Feminist group plans "economic pressure campaign" for access to RU 486.

PIP: A grant for $10 million has boosted the efforts of the Feminist majority Foundation, a Boston activist group committed to bringing RU-486 into the US. The group is planning to research the corporate structure of Hoechst, A.G., the owner of Roussel-Uclaf, and that of its US subsidiary Hoechst Celanese Corporation of Somerville, NJ. Ultimate strategies may include a boycott of Hoechst products in the US, formation of a consortium of small pharmaceutical companies, or of a feminist pharmaceutical firm to research and develop RU-486 or other antiprogestins for the US. The Hoechst Company denies any connection to Roussel-Uclaf. Meanwhile, US researchers have organized in some states to encourage research on the drug, and a bill has been introduced to force the US Food and Drug Administration to lift its ban on importation. An opposition bill to ban importation of RU-486 for any purpose including research has also been introduced by right-to-life forces. New research is underway to test the antineoplastic effects of RU-486 on breast cancer in Canada, and on meningioma in California.^ieng

Contragestion with late luteal administration of RU 486 (Mifepristone).

The efficacy and tolerance of RU 486 prescribed as a late luteal contragestive agent have been evaluated in 139 women at risk of pregnancy. They were given 400 or 600 mg of RU 486 once on the day before the expected menses. Among these women, 48 (34.5%) were pregnant (positive plasma beta-human chorionic gonadotropin, [beta-hCG]) at the time of RU 486 intake. Bleeding occurred in all but six women. An ongoing pregnancy after treatment was found in nine cases (failure rate, 9/48, 18.8%), which was subsequently terminated by surgical procedure in all cases. There was no disturbance in the menstrual cycle, and the tolerance was very satisfactory. In conclusion, this method is acceptable for women at risk of pregnancy in whom other usual postcoital contraceptive methods cannot be prescribed.

PIP: 139 women at risk pregnancy (due to unprotected sexual intercourse) participated in a multicenter assessment of the efficacy and tolerability of RU 486 prescribed as a late luteal contragestive agent. 24 women received 400 mg of RU 486 and the remaining 115 women received 600 mg on the day before the expected menses. 48 women (35%) were found to be pregnant (positive plasma beta-human chorionic gonadotropin) at the time of RU 486 intake. An ongoing pregnancy after RU 486 treatment was found in 9 cases (failure rate, 19%). Bleeding occurred in all but 6 women, 1 of whom was pregnant. The duration of bleeding was 4.6 + or - 2.9 days in pregnant women and 3.8 + or - 1.2 days in nonpregnant women. A posttreatment menstrual period occurred 31.8 + or - 6.2 days after the onset of RU 486-induced bleeding in pregnant women and 30.0 + or - 5.3 days afterwards in nonpregnant women. Few side effects were reported (asthenia, pelvic pain, headache, mailase, and dizziness), and none required specific measures. These results indicate that, when it is too late for postcoital contragestive methods and too early for vacuum aspiration abortion, RU 486 constitutes a technique with at least as much effectiveness as high-dose estrogen therapy and fewer side effects and disturbances in the menstrual cycle. However, since the success rate is only 80%, it is essential to schedule a posttreatment visit to identify women with ongoing pregnancies or incomplete uterine evacuation.

A study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of second trimester pregnancy.

It is well established that abortion can be induced successfully in midtrimester of pregnancy by gemeprost vaginal pessaries. A randomised study was carried out to determine the efficacy of mifepristone and dilapan in combination with gemeprost for second trimester termination between 12-18 weeks' gestation. A contemporary group of women treated with gemeprost alone was used as a control group. A single course of 4 x 1 mg gemeprost pessaries was administered every six hours. If abortion had not occurred after 24 hours, a further course of 5 x 1 mg pessaries was administered every three hours over the next 24 hours. In the first twenty hours after administration of gemeprost, 95%, 85% and 72% of women aborted in the mifepristone, dilapan and the control group, respectively. The median induction-abortion interval in the mifepristone group (6.6h) was significantly shorter than the other two groups and fewer pessaries were required to induce abortion. The incidence of diarrhoea and vomiting was lower in the mifepristone than the other two study groups. This study demonstrated the efficacy of mifepristone in combination with gemeprost and this regimen is associated with fewer gastrointestinal side effects.

