Mechanism of action of emergency contraception

A major barrier to the widespread acceptability and use of emergency contraception (EC) are concerns regarding the mechanisms of action of EC methods. Today, levonorgestrel (LNG) in a single dose of 1.5 mg taken within 120 h of an unprotected intercourse is the most widely used EC method worldwide. It has been demonstrated that LNG-EC acts through an effect on follicular development to delay or inhibit ovulation but has no effect once luteinizing hormone has started to increase. Thereafter, LNG-EC cannot prevent ovulation and it does not prevent fertilization or affect the human fallopian tube. LNG-EC has no effect on endometrial development or function. In an in vitro model, it was demonstrated that LNG did not interfere with blastocyst function or implantation.     

Effectiveness of levonorgestrel emergency contraception given before or after ovulation--a pilot study

BACKGROUND: Although widely used, the mechanisms of action of the levonorgestrel emergency contraceptive pill (LNG ECP) are still unclear. There are increasing data to indicate that LNG is particularly effective as an ECP by interrupting follicular development and ovulation. An important outstanding question is whether it has any effect on fertilization or implantation. METHOD: Ninety-nine women participated; they were recruited at the time they presented with a request for emergency contraception. All women took LNG 1.5 mg in a single dose during the clinic consultation. A blood sample was taken immediately prior to ingestion of the ECP for estimation of serum LH, estradiol and progesterone levels to calculate the day of ovulation. The specimens were analyzed in a single batch. Based on these endocrine data, we estimated the timing of ovulation to be within a +/-24-h period with an accuracy of around 80%. Women were followed up 4-6 weeks later to ascertain pregnancy status. The effectiveness of ECP when taken before and after ovulation was determined. RESULTS: Three women became pregnant despite taking the ECP (pregnancy rate, 3.0%). All three women who became pregnant had unprotected intercourse between Days -1 and 0 and took the ECP on Day +2, based on endocrine data. Day 0 was taken as ovulation day. Among 17 women who had intercourse in the fertile period of the cycle and took the ECP after ovulation occurred (on Days +1 to +2), we could have expected three or four pregnancies; three were observed. Among 34 women who had intercourse on Days -5 to -2 of the fertile period and took ECP before or on the day of ovulation, four pregnancies could have been expected, but none were observed. We found major discrepancies between women's self-report of stage of the cycle and the dating calculation based on endocrine data. CONCLUSION: These data are supportive of the concept that the LNG ECP has little or no effect on postovulation events but is highly effective when taken before ovulation.     

The effects of peri-ovulatory administration of levonorgestrel on the menstrual cycle

Levonorgestrel (LNG) 0.75 mg administered 12 h apart within 72 h of unprotected coitus, is an established method of emergency contraception (EC). The mechanism of action of LNG used in this manner is unknown. We administered LNG 0.75 mg twice immediately before ovulation, to test the hypothesis that LNG acts as an emergency contraceptive by abolishing the pre-ovulatory lutenizing hormone (LH) surge and thereby delaying ovulation. Twelve women took LNG on or before the day of the first significant rise in urinary LH in 12 cycles. In four women, the LH peak and the onset of next menses were significantly delayed (delay of 16.8 days (SD +/- 8.7) from the day of mean LH peak in placebo cycles). One woman did not ovulate at all, despite a normal LH peak and cycle length. In the remaining eight women, LNG did not affect ovulation or the cycle length, but the length of the luteal phase and the total luteal phase LH concentrations were significantly reduced. We suggest that LNG acts as an emergency contraceptive by other mechanisms as well as delaying the LH surge and interfering with ovulation.     

