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Research on New Methods of Emergency Contraception by Helena Von Hertzen and Paul F.A.Van Look

Research on New Methods of Emergency Contraception by Helena Von Hertzen and Paul F.A.Van Look

Research on New Methods of By Helena von Hertzen and Paul F.A.Van Look

he term “emergency contraception” no currently available method is effective struation would raise concerns that the refers to specific contraceptive once implantation has commenced—unless method had failed and add to a woman’s methods that can be used as emer- endometrial aspiration is considered a meth- anxiety. Also, the longer the interval tol- T 4 gency measures to prevent od of emergency contraception. erated between unprotected intercourse after unprotected intercourse. Emergency Emergency contraception could prevent and administration of the ideal method, contraception is used after coitus but be- many unwanted . For exam- the greater would be its practical value. An fore pregnancy has become established; ple, a study carried out among 733 women emergency contraceptive should provide as such, it is considered a back-up meth- requesting pregnancy termination in Ox- full interceptive protection, preferably after od for occasional rather than regular use.1 ford, United Kingdom, found that 410 a single administration. It should also be All methods currently available for women (56%) had had unprotected inter- active in an easily administered form, such emergency use have limitations. That they course or experienced difficulty with the as an oral or vaginal tablet or a nasal spray. can only be administered within a few barrier method used.5 Among these 410 Finally, the method should be affordable: days after intercourse restricts their use- women, 18 used emergency contraception No matter how perfect emergency meth- fulness and disqualifies for treatment without success; the remaining 392 did not ods might be, they will not help people women who cannot meet this deadline. use emergency contraception, mainly be- who cannot afford them. Moreover, the methods, and the hormon- cause they did not know it existed or A thorough knowledge of the physio- al regimens in particular—such as high- where they could get it. logical mechanisms that lead to pregnan- dose estrogen or combined oral contra- Had these 392 women used the Yuzpe cy is indispensable for the development of ceptive tablets (known as the “, about three-quarters of them new compounds or the identification of al- regimen”)—may cause unpleasant side would not have become pregnant.6 Nev- ready existing ones that might be tested for effects, including , , ertheless, the fact that the Yuzpe regimen their potential as emergency methods. To headaches, dizziness and breast tender- would not have prevented 25% of the con- be effective, a method has to disrupt cru- ness. These side effects can limit compli- ceptions among these women illustrates the cial events in the establishment of preg- ance and, in the case of vomiting, may af- very clear need for new and better methods nancy. While unprotected intercourse may fect the methods’ efficacy. of emergency contraception. In this article, take place at any time during the men- Emergency methods are generally not we first explore what the ideal emergency strual cycle, pregnancy can only result as effective as other contraceptive meth- contraception method would be. We then from intercourse during the fertile phase— ods. For example, even when the Yuzpe review those new methods that are now from about five days before until about 24 regimen is administered within the rec- being tested and, finally, we conclude by hours after , a period that corre- ommended 72 hours, it fails to prevent outlining the prospects for improving emer- sponds to the life span of sperm in the fe- one-quarter of the pregnancies that would gency contraception in the future. male genital tract and the time during be expected without the therapy.2 And al- which the oocyte is fertilizable. The human though insertion of an IUD after unpro- Ideal Emergency Contraception blastocyst probably starts to penetrate the tected intercourse is more effective and Method Attributes uterine mucosa by the fifth or sixth day can be initiated later than the hormonal The most important requirement of the after fertilization,7 and implantation is regimens (up until the expected start of ideal emergency contraceptive is that it be completed—and pregnancy established— implantation), its usefulness is limited be- highly effective. Women who seek emer- around the time of missed menses.8 cause of the risk of infection, especially in gency contraception definitely want to While these facts are obviously relevant victims of sexual assault or following in- avoid pregnancy. If a method, such as the in considering emergency contraception, tercourse with a new partner. IUD inser- condom, has already failed, there is no clinicians should always prescribe emer- tion is also not usually recommended for place for another failure. Methods of emer- gency contraception after unprotected in- nulliparous women, and such women gency contraception also have to be as safe tercourse, regardless of when it occurs in constitute a sizable proportion of those re- as other methods, even though they are the menstrual cycle. Women’s cycles vary, questing emergency contraception.3 used only occasionally. The ideal method and even the most sophisticated labora- In addition to the drawbacks of these ex- should be free of side effects, although tory techniques cannot determine retro- isting methods, their variety is very limit- women may accept some side effects as the spectively whether intercourse occurred ed; a woman seeking emergency contra- price to be paid for a high effectiveness. in the fertile or infertile phase. ception has few choices at her disposal. Also, Furthermore, side effects caused by an emergency method may not carry the Mechanisms of Action Helena von Hertzen is medical officer and Paul F.A. Van same weight as those caused by regular All emergency methods currently in use Look is associate director of the Special Programme of methods, since an emergency method may act before implantation. Theoretically, this Research, Development and Research Training in Human Reproduction, World Health Organization (WHO), Gene- be needed only once in a lifetime. could be achieved in several ways; in prac- va, . The views expressed in this article do The method would ideally not disturb tice, however, the possible modes of ac- not necessarily reflect those of WHO. the menstrual cycle, as a delay in men- tion are more limited, because women re-

