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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Summary Progesterone is a steroid hormone that plays a pivotal role in establishing and maintaining pregnancy. It exerts well-documented actions on a number of target tissues within the reproductive system (e.g., uterus, cervix, breast, pituitary-hypothalamic unit), and less well-defined actions on tissues outside the reproductive system (e.g., brain, vascular endothelial cells) and on lipid metabolism. 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. The first antiprogestin was discovered fortuitously by scientists searching for an antiglucocorticoid, a compound that would interfere with the action of a class of adrenal gland hormones called glucocorticoids that are involved in the physiologic regulation of virtually all tissues in the body. Now, more than a decade after the report of this first antiprogestin, mifepristone (RU 486), numerous antiprogestins have been synthesized and studied. Although all of the antiprogestins also have some degree of antiglucocorticoid activity, a property that causes unwanted side effects under many conditions of use, the potential role of these compounds in human health and disease is great. They have applicability to a variety of pregnancy-related conditions—management of labor, contraception, and infertility; endometriosis; the treatment of certain types of tumors; and as a result of their antiglucocorticoid activity, the treatment of Cushing's syndrome (a disease resulting from excess glucocorticoid production by the adrenal glands) and several other conditions.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Although many antiprogestins are under investigation by pharmaceutical companies for various therapeutic purposes, mifepristone is the only antiprogestin that has been extensively studied in human beings. It has been most widely studied as a means of nonsurgical abortion in early pregnancy, and has been licensed for that purpose in France, the United Kingdom, and Sweden. Because of the perceived promise of this class of compounds for a variety of therapeutic uses, the Institute of Medicine (IOM) established a committee of seven individuals to assess the state of scientific knowledge about antiprogestins, to clarify what is and is not known about these compounds, and to make recommendations for future research that might lead to improvements over currently available therapies for a variety of conditions. 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, first-trimester termination of pregnancy, second-trimester termination of pregnancy, as well as induction of labor, and for the treatment of endometriosis, uterine leiomyomas, meningioma, breast cancer, and Cushing's syndrome. The committee made a series of general recommendations that included several cross-cutting issues for investigation, as well as specific recommendations for research on each of the topics discussed at the workshop. Those recommendations appear below. The committee's full report includes a more complete explanation of its conclusions and presents additional materials supporting its recommendations. The background papers prepared for the IOM workshop are included as Appendix B of this report. CROSS-CUTTING RECOMMENDATIONS Recommendation No. 1. Research is needed to define the basic mechanisms and modes of action of mifepristone (RU 486) and other antiprogestins in order to understand the effects that have already been demonstrated and to develop compounds with more specific antiprogestin activity. Recommendation No. 2. Because antiprogestins as a class have clear potential for preventive and therapeutic applica-
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda tions in human health beyond those that have already been documented, the committee strongly recommends additional clinical testing of mifepristone and of newer antiprogestins as they are developed. Recommendation No. 3. Because some uses of antiprogestins may require long-term administration, the committee recommends studies to evaluate the potential toxicity, maintenance of efficacy, and development of drug resistance for antiprogestins used over longer periods of time. USES OF ANTIPROGESTINS: THE REPRODUCTIVE CYCLE Contraception Progesterone is produced by the ovary during the latter half of a normal menstrual cycle, and by the ovary and placenta during pregnancy. Because of the complex hormonal interplay that characterizes the female reproductive cycle and the role that progesterone plays in initiating and maintaining pregnancy, it is clear that antiprogestins could alter many of these functions. As a pharmacologic class, the antiprogestins appear to have great promise as regulators of reproductive potential. Data in humans, however, are limited with respect to most of the possible contraceptive applications, and the data that exist are confined largely, if not exclusively, to mifepristone. The committee reviewed a number of studies on the potential contraceptive effectiveness of mifepristone when given during the follicular, periovulatory, and luteal phases of the cycle. In these studies, administration of the antiprogestin varied: in some cases the drug was given continuously for various periods of time; in other cases it was given intermittently (once weekly or monthly for several days); and in some studies it was given in combination with other agents such as progestins or prostaglandins. In general, single-dose or short-term administration on an intermittent, as opposed to a continuous, basis appears to have limitations. 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. Late luteal phase administration will suppress the corpus luteum and cause bleeding, but it appears to require prostaglandins as well as the antiprogestin for uniform effectiveness. There are no data on the contraceptive efficacy or safety of continuous