Effect of single administration of levonorgestrel on the menstrual cycle

BACKGROUND: Levonorgestrel (LNG) 1.5 mg administered within 72 h of unprotected coitus is an established method of emergency contraception. Currently, there is some, although incomplete, knowledge about the mechanism of action. METHODS: We administered 1.5 mg LNG peri-ovulatory to determine the effects on serum gonadotrophins, estradiol and progesterone levels. Fourteen women were studied in a pretreatment and treatment cycle; eight women (Group A) took LNG 3 days before the expected day of ovulation, while 6 (Group B) took LNG a day before the expected day of ovulation. RESULTS: The women in Group A had a significant delay in their LH peak and onset of the next menses compared with their pretreatment cycles (26.4 vs. 39.1 days, p<.05). Those in Group B had no significant changes in the endocrine parameters but there was a significant shortening of the mean cycle length in comparison with their pretreatment cycles (25.1 vs. 20.2 days). CONCLUSION: Levonorgestrel 1.5 mg acts as an emergency contraception by delaying the LH surge and interfering with ovulation. It may also disrupt corpus luteum formation causing premature luteinization of unruptured follicles.     

Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study

ObjectivesWe assessed intrauterine device (IUD) preference among women presenting for emergency contraception (EC) and the probability of pregnancy among concurrent oral levonorgestrel (LNG) plus LNG 52 mg IUD EC users.MethodsWe offered women presenting for EC at a single family planning clinic the CuT380A IUD (copper IUD) or oral LNG 1.5 mg plus the LNG 52 mg IUD. Two weeks after IUD insertion, participants reported the results of a self-administered home urine pregnancy test. The primary outcome, EC failure, was defined as pregnancies resulting from intercourse occurring within five days prior to IUD insertion.ResultsOne hundred eighty-eight women enrolled and provided information regarding their current menstrual cycle and recent unprotected intercourse. Sixty-seven (36%) chose the copper IUD and 121 (64%) chose oral LNG plus the LNG IUD. The probability of pregnancy two weeks after oral LNG plus LNG IUD EC use was 0.9% (95% CI 0.0–5.1%). The only positive pregnancy test after treatment occurred in a woman who received oral LNG plus the LNG IUD and who had reported multiple episodes of unprotected intercourse including an episode more than 5 days prior to treatment.ConclusionsStudy participants seeking EC who desired an IUD preferentially chose oral LNG 1.5 mg with the LNG 52 mg IUD over the copper IUD. Neither group had EC treatment failures. Including the option of oral LNG 1.5 mg with concomitant insertion of the LNG 52 mg IUD in EC counseling may increase the number of EC users who opt to initiate highly effective reversible contraception.ImplicationsConsideration should be given to LNG IUD insertion with concomitant use of oral LNG 1.5 mg for EC. Use of this combination may increase the number of women initiating highly effective contraception at the time of their EC visit.     

Effect of emergency contraception with levonorgestrel or mifepristone on ovarian function

The mechanism of action of levonorgestrel (LNG) and mifepristone (MIF) in emergency contraception (EC), is still not fully known. The purpose of this study was to evaluate the effect of preovulatory treatment with LNG and MIF on luteal function in more detail. Two days prior to ovulation (day -2; assessed by ultrasound), we administered LNG (0.75 mg twice, 12 h apart) or MIF (10 mg, single dose) to seven women in different cycles. Follicle development was followed by ultrasound. Urinary estrone glucuronide (E1), pregnanediol glucuronide (P4) and luteinizing hormone (LH) were analyzed by enzyme immunoassays daily starting with day -2 for the rest of the menstrual cycle, along with urinary creatinine (C). The treatment caused either a delay or an inhibition of the LH peak in all subjects. A significant delay in P4 levels and an initial suppression of E1 levels were also noted. The development of the leading follicle was either arrested or continued without signs of rupture. This study indicates that, when used for EC, LNG or MIF administered prior to ovulation acts through an impaired ovulatory process and luteal function.     

