Mechanisms of action of mifepristone when used for emergency contraception

An emergency contraceptive method is used after coitus but before pregnancy occurs. The use of emergency contraception is largely underutilized worldwide. Recently, treatment with 10 mg mifepristone as a single dose has emerged as one of the most effective hormonal methods for emergency contraception, with very low side effects. However, the mechanism of action of mifepristone in humans when used for contraceptive purposes and especially for emergency contraception remains largely unknown. The objective of this review is to summarize available data on the effect of mifepristone on female reproductive functions relevant to emergency use of the compound. Taken together, available data from studies in humans indicate that the contraceptive effect of mifepristone used as a single low dose for emergency contraception is mainly due to impairment of ovarian function, either by blocking or postponing the luteinizing hormone surge, rather than to inhibiting of implantation.     

10mg米非司酮与左炔诺酮用于紧急避孕的效果对比研究

通过米非司酮与左炔诺酮的临床效果对比,探讨米非司酮用于紧急避孕的最低有效剂量。选择接收无保护同房或避孕失败后72h内要求紧急避孕的健康育龄妇女400例,年龄29±6岁。米非司酮组200例,单次口服10mg(10mg/片);左炔诺酮组200例,首次口服0.75mg(0.75mg/片),间隔12h后再服0.75mg。以服药后月经来潮为成功标准,以Dixon表格计算避孕有效率。两组各妊娠2例,均明显低于预期妊娠数(15.46与10.84),有非常显著意义(P<0.01)。米非司酮组避孕有效率87.06％,与左炔诺酮组的81.55％相比无显著差异(P>0.05)。米非司酮组用药后副反应及对下次月经的影响均较轻微,且单次口服易于被接受,说明10mg米非司酮用于紧急避孕安全、有效、简便。     

单次服用25mg米非司酮用于紧急避孕的临床效果观察

对300例月经规律,未采取避孕措施或避孕失败72小时以内的妇女,单次口服米非司酮25mg,观察避孕效果、副反应及对经期和经量的影响。300例妇女中6例妊娠,按Dixon方法推算,预期妊娠数为22.983,避孕有效率73.89％。米非司酮25mg的副反应较少,仅11.7％。有不适主诉,主要为恶心,无呕吐发生。于月经前半周期服药的妇女月经推迟明显多于后半周期服药妇女(P<0.05)。低剂量米非司酮是安全有效的紧急避孕方法。     

Cutting unsafe abortions

The use of drugs to terminate pregnancy could cut the number of unsafe abortions, according to the Wellcome Trust and the Population Council. A specialist conference in January this year concluded that the technique is safe and effective and would be particularly valuable in resource-poor countries. In an article in the journal Science staff of the two organizations outline the research that will be necessary before medical abortion can be made widely available in the developing world. It is estimated that half of all surgical abortions are conducted in unsafe conditions. Drug-induced (medical) abortion has been available in developed countries for over 10 years, usually involving the use of the drug mifepristone. A cheaper drug, misoprostol, is already in use in some developing countries. Meanwhile, WHO has published a booklet on "emergency contraception." The term refers to contraceptive methods that can be used by women in the first few days following unprotected intercourse to prevent an unwanted pregnancy. This would not be considered as abortion by most authorities. The emergency methods available are: increased doses of combined oral contraceptive pills, high doses of progestogen-only pills, or inserting of copper releasing IUDs.     

含铜IUD,小剂量米非司酮与单方左炔诺孕酮用于紧急避孕的临床？…

为观察米非司酮（Ｒｕ４８６）、左炔诺孕酮以及活性ＩＵＤ用于紧急避孕（ＥＣ）的临床效果、副反应、对月经的影响和活性ＩＵＤ的长期避孕效果，对１５０例身体健康、月经规律、未避孕或避孕失败１２０ｈ以内的妇女按自愿的方式分为放置ＩＵＤ组或服药组，服药组，服药组按随机方法给予口服Ｒｕ４８６或左炔诺孕酮。结果发现Ｒｕ４８６组和活性ＩＵＤ组有效率为１００％，左炔诺孕酮组为７６．８％（均按Ｄｉｘｏｎ方法计算），对月     

A randomized comparative study on mifepristone alone and in combination with tamoxifen for emergency contraception

