Cushing's Syndrome: Rapid Evidence Review

Cushing's syndrome is a multifaceted and progressive disease caused by chronic exposure to excessive levels of cortisol from iatrogenic or internal sources.^1–10 Exogenous (iatrogenic) Cushing's syndrome, which is caused by the administration of glucocorticoids, is the most common form and must be ruled out.^2,4,6–11 Endogenous Cushing's syndrome is classified as adrenocorticotropic hormone (ACTH) dependent (80% to 85% of cases) or ACTH independent (15% to 20% of cases; Table 1^{1,2,8,10,12–15}). Most cases (75% to 80%) are caused by Cushing's disease, which features a pituitary adenoma excessively secreting ACTH.^2,7,10,11 Endogenous Cushing's syndrome can also be caused by ectopic ACTH syndrome, which results from tumors that excessively produce ACTH (15% to 20% of cases) or corticotropin-releasing hormone (less than 1% of cases).^2,10

ACTH-independent Cushing's syndrome is caused by unilateral adrenal tumors (90% of cases), adrenocortical adenocarcinoma, and, rarely, primary bilateral macronodular adrenal hyperplasia, primary pigmented nodular adrenocortical disease, or McCune-Albright syndrome.^2,10 Endogenous Cushing's syndrome can also present in a cyclical form with fluctuating symptoms. Another form of the disease, pseudo–Cushing's syndrome, results from an activated hypothalamic-pituitary-adrenal axis secondary to multiple common conditions (e.g., alcohol use disorder, obesity, uncontrolled diabetes mellitus, psychiatric conditions, polycystic ovary syndrome).^2,7,10

This article offers a concise overview of diagnostic considerations, current testing guidelines, medical and surgical treatment, radiotherapy, comorbid conditions, and posttreatment follow-up.

1. The estimated annual incidence of endogenous Cushing's syndrome is 2 to 8 cases per million in the United States.^{2 , 10} The actual incidence is probably higher due to an underestimation of ectopic ACTH-producing tumors.^{10 , 16 , 17}
2. Prevalence varies across different populations, with a global range of 39 to 79 cases per million.^{2 , 9 , 17}
3. In children, the annual incidence is 1 to 1.5 cases per million, with Cushing's disease accounting for 75% to 80% of new cases.^{18 – 20} Each year, 10% of all new Cushing's syndrome cases occur in children.^{18 , 20}
4. Females are affected 3 to 4 times more often than males. Ectopic Cushing's syndrome affects males and females at a similar rate.^{2 , 9 , 10}
5. The median age of patients is 41.4 years.^{6 , 7}
6. Patients with hypertension, uncontrolled diabetes, and early-onset osteoporosis have an increased, but variable, prevalence of Cushing's syndrome estimated between 0.5% and 9.0%.^{2 , 4 , 7 , 12 , 21}

1. The Endocrine Society recommends screening for Cushing's syndrome in patients with any of the following features^{1 , 3 , 4 , 8 , 13 , 22}: º Weight gain and central redistribution of fat (increased fat in abdomen, dorsocervical/supraclavicular area, and face)

º Multiple progressive signs and symptoms of the condition (Table 2^{1 , 2 , 7 , 8 , 10 – 13 , 21 , 23})

º In adults, unusual symptoms for the patient's age (e.g., uncontrolled hypertension or osteoporosis in younger adults)

º In children, growth restriction (decreasing height percentile and increasing weight)

º Adrenal incidentaloma consistent with adenoma

1. One study of patients referred to a tertiary center over a 10-year period found the following⁴: º About 73% of new cases had symptoms consistent with the Endocrine Society screening criteria.

º A body mass index greater than 30 kg per m² was a negative predictor of Cushing's syndrome, but recent weight gain (17 of 89 patients) was relatively common in patients with newly diagnosed Cushing's syndrome.

º Patients with myopathy, metabolic syndrome, osteoporosis, adrenal incidentaloma, or multiple symptoms specific to Cushing's syndrome were more likely to be diagnosed with Cushing's syndrome.

