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.

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.

Emergency contraception: past, present and future.

Women have been using emergency contraception (EC) for decades. Population studies have not shown that increased access to EC decreases abortion rates this is likely because of inconsistent and infrequent use even when it is available. Special populations, such as adolescents, have been shown to be just as good as their adult counterparts in comprehending EC instructions, and its use does not lead to more risky sexual practices or behaviors. There is little evidence on the administration of EC to victims of sexual assault, but what is available reveals more women who are victims of sexual assault should be offered EC as an option. Methods of EC include high doses of ethinyl estradiol; DES; Danzaol; combination ethinyl estradiol with a progestin; progestin alone and copper IUDs. This review describes the history of EC as well as newer medications such as the antiprogestins (gestrinone and uliprisatal acetate) and cyclooxygenase inhibitors(meloxifam). These methods have been added to the armamentarium and may prove to be more effective than current regimens. Finding a product that is highly effective with minimal side effects is a worthy goal, for it presents a woman with her last chance to prevent an unwanted pregnancy.

Emergency contraception, efficacy and public health impact.

PURPOSE OF REVIEW: Emergency contraception in the past two decades had been proven to be effective and well tolerated. Counseling and advance provision and prescription of emergency contraception have been embraced by professional organizations in practice guidelines for its potential to reduce the number of unintended pregnancies and abortions. Has emergency contraception lived up to that promise? RECENT FINDINGS: Mifepristone (not available in the USA) is the agent of choice. Emergency contraception has not reduced the number of unintended pregnancies. Acceptance by healthcare providers and the public has not been optimal, and multiple financial and healthcare system barriers to use emergency contraception continue to exist. The public health impact of emergency contraception has been disappointing. SUMMARY: Although emergency contraception may continue to be an important component of contraceptive practice, only increased access to more effective methods of contraception will change unintended pregnancy rates. The use of mifepristone for emergency contraception in the USA must be considered.

Levonorgestrel and mifepristone in emergency contraception.

Research on new technologies by the Special Programme of Research, Development and Research Training in Human Reproduction at WHO has led to the development of two new methods for emergency contraception, the levonorgestrel regimen and a low-dose mifepristone regimen. In 4 years, the levonorgestrel regimen has already been approved in some 95 countries. We review this research and present combined data from our multinational trials and combined estimates of efficacy for mifepristone and for levonorgestrel separately. Data were available for 6283 women in 10 mg mifepristone groups and 4098 women in levonorgestrel groups. One of these studies compared the two methods, namely a randomized, double-blind trial in which we also investigated a single dose of 1.5 mg of levonorgestrel. Both levonorgestrel and mifepristone are effective for emergency contraception and prevent a high percentage of pregnancies when used within a few days after coitus. Mifepristone is associated with later return of menses compared to levonorgestrel.

Levonorgestrel-only emergency contraception: real-world tolerance and efficacy.

Levonorgestrel-only emergency contraception was introduced onto the market in France in May 1999 on the heels of a large-scale clinical trial demonstrating its enhanced efficacy and tolerance over the combined estrogen-progestin reference method. To evaluate the product's real-world tolerance and efficacy in the more than 20 months that it has been on the market, a retrospective study was performed among large-scale prescribers in France. One hundred physicians were asked to complete a written questionnaire outlining their practices with regards to their prescription of the product as well as their knowledge and evaluation of the product's tolerance and efficacy. Results from 82 respondents representing over 2,000 administrations demonstrate that physicians judge levonorgestrel-only emergency contraception to be very well tolerated and without unexpected side effects. Further, respondents report a pregnancy rate similar to that chronicled in the large-scale clinical trial (less than 3%), thus substantiating conclusions regarding the product's considerable efficacy and its potential for reducing the rate of unintended pregnancies.

A possible mechanism of action of danazol and an ethinylestradiol/norgestrel combination used as postcoital contraceptive agents.

Twenty-seven women requesting postcoital contraception were randomly allocated to take an ethinylestradiol/dl-norgestrel combination or danazol. Urine specimens were assayed for luteinising hormone (LH) and pregnanediol-3-glucuronide (P3G) levels from the day of the postcoital treatment to the next period. In addition, the urine samples of these recruits and 12 additional women were assayed for the Beta-subunit of human chorionic gonadotropin (B-hCG). A consistent pattern of alteration in urinary steroids was lacking, indicating a heterogeneous effect on ovarian function. There was no evidence of early pregnancy in successfully treated cases. We suggest that the main mechanism of action of these drugs is at the endometrial level.

