Endometriosis as a prognostic factor for cancer survival.

Studies have shown an increased risk of malignancies in women with endometriosis. Little is known about the impact of endometriosis on cancer survival. We investigated whether the survival after a diagnosis of a malignancy differs in women with a previously diagnosed endometriosis compared to other women. Women with a first time diagnosis of a malignancy in 1969-2005, were identified using the National Swedish Cancer Register (NSCR). By use of the National Swedish Patient Register (NSPR) we identified all women with a diagnosis of endometriosis during the same period and linked these patients with the data from the NSCR. The cohort comprised 4,278 women with endometriosis and a malignancy, and 41,831 randomly selected matched women without endometriosis. Cox regression was used for all calculations to obtain crude and adjusted cause specific mortality rates, measured as hazard ratios (HR) with 95% confidence intervals (CI). A total of 46,109 women entered the study. There was a statistically significant better survival for women with endometriosis for all malignancies combined (HR=0.92) and for breast cancer (HR=0.86) and ovarian cancer (HR=0.81) specifically. For breast cancer the survival enhancing effect in women with endometriosis decreased with increasing parity. There was poorer survival in malignant melanoma for women with endometriosis (HR=1.52). The survival in a malignancy is better in women with a previously diagnosed endometriosis compared to women without endometriosis especially for breast and ovarian cancers. The prognosis of malignant melanoma is poorer in women with endometriosis.

Human chorionic gonadatropin (hCG) during third trimester pregnancy.

OBJECTIVE: Separate reference values were recently established for routine blood samples during last trimester pregnancy. Previously, these were based on blood samples from healthy men or non-pregnant women. Normal changes in variation in the levels of steroid hormones in the last weeks of pregnancy before delivery are also incompletely investigated. This study of the preterm hormone levels was carried out in the search for events leading to increased contractility that might occur in the predelivery weeks and potentially influence the initiation of delivery. MATERIAL AND METHODS: Blood samples during pregnancy weeks 33, 36 and 39 as well as 1-3 h postpartum were collected from pregnant women (19-39 years, mean age 30) with at least one previous pregnancy without hypertension or pre-eclampsia. All women (n = 135) had had a vaginal delivery and spontaneous start of labour. The blood samples were analysed for serum hCG, oestradiol and progesterone. Postpartum, the values were retrospectively rearranged to correspond with the actual week before the day of delivery. RESULTS: During the last trimester of normal pregnancy, a gradual increase was found in oestradiol (median 45980 to 82410 pmol/L), progesterone (median 341 to 675 nmol/L) and a gradual decrease in hCG (median 31833 to 19494 IU/L). Furthermore, a significant (p<0.03) decrease in hCG was found from the third to the second week before delivery, while oestradiol and progesterone continued to increase. CONCLUSIONS: Hormone levels during third-trimester pregnancy have not previously been systematically investigated. Recent data suggest that hCG may have a role as an endogenous tocolytic in normal pregnancy by directly promoting relaxation of uterine contractions. In the present study a significant decrease in serum hCG level was found 2-3 weeks before the spontaneous start of labour. This might contribute to increasing the contractility in the uterine muscle and gradually initiate the onset of labour.

The effect of non-steroidal anti-inflammatory drugs on medical abortion with mifepristone and misoprostol at 13-22 weeks gestation.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the biosynthesis of prostaglandins and concerns have been expressed that they might attenuate the effects of exogenous prostaglandins. This randomized study was conducted to evaluate whether NSAID given during medical abortion with mifepristone/misoprostol in the second trimester has a negative effect on the efficacy of the abortifacient by prolonging the induction-to-abortion interval. METHODS: Seventy-four women were treated with the anti-progesterone mifepristone, followed by repeated doses of misoprostol 36-48 h later. They were randomized to receive a prophylactic pain treatment of either paracetamol and codeine or diclofenac with the first dose of misoprostol. RESULTS: Co-treatment of NSAID with misoprostol did not attenuate the efficacy of mifepristone and misoprostol. There was no significant difference between the NSAID and the non-NSAID group in the induction-to-abortion interval (5.4 versus 6.5 h) or the total doses of misoprostol needed (2 versus 3). The frequency of surgical intervention was similar (55.6 versus 52.6%). Women in the group treated with NSAID required significantly less opiates (P = 0.042). CONCLUSION: Co-treatment with NSAID and misoprostol does not interfere with the action of mifepristone and/or misoprostol to induce uterine contractions and pregnancy expulsion in medical abortion. Prophylactic NSAID administration reduces the need for opiate injections.

Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus.

OBJECTIVE: To compare the efficacy and safety of preprandial administration of rapid-acting lispro analogue with regular short-acting insulin to pregnant women with type 1 diabetes. STUDY DESIGN: Open randomised multicentre study. Women were treated with multiple insulin injections aiming at normoglycaemia. Blood glucose was determined six times daily, HbA(1c) every 4 weeks. Diurnal profiles of blood glucose were analysed at gestational week 14 and during the study period at weeks 21, 28 and 34. PARTICIPANTS: 33 pregnant women with type 1 DM were randomised to treatment with lispro insulin (n=16) or regular insulin (n=17). RESULTS: Blood glucose was significantly lower (P<0.01) after breakfast in the lispro group, while there were no significant group differences in glycemic control during the rest of the day. Severe hypoglycaemia occurred in two patients in the regular group but biochemical hypoglycaemia (blood glucose <3.0 mmol/l) was more frequent in the lispro than in the regular group (5.5 vs. 3.9%, respectively). HbA(1c) values at inclusion were 6.5 and 6.6% in the lispro and regular group respectively. HbA(1c) values declined during the study period and were similar in both groups. There was no perinatal mortality. Complications during pregnancy, route of delivery and foetal outcome did not differ between the groups. Retinopathy progressed in both groups, one patient in the regular group developed proliferative retinopathy. CONCLUSION: The results suggest that it is possible to achieve at least as adequate glycemic control with lispro as with regular insulin therapy in type 1 diabetic pregnancies.

Contraceptive efficacy of daily administration of 0.5 mg mifepristone.

The antiprogestin mifepristone has shown potential to be used as a contraceptive. If 200 mg mifepristone is administered immediately after ovulation, the endometrium shows sufficient impairment of secretory development to prevent implantation. Low daily doses of mifepristone have been shown to reduce several of the local factors regarded as crucial for implantation in human endometrium. To find out if this regimen is sufficient to prevent pregnancy, 32 women were recruited for a study where 0.5 mg mifepristone was administered daily. A total of 141 cycles were studied. Five pregnancies occurred, which was significantly less than if no contraceptive method had been used. However, the dose chosen did not seem sufficient to act as a contraceptive although it is probably not possible to increase the dose without disturbing ovulation and bleeding pattern.

Contraceptive use of antiprogestin.

OBJECTIVES: To study the effect of antiprogestin on ovarian function and endometrial development during the menstrual cycle and the possibility of using these compounds for contraceptive purposes. METHODS: Administration of different doses of the antiprogestin mifepristone during the menstrual cycle; intermittent measurements of luteinizing hormone, progestin and estrogen in blood and/or urine; endometrial morphology and concentration of markers for endometrial receptivity; efficacy trials of the contraceptive effect of mifepristone. RESULTS: A high dose of mifepristone administered in the follicular phase will inhibit follicular development. If mifepristone is given immediately after ovulation, the secretory development of the endometrium and the expression of, for instance, leukemia inhibitory factor and integrins will be inhibited. Similar effects on the endometrium are obtained with small weekly doses (2.5 or 5.0 mg) or small daily doses (0.5 mg) of mifepristone, which do not inhibit ovulation. Once-monthly administration of 200 mg mifepristone on the day after ovulation, and emergency postcoital treatment, are highly effective methods for preventing pregnancy. Even 5 mg once weekly has a significant contraceptive effect. CONCLUSIONS: The antiprogestin mifepristone has a number of effects during the menstrual cycle which makes the compound suitable for contraceptive use. Treatment after a single act of unprotected intercourse, and once-a-month treatment immediately after ovulation, have shown high contraceptive efficacy. A low-dose regimen which does not influence ovulation also has a contraceptive effect, but the efficacy needs to be improved before routine clinical use.