The purpose of the clinical study was to compare the efficacy and side effects of 10 mg of mifepristone alone (Group 1) and with 20 mg of tamoxifen (Group 2) for emergency contraception, especially as used within 72-120 h after coitus. Four-hundred female volunteers with one act of unprotected intercourse or contraception failure (200 cases in each group) were recruited and completed the study. There were 198 women treated < 72 h after coitus (100 in Group 1 and 98 in Group 2), whereas the remaining 202 patients were treated between 72-120 h (100 in Group 1 and 102 in Group 2). In total, four pregnancies occurred; one treated < 72 h in each group, two between 72-120 h in Group 1. Efficacy for prevention of unwanted pregnancy by Trussell method is 84% for Group 1, and 95% for Group 2, and which is not significantly different between the two groups and even subgroups. The side effects (15.5% for Group 1 and 14.5% for Group 2) and changes in menstruation were infrequent and mild in both groups. Further studies should be conducted to determine whether tamoxifen combined with mifepristone for emergency contraception is more effective as compared with mifepristone alone.     

Emergency contraception – knowledge and attitudes in a group of Australian university students

Objective: To explore first year Australian university students' knowledge and attitudes about emergency contraception and their understanding of the risk for pregnancy.
Method: A self-report questionnaire was completed by a convenience sample of 627 first year on-campus students from both health and non-health disciplines.
Results: Knowledge about emergency contraception (EC) was generally poor including misunderstanding that it can only be used the 'morning after', as well as where it may be accessed. Its potential use was, however, more highly accepted as a preventative measure after unprotected sexual intercourse than abortion in the event of unplanned pregnancy. Women had better knowledge than men, and on a number of measures there were significant differences between these groups.
Conclusions: Poor knowledge about the timing, accessibility, action and side effects of EC may act as a barrier to its use in the event of unprotected sexual intercourse. Although EC has been available in Australia as a Schedule 3 medication since 2004, its availability from pharmacies is not well known, nor is access from other primary health care providers.
Implications: The lack of knowledge about EC may lead to its underutilisation and underlines the need for future educational strategies about EC as well as the need for health professionals who provide contraceptive services to discuss EC with clients. Health promotion campaigns which are both general as well as gender-specific may improve overall community knowledge about this method of contraception.     

Luteal phase treatment with mifepristone and misoprostol for fertility regulation

Emergency contraception (EC) with 10 mg mifepristone can prevent pregnancy up to 5 days after a single act of unprotected intercourse. No methods have been shown to be effective when treatment is administered more than 5 days after a single unprotected act or after several unprotected acts. Therefore, we tested, among 699 Chinese women requesting EC and exposed to the risk of pregnancy described, the potential of 100 mg mifepristone followed 2 days later by 0.4 mg misoprostol orally, when administered in the luteal phase of the cycle. At the time of treatment urinary pregnancy test had to be negative. Despite treatment, 25 women (2.7%) became pregnant. Among women with treatment delayed more than 5 days, the pregnancy rate was related to the number of acts of intercourse before treatment, being 1.4% with one episode and increasing to 6.5% when the number of episodes was two or more (relative RISK = 4.62, 95% CI: 1.06–20.18). Side effects within a week after treatment were mild, and most women (57.2%) had menstruation within 3 days as expected. An occasional treatment with mifepristone in combination with misoprostol could provide an option for preventing unwanted pregnancies in women who are late for EC.     

Combined estimates of effectiveness of mifepristone 10 mg in emergency contraception

