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Growth Hormone Deficiency & Growth Hormone Receptor Disorders (Study Outline) For study only—this is not medical advice or a substitute for professional care. 1. Background Definition:Conditions characterized by impaired growth due to inadequate GH secretion (pituitary origin) or impaired GH action (receptor or post-receptor defects). GH Deficiency: Low GH production. GH Resistance (Receptor Disorders): Normal or elevated GH, but defective GH receptor → low IGF-1. Classic example: Laron syndrome (autosomal recessive GH receptor mutation). Pathophysiology: GH normally stimulates hepatic IGF-1 production, promoting bone growth and protein synthesis. Deficiency: ↓ GH → ↓ IGF-1 → reduced linear growth. Resistance: GH present but ineffective → very low IGF-1, elevated GH due to loss of feedback. Etiology: GH Deficiency (GHD): Congenital: pituitary aplasia, midline defects, genetic defects (PROP1, PIT1). Acquired: trauma, CNS tumors (craniopharyngioma), radiation, infections, autoimmune hypophysitis. GH Resistance: GH receptor mutations (Laron syndrome). Post-receptor signaling defects. Liver disease (impaired IGF-1 synthesis). Epidemiology: Presents in childhood with poor linear growth; can also occur in adults with pituitary disease. 2. History Children: Short stature (height

Diabetes Mellitus Type 1 (Study Outline) For study only—this is not medical advice or a substitute for professional care. 1. Background Definition: Autoimmune destruction of pancreatic β-cells → absolute insulin deficiency. Pathophysiology: T-cell–mediated autoimmune attack on islet cells (especially HLA-DR3/DR4 associations). Leads to complete loss of endogenous insulin production. Onset often in childhood or adolescence but can occur at any age (“LADA” in adults). Epidemiology: Peaks at 4–6 years and 10–14 years. ~5–10% of diabetes cases in the U.S. Increased risk with family history or other autoimmune diseases (thyroiditis, celiac disease). Key Mechanism: Autoantibodies (e.g., anti-GAD65, IA-2, insulin autoantibodies) precede hyperglycemia. 2. History Typical Symptoms (Classic Triad): Polyuria, polydipsia, polyphagia. Weight loss despite normal/increased appetite. Fatigue, blurred vision. Acute Presentation: Diabetic ketoacidosis (DKA): nausea, vomiting, abdominal pain, rapid breathing, fruity breath. Risk Factors/Associations: Family history of autoimmune disease. Viral triggers (e.g., coxsackievirus). Historical Clues: Sudden symptom onset over days to weeks. No history of obesity or metabolic syndrome features. 3. Exam Findings General: Thin or underweight body habitus. Dehydration signs: dry mucous membranes, poor skin turgor. DKA Findings: Kussmaul respirations (deep, labored breathing). Fruity (acetone) odor on breath. Hypotension, tachycardia. Altered mental status in severe cases. Associated Autoimmune Conditions: Goiter (thyroid disease), vitiligo, celiac signs. 4. Making the Diagnosis Key Laboratory Findings: Fasting plasma glucose ≥126 mg/dL on two occasions. Random glucose ≥200 mg/dL with classic symptoms. A1C ≥6.5%. Oral glucose tolerance test (OGTT): 2-hour value ≥200 mg/dL. Autoimmune Markers: Positive GAD65, IA-2, insulin autoantibodies, or ZnT8 confirm autoimmune etiology. Additional Testing: Low or undetectable C-peptide (reflects lack of insulin production). Urine ketones positive in DKA or poor control. Gold Standard: Demonstration of autoimmune β-cell destruction with positive diabetes-associated autoantibodies. Distinguishing from Type 2 DM: Younger, leaner, rapid onset, ketosis-prone, autoimmune antibodies present. 5. Management (Exam Concepts) General Principles: Lifelong exogenous insulin therapy is required. Frequent glucose monitoring (SMBG or CGM). Goal A1C: generally