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda long-term administration of low-dose antiprogestins. However, data derived from a number of therapeutic studies of mifepristone to treat endometriosis, leiomyomas, meningiomas, and Cushing's syndrome suggest that long-term use of this compound would inhibit ovulation and induce consistent amenorrhea (lack of menstrual bleeding). Toxicity experienced by women in these various studies was minimal except at the highest doses. Furthermore, the antiglucocorticoid activities of the compound were not manifest at low doses (less than 25 mg/day), even though doses as low as 2 mg/day were effective at inhibiting ovulation. Recommendation No. 4. Clinical research should be undertaken promptly to evaluate the efficacy and safety of mifepristone and other antiprogestins as low-dose contraceptives. Such research should address, among other issues, mechanisms of contraceptive action the effectiveness of various regimens in preventing pregnancy (e.g., continuous versus cyclic administration, possibly with the addition of other hormones) the lowest effective dose to prevent pregnancy for each regimen potential short- and long-term toxicities affecting bone (osteoporosis), lipids (alteration in profile), endometrium (histologic changes), ovary (cyst formation), and brain (mood); and benefits and risks, both contraceptive and noncontraceptive, of antiprogestin contraception relative to other hormonal contraception. Post-Coital Contraception A post-coital contraceptive is a pill or other method that can be used to reduce the chance of undesired pregnancy after unprotected intercourse around the probable time of ovulation (midcycle). In the United States, the most common post-coital approach (termed the ''morning-after pill") 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. Unfortunately, the relatively high amount of estrogen used results in side effects such as nausea and vomiting, and a 25 percent failure rate is highly undesirable. Because of the critical role progesterone plays in early transformation of the uterus, and its possible roles in ovulation and tubal transport, it
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda was reasoned that mifepristone might also be an effective post-coital method. Two available studies (from England and Scotland) on the use of mifepristone for post-coital contraception were reviewed by the committee. These studies compared mifepristone with other post-coital methods and have shown that it is, indeed, effective in this context. Furthermore, it is potentially preferable to the post-coital oral contraceptive regimen in that it appears to have higher efficacy and a lower frequency of side effects. Recommendation No. 5. The committee recommends expeditious submission to the U.S. Food and Drug Administration of existing clinical trial data on the use of mifepristone as a post-coital contraceptive to determine whether these data meet current U.S. regulatory requirements. 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-a-month administration at the end of the luteal phase of each menstrual cycle has also been studied. The major problem with both of these approaches has been that mifepristone alone does not consistently induce menstruation, and administering prostaglandin two days after mifepristone is required for consistently successful results. The need for a second agent makes this regimen less convenient from the patient's point of view, possibly reducing compliance. Given that a more specific antiprogestin compound would be expected to induce menses without any additional treatment, research that resulted in the development of such a compound would be particularly useful for menses induction. Recommendation No. 6. Research is needed to develop the best means for delivering combinations of antiprogestins and prostaglandins for menses induction and regulation, ranging from sequential oral doses of each component, to new ways of providing both drugs simultaneously with delayed release of the prostaglandin. Studies of compliance with these various approaches are needed, especially for sequential drug delivery. Recommendation No. 7. The committee recommends the development and evaluation of new antiprogestins that may in themselves induce menses without the need to add prostaglandin.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Pregnancy Termination During the First Trimester Ample progesterone must be produced by the ovarian corpus luteum to maintain early pregnancy. In fact, low progesterone secretion in the luteal phase has been implicated in habitual abortion. It was, therefore, logical to hypothesize that antiprogestins given during early pregnancy might act as abortifacients, and thus provide a medical alternative to current techniques of surgical abortion. Almost a decade of research is now available on the use of one of the antiprogestins, mifepristone, for first-trimester abortion. 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. 