Cushing Syndrome Diagnosis and Complications

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Questions and Answers

What is the estimated percentage of patients who develop Cushing-induced osteoporosis?

40%

20%

80%

60% (correct)

Which of the following tests is used to determine the etiology of hypercortisolism?

Metyrapone stimulation test

Corticotropin releasing hormone (CRH) stimulation test

Dexamethasone suppression test (DST)

All of the above (correct)

What is the primary goal of treatment for Cushing's syndrome?

To remove the source of hypercortisolism

To minimize pituitary deficiencies

To return the patient to a normal functional state

All of the above (correct)

Which of the following is NOT a common finding in Cushing's syndrome?

Hypoglycemia Signup and view all the answers

What is the estimated percentage of patients who present with back pain?

40% Signup and view all the answers

Which of the following tests is used to measure cortisol levels?

All of the above Signup and view all the answers

What is the estimated percentage of patients who progress to spinal compression fractures?

20% Signup and view all the answers

What is the primary imaging modality used to identify adrenal nodules and masses?

High resolution CT scanning Signup and view all the answers

What is the preferred treatment for Cushing disease?

Transsphenoidal resection of the pituitary tumor Signup and view all the answers

What is the primary mechanism of action of metyrapone?

Inhibition of 11 β hydroxylase Signup and view all the answers

What is a potential benefit of ketoconazole therapy in women?

Anti-androgenic activity Signup and view all the answers

What is a potential adverse effect of metyrapone therapy?

Androgenic side effects Signup and view all the answers

What is the primary indication for laparoscopic adrenalectomy?

Unilateral adrenal adenomas Signup and view all the answers

What is a potential benefit of transsphenoidal resection of the pituitary tumor?

Reduced risk of pituitary dependent hormone deficiencies Signup and view all the answers

What is a potential adverse effect of ketoconazole therapy in men?

Gynecomastia Signup and view all the answers

What is the potential consequence of metyrapone-induced inhibition of aldosterone synthesis?

Natriuresis and blood pressure changes Signup and view all the answers

What is a common side effect of mifepristone?

Hypokalemia Signup and view all the answers

What is the primary indication for the use of mifepristone?

Treatment of endogenous Cushing syndrome in patients with type 2 diabetes or glucose intolerance Signup and view all the answers

What is the primary effect of mitotane on the adrenal cortex?

Degeneration of cells within the zona fasciculata and reticularis Signup and view all the answers

What is a complication of Cushing syndrome that can be reversed with mifepristone treatment?

Hyperglycemia Signup and view all the answers

Which of the following neurotransmitters does not play a role in regulating pituitary secretion of ACTH?

Glutamate Signup and view all the answers

What is the term for glucocorticoid receptor antagonist that is FDA approved for treatment of endogenous Cushing syndrome?

Mifepristone Signup and view all the answers

What is the primary mechanism of action of pasireotide in treating Cushing disease?

Activating somatostatin receptors to inhibit ACTH secretion Signup and view all the answers

What is the most common cause of primary hyperaldosteronism?

Bilateral adrenal hyperplasia Signup and view all the answers

What is a common side effect of mitotane therapy that can be avoided by gradually increasing the dose and/or administering it with food?

Nausea and diarrhea Signup and view all the answers

What is a possible cause of secondary hyperaldosteronism?

Extra adrenal etiologies Signup and view all the answers

Which of the following drugs has demonstrated consistent clinical efficacy for treating Cushing disease?

Pasireotide Signup and view all the answers

What is the effect of cyproheptadine on ACTH secretion in some patients with Cushing disease?

Decrease ACTH secretion Signup and view all the answers

What is a type of familial hyperaldosteronism?

Type I glucocorticoid remediable aldosteronism Signup and view all the answers

What is the primary reason why cyproheptadine is not commonly used to treat Cushing disease?

It is effective but has significant side effects such as sedation and weight gain Signup and view all the answers

What should be monitored closely in patients with Cushing syndrome?

24-hour UFC and serum cortisol Signup and view all the answers

What is the effect of pasireotide on cortisol secretion in patients with Cushing disease?

Decrease cortisol secretion Signup and view all the answers

Which of the following is a common reason for secondary hyperaldosteronism?

Renin-angiotensin system stimulation Signup and view all the answers

Elevated aldosterone concentrations can result from which of the following?

Excessive potassium intake Signup and view all the answers

What is a common sign of primary aldosteronism?

Tetany/paralysis Signup and view all the answers

What is a laboratory finding suggestive of primary aldosteronism?

Elevated plasma aldosterone concentration to plasma renin activity (PAC to PRA) ratio >30 ng/dL per ng/(mL·h) Signup and view all the answers

Who should be screened for primary aldosteronism?

