Am Fam Physician. 2024;110(3):270-280
Author disclosure: No relevant financial relationships.
Cushing's syndrome is a rare, multisystemic disease caused by chronic exposure to supraphysiologic levels of cortisol. Prolonged hypercortisolism is associated with significant multisystem morbidity and mortality and decreased quality of life. Diagnosis of Cushing's syndrome is often delayed by several years due to its insidiously progressive course, diverse clinical presentation, overlap of symptoms with many common conditions, and testing complexity. Exogenous glucocorticoid use must be excluded as the primary etiology. Excessive endogenous cortisol production can be caused by an overproduction of adrenocorticotropic hormone (ACTH) through pituitary tumors or ectopic sources (ACTH-dependent cases), or it can be caused by autonomous cortisol overproduction by the adrenal glands (ACTH-independent cases). The recommended diagnostic approach includes appropriate screening, confirmation of hypercortisolism, and determination of etiology. First-line treatment is surgical removal of the source of cortisol overproduction. Lifelong posttherapy monitoring is required to treat comorbidities and detect recurrence.
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 11,2,8,10,12–15). 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
| In a 2022 study of 89 patients referred to a tertiary center over a 10-year period, myopathy, metabolic syndrome, osteoporosis, adrenal incidentaloma, and the presence of multiple Cushing's syndrome–specific symptoms increased the likelihood of Cushing's syndrome being diagnosed, whereas obesity as the chief symptom did not. |
| If transsphenoidal surgery is performed by an experienced surgeon, the remission rate is approximately 80% for microadenomas and 60% for macroadenomas. |
| One-half of recurrences happen within 5 years after surgery. |
| ACTH dependent (80% to 85% of cases) | ACTH independent (15% to 20% of cases) | Pseudo–Cushing's syndrome* | ||
|---|---|---|---|---|
| Etiology | Cushing's disease (75% to 80% of cases) | Ectopic ACTH syndrome (15% to 20% of cases) | Adrenal adenoma (90% of cases) | Activation of hypothalamic-pituitary-adrenal axis |
| Associated conditions† | Pituitary adenoma | Small cell lung cancer, pulmonary carcinoid tumor, pancreatic or thymic neuroendocrine tumor, gastrinoma, medullary thyroid cancer, pheochromocytoma; most tumors are in the chest Ectopic tumor that secretes corticotropin-releasing hormone (< 1%)‡ | Adrenal carcinoma (1% of cases), primary bilateral macronodular adrenal hyperplasia (< 2% of cases), primary pigmented nodular adrenocortical disease (< 2% of cases), McCune-Albright syndrome (< 2% of cases) | Obesity Poorly controlled diabetes mellitus Obstructive sleep apnea Alcohol use disorder Polycystic ovary syndrome Psychiatric conditions Physical stress (due to hospitalization, severe illness, pain, or surgery) Pregnancy Malnutrition Anorexia nervosa Excessive exercise Hypothalamic amenorrhea High corticosteroid-binding globulin level Glucocorticoid resistance |
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.
EPIDEMIOLOGY
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
Prevalence varies across different populations, with a global range of 39 to 79 cases per million.2,9,17
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
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
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
SCREENING
The Endocrine Society recommends screening for Cushing's syndrome in patients with any of the following features1,3,4,8,13,22:
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 21,2,7,8,10–13,21,23)
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
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
