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

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.

Mild autonomous cortisol secretion (MACS) from benign adrenal tumours is a condition affecting 3% of the population aged >70 years (approx. 300k individuals in the UK). It is associated with insulin resistance and poor bone health as well as increased cardiovascular events, increased frailty and mortality. There are currently no licensed treatments and no consensus as to optimal management. In this proposal, we will define specific mechanisms that drive adverse outcomes and test if these are amenable to therapeutic intervention. We have shown that patients with MACS have elevated nocturnal and evening circulating cortisol levels and blocking cortisol action improves metabolic features, including insulin sensitivity. We have hypothesised that within key tissues, regeneration of active cortisol (from inactive cortisone) by 11B-hydroxysteroid dehydrogenase type 1 (11B-HSD1) may drive these features, independent of circulating levels, and may also represent a potential therapeutic target.

We will adopt a bespoke, experimental medicine approach using state-of-the-art techniques including hyperinsulinaemic clamps with stable isotope infusions and adipose tissue microdialysis combined with adipose tissue biopsies. We will determine the contribution of 11B-HSD1 to the adverse MACS phenotype using a selective 11B-HSD1 inhibitor (Xanamem) aligning the timing of administration of 11B-HSD1 inhibition to coincide with circulating cortisol excess (evening / nocturnal).

These studies have the potential to offer significant mechanistic insight into a common condition where there is an established adverse outcome, no consensus as to the best approach to clinical management and currently no licensed treatment.