Renal handling of phosphate and calcium was studied in 17 hypercalciuric stone-formers, 6 normocalciuric stone-formers and 10 normal subjects before (fasting state) and 45 and 75 min after the ingestion of 100 g glucose. The ratio of fasting urinary calcium to creatinine (UCa/creat) was higher in hypercalciuric than in normocalciuric stone-formers or controls. A positive correlation was found between weight index and fasting UCa/creat for all subjects studied (r = 0.36; P less than 0.05). A negative correlation was apparent between the weight index and the fasting renal threshold phosphate concentration (TmP/GFR) (r = 0.40; P less than 0.02), the latter parameter being slightly but insignificantly lower in hypercalciuric stone-formers than in controls. After glucose ingestion. UCa/creat rose significantly in all groups. The maximal rise in UCa/creat was also positively correlated with the weight index for all patients ( r = 0.42; P less than 0.02), and 75 min after glucose ingestion, TmP/GFR decreased in all groups, dropping to a significantly lower level in the hypercalciuric patients than in the controls. No correlation was apparent between the weight index and the magnitude of the reduction in TmP/GFR. Plasma 1, 25-dihydroxyvitamin D3 and immunoreactive parathyroid hormone were measured before glucose ingestion and were not correlated either with each other or with plasma phosphorus, TmP/GFR, or UCa/creat before or after glucose ingestion. These results imply that weight is a determining factor in the renal handling of calcium and phosphorus. Such findings might be of importance to the clinical investigation and management of calcium stone-formers.

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.

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.

This paper briefly summarizes the pharmacology and pharmacokinetics of nilutamide, emphasizing the value of combining orchidectomy or chemical castration by luteinizing hormone-releasing hormone with nilutamide treatment in animal models and prostate cancer patients Cancer 1993; 72:3828-9.

the statement that "early results are promising."' The department's evaluation, for which we are the principal investigators, does not show early results which are either promising or not promising. We have no early results. When data collection is complete in the middle of next year, but not before, we shall analyse the results to quantify the contribution of the trauma centre to the outcome ofmajor trauma in the region. We believe that the impression that the trauma centre is showing promising results is founded on the results put out by the trauma centre itself. Several points are worth bearing in mind, however. Firstly, the contribution of the trauma centre to the outcomes oftrauma in the region depends on the proportion of patients with major trauma in the region who arrive at the trauma centre as well as on the performance of the centre itself. Secondly, improvements in outcomes may be taking place everywhere in the United Kingdom and therefore it is the relative improvement that matters. Thirdly, reports from outside the United States have not always favoured regionalisation of major trauma services.4 Most importantly, whatever benefits the trauma centre brings, these have to be set against the costs of the service to assess whether regionalisation may be justified. The Department of Health's advisory group on health technology assessment strongly advised that new forms of care should not be offered within the NHS until their effects had been assessed.' We hope that the community of people involved in trauma care will wait until our assessment is complete before making up their minds about the value of regional trauma systems in the United Kingdom.

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.

Objective: To examine endocrine and clinical responses to long-term administration of RU486 in patients with endometriosis.Design: Prospective open trial.Setting: Faculty practice of the authors.Patients, Participants: Six normally cycling women with endometriosis were recruited.Interventions: Subjects received RU486 100 mg/d for 3 months.Main Outcome Measure(s): Hormonal changes during RU486 were compared with control data obtained in the preceding cycle during the early follicular phase. Clinical responses were determined by patient assessment and second-look laparoscopy.Results: All women became amenorrheic, and daily urinary levels of ovarian steroid metabolites remained acyclic. Mean luteinizing hormone (LH) (P < 0.02) and LH pulse amplitude (P < 0.05) were increased without changes in LH pulse frequency. An antiglucocorticoid effect was demonstrated by an increase in serum cortisol (P < 0.01) and adrenocorticotropic hormone (P < 0.05) levels. Treatment resulted in an improvement in pelvic pain in all subjects without significant change in the extent of disease as evaluated by follow-up laparoscopy.Conclusions: Daily administration of RU486 results in acyclic ovarian function and improvement in the subjective painful symptoms of endometriosis.

In preparation for a clinical trial of an antiprogesterone molecule as a postcoital contraceptive method, the authors reviewed the available research on the effectiveness of use of high-dose estrogen and combined estrogen-progesterone preparations for this purpose. The medical literature for the period 1971-87 included 5 studies on the former and 5 studies on the latter regimens that involved over 500 subjects. In each of these studies, the failure rate was calculated by dividing the number of observed pregnancies by the total number of women enrolled. The authors computed true failure rates for the 10 studies in 2 different ways. First, the failure rate derived from the number of reported pregnancies was divided by the number of expected pregnancies according to Tietze's probability of pregnancy. Second, the true failure rate derived from Dixon's table was calculated. Since the latter approach requires data on the date of the intercourse that resulted in pregnancy, it could not be applied to all 10 studies. The 5 studies on the efficacy of high-dose estrogen as a postcoital contraceptive reported failure rates below 1%. However, the authors' recalculations indicated failure rates as high as 48% (Tietze) or 16% (Dixon). COmbined estrogen-progesterone was reported to produce a failure rate of 0.16-5%. Here, the true failure rate was as high as 4.2-100% (Tietze) or 5.9-44% (Dixon). The implication of these recalculations is that use of the total number of women enrolled as the denominator produces a substantially lower failure rate than the number of women potentially pregnant. Given the potential for underestimation of the efficacy of postcoital contraceptives, more prospective controlled studies are urged.

