Medical Treatment in Cushing’s Syndrome: Dopamine Agonists and Cabergoline

Abstract

Dopamine (DA) is a catecholamine with a wide range of functions and whose five subtype receptors are found in different organs where they exert a mainly inhibitory action. Since this action may also appear in a number of secretory tumors in various locations, DA agonists have elicited some interest as a medical treatment for hypercorticism. Non-iatrogenic Cushing’s syndromes are due in 70% of the cases to a pituitary adrenocorticotropic hormone (ACTH)-producing adenoma, and, less frequently, to an adrenal adenoma or an ectopic ACTH secretion by a neuroendocrine tumor. First-line treatment in Cushing’s syndrome consists of the surgical removal of the secreting tumor. However, surgery may not achieve a complete cure in a number of cases, hence emphasizing the potential benefit of a medical complementary treatment, which could also benefit patients as an alternative approach, either when waiting for, or when the patient is not eligible for surgery. Studies of corticotropic adenomas have shown that 80% of these tumors express D2 receptors. Clinical trials of DA agonists in Cushing’s disease have shown an inhibitory effect of these drugs with an inhibition of ACTH secretion and/or a decrease of tumor size. There are only a few cases of documented use of DA agonists in ectopic ACTH secretion, but when the tumor expresses DA receptors, DA agonists may represent a useful complementary treatment. DA receptors are also expressed in normal and tumoral adrenals, suggesting a potential use of DA agonists in Cushing’s syndrome secondary to adrenal tumors. However, clinical data regarding this specific situation are very scarce, maybe due to the relatively high rate of surgical cure of adrenal adenomas. In conclusion, DA agonists represent a potential preparatory or complementary treatment for endogenous Cushing’s syndrome, especially in Cushing’s disease. These compounds may be underused as suggested by the scarce number of publication and case reports in the literature. In the future, association of these drugs with somatostatin analogs may also prove beneficial.

ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms: Functional Pancreatic Endocrine Tumor Syndromes

“…In patients with Cushing's syndrome, the majority of which have metastatic disease at presentation, primarily adrenal-blocking agents (ketoconazole [,]metyrapone) are used prior to adrenectomy. In some cases long-acting somatostatin analogues may be effective and there is increased interest in the use of glucocorticoid receptor antagonists, like mifepristone, which are investigational at present [191,192]. If somatostatin analogues are ineffective or lose efficacy in controlling the hormone excess state, treatment with interferon-α may be effective at controlling the symptoms either alone or in combination with somatostatin analogues.…”

“…Promising results with the multiligand somatostatin receptor congener pasireotide have recently been presented. Also, the dopamine agonist cabergoline might have a role in controlling ectopic ACTH secretion [191,193,194]. …”

The Treatment of Cushing's Disease

“…In clinical practice, bromocriptine treatment has shown variable results in the management of patients with CD, although presently it is not considered an effective therapeutic approach in patients with CD (84,461,463,464,466,470,641). The efficacy of bromocriptine in different studies varied between 0 and 50%, with normalization of urinary and/or plasma cortisol in up to 40% of patients in various case reports and small study series after short-term treatment (642)(643)(644).…”

Bilateral adrenalectomy in the 21st century: when to use it for hypercortisolism?

“…This is particularly the case for the novel pituitarytargeted somatostatin receptor multi-ligand Pasireotide, which demonstrated a 25% antisecretory efficacy in a large phase 3 international multi-centre study after 12 months of follow-up (Colao et al 2012, Pivonello et al 2014. Longterm data are also missing for mifepristone and cabergoline (Petrossians et al 2010.…”