Reversing abnormal metabolism in mild autonomous cortisol secretion (MACS)

About This Grant

PROJECT SUMMARY Mild autonomous cortisol secretion (MACS) is diagnosed in up to 44% of patients with adrenal adenomas, affecting 1-2% of the adult population. MACS is diagnosed based on an abnormal cortisol level following dexamethasone suppression (>1.8 mcg/dL). Patients with MACS develop high rates of cardiovascular morbidity and demonstrate increased mortality. In our preliminary data we showed that patients with MACS have an abnormal steroid metabolome and circadian cortisol secretion, findings similar to what occurs with normal aging. We also found that patients with MACS demonstrate increased markers of inflammation and senescence, have increased cardiovascular morbidity, frailty, and mortality. Metyrapone is a short-acting steroidogenesis inhibitor that is FDA approved for diagnosis of adrenal insufficiency. In our pilot open-label study, we show that when administered overnight in patients with MACS, metyrapone is safe and effective in normalizing hypothalamic-pituitary-adrenal communication. We propose to conduct a randomized double-blinded placebo-controlled trial of overnight metyrapone intervention in patients with MACS. In Aim 1, we will determine safety and tolerance of overnight metyrapone over 12 months of therapy. In Aim 2, we will determine the impact of overnight metyrapone on adrenal steroid metabolome and circadian cortisol secretion. In Aim 3, we will determine the impact of overnight metyrapone on metabolic outcomes and frailty, as well exploratory outcomes, such as cognition and senescence biomarkers. Results of the proposed studies will advance our understanding of how subtle cortisol excess impacts health and test the hypothesis that adverse health outcomes associated with MACS are reversible with therapy.