What is the etiology, pathogenesis, and management of Cushing syndrome, including its symptoms, diagnosis, and treatment options for patients with various underlying causes, such as pituitary tumors, adrenal tumors, or familial Cushing syndrome?

Cushing Syndrome: Etiology, Pathogenesis, and Management

Etiology

Cushing syndrome results from sustained pathologic hypercortisolism, with endogenous causes accounting for 2-8 cases per million people annually, while exogenous glucocorticoid use remains the most common overall cause. 1

ACTH-Dependent Causes (70-85% of endogenous cases)

• Cushing's disease (pituitary corticotroph adenoma) accounts for 60-70% of endogenous Cushing syndrome cases 1
• Ectopic ACTH secretion from non-pituitary tumors represents approximately 15% of cases, with sources including lung, thyroid, pancreas, bowel, and thymus 2, 3
• Thymic neuroendocrine tumors cause up to 2% of Cushing syndrome cases through ectopic ACTH production 2
• Ectopic CRH-secreting tumors are rare causes of ACTH-dependent hypercortisolism 4

ACTH-Independent Causes (15-30% of endogenous cases)

• Adrenocortical tumors (adenomas or carcinomas) account for approximately 15% of endogenous cases 3
• Bilateral macronodular adrenal hyperplasia can occur with aberrant membrane hormone receptor expression or altered eutopic receptor activity 4
• Primary pigmented nodular adrenocortical disease associated with Carney complex 5

Pathogenesis

Molecular Mechanisms in Cushing's Disease

• Somatic USP8 mutations are present in 36-60% of corticotroph adenomas, leading to persistent EGFR overexpression and perpetuating ACTH hypersecretion 6
• Corticotroph adenomas arise from monoclonal expansion of a singular mutated cell and abundantly express EGFR, which signals to induce ACTH production 6
• Rare mutations in glucocorticoid receptor NR3C1, BRAF oncogene, deubiquitinase USP48, and TP53 are occasionally encountered 6

Genetic Predisposition

• Familial tumor syndromes including MEN1, RET, AIP, PRKAR1A, CDKN1B, DICER1, SDHx, and CABLES1 may predispose to Cushing's disease, though corticotroph adenomas rarely develop in these syndromes 6
• In children, germline mutations in these genes warrant screening only when family history or other syndromic features are present 6
• MEN-1 syndrome is associated with 5-15% of thymic carcinoid tumors causing ectopic ACTH secretion 2

Pathophysiologic Consequences

• Chronic cortisol excess causes hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders 1
• Severe complications include left ventricular hypertrophy, cirrhosis, osteoporosis, and increased mortality from pulmonary emboli, infections, myocardial infarction, and cerebrovascular accidents 7, 5

Diagnosis

Initial Screening (Rule Out Exogenous Steroids First)

Screen patients with characteristic features using 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), or overnight 1 mg dexamethasone suppression test (DST). 6, 1, 5

• Look specifically for facial plethora, easy bruising, wide purple striae (>1 cm), proximal muscle weakness, supraclavicular and temporal fat pads, and in children, lack of height gain with continued weight gain 1, 3
• The dexamethasone-CRH test can discriminate between true Cushing syndrome and pseudo-Cushing states 4

Determining Etiology

Measure plasma ACTH levels to distinguish ACTH-dependent (midnormal to elevated ACTH) from ACTH-independent (suppressed ACTH) hypercortisolism. 2, 1, 3

For ACTH-Dependent Disease:

• Bilateral inferior petrosal sinus sampling (IPSS) with CRH stimulation is the gold standard to differentiate pituitary from ectopic ACTH sources 2, 3
• Pituitary MRI should be performed, though IPSS remains more accurate than imaging alone 1, 3
• Somatostatin receptor imaging (68Ga-DOTATATE PET) is valuable for localizing ectopic ACTH-producing tumors including thymic sources 2
• High-dose dexamethasone suppression testing and CRH/desmopressin tests provide additional diagnostic information 4, 3

For ACTH-Independent Disease:

• Adrenal CT scan identifies adrenal lesions (adenomas, carcinomas, or bilateral hyperplasia) 4, 3
• Bilateral adrenal vein sampling may be needed to demonstrate adrenal hyperplasia in complex cases 7

Pediatric Considerations

• In children over age 6, Cushing's disease is most common; in younger children, adrenal causes predominate 6
• IPSS has a more limited role in children compared to adults 6
• Evaluate for growth hormone deficiency (present in 31% severe, 54% partial) using insulin tolerance or glucagon stimulation testing 6

Management

First-Line Treatment: Surgery

Surgical resection of the causative tumor is the optimal first-line therapy for all forms of Cushing syndrome. 1, 4, 5

Cushing's Disease (Pituitary Source):

• Transsphenoidal selective adenomectomy induces remission in approximately 80% of patients, though long-term relapse occurs in up to 30% 4
• Repeat surgery can be successful when residual tumor is visible on MRI but carries high risk of hypopituitarism 4
• In pediatric patients, thromboprophylaxis should not be routinely used due to bleeding risk, reserved only for selected cases 6