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.

Mifepristone: bioavailability, pharmacokinetics and use-effectiveness.

The potentiality of mifepristone as an abortifacient and contraceptive drug along with its pharmacokinetic parameters is reviewed. Mifepristone or RU486 acts as antagonist to progestational and glucocorticoid functions. It is an orally active compound with nearly 70% absorption rate but its bioavailability is reduced to around 40% because of the first-pass effect. Peak plasma concentrations of 1.9 +/- 0.8, 3.8 +/- 0.9 and 5.3 +/- 1.3 micromol/l are reached within 1-2 h after oral administration of 50, 200 and 600 mg mifepristone in women, respectively, and are maintained at relatively high level up to 48 or 72 h depending on the ingested dose. The plasma kinetics of mifepristone followed two-compartment open model with a mean alpha-half-life of 1.4h, volume of distribution 1.47 l/kg and beta-half-life of 20-30 h in most of the subjects studied. Clearance from the body was mainly through feces (83%). Biologically active mono-demethylated, di-demethylated and hydroxylated metabolites were found in plasma soon after oral administration of mifepristone. RU486 and its mono-demethylated metabolite bind to progesterone receptors with high affinity. Mifepristone-bound receptor dimers suppress transcription activation and thus, bring about anti-progestational activity that makes mifepristone a potential abortifacient and contraceptive agent. Clinical trials for termination of early pregnancy with 50-600 mg mifepristone plus a prostaglandin analogue achieved a success rate of 82-97%. However, abdominal pain, cramping, nausea, vomiting, bleeding and delay in onset of the next menstrual cycle were the side effects. Administration of 25 mg mifepristone twice 12h apart, as a post-coital contraceptive showed 100% contraceptive efficacy. A low dose of mifepristone which does not inhibit ovulation reduced fertility significantly by affecting endometrial milieu. These findings suggest that reduced dose(s) of mifepristone, 200 mg or less, may be used as a post-coital contraceptive and in combination with vaginal misoprostol for termination of early pregnancy with high efficacy and minimal or no side effects.

Collaborative research and development on mifepristone in China to reduce unwanted pregnancies and recourse to abortion.

A program proposed and executed by The Concept Foundation and funded by the Rockefeller Foundation demonstrates the feasibility of using private/public-sector collaboration for making mifepristone widely available. The application of mifepristone to emergency, luteal phase and menstrual induction contraception is being assessed in clinical research programs conducted in accordance with international standards for good clinical research. Opportunities for introduction of mifepristone in developing countries are being pursued using mifepristone produced in China in accordance with international standards of good manufacturing practice.

[Danazol: an alternative in postcoital contraception]. / Danazolo: un'alternativa nell'intercezione post-coitale.

Personal experience with postcoital contraception through the use of Danazol is reported.

PIP: During a 5 year period 62 patients requesting post coital contraception were give 2 doses of 200 mg danazol for 5 days after being informed of possible side effects and about the lack of experimental data on its effectiveness. All patients were advised to make notes about side effects, spotting, and the nature, quantity, and duration of menstrual flow, 35 of the women were nulliparae and 27 pluriparae aged 16 to 42, 52 had had unprotected sexual activity and 10 rupture of the condom that motivated them to seek contraception. Nausea occurred in 18, headache in 3, and mastodynia in 5 cases. 57 patients reported regular, 2 early, and 3 late menstruation. Hypomenorrhea occurred in 3 and menorrhagia in 9 cases. The administration of danazol took place between the 11th and 15th day of the menstrual cycle, but it proved ineffective in 1 case when the drug was given on the 20th day, however, this may have been attributable to previous unprotected sex. Danazol proved to be a good post-coital contraceptive with a high rate of efficacy and good tolerability. Treatment exceeding 5 days produced only a minor emotional tension in 4 patients.

Levonelle-2 for emergency contraception.

About 190,000 therapeutic terminations of pregnancy occur in the UK each year. Many of these could be prevented by the use of emergency contraception. We have previously discussed the use of combined hormonal emergency contraception. Now, a progestogen-only emergency contraceptive, levonorgestrel in the form of [symbol: see text]Levonelle-2 (Schering Health), has been licensed in the UK. The manufacturer claims that the treatment offers "unsurpassed efficacy in oral emergency contraception" with "significantly less nausea and vomiting than combined oral emergency contraception". We investigate these claims and discuss whether Levonelle-2 is an advance in emergency contraception.

Adolescent emergency contraception: attitudes and practices of certified nurse-midwives.

