part of MEN4, a rare MEN1-like syndrome due to mutation in the CDKN1B gene. Carney complex (CNC) due to PRKAR1A mutations in most cases is associated with CS, mainly as a cause of bilateral adrenal hyperplasia. The cAMP signaling pathway is affected in this setting. In recent times the involvement of genes such as PDE11A, PDE8B and others have expanded the spectrum of the genetic pathophysiology of CS.
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of tumour formation in the anterior pituitary including adrenocorticotropic hormone (ACTH)-secreting tumours has been intensively studied, but the causative mechanisms involved in pituitary cell transformation and tumourigenesis remain unclear.
We searched PubMed on any paper related with molecular pathology of pituitary corticotroph adenomas and have included to this review all relevant references published up to June 2011.
Current studies increased our knowledge on the genetic basis of McCune-Albright syndrome (MAS), multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC), pituitary adenoma predisposition syndromes and tuberous sclerosis, but they have performed little to elucidate the causes of sporadic pituitary tumours including Cushing disease.
The aim of this review was to focus on the most recently published advances in the molecular pathology of corticotroph adenomas, which are presented in the context of changes seen in all types of pituitary adenomas, as well as in terms of corticotrophin-releasing hormone/ACTH/cortisol-specific pathways.
We would expect that over the next 5 years, more detailed analysis of inter-cellular communication pathways between pituitary cells, including the cadherins and integrins, and their interactions with other signalling pathways such as the β-catenin cascade will help elucidate what exactly goes awry in the formation of a benign corticotroph adenoma. This should in turn predict novel forms of pharmacological tumour control.
European Journal of Clinical Investigation 10/2011; 42(6):665-76. DOI:10.1111/j.1365-2362.2011.02621.x · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 non specific: 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.
[Show abstract][Hide abstract] ABSTRACT: Cushing's syndrome (CS) is a severe endocrine disorder characterized by chronic cortisol excess due to either an adrenocorticotropin (ACTH) secreting pituitary adenoma, ectopic ACTH production or a cortisol producing adrenal neoplasia. Regardless of the underlying cause, untreated CS is associated with considerable morbidity and mortality. Surgery is the primary therapy for all causes of CS, but surgical failure and ineligibility of the patient to undergo surgery necessitate alternative treatment modalities. The role of medical therapy in CS has been limited because of lack of efficacy or intolerability. In recent years, however, new targets for medical therapy have been identified, both at the level of the pituitary gland (e.g. somatostatin-, dopamine- and epidermal growth factor receptors) and the adrenal gland (ectopically expressed receptors in ACTH-independent macronodular adrenal hyperplasia). In this review, results of preclinical and clinical studies with drugs that exert their action through these molecular targets, as well as already established medical treatment options will be discussed.
Endocrine Related Cancer 08/2012; 19(6). DOI:10.1530/ERC-12-0191 · 4.81 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.