Full Guideline: Treatment of Cushing's Syndrome JCEM | August 2015
Lynnette K. Nieman (chair), Beverly M. K. Biller, James W. Findling, M. Hassan Murad, John Newell-Price, Martin O. Savage, and Antoine Tabarin
The 2015 guideline addresses:
Picking the optimal treatment to address the underlying cause (e.g., tumor removal)
Adjuctive management and treatment of cortisol-dependent comorbidities
The Endocrine Society recommends that the first-line treatment for endogenous Cushing’s syndrome be the removal of the tumor unless surgery is not possible or unlikely to address the excess cortisol. Surgical removal of the tumor is optimal because it leaves intact the hypothalamic-pituitary-adrenal axis, which is integral to the body’s central stress response.
Other recommendations from the CPG include:
Tumors should be removed by experienced surgeons in the following situations:
A tumor has formed on one or both of the two adrenal glands.
A tumor that secretes adrenocorticotropic hormone (ACTH) – the hormone that signals the adrenal glands to produce cortisol—has formed somewhere in the body other than the adrenal or pituitary gland.
A tumor has formed on the pituitary gland itself.
Patients who continue to have high levels of cortisol in the blood after surgery should undergo additional treatment.
People who had an ACTH-producing tumor should be screened regularly for the rest of their lives for high cortisol levels to spot recurrences.
If patients’ cortisol levels are too low following surgery, they should receive glucocorticoid replacement medications and be educated about adrenal insufficiency, a condition where the adrenal glands produce too little cortisol. This condition often resolves in 1-2 years.
Morning cortisol and/or ACTH stimulation tests, or insulin-induced hypoglycemia, can be used to test for the recovery of the hypothalamic-pituitary-adrenal axis in people who have low cortisol levels after surgery. Once the tests results return to normal, glucocorticoid replacement can be stopped.
People who have undergone pituitary surgery should be re-evaluated for other pituitary hormone deficiencies during the post-operative period.
Patients who have a pituitary tumor and have undergone surgery to remove both adrenal glands should be regularly evaluated for tumor progression using pituitary MRIs and tests for ACTH levels.
Radiation therapy may be used to treat a pituitary tumor, especially if it is growing. While awaiting the effect of radiation, which may take months to years, treatment with medication is advised.
To assess the effect of radiation therapy, the patient’s cortisol levels should be measured at 6- to 12-month intervals.
Medications may be used to control cortisol levels as a second-line treatment after surgery for a pituitary gland tumor, as a primary treatment for ACTH-secreting tumors that have spread to other parts of the body or suspected ACTH-secreting tumors that cannot be detected on scans. Medications also can be used as adjunctive treatment to reduce cortisol levels in people with adrenal cortical carcinoma, a rare condition where a cancerous growth develops in the adrenal gland.
People with Cushing’s syndrome should be treated for conditions associated with the disease, such as cardiovascular disease risk factors, osteoporosis and psychiatric symptoms.
Patients should be tested for recurrence throughout their lives except in cases where the person had a benign adrenal tumor removed.
Patients should undergo urgent treatment within 24 to 72 hours of detecting excess cortisol if life-threatening complications such as serious infection, pulmonary thromboembolism, cardiovascular complications and acute psychosis are present.
1.1 In patients with overt Cushing's syndrome (CS), we recommend normalizing cortisol levels or action at its receptors to eliminate the signs and symptoms of CS and treating comorbidities associated with hypercortisolism. (1|⊕⊕⊕⚪)
1.2 We recommend against treatment to reduce cortisol levels or action if there is not an established diagnosis of CS. (1|⊕⚪⚪⚪)
1.3 We suggest 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|⊕⚪⚪⚪)
2.1 We recommend providing education to patients and their family/caretaker(s) about their disease, treatment options, and what to expect after remission. (Ungraded best practice statement)
2.2 We recommend that all patients receive monitoring and adjunctive treatment for cortisol-dependent comorbidities (psychiatric disorders, diabetes, hypertension, hypokalemia, infections, dyslipidemia, osteoporosis, and poor physical fitness). (Ungraded best practice statement)
2.3 We recommend 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. (Ungraded best practice statement)
2.4 We suggest evaluating CS patients for risk factors of venous thrombosis. (2|⊕⊕⚪⚪)
2.5 In patients with CS undergoing surgery, we suggest perioperative prophylaxis for venous thromboembolism. (2|⊕⊕⚪⚪)
2.6 We recommend that clinicians discuss and offer age-appropriate vaccinations to CS patients—particularly influenza, Herpes zoster, and pneumococcal vaccinations—due to an increased risk of infection. (Ungraded best practice statement)
3.1 We recommend 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 is unlikely to significantly reduce glucocorticoid excess (Figure 1). (1|⊕⊕⊕⊕)
3.1a We recommend unilateral resection by an experienced adrenal surgeon for all cases of benign unilateral disease. (1|⊕⊕⊕⚪)
3.1b We recommend localizing and resecting ectopic ACTH-secreting tumors with node dissection as appropriate. (1|⊕⊕⊕⊕)
3.1c We recommend transsphenoidal selective adenomectomy (TSS) by an experienced pituitary surgeon as the optimal treatment for CD in pediatric and adult patients. (1|⊕⊕⊕⊕)
3.1ci We recommend measuring serum sodium several times during the first 5–14 days after transsphenoidal surgery. (1|⊕⊕⚪⚪)
3.1cii We recommend assessing free T4 and prolactin within 1–2 weeks of surgery, to evaluate for overt hypopituitarism. (1|⊕⊕⚪⚪)
3.1ciii We recommend obtaining a postoperative pituitary magnetic resonance imaging (MRI) scan within 1–3 months of successful TSS. (Ungraded best practice statement)
3.1d We recommend surgical resection of bilateral adrenal disorders (1|⊕⊕⚪⚪) and suggest medical therapy to block aberrant hormone receptors for bilateral macronodular adrenal hyperplasia (BMAH) (2|⊕⊕⚪⚪).