| General clues Use of exogenous steroids Multiple unexplained symptoms that are not consistent with a particular diagnosis Diagnosis uncommon for patient's age Symptoms that are prolonged and progressing Conditions associated with pseudo–Cushing's syndrome Symptoms that fluctuate Multiple physician office visits for the same or worsening symptom Deteriorated personal relationships or work performance Strained family relationships Appearance Change in appearance Rounded face (moon face; 81% to 90% of cases), facial plethora* (70% to 90% of cases), alopecia (75% of cases), acne (20% to 35% of cases), hirsutism (75% of cases), hypertrichosis on forehead Weight gain* (70% to 95% of cases): abdominal obesity; adipose tissue in temporal, dorsocervical, and supraclavicular areas; buffalo hump in 50% of cases Thin skin* (patients younger than 40 years), purple striae wider than 1 cm* (44% to 50% of cases), frequent fungal skin infections Easy or increased bruising* (35% to 65% of cases), poor wound healing Hyperpigmentation (perioral, buccal, and vaginal areas; over joints and scars) Cardiovascular Hypertension (70% to 85% of cases), dyslipidemia (70% of cases), edema, pulmonary embolism (4% of cases) Increased incidence of dilated cardiomyopathy, left ventricular hypertrophy, and myocardial infarction Uncontrolled hypertension in patients younger than 40 years with a negative evaluation for more common secondary causes* Renal Increased nephrolithiasis (21% to 50% of cases) Reproductive Delayed puberty, hypogonadism, decreased libido (24% to 80% of cases) Menstrual irregularity (70% to 80% of cases), infertility Abnormal uterine bleeding or worsening symptoms of polycystic ovary syndrome Systemic Fatigue, weakness (60% of cases), sleep disorder (60% of cases) In children, weight gain without concomitant vertical growth In children, decreased linear growth (70% to 80% of cases) Worsening bone loss, myopathy, or memory deficits (growth hormone deficiency) | Cognitive Decreased brain volume (hippocampus) Decreased cognitive ability; deficits in memory, verbal learning, spatial information, language, and executive function (70% to 85% of cases) Immunologic Immunosuppression resulting in increased opportunistic infections and sepsis Metabolic Glucose intolerance (45% to 70% of cases), insulin resistance (diabetes mellitus: 20% to 47% of cases) Uncontrolled diabetes mellitus at unexpectedly young age* Musculoskeletal Proximal muscle weakness* (e.g., difficulty climbing stairs, getting out of a chair, or straightening up) and atrophy (60% to 82% of cases) Decreased bone mineral density, osteopenia, and fracture (40% to 70% of cases) Osteoporosis or fracture at young age* Nervous Increased incidence of cerebrovascular accidents Mass effect, which can include visual field defects (18% to 78% of cases), headache (17% to 75% of cases), and anterior hypopituitarism (34% to 89% of cases), due to adenomas larger than 10 mm in greatest diameter (macroadenomas) Ophthalmologic Exophthalmos, cataracts, glaucoma, central serous chorioretinopathy Psychiatric Personality changes, new or worsening psychiatric disorder Increased irritability, anxiety, depression, mood disorder, psychosis, mania, or vivid dreams (70% to 85% of cases) Fatigue, weakness, edema, puffy face and hands, dry skin (central hypothyroidism) Symptoms that affect more than one system Problems smelling or tasting Laboratory Hypokalemia, hyperglycemia, elevated liver enzymes, hypercalciuria Increased triglycerides and total cholesterol levels Abnormal clotting study results (hypercoagulable state due to activated coagulation and impaired fibrinolysis) Increased leukocyte levels and decreased lymphocyte, eosinophil, monocyte, and basophil levels |
DIAGNOSIS
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
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
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 hormone2,10
º ACTH-independent conditions: adrenal adenoma, primary bilateral macronodular adrenal hyperplasia, primary pigmented nodular adrenocortical disease, adrenal carcinoma, and McCune-Albright syndrome2,10
º Pseudo–Cushing's syndrome: usually mild and associated with several common conditions; the underlying cause should be treated and patient retested for hypercortisolism2,7,10
º Cyclic Cushing's syndrome: features fluctuating symptoms; the patient should be retested during symptomatic phase2,7,10
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
DIAGNOSTIC TESTING
To confirm the diagnosis of Cushing's syndrome, physicians must confirm hypercortisolism and determine its source (Figure 21,2,7–10,14,15,25,27–33).
First-line screening comprises 24-hour urinary free cortisol, late-night salivary cortisol, and 1-mg dexamethasone suppression tests (Table 31–4,7,8,10,14,15,21,27,28).