The present paper combines the estimates of efficacy and side effects of 10 mg mifepristone for emergency contraception obtained from randomized trials. A total of 6083 women participating in 12 randomized trials and receiving 10 mg mifepristone for emergency contraception up to 120 h after intercourse, were analyzed for efficacy. Between 4188 and 5833 women were analyzed for side effects and 3601 for delay of menses of more than 7 days. Prevented fractions, the effect of delay and of further acts of intercourse after treatment administration were analyzed in 3440 women, using individual data. The combined pregnancy rate from all the 12 trials was 1.7% [101/6083, 95% confidence interval (CI): 1.3–2.2]. From the three trials providing individual data, the combined pregnancy rate was 1.3% (45/3440, 95% CI: 0.9–1.7) and the estimate of pregnancies prevented was 83.4% (95% CI: 77.4–87.8). There was a sharp decline in efficacy when treatment was administered during the 5th day after intercourse compared to administration during the 1st day, the odds of pregnancy increasing by a factor of 5.3 (95% CI: 1.9–14.9). The relative risk of pregnancy was about 28 times higher among women with unprotected acts of coitus between treatment administration and the onset of next menses, compared with women reporting none [odds ratio (OR) = 27.6, 95% CI: 12.7–60.2]. The increase in risk for women reporting protected acts of intercourse during this interval was not statistically significant (OR = 1.8, 95% CI: 0.9–3.8). There was a large heterogeneity among trials in all side effects and delay of menses of more than 7 days (all had p < 0.0001 for the test of homogeneity). The percentage of women with nausea ranged from 0.0–19.4% (highest upper 95% confidence limit: 23.0%), that of vomiting from 0.0–4.3% (highest upper 95% confidence limit: 6.1%), that of lower abdominal pain from 4.3–19.1% (highest upper 95% confidence limit: 22.7%). The percentage of women with delay of menses of more than 7 days ranged from 4.3–25.8% (highest upper 95% confidence limit: 34.1%). We conclude that 10 mg mifepristone is an effective emergency contraception regimen, with an acceptable side-effects profile. Postponing treatment until the 5th day seriously decreases efficacy. The risk of pregnancy is dramatically increased among women having unprotected acts of intercourse between treatment administration and the onset of next menses. This risk may be enhanced for women whose ovulation is postponed by treatment.     

开展紧急避孕服务保护妇女身心健康

紧急避孕是避孕失败的一种有效补救措施,可有效降低人工流产率,对保护妇女身心健康有积极意义。我国紧急避孕服务尚不普遍,服务提供者和使用者的信息不足及缺乏可行的措施是目前存在的主要问题。通过以报纸为主要媒介的科普宣传后要求紧急避孕咨询和服务的人数明显增加,提示加强宣传是开展紧急避孕的基本措施。据统计,在加强宣传的四个月中,咨询电话的数目多达6000余次,1995年9月～1996年8月共为1000例妇女提供了紧急避孕服务,反映出群众对紧急避孕服务的迫切需求。建立热线电话也是便利群众和加强宣传的有效措施。在提供紧急避孕服务时根据紧急避孕服务使用者的特点,尊重其隐私权。对紧急避孕服务的咨询要点是,应说明所提供的紧急避孕服务方案的效果(失败率),可能的副反应及对下次月经的影响,对采用药物紧急避孕的妇女要强调本周期内用药后的避孕,并对今后常规避孕给予切实的指导。对进一步开展紧急避孕的建议包括:加强临床研究、筛选优选方案及促进紧急避孕获得性;以引入性试验方式推广紧急避孕服务及呼吁媒介加强对紧急避孕服务宣传等。     

Effectiveness of the Yuzpe regimen of emergency contraception by cycle day of intercourse: implications for mechanism of action

OBJECTIVE: The purpose of this study was to provide evidence about the mechanism of action of the Yuzpe method of emergency contraception by examining effectiveness by cycle day of intercourse relative to ovulation. METHODS: Through a literature search, we identified eight studies that present the number of women treated and outcome of treatment by cycle day of unprotected intercourse relative to expected day of ovulation. Using five sets of external estimates of conception probabilities by cycle day of intercourse among women not using contraception, we assessed and compared the effectiveness of the Yuzpe regimen by whether intercourse occurred on or before the second day before ovulation or afterward, and whether intercourse occurred on or before the first day before ovulation or afterward. RESULTS: In 36 of the 45 pairs of estimates of effectiveness, based on eight separate studies and the eight studies combined and five different sets of conception probabilities by cycle day, effectiveness was higher-and in most cases substantially higher-when intercourse occurred on or before the second day before ovulation (day -2) than when it occurred later. When data were stratified by whether intercourse occurred on or before the day before ovulation (day -1), effectiveness was greater when intercourse occurred early in 43 of 45 pairs. CONCLUSIONS: These results suggest that one hypothesized mechanism of action of the Yuzpe method, inhibiting implantation of a fertilized egg, is unlikely to be the primary mechanism of action.     

