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Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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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2
Uses of Antiprogestins: The Reproductive Cycle (Part I)

Progesterone is a steroid hormone produced by the ovary during the latter half of a normal menstrual cycle, and by the ovary and placenta during pregnancy. During the first half of a menstrual cycle (the follicular phase), estrogen is produced by a developing follicle. After ovulation (luteal phase), the follicle transforms to a corpus luteum, which produces both estrogen and progesterone. Each month, the cyclic fluctuations of estrogen and progesterone induce sequential, well-characterized changes in the lining of the uterus (endometrium).

If conception does not occur, the corpus luteum undergoes a process of regression. This regression is accompanied by declining levels of estrogen and progesterone, which in turn precipitate shedding of the endometrium; this shedding is experienced as a woman's monthly menstrual bleeding, or menses. If conception occurs, the corpus luteum continues to produce estrogen and progesterone under the influence of a hormone from the developing embryo (human chorionic gonadotropin), and endometrial shedding is prevented.

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 largely, if not exclusively, confined to mifepristone (RU 486). Therefore, many of the committee recommendations for research on

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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.
×

clinical potential and mechanisms of action must be based on results from limited human studies that use one specific antiprogestin.

CONTRACEPTION

Existing oral contraceptives (synthetic estrogen-progestin combinations, as well as progestin alone) are available and efficacious. Nonetheless, contraceptives based on new approaches (hormonal, antihormonal, or nonhormonal) would be welcome, because there remain some populations for whom use of oral contraceptives is contraindicated, and because not all women comply fully with the various regimens of pill-taking. New methods that are easier to use consistently and properly, and that preserve the beneficial effects of estrogen for women's health while minimizing any possible side effects would be of enormous social value. With regard to possible side effects, for example, currently used estrogen-progestin combination oral contraceptives are undergoing continuing epidemiologic study because of their possible role in increasing the risk of early-onset breast cancer (IOM, 1991). Other possible side effects for which questions persist include alteration in lipid profiles and, for older women who smoke, cardiovascular effects as well as possible thromboembolic events. Even the concern about such effects, whether or not they exist, means that new contraceptive formulations that are free of these worries would be very favorably received.

Antiprogestins present a new pharmacologic approach to contraception. Any such application of mifepristone or other antiprogestins would, of course, require testing in large-scale clinical trials to evaluate formally their efficacy and safety for use as low-dose contraceptives.

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 (see Baird, Appendix B4; Baulieu, Appendix B1; Van Look and von Hertzen, Appendix B12; and Spitz and Bardin, in press). 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, has 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,

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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.
×

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 high effectiveness.

There are no data on the contraceptive efficacy or safety of continuous long-term administration of low-dose antiprogestins. Of interest, however, are data derived from a number of studies using mifepristone to treat endometriosis, leiomyomas, meningiomas, and Cushing's syndrome. These studies suggest that long-term use of this compound would inhibit ovulation and induce consistent amenorrhea (Yen, Appendix B8; Nieman, Appendix B10). In one study reported at the IOM workshop, with perhaps the longest continuous use of mifepristone, 15 women with meningiomas (3 of whom were premenopausal and 12 postmenopausal) were treated for meningiomas with 200 mg daily for six months to five years (Grunberg et al., 1991a, b). During the study, the three premenopausal women became amenorrheic. Toxicity experienced by these women was minimal; reported side effects included fatigue, hot flashes, breast tenderness, thinning of hair, and rash. At low doses (less than 25 mg/day) used for up to six months to treat subjects with uterine leiomyomas, the antiglucocorticoid activities of the compound were not manifest (Yen, Appendix B8), even though doses as low as 5 mg/day were effective at inhibiting ovulation. These data substantiate the fact that mifepristone is more potent as an antiprogestin than as an antiglucocorticoid; however, pure antiprogestins without any associated antiglucocorticoid activity would remain preferable for contraceptive purposes.