Once-a-month treatment with a combination of mifepristone and the prostaglandin analogue misoprostol.

In this two centre study, the efficacy of 200 mg mifepristone orally followed 48 h later by 0.4 mg misoprostol orally for menstrual regulation was investigated. The dose of mifepristone was taken the day before the expected day of menstruation. Each volunteer was planned to participate for up to 6 months. A plasma beta human chorionic gonadotrophin (HCG) was measured on the day of mifepristone intake. The study was disrupted prematurely due to low efficacy. In 125 treatment cycles the overall pregnancy rate was 17.6% (22 pregnancies) and the rate of continuing pregnancies (failure) was 4.0%. Eight women discontinued the study due to bleeding irregularities which were seen in 15 cycles (12%). These effects on bleeding pattern made the timing of treatment day difficult. Late luteal phase treatment with a combination of mifepristone and misoprostol is not adequately effective for menstrual regulation.

PIP: A 2-center study was undertaken to examine the efficacy, safety and acceptability of a once-a-month administration of a combination of 200 mg mifepristone and 0.4 mg misoprostol for menstrual regulation in the late luteal phase. About 24 women from Shanghai and 8 from Stockholm were administered 200 mg mifepristone taken orally before or on the day of menstruation, followed by 0.4 mg misoprostol taken orally after 48 hours. Urine samples were collected during 3 days before to 4 days after ovulation for an analysis of luteinizing hormone. In addition, a plasma beta human chorionic gonadotrophin was measured immediately before intake of mifepristone. Volunteers were to participate for 6 months, but the study was disrupted prematurely due to low efficacy. In 125 treatment cycles, the total pregnancy rate was 17.6% (22 pregnancies) and the failure pregnancy rate was 4.0%. Discontinuation of the study among 8 women was due to bleeding disturbances seen in 15 cycles (12%). In conclusion, late luteal phase treatment with a combination of mifepristone and misoprostol was not effective enough to be used for menstrual regulation.

Contraceptive efficacy of low doses of mifepristone.

OBJECTIVE: To determine whether a 5-mg dose of mifepristone is sufficient to prevent pregnancy. DESIGN: Clinical study. SETTING: Academic research center. SUBJECT(S): Healthy, fertile, sexually active female volunteers. INTERVENTION: Volunteers received a 5-mg dose of mifepristone once weekly, starting on cycle day 2, for up to 6 months. This was their only contraceptive method. MAIN OUTCOME MEASURE(S): Number of pregnancies. RESULT(S): The treatment resulted in a significant decrease in pregnancy rate without affecting the menstrual cycle or causing disturbing side effects. CONCLUSION(S): A low dose of mifepristone, which does not inhibit ovulation, reduces fertility significantly by affecting the endometrium. However, the contraceptive effect needs to be improved for the drug to compete with other contraceptive methods.

