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Review

Advances in the medical management of Cushing's syndrome

, MD & , MD
Pages 2423-2433 | Published online: 08 Sep 2008
 

Abstract

Background: Management of Cushing's syndrome, that is, excess cortisol secretion, has undergone considerable advances since the pioneering studies by Harvey Cushing. Surgery is clearly first choice for all etiologies of Cushing's syndrome, and medical therapy is largely administered in the interim between other therapeutic options. The limited use of medical therapy is a consequence of the lack of a truly efficacious compound to restrain adrenocorticotrophic hormone or cortisol secretion, but this will hopefully change in the near future as molecules developed over the past few years are tested. Conclusion: This paper illustrates present and perspective medical treatments for Cushing's syndrome.

5. Expert opinion

Treatment of Cushing's syndrome, particularly medical therapy, continues to challenge even the most skilled endocrinologist. The advances that occurred in the recent past, however, justify a more optimistic outlook into the future; indeed, the intense interactions between endocrine centers all over the world now enables a more judicious choice among available therapeutic options. Accordingly, surgery, radiation and medical therapy are being used with increasingly better results.

Although steroid synthesis inhibitors, foremost ketoconazole, continue to be the more widely used pharmacological tool for Cushing's syndrome, new, selectively targeted compounds are under investigation and are yielding encouraging results. More potent and at the same time more manageable molecules for a temporary or permanent chemical adrenalectomy will become available, to be used chiefly in primary adrenal hypercortisolism. On the other hand, the possibility of blocking ACTH secretion in patients with Cushing's disease and, hopefully, also in patients with neuroendocrine ACTH-secreting tumors, is rapidly approaching. Newer dopamine receptor agonists at high doses, such as 7 mg/week cabergoline, have been tested in small groups of patients with Cushing's disease and achieved reduction/normalization in UFC secretion in 40 – 70% of patients. Even long-lasting remissions while on cabergoline have been reported. Along the same line, recently developed somatostatin receptor ligands are proving beneficial in patients with Cushing's disease. One such compound, SOM230 or pasireotide, a somatostatin multireceptor ligand, is now in a Phase II multi-center international study and appears to reduce/normalize UFC in up to 50% of patients with Cushing's disease. The development of chimeric dopamine–somatostatin receptor ligands is an obvious progression that is already underway. Somatostatin ligands are also ideal candidates for peptide receptor radionuclide therapy and isotopes can thus deliver concentrated radioactivity to neuroendocrine cells, both outside and within the pituitary. The use of PPAR-γ agonists in Cushing's disease has strong experimental support and, although results obtained so far with rosiglitazone and pioglitazone are not fully satisfactory, further studies could provide more effective molecules. Similar considerations apply to retinoic acid, which has yielded spectacular results in animals but has not been investigated as yet in man.

In summary, medical therapy together with surgery and radiation therapy have significantly improved the outcome for patients with Cushing's syndrome. The near future will probably see further progress in the tools available to cure this severe endocrine disorder.

Figure 1. Therapeutic strategies for Cushing's syndrome. Treatment choices for each etiology of Cushing's syndrome are shown.
Figure 1. Therapeutic strategies for Cushing's syndrome. Treatment choices for each etiology of Cushing's syndrome are shown.
Figure 2. Adrenal steroidogenesis and steroid synthesis inhibitors. Enzymes involved in adrenal steroid synthesis are shown in italic, drugs are underlined. Filled circles indicate blockade by a given compound.
Figure 2. Adrenal steroidogenesis and steroid synthesis inhibitors. Enzymes involved in adrenal steroid synthesis are shown in italic, drugs are underlined. Filled circles indicate blockade by a given compound.

Table 1. Etiology of Cushing's syndrome.

Table 2. Doses of drugs used for treatment of Cushing's syndrome.

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