Monkey embryos were exposed to RU 486 both in vitro and in vivo (with and without progesterone therapy) in the perinidatory interval. These primate embryos were highly tolerant of RU 486, except when RU 486 alone terminated early pregnancy. There were no indications of teratogenicity in this limited trial when the embryos were exposed to RU 486 either before implantation (10-7M in 24-hour cultures) or during the immediate post-implantation interval (50 mg orally/day; days 32 to 39 LMP).

In a double-blind controlled multicentric study involving 94 patients with an intrauterine fetal death, we investigated the efficacy and tolerance of mifepristone (RU 486), a steroid compound that antagonizes progesterone action at the receptor level. Success of treatment was defined as the occurrence of fetal expulsion within 72 hours after the first drug intake. Mifepristone treatment (600 mg per day for 2 days) was considered to be effective in 29 of 46 patients (63%). There were only eight successes in 48 patients (17.4%) in the placebo group (p = 0.001, χ2 test). Tolerance was good in the mifepristone group. In the placebo group, disseminated intravascular coagulation occurred in one woman for whom the investigator waited several weeks for spontaneous expulsion. This large double-blind controlled study provides evidence that mifepristone is of interest in the management of intrauterine fetal death. It could provide a pharmacologic alternative to the use of prostaglandins in this indication.

The noncompetitive antiestrogenic effects of RU 486 were examined using estradiol (E2)-treated ovariectomized monkeys given RU 486, progesterone (P), or both. The E2-induced luteinizing-hormone (LH) surge of control animals was abrogated by P and/or RU 486. Secretory transformation by P was inhibited by RU 486 coadministration. RU 486 alone (1 mg/kg) induced endometrial secretory transformation, but higher doses (5 mg/kg) inhibited proliferation and secretory activity. Thus in the presence of P, RU 486 is antagonistic but, in absence of P, exhibits endometrial progestational effects at low doses and an antiproliferative (antiestrogenic) effect at higher doses. These data encourage continued evaluation of RU 486 as a potential contraceptive agent acting at the pituitary and/or endometrial level.

In previous studies, RU 486 administration arrested spontaneous folliculogenesis. To investigate the central versus peripheral effects of RU 486 on the ovarian/menstrual cycle, including endometrial proliferation, RU 486 was administered daily (10 mg/kg/day, im) from menstrual cycle day 3 or 7 to day 25 in normal adult cynomolgus monkeys receiving hMG treatment (37.5 IU/day) from days 3-8 (n = 6). RU 486 administration with hMG/hCG therapy did not inhibit ovarian response, as evidenced by steroidogenesis and ovulation. Nine of 23 oocytes retrieved by lavage or follicular aspiration at laparotomy after ovulation induction were morphologically classified as mature preovulatory status. Whereas an endometrial biopsy performed on cycle day 25 in control monkeys revealed an in phase mature secretory endometrium, histologic sections from RU 486 plus hMG/hCG treated females uniformly demonstrated atrophic to weakly proliferative endometrium on cycle day 25, despite serum estradiol levels greater than 300 pg/ml. Three months after the initial 25-day study endometrial biopsies revealed persistent atrophic endometrium, even though repeated ovulation induction with hMG/hCG therapy elevated serum estrogen concentrations. The findings prevailed whether RU 486 treatment began on cycle day 3 or 7. The intermenstrual interval was significantly (P less than 0.01) lengthened by RU 486 treatments (28.5 +/- 2.0, control vs 131.3 +/- 11.5 days, RU 486). In summary, RU 486 consistently blocked ovulation unless hCG was provided and elicited a persistent retardation of early proliferative endometrium when administered daily beginning in early or mid-follicular phase. The normal mitogenic effects of elevated ovarian estrogen secretion on endometrial tissue were quelled, uniformly resulting in amenorrhea. The long-lasting action of RU 486, causing ovulation inhibition and atrophic endometrium, may be due to the depot effect of im injection. In addition, RU 486 did not prevent ovarian steroidogenesis, ovulation or oocyte maturation when an ovulation induction regimen of hMG/hCG was given. These findings show that RU 486 prevented ovulation by diminishing pituitary gonadotropin secretion, rather than by direct effects on ovarian folliculogenesis, and induced amenorrhea by inhibiting estrogen-induced endometrial proliferation.