Mechanism of emergency contraception with gestrinone: a preliminary investigation

BACKGROUND: A previous investigation showed that among 120 healthy women treated with a single oral dose of gestrinone for emergency contraception (EC), there was only one pregnancy. The effect of a single oral dose of gestrinone given for EC on ovarian function and endometrial development was studied. STUDY DESIGN: Healthy fertile women were randomly assigned to Group A (n=8) or Group B (n=7). Gestrinone 5 mg was orally administered to each woman before (Group A) or after (Group B) ovulation. The day of ovulation was determined by transvaginal ultrasound and by urinary luteinizing hormone (LH) measured by enzyme immunoassay (One Step LH Ovulation Test). An endometrial biopsy was performed during implantation. Endometrial maturation and expression of markers of endometrial receptivity were analyzed. The tested markers were integrins alpha(1)beta(1), alpha(4)beta(1) and beta(3). Serum estradiol (E(2)) and progesterone (P) levels in serum were determined by radioimmunoassay, and estradiol receptors and progesterone receptors (PRs) in the endometrium were assessed by immunohistochemistry. RESULTS: Gestrinone administered during the periovulatory period did not affect follicular development, ovulation, menstrual cycle length and E(2) and P levels but decreased the expression of PR in the endometrium. Integrin alpha(4)beta(1) tended to increase after treatment with gestrinone without reaching statistical significance. CONCLUSION: The mode of action of gestrinone used for EC is probably inhibition of implantation by acting on the endometrium rather than inhibition of ovulation.     

Postfertilization effects of oral contraceptives and their relationship to informed consent

The primary mechanism of oral contraceptives is to inhibit ovulation, but this mechanism is not always operative. When breakthrough ovulation occurs, then secondary mechanisms operate to prevent clinically recognized pregnancy. These secondary mechanisms may occur either before or after fertilization. Postfertilization effects would be problematic for some patients, who may desire information about this possibility. This article evaluates the available evidence for the postfertilization effects of oral contraceptives and concludes that good evidence exists to support the hypothesis that the effectiveness of oral contraceptives depends to some degree on postfertilization effects. However, there are insufficient data to quantitate the relative contribution of postfertilization effects. Despite the lack of quantitative data, the principles of informed consent suggest that patients who may object to any postfertilization loss should be made aware of this information so that they can give fully informed consent for the use of oral contraceptives.     

Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens

Background

The days just prior to ovulation are the most crucial for emergency contraception (EC) efficacy. Ulipristal acetate (UPA) and levonorgestrel's (LNG) capacity to inhibit follicular rupture have never been compared directly at this time of the cycle.

Study Design

Raw data from three pharmacodynamics studies with similar methodology were pooled to allow direct comparison of UPA, LNG and LNG+meloxicam's ability to prevent ovulation when administered orally in the advanced follicular phase, with a leading follicle of ≥18 mm.

Results

Forty eight LNG-treated (1.5 mg) cycles, 31 LNG (1.5 mg) + meloxicam (15 mg), 34 UPA (30 mg) cycles and 50 placebo cycles were compared. Follicle rupture was delayed for at least 5 days in 14.6%, 38.7%, 58.8% and 4% of the LNG-, LNG+meloxicam-, UPA- and placebo-treated cycles, respectively. UPA was more effective than LNG and placebo in inhibiting follicular rupture (p=.0001), while LNG, when administered at this time of the cycle, was not different than placebo. The addition of meloxicam improved the efficacy of LNG in preventing follicular rupture (p=.0292 vs. LNG; p=.0001 vs. placebo; non-significant vs. UPA). UPA was effective in preventing rupture in the 5 days following treatment, even when administered at the time of the luteinizing hormone (LH) surge (UPA 79%, LNG 14% and placebo 10%). None of the treatments were effective when administered on the day of the LH peak. The median time from treatment to rupture was 6 days during the ulipristal cycles and 2 days in the placebo and LNG/LNG+meloxicam cycles (p=.0015).

Conclusion

Although no EC treatment is 100% effective in inhibiting follicular rupture when administered in the late follicular phase, UPA is the most effective treatment, delaying ovulation for at least 5 days in 59% of the cycles. LNG is not different from placebo in inhibiting follicular rupture at this advanced phase of the cycle. No treatment was effective in postponing rupture when administered on the day of LH peak.     