PIP: The results of a comparative study suggest that a combination of mifepristone and gemeprost is a safe, effective regimen for the termination of second-trimester pregnancy. 98 women who presented for second-trimester abortion at an Edinburgh family planning clinic were included in the study and randomly allocated to 1 of 3 groups: I--58 controls who were treated with gemeprost alone, II--20 women pretreated with gemeprost and dilapan, and III--20 patients pretreated with an oral dose of 200 mg of RU-486 and gemeprost. In all 3 groups, gemeprost pessaries were inserted every 6 hours and, if abortion had not occurred by 24 hours, every 3 hours over the next 24 hours. In the first 24 hours after gemeprost administration, 72% of controls, 85% of women in Group II, and 95% of those in Group III had aborted. The median induction-abortion interval was 6.6 hours in the gemeprost-RU-486 group. The lower dose of both these agents required to effect abortion meant there were fewer side effects (vomiting and diarrhea) in Group III. Although pretreatment with dilapan produced a median cervical dilatation of 9.5 mm, there was no significant difference in the induction-abortion interval between Groups I and II. This finding suggests that it is the increased sensitivity of the myometrium to prostaglandin after RU-486 administration that accelerated abortion in women in Group III rather than an effect on cervical dilatation. Additional research is needed to determine the optimal RU-486 and gemeprost dosages for midtrimester abortions.

Abortion.

In 1990 abortion literature was characterized by articles relating to 1) the safety of surgical abortion procedures, 2) advances in knowledge and experience with medical abortifacients such as mifepristone (RU 486), and 3) reviews of psychologic and ethical considerations. Although technical methods differ greatly between countries and continents, there is increasing similarity between termination protocols in the United States, the United Kingdom, and Europe. The advent of mifepristone will make this even more so. Surgically, although dilatation and evacuation procedures are far more common in the United States than in other countries, the literature reflects a fine-tuning of analysis and technique, with safety the major consideration. Knowledge about the effectiveness of mifepristone continues to grow, and the effective dose for early first-trimester termination appears established. There is increasing evidence that at least in the short term, the negative psychologic sequelae of abortion are infrequent and are inconsequential as a public health issue.

PIP: The recent literature on abortion reflects a refinement of technique and an increased concern with safety. Safety is an especially important concern in developing countries, where abortion-related deaths account for 40-90% of maternal mortality. Dilatation and evacuation has become the method of choice for terminations up to 18 weeks of gestation. The major safety concern associated with this technique is uterine perforation. Preoperative preparation of the cervix with an osmotic or pharmacologic agent is recommended to reduce this risk and sufficient time should be allowed for cervical ripening to reduce the need for mechanical dilatation. Much current research is centered on the use of mifepristone as a cervical ripening method or abortifacient agent. An appropriate dose of mifepristone at an appropriate gestational age in combination with a prostaglandin is an effective means of early pregnancy termination, but the type and dosage of the prostaglandin require further definition. In developing countries, where prostaglandins are costly or unavailable, ethacridine should be investigated as an alternative to mifepristone. The major disadvantage of this agent is the time required to achieve fetal expulsion. Other areas under research include the management of cases in which fertility-enhancing procedures result in a multifetal pregnancy and the value of routine histologic examination of aborted fetal tissue. Finally, studies on the psychological sequelae of induced abortion suggest that social support, especially from the male partner, is the critical factor in outcome.

The antiprogesterone steroid, RU 486 (mifepristone).

RU 486 (Mifepristone) represents a major development in the field of hormone antagonists as the first effective antiprogestogen. A number of therapeutic roles for the drug are envisaged. It is already being used extensively around the world for the procurement of first trimester abortion--particularly in combination with prostaglandins. It also has been shown to be effective as a cervical ripening agent and for the induction of labour. Initial human studies have involved nonviable pregnancies and more work is needed in animal models before the drug can be deemed safe for use in viable human pregnancies in the third trimester.

