B4
Potential Contraceptive Effects of Antigestogens

DAVID T. BAIRD, M.D.

Department of Obstetrics and Gynaecology, Centre for Reproductive Biology, University of Edinburgh

ABSTRACT

Antagonists of progesterone have the potential to be used to interrupt a wide range of reproductive processes that are dependent on this key hormone. Compounds such as mifepristone, onapristone, and lilopristone interact with progesterone receptors throughout the body and block the action of endogenous progesterone. The effect of mifepristone on the ovarian and endometrial cycles depends on the stage of the cycle. Throughout the follicular phase there is little effect on the endometrium. In the early follicular phase it has little effect on the ovarian cycle. In contrast, in midfollicular phase, gonadotropin levels are suppressed and follicular development is arrested. In the early luteal phase, the corpus luteum forms normally, but the development of secretory endometrium is retarded. In the mid- and late luteal phases, bleeding is provoked due to an effect on the endometrium, while luteal regression occurs inconsistently.

The effects of antigestogens on the endometrium and hypothalamic-pituitary system have the potential to be used as antifertility agents by inhibiting ovulation, preventing or disrupting implantation, and/or inducing luteal regression. Ovulation can be suppressed by continuous administration of mifepristone in doses as low as 2 mg/day. Given during the early luteal phase, mifepristone has been shown to be an effective post-coital agent used either in an emergency after unprotected intercourse or as a once-a-month pill. Antigestogens have the ability to alter endometrial histology in doses that have little effect on the ovarian cycle. If these changes in function are incompatible with the establishment of pregnancy, it may be possible to develop an ''endometrial" contraceptive pill.



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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda B4 Potential Contraceptive Effects of Antigestogens DAVID T. BAIRD, M.D. Department of Obstetrics and Gynaecology, Centre for Reproductive Biology, University of Edinburgh ABSTRACT Antagonists of progesterone have the potential to be used to interrupt a wide range of reproductive processes that are dependent on this key hormone. Compounds such as mifepristone, onapristone, and lilopristone interact with progesterone receptors throughout the body and block the action of endogenous progesterone. The effect of mifepristone on the ovarian and endometrial cycles depends on the stage of the cycle. Throughout the follicular phase there is little effect on the endometrium. In the early follicular phase it has little effect on the ovarian cycle. In contrast, in midfollicular phase, gonadotropin levels are suppressed and follicular development is arrested. In the early luteal phase, the corpus luteum forms normally, but the development of secretory endometrium is retarded. In the mid- and late luteal phases, bleeding is provoked due to an effect on the endometrium, while luteal regression occurs inconsistently. The effects of antigestogens on the endometrium and hypothalamic-pituitary system have the potential to be used as antifertility agents by inhibiting ovulation, preventing or disrupting implantation, and/or inducing luteal regression. Ovulation can be suppressed by continuous administration of mifepristone in doses as low as 2 mg/day. Given during the early luteal phase, mifepristone has been shown to be an effective post-coital agent used either in an emergency after unprotected intercourse or as a once-a-month pill. Antigestogens have the ability to alter endometrial histology in doses that have little effect on the ovarian cycle. If these changes in function are incompatible with the establishment of pregnancy, it may be possible to develop an ''endometrial" contraceptive pill.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda TABLE B4.1 Mifepristone and the Ovarian Cycle   Effect     Phase LH/FSH Cycle Endometrium Early follicular ↓ None None Midfollicular ↓ Delayed ovulation None Late follicular ↓ ± Inhibit ovulation None Early luteal ↓ None Retarded Mid to late luteal ↓ ± Luteal regression Low: desynchronization       High: bleeding INTRODUCTION Progesterone is a key hormone in the regulation of many reproductive processes, including the establishment and maintenance of pregnancy. In many species it is involved in the mechanism of ovulation, and both parturition and lactation occur as a result of withdrawal of progesterone secretion. In 1980 a group of chemists at Roussel-Uclaf discovered a synthetic steroid (mifepristone or RU 486) which is a potent antagonist of progesterone and cortisol but has no antiestrogen activity (Philibert et al., 1982). Very soon, it was reported in a pilot study to induce bleeding from the uterus when it was given to women in the luteal phase of the cycle or in early pregnancy (Herrman et al., 1982). This latter property has been utilized in the development of a method of inducing abortion. Mifepristone, in combination with a suitable prostaglandin (gemeprost, sulprostone, or misoprostol), has been shown to be a highly effective alternative to vacuum aspiration to induce abortion in the first nine weeks of pregnancy and has been licensed for this use in France, Great Britain, Sweden, and China (Baird, 1993). The political controversy surrounding the "abortion pill" has obscured the fact that antigestogens have many other potential therapeutic uses. In this paper I describe the effects of mifepristone when given to women at various stages of the menstrual cycle. Although there are several other synthetic antigestogens with slightly different pharmacological properties (e.g., onapristone and lilopristone), the data in women are virtually confined to mifepristone. PHYSIOLOGICAL STUDIES IN THE MENSTRUAL CYCLE The effect of mifepristone on ovarian activity is dependent on the time of the cycle and the dose used (Table B4.1). Since mifepristone binds to progesterone receptors in the hypothalamus and anterior pituitary as well as in the uterus, it is likely that it would interfere with the ovarian as well as the endometrial cycles. In the original clinical report in which mifepristone was given to three women in a dose of 50 mg/day by mouth

