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.

Profiles of prostaglandin metabolites in the human circulation. Identification of late-appearing, long-lived products.

The pattern of metabolites appearing in the circulation after intravenous injection of [9 beta-3H]prostaglandin F2 alpha was investigated in the human. Analysis of profiles of products was performed by two-dimensional TLC and autoradiography. Identification of labeled metabolites was accomplished by comparing their chromatographic behaviour with reference compounds in several chromatographic systems. After injection of [9 beta-3H]prostaglandin F2 alpha the initially formed metabolite was 15-keto-13,14-dihydroprostaglandin F2 alpha. However, this compound only dominated the spectrum of metabolites during the first few minutes, and several more polar products soon appeared. About 20 min after the injection the most prominent metabolite was 5 alpha, 7 alpha-dihydroxy-11-ketotetranorprostane-1,16-dioic acid, which remained the dominating plasma compound and was also the major metabolite in urine. Several other highly oxidized products were also identified in plasma. Also these metabolites appeared later and remained longer in the circulation than the initially formed 15-ketodihydro metabolite. Our findings suggested that the more degraded metabolites might serve as more reliable plasma parameters for monitoring prostaglandin production than the traditional parameter, 15-ketodihydroprostaglandin F2 alpha. This hypothesis was supported by radioimmunoassay of metabolite levels in plasma appearing after either exogenous (intravenous administration) or endogenous prostaglandin F2 alpha (late human pregnancy and parturition). In all cases studied, the tetranor metabolites remained elevated in the circulation for several hours, in contrast to their precursor, 15-ketodihydroprostaglandin F2 alpha, which disappeared rapidly.

Uterine contractility and interaction between prostaglandins and antiprogestins. Clinical implications.

It is generally believed that progesterone and PGF2 alpha are of major importance in the regulation of uterine contractility. The results summarized herein indicate that progesterone withdrawal is essential for the changes in uterine contractility normally observed during the secretory phase of the menstrual cycle and that the inactivity of the early pregnant uterus is progesterone dependent. Treatment with the antiprogestin RU486 will convert the inactive early pregnant uterus to an active organ and will increase the sensitivity of the myometrium to prostaglandin. These latter effects of antiprogestin have resulted in the development of highly effective, nonsurgical procedures to terminate early pregnancy based on a combined treatment with RU486 and different PG analogues administered orally, vaginally, or intramuscularly. RU486 also has a softening effect on the cervix as demonstrated in late first trimester of pregnancy. This effect may be useful as pretreatment to vacuum aspiration in late first and early second trimester abortion performed by vacuum aspiration or dilatation and curettage. In prostaglandin-induced second trimester abortions, pretreatment with RU486 will significantly reduce the induction-to-abortion interval and the dose of prostaglandin needed.

Development of a vaginal gel containing 9-deoxo-16,16-dimethyl-9-methylene PGE2 for cervical dilatation and pregnancy termination.

A stable hydrophilic gel for vaginal administration containing 9-deoxo-16,16-dimethyl-9-methylene PGE2 (9-methylene PGE2) was developed and its clinical usefulness for preoperative cervical dilatation and for termination of first and second trimester pregnancy evaluated in 521 pregnant patients admitted to the hospital for therapeutic abortion. Following vaginal administration of 3 mg of 9-methylene PGE2 gel a peak plasma level of between 3.5 and 10 ng/ml was found 3 to 6 hours following treatment. The "bioavailability" of the drug was in the order of 25-30%. 9-methylene PGE2 was found to be equally effective as 1 mg Cervagem for preoperative cervical dilatation. With a pretreatment period of 3 hours side effects were rare with both compounds. If the pretreatment period was extended to 12 hours the degree of cervical dilatation, but also the frequency of side effects increased significantly. Repeated administration of 9-methylene PGE2 was found to be effective (96% complete abortion) in terminating very early pregnancy provided the total dose was 10 mg or more. During second trimester the minimum effective dose was 4.5 mg of the compound repeated every fourth hour. The results of the present study have shown that with the new gel formulation the amount of 9-methylene PGE2 needed to terminate first and second trimester pregnancy was approximately ten times less in comparison with the previously used lipid base suppositories. The treatment was also associated with a low frequency of side effects.