62 International Family Planning Perspectives quest emergency contraception at differ- New Hormonal Approaches treated with the Yuzpe regimen.12 About ent times during their menstrual cycle. Scientists have known about the impor- 3% of women in the group This variability in timing means that com- tance of ovarian hormones in establishing became pregnant, compared with some pounds that work only through disturb- pregnancy since the early 1930s, and most 2% of the women treated with the Yuzpe ing ovulation or some event closely asso- efforts to identify leads for emergency con- method. ciated with it cannot be highly effective as traception have focused on these hor- Because 0.75 mg levonorgestrel tablets emergency methods. mones. In the 1970s, the regular combined are marketed in several countries for oc- Figure 1 depicts how a drug’s mode of oral contraceptive was tested as an emer- casional contraceptive use, the World action influences its potential value as an gency method in what became known as Health Organization (WHO) supported emergency contraceptive compound. A the Yuzpe regimen. More recently, levo- a prospective randomized trial conduct- drug that acts during the alone was tested as an emer- ed in 1991 that compared the effectiveness only—for example, by interfering with gency method, and a number of studies and side effects of two tablets, each taken oocyte maturation or by blocking ovula- have looked at the efficacy of , a 12 hours apart, with those of the Yuzpe tion—would only be effective at prevent- potent and progesto- regimen among women requesting emer- ing pregnancies that result from inter- gen. Another approach has been to coun- gency contraception within 48 hours of course in the preovulatory phase, if the teract those hormones presumed or unprotected intercourse.13 A total of 424 treatment is started soon enough before known to be involved in the establishment women were assigned the Yuzpe regimen ovulation (see arrow A in figure). of pregnancy—including estrogens, go- and 410 women were given two 0.75 mg Preventing fertilization rather than ovu- nadotropin-releasing hormone (GnRH) doses of levonorgestrel. lation would be a potentially more useful and —through the adminis- There were 15 pregnancies (3.5%) in the approach, since the window of activity tration of antihormones. Yuzpe group and 12 pregnancies (2.9%) in would be wider (see arrow B in figure). the levonorgestrel group. After women Such a compound’s duration of action Levonorgestrel who had had further acts of intercourse would need to be sufficiently long to remain Research undertaken mainly in the 1970s during the remainder of the treatment capable of preventing fertilization, even if concluded that were un- cycle were excluded (18% of the Yuzpe both unprotected intercourse and use of the suitable for regular postcoital use, pri- group and 19% of the levonorgestrel drug take place early in the fertile period. marily because they caused a high degree group), the failure rates were 2.6% and However, if intercourse were to take place of cycle disturbance. However, some stud- 2.4%, respectively. The incidence of nau- late in the fertile period, at about the same ies did indicate levonorgestrel’s potential sea, vomiting and fatigue was signifi- time as or shortly after ovulation, fertiliza- as an occasional method of postcoital con- cantly higher (p<.001) among women tak- tion may not be successfully blocked. Sper- traception. One study, conducted among ing the Yuzpe regimen than among those matozoa reach the site of fertilization with- 50 fertile women in Hungary,11 tested the given levonorgestrel. in a few minutes following intercourse,9 and efficacy of 0.75 mg of levonorgestrel ad- These results suggested that levo- irrespective of whether these “early ar- ministered immediately after intercourse norgestrel could be as effective as the rivals” comprise the spermatozoan most that occurred around the time of ovulation. Yuzpe regimen, but might cause fewer side likely to result in fertilization, the likelihood There were no pregnancies in the 150 effects. With both treatments, pregnancy of achieving an effective drug concentration cycles studied (during which the women rates tended to be slightly lower among in time at the fertilization site seems small, reported 163 acts of intercourse). Admin- women who initiated treatment within 24 even if the woman were to start treatment istering levonorgestrel during this phase hours after intercourse than among those shortly after coitus. of the menstrual cycle also did not seem who began after a longer interval. Thus, to achieve the highest possible ef- to disturb the length of the cycle. Although If these findings are confirmed in a larg- ficacy, the ideal emergency contraceptive the study did not reflect a real-life situa- er study, levonorgestrel could represent drug needs to act interceptively; that is, it tion—the women’s husbands were in the an improvement over currently available should be capable of interfering with a military and were allowed only limited hormonal methods of emergency contra- physiological event that occurs after fer- visits with their wives, tilization—during the period of early em- which corresponded to Figure 1. Timing in the menstrual cycle when emergency contra- bryonic development prior to implanta- four days around the es- ceptive compounds would be effective tion (see arrow C in figure). Obviously, timated time of ovula- such interceptive protection must be tion only—it did give Drug A achieved, even though drug exposure some indication of levo- Drug B may be limited to a single occasion at the norgestrel’s potential as Drug C beginning of the fertile phase of the cycle.10 an emergency contra- For the compound to target one particu- ceptive. lar postovulatory event, such as a critical The first researcher to Fertile period moment in the ’s preparation look at the efficacy of Menses Expected for the implantation of the conceptus levonorgestrel as an menses (known as nidation), it must exert its effect emergency contracep- for the entire duration of the fertile phase, tive gave 205 women a Start of