PIP: Clinical research has demonstrated that the effect of mifepristone on the endometrium is sufficient to prevent pregnancy. The efficacy of a low dose of mifepristone in preventing implantation was investigated in 18 healthy, fertile women with normal menstrual cycles from Stockholm, Sweden. Study participants received 5 mg of mifepristone once/week, starting on cycle day 2, and were followed for 1-6 months. Three pregnancies occurred in the 63 treatment cycles observed. The mean frequency of sexual intercourse was 2.2 times/week. If ovulation occurred 14 days before the onset of menstruation, at least 1 coital act took place during the period 3 days before and 1 day after ovulation in at least 45 cycles, resulting in a probability of pregnancy of 0.067. Without treatment, 14 pregnancies would have been expected. Although ovulation was not measured objectively, the regular bleeding pattern recorded in all cycles but one makes it unlikely that the contraceptive effect of mifepristone was due to ovulation inhibition. Although the failure rate of 5 mg of mifepristone is unacceptably high for a contraceptive regimen, other treatment schedules merit investigation.

Balloon catheter for induction of labor in nulliparous women with prelabor rupture of the membranes at term. A preliminary report.

The balloon catheter method has been described as an effective method for cervical ripening hitherto used exclusively before rupture of the membranes. We found it of interest to perform a pilot study of the balloon catheter method after rupture of the membranes. In 18 nulliparous women, with an unripe cervix (Bishop score < or = 5) 48 h after prelabor rupture of the membranes at term, cervical ripening was performed using a 26-gauge balloon catheter. Seventy six percent of these women delivered vaginally. Clinical and neonatal outcome data did not differ as compared with term pregnant women who entered labor spontaneously or had a ripe cervix (Bishop score >5) and labor induced with oxytocin within 48 h after prelabor rupture of the membranes. Despite visualization of a pool of amniotic fluid in the vagina on speculum examination on admission, there was a high proportion of patients with an intact forebag observed during the birth process. This preliminary report indicates that the balloon catheter method might be a well-tolerated, safe, and effective method for induction of labor after rupture of the membranes at term.

The effect of various doses of mifepristone on endometrial leukaemia inhibitory factor expression in the midluteal phase--an immunohistochemical study.

Leukaemia inhibitory factor (LIF) is a cytokine which plays an obligatory role in mouse blastocyst implantation. In human endometrium, LIF expression is significantly increased in the mid-luteal phase indicating that LIF may also play an important role in the human. We have previously shown that a single dose of 200 mg of mifepristone immediately post-ovulation is an effective contraceptive method, probably due to inhibition of endometrial development and function. The purpose of this study was to investigate the effect of various doses of mifepristone on endometrial LIF expression. A total of 22 fertile, regularly-menstruating women were studied during control and treatment cycles. The subjects were divided into four groups: group I received a single dose of 200 mg of mifepristone on cycle day LH + 2 (n = 7). The subjects in groups II and III were treated with either 5 mg (n = 5) or 2.5 mg (n = 5) once a week for 2 months. Group IV subjects received 0.5 mg per day (n = 5) of mifepristone for 3 months. LIF was measured immunohistochemically in endometrial tissue specimens taken on the corresponding day (cycle day LH + 6 to LH + 8) in hormonally-characterized control and treatment cycles. LIF immunostaining was observed in all controls and located to the cytoplasm of the luminal and glandular epithelial cells and stromal cells. In the treatment cycles the staining of luminal epithelium and stroma was similar to controls, while the glandular staining was reduced in all treatment groups. This study reveals that early luteal phase treatment as well as intermittent or daily low dose treatment with mifepristone reduces endometrial glandular LIF expression at the expected time of implantation. The results further support the contraceptive potential of mifepristone in low doses.

Effect of low daily doses of mifepristone on ovarian function and endometrial development.