PIP: RU 486, developed from norethisterone by Roussel Manufacturers, represents the first effective antiprogestogen. Although RU 486 binds strongly to the progesterone receptor, it inhibits progestogenic effects, making this a receptor blocking drug. When administered in the late follicular phase of the menstrual cycle, RU 486 has been shown to delay ovulation. In the first half of the luteal phase, RU 486 destroys the corpus luteum. If luteolysis occurs, RU 486 administration is followed by a single bleeding episode; in the absence of luteolysis, a second bleeding episode occurs several days later in conjunction with the disappearance of the corpus luteum. No clinical use has been found for RU 486's ability to delay ovulation, and luteal phase administration of RU 486 is not yet an effective means of menstrual induction. RU 486 has been most successfully used to induce early abortion, either alone or in combination with a prostaglandin. In most recent study of RU 486, involving 75 women, complete abortion was achieved in 95% of cases. Animal studies have found RU 486 to be effective as a cervical ripening agent and in the induction of labor. They further suggest that the drug can accelerate lactation, prevent breast cancer proliferation, minimize the need for salpingectomy in ectopic pregnancy, and treat Cushing syndrome and glaucoma. To date, there has been no evidence of any teratogenic or antiglucocorticoid side effects. However, more research is needed to confirm the safety of RU 486 for use in viable human pregnancies.

Mifepristone: antineoplastic studies.

PIP: Emerging research suggests that mifepristone may have significant clinical applications in the treatment of certain neoplastic disorders. For example, in vitro studies have shown that RU-486 can inhibit or stimulate--depending on the cell line and the hormonal milieu of the culture medium--the growth of breast cancer cells. In hormone-sensitive breast cancer, anti-tumor activity is maximized by treatment with a combination of RU-486 and estrogen antagonists such as tamoxifen or luteinizing hormone releasing hormone analogues. The few studies of RU-486 administration in women with advanced breast cancer that had failed to respond to tamoxifen have demonstrated short-term disease stabilization (e.g., 5-10 months). This research has suggested that progesterone receptors are necessary but not sufficient for anti-tumor responses. Also promising, although untested in a large-scale study, is use of RU-486 in women with progressive recurrent and/or unresectable benign meningiomas. In addition, RU-486 has inhibited hormone-insensitive human prostate cancer cell lines grown in vitro and in nude mice xenografts.^ieng

Mifepristone: treatment of Cushing's syndrome.

Mifepristone is a potent antagonist of glucocorticoid and progesterone receptors. It is the only drug administered to humans with these actions. Exploration of mifepristone in the treatment of Cushing's syndrome is in its infancy. The cases reviewed in this report comprise the entire medical literature. Development and availability of mifepristone has been severely restricted because of controversy surrounding its ability to function as an "abortion pill." As the political controversy abates, increasing studies of this drug may be anticipated in patients with glucocorticoid excess. Although the authors have highlighted therapeutic trials with the drug, they also note that diagnostic uses in cases of glucocorticoid excess may be of interest. Some cases of endogenous Cushing's syndrome are difficult to diagnosis and a glucocorticoid antagonist may be as useful as a glucocorticoid agonist (such as dexamethasone) in the dynamic evaluation of glandular function. In particular, mifepristone might be useful in distinguishing pituitary from occult ectopic ACTH-secreting tumors. One of the primary problems surrounding the use of mifepristone in cases of Cushing's syndrome is the long half-life of the drug and the necessity to titrate doses carefully in a manner that avoids signs and symptoms of glucocorticoid deficiency. Biochemical markers reflecting the "glucocorticoid status" of a patient would be useful for dose adjustment and monitoring and would improve the risk to benefit ratio for mifepristone treatment of Cushing's syndrome.