Patients with a blood pressure >150/100 mm Hg on three separate days Signup and view all the answers

What is a common symptom of primary aldosteronism?

Polydipsia Signup and view all the answers

Which of the following is a laboratory finding in primary aldosteronism?

Hypokalemia Signup and view all the answers

What is a risk factor for primary aldosteronism?

Hypertension and sleep apnea Signup and view all the answers

What is the goal of treatment for Cushing's syndrome?

To remove the source of hypercortisolism while minimizing pituitary or adrenal deficiencies Signup and view all the answers

What is a common finding in patients with Cushing's syndrome?

Abdominal striae Signup and view all the answers

Which of the following tests is used to establish hypercortisolism?

24-hour urinary free cortisol Signup and view all the answers

What is a common complication of Cushing's syndrome?

All of the above Signup and view all the answers

What is used to identify adrenal nodules and masses?

Both A and B Signup and view all the answers

What is a psychiatric change associated with Cushing's syndrome?

All of the above Signup and view all the answers

What is the treatment of choice for Cushing disease?

Transsphenoidal resection of the pituitary tumor Signup and view all the answers

Which of the following is a potential side effect of metyrapone therapy?

Hirsutism Signup and view all the answers

What is the primary goal of pharmacologic therapy in patients with Cushing disease?

To prepare patients for surgery Signup and view all the answers

Ketoconazole inhibits which of the following enzymes?

Both 11 β hydroxylase and 17 α hydroxylase Signup and view all the answers

What is the benefit of ketoconazole therapy in women?

It has antiandrogenic activity Signup and view all the answers

Radiotherapy may be preferred in which of the following situations?

When tumors invade the dura or cavernous sinus Signup and view all the answers

What is a potential consequence of metyrapone-induced inhibition of aldosterone synthesis?

Natriuresis Signup and view all the answers

Laparoscopic adrenalectomy is often preferred for which of the following?

Unilateral adrenal adenomas or when transsphenoidal surgery and pituitary radiotherapy have failed or cannot be used Signup and view all the answers

What is the primary treatment option for both ACTH-dependent and ACTH-independent Cushing syndrome?

Surgical resection of offending tumors Signup and view all the answers

Which of the following medications is NOT a steroidogenesis inhibitor?

Pasireotide Signup and view all the answers

What is the usual initial dose of metyrapone in the treatment of Cushing syndrome?

250 mg/day Signup and view all the answers

What is the maximum daily dose of ketoconazole in the treatment of Cushing syndrome?

1600 mg/day Signup and view all the answers

Which of the following medications is used to treat ectopic ACTH syndrome?

Metyrapone Signup and view all the answers

What is the usual initial dose of mitotane in the treatment of adrenal carcinoma?

0.5-1 g/day Signup and view all the answers

Which of the following medications is a glucocorticoid receptor antagonist?

Mifepristone Signup and view all the answers

What is the usual dose range of cabergoline in the treatment of Cushing syndrome?

0.5-7 mg/week Signup and view all the answers

Which of the following medications is used to treat pituitary-dependent Cushing syndrome?

Pasireotide Signup and view all the answers

What is the usual dose range of pasireotide in the treatment of Cushing syndrome?

0.3-0.9 mg twice daily Signup and view all the answers

What is the primary goal of pharmacologic therapy in patients with Cushing disease?

To normalize cortisol levels Signup and view all the answers

Which steroidogenesis inhibitor is used to treat ectopic ACTH syndrome?

Metyrapone Signup and view all the answers

What is the usual range of initial dosing for Metyrapone in treating Cushing syndrome?

1-2 g/day Signup and view all the answers

Which of the following is a treatment option for adrenal carcinoma in Cushing syndrome?

All of the above Signup and view all the answers

What is the maximum dose of Ketoconazole used in treating Cushing syndrome?

1600 mg/day Signup and view all the answers

Which of the following medications is used to treat pituitary-dependent Cushing syndrome?

All of the above Signup and view all the answers

What is the usual dose range for Mifepristone in treating Cushing syndrome?

300-1200 mg/day Signup and view all the answers

Which of the following medications inhibits cortisol production in the adrenal gland?

All of the above Signup and view all the answers

What happens to the zona glomerulosa during acute therapy with mitotane?

It is minimally affected Signup and view all the answers

What is the primary mechanism of action of pasireotide in treating Cushing disease?

Inhibiting ACTH secretion Signup and view all the answers

What is a common side effect of mitotane therapy that can be avoided by gradually increasing the dose and/or administering it with food?

Nausea and diarrhea Signup and view all the answers

Which neurotransmitter does not play a role in regulating pituitary secretion of ACTH?