The effects of low daily doses of the antiprogestin mifepristone (RU 486) on ovarian and endometrial function were studied. The study included one control cycle, three treatment cycles and one follow-up cycle. During the treatment cycles, either 0.1 (n = 5) or 0.5 (n = 5) mg of mifepristone was administered once daily. Urine samples were collected three times weekly during the control and treatment cycles and pregnanediol glucuronide and oestrone glucuronide and luteinizing hormone (LH) were quantified by radioimmunoassay. Blood samples for cortisol measurement were collected once weekly and for serum glycodelin at the onset of menstruation. An endometrial biopsy was obtained in the mid-luteal phase in the control cycle and in the first and third treatment cycles and analysed by morphometric and histochemical methods. Binding of Dolichus biflorus agglutinin (DBA) lectin was measured and expression of progesterone and oestrogen receptors and glycodelin were analysed immunohistochemically. All cycles studied were ovulatory with an LH peak and elevated pregnanediol glucuronide concentrations. Follicular development seemed normal as judged by ultrasound examination. The length of the menstrual cycle and the menstrual bleeding were not significantly altered. Following administration of 0.5 mg mifepristone/day, endometrial development appeared to be slightly retarded and glandular diameter was significantly reduced. Furthermore, significant decreases in DBA lectin binding and endometrial expression of glycodelin were observed. Daily doses of 0.1 mg did not have any significant effect on the endometrium. No differences in oestrogen or progesterone receptor immunoactivity between control and treatment cycles were seen. This study provides further evidence that endometrial function is sensitive even to doses of antiprogestin that are low enough not to disturb ovulation. It remains to be established whether these effects are sufficient to prevent implantation.

The possible use of antiprogestins for contraception.

BACKGROUND: A number of compounds, antiprogestins, e.g. mifepristone, onapristone and lilopristone, have been developed which compete with progesterone at the receptor level. One of these, mifepristone, is in combination with a prostaglandin analogue currently in use for termination of early pregnancy. The possibility to use these compounds for contraceptive purposes is presently under evaluation. METHODS: The possible contraceptive effect of antiprogestins has been evaluated in both clinical and experimental studies. RESULTS: Administration of antiprogestin during the follicular phase has an inhibitory effect on follicular development and ovulation, and on endometrial development and function if administered during the secretory phase of the menstrual cycle. A high dose of mifepristone, 200 mg, administered immediately following ovulation is highly effective in preventing implantation, most likely due to an effect on endometrial receptivity. It seems that the endometrium is more sensitive to antiprogestin than is the ovulatory process. Low weekly, 2.5 mg to 5 mg, and daily doses, 0.5 mg, of mifepristone did not inhibit ovulation, but a significant effect on endometrial development and especially endometrial function judged from measurement of the expression of a number of markers for endometrial receptivity could be demonstrated. CONCLUSION: The effect of mifepristone on the endometrium may be sufficient to prevent implantation, and if so, an oral contraceptive method could be developed which has no effect on ovarian function.

PIP: The potential use of antiprogestins such as mifepristone and onapristone for contraceptive purposes is currently under investigation. Administration of antiprogestins during the follicular phase of the menstrual cycle delays the estrogen rise and the luteinizing hormone surge. As long as treatment is continued, follicular development is delayed or arrested and ovulation is inhibited. It is assumed that the inhibitory effect of antiprogestins on ovulation is mediated by a blocking effect of progesterone on the pituitary level. A 200-mg dose of mifepristone, administered immediately after ovulation, is highly effective in preventing implantation. Although a daily dose of 0.5 mg of mifepristone does not inhibit ovulation, it has a significant effect on endometrial development and receptivity. Intermittent administration of mifepristone, together with periodic administration of a gestagen, both inhibits ovulation and induces regular withdrawal bleeding. The current research indicates that the endometrium is more sensitive to mifepristone than is the ovulatory process. If such effects are sufficient to prevent implantation, a contraceptive method based on very low doses of antiprogestin and without any effect on bleeding patterns is feasible.

Effect of post-coital contraceptive methods on the endometrium and the menstrual cycle.

