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Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
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3
Uses of Antiprogestins: The Reproductive Cycle (Part II)

PREGNANCY TERMINATION DURING THE FIRST TRIMESTER

The need for ample progesterone production by the ovarian corpus luteum to maintain early pregnancy is well established. In fact, low progesterone secretion in the luteal phase has been implicated in habitual abortion (Giudice et al., 1989). 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. On the basis of successful animal experiments (Baulieu, Appendix B1), mifepristone (RU 486) was initially tested as an efficient medical means of early pregnancy termination. The first studies in humans were successfully performed by Herrmann et al. (1982) in Geneva, documenting the ability of mifepristone alone to interrupt early pregnancy. These results were confirmed in a dose-finding study conducted under the auspices of the World Health Organization (Bygdeman, Appendix B5). Two conclusions could be drawn from these early studies. First, the frequency of successful complete abortion using mifepristone decreased with advancing age of the fetus, with approximately a 60 to 70 percent incidence of complete abortion up to eight weeks. Second, there appeared to be no relationship between the success rate and the treatment regime employed for women at the same stage of gestation.

In an attempt to interrupt early gestation more effectively, several groups have used different prostaglandin preparations in combination with mifepristone. In the first study with combined therapy, 25 mg of

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×

mifepristone were given twice daily for three to six days accompanied by 0.25 mg sulprostone, an injectable prostaglandin (PGE2) analogue (Schering AG, Berlin), on the last day. With this combined regime, the overall frequency of complete abortion was 94 percent (Bygdeman and Swahn, 1985).

Subsequent studies (Bygdeman, Appendix B5) reported successful abortion rates of between 95 and 100 percent when mifepristone was combined with vaginal administration of 0.5 to 1 mg gemeprost, a vaginal pessary prostaglandin (PGE1) analogue. These high success rates for complete abortion led to the French approval in September 1988 of mifepristone used in conjunction with prostaglandin administration for pregnancies up to 49 days of amenorrhea as calculated from the last menstrual period.

In Great Britain, successful trials were conducted using gemeprost up to 63 days of amenorrhea. This protocol for medical interruption of pregnancy was approved in Great Britain in July 1991, and subsequently in Sweden in 1992, using the same vaginal prostaglandin protocol. The French have reported the largest experience, treating more than 2,000 women with up to 49 days of amenorrhea with a single 600-mg dose of mifepristone followed 36 to 48 hours later by the administration of either gemeprost (1 mg by vaginal suppository) or sulprostone (0.25 to 0.5 mg by intramuscular injection). In a study reported by Silvestre et al. (1990), the overall efficacy rate was 96 percent, with 1 percent continuing pregnancies, 2.1 percent incomplete expulsions, and 0.9 percent required dilation and curettage (D&C). Only one woman required blood transfusion.

The procedure is not only highly efficient, but it is generally acceptable to women. The clinical events of the mifepristone-gemeprost protocol are quite similar to those of a spontaneous abortion with bleeding and increased uterine contractility. About 50 percent of patients have begun to bleed at the time of prostaglandin treatment, and virtually all bleed within four hours after the administration of prostaglandin, with a mean duration of bleeding of eight days (Bygdeman, Appendix B5). Uterine pain is common, especially in the first few hours following prostaglandin treatment, with approximately 30 percent of women requiring an analgesic and another 30 percent requiring a narcotic.

In a large study in France, serious cardiovascular side effects following prostaglandin administration (sulprostone injection) were reported in 4 out of 16,000 women treated after sulprostone injection (Ulmann et al., 1992). These included one acute myocardial infarction and three cases of severe hypertension. By now, over 60,000 women have used RU 486 for abortions. Two more myocardial infarctions have occurred, one of which was fatal. The overall frequency of severe cardiac complications

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×

after sulprostone is approximately one in 20,000 cases. So far, myocardial infarction has not been reported as a complication of vaginal gemeprost use, but given the French experience with sulprostone, Roussel-Uclaf recommends that mifepristone plus any prostaglandin not be used in women who smoke more than 10 cigarettes per day, who are older than 35, or who have any other cardiovascular risks (Bygdeman, Appendix B5).

