UNDERSTANDING CUSHING’S SYNDROME

Diagnosis & Treatment

Early diagnosis is key to helping address Cushing’s syndrome (CS), potentially improving symptoms and quality of life1

Diagnosis of CS is often delayed because it can take years after onset for noticeable signs and symptoms to appear.2,3

Diagnosis can often be delayed for years2

The mean time to diagnosis for CS is reported as 34 months, but can vary by subtype.4

ACTH-Dependent

  • Cushing’s disease: 38 months
  • Ectopic ACTH syndrome: 14 months

ACTH-Independent

  • ACTH-independent CS: 30 months

Includes adrenal adenoma, carcinoma, and hyperplasia

ACTH, adrenocorticotropic hormone.

Steps to determine a CS diagnosis2,5,6

Diagnosing CS requires biochemical confirmation and determination of an underlying cause.5

The below algorithm is meant to assist in a diagnosis of CS based on currently available guidance, but is not meant to replace a clinician’s judgement.

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Adapted from Fleseriu M et al. Lancet Diabetes Endocrinol. 2021;9(12):847-875.

AA, adrenal adenoma; ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; AH, adrenal hyperplasia; BIPSS, bilateral inferior petrosal sinus sampling; CD, Cushing’s disease; CPC, central peripheral corticotropin; CRH, corticotropin-releasing hormone; CS, Cushing’s syndrome; CT, computed tomography; EAS, ectopic adrenocorticotropic hormone syndrome; HU, Hounsfield unit; MRI, magnetic resonance imaging; UFC, urinary free cortisol.

Except cyclic CS. The diagnosis can be unclear in patients with cyclic CS, a rare condition in which bursts of hypercortisolism are followed by periods of subnormal or normal cortisol secretion. Repeat testing after 3 to 6 months and referral to a specialist is recommended.5

Plasma corticotropin levels of 10 pg/mL or more but less than 20 pg/mL, as well as elevated plasma corticotropin levels but less than 30 pg/mL after stimulation with CRH, is suggestive of adrenal CS. To convert corticotropin from pg/mL to pmol/L, multiply by 0.22.5

For lesions ranging from 6 mm to 9 mm in diameter, expert consensus differs on use of BIPSS.5

Stimulation with desmopressin or CRH.5

Tests to help determine CS

Clinicians should be familiar with the testing methods at their institutions and interpret results according to validated diagnostic measures.5

First-line testing

Use 2 different tests to demonstrate elevated cortisol levels for a diagnosis.5

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Test
Normal rangea
How test is performed
24-h urinary free cortisol (UFC)

Measures increased cortisol excretion over 24 h.5

(Assay-specific cut-off)
20-45 μg/24 h
(55-124 nmol/L)5

Patients collect urine for 24 h starting with a morning collection, then 24-h cortisol and creatinine levels are measured. The test should be performed 2-3 times to improve reliability.5 Results should take into consideration the sex, BMI, age, urinary volume, sodium intake, and renal function of the patient.2

Late-night salivary cortisol (LNSC)

Measures elevated nighttime cortisol levels.5

(Assay-specific)
≤145 ng/dL
(4 nmol/L)1

Salivary cortisol is collected through a cotton swab before bedtime, usually between 11 PM and midnight. The test should be performed 2-3 times to improve reliability of results.5 Not recommended in patients with abnormal sleep/ wake cycle.7 False positives are seen in patients who smoke or chew tobacco, in patients of older age, and in those with hypertension and diabetes.8

1-mg overnight dexamethasone suppression test (DST)

Measures elevated cortisol levels based on impaired glucocorticoid feedback, as dexamethasone suppresses cortisol production in normal cortisol regulation.2

≤1.8 μg/dL
(50 nmol/L)5

Oral dexamethasone is administered at 11 PM (bedtime) and plasma cortisol is measured between 8 AM and 9 AM the following day.5 This is the preferred initial test for patients suspected of having adrenal adenomas.5 False positives are seen in women taking oral contraceptives and during pregnancy.2

Second-line testing

Use additional tests to exclude nonneoplastic hypercortisolism if repeat screening tests show normal or discordant results.2,5

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Test
Normal rangea
How test is performed
Desmopressin test

Measures ACTH levels as ACTH-secreting adenomas express vasopressin 3 receptors, which produce an increase in plasma ACTH concentration after desmopressin injection. Can also be used to differentiate CD vs CS.2,5

(Assay-specific cut-off)
ACTH level
≤71.8 pg/mL
(15.8 pmol/L)8

A patient's plasma ACTH and serum cortisol levels are measured before and after receiving 10 μg of desmopressin.8

