Molecular determinants of the recognition of ulipristal acetate by oxo-steroid receptors.

The human progesterone receptor (PR) plays a key role in reproductive function in women. PR antagonists have numerous applications in female health care including regular and emergency contraception, and treatment of hormone-related pathological conditions such as breast cancer, endometriosis, and leiomyoma. The main factor limiting their long-term administration is the fact that they cross-bind to other oxo-steroid receptors. Ulipristal acetate (UPA), a highly potent PR antagonist, has recently come onto the market and is much more selective for PR than the other oxo-steroid receptors (androgen, AR, glucocorticoid, GR, and mineralocorticoid, MR receptors) and, remarkably, it displays lower GR-inactivating potency than RU486. We adopted a structural approach to characterizing the binding of UPA to the oxo-steroid receptors at the molecular level. We solved the X-ray crystal structure of the ligand-binding domain (LBD) of the human PR complexed with UPA and a peptide from the transcriptional corepressor SMRT. We used the X-ray crystal structure of the GR in its antagonist conformation to dock UPA within its ligand-binding cavity. Finally, we generated three-dimensional models of the LBD of androgen and mineralocorticoid receptors (AR and MR) in an antagonist conformation and docked UPA within them. Comparing the structures revealed that the network of stabilizing contacts between the UPA C11 aryl group and the LBD is responsible for its high PR antagonist potency. It also showed that it is the inability of UPA to contact Gln642 in GR that explains why it has lower potency in inactivating GR than RU486. Finally, we found that the binding pockets of AR and MR are too small to accommodate UPA, and allowed us to propose that the extremely low sensitivity of MR to UPA is due to inappropriate interactions with the C11 substituent. All these findings open new avenues for designing new PR antagonist compounds displaying greater selectivity.

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.

The pharmacokinetics of 750 microg levonorgestrel following administration of one single dose or two doses at 12- or 24-h interval.

The administration of two tablets of 750 microg levonorgestrel at a 12- to 24-h interval has been shown to be a safe and effective means of emergency contraception, and Norlevo/Vikela (N/V) is a dedicated product for this indication. The aim of this study was to characterize the plasma pharmacokinetics of levonorgestrel following a single N/V tablet administration and following a second administration, 12 or 24 h after the first one in young, healthy, female volunteers under the same conditions as during clinical use. This was an open, observer-blind, randomized study with three parallel groups and three treatments performed in 24 white female volunteers randomized into three groups of eight participants, each receiving one of the following treatments: Group A, one tablet of 750 microg levonorgestrel at time -12 h and one tablet at time 0; Group B, one tablet of 750 microg levonorgestrel at time 0; Group C, one tablet of 750 microg levonorgestrel at time -24 h and one tablet at time 0. All treatments started between Day 2 and Day 6 of the menstrual cycle. Plasma levonorgestrel levels were measured at regular intervals from time 0 up to 36 h with a validated radioimmunoassay. The results of this study show that after either one single or two administrations of a tablet containing 750 microg levonorgestrel, levonorgestrel is rapidly absorbed. The absorption, distribution, and elimination profiles of levonorgestrel following the three different treatments were similar. It also indicates that 12 or 24 h after administration there remains a significant level of plasma levonorgestrel. In conclusion, this study reinforces clinical guidelines recommending that N/V tablets for emergency contraception be administered 12 to 24 h apart because levonorgestrel is present in plasma between the two administrations.

The development of mifepristone: a pharmaceutical drama in three acts.

This paper reviews the various steps in development of mifepristone in Europe and in the United States. It is a personal account by the person who was in charge of its worldwide development and has participated in all the major decisions on the product. This paper presents a personal perspective on the development of mifepristone, explaining why this revolutionary medication is still not available in most of the world, including the United States. Briefly, the author's close and continuous involvement with the medical, regulatory, and commercial aspects of mifepristone development for more than 15 years provides a unique insider's view. The development of mifepristone has been so fraught with drama that I present it here as a theatrical piece. Nonetheless, the story has been told as objectively as possible.

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.