plus the time needed until the targeted event 0.6 mg dose within 12 Ovulation Fertilization occurs. If it cannot achieve such a duration hours after unprotected implantation of action, the drug may need to combine pre- intercourse and com- Notes: Arrows indicate the period of compound’s effectiveness. Drug A blocks oocyte matu- ovulatory and postovulatory modes of ac- pared the results with ration or ovulation. Drug B prevents fertilization. Drug C intercepts postfertilization events. tion to be effective. those in 525 women

Volume 22, Number 2, June 1996 63 Research on New Emergency Methods ception. WHO’s Special Programme of Re- length or cause any significant endome- two 400 mg doses of danazol at 48 and 60 search, Development and Research Train- trial changes. This last finding was some- hours after the luteinizing hormone ing in Human Reproduction is now con- what unexpected in view of the proven ef- surge.21 Thus, questions about danazol’s ducting just such a study—a multicenter, fectiveness of levonorgestrel in emergency effectiveness and mechanism of action re- randomized, double-blind trial that will contraception. Clearly, additional research main unresolved. compare the Yuzpe regimen and the levo- is needed to determine how levonor- norgestrel treatment when taken up to 72 gestrel acts when it is administered after Antiestrogens hours after unprotected intercourse. The ovulation has already taken place. The potential value of antiestrogens in study is to include more than 2,000 emergency contraception depends en- women recruited by 22 centers in 15 coun- Danazol tirely on whether or not estrogen plays tries, and the results are expected to be In the search for an effective emergency an essential role in implantation. In par- available in early 1997. contraceptive that would cause fewer side ticular, until recently scientists did not The few studies that have looked at effects than the Yuzpe regimen, danazol know whether 17ß-, a levonorgestrel’s mechanisms of action in was tested in a study of 50 women who re- hormone secreted in large quantities by postcoital contraception suggest that it ceived two 400 mg doses 12 hours apart.16 the , is essential for im- may affect both follicle growth and de- Three pregnancies occurred, yielding a plantation in primates. velopment of the corpus luteum (the prog- failure rate of 6%. In an attempt to resolve this question, esterone-secreting tissue that forms in the The largest study to compare danazol studies were carried out in rhesus mon- ovary immediately after ovulation). One with the Yuzpe regimen included 990 keys involving the transfer of preimplan- women assigned to an tation embryos from donor mothers to 800 mg dose, 730 monkeys from which the ovaries had been “…any substance interfering with the women assigned to a removed. (Some had their ovaries re- 1,200 mg dose and 407 moved and were started on hormone re- synthesis, secretion or peripheral actions of women who were given placement therapy on the day the embryo the Yuzpe regimen.17 was transferred; others from which the progesterone has the potential for use in Women found danazol ovaries had been removed earlier had hor- emergency contraception.” more acceptable than monally induced artificial cycles.) The re- the Yuzpe method be- sults suggest that, in the rhesus monkey, cause it caused fewer, ovarian estrogen may not be necessary for study in which women received 1.6 mg of milder side effects of shorter duration. successful implantation, since implanta- levonorgestrel on day 10 of their cycle Moreover, both danazol groups had low tion took place and normal pregnancies showed that the treatment seemed to sup- failure rates (1.7% with 800 mg and 0.8% ensued in some of the monkeys that were press the midcycle luteinizing hormone with 1,200 mg), although not significant- given progesterone alone and had unde- peak (which induces ovulation), but did ly lower than that for the Yuzpe regimen tectable estrogen levels around the time not appear to influence the formation and (2.2%). of implantation.22 Recently, luteal estra- function of the corpus luteum, since the A more recent WHO-supported study diol was also shown to be unnecessary for urinary of (the failed to confirm these findings, howev- the establishment of pregnancy in hu- main metabolite of progesterone) was nor- er: Nine pregnancies occurred among 193 mans.23 In view of these results, it seems mal.14 women treated with danazol (600 mg unlikely that antiestrogens have a role in Another study, which examined the ef- given twice, 12 hours apart), a failure rate emergency contraception. fects of a daily dose of 0.75 mg of levo- of 4.7%.18 The number of pregnancies ob- norgestrel administered for four days ei- served in that study (nine) was nearly the GnRH Antagonists ther before ovulation, around the time of same as the number that would have been GnRH antagonists, which cause a pro- ovulation or after ovulation, indicated that expected with no treatment (12). found drop in progesterone secretion be- the impact of levonorgestrel depends on Further studies examining danazol’s cause they suppress luteinizing hormone the time of administration.15 When levo- possible mechanisms of action suggest no levels, have also been proposed for post- norgestrel was given during the early fol- clear effect on ovulation.19 Data from an un- coital contraception. Recent research has licular phase, the total cycle length was sig- published study revealed no midcycle peak shown, however, that low doses of human nificantly prolonged due to the increased in luteinizing hormone among four of eight chorionic gonadotropin, which mimic duration of the follicular phase. Post- women given 600 mg of danazol twice on early pregnancy, can prevent luteal re- treatment biopsies taken on cycle days day 12 of the menstrual cycle, while for the gression induced by postovulatory ad- 20–22 still showed proliferative endo- other four, the peak was delayed to a vari- ministration of a potent GnRH antago- metrium in accordance with the delay in able degree; ovarian steroid production nist.24 The