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Interpret cortisol and ACTH levels to assess for Cushing syndrome, Addison disease, and other adrenal disorders. Evaluate the hypothalamic-pituitary-adrenal axis function.
Normal range: 6-23 mcg/dL
Normal range: 3-16 mcg/dL (helps assess diurnal variation)
Normal range: 10-60 pg/mL (critical for diagnosis)
Normal range: 10-100 mcg/day
| Test | Normal Range | Units |
|---|---|---|
| Morning Cortisol (8 AM) | 6 - 23 | mcg/dL |
| Evening Cortisol (4 PM) | 3 - 16 | mcg/dL |
| ACTH | 10 - 60 | pg/mL |
| 24-Hour Urine Cortisol | 10 - 100 | mcg/day |
Note: Reference ranges may vary between laboratories. Always use the reference range provided by your specific laboratory.
| Cortisol | ACTH | Likely Diagnosis |
|---|---|---|
| High | Low | ACTH-independent Cushing (adrenal tumor) |
| High | High | ACTH-dependent Cushing (pituitary or ectopic) |
| Low | High | Primary adrenal insufficiency (Addison disease) |
| Low | Low | Secondary/tertiary adrenal insufficiency |
| Normal | Normal | Normal HPA axis function |
Cortisol is a vital hormone produced by the adrenal glands that regulates metabolism, blood pressure, immune response, and stress response. The hypothalamic-pituitary-adrenal (HPA) axis tightly controls cortisol production through a feedback mechanism.
The hypothalamus releases CRH (corticotropin-releasing hormone), which stimulates the pituitary to release ACTH (adrenocorticotropic hormone). ACTH then stimulates the adrenal glands to produce cortisol. When cortisol levels are adequate, it provides negative feedback to suppress CRH and ACTH production.
Cushing syndrome results from prolonged exposure to excess cortisol. Symptoms include weight gain (especially central obesity), moon facies, buffalo hump, purple striae, easy bruising, muscle weakness, hypertension, diabetes, and mood changes. Causes include pituitary adenomas (Cushing disease), adrenal tumors, ectopic ACTH production, or exogenous glucocorticoid use.
Adrenal insufficiency occurs when the adrenal glands don't produce enough cortisol. Primary adrenal insufficiency (Addison disease) results from adrenal gland destruction, commonly due to autoimmune disease. Symptoms include fatigue, weight loss, low blood pressure, hyperpigmentation (in primary AI), salt craving, and potentially life-threatening adrenal crisis. Secondary and tertiary AI result from pituitary or hypothalamic dysfunction.
Normal cortisol levels follow a diurnal rhythm, with highest levels in the early morning (peak around 8 AM) and lowest levels at midnight. Loss of this normal variation, particularly elevated late-night cortisol, is an important feature of Cushing syndrome.
Testing is indicated for symptoms of cortisol excess (weight gain, easy bruising, muscle weakness, hypertension) or deficiency (fatigue, weight loss, low blood pressure, salt craving). ACTH should always be measured simultaneously with cortisol for diagnostic interpretation. Timing is critical: morning cortisol (8 AM) is best for screening adrenal insufficiency, while late-night cortisol helps diagnose Cushing syndrome.
Cushing syndrome is the general term for any condition causing excess cortisol exposure. Cushing disease specifically refers to a pituitary adenoma secreting excess ACTH, which is the most common endogenous cause (60-70% of cases). Other causes of Cushing syndrome include adrenal tumors (ACTH-independent), ectopic ACTH production from tumors like small cell lung cancer, and exogenous glucocorticoid use.
Random cortisol levels are difficult to interpret due to normal diurnal variation and stress-induced elevation. A morning cortisol < 3 mcg/dL strongly suggests adrenal insufficiency, while > 18 mcg/dL makes it unlikely. Values between 3-18 mcg/dL require ACTH stimulation testing. For Cushing syndrome, random levels are less useful; 24-hour urine free cortisol, late-night salivary cortisol, or dexamethasone suppression tests are preferred.
The ACTH stimulation (cosyntropin) test evaluates the adrenal glands' ability to produce cortisol in response to synthetic ACTH. After measuring baseline cortisol and ACTH, 250 mcg of cosyntropin is given IV or IM. Cortisol is measured at 30 and 60 minutes. A peak cortisol ≥ 18-20 mcg/dL is normal. Inadequate response indicates adrenal insufficiency, though it cannot distinguish primary from secondary causes without baseline ACTH measurement.
Yes, many medications affect cortisol. Exogenous glucocorticoids (prednisone, dexamethasone, hydrocortisone, inhaled or topical steroids) suppress the HPA axis and can cause iatrogenic Cushing syndrome or adrenal suppression. Oral contraceptives and estrogen increase cortisol-binding globulin, elevating total cortisol (free cortisol remains normal). Phenytoin, rifampin, and other enzyme inducers accelerate cortisol metabolism. Always inform your doctor of all medications before testing.
Adrenal crisis is a life-threatening emergency occurring in patients with adrenal insufficiency during severe stress, illness, or if glucocorticoid replacement is missed. Symptoms include severe weakness, confusion, abdominal pain, vomiting, severe hypotension, and shock. Treatment requires immediate IV hydrocortisone 100 mg followed by continuous infusion, aggressive IV fluids, and treatment of precipitating cause. All patients with adrenal insufficiency should wear medical alert identification and have injectable hydrocortisone available.
The patient collects all urine over a 24-hour period in a special container, usually starting with the second morning void and ending with the first void the next morning. The collection must be complete and refrigerated. The laboratory measures total cortisol excreted and creatinine to verify adequate collection. Values > 100 mcg/day (or 3-4 times the upper limit) suggest Cushing syndrome. This test is less affected by stress than serum cortisol but can be falsely elevated with high fluid intake.
Ectopic ACTH syndrome occurs when non-pituitary tumors produce ACTH, causing Cushing syndrome. Small cell lung cancer is the most common cause, but carcinoid tumors, medullary thyroid cancer, and pheochromocytomas can also produce ACTH. These patients typically have very high ACTH and cortisol levels, severe hypokalemia, rapid symptom onset, and may have hyperpigmentation. Imaging of chest, abdomen, and pelvis is needed to locate the tumor. Treatment focuses on tumor removal or control.
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