Understanding Cushing’s Syndrome

Signs & Symptoms

Cushing’s syndrome (CS) is characterized by systemic symptoms of hypercortisolism, but patients may experience CS in vastly different ways1,2

Symptoms of hypercortisolism can mimic other common conditions and can vary greatly by patient, further complicating the path to diagnosis.3 While thin skin, easy bruising, and muscle weakness are key indicators, not all patients exhibit these features.

Hypercortisolism can manifest in CS along a spectrum, being easily diagnosed in some patients and easily misdiagnosed in others2

Illustration of woman showing severe CS symptoms

Mild and gradual disease progression may show the signs and symptoms of hypercortisolism that are nonspecific and/or overlap with other common conditions.1,2,4

  • Weight gain
  • Acne
  • Hirsutism
  • Glucose intolerance
  • Hypertension
  • Menstrual irregularities
  • Anxiety/depression/sleep disturbances

Severe and fully developed disease progression may have more overt features that may be more easily recognized.2,4

  • Central obesity
  • Moon face
  • Dorsocervical fat pad
  • Osteopenia/osteoporosis
  • Muscle weakness
  • Purple striae
  • Easy bruising
  • Thin skin

The clinical presentation of CS can also differ by etiology

Illustration of woman showing mild CS symptoms
  • Cushing’s disease may present with distinct CS features, but may also have symptoms of common conditions5
  • Ectopic CS may present with severe and rapidly developing metabolic signs6
  • Adrenal carcinomas may have rapid onset of symptoms and show signs of virilization due to secretion of androgens in addition to cortisol6,7
  • Adrenal adenomas may have mild to severe symptoms based on the level of cortisol or aldosterone secretion8
  • Adrenal hyperplasia can experience a range of symptoms, from mild in macronodular disease to severe in micronodular disease9
Illustration of woman showing mild CS symptoms

Guidelines recommend urgent treatment of hypercortisolism in CS
(within 24 to 72 hours) if you see signs of any of the following10:

Infection IconInfection
Brain IconAcute
psychosis
Lungs IconPulmonary
thromboembolism
Heart monitor IconCardiovascular
complications
Discover Why Diagnosing CS Can Be Difficult

References: 1. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M. Cushing’s syndrome. Lancet. 2023;402(10418):2237-2252. doi:10.1016/S0140-6736(23)01961-X 2. Nieman LK. Cushing’s syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol. 2015;173(4):M33-M38. doi:10.1530/ EJE-15-0464 3. Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. Clin Endocrinol Metab. 2008;93(5):1526-1540. doi:10.1210/jc.2008-0125 4. Reincke M, Fleseriu M. Cushing syndrome: a review. JAMA. 2023;330(2):170-181. doi:10.1001/jama.2023.11305 5. Pivonello R, De Martino MC, De Leo M, Simeoli C, Colao A. Cushing’s disease: the burden of illness. Endocrine. 2017;56(1):10-18. doi:10.1007/s12020-016-0984-8 6. Juszczak A, Morris D, Grossman A. Cushing’s syndrome. Endotext [Internet]. Accessed March 27, 2025. https://www.ncbi.nlm.nih.gov/books/NBK279088/ 7. Puglisi S, Perotti P, Pia A, Reimondo G, Terzolo M. Adrenocortical carcinoma with hypercortisolism. Endocrinol Metab Clin North Am. 2018;47(2):395-407. doi:10.1016/j.ecl.2018.02.003 8. Mahmood E, Loughner CL, Anastasopoulou C. Adrenal adenoma. StatPearls [Internet]. StatPearls Publishing; 2024. Accessed March 27, 2025. https://www.ncbi.nlm.nih.gov/books/NBK539906/ 9. Chevalier B, Vantyghem MC, Espiard S. Bilateral adrenal hyperplasia: pathogenesis and treatment. Biomedicines. 2021;9(10):1397. doi:10.3390/biomedicines9101397 10. 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.

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