Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Cushing’s disease (#249)

David Torpy 1
  1. Royal Adelaide Hospital, Adelaide, SA, Australia

Cushing’s disease (CD) is the commonest form of endogenous pathological hypercortisolism, first described in relation to its cause, pituitary ACTH excess, in the 1930’s.  Historical turning points in CD diagnosis have included cortisol assays (1930’s), ACTH immunoassay (1960’s), dexamethasone suppression testing (1960’s), corticotropin-releasing hormone stimulation testing (1980’s) as well as pituitary CT/MRI (1980’s-1990’s).  Petrosal sinus sampling (1980s-1990s) remains the most reliable, yet not infallible, differential diagnostic test for ACTH-dependent CD.  The major therapeutic advances have been transphenoidal surgery, pioneered in the 1930’s by H Cushing, reintroduced in the 1960’s with the operating microscope and now refined with endoscopic methods.  In the past 20 years diagnostic advances have included the use of salivary cortisol testing to allow non-invasive (unstressed) testing of the cortisol circadian nadir which is blunted in CD.  In addition there has been better differential diagnostic testing for, as well as more widespread clinical awareness of the pseudocushing’s syndrome.  Novel approaches include the development of new medical therapies incorporating the first moderately effective pituitary-directed agent, the broad spectrum somatostatin receptor agonist Pasireotide, and the glucocorticoid receptor blocker Mifepristone, the first agent formally approved for Cushing’s despite long experience with the steroidogenesis inhibitors ketoconazole and metyrapone.  Early evidence suggests cabergoline may benefit some CD patients.  Novel therapies in development include newer adrenal steroidogenesis inhibitors, particularly directed at the 11-hydroxylase enzyme, and antisense glucocorticoid receptor inhibitors.  These agents are also likely to be used to ameliorate some or all of the features of the metabolic syndrome, especially diabetes mellitus.  Despite these advances, substantial challenges remain in the management of CD, including delayed diagnosis, where various screening strategies aimed at patients with partial features of Cushing’s syndrome, have not been fruitful and have highlighted the persisting difficulty in biochemically diagnosing mild hypercortisolism. In vitro success of an agent targeted at alleviating the lack of negative feedback on corticotropinomas offers hope of more targeted medical therapy for pituitary Cushing’s, as well as the discovery of specific mutations such as those of USP8 that underlie Cushing’s pathogenesis in some cases.  Even after resolution of hypercortisolism, further challenges include the extent to which treatment of CD leads to abatement of the metabolic, cardiovascular, bone and neurocognitive sequelae of CD and the optimal practical management of the near 50% of patients who do not achieve lasting cure of CD with pituitary surgery.