From the Guidelines
To reduce cortisol levels, the most effective approach is to use adrenal steroidogenesis inhibitors such as metyrapone or ketoconazole, as they can be highly effective at reducing cortisol levels, either alone or in combination, as recommended by the most recent guideline update 1.
Methods to Reduce Cortisol Levels
The following methods can be used to reduce cortisol levels:
- Adrenal steroidogenesis inhibitors, such as metyrapone and ketoconazole, which can be prescribed by experienced clinical teams with careful titration 1
- Metyrapone: 15 mg/kg every 4 h for 6 doses, alternatively 300 mg/m2 every 4 h, usual dose 250–750 mg every 4 h 1
- Ketoconazole: for patients over 12 years, initially 400–600 mg per day in 2–3 divided doses, increased to 800–1,200 mg per day until cortisol levels normalize and then reaching a maintenance dose of 400–800 mg per day in 2–3 divided doses 1
Important Considerations
When using these medications, it is essential to consider the potential adverse effects, such as:
- Common adverse effects of metyrapone: hirsutism, dizziness, arthralgia, fatigue, hypokalaemia, and nausea 1
- Prolonged usage of metyrapone can lead to hyperandrogenism and advanced bone age in children 1
- Ketoconazole is associated with hepatotoxicity, and liver function should be monitored on therapy 1
Additional Recommendations
For patients with severe disease, rapid normalization of cortisol is the most important goal, and osilodrostat and metyrapone have the fastest action, as recommended by the guideline update 1 Change in treatment should be considered if cortisol levels are persistently elevated after 2–3 months on maximum tolerated doses, and combination therapy can be considered if cortisol does not normalize but is reduced and/or there is some clinical improvement 1
From the FDA Drug Label
The pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-beta-hydroxylation reaction in the adrenal cortex.
The method to reduce cortisol levels is by using Metyrapone, which inhibits the 11-beta-hydroxylation reaction in the adrenal cortex, thereby reducing cortisol and corticosterone production.
- Metyrapone works by blocking the enzymatic steps leading to production of cortisol and corticosterone, resulting in a marked increase in adrenocortical secretion of their immediate precursors. 2
From the Research
Methods to Reduce Cortisol Levels
The following methods can be used to reduce cortisol levels:
- Adrenal-blocking agents, such as ketoconazole and metyrapone, which suppress adrenal cortisol production via inhibition of steroidogenic enzymes 3, 4, 5, 6
- Neuromodulatory drugs, such as bromocriptine, cyproheptidine, somatostatin, and valproic acid, which modulate corticotropin (ACTH) release from a pituitary tumor 6
- Glucocorticoid receptor antagonists, such as RU 486, which block cortisol action at its receptor 4
- Combination therapy with drugs that target the corticotropic adenoma, such as pasireotide and cabergoline, and low-dose ketoconazole 3
- Etomidate, which suppresses cortisol production primarily by inhibiting 11β-hydroxylase and can be given parenterally 5, 7
- Osilodrostat, a recently approved drug for the treatment of Cushing's Disease, which inhibits various enzymes along the cortisol biosynthetic pathway 7
Specific Treatments for Severe Cushing's Syndrome
In cases of severe Cushing's syndrome, the following treatments can be used:
- Oral metyrapone and/or ketoconazole to rapidly lower cortisol levels 5
- Intravenous etomidate to rapidly reverse cortisol excess in patients with acute complications of hypercortisolism 3, 5, 7
- Combination therapy with multiple drugs to achieve rapid control of cortisol excess and reduce individual drug dosages and adverse effects 5