Clinical Applications of Mifepristone (RU486) and Other Antiprogestins Assessing the Science and Recommending a Research Agenda (1993) / Chapter Skim
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Given the broad role progesterone plays in normal physiology and in certain pathophysiologies, logic suggested that compounds to inhibit its action (termed antiprogestins) might be useful in the pharmacological regulation of a variety of conditions and diseases.
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Political controversy has focused public attention on the use of antiprogestins to induce miscarriage; this committee, however, was specifically charged with considering the full spectrum of clinical applications of antiprogestins, not just their use for medical abortion. Using information provided in the literature, in commissioned papers, and presented during a workshop held at the IOM in April 1993, the committee reviewed and assessed the basic and clinical research available on the use of antiprogestins for post-coital contraception, continuous-use contraception, induction of missed menses, firsttrimester termination of pregnancy, second-trimester termination of pregnancy, as well as induction of labor, and for the treatment of endometriosis, uterine leiomyomas, mening~oma, breast cancer, and Cushing's syndrome.
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Administration during the follicular phase merely delays follicular growth and ovulation Early luteal phase administration delays the development of a secretory endometrium but does not affect the corpus luteum. Timing of such early luteal phase administration must be linked to ovulation, which is not easy to achieve.
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involves a combination oral contraceptive containing both a synthetic estrogen and a progestin. Although the regimen is not 100 percent efficacious, currently available oral contraceptives reduce the risk of pregnancy by at least 75 percent after unprotected midcycle sexual intercourse.
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Menses Induction Studies have evaluated the use of mifepristone to induce menses after an undesired mid-cycle exposure when administered within one week following the day of the expected onset of a menstrual period. Once-amonth administration at the end of the luteal phase of each menstrual cycle has also been studied.
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Drug regulatory officials in France, Sweden, and the United Kingdom have concluded that mifepristone, when given in combination with prostaglandin, is safe and efficacious medical treatment for early pregnancy termination. Recommendation No.
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both to antiprogestins in combination with prostaglandins and to prostaglandins used alone. Such trials should clarify the optimal dose of andprogestin and prostaglandin for this use, and should assess relative pain, interval to fetal expulsion, blood loss, and frequency of infection, uterine perforation, and incomplete expulsion requiring surgical intervention.
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Labor Induction in Late Pregnancy Studies in ewes and monkeys have indicated that, at term, antiprogestins induce uterine contractions and enhance the myometrial sensitivity to oxytocin, a drug used to induce labor. An initial study in humans with promising results compared mifepristone to a placebo for labor induction in term or post-term pregnancies.
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Medical therapies such as high-dose progestin therapy and gonadotropin-releasing hormone agonists decrease overall uterine volume markedly, usually over a three-month treatment period. However, the effect of medical therapy is temporary, and no therapy has thus far been successful on a long-term basis.
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Measures of outcome should not be limited to pain relief alone, but should also address the likelihood of improving fertility. Once such studies are completed, randomized clinical trials should be undertaken to compare the safety and efficacy of mifepristone and other antiprogestins with current therapies for the treatment of endometriosis and uterine leiomyomas.
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In reviewing the literature, the committee concluded that too few clinical data are currently available to assess adequately the clinical potential of antiprogestins in the treatment of metastatic breast cancer, much less to assess their potential applications for adjuvant therapy (postoperative therapy undertaken when no detectable tumor is present to reduce the risk of recurrence) or chemoprevention (treatment of well women to lower the risk of initial development of cancer)
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induction and other potential indicators of cell differentiation d. characterization of the progesterone receptor, including quantitation not only of total receptor content but also of A and B receptors and receptor mutants (Western blot technology currently exists for this analysis)
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For obvious medical reasons, it would be preferable to have separate classes of pure antiprogestins and of pure antiglucocorticoids that do not display any other endocrine effects. Recommendation No.
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