Treatment of endometriosis with the antiprogesterone mifepristone (RU486)

OBJECTIVE: To evaluate the safety and efficacy of an antiprogesterone (mifepristone, RU486; Roussel-Uclaf, Romaineville, France) on endometriosis. DESIGN: An open, prospective clinical trial. SETTING: The clinical practice of an academic faculty. PATIENTS: Nine women with endometriosis were studied. INTERVENTIONS: RU486 (50 mg/d) was administered for 6 months. MAIN OUTCOME MEASURES: Daily symptom inventories and urinary steroid metabolites were assessed before, during, and after treatment. Blood for hormone analysis was obtained weekly for 4 weeks and monthly thereafter. The extent of endometriosis, bone mineral density, circadian rhythm of cortisol, and LH pulsatility were determined before and after treatment. Safety laboratory measurements were made before and at 1, 2, and 6 months of treatment. RESULTS: Pelvic pain and uterine cramping improved in all patients. Endometriosis regressed by 55%. All patients exhibited endocrine features of anovulatory amenorrhea without hypoestrogenism. A rise in serum LH and T levels was observed during the first month of treatment and one patient developed an elevation of liver transaminases during the last month of treatment. All other measurements were unchanged. CONCLUSION: RU486 appears to be effective in improving the symptoms and causing regression of endometriosis in the absence of significant side effects.

[Mifepristone (RU 486): present status, prospectives]. / La mifépristone (RU 486): actualités, perspectives.

Mifepristone (RU 486) has many therapeutic possibilities, which largely exceed simple interruption of pregnancy. They are due to its unique properties of progesterone--and glucocorticosteroid--receptor blockage. In early interruption of pregnancy, the association with a prostaglandin analogue represents an efficient and well-tolerated method. The safety and comfort of the method have been improved by the association with misoprostol, an oral prostaglandin analogue. Mifepristone can also be used in late pregnancy interruptions for medical reasons, as well as for expulsion of an in utero dead fetus. In these indications, its use allows to decrease or even to avoid the use of prostaglandins, thus diminishing the side-effects due to these products. Several other gynaecological and obstetrical indications seem promising in the future: dilatation and ripening of uterine cervix, induction of labour for medical reasons, contraception. Trials are ongoing to evaluate the antitumoral activity of mifepristone in meningiomas and breast cancer. Finally, its anti-glucocorticosteroid effect is used in the treatment of Cushing's syndromes due to ectopic secretion of ACTH and other indications may be foreseen.

Termination of early pregnancy (up to 63 days of amenorrhea) with mifepristone and increasing doses of misoprostol [corrected].

The efficacy and tolerability of mifepristone in combination with misoprostol for termination of early pregnancy (up to 49 days of amenorrhea) are established. We studied the efficacy and tolerability of this combination therapy for termination of pregnancy in women up to 63 days of amenorrhea. We also examined the effect of an additional dose of misoprostol in cases of nonexpulsion within 3 hours after the first dose. The multicenter trial included 1,108 women, mean age 27.9 +/- 6.2 years. The mean duration of pregnancy was 51.7 +/- 9.2 days. On day 1, the women received an oral dose of mifepristone, 600 mg. On day 3, they received an oral dose of misoprostol, 400 micrograms, and were monitored for up to 3 hours. If they did not expel the conceptus within 3 hours, an additional dose of 200 micrograms of misoprostol was given and they were monitored for 2 more hours. From days 10 to 18, the women were followed up with clinical examination, human chorionic gonadotropin measurement, or ultrasound examination. Overall, the procedure was successful in 92.9% of women. Efficacy decreased with the duration of pregnancy, especially after 56 days of amenorrhea. Up to 42 days of amenorrhea, the success rate was 97.6%; between days 42 and 49, 94.8%; between days 50 and 56, 93.4%; between days 57 and 63, 86.8%; and after day 63, 83.3%. The most common side effects were moderate uterine cramps (80.5%) and gastrointestinal (GI) symptoms (34.9%), especially vomiting (18.3%) and diarrhea (10.5%). GI symptoms were generally mild. A second dose of misoprostol was given to 61.6% of the women. In a subgroup analysis, we assessed the efficacy of 600 mg of mifepristone plus 400 or 600 micrograms of misoprostol (one or two doses) in women with up to 49 days of amenorrhea and compared it with the efficacy in women who received mifepristone plus only 400 micrograms (one dose) of misoprostol in a previous study. The overall rate of success (termination of pregnancy) was 95.5% in the current study compared with 95.4% in the previous study. The additional dose of misoprostol did not significantly increase the overall rate of success, but did increase the rate of termination within the monitoring period (69.7% versus 64.9% (and within 72 hours after administration of mifepristone (92.7% versus 90.4%). We have confirmed that the combination of mifepristone and misoprostol was effective, safe, and well tolerated for termination of pregnancies at 49 or fewer days of amenorrhea. The efficacy decreased slightly between 49 and 56 days, and then decreased significantly between 56 and 63 days. For maximal safety and tolerability, we recommend this method only for women with 49 or fewer days of amenorrhea. A second dose of misoprostol did not improve overall efficacy, but did increase the rate of early termination.