Dexamethasone-CRH test (Not available in the United States)2

Measures ACTH and cortisol levels as dexamethasone suppresses serum cortisol levels in individuals without CS. However, when given CRH, patients with CD should respond with an increase in ACTH and cortisol.1

(Assay-specific cut-off)
1.4 μg/dL
(38 nmol/L)1

Patients take 0.5 mg of dexamethasone every 6 hours for 2 days. IV CRH is then administered 2 hours after the last dose of dexamethasone.5 Cortisol is measured 15 minutes later.1 Can distinguish CD from nonneoplastic hypercortisolism.5

Confirming a CS diagnosis

Determine the source of excess cortisol

Use to determine ACTH-dependent or ACTH-independent CS.5

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Test
Normal rangea
How test is performed
Morning plasma corticotropin test

Measures plasma ACTH levels to differentiate between ACTH-dependent and ACTH-independent source.5

ACTH-dependent:

20 pg/mL (4.4 pmol/L)

ACTH-independent:

>10 pg/mL (2.2 pmol/L)

Inconclusive:

10-20 pg/mL (2.2-4.4 pmol/L)

Test morning ACTH
blood levels between 8 AM and 9 AM.5

Determine the subtype (ACTH-dependent CS)

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Test
Normal range
How test is performed
Pituitary MRI

Differentiates between ectopic CS and CD.5

Adenoma ≥6 mm or ≥10 mm in diameter: Indicative of CD

Adenoma <6 mm or <10 mm in diameter: Requires further testing

MRI of the pituitary gland.5

Bilateral inferior petrosal sinus sampling

Measures ACTH levels in the pituitary (petrosal sinus) vs peripheral venous drainage to determine if the source of ACTH is from the pituitary gland or an ectopic source.2

Ectopic CS: Central peripheral corticotropin ratio <2.0 before stimulation or <3.0 after stimulations5

CD: Central peripheral corticotropin ratio ≥2.0 before stimulation or ≥3.0 after stimulations5

After a patient is injected with CRH, a blood sample is taken from the inferior petrosal sinus and compared with a blood sample taken from the inferior vena cava.2,9

Determine the subtype (ACTH-independent CS)

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Test
Normal range
How test is performed
Adrenal CT

Differentiates between adrenal adenoma, carcinoma, and hyperplasia.5

Unilateral:

Adrenal adenoma: <10 HU
Adrenal carcinoma:>10 HU

Bilateral:

Nodules on both adrenal glands with hyperplastic or atrophic adrenal cortex between nodules

CT of the adrenal gland5

Normal ranges are assay dependent.2,8

ACTH, adrenocorticotropic hormone; BMI, body mass index; CD, Cushing’s disease; CRH, corticotropin-releasing hormone; CS, Cushing’s syndrome; CT, computed tomography; HU, Hounsfield unit; IV, intravenous; MRI, magnetic resonance imaging.

Early diagnosis can help patients start treatment sooner1

Cortisol normalization is the main goal of CS treatment that may help address comorbidities and improve quality of life. When choosing a treatment, an individualized approach, taking patient values and preferences into consideration, is recommended.6

First-line treatment: surgery, if appropriate6

Complete resection Icon

Complete resection of the underlying tumor to normalize cortisol

Second-line treatment: repeat surgery or medication or radiation therapy when surgery is not an option or fails to normalize cortisol levels6

Oral Medication Icon

Medication therapy has been increasingly used for all types of endogenous CS when surgical therapies have failed or are not feasible 

Radiation Icon

Radiation can be used as additional treatment for patients with endogenous CS who do not achieve remission when surgery is not feasible

Pharmacologic therapy is a potential treatment choice for patients for whom surgery is not an option or has failed to effectively normalize cortisol2

Pharmacologic therapy may be appropriate for:

  • Patients who have refused or are ineligible for surgery2
  • Patients with persistent or recurrent CS6
Actor portrayal of doctor talking to a patient
Learn How ISTURISA Works

