Understanding Cushing’s Disease

Diagnosis & Treatment

Diagnosis is the first step toward treatment.

The road to diagnosis can be long. A delay in diagnosis can occur as a result of symptoms similar to other diseases.1,2 On average, it takes 5 to 7 years before CD is diagnosed.3

Once diagnosed, pituitary surgery is the recommended first-line treatment for CD. For patients for whom surgery is not an option or has not been curative, pharmacotherapy may be appropriate.4

Overlapping comorbidities may make diagnosis even more challenging1,5

Icon of a man sitting in a chair with his head down Depression or other psychiatric disorders1
Scale Icon Morbid obesity6
Calendar Icon Menstrual irregularities1
Calendar Icon Poorly controlled diabetes1
Bone Icon Peripheral edema6
Ovaries Icon Polycystic ovary syndrome7

When present with any of the discriminatory symptoms of hypercortisolism, consider CD as the cause of other comorbidities, such as:1

  • Cardiovascular disease
  • Glucocorticoid resistance
  • Morbid obesity
  • Poorly controlled diabetes
  • Thromboembolic disease
  • Psychiatric deficits
  • Cognitive deficits
  • Infections

Diagnosing Cushing’s disease is a 2-Step approach8

Step 1 – Diagnose Hypercortisolism
STEP 1

Diagnose Hypercortisolism

Step 2 – Identify the cause of Cortisol Hypersecretion
STEP 2

Identify the cause of Cortisol Hypersecretion

STEP 1

Diagnose Hypercortisolism

Guidelines recommend use of at least two different tests that are complementary and corroborative of each other.5

Selections of tests should be individualized to minimize false positives/negatives.

Test
Description
Considerations
24-hour UFC level
  • Measures free cortisol filtered by the kidney over 24 hours9
  • Sensitivity is 45%-71% with 100% specificity9
  • Sensitivity may not be optimal for initial screening9
  • Need at least two measurements2
Late-night salivary cortisol
  • Measures salivary cortisol levels, commonly by an enzyme-linked immunosorbent assay (ELISA)9
  • Sensitivity and specificity are >90%-95%9
  • Need at least two measurements2
  • Test may not be appropriate for shift workers or those with variable bedtimes2
  • High sensitivity and ease of testing2
  • Cortisol testing done at night, when cortisol levels are at their nadir, may be useful for assessing changes to its diurnal pattern10
  • May not be as accurate for those with diabetes or obesity and hypertension2
Overnight 1-mg DST
  • Serum cortisol is measured by RIA
    • Cutoff for serum cortisol is <1.8 μg/dL2
    • Sensitivity is >95%2
  • 80% specificity for diagnosing Cushing’s disease2
  • Women taking birth control may have false-positive results2
Longer low-dose DST (0.5 mg q6h [2 mg/d] for 48 h)
  • Dexamethasone is a synthetic glucocorticoid that normally suppresses ACTH and cortisol2
  • High sensitivity for diagnosis is maintained if the serum concentration of cortisol cutoff is <1.8 μg/dL2
  • Absorption and metabolism of dexamethasone may vary from patient to patient, which may influence the result of both the overnight and 48-hour DST2
  • Simultaneous cortisol and dexamethasone tests are recommended to confirm adequate plasma dexamethasone levels2
24-hour UFC level

Description

  • Measures free cortisol filtered by the kidney over 24 hours9
  • Sensitivity is 45%-71% with 100% specificity9

Considerations

  • Sensitivity may not be optimal for initial screening9
  • Need at least two measurements2
Late-night salivary cortisol

Description

  • Measures salivary cortisol levels, commonly by an enzyme-linked immunosorbent assay (ELISA)9
  • Sensitivity and specificity are >90%-95%9

Considerations

  • Need at least two measurements2
  • Test may not be appropriate for shift workers or those with variable bedtimes2
  • High sensitivity and ease of testing2
  • Cortisol testing done at night, when cortisol levels are at their nadir, may be useful for assessing changes to its diurnal pattern10
  • May not be as accurate for those with diabetes or obesity and hypertension2
Overnight 1-mg DST

Description

  • Serum cortisol is measured by RIA
    • Cutoff for serum cortisol is <1.8 μg/dL2
    • Sensitivity is >95%2

Considerations

  • 80% specificity for diagnosing Cushing’s disease2
  • Women taking birth control may have false-positive results2
Longer low-dose DST (0.5 mg q6h [2 mg/d] for 48 h)

Description

  • Dexamethasone is a synthetic glucocorticoid that normally suppresses ACTH and cortisol2
  • High sensitivity for diagnosis is maintained if the serum concentration of cortisol cutoff is <1.8 μg/dL2

Considerations

  • Absorption and metabolism of dexamethasone may vary from patient to patient, which may influence the result of both the overnight and 48-hour DST2
  • Simultaneous cortisol and dexamethasone tests are recommended to confirm adequate plasma dexamethasone levels2
ACTH=adrenocorticotropic hormone; DST=dexamethasone suppression test; RIA=radioimmunoassay; UFC=urinary free cortisol.
STEP 2

Identify the cause of Cortisol Hypersecretion

Magnetic resonance imaging (MRI) may confirm presence of a pituitary tumor and a diagnosis of CD11