Prototype for a new class of antifertility agents, 3,5-Bis (dimethylahino)-1,2,4,-dithiazolium chloride

3,5-Bis(dimethylarmino)-1,2,4-dithiazolium chloride [ORF 5513] is considered to be a prototype for a new class of female antifertility agents. When orally administered to rats at dose levels between 0.01 and 0.1 mg/kg/day for 3 days prior to expected ovulation, treatment resulted in a dose-dependent inhibition of ovulation. However, when the compound was administered to animals for 2 days prior to ovulation, ORF 5513 had little or no effect on ovulation at doses as high as 10 mg/kg/day. ORF 5513 also interrupted pregnancy at several stages of gestation, including implantation, placentation and late pregnancy. The minimum effective dose (MED) in the rat for inhibiting implantation (Days 1–6) and interrupting pregnancy immediately after implantation (Days 7–10) appears to be ≤ 10 mg/kg. The MED varies between ≤ 5 mg/kg for days 10–13 or 13–16 to ≤ 20 mg/kg for days 16–19 of gestation. Endocrine bioassays and $\text{in vitro}$ studies revealed that ORF 5513 lacks hormonal activity. Histological studies indicated that the corpora lutea in all animals appeared uninvolved. When the treatment was initiated on day 16 of gestation, the earliest detectable cellular changes occurred in the chorionic villi and chorionic fetal vessels which effectively interfere with fetal circulation. Degeneration of the fetus occurred by day 19 of gestation while maternal placental circulation remained intact.     

Ulipristal acetate: a new emergency contraceptive that is safe and more effective than levonorgestrel

Ulipristal acetate (UPA), a selective progesterone receptor modulator, when taken as a single 30-mg dose, is safe and effective for emergency contraception up to 5 days (120 h) following unprotected intercourse. This indication has been approved in Europe since May 2009 and was approved by the US FDA in August 2010. The older progesterone-only emergency contraceptive, levonorgestrel (LNG), is approved only up to 72 h after unprotected intercourse. UPA is effective in delaying or inhibiting ovulation, even if taken 24 to 48 h prior to expected ovulation, a time when LNG is no longer effective. A recent meta-analysis of two randomized clinical trials showed UPA to have a pregnancy risk 42% lower than LNG up to 72 h, and 65% lower in the first 24 h following unprotected intercourse. In a randomized trial enrolling women up to 5 days after unprotected intercourse, significantly more pregnancies were prevented with UPA than with LNG when taken beyond 72 h.     

Antiprogesterones

Progesterone receptor antagonists such as mifepristone (also known as RU-486) have revolutionary potential as fertility control agents. Proven uses of RU-486 include early pregnancy termination, cervical ripening, postcoital contraception, ovulation inhibition, induction of labor after fetal death, and treatment of Cushing's syndrome. Under investigation is the use of this agent as a contraceptive and for the induction of labor at term, the treatment of progesterone-dependent cancers, and manipulation of the implantation window in in vitro fertilization. Most attention has centered on RU-486's abortifacient properties. Abortion is induced in about 62% of pregnancies under 57 days of gestation. When used in combination with exogenous prostaglandin, RU-486's effectiveness as an abortifacient is increased to 95-100%. RU-486 further provides researchers with an opportunity to explore the effects of progesterone in a variety of physiological situations. When administered in the luteal phase of the menstrual cycle, RU-486 induces luteolysis and vaginal bleeding. At this stage, the agent appears to act as a progesterone against on the hypothalamic- pituitary axis. In the follicular phase,RU-486 delays ovulation and disrupts folliculogenesis.     

