Treatment of Cushing's Syndrome
Fig.1: Specimen of Cushing's tumour of the adrenal removed laparoscopically
Surgical treatment
Surgery is normally the first and best choice of treatment for Cushing's syndrome (Fig. 1). The type of operation depends on the cause of the disease, and can either involve direct surgery on the adrenal or operations on the pituitary. Details of the operation can be found on the webpage Adrenal surgery.
While medical treatments will control symptoms and prevent further complications, they only provide a short-term solution because of their many side effects. They are important however for controlling hypercortisolism around the time of operation, and making the patient safe for surgery. The options for medical therapy are detailed below.
In addition, glucocorticoid (steroid) therapy is required after surgery for up to 18 months to allow the hypothalamo-pituitary-adrenal axis to recover fully from the suppression of adrenal function by a tumour.
The choice of surgical operation depends on the underlying cause:
1. Cushing's disease
The management of a patient with Cushing's disease usually involves removal of microadenomas trans-sphenoidally by a neurosurgeon, with more than a 75% rate of remission. Larger, invasive and more aggressive tumours have a lower success rate.
In some cases, interstitial or external irradiation (radiation applied to the tumour from inside the body or inside the body, respectively) is used. Irradiation of the pituitary has a high success rate for children, although it is of limited value in adults, as its progress is slow and may only be effective in 50-60% of cases.
Occasionally when pituitary surgery has failed or is contraindicated, removal of both the adrenal glands is necessary to prevent the excessive cortisol secretion. This can almost always be done with keyhole surgery (bilateral laparoscopic adrenalectomy).
2. Adrenal adenomas and carcinomas
These should be removed after pre-operative normalisation of cortisol levels using metyrapone or ketoconazole. Adrenal adenomas (benign tumours) can usually be removed by laparoscopic (keyhole) surgery but carcinomas will need open adrenalectomy.
In the case of adrenal carcinomas the prognosis is poor, and although the tumour may be removed surgically, the operation will not account for metastases, so that medical treatment and radiotherapy will also be indicated.
3. Ectopic ACTH-secreting tumours
Where possible, the treatment of choice for ectopic ACTH-secreting tumours is resection of the primary tumour. The best results have been achieved when the tumour is found to be carcinoid in origin. In many cases, the primary is found to be an inoperable carcinoma of the bronchus. In these cases the prognosis is so poor that surgery is often not indicated. In cases where the primary tumour cannot be localised, the treatment of choice is bilateral adrenalectomy.
Medical treatment
Medical treatment of Cushing's syndrome is not curative, and is rarely used as long-term therapy. It is occasionally used as palliative treatment for those with inoperable tumours or metastases. It is useful for controlling cortisol levels while the cause of the raised cortisol is established, and also for making patients safe for surgery.
The drugs used to treat Cushing's syndrome can be classified as:
- those that act on the adrenal gland
- those that act by inhibiting ACTH release from the pituitary
- those that act on the neurotransmitters in the brain that control CRH secretion.
Metyrapone
This is an enzyme inhibitor that acts on the adrenal gland, inhibiting the final step of cortisol synthesis. However, as a consequence, the precursor of cortisol will form androgens and may cause virilisation. It has a rapid onset of action.
Ketoconazole
This is also an enzyme inhibitor, used to suppress ACTH production, as well as interfering with hormone production in the adrenal gland. An unwanted side effect is liver damage, limiting its effectiveness. It has a rapid onset of action.
Mitotane
This is an adrenolytic, used for patients with metastasising adrenal tumours. It has become popular due to its cytotoxicity to the adrenal tissue, but cannot be used long term because of its propensity to raise blood cholesterol levels. It has a delayed onset of action, but its effect tends to be long-lasting.
Octreotide
This is a somatostatin analogue, useful in controlling Cushing's syndrome caused by ectopic ACTH-secreting tumours.