Hypothyroidism (Study Outline) For study only—this is not medical advice or a substitute for professional care. 1. Background Definition:A clinical syndrome resulting from deficient production of thyroid hormones (T₄ and T₃) or impaired action at the tissue level. Pathophysiology: Primary hypothyroidism (most common): failure of the thyroid gland → ↑ TSH, ↓ free T₄. Secondary (central): pituitary dysfunction → ↓ TSH and ↓ T₄. Tertiary: hypothalamic failure (↓ TRH). Common Causes (Primary): Autoimmune (Hashimoto thyroiditis) – most common in the U.S. Iatrogenic: post-thyroidectomy, radioactive iodine, or antithyroid medications. Iodine deficiency or excess. Congenital hypothyroidism (thyroid dysgenesis, enzyme defects). Drugs: lithium, amiodarone, interferon-α, tyrosine kinase inhibitors. Epidemiology: More common in women and older adults. Hashimoto’s thyroiditis often associated with other autoimmune disorders (e.g., type 1 DM, pernicious anemia). 2. History Symptoms (Gradual Onset): Fatigue, weakness, cold intolerance. Weight gain despite decreased appetite. Constipation. Dry skin, hair loss, brittle nails. Depression, memory impairment, slowed thinking. Menstrual irregularities, infertility. Severe Forms: Myxedema: severe, long-standing hypothyroidism → nonpitting edema, facial puffiness, hoarseness, periorbital swelling. Myxedema coma: life-threatening decompensation with hypothermia, bradycardia, hypotension, and hypoventilation (precipitated by illness or sedatives). Historical Clues: Prior thyroid surgery or radioactive iodine therapy. Family history of autoimmune disease. Recent medication changes (e.g., lithium, amiodarone). 3. Exam Findings General: Fatigued appearance, weight gain, coarse dry hair, pallor. Skin: Cool, dry, thickened skin; nonpitting edema (myxedema). Cardiovascular: Bradycardia, diastolic hypertension, pericardial effusion (severe). Neurologic: Delayed relaxation of deep tendon reflexes (especially Achilles). HEENT: Puffy face, periorbital edema, enlarged or atrophic thyroid. Other: Macroglossia, hoarseness, carpal tunnel syndrome. Pediatric Findings: Growth retardation, delayed bone age, developmental delay if congenital. 4. Making the Diagnosis Initial Test (Gold Standard): Serum TSH — most sensitive screening test. Interpretation: Primary hypothyroidism: ↑ TSH, ↓ free T₄. Secondary (pituitary): ↓ or inappropriately normal TSH, ↓ free T₄. Subclinical hypothyroidism: mildly ↑ TSH with normal free T₄. Autoimmune Confirmation: Positive anti-thyroid peroxidase (anti-TPO) or anti-thyroglobulin antibodies → Hashimoto thyroiditis. Other Findings: Lipid abnormalities: hypercholesterolemia, ↑ LDL. Hyponatremia: due to decreased free water clearance. Anemia: normocytic or macrocytic. Imaging: Thyroid ultrasound: heterogenous or atrophic gland (Hashimoto). MRI of pituitary: indicated if secondary hypothyroidism suspected. 5. Management (Exam Concepts) (Conceptual overview only—no dosing or treatment directives.) General Principles: Thyroid hormone replacement (e.g., levothyroxine) is standard. Primary hypothyroidism: lifelong replacement and regular TSH monitoring. Secondary hypothyroidism: monitor free T₄, not TSH, for adjustment. Special Situations (Conceptual): Myxedema coma: medical emergency—requires ICU care and supportive management. Pregnancy: increased thyroid hormone requirement; check TSH each trimester. Exam Tip: Drug-induced hypothyroidism → lithium, amiodarone. Most sensitive test: serum TSH. Hashimoto thyroiditis: firm, irregular, painless goiter + positive anti-TPO antibodies. Monitoring: Reassess TSH every 6–8 weeks after dose adjustment. Evaluate for improvement in symptoms, energy, and metabolic parameters.   QUESTION A 45-year-old woman presents with fatigue, weight gain, and constipation. Physical exam shows dry skin, bradycardia, and delayed relaxation of deep tendon reflexes. Laboratory results reveal TSH 9.8 mIU/L (elevated) and free T₄ below normal. Which of the following additional findings is most likely? A. Elevated anti-thyroid peroxidase (anti-TPO) antibodiesB. Elevated free T₃ and suppressed TSHC. Elevated serum calcium and decreased phosphateD. Decreased LDL cholesterol  