STUDY OBJECTIVE: To evaluate the effect of treatment with ethinylesteradiol-levonorgestrel or danazol on ovarian function, gonadotrophin release and endometrial development during the time when a pregnancy may occur following unprotected intercourse. METHODS: Women with regular menstrual cycles were followed during one control, one treatment and one follow-up month. The women obtained either a combination of 0.5 mg levonorgestrel and 0.1 mg ethinylestradiol (Yuzpe regimen: n = 16) or 600 mg danazol orally and repeated after 12 hours (n = 16). The treatment was administered on either cycle day (cd) 12 or day LH +2. An endometrial biopsy was obtained once on cd LH +6 to +8 in the subjects treated on cd LH +2 both in control and treatment cycles, and morphometric analysis was performed. The concentrations of LH, pregnandiol (P2G), and estrone (EIG) glucuronide were followed daily in morning urine during control and treatment cycles. RESULTS: Following treatment with the Yuzpe regimen on cd 12 the LH surge was either undetectable (three subjects), postponed to cd 16 to 22 (three subjects) or cd 38 to 39 (two subjects) with lower P2G and LH levels than in the control cycle. Following preovulatory treatment with danazol, no LH peak could be detected in four subjects and in the remaining four subjects the LH peak varied between cd 13 and cd 24. The mean area under the curve for LH was significantly lower, the levels of EIG were slightly higher and the P2G levels were unaffected in comparison with the control cycle. Neither of the two treatments administered on cd LH +2 affected the hormonal pattern and only a discreet effect on the development of the endometrium was seen after the EE/LNG treatment. CONCLUSION: The findings indicate that the contraceptive effect of postcoital treatment with EE/LNG and danazol is mainly due to an inhibition or delay of ovulation and insufficient corpus luteum function. The direct effect on the endometrium is limited, if any.

Contraception with anti-progesterone.

Anti-progesterones have potential as contraceptives, acting either by the inhibition of ovulation or the inhibition of endometrial development. Clinical studies have shown that once-a-month treatment with Mifepristone in the early luteal phase is an effective contraceptive method, and that emergency post-coital contraception with Mifepristone is at least as effective as other methods currently used. Recent studies indicate that the endometrium is more susceptible to Mifepristone than are the hypothalamic and pituitary regions, and it may therefore be possible to develop a new contraceptive method based on low daily or once-weekly doses of Mifepristone that does not influence ovarian function.

PIP: The anti-progestin Mifepristone has demonstrated efficacy in inducing early abortion when administered in conjunction with prostaglandin analogues. Also possible, although less researched, is use of Mifepristone as a contraceptive agent. Modes of action include inhibition of ovulation by a long-term daily or intermittent high dose, endometrial contraception by a high Mifepristone dose in the early luteal phase, endometrial contraception by the long-term use of daily or weekly administration of low doses of Mifepristone that do not inhibit ovulation, or a high dose as emergency post-coital contraception. The available research on each of these approaches is reviewed in this article. The most recent studies indicate that the endometrium is more susceptible to Mifepristone than the hypothalamic and pituitary regions, suggesting the feasibility of low daily or once-weekly doses of Mifepristone that do not influence ovarian function.

Replens versus dienoestrol cream in the symptomatic treatment of vaginal atrophy in postmenopausal women.

OBJECTIVES: This study was designed to evaluate the efficacy of Replens, a non-hormonal moisturizing vaginal gel, on symptoms of vaginal atrophy in postmenopausal women, in comparison with Dienoestrol (Cilag), an oestrogenic vaginal cream. METHODS: Thirty-nine patients were randomly allocated to either of the two treatments. Replens was given three times a week during the 12 weeks of the study, while Dienoestrol was administered daily during the first 2 weeks and thereafter three times a week. Vaginal dryness index, itching, irritation, dyspareunia, pH and safety were evaluated every week the first month and every month thereafter. RESULTS: Both treatments had a significant increase on vaginal dryness index as soon as the first week of treatment, and the hormonal compound was significantly better than the non-hormonal one. All symptoms such as itching, irritation and dyspareunia significantly decreased or disappeared without any difference between the two treatments. For pH, no significant difference was seen either in each group or between the two groups. No adverse events related with the two drugs were found. CONCLUSION: This study shows that Replens applied vaginally three times a week, is a full therapy for all symptoms of vaginal atrophy as well as local estrogen. No serious adverse event was related. Replens is an alternative treatment to local estrogen and perhaps a good complement of systemic HRT in patient suffering from vaginal dryness.

