Ketoconazole, an antifungal medication, also influences hormone production, specifically cortisol levels. This article explains how ketoconazole reduces cortisol and its medical applications.
Understanding Cortisol and Hypercortisolism
Cortisol is a steroid hormone produced by the adrenal glands. It regulates the body’s stress response, manages glucose metabolism, heart rate, blood pressure, reduces inflammation, and supports fetal development.
Cortisol production is regulated by the hypothalamus-pituitary-adrenal (HPA) axis, a brain-adrenal system. The hypothalamus releases corticotropin-releasing hormone (CRH), signaling the pituitary to release adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce cortisol. Cortisol levels typically follow a daily pattern, higher in the morning and decreasing towards evening.
Hypercortisolism is excessive cortisol. This imbalance leads to Cushing’s syndrome. Symptoms include rapid weight gain in the face (“moon face”), abdomen, and between the shoulders (“buffalo hump”), and thin arms and legs.
Other effects include high blood pressure, fragile skin, poor wound healing, and type 2 diabetes. Cushing’s disease, a type of Cushing’s syndrome, is often caused by a benign pituitary tumor producing excess ACTH, increasing adrenal cortisol secretion. Without proper treatment, hypercortisolism can lead to serious health complications like infections, blood clots, depression, and bone loss.
How Ketoconazole Affects Cortisol Levels
Ketoconazole reduces cortisol by inhibiting enzymes in adrenal steroid synthesis. It primarily targets cytochrome P450 (CYP) enzymes, key for cortisol production. Blocking these enzymes disrupts cortisol formation.
Specifically, ketoconazole inhibits CYP17A1 17α-hydroxylase, an enzyme for cortisol synthesis. It also inhibits 11β-hydroxylase (CYP11B1) and 18-hydroxylase (CYP11B2). At higher concentrations, ketoconazole can also affect the cholesterol side-chain cleavage enzyme (P450scc), involved in earlier steroid production.
Ketoconazole suppresses new cortisol production, without affecting circulating cortisol. This inhibition rapidly reduces adrenal cortisol production. These mechanisms lower excessive cortisol levels in conditions like Cushing’s syndrome.
Medical Use and Important Considerations
Ketoconazole manages excessive cortisol conditions, particularly Cushing’s syndrome. It often lowers cortisol before surgery or as long-term treatment if surgery is not an option or unsuccessful. Studies indicate ketoconazole can normalize urine cortisol levels in approximately 43% to 80% of patients with Cushing’s syndrome.
This prescription drug requires careful medical supervision due to side effects and ongoing monitoring. Providers monitor liver function and cortisol levels throughout treatment. The typical starting dose in Europe for Cushing’s syndrome is 400-600 mg daily, adjustable up to 1200 mg for cortisol control.
Oral ketoconazole’s primary concern is liver toxicity (hepatotoxicity). Serious cases, including liver transplantation or fatal outcomes, have been reported, even in patients without pre-existing liver conditions. Liver enzyme levels are usually monitored at weeks 2 and 4, then monthly, with treatment discontinued if levels rise significantly.
Patients should be educated about liver problem symptoms (nausea, vomiting, unusual tiredness, dark urine, yellowing skin/eyes) and seek immediate medical attention. Ketoconazole can also lead to adrenal insufficiency, where adrenal activity is over-suppressed, causing weakness, fatigue, nausea, and low blood pressure. Due to these risks, ketoconazole is not for self-treatment and requires strict professional guidance.