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda for four days, bleeding occurred within 48 hours of the first tablet (Herrman et al., 1982). There was a simultaneous decrease in the concentration of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and progesterone, suggesting that luteal regression had occurred prematurely as a result of inhibition of gonadotropins. This finding was surprising because it would be expected that an elevation, not a suppression, of LH would result following antagonism of progesterone. Subsequent studies have detailed the result of administration of mifepristone at different stages of the cycle. In the early follicular phase at a dose of 3 mg/kg, there is a suppression of the concentration of estradiol, although the length of the cycle is unaffected (Stuenkel et al., 1990). However, when given late in the follicular phase, folliculogenesis is arrested and ovulation is delayed (Liu et al., 1987; Shoupe et al., 1987) (Figure B4.1). The mechanism by which follicular growth is inhibited is not entirely clear but probably involves suppression of LH. In one study there was no difference between 10 and 100 mg of RU 486, and the magnitude of suppression was greater in the late follicular phase when the concentration of estradiol was highest (Permezel et al., 1989). This suppression of LH and FSH concentration occurs apparently with little or no change in the frequency or amplitude of LH pulses. However, in the preovulatory phase, it is not possible to arrest follicular development, and an LH surge and ovulation may occur (Spitz et al., 1993). Although mifepristone has agonistic activity when given to postmenopausal women treated with estrogen, it has little effect on the histology of the endometrium in the follicular phase of the cycle (Gravanis et al., 1985; Swahn et al., 1988). The effect of mifepristone in the luteal phase is also dependent on the dose and on the stage of the cycle. When mifepristone is given in the early luteal phase (LH + 2–3 days), the corpus luteum functions normally and menstruation occurs at the appropriate time (Swahn et al., 1990). In the mid-and late luteal phase, however, doses of >50 mg/day mifepristone suppress LH and progesterone, and result in premature luteal regression in approximately 50 percent of cases (Schaison et al., 1985; Garzo et al., 1988; Swahn et al., 1988) (Figure B4.2). In those women in whom the corpus luteum does not regress prematurely, bleeding occurs within 48 hours due to a direct effect on the endometrium and is followed by a second episode at the time of expected menses. The bleeding that occurs after administration of mifepristone in the luteal phase is due to a direct effect on the endometrium and occurs even if the progesterone concentration remains high, for example, when human chorionic gonadotropin (hCG) is injected to maintain the corpus luteum (Croxatto et al., 1989). The exact mechanism by which mifepris-

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda FIGURE B4.1 The effect of 100 mg/day mifepristone from days 10 to 17 of the ovarian cycle. Note that follicular development is arrested and ovulation delayed for more than 14 days. SOURCE: Shoupe et al. (1987).