In France, patients must agree to a surgical termination of pregnancy if the medical therapy is not successful. The six children born after unsuccessful therapy with mifepristone are reported to be normal (Ulmann, IOM workshop). However, there is conflicting evidence about the teratogenicity of the mifepristone-prostaglandin regimen (Spitz and Bardin, in press), resulting in the current recommendation of surgical termination in cases of a failed medical procedure.

The ideal combination of an antiprogestin and prostaglandin remains to be established. Certainly, oral administration of prostaglandin may be advantageous for patient convenience. An oral preparation, misoprostol (G.D. Searle & Co., Chicago), is licensed for sale in many countries as a treatment for gastric and duodenal ulcers. Although one patient death was reported during the first trial of mifepristone plus misoprostol (Aubeny and Baulieu, 1991), a much larger study has documented the safety of this protocol. In the latter, 600 mg of mifepristone, plus 400 µg (two tablets) of misoprostol administered 48 hours later, were given to 895 women (Peyron et al., 1993). Approximately 70 percent of women had completely expelled the conceptus four hours after misoprostol ingestion. If expulsion did not occur, a third misoprostol tablet was given. This increased the efficacy to greater than 98 percent. No adverse treatment events were recorded. In addition, uterine cramping or discomfort was reported to be far less than that experienced with injectable or vaginal prostaglandins, with only 16 percent of patients requiring analgesia and 0.1 percent requiring narcotics.

A recent dose-finding study using 200, 400, and 600 mg of mifepristone suggests that doses as low as 200 mg are equally efficacious in inducing first-trimester abortion (Van Look et al., in press). The lowest effective dose of mifepristone in conjunction with prostaglandin is as yet unknown; however, the committee believes that a dose lower than 600 mg is effective.

The cardiovascular side effects in healthy nonsmoking women under the age of 35 appear to be minimal. The additional oral prostaglandin apparently results in a less painful but equally efficacious procedure compared to other prostaglandin preparations, with minimal bleeding and a failure rate of less than 2 percent.

Drug regulatory officials in France, Sweden, and the United Kingdom have judged that the use of antiprogestins in combination with prostaglandin is a safe and efficacious medical treatment for early pregnancy

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×

termination. There is now a vast world literature with more than 60,000 patients treated in France. Repetition of large Phase 3 trials in the United States (to demonstrate efficacy and document side effects) does not appear necessary.

Recommendation No. 8. The committee recommends expeditious submission to the U.S. Food and Drug Administration of all existing 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.

Health Services Research

At this point, the major research need in using antiprogestin for pregnancy termination is not in efficacy, but rather in health services research. The medical regimens appear to be safe and efficacious, as demonstrated by experience in France, Great Britain, and Sweden. However, the United States has a very different health care system in which access to reproductive health care is a major problem. Research can help clarify how to increase access to a medical program for terminating pregnancy, as well as provide benefit-cost analyses comparing the medical procedure to surgical termination of pregnancy. Another area of research includes the number of visits required to oversee this regimen safely. In France, pregnancies are terminated only in legally authorized centers and under a Roussel-Uclaf protocol requiring that medical termination occur before 49 days of amenorrhea. The protocol is administered during four required visits to the center. An initial visit documents pregnancy and educates the patient about the procedure; at a second visit, 600 mg of mifepristone is given. Thirty-six to forty-eight hours later, the woman returns to the clinic, and prostaglandin is administered either vaginally or orally. Patients are monitored as inpatients for at least four hours on the day of prostaglandin administration. They return for a fourth, follow-up visit 8 to 12 days

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×

after mifepristone administration (Bygdeman, Appendix B5). The apparent safety and efficacy of orally administered misoprostol (which does not require either parenteral administration or refrigeration) raise the possibility of fewer visits for this medical procedure (see also Grimes, Appendix B7). Advantages of this medical procedure are decreased cost (in Sweden, providers are reimbursed $600 for a surgical abortion and $300 for a medical abortion; Bygdeman, IOM workshop), as well as an increased sense of patient privacy and autonomy during the procedure. The safety of decreasing the number of patient visits to the physician must be evaluated.

In the United States, patient acceptability and access are major issues. Although the medical antiprogestin regimen (as distinct from surgical protocols) has found widespread patient acceptability in Europe (David, 1992; Winikoff et al., 1992), the committee suggests additional studies to determine appropriate protocols for this country, which may vary from those used elsewhere. Such research should help to define the optimal number of visits, appropriate doses and delivery route, and patient acceptability and access, including how best to ensure equal access for U.S. women of all economic and social classes.