study also confirmed results ovulation. was essentially unchanged, however.20 from earlier research suggesting that in the When levonorgestrel was administered Furthermore, when women were given absence of human chorionic gonadotropin, around the time of ovulation, however, the 600 mg of danazol twice, two days after the action of the GnRH antagonist has to effects were variable: Ovulation was the peak day of luteinizing hormone lev- continue for at least 72 hours if the corpus blocked in some women, while in others els, biopsies showed no significant influ- luteum is to regress irreversibly; corpus lu- follicular activity was followed by defi- ence on endometrial structure 6–8 days teum function will recover if the drug’s ac- cient luteal function, and still other after the peak. Other research also has tion covers any shorter period. women ovulated normally. On the other been unable to demonstrate any signifi- These results suggest that to be effective hand, administering levonorgestrel dur- cant effect of danazol on steroid as an emergency contraceptive, a GnRH ing the luteal phase did not affect cycle concentrations in the endometrium after antagonist would need not only to be

64 International Family Planning Perspectives given soon after ovulation and before the needed to influence progesterone levels. its growth and ovulation occurred. blastocyst began to secrete human chori- In addition, because of potential contro- Studies conducted to determine onic gonadotropin, but also to be contin- versy surrounding the use of these com- whether affects fertilization ued for at least three days. If given too late pounds in , further research on show that if ovulation occurs despite treat- (once implantation has started), the treat- the most advanced of these inhibitors has ment, the ovum appears capable of fertil- ment would be ineffective; if given too been discontinued by the company that ization. For example, in a study of the ef- early (prior to ovulation), the drug might owns the rights to them.30 fect of mifepristone on in vitro fertilization not block ovulation and fertilization might act directly at the cel- of human oocytes, the researchers ad- occur (since shortly before ovulation, ma- lular level, by binding to the progesterone ministered 100 mg orally 35 hours before ture follicles are not very susceptible to receptor and blocking the action of pro- recovering the oocytes through la- acute gonadotropin withdrawal).25 The gesterone. Their influence is thus more im- paroscopy (when the follicular diameter window of efficacy, therefore, seems too mediate than that of progesterone syn- was greater than 15 mm).35 Although they narrow—and the mode of administration thesis inhibitors. While hundreds of found substantial amounts of mifepris- too complicated—for GnRH antagonists compounds with antiprogestational ac- tone in follicular fluid, the in vitro fertil- to be successful emergency contraceptives. tivity have been identified, only a few ization and cleavage rates of the collect- Also, the cost of currently available an- have been sufficiently evaluated in bio- ed oocytes were not affected. tagonists would be prohibitive, and they logical screening models and only four— Whether mifepristone could influence have been associated on some occasions mifepristone, , the ability of spermatozoa to fertilize in vivo with allergic local reactions.26 and CDB 2914 (also known as HRP is unclear. Researchers have recently shown 2000)—have been given to humans. Most in vitro that high concentrations of mifepri- Progesterone Inhibition research to date has been stone were required to slow sperm move- The common denominator in the chain of on mifepristone (RU 486), but the results ment.36 Such concentrations are unlikely to phenomena leading to pregnancy is the of this research should apply to most if not be reached in vivo in the tubal fluid. influence of progesterone. It is involved all antiprogestogens, with some minor Apart from affecting follicular matura- before ovulation, in follicular maturation modifications. tion and ovulation (and possibly fertil- and the process leading to ovulation;27 it •Mechanisms of action and effects. When an- ization), mifepristone may prevent preg- is a major constituent of follicular fluid tiprogestogens are given prior to ovula- nancy by influencing the development and may be the component responsible for tion, they disrupt the normal sequence of and transport of embryos. Administration inducing the movement of spermatozoa follicular maturation. Depending on the of mifepristone to rats accelerated embryo to the ovum for fertilization;28 it may also dose and timing of administration, the transport through the tube and caused the produce structural changes that facilitate treatment can cause regression of the dom- loss of embryos from the uterus before im- the entry of spermatozoa into the ovum;29 inant follicle and initiate a new cycle of fol- plantation. The treatment also delayed or it influences the transport of the fertilized licle development.31 However, a low dose arrested embryonic development.37 Inhi- egg through the Fallopian tube and caus- may only halt the maturation of the folli- bition of the development of fertilized es endometrial changes (known as de- cle for a short time and, as soon as the an- eggs by mifepristone has also been ob- cidualization) that are required for suc- tiprogestogen’s influence is over, the same served in other species.38 Whether these cessful implantation and establishment of follicle may either proceed to ovulation or mechanisms also contribute to the an- pregnancy; and it affects the function of remain unruptured until the end of the tifertility effects of mifepristone in the the endometrial surface (the endometrial cycle. For example, a single 5 mg dose of human is not known. epithelium) and the interaction between mifepristone given when the leading fol- While treatment with mifepristone in that surface and its supporting structure licle was 14 mm in diameter retarded the the follicular phase inhibits follicle devel- (the endometrial stroma). growth of the follicle for up to 36 hours.32 opment, administration immediately after Thus, any substance interfering with the Data from two studies suggest that to ovulation significantly affects