PIP: As a potent antagonist of glucocorticoid and progesterone receptors, mifepristone (RU-486) has potential use in the treatment of Cushing's syndrome. Initial research in this area has demonstrated that RU-486 acts as an anti-glucocorticoid by antagonizing the negative feedback on the pituitary of endogenous and exogenous glucocorticoids. Since 1985, the literature has reported four studies of the feasibility of RU-486 treatment in Cushing's syndrome patients. In the largest of these studies, 11 patients with inoperable adrenal cancer or ectopic adrenocorticotrophic hormone-secreting neoplasms received 5-22 mg/kg/day of RU-486 for 1-12 months. In seven of these patients, treatment resulted in marked improvement in the Cushingoid phenotype, psychiatric status, hypertension, and carbohydrate intolerance. Three patients discontinued RU-486 because of clinical manifestations of adrenal insufficiency. The most common side effect was nausea. Titration of RU-486 dosing remains imprecise due to the lack of an acceptable rapid biochemical measurement to monitor glucocorticoid action. Regrettably, further research in this area has been hindered by the political controversy regarding RU-486's use as an abortifacient agent.

Effect of mifepristone on dilatation of the pregnant and non-pregnant cervix.

The effect of the progesterone antagonist mifepristone on the cervix was investigated in two randomised double-blind placebo-controlled trials, the first in 30 women undergoing first trimester surgical termination of pregnancy and the second in 30 non-pregnant premenopausal women. 600 mg mifepristone, given orally 48 h before surgery, increased the mean preoperative cervical dilatation in both pregnant and non-pregnant treatment groups and also reduced the force required to dilate the pregnant and non-pregnant cervix.

PIP: Mifepristone (RU-486) has theoretical potential as a softening agent on the pregnant and nonpregnant cervix. Its potential uses include dilatation and softening of the pregnant cervix before abortion and, outside of pregnancy, reducing the discomfort involved in IUD insertion, endometrial sampling, and hysteroscopy. To further investigate the effectiveness of RU-486, 30 women requesting 1st-trimester pregnancy termination were matched with 30 nonpregnant women scheduled to undergo either cervical dilation and diagnostic curettage or laparoscopic sterilization. Women in both groups were randomly allocated to receive either 600 mg of oral RU-486 or a placebo. The force required to dilate both pregnant and nonpregnant cervixes up to 8 mm was significantly lower (p 0.001) in the mifepristone recipients. Only 27% of the RU- 486-treated pregnant women required any surgical dilatation for their abortion compared to 80% of abortion patients who received a placebo. In addition, mean blood loss during abortion was lower in RU-486-tested subjects than in placebo control; among the nonpregnant dilatation and curettage patients, however, there was no difference in blood loss. No adverse effects were recorded among women who received RU-486 in the 2 hour observation period after drug administration. In terms of its mechanism of action, it is possible that mifepristone increases the active estrogen-progesterone ratio at the receptor level. Despite clarity about this process, more widespread use of RU-486 is recommended in both pregnant and nonpregnant women to reduce the risk of cervical trauma.

The clinical use of RU 486 (Mefipristone).

PIP: RU-486, which has proven efficacy as an abortifacient in early pregnancy and potential as a contraceptive or contragestive, represents one of the most promising new approaches to population control. Clinical trials have demonstrated that 60-85% of women with pregnancies of 8 weeks' duration or less will experience complete abortion after a single dose of 6000 mg/os of RU-486 and a further 10-20% will in addition require surgical intervention. These rates are improved significantly by the addition of a small single dose of a synthetic prostaglandin. No side effects directly attributable to the antiprogesterone have been reported, and bleeding in RU-486-induced abortions is comparable to that after vacuum aspiration. Other applications in pregnancy include the induction of labor at or near term in cases of intrauterine death and termination of 2nd-trimester pregnancies in combination with oxytocic agents. When RU-486 is administered during the follicular development phase of the menstrual cycle, ovulation is delayed for several days. Administration shortly after ovulation inhibits corpus luteum formation. Careful timing of RU-486 treatment is essential to gain an effective luteolytic effect, and more study is need to understand the reduced effectiveness of RU-486 as a menstrual inducer in the presence of human chorionic gonadotropin. In short, RU-486 has immense potential, but many unanswered questions remain regarding its mechanism of action during pregnancy and the various phases of the menstrual cycle.^ieng

Antiprogesterones.

PIP: 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.^ieng

RU 486 approved in Britain; U.S. research still limited.