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. 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

Although the specific mechanisms of human labor and delivery are not fully understood, several methods have been examined for inducing

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×

labor during the second and third trimesters of pregnancy. A variety of prostaglandins have been shown to induce uterine contractions in both second- and third-trimester pregnancies. The experience with mifepristone in first-trimester pregnancy termination suggested that mifepristone treatment sensitizes the myometrium to the action of prostaglandins, thereby reducing the amount of prostaglandin necessary to induce expulsion. This led to the hypothesis that antiprogestins might be useful in termination of pregnancies during the second and third trimesters as well.

Currently, second-trimester pregnancy termination is available in the United States by dilation and evacuation (D&E), by intra-amniotic saline injection, intra-amniotic prostaglandin F2a, or prostaglandin E2 vaginal suppositories. These procedures are used for elective pregnancy termination in the second trimester, including termination of pregnancies where fetal genetic or structural abnormalities have been documented. Prostaglandin termination of second-trimester pregnancies requires two to three days of inpatient hospital stay with significant discomfort. The alternative surgical procedure of D&E, although widely used, requires highly skilled technical ability, which may not be available in all clinical settings. A series of clinical trials has been performed to study the efficacy of mifepristone treatment before prostaglandin administration for second-trimester pregnancy termination to determine whether smaller doses of prostaglandin following mifepristone are as effective as larger doses of prostaglandin alone. All of these studies (Ulmann and Silvestre, Appendix B6) have suggested that treatment with mifepristone before prostaglandin, whether gemeprost, sulprostone, or PGE2, decreases significantly the level of prostaglandin needed to complete an abortion and shortens the time interval from administration to abortion. Given the multiday hospital admission required for a second-trimester prostaglandin abortion, as well as the high level of discomfort for the woman, the ability of antiprogestins to shorten the duration of hospitalization by one day would be significant. Other studies comparing the effects of antiprogestins with those of laminaria tents (Dilapan®) in gemeprost-induced second-trimester abortion documented that the use of mifepristone resulted in a significantly shorter induction-to-abortion interval than did the Dilapan (Thong and Baird, 1992).

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,

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×

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

It appears that antiprogestins not only sensitize the myometrium to subsequent prostaglandin installation but also help to ripen the cervix. This property may help to manage clinical situations such as (1) preparation for second-trimester abortion, (2) preparation for labor induction at term or post-term, and (3) preparation of the cervix when labor must be induced because of intrauterine fetal demise.

Animal studies have demonstrated that mifepristone matures and ripens the cervix, as measured by an increase in cervical diameter and decrease in cervical resistance to mechanical dilation (Ulmann and Silvestre, Appendix B6). This effect occurs through the molecular mechanisms that characterize the normal cervical-ripening process, including increase in water and hyaluronic acid content as well as collagenase activation. Several studies documenting the ability of antiprogestins to induce cervical maturation and ripening before vacuum aspiration have shown a significant effect 24 to 48 hours after mifepristone administration (Ulmann and Silvestre, Appendix B6). A dose-finding Canadian study using placebo or 100, 200, 400, or 600 mg of mifepristone as a single dose, administered 24 or 48 hours before cervical calibration, showed a significant increase in cervical diameter that was linearly related to dose up to 400 mg (Lefebvre et al., 1990). Patients treated with mifepristone had either an equivalent or a lower blood loss after vacuum aspiration than those treated with a placebo (Ulmann and Silvestre, Appendix B6). Thus, mifepristone in doses up to 600 mg appears to be efficacious in ripening and dilating the second-trimester cervix before D&E, as well as in decreasing treatment to expulsion time in nonsurgical protocols when used in conjunction with prostaglandin.

It should be noted that prostaglandin alone in an intravaginal formulation is approved by the Food and Drug Administration for the indication of cervical ripening. Studies will be needed to determine the relative efficacy of mifepristone.

Because of the discomfort associated with either elective termination of second-trimester pregnancy or the termination of the genetically abnormal or dead fetus, the ability of antiprogestins to shorten the therapeutic process is attractive. Overall, the antiprogestins in the second trimester are well tolerated, with the most frequently reported side effects being abdominal pain, nausea, and vomiting. All second-trimester pregnancy terminations carry the risk of bleeding and the

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×

potential need for surgical intervention. 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.