郑州市20～30岁育龄妇女对紧急避孕的态度与意愿

采用小组集体访谈和个人深入访谈的定性研究方法,对郑州市部分20～30岁的未婚和新婚妇女进行有关避孕及紧急避孕知识、态度、实践、意愿与建议的调查。发现她们缺乏正确的避孕知识,容易发生未避孕和避孕失败的性生活,渴望得到计划生育部门和医院的指导与服务,是使用紧急避孕重要的潜在人群,在其间推广应用紧急避孕已势在必行。     

紧急避孕的研究进展

目前最为常用的紧急避孕方式为雌激素加孕激素组合或只含孕激素的药物 ,避孕效果可靠 ,副作用小。其它作为紧急避孕的措施还包括米非司酮和内置含铜的宫内节育器。但其避孕效果比不上正规的避孕药 ,通常只作为一种事后补救措施     

低剂量米非司酮用于紧急避孕临床观察

目的:进一步确认米非司酮25mg用于紧急避孕的有效性。在全国11个省市的计划生育技术指导站及综合医院妇产科观察了622例紧急避孕的临床效果,均为避孕失败或无保护性生活后72小时内就诊并符合条件的健康妇女,单次口服米非司酮25mg。结果:失败5例,按Dixon法计算,避孕有效率为91.25％。受试者的月经周期无明显改变且未出现明显副作用。此研究进一步证实米非司酮25mg单次口服可作为理想的紧急避孕药物。     

紧急避孕效果评价的可信性研究

目的:探索以月经周期和末次月经推算受孕期与生化诊断间出现差异的原因,进而评价紧急避孕效果判断的可信性。方法:对100例要求紧急避孕服务的妇女末次月经日期、月经周期和未保护性生活时间的确信程度进行回忆问卷调查,同时以B超作为月经周期、排卵监测手段进行对比性研究。结果:51例(52.04%)妇女确信知道末次月经的日期;9例(9.18%)妇女不能准确回忆无保护性生活时间;58.16%的妇女在该研究周期中有过1次以上的性生活;32例(32.65%)妇女B超证实与她们的周期不符合;2例妊娠,其中1例根据wilcox方法评估其妊娠危险概率为0%。结论:对于一部分妇女依赖于对末次月经、性生活时间的回忆和排卵日的推算来评价紧急避孕效果的方法显然是不准确的,应采用更合理的评价方法。     

The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action

The pharmacokinetics of mifepristone is characterized by rapid absorption, a long half-life of 25–30 h, and high micromolar serum concentrations following ingestion of doses of ≥100 mg of the drug. The serum transport protein— 1-acid glycoprotein (AAG)—regulates the serum kinetics of mifepristone in man. Binding to AAG limits the tissue availability of mifepristone, explaining its low volume of distribution and low metabolic clearance rate of 0.55 L/kg per day. In addition, the similar serum levels of mifepristone following ingestion of single doses exceeding 100 mg can be explained by saturation of the binding capacity of serum AAG. Mifepristone is extensively metabolized by demethylation and hydroxylation, the initial metabolic steps being catalyzed by the cytochrome P-450 enzyme CYP3A4. The three most proximal metabolites, namely, monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward human progesterone and glucocorticoid receptors. Also, the serum levels of these three metabolites are in ranges similar to those of the parent mifepristone. Thus, the combined pool of mifepristone—plus its metabolites—seems to be responsible for the biological actions of mifepristone. Recent clinical studies on pregnancy termination and emergency contraception have focused on optimization of the dose of mifepristone. In these studies it has become apparent that the doses efficient for pregnancy termination differ from those needed in emergency contraception—mifepristone is effective in emergency contraception at a dose of 10 mg, which results in linear pharmacokinetics. However, the ≥200 mg doses of mifepristone needed for optimal abortifacient effects of mifepristone result in saturation of serum AAG and thus nonlinear pharmacokinetics. In view of the pharmacokinetic data, it may be speculated that dosing of mifepristone for pregnancy termination and for emergency contraception could be reduced to approximately 100 mg and 2–5 mg, respectively. It remains to be seen whether the newly synthesized, more selective antiprogestins will prove more efficacious in the clinical arena.     

三种不同方法用于紧急避孕的临床观察

目的:观察三种方法用于紧急避孕的临床效果。方法:选择接收无保护性生活或避孕失败72小时内要求紧急避孕的健康育龄妇女354例。组Ⅰ(119例),单次口服米非司酮25mg(25mg/片);组Ⅱ(120例),左炔诺酮首次口服0.75mg(0.75mg/片),间隔12小时再服0.75mg;组Ⅲ(115例):放置含铜IUD。以服药或放置IUD后月经来潮为成功标准,以Dixon表格计算避孕有效率。结果:三组共有3例失败,均显著低于预期妊娠数(10.945,9.516,8.461)(P<0.05);避孕有效率分别为81.7%、89.5%、100%。对下次月经影响均较轻微(P>0.05),组Ⅰ副反应发生率明显低于组Ⅱ(P<0.01)。结论:三种方法用于紧急避孕安全、有效、简便。     

