Introduction: The Burden of Endogenous Hypercortisolism
Endogenous hypercortisolism, commonly known as Cushing’s syndrome, is a rare but devastating endocrine disorder characterized by chronic overexposure to cortisol. Whether arising from an ACTH-secreting pituitary adenoma (Cushing’s disease), ectopic ACTH production, or autonomous adrenal cortisol secretion, the multisystemic impact of hypercortisolism is profound. Patients frequently suffer from central obesity, proximal muscle weakness, skin fragility, and severe neuropsychiatric disturbances. However, the primary drivers of increased mortality and cardiovascular risk in this population are metabolic: treatment-resistant hypertension and impaired glucose tolerance or diabetes mellitus.
Managing Cushing’s syndrome remains a significant clinical challenge, particularly when surgical intervention—the first-line treatment—is unsuccessful, contraindicated, or not curative. Pharmacological options have historically focused on inhibiting steroidogenesis (e.g., ketoconazole, metyrapone) or blocking the glucocorticoid receptor (GR). While effective, existing GR antagonists like mifepristone are non-selective, also blocking the progesterone receptor (PR). This lack of selectivity leads to significant adverse effects, including endometrial thickening and vaginal bleeding in women, and the saturation of the mineralocorticoid receptor pathway, leading to severe hypokalemia. The GRACE study was designed to evaluate relacorilant, a selective GR modulator, as a next-generation therapeutic that addresses these unmet safety and efficacy needs.
