What effects does ketoconazole have on steroid hormone metabolism?

From the Guidelines

Ketoconazole has a significant impact on steroid hormone metabolism, blocking multiple adrenal enzymes and decreasing gonadal steroid synthesis, which can lead to hypogonadism and gynecomastia in men 1.

Effects on Steroid Hormone Metabolism

• Ketoconazole blocks adrenal enzymes involved in the steroid biosynthetic pathway, avoiding excess circulation of androgen and mineralocorticoid precursors 1
• It decreases gonadal steroid synthesis, leading to potential hypogonadism and gynecomastia in men 1
• Ketoconazole can normalize UFC levels in patients with Cushing's disease, with a median response rate of 64.3% 1

Dosage and Administration

• The typical dose of ketoconazole for patients over 12 years is initially 400-600 mg per day in 2-3 divided doses, increased to 800-1200 mg per day until cortisol levels normalize 1
• The maintenance dose is typically 400-800 mg per day in 2-3 divided doses 1

Adverse Effects

• Hepatotoxicity is a common adverse effect, seen in 10-20% of patients, and requires weekly monitoring of liver function tests (LFTs) 1
• Gastrointestinal disturbances and adrenal insufficiency are also recognized adverse effects of ketoconazole 1

Clinical Use

• Ketoconazole is used off-label in the US for the treatment of Cushing's disease, and its use should be confined to normalizing cortisol levels in preparation for surgery or while awaiting a biochemical response to radiotherapy 1
• Ketoconazole can be effective in controlling cortisol excess, but does not directly target the pituitary ACTH-secreting adenoma, nor restore HPA axis circadian rhythm 1

From the FDA Drug Label

Ketoconazole tablets decrease adrenal corticosteroid secretion at doses of 400 mg and higher. 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 decreases adrenal corticosteroid secretion at doses of 400 mg and higher, which can lead to adrenal insufficiency.

• Key points:
  • Dose-dependent effect: Decrease in adrenal corticosteroid secretion occurs at doses of 400 mg and higher.
  • Monitoring required: Adrenal function should be monitored in patients with adrenal insufficiency, borderline adrenal function, or those under prolonged stress.
  • Clinical significance: Adrenal insufficiency can cause symptoms such as tiredness, weakness, dizziness, nausea, and vomiting. 2

From the Research

Effects of Ketoconazole on Steroid Hormone Metabolism

• Ketoconazole inhibits testicular and adrenal steroid synthesis, with the major site of action appearing to be the inhibition of 17-20 desmolase 3.
• A moderate blockade of 17-hydroxylase may also be present, as well as a marked inhibition of 21- and/or 11-hydroxylase 3.
• The drug impairs steroid hormone synthesis by blocking mitochondrial P450-dependent enzyme systems, making it valuable in controlling hypercortisolism 4.
• Ketoconazole has been shown to inhibit adrenal steroid synthesis, with the cortisol response to adrenocorticotropic hormone significantly blunted 4 hours after a 400-mg or 600-mg dose 5.
• The effect of ketoconazole on adrenal and testicular steroidogenesis is completely reversible, with cells responding normally to hormone stimulation after being washed and exposed to the drug 6.
• The sites of the anti-steroidogenic effect of ketoconazole have been established as the sequence between ACTH/LH binding and pregnenolone production, as well as the inhibition of testicular C-17-C-20 lyase activity 6.
• Low-dose ketoconazole has been shown to inhibit testosterone biosynthesis in men, with a transient decrease in plasma testosterone and a compensatory increase in plasma LH 7.
• Chronic administration of low-dose ketoconazole has minimal effects on testosterone levels, likely due to the relatively selective effects of the drug on the C17-20 lyase enzyme 7.