8. The committee recommends expeditious submission to the U.S. Food and Drug Administration of all existing preclinical and clinical trial data on mifepristone and prostaglandin for early pregnancy termination to determine whether these data meet current U.S. regulatory requirements. Recommendation No. 9. The committee recommends that in considering the use of mifepristone and prostaglandin for early pregnancy termination in women who smoke more than 10 cigarettes per day or are over 35 (two groups of women who were excluded from European studies), the documented risks must be compared with the risks of continuing pregnancy or of surgical termination of pregnancy. Furthermore, such assessment should attempt to distinguish between the risks attributable to mifepristone and those attributable to prostaglandin. Recommendation No. 10. With respect to using mifepristone for first-trimester termination of pregnancy, health services research should be conducted in the United States to determine which approaches (e.g., required number of visits, type of health care provider administering the drugs, site of service delivery) are most suitable from the standpoint of safety, efficacy, accessibility, and acceptability. The committee does not recommend that consideration of a New Drug Application by the Food and Drug Administration for the use of mifepristone for pregnancy termination be delayed until the research outlined in Recommendations Nos. 9 and 10 has been completed.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Recommendation No. 9 addresses a group of potential patients excluded from previous trials. Recommendation No. 10 relates to the appropriate setting for use of the drug combination, reflecting the committee's concern that the imposed criteria of four medical visits, as set by protocols from the innovator-manufacturer, may not be necessary or acceptable to patients in the United States. Pregnancy Termination During the Second Trimester Currently, second-trimester pregnancy termination is available in the United States by dilation and evacuation (D&E), by intra-amniotic saline injection, by intra-amniotic prostaglandin F, or by prostaglandin E2 suppositories. A series of clinical studies has suggested that treatment with mifepristone before the administration of prostaglandin significantly decreases the level of prostaglandin needed to complete an abortion and shortens the time interval from administration to abortion. Overall, in clinical studies to date, the use of antiprogestins for this purpose during the second trimester has been well tolerated with minimal side effects. Given the multiday admission required for a second-trimester prostaglandin abortion, as well as the high level of discomfort for the woman, the ability to shorten by one day the duration of hospitalization using antiprogestin would be significant. Recommendation No. 11. With regard to second-trimester abortion, the committee recommends conducting clinical trials in the United States to compare the established surgical procedure of dilation and evacuation (D&E) both to antiprogestins in combination with prostaglandins and to prostaglandins used alone. Such trials should clarify the optimal dose of antiprogestin 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. Cervical Ripening The application of mifepristone for cervical ripening has been tested and shows promise. This property may help to manage clinical situations such as (1) preparation for second-trimester abortion, (2) preparation for labor induction at term, and (3) preparation of the cervix when labor must be induced because of intrauterine fetal demise. Because of the discomfort associated with either elective termination of second-trimester pregnancy or the termination of the genetically abnormal or
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda dead fetus, the ability of antiprogestins to shorten the therapeutic process is attractive. The use of antiprogestins given 36 to 48 hours before either a surgical procedure or prostaglandin installation appears to be well tolerated without the addition of significant clinical complications. 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. In this study, a significantly higher percentage of women receiving mifepristone experienced a spontaneous onset of labor, and the time to onset of labor was about 24 hours earlier than in the placebo control group. Mifepristone also reduced the amount of oxytocin required to induce labor in the patients who did not have a spontaneous onset of labor. Research should include physiologic studies to assess the effects of antiprogestins on maternal lactation and on primate neonates to evaluate the pulmonary, cardiac and adrenal status of neonates as well as their later development and fertility potential. Recommendation No. 12. The committee recommends studies to determine the minimal dose of antiprogestins necessary to induce labor. Studies in animal models (most likely the primates) should assess possible adverse outcomes on infants. Research is also needed to determine the effect of antiprogestins on maternal lactation. OTHER POTENTIAL THERAPEUTIC USES OF ANTIPROGESTINS Endometriosis Endometriosis is a disease caused by the presence of endometrial tissue in ectopic (outside the endometrium of the uterus) locations, most commonly within the pelvic cavity. During the menstrual cycle this tissue undergoes changes similar to those in the endometrium. Endometriosis is a common disease (some have estimated that 5 to 15 percent of reproductive-age women and 30 to 40 percent of infertile women have this disorder), and it can be painful. The etiology of endometriosis is uncertain, but there is little question about the hormonal responsiveness of the ectopic endometrial tissue. Current therapeutic approaches are designed to interrupt cyclic hor-