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda FIGURE B4.2 The effect of 50 mg/day mifepristone from days 20 to 23 of the ovarian cycle. Five women had only a single episode of bleeding, which was associated with luteal regression. In the remaining four women in whom a second episode of bleeding occurred at the time of expected menses, a normal luteal phase was observed. SOURCE: Swahn et al. (1988). tone acts on the endometrium to induce bleeding is not entirely understood. In the early luteal phase, the development of secretory changes is retarded (Swahn et al., 1990). In the midluteal phase, changes suggestive of degeneration of the endometrium prior to menstruation occur, with shrinkage of glandular lumen, infiltration of leukocytes, and

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda TABLE B4.2 Concentration (pg/mg) of PGF2a and PGE2 in Endometrium Obtained from Women Who Received Mifepristone (5 mg/kg) in the Follicular (day 8–10) or Luteal (day 19–22) Phase of the Cycle, 24 Hours Prior to Sampling (N = 5–7 each group)   Follicular Phase   Luteal Phase   Prostaglandin Control Mifepristone Control Mifepristone PGF2a 193 ± 37 515 ± 204 473 ± 49a 1458 ± 259a PGE2 310 ± 50 489 ± 80 433 ± 106 795 ± 211 a P 8 0.001, Mann-Whitney. necrosis of the blood vessels (Li et al., 1988; Swahn et al., 1988). These latter changes are of particular interest because they occur in the decidua in early pregnancy after administration of mifepristone and are associated with the reduction in prostaglandin dehydrogenase in the vessel wall (Cheng et al., 1993a). At the same time there is a striking increase in the concentration of PGE2 as demonstrated by immunocytochemistry (Cheng et al., 1993b). Mifepristone increases the release of the prostaglandins PGF2a and PGE2 by dispersed endometrial cells cultured in vitro (Kelly et al., 1986), while the "concentration" of PGF2a is increased in endometrium recovered from women who had taken mifepristone (5 mg/kg) 24 hours previously (Table B4.2). Thus antigestogens may increase the effective local concentration of prostaglandins both by provoking their release and by inhibiting their local metabolism (Kelly and Buckman, 1990). In summary, in the follicular phase of the cycle, mifepristone inhibits follicular development and ovulation through an effect on the secretion of gonadotropins but has little effect on the endometrium. Immediately after ovulation, mifepristone retards the development of a secretory endometrium by antagonizing the effect of progesterone. Late in the luteal phase, endometrial bleeding is provoked in a manner that simulates what occurs at menses after regression of the corpus luteum. Although antigestogens do not bind to the estrogen receptor, both onapristone and mifepristone have the ability to antagonize the action of estrogen on the endometrium (van Uem et al., 1989). Endometrial atrophy occurs in castrate monkeys given mifepristone in combination with estrogen. The mechanism of this noncompetitive inhibition of estrogen is unknown but is associated with a striking up-regulation of the estrogen receptor (ER) (Neulen et al., 1990). Another antigestogen (onapristone) produces a similar noncompetitive inhibition of the effect of estrogen on the rabbit uterus (Chwalisz et al., 1991). The antagonism of estrogen is not due to binding to the ER. It is possible that the increase in ER after mifepristone is due to uncontrolled expression of ER, which

