Mifepristone
Mifepristone, and also known by its developmental code name RU-486, is a drug typically used in combination with misoprostol to bring about a medical abortion during pregnancy. This combination is 97% effective during the first 63 days of pregnancy, and is effective in the second trimester as well. It is also used on its own to treat Cushing's syndrome or in low doses as an emergency contraceptive.
The most common adverse effects include abdominal pain, feeling tired, and vaginal bleeding. Serious side effects may include heavy vaginal bleeding, bacterial infection, and, if pregnant, birth defects. When used, appropriate follow-up care needs to be available. Mifepristone is primarily an antiprogestogen. It works by blocking the effects of progesterone, making both the cervix and uterine vessels dilate and causing uterine contraction. Mifepristone also works, to a lesser extent, as an antiglucocorticoid and diminishes the effects of hypercortisolism.
Mifepristone was developed in France in 1980 and came into use there in 1987. It became available in the United States in 2000, for medication abortion, and in 2010, for Cushing's syndrome. It is on the World Health Organization's List of Essential Medicines. Mifepristone was approved in China in 1988, India in 2002, and Canada in 2017.
Medical uses
Abortion
Mifepristone followed by a prostaglandin analog is used for medical abortion. Medical organizations have found this combination to be safe and effective. Guidelines from the Royal College of Obstetricians and Gynaecologists describe medication abortion using mifepristone and misoprostol as effective and appropriate at any gestational age. The World Health Organization and the American College of Obstetricians and Gynecologists recommend mifepristone followed by misoprostol for first- and second-trimester medical abortion. Mifepristone alone is less effective, resulting in abortion within 1–2 weeks in anywhere from 54% to 92% of pregnancies, according to review of 13 studies.Cushing's syndrome
Mifepristone is used for the medical treatment of high blood sugar caused by high cortisol levels in the blood in adults with endogenous Cushing's syndrome who also have type 2 diabetes mellitus or glucose intolerance and have failed surgery or cannot have surgery. In a Phase III trial, it improved glycemic control, increased insulin sensitivity, and reduced body weight regardless of the cause of CS.Medical management of early pregnancy loss
Mifepristone combined with misoprostol is the preferred medication regimen for management of early pregnancy loss. While misoprostol alone can be used, the addition of a dose of mifepristone twenty-four hours before misoprostol administration improves treatment efficacy.Other uses
Mifepristone at low doses has been used for emergency contraception. Mifepristone has also been used to treat symptomatic leiomyoma and endometriosis. As elevated cortisol levels have been implicated in psychotic depression, mifepristone has been used as a treatment.Side effects
Serious complications with mifepristone are rare with about 0.04%–0.09% requiring hospitalization and 0.05% requiring blood transfusion.Nearly all women using the mifepristone/misoprostol regimen experienced abdominal pain, uterine cramping, and vaginal bleeding or spotting for an average of 9–16 days. For most women, the most severe cramps after use of misoprostol last for less than 6 hours and can generally be managed with ibuprofen. Up to 8% of women experienced some type of bleeding for 30 days or more. Other less common side effects included nausea, vomiting, diarrhea, dizziness, fatigue, and fever. Pelvic inflammatory disease is a very rare but serious complication. Excessive bleeding and incomplete termination of a pregnancy require further intervention by a doctor. Mifepristone is contraindicated in the presence of adrenal failure, long-term oral corticosteroid therapy, hemorrhagic disorders, inherited porphyria, and hemophilia or anticoagulant use. Women with an intrauterine device in their uterus should remove the IUD prior to medication abortion to avoid unnecessary cramping. Mifepristone is not effective in treating ectopic pregnancy.
A postmarketing summary found, of about 1.52 million women who had received mifepristone until April 2011 in the United States, 14 were reported to have died after application. Eight of these cases were associated with sepsis; the other six had various causes such as drug abuse and suspected murder. Other incidents reported to the FDA included 612 nonlethal hospitalizations, 339 blood transfusions, 48 severe infections, and 2,207 adverse events altogether.
