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Cushing's syndrome

Background

Overview

Definition
CS is a rare disorder resulting from chronic exposure to excess corticosteroids characterized by obesity, moon face, facial plethora, and hypertension.
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Pathophysiology
CS is caused by ACTH production from a pituitary adenoma (Cushing's disease; 75-80%), ACTH production from nonpituitary tumors (ectopic ACTH syndrome; 15-20%), and corticotropin-releasing hormone-producing tumors (< 1%).
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Disease course
Corticosteroid excess results in CS, which causes clinical manifestations of obesity, moon face, supraclavicular/dorsocervical fat pads, hirsutism, alopecia, facial plethora, violaceous striae, acne, easy bruising, menstrual irregularity, decreased libido, emotional lability, depression, psychosis, cognitive dysfunction, muscle weakness, muscular atrophy, osteopenia, fractures, decreased linear growth in children, hypertension, glucose intolerance, hyperlipidemia, hepatic steatosis, and nephrolithiasis.
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Prognosis and risk of recurrence
CS is associated with a standard mortality ratio of 3.7 (95% CI 2.3-5.3).
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Guidelines

Key sources

The following summarized guidelines for the evaluation and management of Cushing's syndrome are prepared by our editorial team based on guidelines from the American Association of Endocrine Surgeons (AAES 2022), the European Society of Endocrinology (ESE 2021), and the Endocrine Society (ES 2020,2015,2008). ...
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Screening and diagnosis

Indications for testing: as per ES 2008 guidelines, test for CS in patients with an adrenal adenoma.
B
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Diagnostic investigations

Corticosteroid exposure history: as per ES 2008 guidelines, obtain a thorough drug history to exclude iatrogenic CS (due to excessive exogenous corticosteroid exposure) prior to undertaking further diagnostic investigations.
A

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  • Initial laboratory testing

  • Subsequent laboratory testing

  • Adrenal gland imaging

  • Dexamethasone-CRH test

  • Midnight serum cortisol test

  • Desmopressin test

  • Evaluation of cardiovascular risks

Medical management

General principles: as per ES 2015 guidelines, perform surgical resection of any primary lesion identified as the cause of cortisol excess (pituitary, ectopic or adrenal) as the first-line and definitive treatment for CS, unless surgery is not possible or is unlikely to significantly reduce corticosteroid excess.
A
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  • Indications for treatment

  • Corticosteroid antagonists

  • Pituitary-directed therapy

  • Steroidogenesis inhibitors

  • Management of ectopic ACTH syndrome

  • Statin therapy

Therapeutic procedures

Radiotherapy
As per ES 2015 guidelines:
Consider radiation therapy/radiosurgery in patients with Cushing's disease who have failed transsphenoidal surgery or display evidence of disease recurrence.
C
Confirm that medical therapy is effective in normalizing cortisol prior to initiating radiation therapy for Cushing's disease, given that a response to medical therapy is required for disease control while awaiting the effect of radiation.
B

Perioperative care

Perioperative thromboprophylaxis: as per ES 2015 guidelines, consider administering perioperative prophylaxis for VTE in patients with CS undergoing surgery.
C

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  • Perioperative sodium monitoring

Surgical interventions

Adrenal gland resection, adrenal gland disease
As per AAES 2022 guidelines:
Consider performing unilateral laparoscopic adrenalectomy in patients with bilateral macronodular hyperplasia with CS as an attempt to achieve biochemical remission of hypercortisolism without causing permanent adrenal insufficiency.
C
Administer empirical postoperative corticosteroid replacement therapy in all patients with overt CS after unilateral adrenalectomy. Obtain morning cortisol or corticotropin stimulation testing on the first postoperative day to determine the need for corticosteroid replacement therapy in patients with mild autonomous cortisol secretion.
B

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  • Adrenal gland resection (occult ACTH secreting-tumors)

  • Transsphenoidal selective adenomectomy

  • Ectopic ACTH-secreting tumor resection

Specific circumstances

Pregnant patients, evaluation
As per ESE 2021 guidelines:
Consider obtaining testing for a new diagnosis of Cushing's disease during pregnancy only in case of high clinical suspicion.
E
Obtain neuro-ophthalmologic evaluation in pregnant patients with pituitary adenomas impinging visual pathways or in case of suspected tumor progression or pituitary apoplexy. Obtain MRI without contrast in case of symptoms of tumor progression or apoplexy.
E

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  • Pregnant patients (management)

  • Pregnant patients (monitoring)

  • Pregnant patients (delivery and breastfeeding)

  • Patients with suspected cyclic CS

  • Patients with renal failure

  • Patients with epilepsy

  • Patients with life-threatening complications

Patient education

General counseling
As per ES 2015 guidelines:
Counsel patients on the nature of their disease, available treatment options, and what to expect after remission.
B
Provide education about adrenal insufficiency to hypocortisolemic patients.
A

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  • Preconception counseling

Preventative measures

Immunizations: as per ES 2015 guidelines, provide age-appropriate immunizations to patients with CS - particularly influenza, Herpes zoster, and pneumococcal immunizations - due to an increased risk of infection.
B

Follow-up and surveillance

Indications for specialist referral: as per ES 2008 guidelines, refer patients with a high pretest probability of CS in whom biochemical testing is negative for further evaluation by an endocrinologist.
B

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  • Clinical follow-up

  • Laboratory follow-up

  • Imaging follow-up

  • Endocrine follow-up

  • Management of recurrent disease