SUN-474 - Endogenous Cushing'S Syndrome from Bilateral Adrenal Hyperplasia: A Management Dilemma

Medical management of Cushing’s syndrome has expanded in recent years; however, evidence remains limited for adrenal-based etiologies, particularly bilateral adrenal hyperplasia (BAH). While agents such as mifepristone and ketoconazole have demonstrated efficacy in endogenous Cushing’s syndrome, primarily in pituitary-dependent disease, patients with BAH are rarely studied as a distinct subgroup, and guidance for long-term therapy in non-surgical candidates is limited.

A 63-year-old female with poorly controlled type 2 diabetes and resistant hypertension, was referred for endocrine evaluation due to worsening metabolic control despite intensive medical therapy. Her diabetes regimen included metformin, high-dose basal-bolus insulin, and SGLT2 inhibitor, and her hypertension was treated with three antihypertensive agents.

Endocrine evaluation revealed elevated late-night salivary cortisol in three collected samples (0.17, 0.25, and 0.24 µg/dL), and an elevated morning serum cortisol (29 µg/dL). Cortisol failed to adequately suppress following a 1-mg overnight dexamethasone suppression test (post-dexamethasone cortisol 2.3 µg/dL), with a therapeutic dexamethasone level (338 ng/dL), and suppressed plasma ACTH ( < 5 pg/mL), confirming ACTH-independent endogenous Cushing’s syndrome. Abdominal CT demonstrated mild bilateral adrenal hyperplasia, left greater than right, without discrete nodules, limiting definitive lateralization. Given her comorbidities and personal preference, surgical intervention was referred, and levoketoconazole was initiated. Over subsequent weeks, the patient demonstrated biochemical and metabolic response, including improved glycemic control (HbA1c of 10% to 7.1%), reduction in BMI from 28.89 to 25.36 kg/m², transition from high-dose basal-bolus insulin to low-dose basal insulin alone, and improved blood pressure control with de-escalation of antihypertensive therapy. Adrenal steroidogenesis inhibitors are commonly used as a bridge to surgery in overt Cushing’s syndrome, and long-term use has been proposed in selected cases of primary bilateral macronodular adrenal hyperplasia. However, data supporting chronic medical therapy in BAH patients who are not surgical candidates remain limited.

This case highlights the importance of determining whether cortisol hypersecretion is unilateral or bilateral, as this distinction has major therapeutic implications. When imaging is non-localizing and surgery is not immediately feasible, medical therapy plays a critical role in controlling hypercortisolism while allowing reassessment of disease laterality and surgical candidacy. Levoketoconazole was effective in improving biochemical control and metabolic comorbidities in this patient, supporting its potential role as a long-term management strategy in carefully selected patients with BAH.

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