Treatment of Cushing's disease: a mechanistic update

  1. Maria Fleseriu3
  1. 1Department of Medicine, Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
    2Neuroendocrinology Clinic, Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
    3Departments of Medicine and Neurological Surgery, and Northwest Pituitary Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road (BTE 472), Portland, Oregon 97239, USA
  1. Correspondence should be addressed to M Fleseriu; Email: fleseriu{at}
  1. Figure 1

    The hypothalamus–pituitary–adrenal (HPA) axis and targets of drugs used for treating Cushing's disease. Under physiological conditions, cortisol synthesis and production are tightly regulated by the HPA axis. Adrenocorticotropin (ACTH)-producing cells in the anterior pituitary respond to hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). After binding to melanocortin type 2 receptor (MC2R), ACTH induces the steroidogenic enzymes to increase the biosynthesis of cortisol and will decrease ACTH and CRH secretion. Pituitary corticotrope ACTH-secreting adenomas, however, function autonomously and overstimulate cortisol production at the adrenal cortex. The pharmacotherapies for ACTH-secreting pituitary corticotrope adenomas are categorized by the site of action into three groups: i) centrally acting agents or neuromodulators, which inhibit ACTH release from pituitary adenomas, ii) adrenal steroidogenic inhibitors, which block one or several steps in cortisol biosynthesis and iii) the glucocorticoid receptor-blocking agent mifepristone. Green arrows indicate activation and red arrows/lines indicate inhibition.

  2. Figure 2

    Adrenocortical steroidogenic pathways. A simplified diagram of adrenal steroidogenesis is depicted. Cushing's disease is almost always caused by a pituitary corticotrope adenoma that oversecretes corticotropin (ACTH). ACTH stimulates the adrenal gland to start steroid synthesis. After activation of MC2R by ACTH, the StAR protein is phosphorylated. Then, StAR facilitates cholesterol transport across the mitochondrial inner membrane. Cholesterol is the common precursor of the steroid molecules and, after several enzymatic reactions, is ultimately converted into biologically active aldosterone, cortisol, or androstenedione that is further processed to testosterone in testicles. The zona glomerulosa, fasciculata, and reticularis are the three adrenal cortex histological zones, which synthesize steroid hormones with mineralocorticoid, glucocorticoid, or androgenic properties respectively. Enzyme nomenclature is given in detail in Table 1. CYP11A1, CYP11B1, and CYP11B2 are located in the mitochondria, and the remaining enzymes are located in the smooth endoplasmic reticulum.

  3. Figure 3

    Potential novel therapeutic targets for CD. From left to right; the effect of V3 receptor-specific antagonists that could lead to a new class of agents that can suppress ACTH secretion in corticotrope adenomas (Ferone et al. 2013). After blocking of EGFR, a tyrosine kinase receptor, POMC expression is attenuated, and inhibition of corticotrope cell proliferation and apoptosis can be induced (Fukuoka et al. 2011). Through membrane interaction or dimerization (Rocheville et al. 2000), the G-protein-coupled somatostatin receptor (SSTR) and dopamine D2 receptor (D2R) have a synergistic effect on controlling tumor cell growth and ACTH secretion (de Bruin et al. 2009, Ferone et al. 2013). The main proteins of each receptor signaling pathway are depicted. The leading effect of such pathways is cell cycle arrest with a decrease in tumor growth. Interestingly, using a cyclin-dependent kinase 2 (CDK2)/cyclin E inhibitor in animal models, the ACTH and corticosterone levels were suppressed, and xenografted pituitary tumor growth was restrained (Liu et al. 2011b). Red lines/arrows indicate inhibition, whereas green lines/arrows indicate induction. PKA, protein kinase A; PLC, phospholipase C; PKC, protein kinase C; Akt, protein kinase B; ERK, extracellular signal-regulated kinases; GSK3, synthase kinase 3 beta; Rb, retinoblastoma protein; E2F, E2 transcription factors.

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