Cushing Syndrome Diagnosis and Complications

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.

Cushing Syndrome

• Cushing syndrome results from effects of supraphysiologic glucocorticoid concentrations originating from either exogenous administration or endogenous overproduction by the adrenal gland (adrenocorticotropic hormone [ACTH] dependent) or by abnormal adrenocortical tissues (ACTH independent).

Pathophysiology

• ACTH dependent Cushing syndrome (80% of all Cushing syndrome cases) is usually caused by overproduction of ACTH by the pituitary gland, causing bilateral adrenal hyperplasia.
• Pituitary adenomas account for about 85% of these cases (Cushing disease).
• Ectopic ACTH secreting tumors and nonneoplastic corticotropin hypersecretion cause the remaining 20% of ACTH dependent cases.

Ectopic ACTH Syndrome

• Ectopic ACTH syndrome refers to excessive ACTH production resulting from an endocrine or nonendocrine tumor, usually of the pancreas, thyroid, or lung (eg, small cell lung cancer).

ACTH-Independent Cushing Syndrome

• ACTH-independent Cushing syndrome is usually caused by adrenal adenomas and carcinomas.

Clinical Presentation

• The most common findings in Cushing syndrome are central obesity and facial rounding (90% of patients).
• Peripheral obesity and fat accumulation occur in 50% of patients.
• Fat accumulation in the dorsocervical area (buffalo hump) is nonspecific, but increased supraclavicular fat pads are more specific for Cushing syndrome.

Treatment

• 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 and provides clinical improvement in ∼50% of patients within 3–5 years but increases the risk for pituitary dependent hormone deficiencies (hypopituitarism).

Pharmacologic Therapy

• Pharmacotherapy is generally used as a 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.
• Metyrapone inhibits 11β hydroxylase, thereby inhibiting cortisol synthesis, and can cause androgenic side effects such as acne and hirsutism.
• Ketoconazole inhibits cytochrome P450 enzymes, including 11β hydroxylase and 17α hydroxylase, and can cause reversible elevation of hepatic transaminases, GI discomfort, and dermatologic reactions.

Neuromodulators of ACTH Release

• Pituitary secretion of ACTH is normally mediated by neurotransmitters such as serotonin, γ-aminobutyric acid (GABA), acetylcholine, and catecholamines.
• Agents that target these transmitters have been proposed for treatment of Cushing disease, including cyproheptadine, bromocriptine, cabergoline, valproic acid, octreotide, lanreotide, pasireotide, rosiglitazone, and tretinoin.