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda is normally inhibited by very low levels of progesterone such as are present even in the castrate animal. POSSIBLE CONTRACEPTIVE USES OF MIFEPRISTONE Mifepristone could be used as a contraceptive by virtue of its action on the hypothalamic-pituitary system as well as its effect on the endometrium. Inhibition of Ovulation In the follicular phase, when given in relatively large doses (25–600 mg) for several days, mifepristone inhibits follicular development and ovulation. In the monkey, 25 mg but not 12.5 mg once per week inhibited ovulation by preventing the development of the dominant follicle (Luukkainen et al., 1988; Danforth et al., 1989; Spitz et al., 1993). Similar experiments in women have given inconsistent results, although 25 mg/day for 14–21 days combined with norethisterone has been suggested as a possible non-estrogen-based contraceptive (Spitz et al., 1993). Good cycle control was observed, but the necessity to add a synthetic gestogen and the fact that ovulation was not always blocked are disadvantages (Kekkonen et al., 1990). In another small study involving five women, mifepristone (50 mg/day) was given from days 9–11 of the cycle to inhibit ovulation, followed by medroxyprogesterone acetate from days 17–26 (Croxatto et al., 1991). Menstrual bleeding occurred after a second short course of mifepristone was given on days 27–29. In these studies it was thought necessary to give a gestogen to prevent endometrial hypertrophy due to unopposed estrogen and to produce regular menstrual bleeding. However, as mentioned above, mifepristone has the paradoxical effect of antagonizing the effect of estrogen by a noncompetitive action and, hence, inducing a degree of endometrial atrophy. Two recent studies have investigated the effect of daily administration of mifepristone for 30 days in doses from 10 to 1 mg (Ledger et al., 1992; Croxatto et al., 1993). There was a dose-dependent suppression of follicular activity and ovulation. A single dose of 2 mg was the minimum dosage that suppressed ovulation consistently, whereas 1 mg/day resulted in variable effects on cycle length (Figure B4.3). In some women, ovulation apparently occurred normally; in others, there was suppression of ovulation or evidence of luteinized unruptured follicle. At doses ³2 mg, ovulation was suppressed, although follicular development, as assessed by ultrasound measurements and serum estradiol, continued. In spite of levels of estradiol that were similar to those found in the late follicular phase of the cycle, there

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda FIGURE B4.3 The effect of mifepristone (a single dose of 2 mg/day) on ovarian function. Note that during the administration of mifepristone the excretion of pregnanediol remained low, indicating suppression of ovulation. SOURCE: Ledger et al. (1992). was no evidence of endometrial hypertrophy. The women remained amenorrheic as long as they took mifepristone. On stopping the mifepristone, an LH surge and ovulation occurred within 14 days, although the luteal phase of the following cycle was often shorter than normal, suggesting an insufficient corpus luteum. The mechanism by which these low doses of mifepristone prevent ovulation probably involves inhibition of the positive feedback mechanism. In the normal cycle, in the few hours prior to the onset of the LH surge, there is a rise in the concentration of progesterone due to increased secretion by the preovulatory follicle (Hoff et al., 1983). This rise probably facilitates the ability of estrogen to induce an LH surge, as indicated by the fact that it can be delayed for a few days by the administration of mifepristone in doses as low as 1 mg/day (Batista et al., 1992). That this effect is due to its antigestogen action is illustrated by the

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda observation that an LH surge can be induced in these women by the simultaneous injection of 5 mg progesterone. Further evidence that the antigestogen is blocking ovulation by inhibiting the LH surge is provided by the occurrence of a surge within a few days of stopping mifepristone (Ledger et al., 1992). In summary, these studies suggest that mifepristone given in a daily dose that is 100-fold less than that used to induce abortion would be an effective contraceptive by suppressing ovulation. If further studies demonstrate no deleterious effect on the endometrium of long-term administration of mifepristone, this may provide a useful alternative to continuous gestogen (the "mini pill") without the disruptive effect on the pattern of menstruation. Post-Coital Contraception Because antigestogens retard the development of a secretory endometrium and induce bleeding in the luteal phase, it is likely that they would be effective at preventing or disrupting implantation of the early embryo. In two recent studies, 402 and 195 women exposed to the risk of pregnancy were given 600 mg mifepristone within 72 hours of unprotected intercourse (Glasier et al., 1992; Webb et al., 1992). No pregnancies occurred in either study, demonstrating that mifepristone is a highly effective emergency post-coital agent. Although side effects such as nausea and vomiting were much fewer than in a group of women given a large dose of the combined oral contraceptive pill ("Yuzpe" regimen), about 30 percent of the women experienced a delay of more than three days in the onset of the next menstruation (Glasier et al., 1992). This delay probably occurs in those women given mifepristone during the follicular phase, with the subsequent arrest of follicular development and ovulation. Ovulation is delayed until a new follicle is recruited. The delay in the onset of the next period is a source of concern to women who might worry that they may be pregnant. In the study by Webb et al. (1992), three women became pregnant during this time due to further acts of intercourse, indicating that it is necessary to give contraceptive advice at the time of emergency contraception. The efficacy of mifepristone, given in the early luteal phase of the cycle, in preventing pregnancy has recently been tested in trials in Sweden (Gemzell-Daniellson et al., 1993). Twenty-one sexually active women were given 200 mg mifepristone as their sole method of contraception on the second day after the LH peak in urine. Women were studied for periods of 1–12 months. There was only one pregnancy in a total of 157 ovulating cycles. In 124 cycles, at least one act of intercourse occurred in the three days around ovulation. Menses occurred at the expected time, although in 35 percent of the cycles there

