Cushing's Syndrome - drug therapy

Cushing's syndrome - drugs new and old.

Cushing's syndrome remains a challenge. A lovely comment from the days at Bart's under Mike Besser and Ashley Grossman, 'If you think it's simple, you haven't seen enough'; and that only applied to Cushing's disease! When you roll in ectopic ACTH, adrenal adenomas, carcinoma and macronodular hyperplasia it is another tier of complexity all together. Cushing's syndrome causes ill heath and premature death and this can be ameliorated by controlling the hypercortisolaemia.

Removal of the cause of the condition may be the desired option, e.g. trans-sphenoidal adenecomy in Cushing's disease, removal of the source of ectopic ACTH or adrenal surgery, but it is neither always possible, nor effective. Radiotherapy may be tried, particularly for Cushing's disease but it takes time to work. Hence the need for effective medical therapy.

Metyrapone has been a stalwart for nearly 50 years, it works quickly and is an option for long term control in many patients with Cushing's syndrome. Hirsutism and acne in women - due to the androgenic effect of cortisol precursors - limit the use of metyrapone. It is general used under supervision of a specialist.

Ketoconazole had its licence for oral administration as an antifungal withdrawn recently because its risk of hepatotoxicity did not give a favourable benefit vs harm balance particularly as there were other alternatives available, we had always used if off-label for Cushing's. In recognition of the fact that Cushing's is a serious condition, that will have specialist and close monitoring, where the balance of benefit to harm may well be in favour of ketoconazole the CHMP have given it a licence for Cushing's syndrome - under supervision of a specialist and close monitoring of the liver function

Mitotane, a potent inhibitor of adrenal steroid synthesis is also an adrenolytic, it is limited by side effects, is very difficult to dose and monitor appropriately, and is very much a specialist drug and somewhat reserved for adrenocortical carcinoma or Cushing's syndrome (of any cause) refractory to other treatment.

Mifepristone is a potent antagonist at the glucocortoid and progesterone receptor which, because negative feedback at the pituitary raises cortisol levels, is difficult to monitor; because of this it has yet to find a routine place in the management of Cushing's syndrome.

Pasireotide - a new multireceptor somatostatin analogue - is an injectable therapy for Cushing's disease that stops the pituitary from making ACTH; it has just received specialist commissioning approval from NHS England as second or third line therapy, within the auspices of a specialist pituitary MDT closely monitoring the response to therapy.

Cabergoline is a well understood dopamine agonist most commonly used in Parkinson's disease and for the endocrinologist prolactinoma and acromegaly. It may lower cortisol, and this be sustained, in a small number of patients (at most 20%). The median dose to achieve this control - 3mg per week - gives some concern about the development of cardiac valve fibrosis, alongside the other reported side effects of dopamine agonists (http://www.londonswissmedical.com/patient-resources).

Osilodrostat is a potent inhibitor of adrenal steroid production currently in experimental therapeutic studies in humans.

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Dr Philip Kelly & Dr Martin Whyte
King's Private, The Guthrie Wing,

King's College Hospital

London SE5 9RS

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Dr Philip Kelly
25 Harley Street

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