Effect of low weekly doses of mifepristone on ovarian function and endometrial development.

The effect of a low dose of mifepristone (RU486) on ovarian and endometrial function was studied in 14 healthy women. The study included one control and two treatment cycles. During the treatment cycles, either 2.5 mg (n = 9) or 5 mg (n = 5) of mifepristone was administered once weekly. The concentration of ovarian steroids and luteinizing hormone (LH) in urine was measured daily, cortisol in blood once weekly and glycodelin (placental protein 14; PP14) at the time of menstruation. Ovarian function was monitored by vaginal ultrasound. An endometrial biopsy was taken in each cycle in the mid-luteal phase, based on self-measurement of the LH peak, or on cycle day 22 if no LH peak could be detected. In the evaluation of the results, the outcome of the enzyme immunoassay of LH was used to date the biopsy. Endometrial progesterone and oestrogen receptors and Dolichus biflorus agglutinin (DBA) lectin binding were measured. Ovulation was not inhibited by treatment with mifepristone, and an LH peak could be determined in all control and treatment cycles. However, in four subjects (one with the higher and three with the lower dose) the follicular phase was prolonged by 6-13 days. The duration of the luteal phase and the concentrations of pregnanediol and oestrone glucuronide were not affected by treatment. A dose of 5 mg, and to a lesser extent 2.5 mg, mifepristone once weekly caused desynchronization of endometrial development. Endometrial progesterone receptor, but not oestrogen receptor, concentration was significantly increased by the higher dose. A significant reduction in DBA-lectin binding and in serum glycodelin concentrations was also found. Thus, low doses of mifepristone do not inhibit ovulation but delay endometrial development and impair secretory activity. Whether these effects are sufficient to prevent implantation remains to be established.

Effects of a single post-ovulatory dose of RU486 on endometrial maturation in the implantation phase.

The effect of a single post-ovulatory dose of RU486 on endometrial maturation was studied in the implantation phase. A total of 11 healthy women were followed for one control and one or two treatment cycles. In treatment cycles, a dose of 200 or 400 mg RU486 was administered on day luteinizing hormone (LH)+2. In both control and treatment cycles, an endometrial biopsy was obtained on LH+6 to LH+8. These biopsies were assessed by morphometric and immunohistochemical analyses. The treatment with RU486 did not disturb the normal menstrual rhythm but caused a significant inhibition in the endometrial development. Glandular progesterone receptor staining was significantly more pronounced after RU486 treatment, while there was a reduction in the Dolichos biflorus agglutinin lectin binding, indicating inhibition of the normal secretory transformation of the endometrium. It is likely that these effects on endometrial development and secretory activity represent the basis of the contraceptive effect of post-ovulatory RU486 treatment.

