Adrenal hypercortisolism (AHC) is the primary endogenous cause of cortisol excess, resulting from autonomous cortisol production by adrenal tumors. This condition spans a broad clinical and biochemical
spectrum, from mild autonomous cortisol secretion (MACS) to overt Cushing syndrome, affecting millions globally diagnosed via incidental imaging findings or symptomatic presentation. Classified as
ACTH-independent, AHC encompasses unilateral adenomas, adrenocortical carcinomas, and bilateral macronodular or micronodular diseases.

Advances in genetic research have identified somatic and germline mutations driving tumor formation and cortisol autonomy, confirming clonal processes rather than hyperplasia. AHC contributes to significant morbidity, including cardiovascular disease, diabetes, osteoporosis, and neurocognitive deficits, with milder forms often underdiagnosed in adrenal incidentalomas (prevalence 5–30%). The diagnosis relies on the dexamethasone suppression test (DST) to assess cortisol autonomy, supported by ACTH, DHEA-S levels, imaging, and genetic evaluation for subtype classification. Surgical interventions, such as minimally invasive mini back scope adrenalectomy (MBSA), provide curative options and preserve function in bilateral cases.

Pharmacological therapies, including steroidogenesis inhibitors (e.g., osilodrostat, levoketoconazole, ketoconazole, metyrapone), glucocorticoid receptor antagonists (e.g., mifepristone) are critical for patients unsuitable for surgery, preoperative cortisol stabilization, bridging to intervention in severe cases, or managing persistent/recurrent disease. These treatments reduce hypercortisolism-related complications, requiring careful monitoring for side effects like hepatotoxicity or hypertension. Comorbidities, such as hypertension, metabolic syndrome, bone loss, and psychological impairments, increase AHC’s burden, necessitating integrated management strategies.

This Research Topic aims to advance understanding of AHC by integrating insights into its etiology, diagnostic precision, and comprehensive management. The focus is to refine diagnostic protocols, improve comorbidity management, and enhance therapeutic personalization to reduce morbidity and mortality. Contributions will bridge molecular research with clinical practice to improve evidence-based patient-centered care.

The scope focuses on adrenal-origin hypercortisolism, excluding ACTH-dependent forms, and includes:

• Molecular and genetic foundations: Mechanisms of tumor development, cortisol dysregulation, and epigenetic influences.
• Clinical spectrum and stratification: Grading systems for mild to severe AHC using biochemical and clinical markers, including comorbidity profiles.
• Diagnostic innovations: Refinements in cortisol essays, biomarker panels, imaging, and genetic screening for accurate subtype differentiation.
• Therapeutic strategies: Surgical advancements (e.g., function-preserving adrenalectomy); pharmacological and medical therapies for cortisol control, preoperative optimization, and longterm management.
• Comorbidities and management: Cardiovascular, metabolic, skeletal, and neuropsychiatric complications, including preventive strategies, multidisciplinary care, and post-treatment monitoring.
• Long-term outcomes: Recurrence prevention, postoperative hypocortisolism risks, quality of life, glucocorticoid withdrawal syndrome, and the role of high-volume centers in increased access to optimized care.

This collection will foster interdisciplinary collaboration to integrate basic science with clinical practice, promoting comprehensive, patient-centered AHC management.

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Adrenal Hypercortisolism: From Molecular Mechanisms to Clinical Management