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda monally induced changes in the ectopic tissue. Common medical therapies include danazol and gonadotropin-releasing hormone (GnRH) agonists, neither of which is uniformly successful. Surgical therapy is sometimes uses as well, particularly when endometriosis is associated with infertility. The side effects of the currently available therapies for treating endometriosis are sufficient to warrant continued research on alternative treatments. Further, drug and surgical treatments are only palliative, and it would be an important advance to have a curative treatment. Human studies using antiprogestins to treat endometriosis are limited. Only a single antiprogestin (mifepristone) has been evaluated, and treatment periods have been short (three and six months). In these limited studies, mifepristone at several different doses produced uniform amenorrhea and reduced pain in all subjects. However, significant disease regression was observed only with longer treatment (six months). Daily administration of mifepristone in this context seemed to be well tolerated, with limited side effects, particularly at the lowest doses studied (<25 mg/day). A study using 5 mg/day of mifepristone for six months is ongoing and will establish whether dosages this low are effective in treating endometriosis. The main promise offered by antiprogestins for treating endometriosis is preservation of the follicular phase levels of estradiol. This would protect women from the consequences of very low estrogen levels encountered with other forms of therapy (e.g., GnRH agonist). A goal of therapeutic studies should be to develop an antiprogestin regimen that is devoid of antiglucocorticoid side effects such as fatigue, nausea, and vomiting. Uterine Leiomyomas (Fibroids) Uterine leiomyomas, also known as fibroids, are non-malignant tumors of smooth muscle cell origin. Leiomyomas are the most common pelvic tumor; some have estimated that up to 20 percent of women over 30 years of age may have these benign tumors. They represent one of the most frequent reasons for surgery (including hysterectomies) in women of reproductive age. These tumors are clearly hormonally dependent. 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. In the face of persistent symptoms, surgical therapy is usually applied in advanced disease following the failure of medical therapy and, ideally, when no pregnancies are desired.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda There are very limited data from a few small studies on the use of antiprogestins in the treatment of uterine leiomyomas. In these studies, mifepristone at doses ranging from 5 to 50 mg/day for three months produced a marked decrease in leiomyoma volume. Side effects were limited and promptly resolved after discontinuation of the drug. Importantly, estrogen levels were maintained in a range sufficient to prevent bone loss as measured in the spine and hips. At the highest dose studied (50 mg/day), however, antiglucocorticoid effects were observed. These early studies on the use of antiprogestins in the treatment of both endometriosis and uterine leiomyomas appear promising; however, larger studies than those currently available are required to establish the long-term efficacy and safety of these drugs for such purposes. In particular, efforts should be made to determine whether antiprogestins improve fertility as compared to other available regimens. As with many areas of antiprogestin research, substantial additional studies are also needed to elucidate the molecular mechanism of action of antiprogestins in the treatment of these diseases. Understanding the mechanism of action of these compounds is critical and might provide leads for future therapeutic uses. In particular, the noncompetitive "antiestrogenic" properties reported in some studies should be characterized, especially as they relate to defining potential long-term side effects of these therapies. Recommendation No. 13. The committee recommends further studies to determine the minimal effective dose of mifepristone and other antiprogestins for the treatment of endometriosis and uterine leiomyomas. 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. Recommendation No. 14. The committee recommends additional research to elucidate the antiestrogenic property of mifepristone and other antiprogestins. Research models should include endometrial cultures, explants, and in vivo systems. It is also important to clarify the molecular events involved and, in all such investigations, to characterize whenever possible the steroid-receptor status of the endometriotic and fibroid tissues under study.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Breast Cancer Interest in the study of antiprogestins in breast cancer is understandable, given the known prognostic importance of the progesterone receptor in this disease and the current use of diverse endocrine interventions in its treatment. Approximately 30 percent all metastatic breast cancer patients, and 50 to 80 percent of the subset of patients whose tumors have estrogen or progesterone receptors, respond to a variety of endocrine interventions (e.g., drugs such as tamoxifen or progestins, or surgical removal of the ovaries for premenopausal women). Although such patients may improve in response to these treatments, the treatment results are relatively short-lived, lasting about 8 to 12 months. The antiprogestins have potential as growth inhibitory compounds against breast cancers. Whether this antitumor activity will be unique among the many other available endocrine therapies for breast cancer remains to be seen. 