RU486: the French experience.

RU486 (mifepristone) followed by a prostaglandin (PG) analogue has been marketed in France since April 1990 as a medical alternative to surgery for early pregnancy termination. By law, the drug is used only in the centres approved for voluntary pregnancy termination, and its distribution is strictly controlled. Before being marketed, it was distributed to more than 20,000 women, as part of a training programme for the prescribers. Analysis confirmed an efficacy rate of 95.3%. Failures included incomplete ovular expulsion (2.8%), premature vacuum aspiration (0.7%) and ongoing pregnancy (1.2%). Pelvic pain and malaise were reported as side-effects in 1.6 and 1.2% of the cases respectively. Infectious complications were reported in 0.2% of the cases. Three severe adverse events (one of which was fatal) occurred, including myocardial infarction and ventricular arhythmia, in the hours following PG administration and justify a careful medical monitoring in the centre 3-4 h after administration of PG. For this reason, a trial was undertaken to evaluate the efficacy of an oral form of a PGE1 analogue (misoprostol). When RU486 was followed 36-48 h later by 400 micrograms of misoprostol, the efficacy rate was 96.9%, indicating an efficacy equivalent to that obtained with the other PG analogues. The distribution procedures were adequately followed by the prescribers and by the patients. In summary, RU486 constitutes a safe and efficient medical means of pregnancy termination, provided that the manufacturer's recommendations are properly followed.

Glomerular hemodynamics during abortion induced by RU 486 and sepsis in rats.

1. Acute renal failure is a very common consequence of septic abortion. Whole kidney and glomerular hemodynamics were evaluated in virgin (V), pregnant (PREG) and aborted (ABOR) euvolemic Munich-Wistar rats before and after E. coli (0111-B4) endotoxin (LPS) infusion in order to evaluate the effect of septic abortion on the renal microcirculation. 2. Abortion induced by RU 486 blunted the increase in glomerular filtration rate (GFR) induced by normal pregnancy (0.86 +/- 0.03 vs 0.63 +/- 0.07 ml/min, P < 0.05). In virgin rats, RU 486 did not modify the parameters of renal function. Significant alterations occurred in whole kidney and single nephron function. However, the changes in whole kidney function in the ABOR group were significantly higher than those observed for the V group (reductions in GFR were 42% in V and 80% in ABOR, RPF decreased 34% in V and 76% in ABOR, TRVR increased 82% in V and 400% in ABOR). 3. Mean single nephron glomerular filtration rate (SNGFR) was reduced in all groups after LPS (44% in V, 43% in V+RU, 55% in PREG, 60% in ABOR), due to significant decreases in glomerular plasma flow rate, QA (42% in V, 55% in V+RU, 53% in PREG, 57% in ABOR) and in glomerular ultrafiltration coefficient, Kf (46% in V, 47% in V+RU, 45% in PREG, 67% in ABOR). 4. These data show that LPS induced significant alterations in renal function in all groups. However, aborted rats were more sensitive to the effects of LPS than V rats. These results indicate that abortion may potentiate the effects of endotoxemia on renal function elevating the extent of acute renal failure and thus the mortality rate.

Glomerular hemodynamics during abortion induced by RU 486 and sepsis in rats

1. Acute renal failure is a very common consequence of septic abortion. Whole kidney and glomerular hemodynamics were evaluated in virgin (V), pregnant (PREG) and aborted (ABOR) euvolemic Munich-Wistar rats before and after E. coli (0111-B4) endotoxin (LPS) infusion in order to evaluate the effect of septic abortion on the renal microcirculation. 2. Abortion induced by RU 486 blunted the increase in glomerular filtration rate (GFR) induced by normal pregnancy (0.86 +/- 0.03 vs 0.63 +/- 0.07 ml/min, P < 0.05). In virgin rats, RU 486 did not modify the parameters of renal function. Significant alterations occurred in whole kidney and single nephron function. However, the changes in whole kidney function in the ABOR group were significantly higher than those observed for the V group (reductions in GFR were 42 in V and 80 in ABOR, RPF decreased 34 in V and 76 in ABOR, TRVR increased 82 in V and 400 in ABOR). 3. Mean single nephron glomerular filtration rate (SNGFR) was reduced in all groups after LPS (44 in V, 43 in V+RU, 55 in PREG, 60 in ABOR), due to significant decreases in glomerular plasma flow rate, QA (42 in V, 55 in V+RU, 53 in PREG, 57 in ABOR) and in glomerular ultrafiltration coefficient, Kf (46 in V, 47 in V+RU, 45 in PREG, 67 in ABOR). 4. These data show that LPS induced significant alterations in renal function in all groups. However, aborted rats were more sensitive to the effects of LPS than V rats. These results indicate that abortion may potentiate the effects of endotoxemia on renal function elevating the extent of acute renal failure and thus the mortality rate.

