USMLE/COMLEX 3 - Cortisol Physiology & Pathology

Here are key facts for USMLE Step 3 & COMLEX-USA Level 3 from the Cortisol Physiology & Pathology, as well as points of interest at the end of this document that are not directly addressed in this tutorial but should help you prepare for the boards. See the tutorial notes for further details and relevant links.

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1. Screening approach: Screening for hypercortisolism can be done via 24-hour urine samples, midnight salivary samples, or dexamethasone suppression test. 2. Algorithmic diagnosis: If cortisol levels are elevated and/or not suppressed by dexamethasone, Cushing's syndrome is likely; then measure plasma ACTH to determine etiology. 3. Excluding secondary causes: Important to rule out physiologic causes and medical conditions that raise cortisol: pregnancy, alcoholism, anorexia, obesity, depression, and uncontrolled diabetes. 4. Exogenous vs. endogenous: Exogenous glucocorticoids are responsible for most cases of ACTH-independent hypercortisolism, termed exogenous or iatrogenic Cushing's syndrome. 5. Chronic stress effects: Chronic physical and/or psychosocial stress and subsequent hypercortisolism can have widespread negative health effects. 1. Localization techniques: For ACTH-dependent cases, inferior petrosal sampling helps determine source of excess ACTH. 2. Sampling interpretation: Central ACTH levels higher than peripheral levels suggest a pituitary tumor (Cushing's Disease), while central ACTH levels less than or equal to peripheral levels suggest an ectopic tumor. 3. Malignancy workup: Small cell lung cancer and bronchial tumors are common sources of ectopic ACTH, requiring appropriate imaging. 4. Adrenal imaging findings: With adrenal causes, expect a unilateral tumor with contralateral adrenal atrophy due to lack of ACTH stimulation. 5. Adrenal pathology: Adenomas are more common than carcinomas, and carcinomas are more likely to secrete androgens along with cortisol. 1. Pituitary approach: For Cushing's Disease, treatment involves removal of the pituitary tumor, which can reverse effects in many, but not all, patients. 2. Surgical alternatives: Some patients may require bilateral adrenalectomy when pituitary surgery is insufficient. 3. Post-surgical complication: After bilateral adrenalectomy, be alert for Nelson syndrome (corticotroph tumor progression) with headaches, elevated ACTH, and hyperpigmentation. 4. Endocrine consequences: Secretion of thyrotropin, gonadotropin, and growth hormone are suppressed in Cushing's Disease. 5. HPA dysfunction: In Cushing's Disease, the HPA axis becomes dysfunctional and no longer responsive to negative feedback or stress stimuli.

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1. Metabolic complications: Hyperglycemia may progress to diabetes mellitus due to increased gluconeogenesis and insulin resistance. 2. Cardiovascular impact: Hypertension occurs via multiple effects including increased cardiac contractility and extracellular fluid volume. 3. Immunologic considerations: Immunosuppression increases vulnerability to infections requiring robust B- and T-cell responses (tuberculosis, fungal infections). 4. Musculoskeletal effects: Muscle atrophy particularly affects extremities; chronic elevated cortisol leads to osteoporosis and increased fracture risk. 5. Dermatologic findings: Red/purple striae (abdomen, breasts, thighs, buttocks), easy bruising, and fat redistribution (moon facies, buffalo hump, central obesity) are characteristic. 1. Cortisol measurements: Most cortisol (approximately 85%) is bound to plasma proteins giving it a long half-life, while urine free cortisol and salivary cortisol measurements detect unbound cortisol. 2. Circadian variations: Cortisol secretion is pulsatile and circadian with highest levels upon waking and lowest around bedtime, requiring consideration of sleep schedule when assessing levels. 3. Dexamethasone suppression: Dexamethasone, a synthetic glucocorticoid, mimics cortisol's negative feedback effects and is used to help diagnose Cushing's syndrome. 4. ACTH assessment: Measuring plasma ACTH determines if hypercortisolism is ACTH-dependent or independent. 5. HPA axis dysfunction: In Cushing's Disease, the HPA axis is no longer responsive to negative feedback from cortisol or to stressors that would typically stimulate additional ACTH release. 1. Adrenal hyperplasia: Bilateral macro- and micro-nodular adrenal hyperplasias, though rare, can cause ACTH-independent Cushing's syndrome. 2. Pediatric considerations: Hypercortisolism in children can impair linear growth via negative effects on bone growth and impaired secretion of growth hormone and thyroid stimulating hormone. 3. Endocrine comorbidities: Excess androgen secretion with some forms (adrenal tumors) causes hirsutism and menstrual irregularities. 4. Psychiatric manifestations: Patients may experience emotional or psychiatric disturbances, such as irritability or impaired memory. 5. Post-treatment monitoring: After pituitary tumor removal, effects can be reversed in many but not all patients, suggesting need for ongoing monitoring.

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1. Medical therapy: Steroidogenesis inhibitors (ketoconazole, metyrapone) may be used when surgery is contraindicated or as bridge therapy. 2. Receptor antagonists: Mifepristone blocks glucocorticoid receptor action and may rapidly improve glucose metabolism. 3. Targeted therapies: Pasireotide targets somatostatin receptors on corticotroph tumors, particularly useful in persistent/recurrent Cushing's Disease. 4. Radiation options: Stereotactic radiosurgery may provide long-term control for pituitary tumors when surgical resection is incomplete. 5. Combination approaches: Multiple modality treatment may be necessary for refractory cases, including sequential or simultaneous medical therapies. 1. Adrenal insufficiency: Post-treatment glucocorticoid replacement protocols and stress dosing education are critical after cure of Cushing's syndrome. 2. Cardiovascular risk reduction: Long-term monitoring and management of persistent metabolic syndrome components even after biochemical cure. 3. Quality of life assessment: Recognition and management of persistent cognitive, psychological, and physical symptoms that may persist despite normalization of cortisol. 4. Recurrence surveillance: Protocols for long-term biochemical monitoring vary by etiology, with higher recurrence risk in certain subtypes. 5. Special populations: Management adaptations needed for pregnancy, elderly patients, and those with significant comorbidities.