Levonorgestrel administration in emergency contraception: bleeding pattern and pituitary-ovarian function

BACKGROUND: This study was conducted to evaluate the effects of levonorgestrel administration for emergency contraception (EC) on bleeding pattern and pituitary-ovarian function. STUDY DESIGN: In 69 women with a reported stable menstrual cycle length of 24-34 days, we investigated bleeding patterns following EC administration in the follicular (n=26), periovulatory (n=14) and luteal (n=29) phase. In a subgroup of 8 women, hormonal evaluation and ultrasonography were performed. RESULTS: EC taken in the follicular, but not in the periovulatory or luteal phase, significantly shortened cycle length by 10.9+/-1 days. The subsequent cycle was not affected. EC taken in the late preovulatory phase, prior to the gonadotrophin surge, suppressed ovulation (n=7), while ovulation was not blocked when EC was given during an ongoing luteinizing hormone (LH) pulse (n=1). CONCLUSIONS: Our data indicate that EC given before the onset of the luteinizing hormone (LH) surge inhibits ovulation and hastens the end of the current menstrual cycle. Subsequently, the length of the following menstrual cycle returned as prior to treatment. By contrast, levonorgestrel administered after the expected ovulation has no effect on menstrual cycle length.     

Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation

Background

We aimed to evaluate whether emergency contraception with levonorgestrel (LNG-EC) administered after ovulation is equally effective to LNG-EC administered before ovulation.

Study design

We studied a cohort of women attending a family planning clinic for EC. From interview, we recorded menstrual history, time of intercourse and of intake of LNG-EC. On the day of intake of LNG-EC and during 5 days' follow-up, blood samples were taken for examination of luteinizing hormone, estradiol and progesterone concentrations, and vaginal ultrasound examinations were done for size of the leading follicle and/or corpus luteum. Thereafter women were not contacted until next menses or pregnancy occurred.

Results

Of 388 women attending for LNG-EC, 122 women had intercourse on fertile cycle days according to ultrasound and endocrine findings. At the time of LNG-EC intake, 87 women were in Days −5 to −1 and 35 women were in Day 0 (day of ovulation) or beyond. With the use of the probability of clinical pregnancy reported by Wilcox et al. [N Engl J Med 333 (1995) 1517-1521], expected numbers of pregnancies among the 87 and 35 women were 13 and 7, respectively, while 0 and 6 pregnancies, respectively, occurred.

Conclusion

We conclude that LNG-EC prevents pregnancy only when taken before fertilization of the ovum has occurred.     

Emergency contraception

Emergency contraception is used after unprotected intercourse or a contraceptive accident to prevent unwanted pregnancy. It is thought to work by stopping or delaying ovulation or preventing implantation if fertilization has already taken place. Hormonal methods, mifepristone, and intrauterine device insertion are among the methods used worldwide. Combination estrogen-progestin birth control pills are the most commonly used form of emergency contraception in the United States. According to the Yuzpe method, combination pills are taken within 72 hours after intercourse, followed by a second identical dose 12 hours later. With this method, the number of unintended pregnancies is reduced by about 75%. Nausea and vomiting are the most troublesome adverse effects, but these can be controlled with antiemetic medication taken prior to the first dose. The Food and Drug Administration, Washington, DC, has approved an emergency contraception kit consisting of 4 combination pills, a urine pregnancy test, and a patient information book. Most recently, the Food and Drug Administration has approved a progestin-only formulation, which has fewer adverse effects and equal or improved efficacy compared with the combination formula. An intrauterine device can be inserted up to 5 days after unprotected intercourse and is a cost-effective option if it is used as ongoing contraceptive protection. The most readily available form of emergency contraception consists of 2 doses of estrogen-progestin combination birth control pills or 2 levonorgestrel pills taken 12 hours apart. Emergency contraception should not be considered as an alternative to ongoing contraceptive methods, but can prevent unwanted pregnancy.     

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.     