Dopamine Signup and view all the answers

What is the effect of cyproheptadine on ACTH secretion in some patients with Cushing disease?

It decreases ACTH secretion Signup and view all the answers

Why is cyproheptadine not commonly used to treat Cushing disease?

It has significant side effects such as sedation and weight gain Signup and view all the answers

What is the primary goal of pharmacologic therapy in patients with Cushing disease?

To reduce cortisol secretion Signup and view all the answers

What is the primary goal of treatment for Cushing's syndrome?

To remove the source of hypercortisolism Signup and view all the answers

Which of the following drugs has demonstrated consistent clinical efficacy for treating Cushing disease?

Pasireotide Signup and view all the answers

Which of the following is NOT a pharmacologic therapy for Cushing disease?

Spironolactone Signup and view all the answers

What is the mechanism of action of metyrapone?

Inhibiting cortisol synthesis Signup and view all the answers

What is a common complication of Cushing's syndrome that can be reversed with treatment?

Psychiatric changes Signup and view all the answers

Which of the following is a potential side effect of ketoconazole therapy?

Hepatotoxicity Signup and view all the answers

What is the primary reason for using pharmacologic therapy as a second line treatment in patients with Cushing's syndrome?

Because patients are not surgical candidates Signup and view all the answers

Which of the following enzymes is inhibited by ketoconazole, leading to a decrease in cortisol synthesis?

Both 11 β hydroxylase and 17 α hydroxylase Signup and view all the answers

What is the primary effect of pasireotide on cortisol secretion?

Inhibiting cortisol secretion Signup and view all the answers

What is a common finding in patients with Cushing's syndrome?

All of the above Signup and view all the answers

What is the primary effect of metyrapone on adrenal steroidogenesis?

Shunting towards androgen production Signup and view all the answers

What is the potential consequence of metyrapone-induced inhibition of aldosterone synthesis?

Natriuresis and blood pressure changes Signup and view all the answers

Which of the following imaging modalities is used to identify adrenal nodules and masses?

Magnetic Resonance Imaging (MRI) Signup and view all the answers

What is the primary indication for laparoscopic adrenalectomy in patients with Cushing's syndrome?

Unilateral adrenal adenomas Signup and view all the answers

What is the primary mechanism of action of metyrapone in patients with Cushing's syndrome?

Inhibition of 11 β hydroxylase Signup and view all the answers

What is the primary benefit of ketoconazole therapy in women with Cushing's syndrome?

Antiandrogenic activity Signup and view all the answers

What is the primary goal of pharmacologic therapy in patients with Cushing's syndrome?

To lower serum cortisol levels Signup and view all the answers

Which of the following pharmacologic agents inhibits the 11-beta-hydroxylase enzyme in the adrenal cortex, thereby reducing cortisol production?

Metyrapone Signup and view all the answers

What is the primary goal of pharmacologic therapy in patients with Cushing disease?

To reduce cortisol production Signup and view all the answers

Which of the following is a mechanism of action of ketoconazole in treating Cushing disease?

Inhibiting cytochrome P450 enzymes Signup and view all the answers

What is the primary effect of pasireotide on cortisol secretion in patients with Cushing disease?

Suppression of ACTH secretion Signup and view all the answers

Which of the following is a common side effect of metyrapone therapy?

Hypertension Signup and view all the answers

What is the primary mechanism of action of mifepristone in treating Cushing syndrome?

Blocking glucocorticoid receptors Signup and view all the answers

What is the primary indication for the use of pasireotide in patients with Cushing disease?

To suppress ACTH secretion Signup and view all the answers

Which of the following is a potential benefit of ketoconazole therapy in women with Cushing syndrome?

Reduced hirsutism Signup and view all the answers

Study Notes

Cushing's Syndrome

Other findings may include myopathy, abdominal striae, hypertension, glucose intolerance, psychiatric changes, gonadal dysfunction, facial plethora, and amenorrhea and hirsutism in women.
Up to 60% of patients develop Cushing-induced osteoporosis, with 40% presenting with back pain, and 20% progressing to spinal compression fractures.

Diagnosis of Hypercortisolism

Hypercortisolism can be established with one or more of the following tests: 24-hour urinary free cortisol (UFC), midnight plasma cortisol, late-night (11 PM) salivary cortisol, and/or low-dose dexamethasone suppression test (DST).
Other tests to determine etiology include plasma ACTH, adrenal vein catheterization, metyrapone stimulation test, adrenal, chest, or abdominal computed tomography (CT), corticotropin-releasing hormone (CRH) stimulation test, inferior petrosal sinus sampling, and pituitary magnetic resonance imaging (MRI).
Adrenal nodules and masses are identified using high-resolution CT scanning or MRI.

