What Cortisol Synthesis Inhibitors Treat
Cortisol synthesis inhibitors such as ketoconazole are used to treat Cushing's syndrome and Cushing's disease by blocking adrenal steroidogenesis and normalizing hypercortisolism. 1
Primary Indication: Cushing's Syndrome/Disease
Cortisol synthesis inhibitors target the excess cortisol production that defines Cushing's syndrome, regardless of the underlying cause 1:
- Cushing's disease (pituitary ACTH-secreting adenoma) - the most common indication 1
- Ectopic ACTH syndrome from tumors secreting ACTH or CRH 2, 3
- Adrenal tumors (adenomas or carcinomas) causing cortisol excess 2, 4
- Bilateral macronodular adrenal hyperplasia (BMAH) 5
Clinical Scenarios for Use
Severe Hypercortisolism
For patients with severe disease, rapid cortisol normalization is the primary goal, with ketoconazole providing response within days, while osilodrostat and metyrapone work within hours 1. These agents may be combined when monotherapy fails to control severe hypercortisolism 1.
Persistent or Recurrent Disease
Medical therapy is indicated for patients with persistent or recurrent Cushing's disease after failed surgery, or for those who refuse or are not surgical candidates 1. Ketoconazole has been used successfully for long-term control, with studies showing UFC normalization in 64.3% of patients at mean doses of 673.9 mg/day 1.
Bridge to Definitive Therapy
Steroidogenesis inhibitors are frequently used to control hypercortisolism while awaiting the effects of radiation therapy, which can take months to years to achieve full efficacy 6, 2. They also serve as preparation for surgery in patients with severe metabolic complications 2, 7.
Mechanism and Efficacy
Ketoconazole blocks multiple adrenal enzymes including 11β-hydroxylase and 17,20-lyase, decreasing both glucocorticoid synthesis and adrenal androgen production 1, 4. This multi-enzyme blockade avoids excess circulation of androgen and mineralocorticoid precursors 1.
Clinical improvement occurs rapidly alongside biochemical normalization, with regression of diabetes mellitus, hypertension, hypokalemia, and restoration of well-being 7. In one series of 34 patients, urinary cortisol decreased from 1296 to 270 nmol/day with treatment 7.
Critical Monitoring Requirements
Hepatotoxicity is the most serious concern, occurring in 10-20% of patients, typically within the first 6 months 1. The FDA issued a black-box warning for ketoconazole due to fatal hepatotoxicity cases 8. Weekly monitoring of liver function tests is mandatory during treatment 8.
Additional monitoring includes 1:
- Regular assessment for adrenal insufficiency from overtreatment
- Drug-drug interaction review, as ketoconazole has numerous problematic interactions 1
- In men, monitoring for hypogonadism and gynecomastia, which can limit prolonged treatment 1
Treatment Selection Considerations
Ketoconazole may be favored for ease of dose titration but is often under-dosed due to hepatotoxicity concerns 1. For patients with mild-to-moderate disease and no visible tumor, ketoconazole, osilodrostat, or metyrapone are first-line options 9. When visible tumor is present, combining a steroidogenesis inhibitor like ketoconazole with a tumor-targeting agent such as cabergoline is rational 1, 9.
Important Caveats
These medications control cortisol excess but do not directly target the pituitary adenoma or restore normal HPA axis circadian rhythm 1. Up to 23% of initially responsive patients may lose biochemical control and "escape" from therapy over time 1. For very severe hypercortisolism not responsive to optimized medical therapy including combinations, bilateral adrenalectomy should be considered to avoid worsening outcomes 1.