References: 1. Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540. doi:10.1210/jc.2008-0125 2. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847-875. doi:10.1016/S2213-8587(21)00235-7 3. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006;367(9522):1605-1617. doi:10.1016/S0140-6736(06)68699-6 4. Rubinstein G, Osswald A, Hoster E, et al. Time to diagnosis in Cushing’s syndrome: a meta-analysis based on 5367 patients. J Clin Endocrinol Metab. 2020;105(3):dgz136. doi:10.1210/clinem/dgz136 5. Reincke M, Fleseriu M. Cushing syndrome: a review. JAMA. 2023;330(2):170-181. doi:10.1001/jama.2023.11305 6. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831. doi:10.1210/jc.2015-1818 7. Fleseriu M, Castinetti F. Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies. Pituitary. 2016;19(6):643-653. doi:10.1007/s11102-016-0742-1 8. Wright K, van Rossum EFC, Zan E, et al. Emerging diagnostic methods and imaging modalities in Cushing’s syndrome. Front Endocrinol (Lausanne). 2023;14:1230447. doi:10.3389/fendo.2023.1230447 9. Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing’s disease. Best Pract Res Clin Endocrinol Metab. 2009;23(5):607-623. doi:10.1016/j.beem.2009.06.001

INDICATIONS AND USAGE

ISTURISA® (osilodrostat) is indicated for the treatment of endogenous hypercortisolemia in adults with Cushing’s syndrome for whom surgery is not an option or has not been curative.

IMPORTANT SAFETY INFORMATION

Hypocortisolism: ISTURISA lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency. Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia.

Hypocortisolism can occur at any time during ISTURISA treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.). Monitor 24-hr urine free cortisol, serum or plasma cortisol, and patient’s signs and symptoms periodically during ISTURISA treatment.

Decrease or temporarily discontinue ISTURISA if urine free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report symptoms of hypocortisolism. Stop ISTURISA and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency. After ISTURISA interruption or discontinuation, cortisol suppression may persist beyond the 4-hour half-life of ISTURISA.

Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.

QTc Prolongation: ISTURISA is associated with a dose-dependent QT interval prolongation which may cause cardiac arrhythmias. Perform an ECG to obtain a baseline QTc interval measurement prior to initiating therapy with ISTURISA and monitor for an effect on the QTc interval thereafter.

Correct hypokalemia and/or hypomagnesemia prior to ISTURISA initiation and monitor periodically during treatment with ISTURISA. Use with caution in patients with risk factors for QT prolongation and consider more frequent ECG monitoring.

Elevations in Adrenal Hormone Precursors and Androgens: ISTURISA blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors and androgens. This may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension. Hypokalemia should be corrected prior to initiating ISTURISA. Monitor patients treated with ISTURISA for hypokalemia, worsening of hypertension and edema. Inform patients of the symptoms associated with hyperandrogenism and advise them to contact a healthcare provider if they occur.

The most common adverse reactions (incidence >20%) are adrenal insufficiency, fatigue, nausea, headache, edema, decreased appetite, arthralgia, myalgia, and diarrhea.

To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions:

Use in Specific Populations:

Dosage Interruptions and Modifications: If treatment is interrupted, re-initiate ISTURISA at a lower dose when cortisol levels are within target ranges and patient symptoms have been resolved.

ISTURISA® (osilodrostat) tablets, for oral use, is available as 1 mg and 5 mg tablets.

Please see full Prescribing Information.

Patient portrayal.

Meghan, Actor Portrayal
BASELINE CHARACTERISTICS Age: 34 Race: White Height: 5'6" Weight: 80.1 kg (177 lb) BMI: 28.6 kg/m2
Diagnosis Cushing’s disease: recurrent
Time since diagnosis  6 years
Treatment
  • Transsphenoidal surgery was performed within 2 months of diagnosis 
  • Pituitary radiotherapy was performed 2 years ago
Status
  • In remission, but beginning to develop symptoms of recurrence
Symptoms
  • Weight gain in the abdomen
  • Fatigue and sleep disturbances
  • Anxiety and depression
  • Easy bruising
  • Increased thirst and urination
Comorbidities
  • Depression/anxiety
  • Hyperlipidemia
  • Prediabetes
Vital signs and labs Blood pressure: 124/86 mm Hg HR: 72 bpm Total cholesterol: 213 mg/dL (reference range: <200 mg/dL) LDL: 112 mg/dL (reference range: <100 mg/dL) HDL: 45 mg/dL (reference range: >60 mg/dL) Glucose: 123 mg/dL (reference range: <100 mg/dL) HbA1c: 6.2% (reference range: <5.7%) UFC: 217.5 nmol/24 h (78.8 μg/24 h) (reference range: <145 nmol/24 h [approximately 11-53 μg/24 h]) UFC fold ULN: 1.5 x ULN mUFC

Patient portrayal.

Questions to consider when developing a treatment plan

  1. What would be the consequences if this patient’s cortisol levels remain uncontrolled?
  2. How do you evaluate severity of disease in your patients?
  3. What are your treatment goals for this patient?
  4. What do you consider to be the appropriate next therapy option for this patient?
  5. Would you consider ISTURISA an appropriate option for this patient? Why or why not?

