ABSTRACT
Roussel Uclaf in partnership with the INSERM unit of Prof. E.E. Baulieu first discovered mifepristone (RU486) as part of a large research program on steroidal compounds with antihormone properties. Exhibiting a strong affinity to the progesterone and the glucocorticoid receptors, mifepristone exerted competitive antagonism to these hormones both in in vitro and in animal experiments. Due to its antiprogesterone activity, it was proposed that mifepristone be used for the termination of early human pregnancy. Mifepristone, at a dose of 600 mg initially used alone, was then used with a subsequent low dose of prostaglandin that led to a success rate of 95% as a medical method for early termination of pregnancy (TOP). Its use was extended to other indications, such as cervical dilatation prior to surgical TOP in the first trimester, therapeutic TOP for medical reasons beyond the first trimester, and for labor induction in case of fetal death in utero. The efficacy and safety of this treatment has been confirmed based on its use for over a decade, with close adherence to the approved recommendations. This paper describes the safety studies conducted in animals as well as the safety follow-up and side effects reported with use of the compound in various indications either approved or unapproved. The rationale for warnings and contraindications for use of the product are also explained. At lower doses, the molecule has proven promising for contraceptive purposes with few reported side effects. However, development of the product for this indication would require long-term studies. Although political and philosophical obstacles have delayed research, the use of mifepristone for other potential indications in gynecology or oncology should be investigated.
Subject(s)
Contraceptives, Postcoital, Synthetic/pharmacology , Mifepristone/pharmacology , Animals , Clinical Trials as Topic , Contraceptives, Postcoital, Synthetic/adverse effects , Contraceptives, Postcoital, Synthetic/chemistry , Contraceptives, Postcoital, Synthetic/toxicity , Dose-Response Relationship, Drug , Female , Humans , Mifepristone/adverse effects , Mifepristone/chemistry , Mifepristone/toxicity , Models, Animal , Progesterone/antagonists & inhibitors , SafetyABSTRACT
Mifepristone is an orally-active progesterone receptor antagonist. When a single dose of mifepristone is given in the mid- or late follicular phase, it may diminish or inhibit the luteinising hormone (LH) surge. In the early luteal phase, a single dose of mifepristone induces significant changes in the endometrium without affecting the hormonal levels or menstruation. When it is given in the mid-luteal phase, there will also be significant changes in the endometrium and some women may have two episodes of vaginal bleeding. A clinical trial suggests that a single dose of mifepristone in the early luteal phase may be an effective contraceptive agent but the lack of a cheap and easy method to identify the LH surge limits its clinical application. The administration of mifepristone alone or in combination with a prostaglandin does not appear to be an effective form of contraception. When used together with a prostaglandin, it may be an effective method for menstrual regulation but the cost and possible side effects of the prostaglandins limit its use. Mifepristone is a very effective method for emergency contraception. The incidence of side effects was also lower than that of the Yuzpe regimen. Lowering the dose of mifepristone from 600 to 10 mg does not decrease its efficacy but the incidence of delay in onset of the subsequent menses is reduced. Despite its efficacy, the reputation of mifepristone as an abortion pill may limit its access in many countries.
