Mifepristone: a potential clinical agent based on its anti-progesterone and anti-glucocorticoid properties.

Nowadays, unwanted pregnancy is a major globe tragedy for millions of women, associated with significant direct and indirect costs, no matter for individuals or society. The progesterone receptor antagonist steroid, mifepristone has been widely and effectively using throughout the world for medical abortion, but to a lesser extent for emergency contraception. In this review, we hope to explore the role of mifepristone as a contraceptive, particularly for emergency contraception. Studies of mifepristone have also been expanding to the fields of endometriosis and uterine fibroids. Furthermore, this initially considered reproductive medicine has been investigated in some psychotic diseases and various disorders of hypercortisolism, because of its glucocorticoid receptor antagonism. Mifepristone was approved suitable for patients with hyperglycemia secondary to Cushing's syndrome by the United States Food and Drug Administration (FDA) in 2012. The aim of this article is to review published reports on the anti-progesterone and anti-glucocorticoid properties of mifepristone as a clinical agent. There is a new insight into systematically describing and evaluating the potential efficiency of mifepristone administrated in the field of endocrine and neuroendocrine, not only in obstetrics and gynecology.

Defining reality: the potential role of pharmacists in assessing the impact of progesterone receptor modulators and misoprostol in reproductive health.

Medical abortion is increasingly heralded as an ideal method for decreasing maternal mortality in health-care resource-deprived areas and as an answer to the shrinking pool of physicians willing to perform abortions. The advent of progesterone receptor modulators (PRMs) and the recent approval by the Food and Drug Administration of ella (ulipristal) as an emergency contraceptive put pharmacists in the center of abortion controversy. Pharmacists, worldwide, need to be aware of the controversy surrounding the introduction of PRMs, particularly with regard to the effect on health policy, their mechanism of action, associated adverse events, and common off-label uses. Once understood, genuine opportunity exists for pharmacists to serve a fundamental role in positively shaping public health policy.

Centchroman: is unsupervised long-term use warranted? Case report.

OBJECTIVES: Centchroman (Ormeloxifene) is a synthetic non-steroidal compound used as an oral and a post-coital contraceptive. It is currently under trial for treatment of breast cancer and postmenopausal osteoporosis. Centchroman has been reported to induce only minimal side effects and no hormonal imbalance. CASE: A young woman who used centchroman for a long time in an unsupervised fashion presented with menorrhagia, which was controlled with norethisterone. Her massively enlarged uterus showed extensive decidual changes in a hyperplastic endometrium, and diffuse microglandular cervical hyperplasia. CONCLUSIONS: The case suggests a prominent oestrogenic effect of centchroman on the uterus. This could be a significant adverse effect related to prolonged therapy. Lengthy intake of centchroman requires medical surveillance and long-term studies are needed.

Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture.

BACKGROUND: Current methods of hormonal emergency contraception (EC) are ineffective in preventing follicular rupture when administered in the advanced pre-ovulatory phase. This study was designed to determine the capacity of ulipristal acetate (UPA), a selective progesterone receptor modulator developed for EC, to block follicular rupture when administered with a follicle of >or=18 mm. METHODS: This was a double-blind, crossover, randomized, placebo-controlled study. Thirty-five women contributed with UPA (30 mg. oral) and a placebo cycle. Serial blood sampling for luteinizing hormone (LH), estradiol and progesterone measurements and follicular monitoring by ultrasound were performed before and for 5 days following treatment. Follicular rupture inhibition was assessed in the overall study population and in subgroups of women stratified by when treatment was administered in relation to LH levels (before the onset of the LH surge, after the onset of the surge but before the LH peak or after the LH peak). RESULTS: Follicular rupture failed to occur for at least 5 days following UPA administration in 20/34 cycles [59%; 95% confidence interval (CI) (40.7-75.4%)], whereas rupture took place in all cycles within 5 days of placebo intake. When UPA was administered before the onset of the LH surge, or after the onset but before the LH peak, follicle rupture had not occurred within 5 days in 8/8 (100%) and 11/14 [78.6%; 95% CI (49.2-95.3)] cycles, respectively. In contrast, when UPA was given after the LH peak, follicle rupture inhibition was only observed in 1/12 [8.3%; 95% CI (0.2-38.5)] cycles. CONCLUSIONS: This study demonstrates that UPA can significantly delay follicular rupture when given immediately before ovulation. This new generation EC compound could possibly prevent pregnancy when administered in the advanced follicular phase, even if LH levels have already begun to rise, a time when levonorgestrel EC is no longer effective in inhibiting ovulation.