BMI, body mass index; bpm, beats per minute; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HR, heart rate; LDL, low-density lipoprotein; mUFC, mean urinary free cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.

Why ISTURISA May be Right for Your Patient

Patient portrayal.

Mike, Actor Portrayal
BASELINE CHARACTERISTICS Age: 34 Race: White Height: 5'10” Weight: 95.9 kg (211 lb) BMI: 30.3 kg/m2
Diagnosis Cushing’s syndrome: treatment naive
Time since diagnosis 7 months
Treatment
  • Exogenous sources of hypercortisolemia were ruled out
  • Standard imaging techniques were unsuccessful in locating the tumor
  • Inferior petrosal sinus sampling indicated an ectopic source
  • Patient is not a candidate for surgical intervention
Status
  • Further imaging investigation is required
  • Patient is experiencing symptoms of hypercortisolemia that may benefit from medication therapy
  • Cardiometabolic parameters are currently not controlled despite lifestyle changes and maximized treatment
Symptoms
  • Weight gain in the abdomen
  • Rounded face
  • Hypertension
  • Diabetes
  • Daytime fatigue and nighttime insomnia
  • Muscle weakness
Comorbidities
  • Hypertension
  • Diabetes
  • Hyperlipidemia
Vital signs and labs Blood pressure: 146/92 mm Hg HR: 68 bpm Total cholesterol: 238 mg/dL (reference range: <200 mg/dL) LDL: 121 mg/dL (reference range: <100 mg/dL) HDL: 42 mg/dL (reference range: >60 mg/dL) Glucose: 136 mg/dL (reference range: <100 mg/dL) HbA1c: 7.6% (reference range: <5.7%) UFC: 304.5 nmol/24 h (110.3 μg/24 h) (reference range: <145 nmol/24 h [approximately 11-53 μg/24 h]) UFC fold ULN: 2.1 x ULN mUFC

Patient portrayal.

Questions to consider when developing a treatment plan

  1. What would be the consequences if this patient’s cortisol levels remain uncontrolled?
  2. What are your treatment goals for this patient?
  3. What do you consider to be the appropriate next therapy option for this patient?
  4. Would you consider ISTURISA an appropriate option for this patient? Why or why not?

BMI, body mass index; bpm, beats per minute; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HR, heart rate; LDL, low-density lipoprotein; mUFC, mean urinary free cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.

Why ISTURISA May be Right for Your Patient

Patient portrayal.

Stephanie, Actor Portrayal
BASELINE CHARACTERISTICS Age: 31 Race: African American Height: 5'4” Weight: 75.0 kg (165 lb) BMI: 28.3 kg/m2
Diagnosis High clinical suspicion of hypercortisolemia in Cushing’s syndrome; further testing is required
Time since diagnosis Pending diagnosis
Notes
  • UFC labs were repeated twice over several weeks with consistent findings of elevated cortisol
  • Exogenous sources of hypercortisolemia were ruled out
  • Imaging investigation is required
Treatment
  • None
Status
  • Patient has seen an endocrinologist to discuss lack of symptom relief despite lifestyle modification and reported that symptoms are worsening
Symptoms
  • Weight gain in the abdomen
  • Weight gain in the face
  • Facial plethora
  • Muscle weakness
  • Menstrual irregularities
  • Fatigue and sleep disturbances
  • Anxiety and depression
Comorbidities
  • Diabetes
  • Polycystic ovarian syndrome
Vital signs and labs Blood pressure: 130/84 mm Hg HR: 86 bpm Total cholesterol: 208 mg/dL (reference range: <200 mg/dL) LDL: 106 mg/dL (reference range: <100 mg/dL) HDL: 58 mg/dL (reference range: >60 mg/dL) Glucose: 131 mg/dL (reference range: <100 mg/dL) HbA1c: 7.2% (reference range: <5.7%) UFC: 246.5 nmol/24 h (89.3μg/24 h) (reference range: <145 nmol/24 h [approximately 11-53 μg/24 h]) UFC fold ULN: 1.7 x ULN mUFC

Patient portrayal.

Questions to consider when developing a treatment plan

  1. What symptoms lead you to a high clinical suspicion of hypercortisolemia in Cushing’s syndrome?
  2. What would be the consequences if this patient’s cortisol levels remain uncontrolled?
  3. What are your treatment goals for this patient?

BMI, body mass index; bpm, beats per minute; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HR, heart rate; LDL, low-density lipoprotein; mUFC, mean urinary free cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.

Why ISTURISA May be Right for Your Patient