1. Introduction
Adrenal corticosteroid inhibitors are drugs that reduce the synthesis or action of corticosteroids produced by the adrenal cortex. They are primarily used in the management of Cushing’s syndrome, hyperaldosteronism, and other adrenal hormone excess states. These agents target enzymes in steroid biosynthesis or act as receptor antagonists, modulating the effects of glucocorticoids or mineralocorticoids.
Understanding their pharmacology, clinical applications, and safety profile is critical for medical education and therapeutic decision-making.
2. Classification
Adrenal corticosteroid inhibitors can be broadly classified into:
2.1 11β-Hydroxylase Inhibitors (Glucocorticoid Synthesis Inhibitors)
- Examples: Metyrapone, Ketoconazole (at high doses)
- Mechanism: Inhibit 11β-hydroxylase (CYP11B1), the final enzyme in cortisol biosynthesis, leading to decreased cortisol production
- Clinical Use:
- Cushing’s syndrome (endogenous hypercortisolism)
- Diagnostic testing for adrenal function
2.2 17α-Hydroxylase / 17,20-Lyase Inhibitors
- Example: Abiraterone acetate
- Mechanism: Blocks CYP17, reducing androgen and cortisol synthesis
- Clinical Use:
- Prostate cancer (androgen-dependent)
- Cushing’s syndrome secondary to adrenal or ectopic ACTH production
2.3 21-Hydroxylase / 18-Hydroxylase Inhibitors
- Example: Osilodrostat
- Mechanism: Inhibits CYP11B1 and CYP11B2, reducing cortisol and sometimes aldosterone
- Clinical Use:
- Cushing’s disease
- Severe hypercortisolism refractory to surgery
2.4 Mineralocorticoid Receptor Antagonists
- Examples: Spironolactone, Eplerenone
- Mechanism: Block aldosterone binding at the mineralocorticoid receptor in the kidney
- Clinical Use:
- Primary hyperaldosteronism (Conn’s syndrome)
- Resistant hypertension
- Heart failure with reduced ejection fraction
3. Mechanism of Action
| Drug Class | Target | Effect on Adrenal Hormones |
|---|---|---|
| Metyrapone / Ketoconazole | 11β-hydroxylase | ↓ Cortisol |
| Abiraterone | CYP17 | ↓ Cortisol, ↓ Androgens |
| Osilodrostat | CYP11B1 / CYP11B2 | ↓ Cortisol, sometimes ↓ Aldosterone |
| Spironolactone / Eplerenone | Mineralocorticoid receptor | ↓ Aldosterone effects (Na+ retention, K+ excretion) |
Key Point: Cortisol reduction may lead to ACTH-driven adrenal hyperplasia, requiring monitoring and sometimes glucocorticoid supplementation.
4. Clinical Applications
- Cushing’s Syndrome / Disease
- First-line: Surgery (pituitary or adrenal)
- Medical therapy: Ketoconazole, Metyrapone, Osilodrostat for preoperative or refractory cases
- Primary Hyperaldosteronism
- Mineralocorticoid receptor antagonists (spironolactone, eplerenone)
- Used when surgery is not feasible
- Prostate Cancer
- Abiraterone acetate reduces androgen synthesis
- Combined with prednisone to prevent secondary hypercortisolism
- Ectopic ACTH Syndrome
- Ketoconazole, metyrapone, or osilodrostat reduce cortisol excess before definitive treatment
5. Adverse Effects
5.1 Glucocorticoid Synthesis Inhibitors
- Ketoconazole: Hepatotoxicity, gynecomastia, menstrual irregularities
- Metyrapone: Hirsutism, hypertension, hypokalemia
- Osilodrostat: Fatigue, nausea, adrenal insufficiency, hypokalemia
5.2 Mineralocorticoid Receptor Antagonists
- Spironolactone: Hyperkalemia, gynecomastia, menstrual irregularities
- Eplerenone: Hyperkalemia, dizziness (more selective → fewer hormonal side effects)
6. Drug Interactions
- Ketoconazole / Abiraterone: CYP3A4 substrates → interactions with statins, anticoagulants, antifungals
- Metyrapone: Can interact with antihypertensives due to volume retention
- Spironolactone / Eplerenone: Risk of hyperkalemia with ACEIs, ARBs, or potassium supplements
7. Monitoring Parameters
| Parameter | Frequency | Notes |
|---|---|---|
| Serum cortisol | Weekly to monthly | Adjust dose to avoid adrenal insufficiency |
| Plasma ACTH | Monthly | Monitor for compensatory rise |
| Liver function tests | Monthly (ketoconazole) | Hepatotoxicity risk |
| Serum electrolytes (Na, K) | Biweekly to monthly | Hyper/hypokalemia prevention |
| Blood pressure | Ongoing | Monitor antihypertensive effects |
8. Special Considerations
- Pregnancy: Most adrenal inhibitors are contraindicated
- Liver disease: Ketoconazole hepatotoxicity risk
- Renal impairment: Mineralocorticoid receptor antagonists require dose adjustment
- Combination therapy: Sometimes multiple inhibitors are combined for severe hypercortisolism, under specialist supervision
9. Research and Evidence Base
- Metyrapone: Shown to rapidly reduce cortisol levels in Cushing’s syndrome (Newell-Price et al., 2006, Lancet Diabetes Endocrinol)
- Ketoconazole: Effective as first-line medical therapy; monitor for liver toxicity (Fleseriu et al., 2016, J Clin Endocrinol Metab)
- Abiraterone: Significant survival benefit in metastatic castration-resistant prostate cancer (Ryan et al., 2013, NEJM)
- Osilodrostat: Phase III trials (LINC 3) show robust cortisol normalization in Cushing’s disease (Fleseriu et al., 2020, Lancet Diabetes Endocrinol)
10. Summary
Adrenal corticosteroid inhibitors are essential in managing corticosteroid excess and hormone-dependent conditions. Their use requires:
- Understanding enzyme targets and receptor mechanisms
- Monitoring electrolytes, liver function, and cortisol levels
- Awareness of drug interactions and adverse effects
- Specialist oversight in complex endocrine disorders
These agents represent a cornerstone of medical therapy for Cushing’s syndrome, primary hyperaldosteronism, and certain hormone-sensitive cancers.
11. References
- Newell-Price J, et al. Cushing’s syndrome. Lancet. 2006;367:1605–1617.
- Fleseriu M, et al. Ketoconazole therapy in Cushing’s syndrome. J Clin Endocrinol Metab. 2016;101:1232–1244.
- Ryan CJ, et al. Abiraterone acetate in metastatic prostate cancer. N Engl J Med. 2013;368:138–148.
- Fleseriu M, et al. Osilodrostat in Cushing’s disease: LINC 3 study. Lancet Diabetes Endocrinol. 2020;8:748–760.
- Arlt W, Allolio B. Adrenal insufficiency and steroidogenesis inhibitors. Lancet. 2003;361:1881–1893.
- Brunton LL, et al. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th Edition, 2021.