PIP: RU-486 has been used as an alternative to surgical abortion in France, it has recently been approved for use in Britain. There is still a ban in the US on the importation of RU-486 even for medical research. Technically the US has not banned RU-486, it is just that no one has yet to apply to the FDA for new product approval. RU-486 promises to have many benefits beyond being a safe alternative to surgical abortion. It is theorized to be a possible treatment for breast cancer, endometriosis and other reproductive health concerns. It can be used to terminate pregnancies up to the 9th week and over 80,000 French women have used it as such. Its manufacturer, Roussel-Uclaf is planning to apply for approval in Scandinavia next, but is very unlikely to try to bring it to the US because of strong anti-abortion sentiment. RU-486 has proven to be 95% effective, when used in conjunction with prostaglandins, in inducing abortion. RU-486 could also be used as a once a month pill or as a post-coital contraceptive. The anti-abortion advocates in the US plan to apply a great deal of pressure if any one tries to bring RU-486 into the country, even if it is done so for reasons other than abortion.^ieng

Delayed endometrial maturation induced by daily administration of the antiprogestin RU 486: a potential new contraceptive strategy.

OBJECTIVE: Our objective was to determine if a progesterone antagonist might interdict the development of a secretory endometrium. STUDY DESIGN: Eleven normally cycling women not at risk for pregnancy received RU 486 (1 mg/day orally) or placebo throughout one menstrual cycle in a randomized, double-blind, crossover fashion. Estradiol, progesterone, and placental protein 14 were measured every 3 days; luteinizing hormone was measured until the midcycle surge was detected. An endometrial biopsy was performed on luteal phase day 7 to 9 and interpreted with Noyes' criteria. Differences between treatment groups were analyzed by the Student t test. RESULTS: RU 486 delayed ovulation, retarded endometrial maturation, and reduced peak levels of placental protein 14 without affecting gonadal steroid production. The abnormalities in endometrial morphology and function are similar to those seen in infertile women with luteal phase defects. CONCLUSION: We hypothesize that this regimen of antiprogestin administration may prevent implantation and offer a novel strategy for fertility control.

PIP: A small clinical study has provided preliminary evidence that a daily dose of 1 mg of RU-486 produces disruption of the morphology and function of the endometrium while preserving steroidogenesis, ovulation, and timing of the cycle. Enrolled in the study were 11 nonpregnant volunteers with regular menstrual cycles who received either RU-486 or a placebo during 2 treatment cycles in a randomized, crossover fashion. RU-486 delayed the midcycle luteinizing hormone surge and prolonged the follicular phase by 1-11 days in the 9 subjects included in the final analysis but did not alter the duration of the luteal phase. The mean length of the entire cycle increased an average of 6 days in RU-486 recipients. RU-486 also caused follicular phase estradiol and luteal phase progesterone concentrations to peak later compared with the placebo group. 6 of the 10 women who ovulated during RU-486 administration had delayed endometrial morphologic characteristics; another exhibited dyssynchrony between glandular and stromal tissue. Additional evidence for the antiprogestin effect of RU-486 on the endometrium was provided by finding of significantly lower peak placental protein 14 concentrations in treated subjects. RU-486 produced no effect on premenstrual symptoms, libido, dysmenorrhea, electrolytes, liver and renal functions, and cell blood counts. The potential of a small daily dose of a progesterone antagonist such as RU-486 as a fertility control agent merits further study.

RU486 (mifepristone): mechanisms of action and clinical uses.

RU486 (mifepristone) has proved to be a remarkably active antiprogesterone and antiglucocorticosteroid agent in human beings. The mechanism of action involves the intracellular receptors of the antagonized hormones (progesterone and glucocorticosteroids). At the molecular level, the most important features are high binding affinity to the receptor, interaction of the phenylaminodimethyl group in the 11 beta-position with a specific region of the receptor binding pocket, and RU486-induced transconformation differences in the ligand-binding domain. These particularities have consequences at different steps of the receptor function as compared with agonists. However, the reasoning cannot be limited to the RU486-receptor interaction, and, for instance, there is the possibility of a switch from antagonistic property to agonist activity, depending on the intervention of other signaling pathways. It would be desirable to have derivatives with only one of the two antagonistic properties (antiprogestin, antiglucocorticosteroid) in spite of similarities between steroid structures, receptors involved, and responsive machineries in target cells. Clinically, the RU486-plus-prostaglandin method is ready to be used on a large scale and is close to being as convenient and safe as any medical method of abortion may be. The early use of RU486 as a contragestive as soon as a woman fears a pregnancy she does not want will help to defuse the abortion issue. Research should now be conducted to define an efficient and convenient contraceptive method with RU486 or other antiprogestins. The usefulness of RU486 for obstetric indications, including facilitation of difficult delivery, has to be assessed rapidly. Gynecologic trials, particularly in leiomyomata, should be systemically continued. The very preliminary results obtained with tumors, including breast cancers, indicate that further studies are necessary.

