A glucocorticoid receptor antagonist is a medication that works by blocking the effects of glucocorticoids, a class of steroid hormones. The most well-known glucocorticoid in humans is cortisol, the body’s primary stress hormone. Produced by the adrenal glands, these hormones are involved in metabolism, immune response, and stress adaptation. To exert their effects, glucocorticoids must bind to specific receptors present in nearly every cell in the body.
A glucocorticoid receptor antagonist binds to these receptors but does not activate them. By occupying the receptor site, the antagonist prevents cortisol from binding and initiating its normal cellular response, which in turn reduces the impact of high cortisol levels on the body’s tissues.
Mechanism of Action
The mechanism can be understood using a “lock and key” analogy. The glucocorticoid receptor (GR) is the lock, and a hormone like cortisol is the key that fits and turns it to initiate a cellular response. A glucocorticoid receptor antagonist is like a key that fits the lock but cannot turn it, thereby preventing cortisol from activating the receptor.
Normally, when cortisol binds to its receptor in the cell’s cytoplasm, the complex moves into the nucleus. Inside the nucleus, this complex influences the transcription of specific genes, which regulates functions like increasing blood sugar and suppressing inflammation. A GR antagonist physically blocks this first step.
This blockade prevents the necessary conformational changes in the receptor, so it cannot become active, move into the nucleus, or interact with DNA. The downstream signaling pathways triggered by high cortisol are therefore shut down, mitigating the widespread effects of hypercortisolism.
Therapeutic Applications
The primary therapeutic use for glucocorticoid receptor antagonists is managing hyperglycemia in adults with endogenous Cushing’s syndrome. This condition is caused by prolonged exposure to high cortisol levels, often from tumors, leading to weight gain, high blood pressure, and type 2 diabetes. For patients who are not candidates for surgery or for whom surgery has not been successful, an antagonist can be a valuable treatment option. It directly addresses the metabolic consequences of excess cortisol, and clinical studies show it can improve blood glucose control, blood pressure, and body weight.
Beyond its approved use, this class of drugs is investigated for other conditions linked to cortisol dysregulation. Research has explored their potential in psychiatric disorders like psychotic depression, where cortisol levels are often elevated. There is also ongoing research into their role in oncology, as blocking overexpressed glucocorticoid receptors in some cancers may inhibit tumor cell proliferation.
Types and Examples
The most well-known glucocorticoid receptor antagonist is mifepristone, marketed as Korlym for treating Cushing’s syndrome. Mifepristone is not entirely selective, as it also potently blocks progesterone receptors. This dual action is responsible for some of its side effects and is why the drug was originally developed for its antiprogestational effects.
To address the limitations of non-selective agents, newer drugs are being developed that are more selective for the glucocorticoid receptor. One such investigational drug is relacorilant, which is designed as a selective glucocorticoid receptor modulator. Relacorilant binds to the glucocorticoid receptor but has no affinity for the progesterone receptor, potentially offering a safer profile for long-term use by avoiding progesterone-related side effects.
Side Effects and Safety Considerations
Patients taking these antagonists must be monitored for potential side effects. Common adverse reactions include:
- Nausea
- Fatigue
- Headache
- Dizziness
- Swelling in the arms and legs
The body may respond by increasing its production of cortisol and ACTH, which can complicate monitoring but does not override the drug’s effect.
A primary safety concern is the risk of adrenal insufficiency, which can occur if the dosage is too high. This condition mimics a state where the adrenal glands do not produce enough hormones, with symptoms like fatigue and weakness that can progress to a life-threatening adrenal crisis. Treatment is complicated, as standard hydrocortisone is ineffective and high doses of a different steroid are required.
Dosing is adjusted based on clinical symptoms, not hormone levels, and regular monitoring for issues like low potassium (hypokalemia) is necessary. Due to its potent blocking of progesterone receptors, mifepristone is strictly contraindicated during pregnancy, and a negative pregnancy test is required before starting treatment.