Cushing’s disease occurs when a benign pituitary adenoma secretes excess levels of adrenocorticotropic hormone (ACTH). This, in turn, causes the adrenal glands to secrete cortisol, resulting in excessive levels of circulating cortisol.1
What causes Cushing’s disease?
What is the exaggerated cascade of ACTH overproduction?
Under normal conditions, circulating cortisol provides physiologic control through negative feedback inhibition on hypothalamic corticotropin-releasing hormone (CRH) and pituitary ACTH secretion.
In Cushing’s disease, the hypothalamic-pituitary-adrenal (HPA) feedback loop is disrupted, leaving CRH and ACTH production uncontrolled. Additionally, the pituitary adenoma becomes resistant to cortisol inhibition, continues to oversecrete ACTH, and stimulates the adrenal glands to produce excess cortisol.1
What are the signs and symptoms of Cushing’s disease?
Patients with Cushing’s disease are most likely to present with one or more of the signs and symptoms that result from elevated levels of cortisol or ACTH. These include sudden weight gain (especially with central obesity), hypertension, facial rounding, easy bruising, striae, glucose intolerance or diabetes mellitus, hyperlipidemia, decreased libido or impotence, menstrual disorders, osteopenia or osteoporosis, acne, hirsutism, recurrent opportunistic bacterial infections, and depression or psychosis.2
What is the role of somatostatin (SST) receptors in Cushing’s disease?
Somatostatin receptors are expressed in many tissues including neuroendocrine tumors such as ACTH-secreting pituitary adenomas. Corticotroph tumor cells from patients with Cushing’s disease frequently overexpress SST5, whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Binding and activating the SST receptors results in inhibition of ACTH secretion, which leads to decreased cortisol secretion.3
How does SIGNIFOR® LAR decrease cortisol levels?
SIGNIFOR LAR exerts its pharmacologic effect by binding to SST receptors. Of the 5 known human somatostatin receptor subtypes—SST1, SST2, SST3, SST4, and SST5—SIGNIFOR LAR binds with high affinity to four of the five. By targeting key SST receptors of pituitary adenoma cells, SIGNIFOR LAR decreases cortisol levels through inhibition of ACTH secretion.3
What is the pharmacologic profile of SIGNIFOR LAR?
SIGNIFOR LAR targets four of the five SST receptors. SIGNIFOR LAR has the highest binding affinity for SST5 and SST2, which regulate most ACTH secretion. SST5 is known to be the most overexpressed SST receptor in Cushing’s disease.3
References: 1. Lonser RR, Nieman L, Oldfield EH. J Neurosurg. 2017;126(2):404-417. 2. Kirk LF, Hash RB, Katner HP, et al. Am Fam Physician. 2000;62(5):1119-1127. 3. SIGNIFOR LAR (pasireotide) for injectable suspension, for intramuscular use [prescribing information]. Lebanon, NJ: Recordati Rare Diseases Inc.; 2020.