Treatment of Cushing's Syndrome

Goals of treatment: limit morbidity and mortality, return the patient to a normal functional state by removing the source of hypercortisolism while minimizing pituitary or adrenal deficiencies.
Transsphenoidal resection of the pituitary tumor is the treatment of choice for Cushing's disease.
Radiotherapy may be preferred for tumors invading the dura or cavernous sinus and provides clinical improvement in ∼50% of patients within 3–5 years but increases the risk for pituitary-dependent hormone deficiencies (hypopituitarism).
Laparoscopic adrenalectomy is often preferred for unilateral adrenal adenomas or when transsphenoidal surgery and pituitary radiotherapy have failed or cannot be used.

Pharmacologic Therapy

Pharmacotherapy is generally used as second-line treatment in patients who are not surgical candidates and may also be used preoperatively or as adjunctive therapy in postoperative patients awaiting response.
Rarely, monotherapy is used as a palliative treatment when surgery is not indicated.

Steroidogenesis Inhibitors

Metyrapone inhibits 11β-hydroxylase, thereby inhibiting cortisol synthesis.
Ketoconazole inhibits cytochrome P450 enzymes, including 11β-hydroxylase and 17α-hydroxylase.
Mitotane degenerates cells within the zona fasciculata and reticularis, resulting in atrophy of the adrenal cortex.

Neuromodulators of ACTH Release

Pituitary secretion of ACTH is normally mediated by neurotransmitters such as serotonin, γ-aminobutyric acid (GABA), acetylcholine, and catecholamines.

Pasireotide (Signifor) is a somatostatin analog that binds and activates somatostatin receptors, thereby inhibiting ACTH secretion, leading to decreased cortisol secretion.

Glucocorticoid Receptor Blocking Agents

Mifepristone (Korlym) is a progesterone and glucocorticoid receptor antagonist that inhibits dexamethasone suppression and increases endogenous cortisol and ACTH levels in normal subjects.
Evidence suggests that mifepristone is highly effective in reversing the manifestations of hypercortisolism.

Hyperaldosteronism

Hyperaldosteronism involves excess aldosterone secretion and is categorized as either primary (stimulus arising from within the adrenal gland) or secondary (stimulus from extra-adrenal etiologies).
Primary hyperaldosteronism (PA) is usually caused by bilateral adrenal hyperplasia and aldosterone-producing adenoma (Conn syndrome).
Secondary hyperaldosteronism results from excessive stimulation of the zona glomerulosa by an extra-adrenal factor, usually the renin-angiotensin system.

Treatment of Cushing Syndrome

Transsphenoidal resection of the pituitary tumor is the treatment of choice for Cushing disease.
Radiotherapy may be preferred for tumors invading the dura or cavernous sinus, providing clinical improvement in ~50% of patients within 3-5 years.
Laparoscopic adrenalectomy is often preferred for unilateral adrenal adenomas or when transsphenoidal surgery and pituitary radiotherapy have failed or cannot be used.

Pharmacologic Therapy

Pharmacotherapy is generally used as a second-line treatment in patients who are not surgical candidates.
Steroidogenesis inhibitors, such as metyrapone and ketoconazole, are used to reduce cortisol levels.
Metyrapone inhibits 11 β hydroxylase, blocking cortisol synthesis, which can lead to androgenic side effects.
Ketoconazole inhibits cytochrome P 450 enzymes, including 11 β hydroxylase and 17 α hydroxylase, and may cause gynecomastia and hypogonadism in men.

Treatment Plans Based on Etiology

Ectopic ACTH syndrome: surgery, chemotherapy, and irradiation, with medical therapy including metyrapone and ketoconazole.
Pituitary-dependent Cushing syndrome: surgery, irradiation, and medical therapy including mitotane, metyrapone, mifepristone, cabergoline, and pasireotide.
Adrenal adenoma: surgery, with ketoconazole as a treatment option.
Adrenal carcinoma: surgery, with mitotane as a treatment option.

Other Findings and Diagnosis

Non-pharmacologic therapy involves surgical resection of offending tumors.
Cushing syndrome can lead to myopathy, muscular weakness, hypertension, glucose intolerance, psychiatric changes, gonadal dysfunction, and osteoporosis.
Diagnosis can be established with 24-hour urinary free cortisol, midnight plasma cortisol, late-night salivary cortisol, and/or low-dose dexamethasone suppression test.

Goals of Treatment

Limit morbidity and mortality and return the patient to a normal functional state by removing the source of hypercortisolism while minimizing pituitary or adrenal deficiencies.