º Obesity as the chief symptom did not increase the likelihood of diagnosis. The authors of the study concluded that widespread screening of patients who are chronically overweight or have hypertension is generally not recommended.^{2 , 4 , 8 , 10}

1. Diagnosis often occurs after 2 to 5 years due to the insidious nature of the disease, delayed presentation by the patient, and evaluation by an average of four physicians before confirmation of the diagnosis.^{1 , 2 , 7 , 12 , 13 , 24}
2. A high index of suspicion is key to recognizing signs and symptoms that are insidious and progressive along with conditions that are uncontrolled, present with uncommon features at an unanticipated age, or do not fit with a particular clinical scenario.^{1 , 7 , 8 , 10 , 12 – 15 , 23 – 26}
3. The differential diagnosis of hypercortisolism includes: º Exogenous glucocorticoid use (e.g., prescription and over-the-counter medications, including oral, inhaled, injectable [intrathecal, epidural, intra-articular], ocular, and topical drugs)^{8 , 14 , 15 , 18 , 25}

º ACTH-dependent conditions: Cushing's disease, ectopic ACTH syndrome (small cell carcinoma, pulmonary carcinoid tumor, pancreatic or thymic neuroendocrine tumor, gastrinoma, medullary thyroid cancer, and pheochromocytoma), and ectopic tumor that secretes corticotropin-releasing hormone^{2 , 10}

º ACTH-independent conditions: adrenal adenoma, primary bilateral macronodular adrenal hyperplasia, primary pigmented nodular adrenocortical disease, adrenal carcinoma, and McCune-Albright syndrome^{2 , 10}

º Pseudo–Cushing's syndrome: usually mild and associated with several common conditions; the underlying cause should be treated and patient retested for hypercortisolism^{2 , 7 , 10}

º Cyclic Cushing's syndrome: features fluctuating symptoms; the patient should be retested during symptomatic phase^{2 , 7 , 10}

1. Signs and symptoms that should prompt consideration of Cushing's syndrome include proximal muscle weakness, osteoporosis or bone fractures and thin skin at an early age, cognitive and mood changes, recent weight gain with central distribution, easy bruising, purple striae greater than 1 cm (Figure 1¹¹), or uncontrolled diabetes and hypertension at a young age. Menstrual irregularities are also common.^{1 , 2 , 4 , 7 , 8 , 10 , 14 , 15 , 21 , 23 , 26}

1. To confirm the diagnosis of Cushing's syndrome, physicians must confirm hypercortisolism and determine its source (Figure 2^{1 , 2 , 7 – 10 , 14 , 15 , 25 , 27 – 33}).
2. First-line screening comprises 24-hour urinary free cortisol, late-night salivary cortisol, and 1-mg dexamethasone suppression tests (Table 3^{1 – 4 , 7 , 8 , 10 , 14 , 15 , 21 , 27 , 28}).
3. When two different tests demonstrate elevated cortisol levels in a patient with a high probability for Cushing's syndrome, the diagnosis is confirmed; typically, two negative test results exclude a diagnosis of Cushing's syndrome. Reevaluation with a different test might be indicated based on the clinical course.^{1 , 2 , 7 , 8 , 10}
4. A dexamethasone suppression test is the preferred initial test if an adrenal tumor is suspected and for patients who work night shifts or have a disrupted circadian rhythm.^{1 , 7 , 10} Patients with adrenal disease usually do not have high levels of salivary or urinary cortisol; patients who work night shifts or have a disrupted circadian rhythm may have high cortisol levels at night.^{1 , 7}
5. Urinary free cortisol and late-night salivary cortisol tests require at least two or three separate collections due to variation in consecutive test results in up to one-half of patients.^{1 – 3 , 7 , 8 , 10 , 14 , 27 , 28}
6. Dexamethasone suppression and late-night salivary cortisol tests have the highest sensitivity, and the late-night salivary cortisol test is the most specific. A negative 1-mg dexamethasone suppression test strongly predicts the absence of Cushing's syndrome.^{1 – 3 , 25 , 27 , 28}
7. After confirmation of hypercortisolism, plasma ACTH measurement is used to determine whether the cause is ACTH dependent or ACTH independent (Figure 2).^{1 , 2 , 7 – 10 , 14 , 15 , 25 , 27 – 33}
8. When ACTH is low (due to an ACTH-independent cause), adrenal computed tomography or magnetic resonance imaging should be performed to identify unilateral or bilateral adrenal causes.^{1 , 3 , 10 , 29 – 32}
9. When ACTH is normal or high (due to an ACTH-dependent cause), pituitary magnetic resonance imaging should be performed to confirm Cushing's disease caused by an adenoma.^{2 , 8 , 9 , 30}
10. If an adenoma at least 6 mm in diameter is not seen, whole-body computed tomography should be performed with either inferior petrosal sinus sampling or a corticotropin-releasing hormone/desmopressin test to differentiate Cushing's disease from ectopic ACTH syndrome.^{2 , 8 , 9 , 15 , 30} Inferior petrosal sinus sampling is considered the diagnostic standard to differentiate Cushing's disease from ectopic ACTH syndrome.^{2 , 8 , 9 , 30}