Recent advances in molecular biology and genetic, karyotypic diagnosis, as well as our increased ability to diagnose early structural abnormalities with ultrasonography, will inevitably increase the number of abnormal second-trimester gestations identified. The emotional stress of terminating such a pregnancy is great, as is the case of fetal demise, and therapeutic modalities to reduce both the time necessary for such a procedure and the discomfort involved merit further investigation.

LABOR INDUCTION IN LATE PREGNANCY

In addition to its possible use in cervical ripening in preparation for labor induction, mifepristone may also be useful in inducing labor, for instance in cases of intrauterine fetal demise and during late pregnancy when the medical complications require prompt delivery.

Fetal Demise

Fetal demise is an unfortunate occurrence in both second- and third-trimester pregnancies, and requires evacuation of the uterus. Studies have evaluated mifepristone's ability to initiate labor in cases of fetal demise. In the study of Cabrol et al. (1990), 600 mg of mifepristone, given on two consecutive days after diagnosis of fetal death, caused the initiation of labor within 72 hours in 63 percent of women, compared to spontaneous initiation of labor in 17 percent of the placebo-treated women. Thus, it appears that mifepristone alone is able to induce labor in patients with intrauterine fetal demise and that expulsion takes place significantly earlier than in placebo-treated patients.

Studies in ewes and monkeys have indicated that, at term, antiprogestins induce uterine contractions and enhance the myometrial sensitivity to oxytocin. Newborn monkeys of mothers treated with antiprogestins were normal and, in fact, grew more rapidly than did newborns from untreated mothers (Wolff et al., 1989). This is thought to be an effect of increased milk output in primate mothers treated with antiprogestins and is believed to be secondary to abrogation of the suppressive effect of progesterone on prolactin secretion. An initial study in humans by Frydman et al. (1992) evaluated the efficacy and safety of mifepristone for induction of labor in post-term pregnancies or in term pregnancies when other medical indications for labor induction were present. This placebo-controlled study used 200 mg of mifepristone daily for two consecutive days and showed a marked increase in the number of

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×

women with spontaneous onset of labor. Of those women receiving mifepristone, 54 percent had spontaneous onset of labor, compared with only 18.2 percent of those given a placebo. The interval between day 1 of treatment and the onset of labor for patients given mifepristone was 51.7 hours; for those on placebo it was 74.5 hours. In addition, the total dose of oxytocin required in mifepristone-treated patients was significantly lower than in those treated with placebo, although the cesarean section rate was equivalent. The evaluation of newborns by Apgar scores and measurement of umbilical vein pH levels showed no difference in outcome between mifepristone and placebo-treated patients. The authors concluded that mifepristone appeared to be a safe, efficient, and suitable induction agent for initiation of labor in women at term (Frydman et al., 1992).

It would be valuable in clinical practice to initiate labor more easily in post-term patients, as well as in women with medical conditions requiring relatively immediate (within two to four days) delivery. As mifepristone has been, and presumably will continue to be, given to women in late gestation, the opportunity to study any effects should be used. Prudence and caution dictate follow-up of infants born when labor is induced using antiprogestins. Assessments should include pulmonary, cardiac, and adrenal status of neonates as well as their later development and fertility potential. In addition, the early initiation of abundant lactation reported in the primate model suggests the need for studies in women to determine the impact of antiprogestins on lactation. The committee encourages dose-finding studies to determine the minimal dosage of antiprogestin necessary to induce labor.

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.

SUMMARY

Mifepristone is currently used with government approval in France, the United Kingdom, and Sweden. There are a variety of applications during pregnancy ranging from early first-trimester pregnancy termination to termination during second-trimester and even third-trimester labor induction (e.g., preeclampsia, post-term pregnancy, fetal demise). The application of mifepristone for cervical ripening at term, and for labor induction in late pregnancy when medical complications require it, has been tested and shows promise. Mifepristone appears to be effica-

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×

cious and safe and to add valuable alternatives to the obstetrical armamentarium. Studies to determine optimal doses, administration regimens, and the incidence of complications or side effects, as well as benefit-cost analyses, are warranted. The therapeutic options offered by antiprogestins have the potential to enhance clinical care during pregnancy.