endometri- synthesis, secretion or peripheral actions exert a blocking effect on ovulation, the al maturation. For example, in one study, of progesterone has the potential for use antiprogestogen has to be given before the a 200 mg dose given in the evening of the in emergency contraception. Compounds onset of the luteinizing hormone surge; if second day after the luteinizing hormone that fall into this category include sub- the surge has already started, it may be too peak delayed endometrial development stances that disrupt the corpus luteum (re- late to inhibit ovulation with an anti- for at least six days, even though circulat- ferred to as luteolytic agents), inhibitors .33 ing levels of progesterone were normal.39 of progesterone synthesis (such as This effect on follicular growth may be Similarly, onapristone had a strong in- ), and a general property of compounds that in- hibitory effect on endometrial develop- blockers (such as antiprogestogens). terfere with progesterone receptor function. ment when administered on the second The maintenance of the corpus luteum A recent study that investigated the effect day after the luteinizing hormone peak.40 is essential for establishing pregnancy; on follicular growth of the antiprogesterone Furthermore, studies have shown that a therefore, compounds with luteolytic action onapristone (administered in daily doses single dose of mifepristone administered would be useful emergency contraceptives. of 5 mg, 15 mg and 50 mg on days 5–11 of in the early luteal phase effectively pre- However, research to discover such lute- the cycle) found that the lowest dose af- vented pregnancy in the rhesus monkey41 olytic agents has so far been unsuccessful. fected follicular growth inconsistently, but and in humans.42 In the latter study, 21 fer- Progesterone synthesis inhibitors such that the two higher doses arrested both fol- tile women took 200 mg of mifepristone two as epostane could be effective, as they in- licular growth and the preovulatory surge days after the luteinizing hormone surge terfere at several levels in the establish- in estradiol, and also delayed the go- as their only method of contraception; only ment of pregnancy. However, repeated nadotropin surge.34 After treatment was one pregnancy resulted during 157 cycles. doses for several days are likely to be discontinued, the leading follicle resumed •Efficacy of mifepristone. Since mifepristone

Volume 22, Number 2, June 1996 65 Research on New Emergency Methods disturbs several stages in the establish- An examination of different doses of implantation process. Even before implan- ment of pregnancy, its promise as an emer- mifepristone (ranging from 5 mg to 200 tation, the human embryo produces a num- gency contraceptive led WHO to support mg), taken from the second until the fifth ber of substances, including growth factors two studies in the United Kingdom. Both day after the luteinizing hormone peak, and hormones such as GnRH, human chori- studies compared the efficacy and side ef- found that the effects on secretory activi- onic gonadotropin, estrogens and proges- fects of 600 mg of mifepristone and the ty of endometrial glandular cells on any terone. Before implantation begins, an ac- Yuzpe regimen when administered with- given day were essentially similar, irre- tive exchange of messages is established in 72 hours after unprotected intercourse.43 spective of the dose.47 Another study ob- between the embryo and the endometrium; served abnormal secre- signals such as early pregnancy factor, em- tory maturation of the bryo-derived pregnancy-associated factor “Research on invasive tumor growth endometrium—consid- and human chorionic gonadotropin (in ad- ered to be incompatible dition to signals yet to be discovered) might may provide some clues for the prevention with successful implan- be candidates for targeting.50 tation—after two doses These embryonic signals appear to be of implantation—leads that could be of 10 mg of mifepristone important in endometrial preparation for taken 72 hours apart on implantation. For instance, recent research exploited in future methods of emergency the fifth day and the in the rhesus monkey has shown that in contraception.” eighth day after the the presence of a preimplantation blasto- luteinizing hormone cyst, luteal-phase endometrium differs surge.48 A similar de- morphologically from the comparable en- The studies confirmed the potential value synchronization of the endometrium oc- dometrial stage in nonfecund cycles.51 of antiprogestogens: There were no preg- curred after 10 mg of mifepristone was Whether similar changes occur in the nancies among 597 women treated with given daily for four days starting on the human is not known, but it is possible that mifepristone, while nine occurred among day of ovulation.49 the human endometrium may be mor- 589 women who received the Yuzpe reg- These studies suggest that mifepristone phologically and functionally different imen. In addition, the women who used doses below 600 mg could be effective in during conception cycles than during non- mifepristone reported less nausea and emergency contraception. A WHO multi- conception cycles. This should be taken vomiting and fewer other side effects than center study currently under way will test into account when results from research did those receiving the Yuzpe regimen. this hypothesis by first confirming the ef- into mechanisms of action of emergency However, the women who took mifepri- fectiveness of the 600 mg dose and then as- contraception are interpreted.