Treatment of Cushing's Syndrome

Publication Date: August 1, 2015
Last Updated: July 25, 2023

Treatment

Treatment Goals for Cushing’s Syndrome

In patients with overt CS, the Endocrine Society (ES) recommends normalizing cortisol levels or action at its receptors to eliminate the signs and symptoms of CS and treating comorbidities associated with hypercortisolism. ( 1-M )
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ES recommends against treatment to reduce cortisol levels or action if there is not an established diagnosis of CS. ( 1-VL )
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ES suggests against treatments designed to normalize cortisol or its action when there is only borderline biochemical abnormality of the hypothalamic-pituitary-adrenal (HPA) axis without any specific signs of CS. The benefit of treating to normalize cortisol is not established in this setting. ( 2-VL )
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Optimal Adjunctive Management

ES recommends providing education to patients and their family/caretaker(s) about their disease, treatment options, and what to expect after remission. (UGPS)
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ES recommends that all patients receive monitoring and adjunctive treatment for cortisol-dependent comorbidities (psychiatric disorders, diabetes, hypertension, hypokalemia, infections, dyslipidemia, osteoporosis, and poor physical fitness). (UGPS)
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ES recommends that a multidisciplinary team, including an experienced endocrinologist, takes patient values and preferences into consideration and provides education about the treatment options to the patient. (UGPS)
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ES suggests evaluating CS patients for risk factors for venous thrombosis. (2-L)
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In patients with CS undergoing surgery, ES suggests perioperative prophylaxis for venous thromboembolism. ( 2-L )
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ES recommends that clinicians discuss and offer age-appropriate vaccinations to CS patients—particularly influenza, H. zoster, and pneumococcal vaccinations—due to an increased risk of infection. (UGPS)
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First-line Treatment Options

ES recommends initial resection of primary lesion(s) underlying Cushing’s disease (CD), ectopic and adrenal (cancer, adenoma, and bilateral disease) etiologies, unless surgery is not possible or unlikely to significantly reduce glucocorticoid excess. (1-H)
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ES recommends unilateral resection by an experienced adrenal surgeon for all cases of benign unilateral disease. (1-M)
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ES recommends localizing and resecting ectopic ACTH-secreting tumors with node dissection as appropriate. (1-H)
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ES recommends transsphenoidal selective adenomectomy (TSS) by an experienced pituitary surgeon as the optimal treatment for CD in pediatric and adult patients. (1-H)
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ES recommends measuring serum sodium several times during the first 5–14 days after transsphenoidal surgery. ( 1-L )
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ES recommends assessing free thyroxine and prolactin within 1–2 weeks of surgery, to evaluate for overt hypopituitarism. (1-L)
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ES recommends obtaining a postoperative pituitary MRI within 1–3 months of successful TSS. (UGPS)
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ES recommends surgical resection of bilateral adrenal disorders, and suggest medical therapy to block aberrant hormone receptors for bilateral macronodular adrenal hyperplasia (BMAH). (2-L)
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Remission and Recurrence After Surgical Tumor Resection

ES suggests an individualized management approach based on whether the post-operative serum cortisol values categorize the patient as hypocortisolism, hypercortisolism, or eucortisolism. ( UGPS )
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ES recommends additional treatments in patients with persistent overt hypercortisolism. (1-H)
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ESS recommends measuring late-night salivary or serum cortisol in patients with eucortisolism after TSS, including those cases where eucortisolism was established by medical treatment before surgery. (1-L)
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ES recommends using tests to screen for hypercortisolism to assess for recurrence in patients with ACTH-dependent CS. (1-M)
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Glucocorticoid Replacement and Discontinuation, and Resolution of Other Hormonal Deficiencies

ES recommends that hypocortisolemic patients receive glucocorticoid replacement and education about adrenal insufficiency after surgical remission. (1-H)
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ES recommends follow-up morning cortisol and/or ACTH stimulation tests or insulin-induced hypoglycemia to assess the recovery of the HPA axis in patients with at least one intact adrenal gland, assuming there are no contraindications. ES also recommends discontinuing glucocorticoid when the response to these test(s) is normal. (1-M)
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ES recommends re-evaluating the need for treatment of other pituitary hormone deficiencies in the postoperative period. (1-M)
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Second-line Therapeutic Options

