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Mild autonomous cortisol secretion: pathophysiology, comorbidities and management approaches

Nature Reviews Endocrinology (2024)Cite this article

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Abstract

The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1–7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20–50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS.

Key points

  • Mild autonomous cortisol secretion (MACS) is diagnosed based on the 1 mg overnight dexamethasone test and is found in 20–50% of patients with adrenal adenomas lacking signs and symptoms of Cushing syndrome.

  • Patients with adrenal adenomas show distinct changes in the steroid and global metabolome, which correlate with the degree of cortisol excess across MACS and Cushing syndrome.

  • MACS is associated with an increased likelihood of having cardiovascular risk factors and an increased risk of mortality.

  • Management of MACS must be individualized based on patient characteristics; the options range from adrenalectomy to long-term follow-up and conservative management of comorbidities.

  • Post-operative adrenal insufficiency is seen in around 50% of patients with MACS who undergo unilateral adrenalectomy.

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Fig. 1: Pathophysiology of mild autonomous cortisol secretion.
Fig. 2: Natural history of mild autonomous cortisol secretion.
Fig. 3: Schematic overview of steroidogenesis and corresponding urine steroid metabolites.
Fig. 4: Diagnosis and management of mild autonomous cortisol secretion.
Fig. 5: Surgical management in patients with mild autonomous cortisol secretion.

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Acknowledgements

A.P. receives support from the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (grant reference number NIHR203326) and the European Union’s Horizon 2022 Research and Innovation Programme (call HORIZON-HLTH-2022-TOOL-11; project number 101095407). The views expressed are those of the author (authors) and not necessarily those of the NIHR or the Department of Health and Social Care UK. I.B. is partly supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Aging (NIA) of the National Institutes of Health (NIH) USA under awards K23DK121888, R03DK132121 and R03AG71934 (to I.B). The views expressed are those of the authors and not necessarily those of the National Institutes of Health. The authors thank W. Young (Mayo Clinic, Rochester, MN, USA), W. Arlt (Imperial College London, UK), R. Sandooja (Mayo Clinic, Rochester, MN, USA), L. Rahimi (Mayo Clinic, Rochester, MN, USA), C. Ronchi (University of Birmingham, UK), O. Suntornlohanakul (University of Birmingham, UK) and G. Di Dalmazi (University of Bologna, Italy) for their critical review of the manuscript and useful suggestions.

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  1. Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

    Alessandro Prete

  2. NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

    Alessandro Prete

  3. Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA

    Irina Bancos

  4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Irina Bancos

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A.P. and I.B. contributed equally to all aspects of the article.

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A.P. received research funding and consultancy fees from Recordati, Diurnal and HRA Pharma. I.B. reports consulting, advisory board or data safety monitoring board participation fees (to institution) from Diurnal, Neurocrine, Spruce, Adrenas, Recordati, Corcept, Sparrow, and HRA Pharma, NovoNordisk, AstraZeneca, Xeris outside this work. I.B. received research funding (to institution) from Recordati and HRA Pharma for investigator-initiated awards.

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Prete, A., Bancos, I. Mild autonomous cortisol secretion: pathophysiology, comorbidities and management approaches. Nat Rev Endocrinol (2024). https://doi.org/10.1038/s41574-024-00984-y

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