In studies to evaluate potential contraceptive efficacy, experience with continuous low-dose mifepristone appears to be limited to only 30 days of treatment and doses of 2 to 10 mg/day of mifepristone (see Baird, Appendix B4; Ledger et al., 1992; Croxatto et al., 1993). The 2-mg/day dose consistently suppressed ovulation; a 1-mg dose did not. A possible advantage of continuous, low-dose mifepristone administration is that it appears to "spare" estrogen despite the inhibition of ovulation. Serum estrogen levels similar to those seen in late follicular phase were noted in these studies (see Baird, Appendix B4, and Croxatto et al., 1993, referenced therein), suggesting that such estrogen-affected factors as bone density, lipids, and sense of well-being should be well maintained. However, the few samples of endometrial tissue that have been obtained from women using mifepristone do not show proliferative effects, nor do they show a progestin-induced secretory effect. If changes in the endometrium caused by mifepristone are sufficient to prevent implantation, then a dose lower than the 2 mg daily required to suppress ovulation may be adequate. Endometrial changes associated with mifepristone require further study. Evaluation of possible ovarian follicular cysts, which have been reported to occur, and the recognized antiglucocorticoid effects will also require study.

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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.
×

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,

  1. mechanisms of contraceptive action

  2. the effectiveness of various regimens in preventing pregnancy (e.g., continuous versus cyclic administration, possibly with the addition of other hormones)

  3. the lowest effective dose to prevent pregnancy for each regimen

  4. potential short- and long-term toxicities affecting bone (osteoporosis), lipids (alteration in profile), endometrium (histologic changes), ovary (cyst formation), and brain (mood); and

  5. 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). Post-coital contraception is frequently desired after unplanned or unwanted sexual intercourse, or after a contraceptive failure such as a skipped pill, slipped diaphragm, or a loose or broken condom. In the United States, the most common post-coital approach (commonly called the "morning-after pill") involves using an oral contraceptive containing both a synthetic estrogen and a progestin. Although this regimen is not 100 percent efficacious, oral contraceptives reduce the risk of pregnancy by at least 75 percent after unprotected midcycle sexual intercourse (Trussell and Stewart, 1992). The treatment schedule is one dose (100 µg of ethinyl estradiol and 1.0 mg of dl-norgestrel) as soon as possible (beginning no more than 72 hours after unprotected intercourse), and a second dose 12 hours after the first. The total regimen is therefore 200 µg of ethinyl estradiol and 2.0 mg of dl-norgestrel. Because of the relatively high dose of estrogen, this method has a high frequency of estrogen-related side effects such as nausea and vomiting, and a 25 percent failure rate is undesirable.

A more recently studied experimental post-coital therapy consists of three 200-mg tablets of danazol taken within 72 hours of unprotected intercourse and repeated 12 hours later. Danazol, a synthetic steroid used in the treatment of endometriosis, lowers the estrogen level and so produces a lower incidence of nausea, vomiting, and breast tenderness

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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.
×

when compared to oral contraceptives in post-coital administration (Rowlands et al., 1983; Zuliani et al., 1990; Webb et al., 1992). However, the efficacy of danazol is not uniform, and it has a variety of undesired side effects with sustained use.

Two studies have been reported on the use of mifepristone as a post-coital contraceptive (Glasier et al., 1992; Webb et al., 1992). In these studies, mifepristone was better than combined oral contraceptives or danazol. In a British randomized trial involving all three regimens, women assigned to mifepristone and danazol experienced much lower incidences of nausea and vomiting; none of 195 women assigned to mifepristone became pregnant, compared with 2.6 percent and 4.7 percent of those receiving combined oral contraceptives and danazol, respectively (Webb et al., 1992). In a larger Scottish trial, 800 women were randomly assigned to use either mifepristone or the combined oral contraceptives regimen. Although 23 pregnancies were expected in each group had no interference been made, there were only 4 pregnancies in the group receiving combined oral contraceptives, and there were no pregnancies in the group receiving mifepristone alone. Rates of nausea, vomiting, headache, and breast tenderness were significantly lower in the group receiving mifepristone (Glasier et al., 1992). In both trials, a significantly greater proportion of women receiving mifepristone experienced a delay in the onset of the following menses.