* stone were more likely than those receiv- sessing whether the same effectiveness can Since decidualization of the endo- ing the Yuzpe regimen to experience a be achieved with lower doses—of 50 mg metrium is obligatory if implantation is to delay in the onset of menstruation (50% and 10 mg—and with longer intervals after occur, any compound that impairs this en- vs. 16%); this delay was presumably tied unprotected coitus (up to 120 hours). The dometrial process is likely to interfere with to the antiprogestogen’s effect on follicu- study will also evaluate side effects, in- implantation. Some research carried out lar development and ovulation when it is cluding changes in the onset of the next in the context of in vitro fertilization also taken in the preovulatory phase. menstrual period following use of the three suggests that the developmental stage of The 600 mg dose of mifepristone in the antiprogestogen doses under examination. the endometrium appears to be important above studies is the same dose as that rec- If this study should show that mifepristone for successful implantation: If endometri- ommended for use with a is an effective emergency contraceptive in al development is “out of phase” (espe- to induce early . Results from a dose that is much lower than that re- cially if it is delayed with regard to the de- many studies on different aspects of the quired for inducing early abortion, it may velopmental stage of the embryo), compound suggest that much lower doses be possible to obtain marketing approval implantation is less likely to succeed.52 may be effective in emergency contracep- of the compound for an emergency con- On the other hand, other evidence sug- tion. For example, a dose as low as 5 mg ar- traception indication, even in countries that gests that the window for implantation in the rested follicular maturation,44 and a study have restrictive abortion legislation. human is relatively wide, compared with examining the effects of 10 mg and 100 mg that of laboratory animals.53 The extent to doses of mifepristone when given on day Potential Research Directions which findings collected during the course six and day 10 found similar declines in lev- Scant information exists about the post- of assisted conception apply to normal, fer- els of both luteinizing hormone and folli- fertilization events critical for successful tile women is uncertain. As the human blas- cle-stimulating hormone.45 Further, a 10 mg establishment of pregnancy in the human. tocyst is capable of implanting at extrauter- dose administered prior to ovulation— Research is in progress, however, in a num- ine locations, there may not be rigorous when the follicular diameter is 18 mm or ber of areas, including embryonic devel- requirements for nidation to succeed. more—appears to block ovulation.46 opment and signaling before implantation, Despite the uncertainty about the need The earlier during the secretory phase tubal transport and milieu, endometrial for close synchrony between the embryo that mifepristone is administered, the more development before implantation and the and the endometrium, events in the en- marked is its effect on the endometrium. interrelationships between the embryo and dometrium around the time of implanta- the uterus during implantation. Each of tion indicate that at least some preparation *Such research is by necessity done in women not ex- these topics may provide leads to the de- of the endometrium for nidation does take posed to the risk of pregnancy, and changes (or lack of velopment of more effective approaches place, even in nonfecund cycles. The en- changes) observed in, for example, the endometrium of these women following treatment with emergency con- to emergency contraception. dometrial epithelium has a highly specif- traception may not coincide with what would have been There is increasing evidence, for example, ic appearance: Microvilli, which are pres- observed if a preimplantation embryo had been present. that the embryo plays an active role in the ent after ovulation, disappear six days after

66 International Family Planning Perspectives ovulation; the cells are then covered with gency postcoital methods. Mifepristone 3. P.C. Ho and M. S. W. Kwan, “A Prospective Ran- pyramidal protrusions called pinopodes, appears to have many advantages over domized Comparison of Levonorgestrel with the Yuzpe which disappear, in turn, nine days after the Yuzpe regimen, since it is easier to ad- Regimen in Post-Coital Contraception,” Human Repro- duction, 8:389–392, 1993. ovulation.54 The transient appearance of minister (only one dose is needed), is more pinopodes corresponds to the presumed effective and causes fewer side effects. In 4. L. Harel and B. Kaplan, “Endometrial Suction in Luteal Phase as a Method of Late Postcoital Contraception,” Con- time of nidation. These protrusions ap- countries where an antiprogestogen-based traception, 47:469–474, 1993. parently absorb uterine fluid and facilitate method cannot be made available, levo- 5. G. Duncan et al., “Termination of Pregnancy: Lessons implantation by bringing blastocysts and norgestrel may prove a better option than for Prevention,” British Journal of Family Planning, the uterine epithelium into intimate con- the Yuzpe regimen, if further trials confirm 15:112–117, 1990. 55 tact, thus permitting adhesion. its efficacy as an emergency method. 6. C. Ellertson, 1996, op. cit. (see reference 2). Specific binding proteins expressed Antiprogestogens might also broaden while the embryo adheres to the en- the window of efficacy if they can extend 7. T. W. Sadler, Langman’s Medical Embryology, 6th ed., Williams & Wilkins, Baltimore, 1990; and P.A. Bergh and dometrial epithelium may also offer a po- the deadline for administration of the D. Navot, “The Impact of Embryonic Development and tential means of interfering with implan- method. The ongoing WHO multicenter Endometrial Maturity on the Timing of Implantation,” tation. However, realization of this trial, for example, is examining whether Fertility and Sterility, 58:537–542, 1992. potential will require more detailed mifepristone is effective up to five days 8. E. C. Hughes and Committee of Terminology of the knowledge of the adhesion process in hu- after intercourse. This may be the outside American College of Obstetricians and Gynecologists, mans and the factors regulating it. limit of effectiveness, however, since sev- Obstetrics-Gynecologic Terminology, F.A. Davis, Philadel- Toward the time of implantation, the eral studies have concluded that an an- phia, 1972, pp. 299 and 327. number of large granular lymphocytes in tiprogestogen alone is no longer very ef- 9. D. S. F. Settlage, M. Motoshima and D. R. Tredway, the endometrium increases. It has been sug- fective once implantation has started.59 “Sperm Transport from External Cervical Os to the Fal- lopian Tubes in Women: A Time and Quantitation Study,” gested that the products made by these cells Women who are given mifepristone Fertility and Sterility, 24:655–661, 1993. control the process of the invasion of the en- should be informed of the possible delay in 10. 