What are the best ways to reduce elevated cortisol levels in a healthy adult?

How to Reduce High Cortisol

The approach to reducing elevated cortisol depends entirely on whether you have pathological hypercortisolism (Cushing's syndrome/disease) or physiological stress-related elevation—if pathological, transsphenoidal surgery is first-line for pituitary disease, while medical therapy with steroidogenesis inhibitors is used for severe disease or as a bridge to definitive treatment. 1, 2

Critical First Step: Determine the Source

Before any treatment, you must distinguish between:

• Pathological hypercortisolism (Cushing's syndrome): Requires 24-hour urinary free cortisol confirmation, then ACTH testing to determine if pituitary (Cushing's disease), adrenal, or ectopic source 2
• Physiological stress elevation: Normal cortisol response to life stressors, not requiring medical intervention 3

This distinction is critical because treating physiological elevation with steroidogenesis inhibitors can cause life-threatening adrenal insufficiency. 4

For Pathological Hypercortisolism (Cushing's Syndrome)

Severity-Based Treatment Algorithm

Severe Disease (life-threatening hypercortisolism):

• Rapid cortisol normalization is the primary goal 1, 2
• First-line: Osilodrostat or metyrapone (response within hours) 1, 2
• Alternative: Ketoconazole (response within days, normalizes cortisol in 64% of patients) 1, 5
• If hospitalized and unable to take oral medications: Etomidate 1
• If medical therapy fails at optimized doses, bilateral adrenalectomy should be considered immediately to prevent mortality 1, 6

Mild Disease with no visible tumor on MRI:

• First-line: Ketoconazole, osilodrostat, or metyrapone 1, 2
• Alternative: Cabergoline (less effective, slower onset, but requires less frequent dosing) 1, 2

Mild-to-Moderate Disease with residual tumor:

• Consider cabergoline or pasireotide due to potential for tumor shrinkage 1, 2
• Critical caveat: Pasireotide has high rates of hyperglycemia—avoid in patients with elevated A1C 1, 5

Definitive Treatment by Source

Pituitary source (Cushing's disease):

• Transsphenoidal surgery is first-line definitive treatment 6, 5
• If surgery fails: Repeat surgery, radiotherapy (45 Gy in 25 fractions over 35 days), or long-term medical therapy 1
• Radiotherapy achieves biochemical control in approximately 80% within 12-18 months 1

Adrenal source:

• Laparoscopic adrenalectomy for benign adenomas 6
• Open adrenalectomy with lymph node removal for suspected carcinomas 6

Ectopic ACTH source:

• Surgical removal of ectopic tumor is first-line 6
• Medical therapy or bilateral adrenalectomy if surgery not possible 6

Combination Therapy When Monotherapy Fails

• Ketoconazole + metyrapone to maximize adrenal blockade 1, 2, 6
• Ketoconazole + cabergoline when visible tumor present (combines steroidogenesis inhibition with tumor-targeting) 1, 2
• Monitor for QTc prolongation with combination therapy 1, 6

Monitoring Treatment Response

• Define response by both clinical (weight, blood pressure, glucose, quality of life) and biochemical (urinary free cortisol) endpoints 2
• Change treatment if cortisol remains elevated after 2-3 months on maximum tolerated doses 2
• Obtain MRI 6-12 months after initiating treatment, then every few years 2, 6
• Monitor ACTH levels—progressive elevations indicate tumor growth 2, 6

Critical Pitfalls to Avoid

• Monitor for adrenal insufficiency with steroidogenesis inhibitors (symptoms: fatigue, weakness, nausea, hypotension, hypoglycemia) 5, 4
• Mifepristone should only be used by clinicians with extensive Cushing's disease experience—no reliable biochemical markers exist for monitoring, increasing risk of adrenal insufficiency 1, 2
• Patients with cirrhosis may have impaired response to metyrapone 4
• Ketoconazole requires liver function monitoring due to hepatotoxicity risk 1
• Metyrapone can cause hirsutism, hyperandrogenism, and advanced bone age in children with prolonged use 1

For Physiological Stress-Related Cortisol Elevation

If you have confirmed there is no pathological hypercortisolism, non-pharmacological approaches are appropriate:

Most Effective Interventions

Mindfulness and meditation:

• Medium effect size (g = 0.345) for reducing cortisol levels 3
• Particularly effective for at-risk populations (patients with somatic illness, those in stressful life situations) 7
• Significantly lowers serum cortisol (381.93 nmol/L to 306.38 nmol/L in medical students) 8

Relaxation techniques:

• Effect size g = 0.347 for cortisol reduction 3
• Comparable efficacy to mindfulness interventions 3

Cortisol awakening response measures:

• Interventions targeting morning cortisol show larger effects (g = 0.644) than diurnal measures 3

Important Context

• Mind-body therapies (g = 0.129) and talking therapies (g = 0.107) show smaller, non-significant effects on cortisol 3
• Length of intervention, age, and gender do not significantly influence effectiveness 3
• Benefits may not fade with time based on preliminary evidence 7

Why This Matters

Elevated cortisol from chronic stress increases risk of psychiatric disorders, peptic ulcer, migraine, and cardiovascular events 8, 9—addressing it through stress management can prevent these complications without the risks of pharmacological intervention.