From the Guidelines
Ketoconazole lowers cortisol by inhibiting the enzymes involved in steroid hormone synthesis, particularly the cytochrome P450 enzyme 17α-hydroxylase and 11β-hydroxylase, as reported in a 2021 guideline update published in The Lancet Diabetes and Endocrinology 1.
Mechanism of Action
The mechanism of action of ketoconazole involves blocking multiple adrenal enzymes, including those involved early in the steroid biosynthetic pathway, which avoids excess circulation of androgen and mineralocorticoid precursors 1.
- This blockade prevents the adrenal glands from producing normal amounts of cortisol, effectively reducing circulating cortisol levels in the body.
- The cortisol-lowering effect of ketoconazole begins within hours of administration but may take several days to reach maximum effect.
Dosage and Administration
When used for cortisol reduction, ketoconazole is typically prescribed at doses of 400-1200 mg daily, divided into 2-3 doses, as indicated in a 2021 study published in The Lancet Diabetes and Endocrinology 1.
- The medication should be taken with food or acidic beverages to enhance absorption.
- Patients should avoid antacids or acid-reducing medications, which can decrease the effectiveness of ketoconazole.
Safety and Monitoring
Patients taking ketoconazole should be aware that it can cause liver toxicity, so regular liver function tests are necessary, as recommended by the United States Food and Drug Administration (FDA) 1.
- The risk of serious hepatotoxicity, although rare, necessitates careful monitoring of liver function tests (LFTs) in patients treated with ketoconazole.
- Other potential adverse effects include gastrointestinal disturbances, gynecomastia, skin rash, and adrenal insufficiency (AI) 1.
From the FDA Drug Label
Ketoconazole tablets decrease adrenal corticosteroid secretion at doses of 400 mg and higher. The recommended dose of 200 mg to 400 mg daily should not be exceeded Adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.)
Ketoconazole lowers cortisol by decreasing adrenal corticosteroid secretion at doses of 400 mg and higher 2.
- This effect is not shared with other azoles.
- Adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function.
From the Research
Mechanism of Ketoconazole in Lowering Cortisol
- Ketoconazole inhibits cortisol secretion by blocking mitochondrial P450-dependent enzyme systems, which are essential for steroid hormone synthesis 3.
- The drug impairs steroid hormone synthesis, making it valuable in controlling hypercortisolism 3, 4.
- Ketoconazole specifically inhibits 17-hydroxylase, a cytochrome P-450-dependent monooxygenase reaction, which is involved in corticosteroidogenesis 5.
Effects of Ketoconazole on Cortisol Levels
- Repeated oral doses of ketoconazole can induce a clear-cut fall of serum cortisol levels, with the inhibitory effect detectable 5 hours after the first dose 6.
- Ketoconazole can normalize cortisol levels in about 50% of patients, although its long-term use is limited by liver toxicity 7.
- The drug can be used to rapidly reduce cortisol levels, and its effects can be reproduced in vitro by incubating tissue slices of the excised adrenal tumor with the antifungal agent 6.
Comparison with Other Treatments
- Ketoconazole is often used in combination with other drugs, such as metyrapone, etomidate, and cabergoline, to achieve biochemical control in patients with Cushing's disease 4, 7.
- Compared to other treatments, ketoconazole has a more potent inhibitory effect on adrenal steroidogenesis, making it a valuable option for controlling hypercortisolism 3, 4.