56 P.F.A. Van Look, “Postcoital Contraception: A Cover- dometrium by the implanting blastocyst. the onset of menstruation, since such a delay up Story,” in E. Diczfalusy and M. Bygdeman, eds., Fer- In addition, other factors of potential in- may cause anxiety and uncertainty about tility Regulation Today and Tomorrow, Raven Press, New terest include the leukemia inhibitory fac- the treatment’s success. Counseling women York, 1987. tor, which is expressed in the surface and about the potential risk of conceiving later 11. L. Kovacs, G. Seregely and J. Szilagyi, “Investigation glandular epithelium of the endometrium. in the same cycle in case of further unpro- of the Pregnancy Preventive Effect of Postcoital d- This factor has been shown to be indis- tected coitus is also important. The possi- Norgestrel Under Special Experimental Conditions,” pensable for implantation in the mouse. bility of further unprotected intercourse Honvedorvos, 3–4:289–293, 1979. Without it, implantation cannot take place, should be taken into account when design- 12. K. O. K. Hoffmann, “Postcoital Contraception: Ex- even though embryonic development is ing efficacy studies: If a woman becomes periences with /Norgestrel and Lev- onorgestrel Only,” in R.F. Harrison, J. Bonnar and W. normal and transferred embryos from mice pregnant in the treatment cycle, it may not Thompson, eds., Fertility and Sterility, MTP Press, Lan- deficient in this factor implant and devel- necessarily reflect a method failure. The caster, UK, pp. 311–316, 1984. 57 op normally in surrogate mothers. study design should provide for the most 13. P.C. Ho and M. S. W. Kwan, 1993, op. cit. (see refer- Leukemia inhibitory factor has also been accurate estimate of the timing of concep- ence 3). 58 identified in the human endometrium, but tion possible, preferably by ultrasound. 14. E. Kesserü et al., “The Hormonal and Peripheral Ef- whether this factor has the same importance Women should also be warned about the fects of d-Norgestrel in Postcoital Contraception,” Con- in humans as in the mouse remains to be de- possibility that the antiprogestogen may in- traception, 10:411–424, 1974. termined. Other substances, especially pro- duce a vaginal bleeding episode within the 15. B-M. Landgren et al., “The Effect of Levonorgestrel teins produced by the endometrial stroma, first few days after taking the drug. Drug- Administered in Large Doses at Different Stages of the are also of interest in this context, but their induced bleeding is uncommon after treat- Cycle on Ovarian Function and Endometrial Morphol- role in implantation remains unclear. ment in the early luteal phase, but it may ogy,” Contraception, 39:275–289, 1989. Finally, the high invasiveness of the occur if the drug is taken in the middle of 16. S. Rowlands et al., “Side Effects of Danazol Compared human resembles the behav- the luteal phase, and women need to be with an Ethinylestradiol/Norgestrel Combination when Used for Postcoital Contraception,” Contraception, ior of malignant tissues. In addition, the in- aware that it does not necessarily signify 27:39–49, 1983. teraction between the trophoblast and the that the treatment has been successful. 17. G. Zuliani, U.F. Colombo and R. Molla, “Hormonal uterus appears, immunologically, to be Women should be in a position to ben- Postcoital Contraception with an Ethinylestradiol- more akin to a tumor-host relationship than efit from new methods of emergency con- Norgestrel Combination and Two Danazol Regimens,” to a graft-host relationship. Thus, results traception that prevent unwanted preg- European Journal of Obstetrics & Gynecology and Repro- from research on invasive tumor growth nancies and avoid unnecessary abortions. ductive Biology, 37:253–260, 1990. may also provide some clues on potential Thus, as soon as researchers have estab- 18. A. M. C. Webb, J. Russell and M. Elstein, “Compari- leads for the prevention of implantation— lished the lowest effective dose of mifepri- son of Yuzpe Regimen, Danazol and Mifepristone leads that could be exploited in future stone, this method of emergency contra- (RU486) in Oral Postcoital Contraception,” British Med- ical Journal, 305:927–931, 1992. methods of emergency contraception. ception should be introduced into clinical practice, wherever this can be done. 19. S. Rowlands et al., “A Possible Mechanism of Action of Danazol and an Ethinylestradiol/Norgestrel Combi- Conclusions nation Used as Postcoital Agents,” Contraception, This review of prospects for new ap- References 33:539–545, 1986. 1. P.F.A. Van Look and H. von Hertzen, “Emergency proaches to emergency contraception 20. M-L. Swahn et al., “Effect of Danazol and Yuzpe Reg- Contraception,” British Medical Bulletin, 49:158–170, 1993. suggests that basic research is unlikely to imen on the Menstrual Cycle,” unpublished paper, De- yield any new methods in the near future. 2. C. Ellertson, “History and Efficacy of Emergency Con- partment of Obstetrics and Gynecology, Karolinska Hos- pital, Stockholm, , 1996. Currently, the most pressing need is to de- traception: Beyond Coca-Cola,” Family Planning Per- velop antiprogestogens to serve as emer- spectives, 28:44–48, 1996. 21. A. A. Kubba et al., “The Biochemistry of Human En-

Volume 22, Number 2, June 1996 67 Research on New Emergency Methods dometrium After Two Regimens of Postcoital Contra- pristone on Follicular Growth in Women,” Human Re- 49. Y. Berthois et al., “A Multiparametric Analysis of En- ception: A dl-Norgestrel/Ethinylestradiol Combination production, 9:1442–1447, 1994. dometrial Estrogen and Progestogen Receptors After the or Danazol,” Fertility and Sterility, 45:512–516, 1986. Postovulatory Administration of Mifepristone,” Fertili- 35. I. Messinis and A. Templeton, “The Effect of the An- ty and Sterility, 55:547–554, 1991. 22. D. Ghosh, P. De and J. Sengupta, “Luteal Phase Ovar- tiprogestin Mifepristone (RU 486) on Maturation and In- ian Estrogen Is Not Essential for Implantation and Main- Vitro Fertilization of Human Oocytes,” British Journal of 50. R. G. Edwards, “Implantation, Interception and Con- tenance of Pregnancy from Surrogate Embryo Transfer in Obstetrics and Gynaecology, 95:592–595, 1988. traception,” Human Reproduction, 9:985–995, 1994. the Rhesus Monkey,” Human Reproduction, 9:629–637, 1994. 