Progesterone antagonist RU 486 accommodates but does not induce labour and delivery in primates.

The hormonal mechanisms of parturition in primates remain controversial. Even so, the well-known decrease of plasma progesterone concentration near term is considered by many as the 'labour inducer'. The progesterone antagonist RU 486, which blocks progesterone activity at the cellular receptor level, appears to be a useful hormonal tool by which to study this tissue. Here, we tested its capacity to induce labour and delivery. A total of 23 Cynomolgus monkeys (Macaca fascicularis), within 9-17 days of expected term, were assigned to four different protocols to study various doses, routes and regimens of RU 486 administration. Observations included uterine contractile patterns, pharmacokinetics of RU 486 in plasma and passage of RU 486 into breast milk. None of the protocols tested successfully induced labour resulting in vaginal delivery within 24 h. Instead, the data demonstrate that blockade of progesterone activity by the progesterone antagonist was not sufficient by itself to achieve parturition in these primates. Uterine myometrial contractile activity under RU 486 exposure was not sufficient to induce labour and delivery. Moreover, the progesterone antagonist concentration in breast milk was very low, indicating little passage to suckling newborn infants.

Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol.

BACKGROUND AND METHODS: The combination of mifepristone (RU 486) and a prostaglandin analogue given either intramuscularly or intravaginally is effective in terminating early pregnancy, but the prostaglandin component of the regimen is cumbersome to administer and has side effects. We conducted two studies to determine the efficacy of 600 mg of mifepristone followed by a small dose of misoprostol, an orally active prostaglandin E1 analogue, for the same purpose. In the first study, 505 women who had had amenorrhea for less than 50 days received 400 micrograms of misoprostol 48 hours after receiving mifepristone, if the pregnancy was not terminated within that period. In the second study, 390 women initially received the same treatment, but if the pregnancy was not terminated within four hours after the administration of misoprostol, they were offered an additional 200-micrograms dose of misoprostol. RESULTS: In study 1, the rate of success (termination of pregnancy and complete expulsion of the conceptus) was 96.9 percent (95 percent confidence interval, 94.1 to 97.7 percent)--similar to the success rate of approximately 95 percent for mifepristone followed by the intramuscular or intravaginal administration of prostaglandin. Abortion occurred in 2.9 percent of the women within 48 hours after the administration of mifepristone, in 60.9 percent within 4 hours after the administration of misoprostol, and in 33.2 percent thereafter. The failures included ongoing pregnancies in four women (0.8 percent) and incomplete abortions in nine (1.8 percent); two other women (0.4 percent) required vacuum aspiration for prolonged uterine bleeding. In study 2, pregnancy was terminated in 5.5 percent of the women before the administration of misoprostol and within four hours after the first dose of misoprostol in 69.1 percent. Among the 71 women who received a second dose of misoprostol, 67 had complete abortions, 2 had partial retention of the conceptus, 1 had synechia with ongoing pregnancy, and 1 had an ectopic pregnancy. One ongoing pregnancy, which was terminated by vacuum aspiration, was recorded among the 27 women who declined to take the second dose of misoprostol. The overall rate of success of the regimen with the optional second dose of misoprostol was 98.7 percent (95 percent confidence interval, 96.8 to 99.5 percent). No woman had any serious adverse event. CONCLUSIONS: The combination of mifepristone and misoprostol is effective for the termination of early pregnancy in terms of success, tolerance, safety, and practicality.