A randomized trial of mifepristone (10 mg) and levonorgestrel for emergency contraception.

OBJECTIVE: To compare the efficacy, patient acceptability and adverse effects of low-dose mifepristone (10 mg) with the levonorgestrel regimen (2 doses of 750 microg given 12 hours apart) for emergency contraception. METHODS: This randomized controlled trial compared mifepristone (10 mg) to levonorgestrel (2 doses of 750 microg given 12 hours apart) in the context of emergency contraception within 120 hours of unprotected intercourse. The primary outcome measure was unintended pregnancy. Secondary outcomes included adverse effects experienced by women, acceptability of the method of emergency contraception used, and the timing of the first menstrual cycle after treatment. RESULTS: The total number of women recruited was 2,065. The crude pregnancy rates were 1.3% and 2.0% for mifepristone and levonorgestrel (P = .46), with 77% and 64% of expected pregnancies prevented, respectively. Women receiving mifepristone were more likely to have a delayed onset of the subsequent menstrual cycle after treatment (P < .001), whereas those having levonorgestrel were more likely to have an early onset of the subsequent menstrual cycle (P < .001). Acceptability levels were high for both methods, with 94% of women receiving mifepristone and 91% receiving levonorgestrel expressing satisfaction. There was no difference in adverse effects (nausea, vomiting, breast tenderness, abdominal pain, lethargy, headache, hot flushes, and dizziness) experienced by women in the 2 groups. CONCLUSION: This study suggests that a small dose of mifepristone is not less effective than levonorgestrel for emergency contraception. Both regimens were highly acceptable to women.

Ectopic gestation following emergency contraceptive pill administration.

Emergency contraceptive pill prescription following rape is common. We report a case of ectopic gestation after emergency contraceptive pill failure and review the literature on this rare complication. A 26-year-old woman with a normal menstrual period 2 weeks before was administered an emergency contraceptive pill 8 hours after a single sexual assault. The assault was her only sexual activity before and after the emergency contraceptive pill use. Forty-six days following the assault, the patient presented with a right ampullary tubal pregnancy of 59 days gestation and underwent emergent surgery for ectopic gestation. To prevent a delay in the diagnosis of ectopic pregnancy, we recommend that providers and the package insert advise women, that ectopic gestation can occur with emergency contraceptive pill failure.

Expanded clinical trial of emergency contraception with 10 mg mifepristone.

We conducted a clinical single-arm trial to evaluate the effectiveness of 10 mg mifepristone for emergency contraception (EC) in a large population in China. The participating centers were 31 family-planning clinics and hospitals in the following 19 provinces or municipalities in China: Beijing, Shanghai, Tianjin, Harbin, Changchun, Shengyang, Shijiazhuang, Zhengzhou, Taiyuan, Nanjing, Jinan, Hangzhou, Guangzhou, Wuhan, Changsha, Chongqing, Guiyang, Chengdu, Kunming. A total of 4945 women requesting EC within 120 h after a single act of unprotected intercourse were recruited and treated with 10 mg mifepristone. A total of 28 women were lost to follow-up, and 4917 women were included in the analysis, of whom, 69 became pregnant. The combined pregnancy rate was 1.4 [95% confidence interval (CI): 1.0-1.9] and the percentage of pregnancies prevented was 82.2% (95% CI: 77.5-86.2%). There was a significant inverse trend in pregnancy rate with body mass index that disappeared when adjusted for other variables. The pregnancy risk was double among nulliparous women compared to parous women (2.3% compared to 1.0%), and it increased by a factor of 1.5 when the treatment was administered at 25-48 h and at 49-72 h compared to administration within 24 h, although this association was not significant. The risk of pregnancy was higher if intercourse took place during the follicular or preovulatory phase of the cycle. Women having repeated intercourse after treatment without any contraceptive methods had a dramatic increase in the risk of pregnancy, while those who used contraceptives had similar risk to those without acts. Side effects were mild and present in only small proportions of women: nausea and vomiting in 9% and other side effects in 2-3%. Delay of menstruation of 7 days or more occurred in 6.5% of women. The expanded study confirmed the high efficacy and safety of 10 mg mifepristone for EC.

