MICA: Dissecting the Contribution of glucocorticoid metabolism in Mild Autonomous Cortisol Secretion (DC-MACS)

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Benign, non-cancerous, nodules of the adrenal gland are common and can frequently produce too much of the steroid stress hormone, cortisol (a condition called mild autonomous cortisol secretion, MACS). It is estimated that 3% of the population aged over 70 have MACS and this is associated with increased risks of frailty, development of diabetes, heart attacks and strokes. Cortisol has profound effects on many tissues including the circulatory system, fat, muscle and the brain. Currently there is no specific treatment to limit the effects of the excess cortisol in patients with MACS. In tissues (fat, muscle, liver, bone, brain) we have shown that there is further generation of excess cortisol through the activity of an enzyme called 11B-hydroxysteroid dehydrogenase type 1 (11B-HSD1); this exacerbates the problem of too much cortisol and drives many of the adverse features that we observe in patients with MACS. Using a drug to block the action of this enzyme, a so-called 11B-HSD1 inhibitor, we have been able to block the undesirable effects of prescribed steroids that have been taken by mouth. We now want to see if using a similar approach in patients with MACS improves their symptoms by reducing the action of the naturally occurring cortisol that is present at slightly higher levels in their bodies. We will use very sensitive techniques to look at how the body handles glucose, as well as fat and muscle distribution, brain function and bone health, which are all well-documented to be adversely affected in patients with MACS. We aim to discover if these are improved with an 11B-HSD1 inhibitor (Xanamem). In addition, we will time the administration of the 11B-HSD1 inhibitor to coincide with the highest cortisol levels to assess the beneficial effect. These studies will not only demonstrate the fundamental role of 11B-HSD1 in the development of MACS, but also begin to explore the potential that 11B-HSD1 inhibitors may be an option for future drug treatment in these patients where currently none are available.