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
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
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
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
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
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
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
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
| Test | Method | Causes of false positives | Causes of false negatives |
|---|---|---|---|
| 1-mg DST (85% to 90% sensitivity; 95% to 99% specificity) | Administer oral dexamethasone at 11 p.m., then measure plasma cortisol the next morning between 8 and 9 a.m.; accuracy can be improved by measuring both cortisol and dexamethasone levels | Increased gut transit time (e.g., celiac disease, chronic diarrhea) Drugs increasing dexamethasone metabolism by CYP3A4 enzyme (e.g., barbiturates, carbamazepine, phenytoin, St. John's wort) Elevated corticosteroid-binding globulin level (caused by estrogen, pregnancy, or chronic hepatitis) Pseudo–Cushing's syndrome | Impaired liver or kidney function (glomerular filtration rate < 60 mL per minute per 1.73 m2) Drugs inhibiting dexamethasone metabolism by CYP3A4 enzyme (e.g., cimetidine, diltiazem, fluoxetine, itraconazole, ritonavir) Decreased albumin or corticosteroid-binding globulin level, as seen in nephrotic syndrome |
| 24-hour UFC test (80% to 98% sensitivity; 45% to 98% specificity) | Collect urine for 24 hours, starting in the morning after voiding and finishing the next morning after the first voided urine Measure cortisol and creatinine Perform test two or three times due to test variability in one-half of patients | Incorrect collection Fluid intake > 5 L per day Pregnancy Pseudo–Cushing's syndrome Carbamazepine or fenofibrate (Tricor) use Inhibition of cross reactivity with metabolites or synthetic glucocorticoids by the 11-beta hydroxysteroid dehydrogenase type 2 enzyme (due to licorice, carbenoxolone, or other drugs) | Incorrect collection Impaired kidney function (glomerular filtration rate < 60 mL per minute per 1.73 m2) Mild Cushing's syndrome |
| LNSC test (92% to 100% sensitivity; 93% to 100% specificity) | Collect salivary cortisol with a cotton swab at 11 p.m. before the patient goes to bed Chewing tobacco, brushing teeth, and smoking must be avoided before collecting the sample Perform test two to three times to ensure accuracy | Incorrect collection Nocturnal or shift workers Inhibition of the 11-beta hydroxysteroid dehydrogenase type 2 enzyme (due to licorice, carbenoxolone, or other drugs) Blood contamination Oral diseases | Incorrect collection |
TREATMENT
Due to the complexity of diagnosing and managing Cushing's syndrome, the Endocrine Society recommends referral to a specialized center after confirmation of hypercortisolism.
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
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.
SURGICAL THERAPY
The definitive treatment for any form of Cushing's syndrome is surgery.1–3,7,8,10,33
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
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
Cancerous lesions are removed by open adrenalectomy.1,3,10,33
Glucocorticoids are necessary until the hypothalamic-pituitary-adrenal axis returns to normal function.1,3,7,10,33
DRUG THERAPY
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
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
Steroidogenesis inhibitors, pituitary-directed drugs, and glucocorticoid receptor antagonists are the main drug classes (Table 41,3,7,8,10,11,34–39).
Ketoconazole, osilodrostat (Isturisa), and metyrapone (Metopirone) are typically preferred as initial therapy due to their effectiveness.1,3,10,34–39
Radiotherapy is indicated as adjuvant therapy for patients with aggressive tumor growth or persistent or recurrent disease after transsphenoidal surgery.1–3,10,33
| Indications for medical treatment: Patient declines surgery, is not a surgical candidate (due to high risk or unresectable or metastatic tumor), or has persistent or recurrent Cushing's disease after transsphenoidal surgery; if surgery is delayed, medication can be used for pretreatment Acute complications of hypercortisolism (e.g., psychosis, infection) Awaiting response to radiotherapy Hypercortisolism due to occult ectopic adrenocorticotropic hormone–producing neuroendocrine tumor | ||
| Drug | Dosage | Adverse effects |
| Steroidogenesis inhibitors* | ||
| Ketoconazole | 400 to 1,600 mg per day | Hepatotoxicity (15% of cases), adrenal insufficiency (20% of cases), gastrointestinal upset, hypogonadism, QT prolongation |
| Levoketoconazole (Recorlev) | 300 to 1,200 mg per day (investigational treatment) | Hepatotoxicity, gastrointestinal upset, QT prolongation (2.1% of cases) |
| Metyrapone (Metopirone) | 500 to 600 mg per day | Hirsutism (36% of cases), hypokalemia, adrenal insufficiency (12% of cases), nausea, headache |
| Osilodrostat (Isturisa) | 4 to 14 mg per day | Nausea (42% of cases), headache (34% of cases), hirsutism, acne, hypertrichosis, QT prolongation, hypertension, pituitary tumor enlargement |
| Etomidate (Amidate) | 0.02 to 0.1 mg per kg per hour | Adrenal insufficiency, sedation, propylene glycol toxicity, rapid onset of action |
| Mitotane (Lysodren) | 2,000 to 6,000 mg, divided, three or four times per day; plasma levels must be monitored for dose adjustment | Gastrointestinal disturbances, dizziness, cognitive alterations, hepatotoxicity, adrenal insufficiency, slow onset of action. Potentially hazardous drug; caregiver should wear gloves and patient should be monitored for adrenal insufficiency, adrenal crisis, and neurotoxicity |
| Pituitary-directed therapies | ||
| Somatostatin receptor ligands | ||
| Pasireotide (Signifor) | 300 to 1,800 mcg per day; intensive care unit use | Hyperglycemia (73% of cases), gallstones (20% of cases), adrenal insufficiency (2% of cases), prolonged QT |
| Pasireotide LAR (Signifor LAR) | 10 to 14 mg per month | Hyperglycemia (48% of cases), gallstones (15% to 45% of cases), diabetes mellitus, nausea |
| Dopamine receptor agonists | ||
| Cabergoline | 0.5 to 7 mg per week | Dizziness (14% of cases), dyspepsia, nausea, alopecia, hypotension, abdominal pain, muscle pain (2% of cases) |
| Glucocorticoid receptor antagonist | ||
| Mifepristone | 300 to 1,200 mg per day | Hypokalemia (44% of cases), endometrial thickening, cytochrome P450 3A4 inhibition, abnormal thyroid function |
LIFESTYLE AND BEHAVIOR MODIFICATIONS
Cushing's syndrome adversely affects quality of life.1–3,40–44
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 51–8,10,13,38–44).