Unsuccessful treatment of missed abortion with a combination of an antiprogesterone and a prostaglandin E1 analogue.

In a prospective clinical trial the effectiveness of a combination of 400 mg of mifepristone (antiprogesterone) and 400 g misoprostol (synthetic prostaglandin E1 analogue), both taken orally, was evaluated for the treatment of missed abortion. Of the 31 patients included, 16 (52%) had an empty uterine cavity at follow up six days after inclusion, 11 (35%) required surgical evacuation for retained intrauterine products of conception found at follow up, and four (13%) required emergency surgical evacuation due to severe pain or bleeding. The results do not support the use of mifepristone and misoprostol for women wishing the miscarriage to be resolved quickly.

PIP: A prospective clinical trial involving 31 Swedish women failed to demonstrate the effectiveness of a combination of 400 mg of mifepristone and 400 g of misoprostol for the treatment of missed spontaneous abortion. Transvaginal ultrasound examination showed intrauterine products of conception with an antero-posterior diameter of 15-50 mm in all study participants. 6 days after treatment, only 16 women (52%) had an empty uterine cavity. Surgical evacuation was required in the remaining 15 women, 11 because of retained products of conception (mean diameter, 26.7 mm). An additional 4 women underwent emergency surgical evacuation due to severe pain or bleeding. Women who successfully aborted after treatment had a significantly greater number of prior pregnancies than women who failed to abort. There were no differences between groups, however, in gestational length, size of the pregnancy products, or serum levels of human chorionic gonadotropin and progesterone. These results do not support the use of mifepristone and misoprostol for pharmacologic treatment in women who want their spontaneous abortions to be resolved quickly.

Round table on RU486.

PIP: As a non-invasive means of early abortion, RU-486 has the potential to increase women's reproductive options; at the same time, the "abortion pill" has stimulated debate about the ethics and safety of new medical technologies. When combined with a prostaglandin (PG), the success rate for RU-486 is 96% for pregnancies of up to 9 weeks' gestation. In France, over 120,000 women have used RU-486/PG to terminate pregnancy, and this regimen is now used in about 25% of abortions. Clinical trials of RU-486 are underway in Cuba, China, India, Singapore, and Zambia. The Program for Appropriate Technology has identified four considerations for introducing RU-486 to developing countries: whether abortion or menstrual regulation is legal; whether women find the method acceptable and can comply with the multiple visit treatment regimen; whether the health infrastructure can support safe method use, including prevention of misuse and provision of appropriate medical backup personnel and facilities; and whether the cost of the regimen is affordable to individuals and/or programs --conditions unlikely to be met in most such countries. Ideal would be development of a medical abortifacient that is single dose and the lowest possible dose of each drug, provokes miscarriage within a more predictable time frame with less acute and prolonged bleeding, is safe and effective beyond two months, has minimal side effects, and maximizes short-term safety and minimizes long-term effects. Technological advances are being undermined, however, by political and religious attacks on the method. Even some feminists have expressed concerns about potential long-term effects of RU-486 use.^ieng

RU486: pharmacology and potential use in the treatment of endometriosis and leiomyomata uteri.

More than a decade after the serendipidous discovery of RU486, numerous antiprogestins have been synthesized and studied. Interest in how antiprogestins exert their antagonist effect has led to novel information about the molecular mechanisms of progesterone action. The pivotal role that progesterone plays in reproductive biology has led to research in many areas where a potential role for these compounds may be found in health and disease. RU486 has been shown to relieve pelvic pain associated with endometriosis and to decrease American Fertility Society endometriosis scores. Uterine leiomyomata show a significant reduction in size after administration of RU486 for 3 months. Although much research remains to be carried out, RU486 appears promising as alternative therapies for these diseases.