No long-term studies to evaluate the carcinogenic potential of mifepristone have been performed. This is in accord with ICH guidelines, which do not require carcinogenicity testing in nongenotoxic drugs intended for administration for less than six months.
Pregnancy
Mifepristone alone results in abortion within 1–2 weeks in 54% to 92% of pregnancies. The effectiveness increases to greater than 90% if misoprostol is given after the mifepristone. There is no evidence that the effects of mifepristone can be reversed, although some anti-abortion groups claim that it can be reversed by giving progesterone. Researchers in the United States initiated a trial of the so-called "reversal" regimen in 2019, but stopped prematurely due to serious safety concerns about using mifepristone without follow-up misoprostol. Giving progesterone has not been shown to halt medication abortion, and not completing the combination regimen of mifepristone and misoprostol may cause serious bleeding.In those who continue pregnancy after use of mifepristone together with misoprostol for termination, birth defects may occur. Exposure to a single large dose of mifepristone in newborn rats was not associated with any reproductive problems, although chronic low-dose exposure of newborn rats to mifepristone was associated with structural and functional reproductive abnormalities. Studies in mice, rats, and rabbits revealed developmental abnormalities for rabbits, but not rats or mice.
Pharmacology
Pharmacodynamics
Mifepristone is a steroidal antiprogestogen, as well as an antiglucocorticoid and antiandrogen to a much lesser extent. It antagonizes cortisol action competitively at the receptor level.In the presence of progesterone, mifepristone acts as a competitive progesterone receptor antagonist. Mifepristone is a 19-nor steroid with a bulky p- phenyl substituent above the plane of the molecule at the 11β-position responsible for inducing or stabilizing an inactive receptor conformation and a hydrophobic 1-propynyl substituent below the plane of the molecule at the 17α-position that increases its progesterone receptor binding affinity.
In addition to being an antiprogestogen, mifepristone is also an antiglucocorticoid and a weak antiandrogen. Mifepristone's relative binding affinity at the progesterone receptor is more than twice that of progesterone, its relative binding affinity at the glucocorticoid receptor is more than three times that of dexamethasone and more than ten times that of cortisol. Its relative binding affinity at the androgen receptor is less than one-third that of testosterone, and it does not bind to the estrogen receptor or the mineralocorticoid receptor.
Mifepristone as a regular contraceptive at 2 mg daily prevents ovulation. A single preovulatory 10-mg dose of mifepristone delays ovulation by three to four days and is as effective an emergency contraceptive as a single 1.5-mg dose of the progestin levonorgestrel.
In women, mifepristone at doses greater or equal to 1 mg/kg antagonizes the endometrial and myometrial effects of progesterone. In humans, an antiglucocorticoid effect of mifepristone is manifested at doses greater or equal to 4.5 mg/kg by a compensatory increase in ACTH and cortisol. In animals, a weak antiandrogenic effect is seen with prolonged administration of very high doses of 10 to 100 mg/kg.
In medication abortion regimens, mifepristone blockade of progesterone receptors directly causes endometrial decidual degeneration, cervical softening and dilatation, release of endogenous prostaglandins, and an increase in the sensitivity of the myometrium to the contractile effects of prostaglandins. Mifepristone-induced decidual breakdown indirectly leads to trophoblast detachment, resulting in decreased syncytiotrophoblast production of hCG, which in turn causes decreased production of progesterone by the corpus luteum. When followed sequentially by a prostaglandin, mifepristone 200 mg is as effective as 600 mg in producing a medical abortion.
'Contragestion' is a term promoted by Étienne-Émile Baulieu in the context of his advocacy of mifepristone, defining it as inclusive of some hypothesized mechanisms of action of some contraceptives and those of mifepristone to induce abortion. Baulieu's definition of a 'contragestive' included any birth control method that could possibly act after fertilization and before nine-weeks gestational age.