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
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.
| Symptoms that can affect a patient's appearance and potentially impact social relationships, school performance, or ability to work Acne Central obesity Easy bruising Facial plethora Growth retardation Hirsutism Poor wound healing Purple striae Recent weight gain Supraclavicular fat accumulation Ulcerations Clinical problems with systemic effects that can potentially affect social relationships, school performance, or ability to work Atherosclerotic cardiovascular disease Central hypothyroidism Decreased bone mass Diabetes mellitus Dyslipidemia Fatigue Growth hormone deficiency | Hypercoagulopathy Hypertension Hypogonadism Menstrual or libido disturbances Myopathy Sleep disturbances Vascular disease Psychological problems that can potentially affect social relationships, school performance, or ability to work Anxiety Apathy Cognitive decline Depression Emotional lability Suicidal ideation Comorbid conditions that affect morbidity and increase mortality by 3.5- to 5-fold Cardiovascular conditions (4.5-fold increased risk of myocardial infarction) Infection Thromboembolism (10-fold increased risk) |
PROGNOSIS
Recurrence rates vary widely between 5% and 35%. After surgery, approximately one-half of recurrences happen within 5 years.1,10
Mortality is not substantially improved after treatment.1,3–7,10,44
Cardiovascular and cerebrovascular events, diabetes, hyperlipidemia, hypertension, infections, and venous thromboembolism are major causes of morbidity and mortality.1,3,5,10,44
In children, growth and development are affected.18
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
This article updates a previous article on this topic by Kirk, et al.11
Data Sources: An online search was conducted using the key terms Cushing’s syndrome, Cushing’s disease, pseudo–Cushing’s syndrome, cyclic Cushing’s syndrome, ectopic Cushing’s syndrome, hypercortisolism, glucocorticoids, risk factors for Cushing’s syndrome, endogenous hypercortisolism, exogenous glucocorticoids, treatment, comorbidities, hypercortisolism causes and effects, morbidity, mortality, complications, prognosis, medications, surgical and medical treatment, radiation therapy, complications, coinfections and morbidity, Endocrine Society guidelines, screening tests, pituitary tumors, incidental pituitary tumors, quality of life, adrenal tumors, guidelines from the Centers for Disease Control and Prevention (CDC) and the U.S. Preventive Services Task Force (USPSTF), diagnostic methods, complimentary therapy, follow-up after treatment, cost, when to refer, family medicine’s role, and interdisciplinary team. The evidence summary sent by the AFP medical editor was used. A broad-based overview of the topic was done on national websites such as the Agency for Healthcare Research and Quality (AHRQ), Cushing’s syndrome guidelines, the Endocrine Society, ClinicalTrials.gov, Endocrine.org, National Guideline Clearinghouse, PubMed, the CDC, and the USPSTF. After the background reading, the search was refined to identify major scholarly and professional resources using the following databases: CDC, National Guideline Clearinghouse, PubMed, the Cochrane database, OVID, the USPSTF recommendation database, as well as the AHRQ evidence reports. Search dates: August 1 to November 9, 2023, and July 2024.
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army, the U.S. Department of Defense, or the U.S. government.
