Recent advances in the medical treatment of Cushing's disease.

Cushing’s disease is a condition of hypercortisolism caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. While rare, it is associated with significant morbidity and mortality, which suggests that early and aggressive intervention is required. The primary, definitive therapy for patients with Cushing’s disease in the majority of patients is pituitary surgery, generally performed via a transsphenoidal approach. However, many patients will not achieve remission or they will have recurrences. The consequences of persistent hypercortisolism are severe and, as such, early identification of those patients at risk of treatment failure is exigent. Medical management of Cushing’s disease patients plays an important role in achieving long-term remission after failed transsphenoidal surgery, while awaiting effects of radiation or before surgery to decrease the hypercortisolemia and potentially reducing perioperative complications and improving outcome. Medical therapies include centrally acting agents, adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Furthermore, several new agents are in clinical trials. To normalize the devastating disease effects of hypercortisolemia, it is paramount that successful patient disease management includes individualized, multidisciplinary care, with close collaboration between endocrinologists, neurosurgeons, radiation oncologists, and general surgeons. This commentary will focus on recent advances in the medical treatment of Cushing’s, with a focus on newly approved ACTH modulators and glucocorticoid receptor blockers.

[1]  M. Fleseriu,et al.  Medical treatment of Cushing's Disease. , 2016, Minerva endocrinologica.

[2]  X. Bertagna,et al.  LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing's disease: results from a multicenter, proof-of-concept study. , 2014, The Journal of clinical endocrinology and metabolism.

[3]  M. Gadelha,et al.  Efficacy of medical treatment in Cushing's disease: a systematic review , 2014, Clinical endocrinology.

[4]  G. Braunstein,et al.  Global clinical response in Cushing’s syndrome patients treated with mifepristone , 2014, Clinical endocrinology.

[5]  L. Denaro,et al.  Combination therapy for Cushing’s disease: effectiveness of two schedules of treatment. Should we start with cabergoline or ketoconazole? , 2014, Pituitary.

[6]  J. Bertherat,et al.  Extended treatment of Cushing’s disease with pasireotide: results from a 2-year, Phase II study , 2013, Pituitary.

[7]  L. Nieman Update in the medical therapy of Cushing's disease , 2013, Current opinion in endocrinology, diabetes, and obesity.

[8]  X. Bertagna,et al.  Approach to the Cushing's disease patient with persistent/recurrent hypercortisolism after pituitary surgery. , 2013, The Journal of clinical endocrinology and metabolism.

[9]  S. Mudaliar,et al.  Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. , 2013, The Journal of clinical endocrinology and metabolism.

[10]  M. Fleseriu,et al.  A new therapeutic approach in the medical treatment of Cushing's syndrome: glucocorticoid receptor blockade with mifepristone. , 2013, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[11]  P. Chanson,et al.  Management of hyperglycaemia in Cushing's disease: experts' proposals on the use of pasireotide. , 2012, Diabetes & metabolism.

[12]  S. Gultekin,et al.  Remission rate after transsphenoidal surgery in patients with pathologically confirmed Cushing’s disease, the role of cortisol, ACTH assessment and immediate reoperation: a large single center experience , 2013, Pituitary.

[13]  M. Fleseriu,et al.  Mifepristone: is there a place in the treatment of Cushing’s disease? , 2013, Endocrine.

[14]  J. Bertherat,et al.  Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center. , 2012, European journal of endocrinology.

[15]  I. Shimon,et al.  Pituitary-directed medical therapy with pasireotide for a corticotroph macroadenoma: pituitary volume reduction and literature review , 2012, Pituitary.

[16]  E. Arvat,et al.  Potential role for retinoic acid in patients with Cushing's disease. , 2012, The Journal of clinical endocrinology and metabolism.

[17]  M. Fleseriu,et al.  Medical management of Cushing’s disease: what is the future? , 2012, Pituitary.

[18]  G. Targher Pasireotide in Cushing's disease. , 2012, The New England journal of medicine.

[19]  M. Fleseriu,et al.  Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. , 2012, The Journal of clinical endocrinology and metabolism.

[20]  A. Colao,et al.  A 12-month phase 3 study of pasireotide in Cushing's disease. , 2012, The New England journal of medicine.

[21]  N. Tritos,et al.  Advances in medical therapies for Cushing's syndrome. , 2012, Discovery medicine.

[22]  J. Briegel,et al.  Medical suppression of hypercortisolemia in Cushing’s syndrome with particular consideration of etomidate , 2012, Pituitary.

[23]  A. Mamelak,et al.  EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. , 2011, The Journal of clinical investigation.

[24]  P. Chanson,et al.  Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing's syndrome. , 2011, The Journal of clinical endocrinology and metabolism.

[25]  P. Jones,et al.  Mortality and morbidity in Cushing's disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. , 2011, The Journal of clinical endocrinology and metabolism.

[26]  S. Gultekin,et al.  Temozolomide for corticotroph pituitary adenomas refractory to standard therapy , 2011, Pituitary.

[27]  A. Lacroix,et al.  Cabergoline monotherapy in the long-term treatment of Cushing's disease. , 2010, European journal of endocrinology.

[28]  N. Shah,et al.  Efficacy of cabergoline in uncured (persistent or recurrent) Cushing disease after pituitary surgical treatment with or without radiotherapy. , 2010, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[29]  J. Bertherat,et al.  Management of Cushing's syndrome due to ectopic adrenocorticotropin secretion with 1,ortho-1, para'-dichloro-diphenyl-dichloro-ethane: findings in 23 patients from a single center. , 2010, The Journal of clinical endocrinology and metabolism.

[30]  L. Vilar,et al.  Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease , 2010, Pituitary.

[31]  Y. Wang,et al.  Treatment of pituitary-dependent Cushing's disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. , 2009, The Journal of clinical endocrinology and metabolism.

[32]  L. Nieman,et al.  Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. , 2008, The Journal of clinical endocrinology and metabolism.

[33]  I. Morange,et al.  Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease. , 2008, European journal of endocrinology.

[34]  M. Fleseriu,et al.  Second-line treatment for Cushing's disease when initial pituitary surgery is unsuccessful , 2007, Current opinion in endocrinology, diabetes, and obesity.