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda was slight bleeding for two or three days after taking the mifepristone. This preliminary study confirms that mifepristone, given at this time, is highly effective at preventing pregnancy and could be used as a once-a-month contraceptive. However, in order to avoid disruption in the cycle it must be given within two or three days of ovulation. Unless a cheap, simple, and robust method of detecting ovulation is developed, it is difficult to see how this method could be used widely. Endometrial Contraception An alternative approach to contraception is the administration of an antigestogen during the luteal phase in a dose sufficient to cause asynchrony of the endometrium but insufficient to disrupt ovarian function or induce menstrual bleeding. In one study in which 10 mg mifepristone was given on days 5 and 8 of the luteal phase, there was no disturbance in ovarian function (Greene et al., 1992). In seven of eight cycles there was reduced stromal edema as well as delayed development of the endometrial glands. Asynchrony of endometrial histology has been described following single doses of mifepristone during the luteal phase with an increase in the number of apoptotic bodies, suggesting programmed cell death (Li et al., 1988b). Some aspects of endometrial function were retarded (e.g., reduction of secretory material in the glands), while other aspects (e.g., reduction in stromal edema and increase in stromal mitosis) were advanced. Whether these changes, which result in desynchronization of the endometrium, are incompatible with the establishment or maintenance of pregnancy is not yet known. Large doses of mifepristone (200–600 mg) in the early luteal phase retard the development of a secretory endometrium and prevent pregnancy (see below), but have a significant failure rate when given on day 27 after implantation, has become established (van Santen and Haspels, 1987; Dubois et al., 1988; Couzinet et al., 1990). The efficacy of giving mifepristone at this stage of the cycle to prevent implantation could be tested as a late post-coital agent given more than 72 hours after coitus but earlier than the time of missed menses. Late Post-Coital Contraception Mifepristone induces menstrual bleeding when given in doses from 50 to 600 mg in the mid- and late luteal phases of the cycle and, hence, might be expected to prevent pregnancy by disrupting implantation. In a prospective trial, 12 women were given a single 600-mg dose of mifepristone on the day before their expected menses (day 27), and eight days later if a continuing pregnancy was diagnosed after failure of the first dose (Couzinet et al., 1990). In a total of 137 cycles of exposure

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda there were 22 pregnancies (16 percent); 4 (18.2 percent) were ongoing after the second dose of mifepristone. The failure rate was similar to that found in women who are given the same dose of mifepristone to induce abortion in very early pregnancy (within 10 days of a missed menstrual period) and is clearly too high to be used as a regular method of contraception (Couzinet et al., 1986). It is likely that the efficacy could be increased by giving an oral prostaglandin such as misoprostol 24–48 hours after the mifepristone, as has been used to induce abortion (Aubeney and Baulieu, 1991; Norman et al., 1991; Thong and Baird, 1992). However, there are doubts as to whether such a method would be acceptable to all women as a regular method of contraception. In a study involving more than 400 women in Edinburgh, less than 25 percent would use a method that disrupted implantation, although the vast majority were in favor of a once-a-month pill that inhibited ovulation (Rimmer et al., 1992). Presumably, the thought of willingly exposing themselves to the risk of pregnancy and then inducing a very early abortion was usually unacceptable to the majority. Such an approach, however, could be used as a late post-coital emergency contraceptive following unplanned, unprotected intercourse. In one study, 139 women at risk of pregnancy were given 400 or 600 mg mifepristone on the day before expected menses (Dubois et al., 1988). Of the 48 who were pregnant (as detected by measurement of ß-hCG in plasma) there were 9 ongoing pregnancies. The failure rate (18.8 percent) was similar to that in the studies above. The reason some women fail to abort following mifepristone is not entirely clear but may be related to incomplete shedding of the endometrium (Li et al., 1988a). However, the fact that the complete abortion rate is increased to nearly 100 percent by combining the treatment with a suitable prostaglandin suggests that inadequate uterine contractions, due possibly to lack of endogenous prostaglandins, may be responsible. In summary, although administration of mifepristone will induce bleeding and disrupt pregnancy in the majority of women during the luteal phase, the failure rate is too high for it to be used as a regular method of contraception, although in combination with a prostaglandin it may be effective as a late post-coital pill. FUTURE DEVELOPMENTS The ideal contraceptive would prevent pregnancy without disrupting the ovarian or menstrual cycle. The approaches described above involve inhibition of ovulation and disruption of ovarian cyclicity or disruption of endometrial development. It has been suggested that the problems of timing the administration of mifepristone could be avoided by the daily administration of an antigestogen in a dose too