Meta-analyses of randomized trials comparing different doses of mifepristone in emergency contraception.

There is some evidence from randomized trials that different doses of mifepristone for emergency contraception do not differ in efficacy in the range from 10 mg to 600 mg. Lower doses have a better side effect profile and are cheaper and therefore they would be preferable in the absence of a dose effect. However, the lack of significance is not evidence of absence of an effect. More evidence can be obtained by combining results of trials. We present meta-analyses of randomized trials comparing doses of mifepristone for emergency contraception from 5 mg to 600 mg, with regard to the efficacy to prevent unwanted pregnancies. We use two approaches for analysis, one using only within-trial information and another one combining within-trial with between-trial information. We discuss the results in terms of equivalence. There is some evidence of a small dose effect on efficacy in the lower range of doses (<50 mg). The pregnancy rate increases by a factor of 1.6 when the dose of 10 mg is used instead of 25 mg (95% confidence interval: 1.1-2.4). In terms of the number of women needed to treat, however, using 10 mg in the place of 25 mg implies having one extra pregnancy every 146 women requesting emergency contraception, which might be a low cost compared to the benefit of more women having access to treatment.

Pharmacological properties of mifepristone: toxicology and safety in animal and human studies.

Roussel Uclaf in partnership with the INSERM unit of Prof. E.E. Baulieu first discovered mifepristone (RU486) as part of a large research program on steroidal compounds with antihormone properties. Exhibiting a strong affinity to the progesterone and the glucocorticoid receptors, mifepristone exerted competitive antagonism to these hormones both in in vitro and in animal experiments. Due to its antiprogesterone activity, it was proposed that mifepristone be used for the termination of early human pregnancy. Mifepristone, at a dose of 600 mg initially used alone, was then used with a subsequent low dose of prostaglandin that led to a success rate of 95% as a medical method for early termination of pregnancy (TOP). Its use was extended to other indications, such as cervical dilatation prior to surgical TOP in the first trimester, therapeutic TOP for medical reasons beyond the first trimester, and for labor induction in case of fetal death in utero. The efficacy and safety of this treatment has been confirmed based on its use for over a decade, with close adherence to the approved recommendations. This paper describes the safety studies conducted in animals as well as the safety follow-up and side effects reported with use of the compound in various indications either approved or unapproved. The rationale for warnings and contraindications for use of the product are also explained. At lower doses, the molecule has proven promising for contraceptive purposes with few reported side effects. However, development of the product for this indication would require long-term studies. Although political and philosophical obstacles have delayed research, the use of mifepristone for other potential indications in gynecology or oncology should be investigated.

Young women requesting emergency contraception are, despite contraceptive counseling, a high risk group for new unintended pregnancies.

Since its introduction in Sweden in 1994, emergency contraception has become a welcome addition to the campaign against unwanted pregnancy. In addition to an unplanned pregnancy, unprotected sexual intercourse may also involve the risk of contracting sexually transmitted diseases (STD). The aim of this study was to assess the short- and long-term risk of unintended pregnancy and to determine the frequency of chlamydia infections in women receiving emergency contraception. Between September 1998 and February 1999 young women aged 15-25 years had the opportunity to obtain emergency contraception (Yuzpe method) at a youth clinic in the city of Orebro where the opening hours were extended to include Saturdays and Sundays. A follow-up visit 3 weeks after treatment, which included contraceptive counseling, was offered to all participants. At both visits, a pregnancy test and a chlamydia test were performed, and the women completed a questionnaire. After the initial visit, the young women where monitored for new pregnancies during the following 12 months. One pregnancy occurred in the 134 young women who received emergency contraception during the study period. None of the women had a positive chlamydia test. Of those requesting emergency contraception, 54% did so because no contraception was used, 32% because of a ruptured condom, 11% because of missed oral contraceptives (OC), and 5% had mixed reasons. At long-term follow-up 1 year after the initial visit, 10 of the 134 young women had experienced an unplanned pregnancy that terminated in legal abortion in 9 women. All these women had either started and terminated OC or had never commenced the prescribed OC. Young women who request emergency contraception are, despite a planned follow-up with contraceptive counseling, a high risk group for new unintended pregnancies. In Sweden they do not seem to be a high risk group for STD.

