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  • Review Article
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An individualized approach to the management of Cushing disease

Nature Reviews Endocrinology volume 19, pages 581–599 (2023)Cite this article

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Abstract

Cushing disease caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary corticotroph adenoma leads to hypercortisolaemia with high mortality due to metabolic, cardiovascular, immunological, neurocognitive, haematological and infectious conditions. The disorder is challenging to diagnose because of its common and heterogenous presenting features and the biochemical pitfalls of testing levels of hormones in the hypothalamic–pituitary–adrenal axis. Several late-night salivary cortisol and 24-h urinary free cortisol tests are usually required as well as serum levels of cortisol after a dexamethasone suppression test. MRI might only identify an adenoma in 60–75% of patients and many adenomas are small. Therefore, inferior petrosal sinus sampling remains the gold standard for confirmation of ACTH secretion from a pituitary source. Initial treatment is usually transsphenoidal adenoma resection, but preoperative medical therapy is increasingly being used in some countries and regions. Other management approaches are required if Cushing disease persists or recurs following surgery, including medications to modulate ACTH or block cortisol secretion or actions, pituitary radiation, and/or bilateral adrenalectomy. All patients require lifelong surveillance for persistent comorbidities, clinical and biochemical recurrence, and treatment-related adverse effects (including development of treatment-associated hypopituitarism). In this Review, we discuss challenges in the management of Cushing disease in adults and provide information to guide clinicians when planning an integrated and individualized approach for each patient.

Key points

  • Cushing disease, an adrenocorticotropic hormone-secreting pituitary adenoma, is the most frequent cause of endogenous Cushing syndrome; sustained hypercortisolism produced by increased levels of adrenocorticotropic hormone leads to substantial morbidity and mortality.

  • Surgery is the first-line treatment for most patients, with preoperative medical therapy increasingly being used in some countries; biochemical postoperative remission largely depends on adenoma size and surgeon experience.

  • Up to 35% of cases recur after surgery, and recurrence might be delayed by decades; patient management should be individualized and lifelong follow-up is required.

  • Practice standards for the use of pituitary-directed agents, adrenal steroidogenesis inhibitors and glucocorticoid receptor antagonists as well as for repeat surgery and for radiotherapy differ and are often specific to the centre and region.

  • Bilateral adrenalectomy is often recommended for patients desiring pregnancy and those with severe persistent hypercortisolaemia; resultant permanent adrenal insufficiency and potential for corticotroph adenoma progression are precautionary clinical considerations.

  • Clinical and biochemical responses to therapy and quality-of-life changes should be assessed within weeks of treatment initiation; all patients require lifelong monitoring and management of comorbidities and treatment-related adverse effects.

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Fig. 1: Algorithm for individualizing management of Cushing disease.
Fig. 2: Mechanisms of medical therapies for Cushing disease.
Fig. 3: Case examples: effectiveness of surgical tumour resection in challenging cases.
Fig. 4: Case example: corticotroph tumour progression after bilateral adrenalectomy.
Fig. 5: Assessment of comorbidities and complications in patients with Cushing disease.

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Acknowledgements

The authors thank Shira Berman from Cedars-Sinai Medical Center for editorial assistance. Images of staining patterns (Fig. 3Ac–Af) are courtesy of Matthew Wood (Department of Pathology, Oregon Health & Science University).

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Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health & Science University, Portland, OR, USA

    Maria Fleseriu & Elena V. Varlamov

  2. Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, USA

    Maria Fleseriu

  3. Pituitary Center, Oregon Health & Science University, Portland, OR, USA

    Maria Fleseriu

  4. Division of Endocrinology, Department of Medicine, Hospital Universitario “Dr. José E. González”, Autonomous University of Nuevo León, Monterrey, Mexico

    Jose M. Hinojosa-Amaya

  5. Division of Endocrinology, Department of Medicine, Centre intégré universitaire de santé et de services sociaux de l’Estrie — Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada

    Fabienne Langlois

  6. Department of Medicine and Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Shlomo Melmed

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The authors contributed equally to all aspects of the article.

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Correspondence to Maria Fleseriu.

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Competing interests

M.F. has received grants to the institution from Crinetics, Novartis, Recordati, Sparrow, and Xeris (formerly Strongbridge), consulting fees from Crinetics, HRA Pharma, Novartis, Recordati, Sparrow, and Xeris (formerly Strongbridge), and serves as a member of the Board of Directors (non-compensated) for the Pituitary Society. E.V.V. has received grants to the institution from Recordati. F.L. has served as an adviser to Novartis and Recordati, and has served as a member of the Continuing Medical Education Committee for AMEQ (Association des Médecins Endocrinologues du Québec). S.M. has received grants to the institution from the US Food and Drug Administration and Recordati and non-financial support from Cyclacel, and serves as Secretary (non-compensated) for the Pituitary Society. J.M.H.-A. declares no competing interests.

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Nature Reviews Endocrinology thanks Irina Bancos, who co-reviewed with Rashi Sandooja; Prashant Chittiboina; and Constantine Stratakis for their contribution to the peer review of this work.

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We searched PubMed for full-text articles published in English, French and Spanish from January 2000 through January 2023 using the terms “Cushing’s disease”, “ACTH-secreting adenoma”, “hypercortisolism”, “hypercortisolemia”, and “pituitary adenoma”, in combination with the terms “treatment”, “surgery” and “radiation therapy”. Inclusion preference was for articles published within the past 5 years. Some articles were not included in the review due to space limitations or low patient numbers.

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Fleseriu, M., Varlamov, E.V., Hinojosa-Amaya, J.M. et al. An individualized approach to the management of Cushing disease. Nat Rev Endocrinol 19, 581–599 (2023). https://doi.org/10.1038/s41574-023-00868-7

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