Cushing Syndrome (Study Outline) For study only—this is not medical advice or a substitute for professional care. 1. Background Definition:A disorder caused by prolonged exposure to elevated glucocorticoids (cortisol), whether from endogenous overproduction or exogenous administration. Terminology: Cushing syndrome: the clinical state of cortisol excess (any cause). Cushing disease: specifically from an ACTH-secreting pituitary adenoma. Pathophysiology: ACTH-dependent: Pituitary adenoma (Cushing disease, ~70% of endogenous cases). Ectopic ACTH secretion (e.g., small cell lung carcinoma). ACTH-independent: Adrenal adenoma or carcinoma. Exogenous corticosteroids (most common overall). Cortisol excess → ↑ gluconeogenesis, protein catabolism, lipolysis, and mineralocorticoid activity → metabolic, cardiovascular, and immune effects. Epidemiology: More common in women aged 20–50 years for endogenous disease. Exogenous corticosteroid use is the leading cause overall. 2. History Gradual onset over months to years. Typical Symptoms: Weight gain (central/truncal). Fatigue, weakness, depression, irritability. Menstrual irregularities, decreased libido. Headache or vision changes (pituitary tumor). Metabolic/Endocrine: Glucose intolerance or diabetes. Hypertension, osteoporosis, edema. Physical Appearance (classic triad): Truncal obesity, moon facies, buffalo hump. Other Findings: Purple (>1 cm) abdominal striae, easy bruising, thin skin, poor wound healing. Hirsutism and acne (from adrenal androgens). 3. Exam Findings General: Central obesity with thin limbs, proximal muscle wasting. Skin: Fragile skin, violaceous striae, acne, easy bruising. HEENT: Facial rounding, plethora, supraclavicular fat pads. CV: Hypertension, possible edema. Neuropsych: Depression, insomnia, irritability. Reproductive: Decreased libido, menstrual changes, infertility. 4. Making the Diagnosis Step 1 – Confirm Hypercortisolism (screening): 24-hour urinary free cortisol: elevated. Late-night salivary cortisol: elevated. Low-dose dexamethasone suppression test: failure to suppress cortisol confirms Cushing syndrome. Step 2 – Determine ACTH Dependence: Low ACTH: adrenal tumor or exogenous steroids. High/normal ACTH: pituitary adenoma or ectopic ACTH source. Step 3 – Identify the Source: High-dose dexamethasone suppression test: Pituitary (Cushing disease): partial suppression. Ectopic ACTH: no suppression. CRH stimulation test: Pituitary: ACTH rises. Ectopic: no response. Imaging: Pituitary MRI for suspected adenoma. CT chest/abdomen for ectopic or adrenal tumors. Gold Standard: Demonstration of hypercortisolism via ≥2 positive screening tests, followed by ACTH level determination and localization studies. 5. Management (Exam Concepts) (Conceptual overview only—no dosing or treatment regimens.) Iatrogenic (exogenous steroids): gradual taper of glucocorticoids. Cushing disease (pituitary adenoma): transsphenoidal surgical resection. Adrenal adenoma/carcinoma: adrenalectomy. Ectopic ACTH tumor: surgical resection if possible; medical suppression if unresectable. Medical therapy (for refractory disease): Steroidogenesis inhibitors (ketoconazole, metyrapone, mitotane). Glucocorticoid receptor antagonist (mifepristone). Postoperative care: monitor for adrenal insufficiency and hormone replacement needs. Complications: hypertension, diabetes, osteoporosis, infections, psychiatric symptoms. Exam Tips: Most common cause overall: exogenous corticosteroids. Most common endogenous cause: pituitary adenoma. Ectopic ACTH: severe hypokalemia, rapid onset, hyperpigmentation. Adrenal tumor: low ACTH, unilateral adrenal mass. NBME-Style Practice Question A 39-year-old woman presents with progressive weight gain, fatigue, and easy bruising. She has a rounded face, dorsocervical fat pad, and violaceous abdominal striae. Laboratory testing reveals elevated urinary free cortisol and failure to suppress cortisol on a low-dose dexamethasone suppression test. Plasma ACTH is elevated. Which of the following tests best distinguishes a pituitary from an ectopic source of ACTH? A. Serum DHEA-S levelB. High-dose dexamethasone suppression testC. MRI of the adrenal glandsD. 24-hour urinary metanephrine level