The results of these studies indicate that the mifepristone regimen is potentially preferable to existing therapies in that it has higher efficacy and fewer side effects (nausea and vomiting). A significant advantage of mifepristone is that only a single 600-mg dose is required within 72 hours of unprotected intercourse; compliance in taking a second dose is therefore not an issue. Delay of menses by a few days following post-coital mifepristone should not be a serious disadvantage if women are informed that this delay may occur.

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 (e.g., 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 (Baulieu, Appendix B1; Van Look

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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 von Hertzen, Appendix B12; Baird, Appendix B4). The major problem with both of these approaches has been that mifepristone alone does not consistently induce menstruation, and administering prostaglandin two days after the mifepristone is required for consistently successful results. In the few small studies reported, pregnancy rates on the order of 20 percent were seen either when mifepristone was used before the day of expected menses or when mifepristone alone was used to induce abortion within 10 days of missed menses (Baird, Appendix B4, and references therein). These studies suggest the need for prostaglandin to increase efficacy. This need for a second agent makes the regimen less convenient from the patient's point of view, possibly reducing compliance. Research on new methods to deliver antiprogestins and prostaglandins is warranted. These methods of delivery might include vaginal suppositories, intramuscular administration, cutaneous patches, or sustained-release capsules. Given that a more specific antiprogestin compound would be expected to induce menses without any additional treatment, research that results 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.

REFERENCES

Croxatto, H.B., Salvatierra, A.M., Croxatto, H.D., et al. Effects of continuous treatment with low dose mifepristone throughout one menstrual cycle. Human Reproduction 8:201–207, 1993.


Glasier, A., Thong, K.J., Dewar, M., et al. Mifepristone (RU 486) compared with high-dose estrogen and progestogen for emergency post-coital contraception. New England Journal of Medicine 327:1041–1044, 1992.

Grunberg, S.M., Weiss, M.H., Spitz, I.M., et al. Treatment of meningioma with the oral antiprogestational agent mifepristone. Proceedings of the American Society of Clinical Oncology 10:126, 1991a.

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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.
×

Grunberg, S.M., Weiss, M.H., Spitz, I.M., et al. Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. Journal of Neurosurgery 74:861–866, 1991b.

Institute of Medicine (IOM). Developing New Contraceptives. Obstacles and Opportunities. Mastroianni, L., Jr., Donaldson, P.J., and Kane, T.T., eds. Washington, D.C.: National Academy Press, 1990.

IOM. Oral Contraceptives and Breast Cancer. Washington, D.C.: National Academy Press, 1991.


Ledger, W.L., Sweeting, V.M., Hillier, H., et al. Inhibition of ovulation by low dose mifepristone (RU 486). Human Reproduction 7:945–950, 1992.


Rowlands, S., Guillebaud, J., Bounds, W., and Booth, M. Side effects of danazol compared with an ethinyloestradiol/norgestrel combination when used for post-coital contraception. Contraception 27:39–49, 1993.


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).


Trussell, J., and Stewart, F. The effectiveness of post-coital hormonal contraception. Family Planning Perspectives 24:262–264, 1992.


Webb, A.M.C., Russell, J., and Elstein, M. Comparison of Yuzpe regimen, danazol, and mifepristone (RU 486) in oral post-coital contraception. British Medical Journal 305:927–931, 1992.


Zuliani, G., Colombo, U.F., and Molla, R. Hormonal post-coital contraception with an ethinylestradiol-norgestrel combination and two danazol regimens. European Journal of Obstetrics & Gynecology and Reproductive Biology 37:253–260, 1990.

Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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 I)." 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 20
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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 21
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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 22
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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 23
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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 24
Suggested Citation:"Uses of Antiprogestins: The Reproductive Cycle (Part I)." 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 25
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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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