REFERENCES

Aubény, E. and Baulieu, E.-E. Activité contragestive de l'association au RU 486 d'une prostaglandin active par voie orale. Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences (Paris) 312:539–545, 1991.


Bygdeman, M. and Swahn, M.L. Progesterone receptor blockage. Effect on uterine contractility in early pregnancy. Contraception 32:45–51, 1985.


Cabrol, D., Dubois, C., Cronje, H., et al. Induction of labor with mifepristone (RU-486) in intrauterine fetal death. American Journal of Obstetrics and Gynecology 162:540–542, 1990.


David, H.P. Acceptability of mifepristone for early pregnancy interruption. Law, Medicine & Health Care 20:188–194, 1992.


Frydman, R.C., Lelaidier, C., Baton-Saint-Mleux, C., et al. Labor induction in women at term with mifepristone (RU-486): A double-blind, randomized, placebo-controlled study. Obstetrics and Gynecology 80:972–975, 1992.


Giudice, L.C., Brody, S.A., and Ueland, K. The endocrinology of recurrent spontaneous abortion. Endocrine Disorders in Pregnancy. Norwalk, Conn.: Appleton and Lange, 1989.


Herrmann, W., Wyss, R., Riondel, A., et al. Effet d'un steroide antiprogestine chez la femme interruption du cycle menstruel et de la grossesse au debut. Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences (Paris) 294:933–938, 1982.


Lefebvre, Y., Proulx, L., Elie, R., et al. The effects of RU-38486 on cervical ripening. Clinical studies. American Journal of Obstetrics and Gynecology 162:61–65, 1990.


Peyron, R., Aubény, E., Targosz, V., et al. Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol. New England Journal of Medicine 328:1509–1513, 1993.


Silvestre, L., Dubois, C., Renault, M., et al. Voluntary interruption of pregnancy with mifepristone (RU-486) and a prostaglandin analogue. New England Journal of Medicine 322:645–648, 1990.

Spitz, I.M. and Bardin, C.W. Clinical pharmacology of RU 486—An antiprogestin and antiglucocorticoid. Contraception, in press (also see: RU 486—A modulator of progestin and glucocorticoid action. New England Journal of Medicine, in press).


Thong, K.J. and Baird, D.T. A study of gemeprost alone, Dilapan or mifepristone in combination with gemeprost for the termination of second trimester pregnancy. Contraception 46:11–17, 1992.


Ulmann, A., Silvestre, L., Chemm, L., et al. Medical termination of early pregnancy with mifepristone (RU 486) followed by a prostaglandin analogue. Acta Obstetricia et Gynecologica Scandinavica (Umea) 71:278–283, 1992.


Van Look, P.F., von Hertzen, H., and Noonan, E. Pregnancy termination with reduced doses of mifepristone. British Medical Journal, in press.


Winikoff, B., Coyaji, K., Cabezas, E., et al. Studying the acceptability and feasibility of medical abortion. Law, Medicine & Health Care 20:195–198, 1992.

Wolf, J.P., Sinosich, M., Anderson, T.L., et al. Progesterone antagonist (RU 486) for cervical dilation, labor induction and delivery in monkeys: Effectiveness in combination with oxytocin. American Journal of Obstetrics and Gynecology 160:45–47, 1989.

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×
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Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×
Page 27
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×
Page 28
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×
Page 29
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×
Page 30
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×
Page 31
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×
Page 32
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×
Page 33
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×
Page 34
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part II)." Institute of Medicine. 1993. Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press. doi: 10.17226/2203.
×
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Mifepristone (RU486), the first clinically available antiprogestin, has generated great interest since its discovery in the early 1980s. Today, it is recognized that mifepristone, along with other antiprogestins, has a potentially significant therapeutic role in human health and disease, with likely applicability to a variety of pregnancy-related conditions (e.g., management of labor) and to contraception, endometriosis, and cancer, among others. But because mifepristone has been studied and used most widely as a means of nonsurgical abortion, political issues have thus far limited research on the drug and prevented its introduction into the U.S. market.

This book provides an unbiased evaluation of current knowledge about both the fundamental nature of antiprogestins as well as their possible use in treating numerous diseases and conditions, and it contains recommendations for future research.

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