Diabetes Mellitus Type 1 (Study Outline) For study only—this is not medical advice or a substitute for professional care. 1. Background Definition: Autoimmune destruction of pancreatic β-cells → absolute insulin deficiency. Pathophysiology: T-cell–mediated autoimmune attack on islet cells (especially HLA-DR3/DR4 associations). Leads to complete loss of endogenous insulin production. Onset often in childhood or adolescence but can occur at any age (“LADA” in adults). Epidemiology: Peaks at 4–6 years and 10–14 years. ~5–10% of diabetes cases in the U.S. Increased risk with family history or other autoimmune diseases (thyroiditis, celiac disease). Key Mechanism: Autoantibodies (e.g., anti-GAD65, IA-2, insulin autoantibodies) precede hyperglycemia. 2. History Typical Symptoms (Classic Triad): Polyuria, polydipsia, polyphagia. Weight loss despite normal/increased appetite. Fatigue, blurred vision. Acute Presentation: Diabetic ketoacidosis (DKA): nausea, vomiting, abdominal pain, rapid breathing, fruity breath. Risk Factors/Associations: Family history of autoimmune disease. Viral triggers (e.g., coxsackievirus). Historical Clues: Sudden symptom onset over days to weeks. No history of obesity or metabolic syndrome features. 3. Exam Findings General: Thin or underweight body habitus. Dehydration signs: dry mucous membranes, poor skin turgor. DKA Findings: Kussmaul respirations (deep, labored breathing). Fruity (acetone) odor on breath. Hypotension, tachycardia. Altered mental status in severe cases. Associated Autoimmune Conditions: Goiter (thyroid disease), vitiligo, celiac signs. 4. Making the Diagnosis Key Laboratory Findings: Fasting plasma glucose ≥126 mg/dL on two occasions. Random glucose ≥200 mg/dL with classic symptoms. A1C ≥6.5%. Oral glucose tolerance test (OGTT): 2-hour value ≥200 mg/dL. Autoimmune Markers: Positive GAD65, IA-2, insulin autoantibodies, or ZnT8 confirm autoimmune etiology. Additional Testing: Low or undetectable C-peptide (reflects lack of insulin production). Urine ketones positive in DKA or poor control. Gold Standard: Demonstration of autoimmune β-cell destruction with positive diabetes-associated autoantibodies. Distinguishing from Type 2 DM: Younger, leaner, rapid onset, ketosis-prone, autoimmune antibodies present. 5. Management (Exam Concepts) General Principles: Lifelong exogenous insulin therapy is required. Frequent glucose monitoring (SMBG or CGM). Goal A1C: generally

Growth Hormone Deficiency & Growth Hormone Receptor Disorders (Study Outline) For study only—this is not medical advice or a substitute for professional care. 1. Background Definition:Conditions characterized by impaired growth due to inadequate GH secretion (pituitary origin) or impaired GH action (receptor or post-receptor defects). GH Deficiency: Low GH production. GH Resistance (Receptor Disorders): Normal or elevated GH, but defective GH receptor → low IGF-1. Classic example: Laron syndrome (autosomal recessive GH receptor mutation). Pathophysiology: GH normally stimulates hepatic IGF-1 production, promoting bone growth and protein synthesis. Deficiency: ↓ GH → ↓ IGF-1 → reduced linear growth. Resistance: GH present but ineffective → very low IGF-1, elevated GH due to loss of feedback. Etiology: GH Deficiency (GHD): Congenital: pituitary aplasia, midline defects, genetic defects (PROP1, PIT1). Acquired: trauma, CNS tumors (craniopharyngioma), radiation, infections, autoimmune hypophysitis. GH Resistance: GH receptor mutations (Laron syndrome). Post-receptor signaling defects. Liver disease (impaired IGF-1 synthesis). Epidemiology: Presents in childhood with poor linear growth; can also occur in adults with pituitary disease. 2. History Children: Short stature (height