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda low to interfere with the hypothalamic-pituitary axis and ovarian cyclicity but sufficient to desynchronize the endometrium (''endometrial contraception"). In a recent study in which women received 1 mg mifepristone per day, endometrial development was delayed, and there were lower levels of placental protein 14 (PP14), suggesting insufficient endometrial function (Batista et al., in press). However, the follicular phase was extended and ovulation delayed. Whether doses of mifepristone 81 mg/day would induce changes in endometrium incompatible with pregnancy, while at the same time having no effect on ovarian cycles, is not yet known. Further research is necessary in several areas before mifepristone or other antigestogens can be used as contraceptives. Basic Research Mode of Action We still do not fully understand how mifepristone inhibits follicular development and ovulation. Current evidence suggests that suppression of ovarian activity is secondary to inhibition of gonadotropins at least in high doses. Why blocking the hypothalamus or pituitary receptors for progesterone should inhibit rather than stimulate LH release is not clear. In lower doses (1–5 mg), there is little if any measurable effect on gonadotropin levels; yet the rate of follicular development and ovulation is suppressed. In the luteal phase, the effects on the corpus luteum are dependent on the stage of the cycle and are inconsistent. There is really still no indication as to why luteal regression occurs only in approximately half the women who are given mifepristone in the midluteal phase. An even more intriguing question is how mifepristone affects the endometrium. Many of the events that occur after its administration during the luteal phase simulate those that occur in response to withdrawal of progesterone at the time of luteal regression. Mifepristone in large doses (200–600 mg) has been shown to prevent pregnancy when given in the early luteal phase of the cycle. However, the minimum dose that will prevent implantation is not known. Although abnormalities have been reported in the secretory endometrium after single doses as low as 5 mg and after daily administration of 1 mg, a dose insufficient to inhibit ovulation consistently, it is not known whether these are incompatible with the establishment of pregnancy. Although mifepristone does not bind (at least in vitro) to the ER, studies in rabbits and monkeys have demonstrated that it will prevent the estrogen-induced hypertrophy of the endometrium. The mechanism by which this "noncompetitive" inhibition is produced is not known,

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda although it has been suggested that the striking dose-dependent increase in ER sets in motion an irreversible destruction of the cell. Clinical Studies When started in the follicular phase of the cycle, mifepristone inhibits ovulation and would clearly be contraceptive. However, the effects on the endometrium and on bleeding patterns of different modes of administration require investigation. The optimal amount of mifepristone given as a single weekly dose that will inhibit ovulation as is seen in the monkey has not yet been established (Spitz et al., 1993). The effect on the endometrium of chronic anovulation induced by mifepristone, given either as a single weekly dose or in smaller daily amounts, requires investigation. Is it necessary or practical to give additional progestogen to prevent endometrial hypertrophy? Studies are required to establish the minimum dose of mifepristone that is effective as a post-coital agent. Used as an emergency contraceptive, it is unlikely that the dose could be reduced much lower than 50 mg because it is probably necessary to inhibit ovulation in those women who have unprotected intercourse in the first half of the cycle. However, used as a once-a-month pill in the luteal phase of the cycle, a lower dose (5–10 mg) may still be effective at preventing implantation. It will be very difficult to design clinical studies to determine the minimum changes in endometrial function that are incompatible with pregnancy. Fertility studies in primates may be necessary before it would be ethical to expose women to the risk of pregnancy. The clinical efficacy of mifepristone as a late post-coital agent, in combination with an oral prostaglandin analogue such as misoprostol, requires further investigation. The acceptability of this form of "menstrual induction" as a regular form of contraception is likely to differ depending on the particular society. Moreover, although repeated administration of mifepristone on day 27 has no effect on the length of the subsequent cycle, we know little about what might happen if pregnancy had occurred (Croxatto et al., 1987). In an unpublished study sponsored by the World Health Organization (WHO), involving induction of abortion with 600 mg mifepristone and 1 mg gemeprost in 140 women within seven days of the missed menstrual period, the subsequent cycle was prolonged by a mean of seven days (Table B4.3). Moreover, there was great variability among women in the return to menstruation (median 35 days, range 2–68 days), which would make it very difficult to predict when to take the next once-a-month pill (Baird and Cameron, 1985). In summary, although there are several studies suggesting that antigestogens have a range of antifertility properties, considerable