Teenage pregnancy has reached epidemic proportions in the United States with I million pregnancies and more than 500,000 live births occurring each year among women under the age of 20. The safety and efficacy of postcoital administration of oral contraceptives, commonly called "emergency contraception" (EC), have been well documented. However, EC is dramatically underused in the United States. Because low use of EC may be attributable, in part, to both lack of knowledge, as well as misinformation on the part of health care providers, further research in this area is warranted. Because midwives play a significant role in the provision of reproductive health care to adolescents, their attitudes about the use of EC among teens may impact the availability of emergency contraception options to these clients. This article presents results of a survey of certified nurse-midwives with respect to their attitudes, practices, and policies related to EC and provides recommendations specific to this provider population.

[Present and potential uses of mifepristone in gynecology, obstetrics and other medical specialties]. / Utilisations actuelles et potentielles de la mifépristone en gynécologie-obstétrique et dans les autres disciplines médicales.

Mifepristone, a derivative of norethindrone, a first generation synthetic progestative, has a very potent antiprogestative activity and to a lesser degree antiandrogenic and antiglucocorticoid activities. This action makes it potentially useful in the treatment of multiple hormone dependent diseases in obstetrics-gynecology as well as in a variety of medical specialties such as neurology, ophthalmology, and oncology. Nevertheless, the label of abortive pill has incited numerous ethical and political debates concerning the permission to market this drug, and this has contributed to the delay in the assessment of the potential indications of mifepristone. Largely under-utilized in practice despite its increasing theoretical benefit, clinical studies should now de conducted. Thus, based on an international review of literature during the last ten years, we have shed light on the present and potential indications of mifepristone in medical practice.

[RU 486: current and potential indications. Great expectations and strong resistance]. / RU 486: indications actuelles et potentielles. Riches promesses et vives résistances.

RU 486 is the code name for mifepristone, a 19-norsteroid first synthesized in 1980. Its chemical structure is similar to progesterone and progesterone derivatives. The difference lies in an 11 beta ring substitution which results in high affinity for progesterone and cortisol receptors. Once linked to the receptor, RU 486 temporarily blocks the action of the corresponding hormone. In vitro and in vivo, RU 486 has a powerful anti-progesterone and anti-glucocorticoid effect and a less powerful but nevertheless important anti-androgen effect. The essential clinical application for RU 486 involves its anti-progesterone effect, currently used in several indications including voluntary pregnancy termination and preparation for the prostaglandin action used to induce labour in interrupted pregnancies. Potential indications have been suggested for preparing the cervix for endo-uterine manoeuvres, induction of labour in term pregnancy and contraception. Other potential indications in gynaecology include breast cancer, endometriosis and uterine fibroma. Meningioma and Cushing's syndrome would be further indications. How far will we go with RU 486? All will depend on the social and economic resistance to the drug and to an even greater extent on ethical considerations. The strength of the anti-RU 486 lobby may well dampen the development of non-contraception indications for this effective anti-progesterone agent.

[A randomized, double-blind, multicentre study on comparing levonorgestrel and mifepristone for emergency contraception].

OBJECTIVE: To compare the efficacy, side effects and the effect on next menstruation of levonorgestrel(LNG) to low dose mifepristone in emergency contraception. METHODS: The study is a randomized double-blind multicenter comparative trial. The clients who have unprotected intercourse within 72 hours were allocated to one of the two study groups. In LNG group, 0.75 mg LNG was taken twice with 12 hours apart. In mifepristone (Mife-) group, single dose of 10 mg mifepristone was taken and a placebo 12 hours after. Follow-up visit was paid on the seventh day of the expected next menstruation to evaluate the contraceptive efficacy and to record side effects and menstruation. Contraceptive efficacy was calculated by Dixon's method. RESULTS: The total valid subjects in LNG and Mife- group were 643 and 633, respectively. There were 20 and 9 pregnancies occurred respectively in each group. The failure rate was 3.1% and 1.4%. Contraceptive efficacy rate of preventing pregnancy was 59.2% and 79.7%, the difference was statistically significant (P < 0.05). The incidence of various side effects was less than 10.0% which were mild. There was no statistically difference between the two groups. The percentage of subjects who had their next menstruation before or after their expected menstruation 3 days in LNG group and Mife- group was 77.7% and 78.5% respectively. The menstrual period less than 7 days was 95.0% and 93.3%. CONCLUSION: Use of levonorgestrel or low dose mifepristone for emergency contraception is effective and safe.