36. J. Yang et al., “Progesterone and RU 486: Opposing 51. D. Ghosh et al., “Morphological Characteristics of 23. F. Zegers-Hochschild and E. Altieri, “Luteal Estro- Effects on Human Sperm,” Proceedings of the U.S. National Preimplantation Endometrium in the Rhesus Monkey,” gen (E2) Is Not Required for the Establishment of Preg- Academy of Sciences, 91:529–533, 1994. Human Reproduction, 8:1579–1587, 1993. nancy in the Human,” Journal of Assisted Reproduction and 37. L. S. Roblero and H. B. Croxatto, “Effects of RU 486 52. E. Serle et al., “Endometrial Differentiation in the Peri- Genetics, 12:157–228, 1995. on Development and Implantation of Rat Embryos,” Mo- Implantation Phase of Women with Recurrent Miscar- 24. S. Doubourdieu et al., “Suppression of Corpus Lu- lecular Reproduction and Development, 29:342–346, 1991. riage: A Morphological and Immunohistochemical teum Function by Gonadotrophin-Releasing Hormone 38. S. H. Chen et al., “RU 486 Inhibits Ovulation, Fertil- Study,” Fertility and Sterility, 62:989–996, 1994. Antagonist Nal-Glu: Effect of the Dose and Timing of ization and Early Embryonic Development in Rabbits: 53. J. F. Strauss and E. Gurpide, “The Endometrium: Reg- Human Chorionic Gonadotrophin Administration,” Fer- In Vivo and In Vitro Studies,” Fertility and Sterility, ulation and Dysfunction,” in S. S. C. Yen and R.B. Jaffe, tility and Sterility, 56:440–445, 1991. 64:627–633, 1995. eds., Reproductive Endocrinology, third ed., W.B. Saunders, 25. M. R. Fluker et al., “Variable Ovarian Response to Go- 39. K. Gemzell-Danielsson et al., “Effects of a Single Post- Philadelphia, 1991, pp. 309–356. nadotropin-Releasing Hormone Antagonist–Induced Go- Ovulatory Dose of RU 486 on Endometrial Maturation 54. Ibid. nadotropin Deprivation During Different Phases of the in the Implantation Phase,” Human Reproduction, Menstrual Cycle,” Journal of Clinical Endocrinology and Me- 9:2398–2404, 1994. 55. R. Vokaer and F. Leroy, “Experimental Study on Local tabolism, 72:912–919, 1991. Factors in the Process of Ova Implantation in the Rat,” Amer- 40. S. T. Cameron et al., “Effect of Post-Ovulatory Ad- ican Journal of Obstetrics and Gynecology, 83:141–148, 1962. 26. Ibid. ministration of Onapristone on the Endometrium,” Jour- 27. M. C. Batista et al., “Evidence for a Critical Role of nal of Endocrinology, Vol. 144, Supplement, p. 146, 1995. 56. A. King and Y.W. Loke, “On the Nature and Func- tion of Human Uterine Granular Lymphocytes,” Im- Progesterone in the Regulation of the Midcycle Go- 41. D. Ghosh and J. Sengupta, “Anti-Nidatory Effect of a munology Today, 12:432–435, 1991. nadotrophin Surge and Ovulation,” Journal of Clinical En- Single, Early Post-Ovulatory Administration of RU 486 in docrinology and Metabolism, 74:565–570, 1992. the Rhesus Monkey,” Human Reproduction, 8:552–558, 1993. 57. C. L. Stewart et al., “Blastocyst Implantation Depends on Maternal Expression of Leukemia Inhibitory Factor,” 28. F. Vadilli-Ortega et al., “Chemotactic Factor for Sper- 42. K. Gemzell-Danielsson et al., “Early Luteal Phase Nature, 359:76–79, 1992. matozoa: New Biological Function of Progesterone,” Treatment with Mifepristone (RU 486) for Fertility Reg- Ginecología y Obstetricia de México, 62:127–130, 1994. ulation,” Human Reproduction, 8:870–873, 1993. 58. D. S. Charnock-Jones et al., “Leukaemia Inhibitory Factor mRNA Concentration Peaks in Human En- 29. R. A. Osman et al., “Steroid Induced Exocytosis: The 43. A. Glasier et al., “Mifepristone (RU 486) Compared dometrium at the Time of Implantation and the Blasto- Human Sperm Acrosome Reaction,” Biochemical and Bio- with High-Dose Estrogen and Progestogen for Emer- cyst Contains mRNA for the Receptor at this Time,” Jour- physical Research Communications, 160:828–833, 1989; and gency Postcoital Contraception,” New England Journal of 101: S. Meizel and K. O. Turner, “Progesterone Acts at the Plas- Medicine, 327:1041–1044, 1992; and A. M. C. Webb, J. Rus- nal of Reproduction and Fertility, 421–426, 1994; and K. ma Membrane of Human Sperm,” Molecular and Cellu- sell and M. Elstein, 1992, op. cit. (see reference 18). Kojima et al., “Expression of Leukemia Inhibitory Fac- lar Endocrinology, 11:R1–R5, 1991. tor in Human Endometrium and ,” Biology of Re- 44. H. B. Croxatto, A. M. Salvatierra and B. Fuentealba, production, 50:882–887, 1994. 30. P.F.A. Van Look and H. von Hertzen, “Antipro- 1993, op. cit. (see reference 32). gestogens: Perspectives from a Global Research Pro- 59. C. Dubois, A. Ulmann and E. E. Baulieu, “Con- 45. J. M. Permezel et al., “Acute Effects of Progesterone and gramme,” in M. S. Donaldson et al., eds., Clinical Appli- tragestion with Late Luteal Administration of RU 486 the Antiprogestin RU 486 on Gonadotrophin Secretion in cations of Mifepristone (RU 486) and Other Antiprogestins: (Mifepristone),” Fertility and Sterility, 50:593–596, 1988; the Follicular Phase of the Menstrual Cycle,” Journal of Clin- Assessing the Science and Recommending a Research Agen- M. R. Van Santen and A.A. Haspels, “Interception III: ical Endocrinology and Metabolism, 68:960–965, 1989. da, Institute of Medicine, National Academy Press, Wash- Postcoital Luteal Contragestion by an Antiprogestin ington, D. C., 1993. 46. S. Zalányi, Department of Obstetrics and Gynaecol- (Mifepristone, RU 486) in 62 Women,” Contraception, ogy, Albert Szent-Györgi Medical University, Szeged, 35:423–431, 1987; M.R. Van Santen and A.A. Haspels, “In- 31. J. H. Liu et al., “Disruption of Follicular Maturation Hungary, personal communication, July 25, 1995. terception IV: Failure of Mifepristone (RU 486) as a and Delay of Ovulation After Administration of the An- Monthly Contragestive, ‘Lunarette’,” Contraception, 47. tiprogesterone RU 486,” Journal of Clinical Endocrinology R. A. Graham et al., “The Effects of the Antiproges- 35:433–438, 1987; T. C. Li et al., “Why Does RU 486 Fail 65: and Metabolism, 1135–1140, 1987. terone RU 486 (Mifepristone) on an Endometrial Secre- to Prevent Implantation Despite Success in Inducing tory Glycan: An Immunocytochemical Study,” Fertility 32. H. B. Croxatto, A. M. Salvatierra and B. Fuentealba, Menstruation?” Contraception, 38:401–406, 1988; P. 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