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.

Experimental study on relationship between exogenous estrogen and breast cancer risk.

OBJECTIVE: To investigate the relationship between exogenous estrogen and breast cancer risk. METHODS: Female rats were randomly divided into three groups, namely diethylstilbestrol (DES), norethindrone compositae (CoNET) and control group. The histological structure and ultrastructural changes of mammae were observed. The levels of sexual hormones in serum were determined and the AgNOR counts, DNA contents and steroid receptor contents in mammary epithelium were also detected. RESULTS: In DES group, the level of progesterone (10.38 ng/ml) was obviously lower than that in the control group (13.37 ng/ml); the incidence of hyperplasia of mammary gland (73.33%) was significantly higher than that in the control group (7.69%); and the degree of hyperplasia was obviously more serious than that in the control group. Moreover, there were 13.33% of rats with atypical hyperplasia in DES group. The DNA contents, AgNOR counts and estrogen receptor (ER) positive rate were markedly higher in DES group (95.60, 2.43 and 71.71% respectively) than in the control group (83.07, 1.88 and 40% respectively). However, in CoNET group, there were no obvious influences on ER, AgNOR and DNA in mammary epithelium. CONCLUSIONS: Exogenous estrogen (DES) could affect the levels of sexual hormones in serum, accelerate the DNA duplication, increase the AgNOR counts and ER contents, and induce atypical hyperplasia and ultrastructural changes of mammary gland, hence becoming a latent risk factor of breast cancer. However, the results failed to suggest that the contraceptive, CoNET, could increase the risk of breast cancer.

[Postcoital contraception]. / Postcoïtale anticonceptie.

PIP: Some form of postcoital contraception for protection against unwanted pregnancy is indispensable today especially in cases of rape, failed mechanical contraception, or 1st sexual contact without contraception. A tabletform of postcoital contraceptive would be acceptable if 100% certainty is assured and it doesn't involve adverse effects. Postcoitally administered high-dose estrogens proved effective in Macaca mulatta. Diethylstilbestrol in variable dosages with or without ethinylestradiol was used in various studies and with variable results. Pregnancy rates depended on time of coitus in cycle, contraceptive dosage, and time of administration after coitus (within 72 hours). Conjugated estrogens and various progestagens or combinations of both have been tried with variable success. Another form of postcoital contraception is IUD insertion within 7 days following unprotected coitus. Advantages of this method are the time factors and absence of adverse effects of hormonal contraceptives. Postcoital hormonal contraceptives cause changes in the endometrium which prevent blastocyst implantation. They alter tubal function affecting zygote movement towards the uterus. They have an antiovulatory effect and may be luteolytic. Estrogens have more severe side effects than progestagens. Nausea, vomiting, mastodynia, fluid retention, and vaginal bleeding can result from estrogens. Progestagens can cause irregular bleeding. Combination of both can cause menstrual irregularity. Postcoital hormonal contraceptives are contraindicated in heart and liver diseases, thrombosis, and pregnancy (teratogenic and carcinogenic effects on offspring). Pregnancy despite postcoital contraception results in extrauterine pregnancy in 10% of patients. The most important reservations in evaluating publications on this subject are: 1) lack of control group; 2) estimation of pregnancy probability is not reliable because of study population used; 3) patient fertility cannot be ascertained; and 4) reliability of information provided by patient. Conclusion from literature studies is that postcoital hormonal contraception is of value but effectiveness is not proven. More research is needed and indications are that other less radical drugs may be found in near future.^ieng

[Emergency contraception: a simple, safe, effective and economical method for preventing undesired pregnancy]. / Anticoncepción de emergencia: un método simple, seguro, efectivo y económico para prevenir embarazos no deseados.

