The dopaminergic control of Cushing's syndrome

Abstract

Cushing's Syndrome (CS), or chronic endogenous hypercortisolism, is a rare and serious disease due to corticotroph pituitary (Cushing's disease, CD) and extra-pituitary (ectopic CS) tumours overproducing ACTH, or cortisol-secreting adrenal tumours or lesions (adrenal CS). The first-line treatment for CS is represented by the surgical removal of the responsible tumour, but surgery might be unfeasible or ineffective and medical treatment can be required in a relevant percentage of patients with CS, especially CD and ectopic CS. Corticotroph pituitary and extra-pituitary tumours, as well as adrenal tumours and lesions responsible for CS express dopamine receptors (DRs), which have been found to mediate inhibition of hormone secretion and/or cell proliferation in experimental setting, suggesting that dopaminergic system, particularly DRs, might represent a target for the treatment of CS. Dopamine agonists (DAs), particularly cabergoline (CAB), are currently used as off-label treatment for CD, the most common form of CS, demonstrating efficacy in controlling hormone secretion and tumour growth in a relevant number of cases, with the improvement of clinical picture, and displaying good safety profile. Therefore, CAB may be considered a reasonable alternative treatment for persistent or recurrent CD after pituitary surgery failure, but occasionally also before pituitary surgery, as adjuvant treatment, or even instead of pituitary surgery as first-line treatment in case of surgery contraindications or refusal. A certain beneficial effect of CAB has been also reported in ectopic CS. However, the role of DAs in the clinical management of the different types of CS requires further evaluations.

Keywords: Cabergoline; Cushing’s disease; Cushing’s syndrome; Dopamine; Dopaminergic system.

Fig. 1

Dopamine synthesis and release by neurons and neuroendocrine cells. Dopamine synthesis starts from l-tyrosine. In the first step, tyrosine hydroxylase (TH) catalyses the production of l-DOPA that, in the second step, is converted in dopamine by the action of the DOPA decarboxylase (AADC). After the synthesis, vesicular monoamine transporter (VMAT) transports dopamine from the cytoplasmic space into secretory vesicles that by exocytosis induce dopamine release in the synaptic cleft, extracellular space or in bloodstream. After the release, dopamine can bind and activate dopamine receptors (DRs) (Created with BioRender.com)

Fig. 2

A Main molecular signalling pathways induced by dopamine and DAs. Dopamine (or DAs) binding to D1-like and D2-like receptors, via interaction with G_αs or G_αi/o proteins, stimulates or inhibits adenylyl cyclase (AC) activity, cyclic AMP (cAMP) and protein kinase A (PKA), modulates K⁺ channels and Ca²⁺ currents in an opposite manner, regulating hormone secretive effects in neuroendocrine cells. D2-like receptors activation modulates mitogen-activated protein kinases (MAPKs) increasing apoptosis and inhibiting cell growth. Moreover, D2-like receptors are involved in receptor desensitization and degradation signals recruiting β-arrestin via GRKs and protein kinase C (PKC) activation. B Main molecular signalling pathways specifically triggered by D2 receptor (D2S and D2L) and D5 receptors. D2S activation induces hormone secretion inhibition by the suppression of AC activity, cAMP and PKA. However, in lactotroph cells, extracellular-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) pathways are oppositely regulated by D2S and D2L, with D2S stimulating both and D2L inhibiting both pathways involved in cell growth, proliferation, and lactotroph homeostasis. D2 receptor is also involved in apoptotic process through the activation of ERK1/2, c-Jun N-terminal kinase (JNK) and early growth response protein 1 (EGR1), and specifically by D2S via p38 MAPK. Cell proliferation and growth are also inhibited by the induction of autophagic dependent cell death triggered by D5 receptor via PI3K/AKT/mTOR pathway. (Created with BioRender.com)

Fig. 3

A D2 receptor expression in I the entire gland, with magnification on II anterior lobe, III and IV “pars intermedia” and V posterior lobe of human normal pituitary. III Red arrows: D2 receptor expression in cells lining the colloid-filled cysts belonging to the pars intermedia and in cell cluster belonging to the anterior lobe and located within the cysts adjacent to the neural posterior lobe. IV The picture focuses on the intermediate zone between the anterior and the posterior lobe containing the basophilic invasion of the neurohypophysis. The picture shows a strong homogeneous and diffused expression of D2 receptor in the corticotroph cell population invading the neurohypophysis. B Exemplary pictures of D2 receptor protein expression and the relative rate of expression in normal pituitary and adrenal glands, corticotroph pituitary tumours, adrenocortical tumours and in a case of ectopic corticotroph tumours. The different shades of brown highlight the immunostaining for D2 receptor with a specific polyclonal D2 receptor antibody. (Created with BioRender.com)