PIP: More than a decade after the discovery of RU-486, numerous antiprogestins have been synthesized. Interest in the antagonist effect of antiprogestins has revealed novel information about the molecular mechanisms of progesterone action owing to the pivotal role that progesterone plays in reproductive biology. RU-486 side effects include hot flashes and transient increases in liver transaminases. Generalized cystic changes in the endometrium have been demonstrated consistent with a chronic unopposed estrogen effect. RU-486 has been shown to relieve pelvic pain associated with endometriosis and to decrease American Fertility Society endometriosis scores. Since uterine leiomyomas appear to be ovarian steroid dependent, it was attempted to reduce the growth of uterine fibroids by using low-dose (50 mg/day or approximately 1 mg/kg/day) RU-486 for 3 months in 10 patients. 10 patients were studied at a 25 mg daily dose for 3 months and 7 patients received 5 mg daily for the same length of time. Additionally, leiomyomata and myometrium of 5 patients treated with 50 mg daily of RU-486 and 5 untreated patients in the follicular phase of the cycle were examined immunohistochemically using antibodies recognizing estrogen receptor protein and progesterone receptor protein. Myoma size decreased approximately 22% at 4 weeks, 39% at 8 weeks, and 40% at 12 weeks. It has been shown, for the first time, that an antiprogesterone which induces acyclicity also induces a decrease in size of leiomyomata. Additionally, a small randomized study attests to the probable efficacy of RU-486 in the treatment of leiomyomata. This decrease in size is seen in the face of follicular phase levels of estrogen, and data suggest that the decrease may be mediated through its antiprogestin properties. RU-486 appears promising as a safe and well-tolerated alternative therapy for these diseases. Further investigation of the endometrial effects of RU-486 must be conducted if RU-486 is to be used for longer than 3-6 months.

Hormonal contraception.

PIP: When used correctly, hormonal contraception--oral contraceptives (OCs), injectable progestins, and subdermal implants, in particular--can offer the most effective reversible method of pregnancy prevention available. The availability of OCs with lower hormonal dosages and more careful screening of OC acceptors have apparently eliminated the increased risk of vascular disease documented among OC users in the 1970s. Lower-dose OCs also have a lesser adverse effect on lipids and glucose metabolism. In fact, use of low-dose OCs may have a beneficial impact from the standpoint of lipid changes. The association between OC use and breast cancer remains unresolved, although recent studies suggest that the apparently increased risk among women 20-44 years of age is followed by a decreased risk among nulliparous women 45-54 years old. The reduced androgenic potency of 3 new progestins--gestodene, desogestrel, and norgestimate--is expected to increase further the safety of OC use and reduce side effects such as withdrawal bleeding. The most important recent development in the field of hormonal contraception has been the use of antiprogesterones such as RU-486. These agents not only have numerous therapeutic uses (e.g., as abortifacients or inhibitors of ovulation), but also offer insight into the mechanisms of steroid hormone action. Less productive has been research into steroidal contraception for men, although early trials of weekly injections with long-acting androgens have produced promising results.^ieng

The placental transfer of mifepristone (RU 486) during the second trimester and its influence upon maternal and fetal steroid concentrations.

A double-blind, placebo-controlled study has assessed the maternal and fetal endocrine effects of the maternal administration of the anti-progestin mifepristone in mid-pregnancy. There were six women in each group. Four hours after oral administration of 600 mg mifepristone, the drug was detected in both maternal and fetal circulations and in the amniotic fluid. No significant changes in progesterone, cortisol, oestradiol, or aldosterone concentrations were detected in the maternal circulation after treatment with mifepristone or placebo. In women treated with mifepristone, the mean fetal aldosterone level was 1699 (SD 217) pmol/l which was significantly higher than the mean level of 999 (SD 84) pmol/l in the control group but no significant changes occurred in the fetal progesterone, oestradiol or cortisol concentrations. The significance of these results is discussed in relation to the possible therapeutic uses of mifepristone for inducing labour.

