Mifepristone, also known as RU-486, is a medication with a complex profile, primarily known for its FDA-approved role in the medical termination of pregnancy [1.2.1]. However, its unique mechanism of action has led to a variety of other applications. The practice of prescribing a drug for a condition other than what it was officially approved for is known as "off-label" use [1.2.3]. Off-label prescribing is a common and legal practice in medicine, accounting for a significant percentage of all prescriptions [1.9.2].
Understanding Mifepristone's Dual Mechanism of Action
Mifepristone is a synthetic steroid that functions as a competitive receptor antagonist for both progesterone and glucocorticoids [1.6.3]. Its versatility stems from this dual action:
- As a Progesterone Receptor Antagonist: At lower doses, mifepristone primarily binds to and blocks progesterone receptors. Since progesterone is crucial for maintaining pregnancy and influences the growth of certain tissues in the female reproductive system, blocking it is the basis for its on-label use in abortion and its off-label use in gynecology [1.6.1, 1.6.3].
- As a Glucocorticoid Receptor Antagonist: At higher doses, mifepristone potently blocks the action of cortisol at the glucocorticoid receptor [1.6.1]. This effect is utilized in treating conditions characterized by excess cortisol, such as Cushing's syndrome [1.5.1]. This action leads to a compensatory increase in circulating cortisol, but its effects on the body's tissues are blocked [1.6.1].
What is the off-label use of mifepristone for Gynecological Conditions?
Much of the research into mifepristone's off-label applications focuses on its anti-progestogenic effects in treating common and often debilitating gynecological disorders.
Management of Uterine Fibroids (Leiomyomas)
Uterine fibroids are the most common benign tumors in women of reproductive age and can cause symptoms like excessive menstrual bleeding, anemia, and pelvic pain [1.3.1]. Mifepristone has proven effective in their management:
- Reduces Fibroid Volume: Clinical trials show that daily doses of 10 mg and 25 mg of mifepristone significantly reduce the volume of uterine fibroids over a three-month period, with efficacy comparable to other medical treatments [1.3.1]. Some studies show a reduction in tumor volume of around 40-50% [1.3.1, 1.3.4].
- Controls Bleeding and Anemia: A primary benefit is the rapid control of heavy bleeding, with a majority of patients achieving amenorrhea (cessation of menstruation) [1.3.3, 1.3.6]. This helps correct associated anemia, with significant increases in hemoglobin levels observed during treatment [1.3.1, 1.3.5].
- Improves Quality of Life: By reducing bleeding and pelvic pain, the treatment significantly improves the patient's general well-being and energy levels [1.3.1, 1.3.3].
Treatment for Endometriosis
Endometriosis is a condition where tissue similar to the lining inside the uterus grows outside the uterus, causing chronic pelvic pain. As an anti-progesterone, mifepristone can be an effective treatment [1.6.3].
- Pain Relief: Studies using doses from 5 mg to 50 mg daily have shown that mifepristone effectively reduces pelvic pain associated with endometriosis [1.4.1, 1.6.3].
- Regression of Lesions: A daily dose of 50 mg for six months has been shown to cause a significant regression in visible endometriotic lesions [1.6.3]. While lower doses like 5 mg can improve symptoms, they may be less effective at stabilizing the endometrium and can cause irregular bleeding [1.4.1, 1.4.6].
Mifepristone for Hyperglycemia in Cushing's Syndrome
While once considered an off-label use, mifepristone is now FDA-approved under the brand name Korlym to treat hyperglycemia (high blood sugar) in adult patients with endogenous Cushing's syndrome [1.5.1, 1.2.1]. This condition is caused by prolonged exposure to high levels of the hormone cortisol [1.5.2]. Mifepristone works by blocking the glucocorticoid receptor, thereby inhibiting the effects of excess cortisol and leading to improved glucose control [1.5.3, 1.6.4].
Other Investigational Off-Label Uses
Mifepristone's properties have led to its investigation in a wide range of other medical fields:
- Emergency Contraception: A single dose can be used as an effective postcoital emergency contraceptive [1.2.1, 1.2.3].
- Cancer Treatment: Research is ongoing for its use in various cancers. It has been studied in breast, ovarian, and prostate cancer [1.2.4, 1.6.3]. Studies have also explored its potential in treating pancreatic cancer, glioblastoma, and uveal melanoma, often by mechanisms independent of the classic progesterone receptor [1.8.1, 1.8.2, 1.8.5].
- Meningioma: Mifepristone is used off-label to treat meningioma, a type of benign tumor in the central nervous system that is often positive for progesterone receptors [1.2.4, 1.6.3].
On-Label vs. Off-Label Use: A Comparison
The application of mifepristone differs significantly between its on-label and off-label uses.
| Feature | On-Label Use (Medical Abortion) | Common Off-Label Uses (e.g., Fibroids, Endometriosis) |
|---|---|---|
| Primary Goal | Termination of intrauterine pregnancy [1.2.1] | Symptom management, tumor reduction, pain relief [1.3.1, 1.4.2] |
| Dosage Regimen | A single oral dose of 200 mg [1.6.3] | Lower, continuous daily doses (e.g., 5-50 mg) [1.3.1, 1.6.3] |
| Duration of Use | Short-term (one-time use with misoprostol) [1.6.3] | Chronic or long-term (weeks to months) [1.3.4, 1.4.3] |
| FDA Approval | Approved for this specific indication [1.2.1] | Use is based on clinical evidence, not specific FDA approval [1.2.3] |
Safety Profile and Side Effects of Long-Term Use
The safety of mifepristone varies with the dose and duration of use. Its on-label use for abortion involves a single high dose and is associated with bleeding and cramping [1.7.1, 1.7.4].
For long-term, low-dose off-label use, the side effect profile is different. Common side effects can include fatigue, nausea, headache, and back pain [1.7.1]. A key concern with long-term use is its effect on the endometrium, as the unopposed estrogen can lead to endometrial thickening [1.5.4, 1.4.4]. This is typically benign but requires monitoring [1.5.4]. When used for Cushing's syndrome, side effects can include symptoms of cortisol withdrawal, low potassium (hypokalemia), and potential changes in thyroid function [1.5.4, 1.7.5]. For gynecological uses, mifepristone often maintains estrogen levels in the normal premenopausal range, which avoids the menopausal side effects like hot flashes seen with other treatments [1.3.1].
Conclusion
The off-label use of mifepristone extends far beyond its public perception, offering a valuable therapeutic option for a range of challenging conditions. Its dual ability to block both progesterone and glucocorticoid receptors makes it a powerful tool for managing uterine fibroids, endometriosis, and hyperglycemia in Cushing's syndrome. While its use in oncology and other areas is still being investigated, mifepristone's role in medicine is expanding. As with any off-label prescription, its use must be guided by strong clinical evidence and careful physician oversight to ensure patient safety and efficacy.