Hyperthyroidism (Study Outline) For study only—this is not medical advice or a substitute for professional care. 1. Background Definition:Clinical state resulting from excess thyroid hormone (T₃ and/or T₄) production or release, leading to increased metabolic activity in multiple organ systems. Pathophysiology: Primary hyperthyroidism: Overproduction from the thyroid gland → ↓ TSH, ↑ T₄/T₃. Secondary: Pituitary overproduction of TSH (rare). Tertiary: Hypothalamic TRH excess (very rare). Common Causes (Primary): Graves disease (autoimmune; TSH receptor–stimulating antibodies). Toxic multinodular goiter (autonomous nodules secreting thyroid hormone). Toxic adenoma (single hyperfunctioning nodule). Thyroiditis (subacute, painless, postpartum — transient release of stored hormone). Iatrogenic or exogenous thyroxine ingestion. Epidemiology: Women > men; peak onset 20–40 years. Graves disease most common cause in the U.S. 2. History Symptoms (due to increased metabolism and sympathetic activity): Nervousness, irritability, anxiety, insomnia. Heat intolerance, excessive sweating. Weight loss despite increased appetite. Palpitations, tachycardia, dyspnea on exertion. Increased bowel movements or diarrhea. Menstrual irregularities, infertility. Tremor, fatigue, muscle weakness. Special Presentations: Graves disease: ophthalmopathy (proptosis, lid lag), pretibial myxedema, diffuse goiter. Thyroiditis: transient hyperthyroid phase following viral or postpartum inflammation. Thyrotoxicosis factitia: from exogenous thyroid hormone ingestion (suppressed thyroglobulin). 3. Exam Findings General: Warm, moist skin; thin habitus; hyperactivity. Vital Signs: Tachycardia, widened pulse pressure, possible atrial fibrillation. HEENT: Graves ophthalmopathy: exophthalmos, periorbital edema, conjunctival injection. Lid lag, stare. Thyroid: Diffusely enlarged (Graves) or nodular (toxic goiter). May have bruit. Cardiovascular: Tachyarrhythmias, systolic flow murmur. Neurologic: Fine tremor, hyperreflexia. Skin: Warm, moist, fine hair, onycholysis; pretibial myxedema (Graves). Elderly (“apathetic hyperthyroidism”): may lack classic hypermetabolic symptoms—present with fatigue or weight loss only. 4. Making the Diagnosis Initial and Most Sensitive Test: Serum TSH (low or undetectable in primary hyperthyroidism). Confirmatory Tests: Free T₄ and/or T₃: elevated. TSH-receptor antibodies (TRAb): diagnostic for Graves disease. Thyroglobulin: elevated in endogenous hyperthyroidism, suppressed in exogenous hormone use. Radioactive Iodine Uptake (RAIU) Scan: Diffuse uptake: Graves disease. Focal uptake: toxic adenoma. Patchy uptake: multinodular goiter. Low uptake: thyroiditis or factitious thyrotoxicosis. Additional Findings: Hypercalcemia (from bone turnover). Elevated alkaline phosphatase (bone isoenzyme). Mild anemia; increased hepatic enzymes possible. Gold Standard: Biochemical confirmation of low TSH with elevated free T₄/T₃ and characteristic uptake pattern. 5. Management (Exam Concepts) (Conceptual overview only—no dosing or treatment regimens.) General Principles: Goal: normalize thyroid hormone levels and control symptoms. Symptom control: beta-blockers (e.g., propranolol) for adrenergic manifestations. Definitive Therapy Options (exam-level concepts): Antithyroid medications: inhibit hormone synthesis (e.g., thionamides). Radioactive iodine ablation: destroys overactive thyroid tissue (commonly used for Graves). Surgery (thyroidectomy): for large goiters, compressive symptoms, or intolerance to medical therapy. Special Clinical Scenarios: Thyroid storm: life-threatening thyrotoxic crisis—fever, tachycardia, delirium; requires ICU-level care and emergent management. Pregnancy: use of specific antithyroid drugs varies by trimester (exam point only). Thyroiditis: often transient—treat symptomatically. Follow-up: Regular TSH and free T₄ monitoring after treatment. Screen for and manage osteoporosis and atrial fibrillation in long-standing disease. Exam Tip: Graves: diffuse goiter + ophthalmopathy + pretibial myxedema + positive TRAb. Thyroiditis: low RAI uptake and transient course.     QUESTION A 32-year-old woman presents with palpitations, anxiety, heat intolerance, and weight loss. Exam reveals a diffusely enlarged thyroid gland with a bruit, fine tremor, and mild exophthalmos. Laboratory results show TSH