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda TABLE B4.3 Use of Mifepristone and Cervagem for Medical Abortion £35 Days   Nonpregnant     Pregnant       Median Range (N) Median Range (N) Duration of bleeding 6 2–12 (31) 9 3–39 (140) Time to return of meanses (days) 33 29-71 (31) 35 2-68 (135) NOTE: 600 mg mifepristone + 1 mg cervagem; complete abortion rate: 97%. SOURCE: WHO (1993). research is required before they could be used clinically as contraceptives. Moreover, virtually all the data in women are confined to mifepristone. The effect of other antigestogens such as onapristone, which has different pharmacological properties, requires investigation. REFERENCES Aubény, E., and Baulieu, E.E. Activité contragestive de l'association au RU 486 d'une prostaglandine active pour voie orale. Comptes Rendus de l'Académie des Sciences (Paris) 312:539–545, 1991. Baird, D.T., and Cameron, I.T. Menstrual induction: Surgery versus prostaglandins. Pp. 178–186 in Abortion: Medical Progress and Social Implications. O'Connor. M., ed. Ciba Foundation Symposium 115. London: Pitman, 1985. Baird, D.T. Antigestogens. British Medical Bulletin 49:73–87, 1993. Batista, M.C., Cartledge, T.P., Zellmer, W., et al. Evidence for a critical role of progesterone in the regulation of the mid cycle gonadotropin surge and ovulation. Journal of Clinical Endocrinology and Metabolism 74:565–570, 1992. Batista, M.C., Cartledge, T.P., Zellmer, A.W., et al. Delayed endometrial maturation induced by daily administration of the antiprogestin RU 486: A potential new contraceptive strategy. American Journal of Obstetrics and Gynecology 167:60–65, 1992. Cheng, L., Kelly, R.W., Thong, K.J., et al. The effects of mifepristone (RU 486) on prostaglandin dehydrogenase in decidual and chorionic tissue in early pregnancy. Human Reproduction 8:705–709, 1993a. Cheng, L., Kelly, R.W., Thong, K.J., et al. The effect of mifepristone (RU 486) on the immunohistochemical distribution of prostaglandin E and its metabolite in decidual and chorionic tissue in early pregnancy. Journal of Clinical Endocrinology and Metabolism 1993b, in press. Chwalisz, K., Hegele-Hartung, C., Fritzemeier, K.H., et al. Inhibition of estradiol-mediated endometrial gland formation by the antigestagen onapristone in rabbits: Relationship to uterine estrogen receptors. Endocrinology 129:312–322, 1991. Couzinet, B., Le Strat, N., Ulmann, A., et al. Termination of early pregnancy by the progesterone antagonist RU 486 (mifepristone). New England Journal of Medicine 315:1565–1570, 1986. Couzinet, B., Le Strat, N., Silvestre, L., et al. Late luteal administration of the antiprogesterone RU 486 in normal women: Effects on the menstrual cycle events and fertility control in a long term study. Fertility and Sterility 54:1039–1043, 1990. Croxatto, H.B., Salvatierra, A.M., Romero, C., et al. Late luteal phase administration of RU 486 for three successive cycles does not disrupt bleeding patterns on ovulation.

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