PIP: The effects of RU 486, a competitive progesterone receptor antagonist, on maternal and fetal steroid concentrations were investigated in a double-blind study of 12 women in the 16th-19th weeks of pregnancy. The 6 study subjects received 600 mg of oral RU 486 on the day of abortion induction, while 6 controls received a placebo tablet. RU 486 was detected in maternal and fetal circulations and amniotic fluid 4 hours after administration to the 6 subjects, indicating that RU 486 and its metabolite, RU 42,6333, rapidly cross the placenta. There were no significant differences between cases and controls in terms of maternal progesterone, cortisol, estradiol, or aldosterone concentrations. In addition, fetal progesterone, estradiol, and cortisol concentrations did not differ between the RU 486 and placebo groups; however, fetal aldosterone levels were significantly higher in the treatment group (mean, 1699 pmol/l) than in controls (mean, 999 pmol/l). It is not known whether this unexpected f inding reflects the action of RU 486 blocking fetal mineralocorticoid receptors or was attributable to chance. Although more research is needed on the fetal endocrine effects of mifepristone, it appears that RU 486 has substantial potential for inducing labor in 2nd trimester abortion without serious drug-related side effects.

Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU 486).

OBJECTIVE: We have previously shown that treatment with mifepristone, 50 to 100 mg daily, results in amenorrhea, anovulation, and symptomatic improvement in women with endometriosis. In this study we lowered the dose to 5 mg daily to determine whether clinical efficacy is altered without other adverse actions. STUDY DESIGN: After a baseline cycle, seven women with endometriosis were given mifepristone, 5 mg daily, for 6 months. Daily symptom inventories were recorded. Laparoscopy was performed during the sixth month of therapy. RESULTS: Pelvic pain improved in six of seven patients. Cyclic bleeding ceased in all patients, but four of the seven patients complained of irregular bleeding. Surgical staging at the conclusion of the study (five of seven patients) did not detect a change in endometriosis. CONCLUSIONS: Mifepristone, 5 mg daily, resulted in symptomatic improvement, but did not stabilize the endometrium. From our experience with three doses of mifepristone, we would recommend a dose of 50 mg be used for continued investigations.

PIP: The authors' previous research has demonstrated that treatment with 50-100 mg/day of mifepristone produces symptomatic improvement of endometriosis. The present study assessed the efficacy of a substantially reduced antiprogesterone dose. After a baseline cycle, 7 US women with pelvic pain caused by endometriosis were administered 5 mg of mifepristone daily for 6 months. Clinical responsiveness was evaluated in daily symptom inventories completed by study participants. Pelvic pain improved significantly within 1 month of treatment initiation in 6 of 7 patients. Cyclic bleeding ceased in all 7 patients, but 4 women complained of irregular bleeding that begin 3-5 months into treatment. Menstrual cyclicity returned 23-37 days after study completion. 2 women did not complete the study--1 because of continued pelvic pain and 1 because of heavy bleeding during the fifth cycle. Surgical staging through laparoscopy in the 5 remaining women failed to document a significant change in endometriosis. 1 woman had a slight increase in endometriosis score compared to baseline, 1 had no change, and the remaining 3 women showed decreases from 32-45%. Given the failure of the 5 mg dose to stabilize the endometrium and the high rate of uterine bleeding, a dose of 50 mg of mifepristone is recommended for future investigations.

Mifepristone: clinical application in general gynecology.

PIP: RU-486, the first clinically available antiprogestin, has numerous gynecologic applications beyond first-trimester pregnancy termination. Long-term administration of 2 mg/day of RU-486 suppresses ovulation while maintaining serum estrogen levels and ovarian follicular activity. In the endometrium, long-term RU-486 administration results in significant endometrial dysynchrony and stromal compaction. RU-486 has been demonstrated to relieve pain in women with symptomatic endometriosis and decrease the size of uterine leiomyomata by about 50%. There are preliminary findings indicating that RU-486 is effective in the treatment of premenstrual syndrome, ectopic pregnancy, and anovulatory uterine bleeding. In need of further investigation is the RU-486 dosage that can treat pathophysiologic states while minimizing the endometrial effects.^ieng