Medical Therapy for Cushing’s Disease – Past and Future Modes of Treatment

Medical Therapy for Cushing’s Disease – Past and Future Modes of Treatment

Ashley B Grossman, Krystallenia I Alexandra


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Cushing’s disease is the most frequent cause of endogenous hypercortisolaemia.1 As in other cases of Cushing’s syndrome, the goals of treatment are the normalisation of cortisol levels with a reversal of clinical symptoms in order to avoid the long-term consequences of hypercortisolism. Surgical removal of the adenoma is the current first-line therapeutic approach, which may be followed by radiotherapy in cases of surgical failure.2

When these treatments have failed, drugs represent the next step in therapy, although they do not play a role in primary therapy as in other types of secretory pituitary tumours such as prolactinomas or acromegaly. However, their utility is reflected by the necessity to treat glucocorticoid excess in order to reverse the metabolic consequences and poor healing in severely affected patients, and this may be required before surgery. In cases where surgical treatment fails, drugs are an alternative as monotherapy or in addition to radiotherapy while awaiting its delayed effects. Finally, medical treatment may be considered in patients who cannot be submitted to surgical procedures because of co-morbidities, or who are unwilling to receive other types of treatment.

The ideal drug for Cushing’s disease that targets the pituitary has not been found. Variable compounds with neuromodulatory properties, including dopamine agonists and somatostatin analogues, gamma-aminobutyric acid (GABA) agonists, serotonin antagonists and different nuclear hormone receptor ligands involved in hypothalamo–pituitary regulation (thiazolidinediones and retinoic acid), have been tested. On the other hand, compounds that target glucocorticoid synthesis (adrenal secretion inhibitors or adrenolytic drugs, such as aminoglutethimide, metyrapone, ketoconazole, etomidate, mitotane or trilostane) or function (glucocorticoid antagonists: mifepristone) have so far been broadly used to control the deleterious effects of the hypercortisolaemic state. Those pharmaceutical agents will be summarised in this article.

Neuromodulatory Compounds

Somatostatin Analogues
Somatostatin (SST) is a neuropeptide whose actions are mediated through five different membrane-bound receptors (SSTR1–5). SSTRI 2, 4 and 5 inhibit cell proliferation via a phosphotyrosine–phosphatase-dependent pathway and interact with the mitogen-activated protein kinase pathway,3,4 although recent data suggest an additional interaction with a serine–threonine phosphatase.5 SSTR3 is cytotoxic and causes cell death or apoptosis through a phosphotyrosine–phosphatase-dependent mechanism and activation of the p53 and Bax proteins.4 Although the heterogeneity of the studies performed and the differences in methodology have resulted in some contradictory findings, human corticotroph adenomas express multiple SSTR subtypes, with 1, 2 and 5 being the most frequently found; both SSTR2 and 5 seem to be implicated in the regulation of adrenocorticotropin (ACTH) release, but SSTR5 is considered to be the predominant receptor.6–10 In in vitro studies of animal-derived and human corticotroph adenoma cell lines, native SST and octreotide, a predominantly SSTR2-selective ligand having moderate affinity for SSTR5, inhibit basal and stimulated adrenocorticotropic hormone (ACTH) secretion.7–9,11 However, in vitro studies support the fact that this inhibition is present when the corticotroph cells have been cultured in corticosteroid-free medium.12–16 In patients with Cushing’s disease most experience has been gained with octreotide; however, this has been proved to be virtually ineffective.17–20 Pasireotide or SOM-230 (Novartis, Basel, Switzerland) is a new multiligand SST analogue that has high binding affinity to SSTR5 and 1, 2 and 3 subtypes.21 It was found to inhibit basal and stimulated ACTH release from human ACTH-secreting pituitary adenomas and the murine corticotroph tumour cell line AtT-20 in vitro, without inhibiting AtT20 cell proliferation, nor inducing apoptosis or inhibiting pro-opiomelanocortin synthesis, implying an action through a possible blockade of ACTH release or an increased breakdown of ACTH.7,22,23 The functional activity of pasireotide compared with octreotide has been found to be 30-, 11- and 158-fold higher on SSTR1, 3 and 5, respectively, and approximately seven-fold lower on SSTR2,21 being more potent compared with octreotide in inhibiting basal ACTH release.7 In in vitro studies in both human ACTH-secreting adenomas and the murine AtT-20 cell line, pasireotide suppressed ACTH secretion and corticotrophin-releasing hormone (CRH)-induced ACTH release more than octreotide.7,22 Pre-incubation with dexamethasone did not affect the ability of pasireotide to inhibit CRH-induced ACTH release, while the suppressive action of octreotide was virtually lost.7,22 Furthermore, SSTR2A and 2B (but not SSTR5) messenger RNA (mRNA) levels were significantly suppressed after 24 and 48 hours of dexamethasone treatment.7 These findings imply a differential impact of glucocorticoids on the expression of the different SSTRs,17,19–21,24 with SSTR2 being downregulated and SSTR5 resistant to corticosteroid modulation.

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