In patients with ACTH-dependent CS who underwent a non-curative surgery or for whom surgery was not possible, ES suggests a shared decision-making approach, as there are several available second-line therapies (e.g., repeat transsphenoidal surgery, radiotherapy, medical therapy, and bilateral adrenalectomy). (2-L)
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ES suggests bilateral adrenalectomy for occult or metastatic EAS or as a life-preserving emergency treatment in patients with very severe ACTH-dependent disease who cannot be promptly controlled by medical therapy. (2-M)
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ES recommends regularly evaluating for corticotroph tumor progression using pituitary MRIs and ACTH levels in patients with known CD who undergo bilateral adrenalectomy and in patients who undergo this procedure for presumed occult EAS (as some of the latter have a pituitary and not ectopic tumor). (1-M)
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Repeat Transsphenoidal Surgery

ES suggests repeat transsphenoidal surgery, particularly in patients with evidence of incomplete resection or a pituitary lesion on imaging. (2-L)
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Radiation Therapy/Radiosurgery for Cushing's Disease

ES recommends confirming that medical therapy is effective in normalizing cortisol before administering radiation therapy (RT)/radiosurgery for this goal, because this will be needed while awaiting the effect of radiation. (1-VL)
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ES suggests RT/radiosurgery in patients who have failed TSS or have recurrent CD. ( 2-L )
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ES recommends using RT where there are concerns about the mass effects or invasion associated with corticotroph adenomas. ( 1-M )
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ES recommends measuring serum cortisol or UFC off-medication at 6- to 12-month intervals to assess the effect of RT and also if patients develop new adrenal insufficiency symptoms while on stable medical therapy. (1-M)
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Medical Rx

ES recommends steroidogenesis inhibitors under the following conditions: as second-line treatment after TSS in patients with CD, either with or without RT/radiosurgery; as primary treatment of ectopic ACTH secretion in patients with occult or metastatic ectopic ACTH secretion; and as adjunctive treatment to reduce cortisol levels in ACC. (1-M)
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ES suggests pituitary-directed medical treatments in patients with CD who are not surgical candidates or who have persistent disease after TSS. (2-M)
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ES suggests administering a glucocorticoid antagonist in patients with diabetes or glucose intolerance who are not surgical candidates or who have persistent disease after TSS. (2-M)
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ES suggests targeted therapies to treat ectopic ACTH syndrome. (2-VL)
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Special Populations/Considerations

ES recommends urgent treatment (within 24-72 hours) of hypercortisolism if life-threatening complications of CS such as infection, pulmonary thromboembolism, cardiovascular complications and acute psychosis are present. (1-M)
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The associated disorder(s) should be addressed as well
(e.g., anticoagulation, antibiotics).

Approach for Long-term Follow-up

ES recommends treating the specific comorbidities associated with CS (e.g., cardiovascular risk factors, osteoporosis and psychiatric symptoms) in all patients with CS throughout their lives until resolution. ES also recommends testing for recurrence throughout life, except in patients who underwent resection of an adrenal adenoma with a CT density of <10 Hounsfield units. (1-M)
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ES recommends educating patients and families about the clinical features of remission. (UGPS)
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In patients with adrenal adenoma, ES suggests follow-up tests for the specific comorbidities associated with CS if the adenoma density on CT was <10 Hounsfield units. ( 2-L )
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In patients with adrenal adenoma, ES suggests follow-up tests for the specific comorbidities associated with CS if the adenoma density on CT was <10 Hounsfield units. ( 2-VL )
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ES recommends that patients with Carney complex have lifelong follow-up tests for cardiac myxoma and other associated disease (testicular tumors, acromegaly, thyroid lesions) ( 1-H )
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Recommendation Grading

Disclaimer

The information in this patient summary should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.

Overview

Title

Treatment of Cushing's Syndrome

Authoring Organization

Publication Month/Year

August 1, 2015

Last Updated Month/Year

April 1, 2024

Supplemental Implementation Tools

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Document Objectives

The objective is to formulate clinical practice guidelines for treating Cushing's syndrome.

Inclusion Criteria

Male, Female, Adolescent, Adult, Child, Older adult

Health Care Settings

Ambulatory

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Treatment

Diseases/Conditions (MeSH)

D003480 - Cushing Syndrome

Keywords

corticosteroids, Cushing's syndrome, cortisol

Source Citation

Lynnette K. Nieman, Beverly M. K. Biller, James W. Findling, M. Hassan Murad, John Newell-Price, Martin O. Savage, Antoine Tabarin, Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 8, 1 August 2015, Pages 2807–2831, https://doi.org/10.1210/jc.2015-1818