In the following article, the most recent knowledge on emergency contraception (EC) is reviewed. EC is defined as those contraceptive methods that may be used to prevent an unwanted pregnancy up to 3 days after unprotected intercourse, contraceptive failure or rape. In case of non-hormonal methods (IUD), the time window for pregnancy prevention goes up to 5 days after intercourse. The different regimens now available, hormonal and non-hormonal methods, indications, contraceptive effectiveness, side effects and safety profile, possible mechanisms of action and counseling strategies will be reviewed. The potential benefits on reproductive health of wide-spread knowledge and easy, non-restrictive access to this methodology are emphasized. An extensive list of recent references is enclosed.

[Low doses of mifepristone for emergency contraception].

OBJECTIVE: To investigate the efficacy of three different low doses of mifepristone for emergency contraception, the side effects and the influence to the next menstruation. METHODS: A randomized multicentre trial was conducted in Shanghai. 639 women with regular cycles and history of unprotected intercourse within 120 h of attendance were recruited, and they were randomly assigned to three groups. Group I (n = 214) mifepristone 50 mg was given, group II (n = 214) 25 mg and group III (n = 211) 10 mg. RESULTS: There were eight pregnancies totally, 2 cases in group I, 1 in group II and 5 in group III. After correction for method failure there was only 1 pregnancy in each group and the contraceptive effectiveness rate were 93.4%, 93.3% and 93.8% respectively. The side effects of mifepristone were slight and tolerable and there was significant difference between the 50 mg group and the lower doses (25 mg and 10 mg) groups (P < 0.05) in women with no complaints. There were about 12%-14% women had a early onset of menses and about 25%-28% had a late one, but no significant differences were found among the 3 groups. The average days of delayed onset of next menstruation were significant longer in group I than that in group III (P < 0.05). CONCLUSION: All the 3 doses of mifepristone could be used as an effective emergency contraception.

[Postcoital emergency contraception]. / Postkoitale Notfall-Kontrazeption.

The actual methods of postcoital emergency contraception are described and compared. The method of choice is the administration of a progestagen-only pill because this method is more reliable and effective than the use of a combined estrogen-progestagen pill ("Yuzpe-Method"), and because the incidence of side-effects is considerably lower. The results obtained with levonorgestrel alone are presented by the authors. The postcoital introduction of a copper intrauterine device is highly effective, but invasive. This method is indicated if it is too late to use the pill. An open and accepting setting of the consultation and a way of taking the medical history that is pointing to the auto-responsibility are essential, especially for adolescents. Low conditions for the admission to the counselling are postulated, and the obligation to possess a medical prescription to obtain the only progestagen-only pill is questioned.

[Our experience with the clinical trial of postinor--an oral hormonal preparation for postcoital contraception]. / Nashiiat opit ot klinichnoto izpitvane na postinor--khormonalen oralen preparat za postkoitalna kontratseptsiia.

PIP: Postcoital contraception aims at the avoidance of unwanted pregnancy in women who have a regimen of rare or accidental sexual contacts. For the 1st time in Bulgaria, the authors examined clinically an oral postcoital preparation, Postinor, which originated in Hungary. Each tablet contains 0.75 mcg of d-norgestrel. The observation included 49 volunteers, ages 19-38, with proven fertility. The preparations were given during the course of 150 menstrual cycles. 1 women became pregnant as a result of improper dosage/multiple contacts during incomplete hormonal protection. There were 3 cases of bleeding (6.1%) and 1 required estrogen correction. The authors found that the best administration regimen was 1 tablet, with the exception of 2 tablets/week. The authors suggest that Postinor could be successfully combined with the rhythm method of Ogion-Knaus. They recommend it for daily contraceptive practice. (author's modified)^ieng