- Treatment of Cushing’s syndrome (CS) is essential to reduce mortality and associated comorbidities.
- Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities via directly treating the cause of CS and by adjunctive treatments (e.g., antihypertensives).
- Surgical resection of the causal lesion(s) is generally the first-line approach.
- The choice of second-line treatments, including medication, bilateral adrenalectomy, and RT (for corticotroph tumors), must be individualized to each patient.
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|⊕⊕⊕o)
- ES recommends against treatment to reduce cortisol levels or action if there is not an established diagnosis of CS. (1|⊕ooo)
- 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|⊕ooo)
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. (US)
- 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). (US)
- 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. (US)
- ES suggests evaluating CS patients for risk factors for venous thrombosis. (2|⊕⊕oo)
- In patients with CS undergoing surgery, ES suggests perioperative prophylaxis for venous thromboembolism. (2|⊕⊕oo)
- 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. (US)
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|⊕⊕⊕⊕)
- ES recommends unilateral resection by an experienced adrenal surgeon for all cases of benign unilateral disease. (1|⊕⊕⊕o)
- ES recommends localizing and resecting ectopic ACTH-secreting tumors with node dissection as appropriate. (1|⊕⊕⊕⊕)
- ES recommends transsphenoidal selective adenomectomy (TSS) by an experienced pituitary surgeon as the optimal treatment for CD in pediatric and adult patients. (1|⊕⊕⊕⊕)
- ES recommends measuring serum sodium several times during the first 5–14 days after transsphenoidal surgery. (1|⊕⊕oo)
- ES recommends assessing free thyroxine and prolactin within 1–2 weeks of surgery, to evaluate for overt hypopituitarism. (1|⊕⊕oo)
- ES recommends obtaining a postoperative pituitary MRI within 1–3 months of successful TSS. (US)
- ES recommends surgical resection of bilateral adrenal disorders (1|⊕⊕oo), and suggest medical therapy to block aberrant hormone receptors for bilateral macronodular adrenal hyperplasia (BMAH) (2|⊕⊕oo).
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. (US)
- ES recommends additional treatments in patients with persistent overt hypercortisolism. (1|⊕⊕⊕⊕)
- ES 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|⊕⊕oo)
- ES recommends using tests to screen for hypercortisolism to assess for recurrence in patients with ACTH-dependent CS. (1|⊕⊕⊕o)
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|⊕⊕⊕⊕)
- 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|⊕⊕⊕o)
- ES recommends re-evaluating the need for treatment of other pituitary hormone deficiencies in the postoperative period. (1|⊕⊕⊕o)
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|⊕⊕oo)
- 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|⊕⊕⊕o)
- 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|⊕⊕⊕o)
Repeat Transsphenoidal Surgery
- ES suggests repeat transsphenoidal surgery, particularly in patients with evidence of incomplete resection or a pituitary lesion on imaging. (2|⊕⊕oo)
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|⊕ooo)
- ES suggests RT/radiosurgery in patients who have failed TSS or have recurrent CD. (2|⊕⊕oo)
- ES recommends using RT where there are concerns about the mass effects or invasion associated with corticotroph adenomas. (1|⊕⊕⊕o)
- 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|⊕⊕⊕o)
- 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|⊕⊕⊕o)
- ES suggests pituitary-directed medical treatments in patients with CD who are not surgical candidates or who have persistent disease after TSS. (2|⊕⊕⊕o)
- 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|⊕⊕⊕o)
- 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|⊕⊕⊕o).
- 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|⊕⊕⊕o)
- ES recommends educating patients and families about the clinical features of remission. (US)
- 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|⊕⊕oo) For those with higher Hounsfield unit values or pathology consistent with possible carcinoma, ES suggests evaluating for malignancy using imaging. (2|⊕ooo)
- 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|⊕⊕⊕⊕)
Table 1. Medical Treatment of Cushing’s Syndrome
|Ketoconazoleb||Quick onset of action||Adverse effects: GI, hepatic dyscrasia|
(death), male hypogonadism; requires acid for biologic
|Metyraponeb||Quick onset of action||Adverse effects: GI, hirsutism, HT,|
hypokalemia; accessibility variable across countries
|500 mg–6 g/d;|
|Mitotanec||Adrenolytic; approved for adrenal cancer||Slow onset action; lipophilic/long|
half life, teratogenic
Adverse effects: GI and CNS,
gynecomastia, low WBC and T4, ↑LFTs; ↑CBG, DDIs
|Starting dose 250 mg;|
500 mg–8 g/d
|Etomidate||Intravenous, quick onset of action||Requires monitoring in ICU||Bolus and titrate|
|Cabergoline||Adverse effects: asthenia, GI, dizziness||1–7 mg/week|
|Pasireotided||Most successful when UFC <2-fold normal; subcutaneous |
Adverse effects: diarrhea, nausea, cholelithiasis,
hyperglycemia, transient ↑LFTs; ↑QTc interval
|600–900 mcg bid|
|Mifepristonee||Difficult to titrate (no biomarker); abortifacient|
Adverse effects: fatigue, nausea,
vomiting, arthralgias, headache, hypertension, hypokalemia,
edema, endometrial thickening
|a Except as noted, the lowest dose may be used initially, unless the patient has severe hypercortisolism (UFC >5-times normal), in which case the starting dose may be doubled.|
b Ketoconazole and metyrapone are approved by the EMA for the treatment of CS.
c Mitotane has FDA approval for treatment of adrenal cancer.
d Pasireotide has FDA approval for treatment of patients with CD who are not surgical candidates or have failed surgery. The agent is approved in Europe also.
e Mifepristone has FDA approval for treatment of patients with CS and diabetes or glucose intolerance who are not surgical candidates or have failed surgery.
Other treatments listed here represent off-label uses.