1. Due to the complexity of diagnosing and managing Cushing's syndrome, the Endocrine Society recommends referral to a specialized center after confirmation of hypercortisolism.
2. Specific challenges include the constellation and overlapping of symptoms with common conditions, its potentially cyclical nature, difficulty with the interpretation of laboratory and imaging test results, the need for experienced surgeons, and the requirement of lifelong monitoring by an experienced multi-disciplinary team.^{1 , 3 , 9 , 32}
3. Family physicians have an important role in recognizing the symptoms of Cushing's syndrome, ordering initial tests, referring to appropriate specialists, and following up with patients and their families.

1. The definitive treatment for any form of Cushing's syndrome is surgery.^{1 – 3 , 7 , 8 , 10 , 33}
2. When transsphenoidal surgery for Cushing's disease is performed by an experienced pituitary surgeon, the rate of remission (cortisol less than 55 nmol per L) is approximately 80% for microadenomas and 60% for macroadenomas.^{1 – 3 , 7 , 8 , 10 , 33}
3. Minimally invasive laparoscopy is preferred for unilateral adrenal adenomas, and bilateral adrenalectomy is preferred for primary bilateral macronodular adrenal hyperplasia and primary pigmented nodular adrenal disease.^{1 , 3 , 10 , 33}
4. Cancerous lesions are removed by open adrenalectomy.^{1 , 3 , 10 , 33}
5. Glucocorticoids are necessary until the hypothalamic-pituitary-adrenal axis returns to normal function.^{1 , 3 , 7 , 10 , 33}

1. Medications are second-line therapy for Cushing's syndrome. They are indicated when a patient declines surgery, is not a surgical candidate, or has persistent or recurrent Cushing's disease after transsphenoidal surgery. They can also be used for pretreatment if surgery is delayed.^{1 , 3 , 9 , 10 , 34 – 39}
2. Limited effectiveness, a lack of measurable markers to predict the response to drug therapy, significant adverse effects, and high discontinuation rates by patients are areas of concern.^{1 , 10 , 34 – 39}
3. Steroidogenesis inhibitors, pituitary-directed drugs, and glucocorticoid receptor antagonists are the main drug classes (Table 4^{1 , 3 , 7 , 8 , 10 , 11 , 34 – 39}).
4. Ketoconazole, osilodrostat (Isturisa), and metyrapone (Metopirone) are typically preferred as initial therapy due to their effectiveness.^{1 , 3 , 10 , 34 – 39}
5. Radiotherapy is indicated as adjuvant therapy for patients with aggressive tumor growth or persistent or recurrent disease after transsphenoidal surgery.^{1 – 3 , 10 , 33}

1. Cushing's syndrome adversely affects quality of life.^{1 – 3 , 40 – 44}
2. The presence of two or more postoperative comorbidities predicts poor quality of life.^{40 – 43} Cognitive changes, mental health issues, and other conditions, alone or in combination, affect the patient's appearance, socialization skills, school performance, and ability to work (Table 5^{1 – 8 , 10 , 13 , 38 – 44}).
3. Patient and family education, counseling, and treatment for each cognitive, psychiatric, and medical condition are essential to provide the best chance for recovery.^{40 – 44}
4. Diet, exercise, and weight loss may help improve self-image, energy level, mental outlook, sleep, and family life.^{40 – 44} Retraining might help patients reenter the workforce.

1. Recurrence rates vary widely between 5% and 35%. After surgery, approximately one-half of recurrences happen within 5 years.^{1 , 10}
2. Mortality is not substantially improved after treatment.^{1 , 3 – 7 , 10 , 44}
3. Cardiovascular and cerebrovascular events, diabetes, hyperlipidemia, hypertension, infections, and venous thromboembolism are major causes of morbidity and mortality.^{1 , 3 , 5 , 10 , 44}
4. In children, growth and development are affected.¹⁸
5. Lifelong monitoring by a multidisciplinary team is necessary. Monitoring should begin once the hypothalamic-pituitary-adrenal axis is restored and annually thereafter.^{1 – 4 , 10 , 15 , 40 – 44}