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). The exact mechanism by which antiprogestins exert their antitumor effect is unclear at present. However, data suggest that more than one mechanism exists. Although animal models can provide hypotheses, the biologic complexity and heterogeneity of breast cancer, and the limitations of these models, will require that many questions be addressed in basic research and in human clinical trials. Recommendation No. 15. The committee recommends research to clarify the activity of antiprogestins in women with advanced (metastatic) breast cancer. Trials should be conducted by using more homogeneous groups of patients. Potential sources of heterogeneity should be reduced by including patients with only minimal prior therapy for their breast cancer and by performing pharmacokinetic evaluations to ensure consistent drug exposure and to facilitate concentration-response correlations. In these studies, tumor progesterone-receptor and estrogen-receptor status should be measured routinely. Recommendation No. 16. Clinical trials of antiprogestins for treatment of breast cancer should include ancillary investigations to clarify mechanisms underlying the activity of antiprogestins. Examples of such studies include
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda histologic evaluation of tumor tissue before and after treatment assessment of cell-cycle distribution before and after therapy by use of flow cytometry assays of transforming growth factor (TGFß)induction and other potential indicators of cell differentiation 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); and assays for the expression of other growth factors such as TGFa epidermal growth factor (EGF), and insulin-like growth factor (IGF), which may be modulated by antiprogestins. Recommendation No. 17. The committee recommends that studies establish the maximum tolerated dose of antiprogestins for treatment of breast cancer. Further exploration of potential toxicity at various doses should be undertaken in additional Phase 1 clinical trials. Recommendation No. 18. The committee recommends additional preclinical exploration of the molecular mechanisms of action of antiprogestins for treatment of breast cancer. Such studies should include further characterization of progesterone receptors, including the natural A and B forms, as well as possible genetic mutants, and their distribution in normal and malignant tissue; this will be important for the rational use of antiprogestins in future clinical trials. investigation of the use of antiprogestins as differentiating agents that produce programmed cell death (apoptosis)—a possible novel mechanism of action; and exploration of the mechanism of tumor resistance to antiprogestins and other effects of long-term administration. Meningioma Meningiomas are tumors arising from the membranes surrounding the brain. Although they are not usually malignant in the sense of bringing about a patient's death through metastasis, the enlarging mass can be life threatening. The vast majority of meningiomas have progesterone receptors, though there is some controversy as to whether the progesterone receptors are functional in meningiomas.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda The committee reviewed results of a small initial clinical trial using an antiprogestin, mifepristone, in patients with meningiomas. About 25 percent (6 of 24 patients) had some improvement in their disease. Toxicities associated with daily chronic administration of the drug appeared tolerable. Although mifepristone appears to have some activity in recurrent or unresectable (inoperable) meningiomas, its clinical importance for treating a disease with a highly variable natural history remains to be defined. However, the lack of good alternative treatments for this group of patients and the mechanistic rationale make this an attractive treatment for further study. Recommendation No. 19. A randomized Phase 3 trial will be required to define the role of antiprogestins in the management of patients with unresectable meningioma. Such a trial is ongoing in the Southwest Oncology Group. The committee recommends that these data be reviewed carefully to define directions for further research on this disease. ANTIGLUCOCORTICOID EFFECTS OF ANTIPROGESTINS Glucocorticoids are steroid hormones that are produced by the adrenal glands and that have biological effects in virtually every system of the body. Like other steroids (e.g., estrogens, progestins), glucocorticoids exert their actions through specific receptors in target cells. All antiprogestins identified to date can bind to glucocorticoid receptors and exert some glucocorticoid antagonist activity (antiglucocorticoid effects). In the context of most uses of antiprogestins, these antiglucocorticoid effects are undesirable. There are, however, diseases that involve excess adrenal production of glucocorticoid hormones (generically termed Cushing's syndrome) for which drugs that have antiglucocorticoid activity would be highly desirable. Indeed, the committee reviewed the literature on the use of mifepristone in the treatment of Cushing's syndrome, and found the results promising. For most of the documented uses of the drugs as antiprogestins, their antiglucocorticoid actions were clearly viewed as undesired side effects. 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. 20. Antiglucocorticoid effects are an unwanted property of existing antiprogestins. Therefore, the committee recommends expanded efforts to produce pure antiprogestins that would not display any other endocrine effects at therapeutic doses.
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