  • MRI reveals a pituitary adenoma in 40%-60% of cases of CD8
  • Most ACTH secreting adenomas are microadenomas <1 cm in diameter and difficult to detect8
    • 85%-87% of patients may present with a microadenoma at the time of diagnosis12
  • Even in the absence of a positive MRI, patients with biochemical testing indicative of CD should be referred to an experienced pituitary surgeon for evaluation8
MRI Icon

Surgery is the first-line treatment

Pituitary surgery is the recommended first-line treatment for CD, but recurrence after surgery is possible.4

ANTERIOR PITUITARY TUMORS AND SURGICAL SUCCESS RATES

Microadenomas
Macroadenomas
Size
<10 mm in diameter13
>10 mm in diameter13
Frequency
  • Most common14
  • Account for ≈90% of tumors in patients with CD13
  • Infrequent15
  • Account for ≈10% of tumors in patients with CD13
Initial Surgical Success Rate
89%16
63%16
Microadenomas

Size

<10 mm in diameter13

Frequency

  • Most common14
  • Account for ≈90% of tumors in patients with CD13

Initial Surgical Success Rate

89%16

Macroadenomas

Size

<10 mm in diameter13

Frequency

  • Infrequent15
  • Account for ≈10% of tumors in patients with CD13

Initial Surgical Success Rate

63%16

Surgery may not be curative for CD

Scalpel Icon
RECURRENCE RATES AFTER SURGERY:17,18
~25%
up to 5 years
~46%
up to 10 years or more

Pharmacotherapy can be used to manage high cortisol levels19

Pharmacologic therapy may be an appropriate therapeutic option for patients with persistent disease after surgery17

Which patients are appropriate for pharmacotherapy?17,20

  • Those who are ineligible or unwilling to undergo transsphenoidal surgery (TSS)
  • As a second-line treatment in patients for whom TSS did not induce remission (before considering bilateral adrenalectomy or radiotherapy)
  • Those waiting for the effects of radiotherapy

ISTURISA, the first FDA-approved therapy for Cushing’s disease (CD), is proven to normalize and sustain cortisol levels in the majority of patients.21

Learn how ISTURISA works

INDICATIONS AND USAGE

ISTURISA (osilodrostat) is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

  • 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 discontinuation, cortisol suppression may persist beyond the 4-hour half-life of ISTURISA. Please see section 5.1 of full Prescribing Information.

    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. Please see section 5.2 of full Prescribing Information.
  • 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. Please see section 5.3 of full Prescribing Information.

Adverse Reactions

  • Most common adverse reactions (incidence >20%) are adrenal insufficiency, fatigue, nausea, headache, and edema.
  • 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

  • CYP3A4 Inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor.
  • CYP3A4 and CYP2B6 Inducers: An increase of ISTURISA dosage may be needed if ISTURISA is used concomitantly with strong CYP3A4 and CYP2B6 inducers. A reduction in ISTURISA dosage may be needed if strong CYP3A4 and CYP2B6 inducers are discontinued while using ISTURISA.

Use in Specific Populations

  • Lactation: Breastfeeding is not recommended during treatment with ISTURISA and for at least one week after treatment.

INDICATIONS AND USAGE

ISTURISA (osilodrostat) is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

  • 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 discontinuation, cortisol suppression may persist beyond the 4-hour half-life of ISTURISA. Please see section 5.1 of full Prescribing Information.

    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. Please see section 5.2 of full Prescribing Information.
  • 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. Please see section 5.3 of full Prescribing Information.

Adverse Reactions

  • Most common adverse reactions (incidence >20%) are adrenal insufficiency, fatigue, nausea, headache, and edema.
  • 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

  • CYP3A4 Inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor.
  • CYP3A4 and CYP2B6 Inducers: An increase of ISTURISA dosage may be needed if ISTURISA is used concomitantly with strong CYP3A4 and CYP2B6 inducers. A reduction in ISTURISA dosage may be needed if strong CYP3A4 and CYP2B6 inducers are discontinued while using ISTURISA.

Use in Specific Populations

  • Lactation: Breastfeeding is not recommended during treatment with ISTURISA and for at least one week after treatment.
References: 1. Geer EB, Shafiq I, Gordon MB, et al. Biochemical control during long-term follow-up of 230 adult patients with Cushing disease: a multicenter retrospective study. Endocr Pract. 2017;23(8):962-970. 2. Dekkers OM, Horváth-Puhó E, Jørgensen JOL, et al. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab. 2013;98(6):2277-2284. 3. Geer EB, Ayala A, Bonert V, et al. Follow-up intervals in patients with Cushing’s disease: recommendations from a panel of experienced pituitary clinicians. Pituitary. 2017;20(4):422-429. 4. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet. 2021; https://doi.org/10.1016/S2213-8587(21)00235-7. 5. ISTURISA® (osilodrostat) [prescribing information]. Lebanon, NJ: Recordati Rare Diseases Inc.; 2020. 6. Bertagna X, Pivonello R, Fleseriu M, et al. LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing’s disease: results from a multicenter, proof-of-concept study. The Journal of Clinical Endocrinology & Metabolism. 2014;99(4):1375-1383.