Adrenal Causes:

• Unilateral adrenalectomy for cortisol-secreting adenomas or carcinomas 4, 5
• Bilateral adrenalectomy for bilateral disease or as definitive therapy for refractory Cushing's disease 4, 5

Ectopic ACTH Sources:

• Surgical resection of ectopic ACTH/CRH-secreting tumors when feasible 4
• For thymic sources, complete surgical resection is the treatment of choice 2

Second-Line Medical Therapy

Pituitary-Targeted Therapy:

• Pasireotide (SIGNIFOR) is FDA-approved for Cushing's disease when surgery is not an option or has failed 8
• Initial dosing: 0.6 mg or 0.9 mg subcutaneously twice daily, with maximum UFC reduction typically seen by 2 months 8
• Critical monitoring required: Weekly glycemic monitoring for first 2-3 months (nearly all patients develop worsening glycemia in first 2 weeks), baseline and periodic ECG for QT prolongation and bradycardia, baseline gallbladder ultrasound 8
• Dose reduction to 0.3 mg twice daily for moderate hepatic impairment; avoid in severe hepatic impairment 8

Adrenal Steroidogenesis Inhibitors:

• Ketoconazole is the medical treatment of choice for rapidly controlling hypercortisolism 4, 3
• Metyrapone, aminoglutethimide, and mitotane are alternatives for inhibiting steroid synthesis 4, 9
• These agents are effective in preparation for surgery, after unsuccessful tumor removal, or while awaiting radiotherapy effects 4

For Ectopic ACTH from Thymic Tumors:

• Adrenostatic agents (ketoconazole, mitotane) control hypercortisolism when tumor is unresectable 2
• Octreotide may be considered if tumor is Octreoscan-positive, though less effective than in other contexts 2

Glucocorticoid Receptor Blockers:

• Available as alternative medical therapy for various causes of Cushing syndrome 5

Aberrant Receptor Antagonists:

• Specific ligand receptor antagonists can normalize cortisol secretion in limited cases of bilateral macronodular adrenal hyperplasia with aberrant adrenal receptors 4

Bilateral Adrenalectomy (BLA) as Definitive Therapy

For severe, refractory Cushing's disease with life-threatening complications (such as left ventricular hypertrophy and cirrhosis), bilateral adrenalectomy should be performed to achieve rapid, definitive cortisol control. 7

• Laparoscopic BLA (transperitoneal or posterior retroperitoneal) has 10-18% complication rate and <1% mortality 6
• Clinical improvement in BMI, diabetes, hypertension, and muscle weakness occurs in >80% of patients 6
• Long-term hypercortisolism relapse from adrenal rest stimulation is uncommon (<10%) 6
• BLA may be warranted earlier in patients with severe hypercortisolism requiring rapid cortisol normalization or in females desiring pregnancy 6

Post-BLA Monitoring:

• Lifelong glucocorticoid and mineralocorticoid replacement is mandatory 7
• Monitor for Nelson syndrome (corticotroph tumor progression) with plasma ACTH and serial pituitary MRI starting 6 months post-surgery, as this occurs in 25-40% of patients after 5-10 years 6, 7
• Nelson syndrome risk appears higher in younger patients 7
• Most corticotroph tumor progression cases can be managed with surgery, radiation, or medical therapy 6

Radiation Therapy

• Pituitary radiation combined with ketoconazole or radiosurgery is effective for Cushing's disease, though longer-term evaluation of hypopituitarism and brain function is required 4
• Current evidence does not support systematic prophylactic radiotherapy after BLA to prevent Nelson syndrome 4
• When residual tumor progresses post-BLA, initiate surgery and radiotherapy promptly 4
• Long-term monitoring for hypopituitary deficiencies and secondary neoplasia in radiation field is required 6

Management of Hypocortisolism

• Monitor for signs of hypocortisolism (weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia, hypoglycemia) during medical therapy 8
• Consider temporary dose reduction or interruption with temporary exogenous glucocorticoid replacement if hypocortisolism develops 8
• After successful surgery, adrenal function typically recovers within approximately 12 months in children 6
• Temporary corticosteroid supplementation is required during HPA axis recovery 7

Pediatric-Specific Management

• Evaluate for growth hormone deficiency 3-6 months postoperatively and provide immediate GH replacement if indicated 6
• Monitor for recovery of hypothalamic-pituitary-adrenal axis with appropriate glucocorticoid replacement 6

Critical Pitfalls to Avoid

• Do not start pasireotide without optimizing glycemic control first in patients with poorly controlled diabetes (HbA1c >8%), as they are at higher risk for severe hyperglycemia and ketoacidosis 8
• Correct hypokalemia and hypomagnesemia before initiating pasireotide to minimize QT prolongation risk 8
• Do not use routine thromboprophylaxis in pediatric Cushing's surgery due to bleeding risk 6
• Be aware of carcinoid crisis risk with thymic carcinoid manipulation during surgery 2
• Monitor closely for hypoglycemia when discontinuing anti-diabetic therapy started during pasireotide treatment 8