4.1 We suggest an individualized management approach based on whether the postoperative serum cortisol values categorize the patient's condition as hypocortisolism, hypercortisolism, or eucortisolism. (Ungraded best practice statement)
4.2 We recommend additional treatments in patients with persistent overt hypercortisolism. (1|⊕⊕⊕⊕)
4.3 We recommend 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|⊕⊕⚪⚪)
4.4 We recommend using tests to screen for hypercortisolism to assess for recurrence in patients with ACTH-dependent CS. (1|⊕⊕⊕⚪)
5.1 We recommend that hypocortisolemic patients receive glucocorticoid replacement and education about adrenal insufficiency after surgical remission. (1|⊕⊕⊕⊕)
5.2 We recommend 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. We also recommend discontinuing glucocorticoid when the response to these test(s) is normal. (1|⊕⊕⊕⚪)
5.3 We recommend re-evaluating the need for treatment of other pituitary hormone deficiencies in the postoperative period. (1|⊕⊕⊕⚪)
6.1 In patients with ACTH-dependent CS who underwent a noncurative surgery or for whom surgery was not possible, we suggest a shared decision-making approach because there are several available second-line therapies (eg, repeat transsphenoidal surgery, radiotherapy, medical therapy, and bilateral adrenalectomy). (2|⊕⊕⚪⚪)
6.1a We suggest bilateral adrenalectomy for occult or metastatic ectopic ACTH secretion (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|⊕⊕⊕⚪)
6.1b We recommend regularly evaluating for corticotrope 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 (because some of the latter have a pituitary and not ectopic tumor). (1|⊕⊕⊕⚪)
6.2 Repeat transsphenoidal surgery
6.2 We suggest repeat transsphenoidal surgery, particularly in patients with evidence of incomplete resection, or a pituitary lesion on imaging. (2|⊕⊕⚪⚪)
6.3 Radiation therapy/radiosurgery for CD
6.3 We recommend 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|⊕⚪⚪⚪)
6.3a We suggest RT/radiosurgery in patients who have failed TSS or have recurrent CD. (2|⊕⊕⚪⚪)
6.3b We recommend using RT where there are concerns about the mass effects or invasion associated with corticotroph adenomas. (1|⊕⊕⊕⚪)
6.3c We recommend measuring serum cortisol or urine free cortisol (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|⊕⊕⊕⚪)
6.4 Medical treatment
6.4 We recommend 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 EAS in patients with occult or metastatic EAS; and as adjunctive treatment to reduce cortisol levels in adrenocortical carcinoma (ACC). (1|⊕⊕⊕⚪)
6.4a We suggest pituitary-directed medical treatments in patients with CD who are not surgical candidates or who have persistent disease after TSS. (2|⊕⊕⊕⚪)
6.4b We suggest administering a glucocorticoid antagonist in patients with diabetes or glucose intolerance who are not surgical candidates or who have persistent disease after TSS. (2|⊕⊕⊕⚪)
6.4c We suggest targeted therapies to treat ectopic ACTH syndrome. (2|⊕⚪⚪⚪)
7.1 We recommend treating the specific comorbidities associated with CS (eg, cardiovascular risk factors, osteoporosis and psychiatric symptoms) in all patients with CS throughout their lives until resolution (Figure 1). We also recommend testing for recurrence throughout life, except in patients who underwent resection of an adrenal adenoma with a computerized tomography (CT) density of < 10 Hounsfield units. (1|⊕⊕⊕⚪)
7.2 We recommend educating patients and families about the clinical features of remission. (Ungraded best practice statement)
7.3 In patients with adrenal adenoma, we suggest follow-up tests for the specific comorbidities associated with CS if the adenoma density on CT was < 10 Hounsfield units. (2|⊕⊕⚪⚪) For those with higher Hounsfield unit values or pathology consistent with possible carcinoma, we suggest evaluating for malignancy using imaging. (2|⊕⚪⚪⚪)
7.4 We recommend that patients with Carney complex have lifelong follow-up tests for cardiac myxoma and other associated disease (testicular tumors, acromegaly, thyroid lesions). (1|⊕⊕⊕⊕)
8.1 We recommend urgent treatment (within 24–72 h) of hypercortisolism if life-threatening complications of CS such as infection, pulmonary thromboembolism, cardiovascular complications, and acute psychosis are present. (1|⊕⊕⊕⚪). The associated disorder(s) should be addressed as well (eg, anticoagulation, antibiotics).