PIP: Between June and October 1991 health workers administered 1 dose of 600 mg mifepristone (RU-486) and a single oral dose of 400 mcg misoprostol on day 3 to at least 488 women at 25 centers in France to terminate pregnancy of less than 50 days duration. Pregnancy termination occurred within 48 hours in 2.9% of all women. They had only received RU-486. 1% vomited after taking the first dose of misoprostol, necessitating a second dose. The overall success rate for this regimen was 96.9%. 12 hours was the mean time between taking misoprostol and expulsion of the conceptus. The median time was 3 hours. The types of failure were incomplete expulsion of the conceptus (1.8%), ongoing pregnancy (0.8%), and prolonged bleeding (0.4%). Mean duration of bleeding following the regimen was 9 days. A second study occurred between March 1991 and March 1992 among at least 385 women at 1 center in France. They received RU-486 and misoprostol in the same manner as the women in study 1, but those who did not experience pregnancy termination within 4 hours after the initial dose received another 200 mcg dose of misoprostol. 5/5% experienced pregnancy termination before administration of misoprostol. 69.1% experienced termination within 4 hours. Pregnancy termination occurred within the first 3 hours in almost 90% of them. 27 women who did not abort within 4 hours did not take the additional dose and 26 of them aborted completely. The sole woman with a continued pregnancy underwent vacuum aspiration. 67 of the 71 women who took the second dose completely expelled the conceptus within 48 hours. Thus, 79.2% of all women aborted while being monitored at the center. The overall success rate was 98.7% . The leading side effects in both studies in order of frequency were uterine cramps and nausea, vomiting, and diarrhea. These results showed that oral administration of misoprostol is as effective and well tolerated as other prostaglandins administered parenterally or vaginally.

Medical termination of early pregnancy with mifepristone (RU 486) followed by a prostaglandin analogue. Study in 16,369 women.

We report the results of a large-scale trial with mifepristone (RU 486) followed by the administration of a prostaglandin (PG) analogue for the medical termination of early pregnancy. Altogether, 16,173 patients from 300 centers were evaluated. 48 women (0.3%) were lost to follow-up prior to, and 416 (2.6%) after the PG administration, and therefore the efficacy was evaluated in 15,709 women. Overall, the success rate was 95.3%, with no statistical difference regarding the nature and dose of PG used. The median duration of bleeding was 8 days, being 12 days or less in 89.7% of the women. Bleeding was significant enough to necessitate a vacuum aspiration or a dilatation and curettage in 0.8% of the cases. A blood transfusion was necessary in 0.1% of the women (11 patients). Serious cardio-vascular side-effects were reported in 4 cases after the PG (sulprostone) injection: they consisted of one acute myocardial infarction attributed to a coronary spasm, and in marked hypotension in the other 3 women. All patients recovered uneventfully. In conclusion, RU 486 followed by a PG analogue provides an efficient and safe medical alternative to surgery for early pregnancy termination, provided that the recommended protocol is adequately followed and the contraindications to prostaglandins are respected.

PIP: Between May 1988 and September 1989, physicians administered 600 mg of RU-486 followed by either 1 mg gemeprost vaginal pessary or im injection of 0.125-1.0 mg sulprostone to 16,369 11-48 year old women attending 30 centers in France to evaluate this regimen's safety and efficacy and whether trained prescribers could adequately comply with recommended protocol. 13.6% patients whose gestational age was greater than the recommended 50 days, underwent RU-486 and prostaglandin (PG) analogue administration. 78% of 571 patients did not receive a PG analogue because they expelled the conceptus after RU-486 administration. The remaining 126 women did not receive RU-486 even though they had not expelled the conceptus. Clinicians administered to PG analogue to 88.4% of all women within the recommended 36-48 hours after RU-486 administration. The RU-486 and PG analogue regimen had a success rate of 95.3%. Women who received the PG analogue within the recommended time period had a higher success rate than those who received it either too early or too late (95.8% vs. 92.8% and 93.9%, respectively; p = .001). In those women who did not receive the PG analogue, RU-486's success rate was considerably lower (88.6%; p .001). The nature and does of the PG analogue greatly influenced expulsion within 4 hours after its administration (44.1% after 1 mg gemeprost vs. 57.3%, 55.8%, 73.5%, and 67.6% after 0.125, 0.25, 0.375, and 0.5 mg sulprostone respectively; p .001). The higher doses of sulprostone had a significant effect on duration of bleeding (e.g., 9.1 days for 0.5 mg vs. 7.1 days for 0.125 mg p .001). 89.7% of the women bled for no more than 12 days. The bleeding was so profuse in 0.8% of the cases that either vacuum aspiration or dilatation and curettage was needed. 11 women required 1-3 units of blood. 8.5% experienced at least 1 side effect, the most common being uterine cramps (1.6% of all cases). 4 women suffered from grave cardiovascular effects (myocardial infarction in 1 case, severe hypotension in 3 cases). As long as prescribers consider contraindications and follow the protocol, this regimen is a viable alternative to surgical abortion.