口服避孕药预处理对长效长方案体外受精-胚胎移植临床结局的影响

目的探讨口服避孕药(oral contraception pill,OCP)前期预处理对接受长效长方案控制性超排卵患者临床结局的影响。方法对2011年1月至2013年4月在广州市妇女儿童医疗中心生殖医学中心进行长效长方案治疗的正常卵巢储备患者325例的临床资料进行分析。采用OCP前期预处理的185例患者为OCP组,未采用OCP预处理140例患者为对照组。比较两组卵巢过度刺激综合征(ovarian hyperstimulation syndrome,OHSS)发生率、促性腺激素用量与天数、获卵数、临床妊娠率、着床率。结果 OCP组OHSS发生率(5.9%)高于对照组(1.4%)(P0.05);两组间促性腺激素的用量、获卵数、临床妊娠率、着床率比较差异无统计学意义(P0.05)。结论长效长方案治疗中,OCP预处理可能增加了正常卵巢储备患者OHSS的发生率。     

Emergency contraception with a copper IUD or oral levonorgestrel: an observational study of 1-year pregnancy rates

Objective

We investigated the 1-year pregnancy rates for emergency contraception (EC) users who selected the copper T380 intrauterine device (IUD) or oral levonorgestrel (LNG) for EC.

Study Design

This prospective study followed women for 1 year after choosing either the copper T380 IUD or oral LNG for EC. The study was powered to detect a 6% difference in pregnancy rates within the year after presenting for EC.

Results

Of the 542 women who presented for EC, agreed to participate in the trial and met the inclusion criteria, 215 (40%) chose the copper IUD and 327 (60%) chose oral LNG. In the IUD group, 127 (59%) were nulligravid. IUD insertion failed in 42 women (19%). The 1-year follow-up rate was 443/542 (82%); 64% of IUD users contacted at 1 year still had their IUDs in place. The 1-year cumulative pregnancy rate in women choosing the IUD was 6.5% vs. 12.2% in those choosing oral LNG [hazard ratio (HR) 0.53, 95% confidence interval (CI): 0.29–0.97, p=.041]. By type of EC method actually received, corresponding values were 5.2% for copper IUD users vs. 12.3% for oral LNG users (HR 0.42, 95% CI: 0.20–0.85, p=.017). A multivariable logistic regression model controlling for demographic variables demonstrates that women who chose the IUD for EC had fewer pregnancies in the following year than those who chose oral LNG (HR 0.50, 95% CI: 0.26–0.96, p=.037).

Conclusion

One year after presenting for EC, women choosing the copper IUD for EC were half as likely to have a pregnancy compared to those choosing oral LNG.

Implications

Compared to EC users who choose oral levonorgestrel, those who select the copper IUD have lower rates of pregnancy in the next year. Greater use of the copper IUD for EC may lower rates of unintended pregnancy in high-risk women.     

IMAP statement on emergency contraception

Unplanned or unwanted pregnancies are at higher risk of morbidity and mortality, often due to unsafe abortion. For the woman exposed to unprotected sexual intercourse, however, postcoital contraception can be used to avoid an unwanted pregnancy. The postcoital use of certain orally administered steroid hormones has been shown since the mid-1960s to be highly effective in preventing pregnancy although the approach should be only considered as an emergency procedure since data on the efficacy and safety of long-term use is not available. Copper-releasing IUDs have also been used effectively for emergency contraception. The precise mode of action of emergency contraceptive methods is uncertain, but it is thought that they inhibit ovum transport, ovulation, and implantation. This statement briefly discusses established methods, the use of copper-releasing IUDs, counseling, methods under investigation, and access to emergency contraception.     

可生物降解皮下埋植剂CaproF的临床初步研究

<正> 多年来研究人员对缓释皮下埋植避孕系统进行了大量、广泛的研究,其中成功地开发和推广使用了释放左旋18甲基炔诺酮(LNG)皮下埋植避孕剂Norplant。经临床研究证实,Norplant是一种高效、安全、可逆、接受性高的长效避孕方法,但放置有效期满5年后必须取出,增加使用者痛苦和花费,而且难于保证所有使用者均能按期取出从而增加避孕失败的危险。由此引发了可生物降解皮下埋植避孕剂的研究,即以一种兼具生物降解性和甾体药物通透性的聚合物,代替硅胶作为释放孕激素的载体,孕激素释放完毕后载体在体内降解吸收而无须取出。研究证实,具有可生物降解性的高分子材料中聚