PIP: The aim was to evaluate further the effect of a single, immediate, post-ovulatory dose of RU-486 on endometrial maturation at the time of implantation. A total of 11 healthy women, 21-40 years old, with regular menstrual cycles, volunteered for the study (height 167 cm; weight 66 kg). None of them had used steroidal contraceptives or an IUD for a minimum of 3 months prior to the study. The study included 1 control cycle and 1 or 2 treatment cycles, the subjects serving as their own controls. During the 1st treatment cycle, 200 mg mifepristone (RU-486) were given orally between 8 and 10 p.m. on cycle day LH+2. Four subjects participated in a 2nd treatment cycle in which the dose of RU-486 was increased to 400 mg. Blood samples were obtained 3 times weekly during the entire study period and were analyzed for estradiol and progesterone by radioimmunoassay. One endometrial tissue specimen was obtained in the control and the treatment cycle(s) from the anterior and lateral walls of the uterine cavity using a Randall curette. The secretory components of endometrial glands were detected by lectin cytochemistry using biotinylated Dolichos biflorus agglutinin (DBA) and the Vectastain Elite ABC immunoperoxidase detection system. The treatment did not disturb the menstrual cycle, but it produced profound endometrial changes in all subjects. A histological pattern corresponding to the proliferative phase was seen in 7 subjects, whereas 2 others demonstrated irregular secretory activity, and 2 biopsies showed a pattern corresponding to LH+4. Significantly decreased glandular diameter (p 0.01), as well as increased number of glandular (p 0.01) and stromal (p 0.01) mitoses, occurred in comparison with biopsies taken in the control cycle. In all endometrial specimens examined after RU-486 treatment there was a reduction in the DBA staining. The profound effects of RU-486 on endometrial development and secretory activity are most likely the underlying reason for the contraceptive effect of RU-486 when administered immediately following ovulation.

The use of progesterone antagonists in combination with prostaglandin for termination of pregnancy.

Antiprogestin alone is not sufficiently effective in terminating early pregnancy to be clinically useful. The only exception seems to be immediate post-ovulatory administration which inhibits endometrial development to an extent that prevents implantation of the fertilized ovum. During early pregnancy the uterus is inactive. Treatment with antiprogestin with result in an increased uterine contractility and a significant increase of myometrial sensitivity to prostaglandin. The effect is probably mainly due to the release of the inhibitory effect of progesterone. Antiprogestin not only activates the uterus, it also causes a ripening of the cervix. The combination of RU486 and either vaginal administration of gemeprost or i.m. injections of nalador provide a safe and effective medical abortion in the first 8 weeks of pregnancy. Recent clinical studies indicate that it may be possible to replace the prostaglandin analogues in current use by the orally active analogue misoprostol. Misoprostol is inexpensive and stable at room temperature and would facilitate the provision of medical abortion with mifepristone. Experimental data also indicate that a combination of RU486 and misoprostol may be developed into an effective once-a-month late luteal method to regulate fertility. Pre-treatment with RU486 is also useful in later stages of gestation. A combination of RU486 and the vaginal administration of gemeprost is a highly effective, safe and simple non-invasive method for terminating both early and late second trimester pregnancy.

Termination of early pregnancy with ZK 98,734: pharmacokinetic behaviour and clinical effect.

The antiprogestin RU 486 (mifepristone) is highly effective in inducing early abortion in women only if the compound is combined with a prostaglandin analogue. A new related antiprogestin, ZK 98,734, has been reported in animal studies to be much more potent as an abortifacient than mifepristone, concomitant with less antiglucocorticoid activity. The aim of the present two-centre study was to explore the abortifacient efficacy and plasma concentrations of ZK 98,734 in women seeking abortion. A total of 96 pregnant women with amenorrhoea of < 49 days were treated with oral doses of 12.5, 25, 50 or 100 mg ZK 98,734 twice daily for 4 days. The overall rate of complete abortion and continuing live pregnancies was 68 and 20% respectively, i.e. results comparable with treatment with mifepristone alone. No dose-response relationship was noted. In patients with complete abortion, signs of luteal dysfunction in terms of oestradiol and progesterone production were evident on the fourth treatment day, in contrast to patients with failures. Increased amounts of cortisol and prolactin were found during treatment both in successfully treated patients and failures, whereas aldosterone values remained unaffected. The effect on cortisol may indicate some antiglucocorticoid activity in the human. The concentrations of ZK 98,734 in peripheral blood after 25, 50 and 100 mg twice daily for 4 days were similar. The values were slightly above 0.5 mumol/l on the second day of treatment. Maximal concentrations of 0.7 mumol/l were seen on treatment day 4. Plasma concentrations of ZK 98,734 did not differ in cases of complete abortion and failures.(ABSTRACT TRUNCATED AT 250 WORDS)