Management of Abnormal Cortisol Levels
Low Cortisol (Adrenal Insufficiency)
For patients with confirmed adrenal insufficiency, initiate hydrocortisone 15-20 mg daily in divided doses (typically 2/3 in morning, 1/3 early afternoon) with endocrinology consultation, and educate immediately on stress dosing and emergency management. 1
Diagnostic Workup
- Measure morning (AM) cortisol and ACTH simultaneously to distinguish primary from secondary adrenal insufficiency 1
- If ACTH is low with low cortisol, this indicates secondary (central) adrenal insufficiency from pituitary dysfunction 1
- If ACTH is elevated with low cortisol, this indicates primary adrenal insufficiency 1
- Consider ACTH stimulation testing when AM cortisol is indeterminate (between 3-15 mcg/dL) 1
- Check electrolytes, TSH, and free T4 1
- Obtain adrenal CT to evaluate for metastasis or hemorrhage in primary adrenal insufficiency 1
Treatment by Severity
Grade 1 (Asymptomatic or Mild Symptoms):
- Start hydrocortisone 15-20 mg daily in divided doses 1
- Titrate up to maximum 30 mg daily for residual symptoms 1
- Most primary adrenal insufficiency requires fludrocortisone 0.05-0.1 mg daily, adjusted based on volume status, sodium, and renin (target upper half of reference range) 1
- Consider holding immune checkpoint inhibitors until stabilized on replacement 1
- Reduce dosing if iatrogenic Cushing's symptoms develop (bruising, thin skin, edema, weight gain, hypertension, hyperglycemia) 1
Grade 2 (Moderate Symptoms, Able to Perform ADL):
- Initiate stress-dose corticosteroids at 2-3 times maintenance (hydrocortisone 30-50 mg total or prednisone 20 mg daily) 1
- Start fludrocortisone 0.05-0.1 mg daily 1
- Decrease to maintenance doses after 2 days 1
- Assess need for IV hydration and possible hospitalization 1
Grade 3-4 (Severe/Life-Threatening, Unable to Perform ADL):
- Hospitalize for IV stress-dose steroids: hydrocortisone 50-100 mg every 6-8 hours 1
- Administer at least 2L normal saline 1
- Taper stress-dose corticosteroids to oral maintenance over 5-7 days 1
- Hold immune checkpoint inhibitors until stabilized 1
Critical Patient Education
- All patients require education on stress dosing for sick days, emergency injectable use, and when to seek medical attention for impending adrenal crisis 1
- Provide medical alert bracelet or necklace indicating adrenal insufficiency 1
- Prescribe emergency IM steroid with instructions 1
- Warn patients on immunosuppressant doses to avoid chicken pox or measles exposure and seek immediate medical advice if exposed 2
Important Considerations
- Hydrocortisone allows recreation of diurnal cortisol rhythm; long-acting steroids like prednisone carry over-replacement risk but may be used if adherence to short-acting regimen is problematic 1
- Hydrocortisone 20 mg equals prednisone 5 mg 1
- Secondary adrenal insufficiency rarely requires mineralocorticoid replacement 1
- Drug-induced secondary adrenocortical insufficiency may persist for months after discontinuation; reinstitute hormone therapy during any stress period 2
- Monitor thyroid function, as there is enhanced corticosteroid effect in hypothyroidism 2, 3
High Cortisol (Cushing's Syndrome)
For confirmed hypercortisolism with non-elevated ACTH (suggesting adrenal source), obtain adrenal imaging immediately and proceed to surgical adrenalectomy for adenoma or medical management with ketoconazole 400-1200 mg/day for non-surgical candidates. 4, 5
Diagnostic Algorithm
- Confirm hypercortisolism with 24-hour urinary free cortisol test 4, 5
- Measure ACTH level to determine if ACTH-dependent or ACTH-independent 4, 5
- Normal or low ACTH with elevated cortisol indicates adrenal source (adenoma, carcinoma, or bilateral hyperplasia) 4, 5
- Elevated ACTH suggests pituitary or ectopic source 5
- Obtain adrenal CT or MRI with adrenal protocol to assess mass size, unilateral vs bilateral abnormalities, and malignancy features 4
- For suspected pituitary source, obtain pituitary MRI 5
Treatment Based on Source and Severity
Adrenal Adenoma:
- Laparoscopic adrenalectomy is treatment of choice 4
- Postoperative corticosteroid supplementation required until HPA axis recovery 4
Adrenal Carcinoma:
- Open adrenalectomy with removal of adjacent lymph nodes and possibly adjacent structures for complete resection 4
- Follow-up imaging and biomarkers every 3-6 months 4
Medical Management Options:
Mild Disease (No Visible Tumor):
Mild-to-Moderate Disease (Residual Tumor):
- Consider cabergoline or pasireotide for potential tumor shrinkage 5
- Note: pasireotide has high rate of hyperglycemia 5
Severe Disease:
- Rapid cortisol normalization is primary goal 5
- Options: osilodrostat, metyrapone, ketoconazole (400-1200 mg/day), or etomidate 4, 5
- Mitotane is another option 4
Combination Therapy:
- Consider ketoconazole plus metyrapone or osilodrostat to maximize adrenal blockade 5
- For visible tumor: ketoconazole plus cabergoline or pasireotide 5
Monitoring Treatment Response
- Define response by both clinical endpoints (improved phenotype, weight, hypertension, glucose metabolism, quality of life) and biochemical endpoints (urinary free cortisol levels) 5
- Monitor for symptoms of adrenal insufficiency with steroidogenesis inhibitors 5
- Consider changing treatment if cortisol remains persistently elevated after 2-3 months on maximum tolerated doses 5
- Obtain MRI typically 6-12 months after initiating treatment and repeat every few years 5
- Monitor ACTH levels for progressive elevations indicating tumor growth 5
- Monitor for improvement of Cushing's manifestations: hypertension, hyperglycemia, hypokalemia, muscle atrophy 4
Special Considerations
- Mifepristone is effective regardless of etiology and improves glucose tolerance, blood pressure, insulin resistance, weight, and quality of life, but requires careful monitoring 5
- Monitor thyroid function and adjust thyroid hormone replacement in patients taking mifepristone 5
- Patients with cirrhosis may have impaired response to metyrapone 5