Table 2 summarizes the proven and potential uses of anti-progesterones in obstetrics and gynaecology. In addition to their role in the induction of menstruation and the interruption of first-trimester pregnancy, anti-progesterones can definitely accelerate cervical ripening and promote the termination of second-trimester pregnancy, especially in combination with exogenous prostaglandins. Furthermore, anti-progesterones can also initiate labour in the obstetric complication of fetal death in utero, leading to delivery of the fetus and placenta without additional medical treatment and without surgery in the majority of patients. The wider use of anti-progesterones for the induction of labour, with or without other adjuvants such as oxytocin or prostaglandin analogues, is still uncertain and awaits further study. Anti-progesterones may also be useful in the medical treatment of early ectopic pregnancy, either alone or in combination with other medicines. Preliminary results indicate that progesterone receptor antagonists may also be useful both for the initiation and promotion of lactation as well as the possible management of advanced breast cancer containing progesterone receptors. Finally, the usefulness of anti-progesterones in other gynaecological malignancies containing progesterone receptors, such as endometrial or ovarian cancers, awaits further study.

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.

The progesterone antagonist RU 486 dramatically increases myometrial contractility of the pregnant uterus, making it a potential adjunctive therapy for labor induction or therapeutic pregnancy termination. Sixteen female cynomolgus monkeys were studied during the second or third trimester of pregnancy. Hysterotomies were performed with the animals under anesthesia, providing access to the intact placental vasculature. RU 486 (25 mg) was injected intravenously into the mothers. Serial blood samples were drawn from the maternal and fetal-placental compartments for a period of 2 hours. RU 486 achieved a gradient equilibrium between the maternal and fetal-placental circulation within 5 minutes, suggesting free passage by simple diffusion. The clearance kinetics of immunoreactive RU 486 are consistent with an open three-compartment system in mother and fetus. The fetal-placental index decreased from 31.2% to 17.8% between the second and the third trimester of pregnancy. There was no acute toxicity of the RU 486 noticed during the experimental course.

The impact of the antiprogesterone RU486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl) 17 alpha-(1-propynyl)estra- 4,9-dien-3-one] on the hypothalamic-pituitary-ovarian-endometrial axis was examined in normal cycling women during the mid (MLP)- and late (LLP) luteal phases. During the MLP, 10 women received 3 mg/kg RU486 for 3 days. During the LLP, a single dose of 600 mg RU486 was administered to 4 women, and in another 4 women a single dose of 3 mg/kg was given during corpus luteum rescue by hCG. Longitudinal studies with daily and frequent blood samples (every 10 min for 10 h) were conducted during 3 consecutive cycles (control-treatment-recovery). During the MLP, RU486-induced uterine bleeding occurred in all 10 women 36-72 h after the first dose. No histological evidence of endometrial breakdown was found in endometrial biopsies taken 12-24 h before the onset of bleeding. Significant decreases in LH secretion (P less than 0.001) and LH pulse amplitude (P less than 0.006) and blunted pituitary responses to GnRH (P less than 0.01) were evident by the last treatment day, but LH pulse frequency did not change. Complete luteolysis occurred in 2 of the 10 women. Incomplete luteolysis occurred in 8 women and was associated with an initial decline of serum estradiol (P less than 0.001), but not progesterone levels, followed by rebound increases (P less than 0.001) in LH, estradiol, and progesterone levels 3 days later, which may have reversed the luteolytic processes and prolonged corpus luteum function. Spontaneous luteolysis ensued 3-5 days later with the onset of second episodes of uterine bleeding. For serum FSH, an early rise occurred during the luteal phase in advance of the onset of the second episodes of uterine bleeding. This rise may have resulted in early follicle recruitment and accounted for the shorter duration of the follicular phase during recovery cycles. During the LLP, the single RU486 dose resulted in significant decreases in LH pulse amplitude (P less than 0.03), frequency (P less than 0.05), and secretion (not significant) within 12 h. The recovery cycle was entirely normal. Corpus luteum rescue with incremental doses of hCG did not prevent uterine bleeding after RU486 treatment. These findings indicate that RU486 operates at multiple sites and implies that progesterone is important in the control of luteal function. Further, our data provide a basis for exploring the potential use of RU486 as a once a month birth control agent.

The steroidal derivative RU 486 (17β-hydroxy-11β-(4-dimethyl-aminopheny 1)-17α-(prop-1-ynyl)-estra-4,9-dien-3-one) is the first potent antiprogestin in medical use. Acting reversibly at the molecular level of receptor binding, RU 486 blocks progesterone action and allows endocrine functions to return quickly to normal after its use. However, target cells dynamics that depend upon a continuity of progesterone action will be irreversibly disrupted. In normal women RU 486 acts during the luteal phase in the endometrium, provoking bleeding, and also decreases LH secretion which results in luteolysis. In pregnant women, if affects the decidual, increases myometrial contractility and ripening of the cervix, and ultimately leads to termination of pregnancy. Detachment of the trophoblast leads to a fall in chronic gonadotrophin. Clinical studies indicate that RU 486 can be a very efficient agent for the termination of early pregnancy, and as a postcoital menstrual regulator. The failures observed when RU 486 is given alone may be overcome by the additional use of oxytocics. A small amount of prostaglandin given at the end of RU 486 treatment gives satisfactory results at up to 8 weeks of amenorrhea. Treatment with RU 486 is short term, and apparently has no significant side-effects despite the compound's antiglucocorticosteroid activity.