Diabetes Mellitus Type 2 (Study Outline) For study only—this is not medical advice or a substitute for professional care. 1. Background Definition: Chronic hyperglycemia resulting from insulin resistance and progressive β-cell dysfunction. Pathophysiology: Peripheral tissues (muscle, liver, adipose) become resistant to insulin’s effects. Pancreatic β-cells initially increase insulin output but eventually fail. Associated metabolic disturbances: ↑ hepatic glucose production, ↓ peripheral glucose uptake. Epidemiology: 90% of diabetes cases. Typically develops after age 40, but increasing prevalence in adolescents with obesity. Strongly linked to obesity, sedentary lifestyle, and family history. Risk Factors: Obesity (especially central/visceral). Family history, hypertension, dyslipidemia, polycystic ovary syndrome. Certain ethnicities: African American, Hispanic, Native American, Pacific Islander. 2. History Gradual Onset Symptoms: Polyuria, polydipsia, polyphagia. Fatigue, blurred vision. Recurrent infections (e.g., skin, vaginal, urinary). Poor wound healing, acanthosis nigricans. Often Asymptomatic: May be discovered incidentally on labs. Associated Conditions: Metabolic syndrome (obesity, hypertension, dyslipidemia, insulin resistance). DKA Rare: Hyperosmolar hyperglycemic state (HHS) more common. 3. Exam Findings General: Overweight or obese body habitus. Blood pressure often elevated. Skin: Acanthosis nigricans: hyperpigmented, velvety plaques (neck, axilla). Skin tags (acrochordons). Complications: Peripheral neuropathy (sensory loss, paresthesias). Retinopathy signs on fundoscopic exam (microaneurysms, exudates). Decreased vibratory sense or absent reflexes in feet. 4. Making the Diagnosis Diagnostic Criteria (any of the following): Fasting plasma glucose ≥126 mg/dL (×2). A1C ≥6.5%. 2-hour OGTT glucose ≥200 mg/dL after 75 g glucose load. Random glucose ≥200 mg/dL with classic symptoms. Laboratory Findings: Elevated or normal C-peptide (reflects continued endogenous insulin production). No pancreatic autoantibodies (distinguishes from Type 1 DM). Screening Recommendations: Adults ≥35 years, or earlier if overweight with additional risk factors. Repeat every 3 years if normal. Gold Standard: Biochemical confirmation of hyperglycemia (fasting glucose or A1C). Common Associated Labs: Dyslipidemia: ↑ triglycerides, ↓ HDL, ↑ LDL. Possible hepatic steatosis on imaging. 5. Management (Exam Concepts) Lifestyle Modifications: Weight loss (5–10% body weight), healthy diet, regular exercise. First-line for all patients and may normalize glucose in early disease. Pharmacologic Therapy: First-line: Oral antihyperglycemics (mechanisms emphasized on PANCE): Biguanides (e.g., metformin): ↓ hepatic glucose output, ↑ insulin sensitivity. Other classes: SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, sulfonylureas. Insulin may be required for severe hyperglycemia or β-cell exhaustion. Monitoring: A1C every 3 months until stable (

Hypoglycemia (Study Outline) For study only—this is not medical advice or a substitute for professional care. 1. Background Definition:Blood glucose level