Clinical guidelines. Labor induction abortion in the second trimester

Labor induction abortion is effective throughout the second trimester. Patterns of use and gestational age limits vary by locality. Earlier gestations (typically 12 to 20 weeks) have shorter abortion times than later gestational ages, but differences in complication rates within the second trimester according to gestational age have not been demonstrated. The combination of mifepristone and misoprostol is the most effective and fastest regimen. Typically, mifepristone 200 mg is followed by use of misoprostol 24–48 h later. Ninety-five percent of abortions are complete within 24 h of misoprostol administration. Compared with misoprostol alone, the combined regimen results in a clinically significant reduction of 40% to 50% in time to abortion and can be used at all gestational ages. However, mifepristone is not widely available. Accordingly, prostaglandin analogues without mifepristone (most commonly misoprostol or gemeprost) or high-dose oxytocin are used. Misoprostol is more widely used because it is inexpensive and stable at room temperature. Misoprostol alone is best used vaginally or sublingually, and doses of 400 mcg are generally superior to 200 mcg or less. Dosing every 3 h is superior to less frequent dosing, although intervals of up to 12 h are effective when using higher doses (600 or 800 mcg) of misoprostol. Abortion rates at 24 h are approximately 80%–85%. Although gemeprost has similar outcomes as compared to misoprostol, it has higher cost, requires refrigeration, and can only be used vaginally. High-dose oxytocin can be used in circumstances when prostaglandins are not available or are contraindicated. Osmotic dilators do not shorten induction times when inserted at the same time as misoprostol; however, their use prior to induction using misoprostol has not been studied. Preprocedure-induced fetal demise has not been studied systematically for possible effects on time to abortion. While isolated case reports and retrospective reviews document uterine rupture during second-trimester induction with misoprostol, the magnitude of the risk is not known. The relationship of individual uterotonic agents to uterine rupture is not clear. Based on existing evidence, the Society of Family Planning recommends that, when labor induction abortion is performed in the second trimester, combined use of mifepristone and misoprostol is the ideal regimen to effect abortion quickly and completely. The Society of Family Planning further recommends that alternative regimens, primarily misoprostol alone, should only be used when mifepristone is not available.     

Estimating the effectiveness of emergency contraceptive pills

OBJECTIVE: We use new estimates of conception probabilities by cycle day of intercourse, where cycle day is measured with day 1 being the first day of bleeding in a cycle, to propose a new approach for estimating the effectiveness of emergency contraceptive pills (ECPs). We use this new approach to examine the absolute effectiveness and the cost-effectiveness of ECPs and whether ECPs are more effective the sooner after unprotected intercourse they are initiated. METHODS: Using the new set of conception probabilities, we employ data from two recent clinical trials of ECPs, one from the Population Council and the other from the World Health Organization (WHO), to examine the effectiveness of the combined ECP regimen. RESULTS: The expected pregnancy rate among typical users was 6.2% in the Population Council trial and 7.4% in the WHO trial based on conception probabilities by cycle day relative to the day of ovulation. Based on conception probabilities by cycle day relative to the first day of bleeding, the expected pregnancy rates dropped to 5.4% and 5.2%, respectively. The two trials yield conflicting evidence regarding whether effectiveness declines with treatment delay. CONCLUSIONS: Our results suggest that the absolute levels of effectiveness for the Yuzpe regimen of emergency contraception and the cost-effectiveness of this regimen have probably been overstated when based on conception probabilities by cycle day relative to day of ovulation.     

Release of progestin-only emergency contraception

Progestin-only emergency contraception has been available in a prepackaged product since 1999. In a multicenter randomized trial, the levonorgestrel-only regimen was better tolerated and significantly more effective than the previous standard of care, the Yuzpe regimen. The levonorgestrel-only regimen prevented 85% of unintended pregnancies compared with 57% in the Yuzpe regimen. Emergency contraception is more effective the earlier the treatment begins. With the emergence of specifically prepackaged kits, emergency contraception appears to be more accessible and convenient to providers and to women. However, substantial barriers still exist to women who wish to obtain emergency contraceptive within the recommended initiation of 72 hours after unprotected intercourse. More recent information that emergency contraception is more effective the sooner it is initiated underscores the need for effective educational and distribution strategies.