What are the medical methods to lower cortisol levels?

From the Guidelines

To lower cortisol medically, metyrapone or ketoconazole are recommended as oral medical therapies to reduce the cortisol burden in patients with Cushing disease, with careful titration and monitoring by experienced clinical teams. When considering medical therapies to lower cortisol levels, several factors should be taken into account, including the need for rapid normalization of cortisol, the presence of residual tumor, and the potential for tumor shrinkage 1. In the context of Cushing disease, adrenal steroidogenesis inhibitors such as metyrapone and ketoconazole are well tolerated and can be highly effective at reducing cortisol levels, either alone or in combination 1. The dosage of metyrapone can range from 250-750 mg every 4 hours, while ketoconazole can be initiated at 400-600 mg per day in 2-3 divided doses and increased to 800-1,200 mg per day until cortisol levels normalize 1. However, it is essential to note that these medications can have adverse effects, including hirsutism, dizziness, arthralgia, fatigue, hypokalaemia, and nausea for metyrapone, and hepatotoxicity for ketoconazole, emphasizing the need for careful monitoring and titration 1. Other options, such as osilodrostat, cabergoline, mifepristone, and pasireotide, may also be considered, but their use in children is limited or unknown, and they should be prescribed with caution and under the guidance of an expert pituitary endocrinologist 1. Ultimately, the choice of medical therapy should be individualized based on the patient's specific needs and circumstances, and should only be pursued under the supervision of a healthcare provider after proper diagnosis.

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. Induction doses of etomidate have been associated with reduction in plasma cortisol and aldosterone concentrations

Medications to lower cortisol medically:

• Metyrapone (PO): reduces cortisol production by inhibiting the 11-beta-hydroxylation reaction in the adrenal cortex 2
• Etomidate (IV): associated with reduction in plasma cortisol concentrations, but its use is typically limited to anesthesia and sedation 3

From the Research

Medical Treatments to Lower Cortisol

• Metyrapone is an inhibitor of 11β-hydroxylase that has been shown to decrease cortisol secretion in patients with Cushing's syndrome (CS) 4, 5.
• Osilodrostat is a steroidogenesis inhibitor that has been approved for the treatment of Cushing's disease (CD) and has been shown to be highly effective in maintaining normal urinary free cortisol in patients with CD 6.
• Etomidate is a steroidogenesis enzyme inhibitor that suppresses cortisol production primarily by inhibiting 11β-hydroxylase and can be used to rapidly reduce cortisol levels in patients with CS 7, 8.
• Ketoconazole is an antifungal agent that can inhibit steroidogenesis and has been used to treat CS, but its use is limited by liver toxicity 6, 8.
• Mitotane is an adrenolytic agent that has been used to treat CS, but its use is limited by its potential to cause adrenal insufficiency 8.
• Cabergoline and pasireotide are dopamine agonists that can normalize cortisol levels in patients with CD, but their use is limited by potential side effects such as worsening of glucose tolerance 8.
• Mifepristone is a blocker of cortisol receptors that can improve clinical aspects of CD, but its use is limited by potential side effects such as adrenal insufficiency, hypokalemia, and endometrial hyperplasia 8.

Dosage and Administration

• The dosage of metyrapone varies depending on the patient and the severity of their CS, but a median dose of 1000 mg per day has been used in some studies 4.
• The dosage of osilodrostat varies depending on the patient and the severity of their CD, but it is typically started at a low dose and titrated up to achieve normal urinary free cortisol levels 6.
• Etomidate can be administered parenterally and is typically used in intensive care settings due to its sedative-hypnotic actions 7.
• Ketoconazole, mitotane, cabergoline, and pasireotide are typically administered orally, while mifepristone can be administered orally or intravenously 6, 8.

Efficacy and Safety

• Metyrapone has been shown to be effective in controlling cortisol excess in patients with CS, with significant improvements in biochemical parameters such as mean serum cortisol and 24-hour urinary free cortisol 4, 5.
• Osilodrostat has been shown to be highly effective in maintaining normal urinary free cortisol in patients with CD 6.
• Etomidate has been shown to be effective in rapidly reducing cortisol levels in patients with CS, but its use is limited by potential side effects such as sedation and adrenal insufficiency 7, 8.
• Ketoconazole, mitotane, cabergoline, and pasireotide have been shown to be effective in normalizing cortisol levels in patients with CS, but their use is limited by potential side effects such as liver toxicity, adrenal insufficiency, and worsening of glucose tolerance 6, 8.
• Mifepristone has been shown to be effective in improving clinical aspects of CD, but its use is limited by potential side effects such as adrenal insufficiency, hypokalemia, and endometrial hyperplasia 8.