Cushing Syndrome (Study Outline) For study only—this is not medical advice or a substitute for professional care. 1. Background Definition:A disorder caused by prolonged exposure to elevated glucocorticoids (cortisol), whether from endogenous overproduction or exogenous administration. Terminology: Cushing syndrome: the clinical state of cortisol excess (any cause). Cushing disease: specifically from an ACTH-secreting pituitary adenoma. Pathophysiology: ACTH-dependent: Pituitary adenoma (Cushing disease, ~70% of endogenous cases). Ectopic ACTH secretion (e.g., small cell lung carcinoma). ACTH-independent: Adrenal adenoma or carcinoma. Exogenous corticosteroids (most common overall). Cortisol excess → ↑ gluconeogenesis, protein catabolism, lipolysis, and mineralocorticoid activity → metabolic, cardiovascular, and immune effects. Epidemiology: More common in women aged 20–50 years for endogenous disease. Exogenous corticosteroid use is the leading cause overall. 2. History Gradual onset over months to years. Typical Symptoms: Weight gain (central/truncal). Fatigue, weakness, depression, irritability. Menstrual irregularities, decreased libido. Headache or vision changes (pituitary tumor). Metabolic/Endocrine: Glucose intolerance or diabetes. Hypertension, osteoporosis, edema. Physical Appearance (classic triad): Truncal obesity, moon facies, buffalo hump. Other Findings: Purple (>1 cm) abdominal striae, easy bruising, thin skin, poor wound healing. Hirsutism and acne (from adrenal androgens). 3. Exam Findings General: Central obesity with thin limbs, proximal muscle wasting. Skin: Fragile skin, violaceous striae, acne, easy bruising. HEENT: Facial rounding, plethora, supraclavicular fat pads. CV: Hypertension, possible edema. Neuropsych: Depression, insomnia, irritability. Reproductive: Decreased libido, menstrual changes, infertility. 4. Making the Diagnosis Step 1 – Confirm Hypercortisolism (screening): 24-hour urinary free cortisol: elevated. Late-night salivary cortisol: elevated. Low-dose dexamethasone suppression test: failure to suppress cortisol confirms Cushing syndrome. Step 2 – Determine ACTH Dependence: Low ACTH: adrenal tumor or exogenous steroids. High/normal ACTH: pituitary adenoma or ectopic ACTH source. Step 3 – Identify the Source: High-dose dexamethasone suppression test: Pituitary (Cushing disease): partial suppression. Ectopic ACTH: no suppression. CRH stimulation test: Pituitary: ACTH rises. Ectopic: no response. Imaging: Pituitary MRI for suspected adenoma. CT chest/abdomen for ectopic or adrenal tumors. Gold Standard: Demonstration of hypercortisolism via ≥2 positive screening tests, followed by ACTH level determination and localization studies. 5. Management (Exam Concepts) (Conceptual overview only—no dosing or treatment regimens.) Iatrogenic (exogenous steroids): gradual taper of glucocorticoids. Cushing disease (pituitary adenoma): transsphenoidal surgical resection. Adrenal adenoma/carcinoma: adrenalectomy. Ectopic ACTH tumor: surgical resection if possible; medical suppression if unresectable. Medical therapy (for refractory disease): Steroidogenesis inhibitors (ketoconazole, metyrapone, mitotane). Glucocorticoid receptor antagonist (mifepristone). Postoperative care: monitor for adrenal insufficiency and hormone replacement needs. Complications: hypertension, diabetes, osteoporosis, infections, psychiatric symptoms. Exam Tips: Most common cause overall: exogenous corticosteroids. Most common endogenous cause: pituitary adenoma. Ectopic ACTH: severe hypokalemia, rapid onset, hyperpigmentation. Adrenal tumor: low ACTH, unilateral adrenal mass. NBME-Style Practice Question A 39-year-old woman presents with progressive weight gain, fatigue, and easy bruising. She has a rounded face, dorsocervical fat pad, and violaceous abdominal striae. Laboratory testing reveals elevated urinary free cortisol and failure to suppress cortisol on a low-dose dexamethasone suppression test. Plasma ACTH is elevated. Which of the following tests best distinguishes a pituitary from an ectopic source of ACTH? A. Serum DHEA-S levelB. High-dose dexamethasone suppression testC. MRI of the adrenal glandsD. 24-hour urinary metanephrine level