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.

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.

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.

Progesterone receptor blockage. Effect on uterine contractility and early pregnancy.

RU 486 is an antiprogestin which acts at the receptor level. In the present study the effect of this compound on uterine contractility and sensitivity during early pregnancy was evaluated in 10 patients. Five patients in the 6th to 7th week of pregnancy received 25 mg RU 486 twice daily for four days. On the fourth day of treatment, uterine contractility was recorded. The remaining five early pregnant patients were untreated and served as control. Withdrawal of progesterone locally by RU 486 treatment resulted in the development of a regular uterine activity which was in sharp contrast to the low level contractility pattern found in the untreated control patients. Also the sensitivity to prostaglandin increased following RU 486 treatment. The efficacy of a sequential therapy of RU 486 and the PGE analogue 16-phenoxy-tetranor-PGE2 methyl sulfonylamide for termination of early pregnancy was also studied. Thirty-four early pregnant women (duration of amenorrhea for up to 49 days) admitted to the hospital for termination of their pregnancy volunteered for the study. The patients received 25 mg RU 486 twice or four times daily for four days. In the morning of the fourth day of RU 486 treatment, a small dose (0.25 mg) of the PGE analogue was given as a single intramuscular injection. The combined treatment resulted in complete abortion in 32 patients (94%). One patient experienced an incomplete abortion and in one patient the pregnancy continued unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of non-pregnant human uterine contractility. Effect of antihormones.

Uterine contractility was recorded on cycle day LH+6 to LH+8 in a control and treatment cycle in 14 healthy non-pregnant volunteers. In the treatment cycle the subjects received either 50 mg of the antiprogestin RU 486 daily for three days or 40 mg of the anti-estrogen tamoxifen daily for two days. The treatment started on day LH+2. During the recording, 2 to 5 micrograms PGF2 alpha was administered into the uterine cavity. The plasma levels of progesterone and estrogen were the same in both the control and treatment cycles. RU 486 caused a significant increase in uterine contractility expressed in Montevideo Units (MU) and a decrease in uterine tonus in comparison with corresponding data obtained in the control cycle. Following treatment with tamoxifen, uterine contractility was lower but the difference was not significant. PGF2 alpha invariably caused a stimulation of uterine contractility. However, treatment with the antihormones did not influence the response. The result of the present study indicates that the change in uterine contractility occurring in the latter part of the menstrual cycle and during menstruation is due to progesterone withdrawal.

Effect of antiprogestin, hCG and a prostaglandin analogue on human uterine contractility.

In the present study, the effect of hCG and RU 486 on non-pregnant uterine contractility and the sensitivity of the myometrium to the prostaglandin analogue misoprostol (GD Searle, Chicago, IL, USA) was evaluated. Seven healthy female volunteers participated in the study. Uterine contractility was recorded on cycle day LH+13 in two cycles. After recording the spontaneous contractility, 200 micrograms and 400 micrograms of misoprostol were administered orally at an interval of 45-60 minutes. In the second month, 5,000 IU hCG was administered on cycle day LH+8 and 10,000 hCG on cycle days LH+10 and LH+12, and 200 mg RU 486 on cycle day LH+11, 48 hours prior to the recording. In three women, a third month was included in which the same treatment, except for RU 486, was given. Treatment with hCG delayed menstrual bleeding and resulted in a significant increase in the concentration of plasma progesterone. Following hCG, the degree of uterine contractility was reduced, while after hCG and RU 486 the uterus was significantly more active. In the control cycle and following hCG alone, misoprostol had a slight stimulatory effect. When RU 486 was added, the degree of contractility following misoprostol was 4 to 9 times greater than that found if RU 486 was not given. Late luteal administration of RU 486 is not an effective method of fertility regulation. The results of the present study indicate that a combination of RU 486 and misoprostol will be more suitable for this purpose.

Oral administration of RU 486 and 9-methylene PGE2 for termination of early pregnancy.

It has been shown that the antiprogestin RU 486 increases the sensitivity of the early pregnant human uterus to the stimulatory action of prostaglandin E analogues administered vaginally or intramuscularly. To examine if RU 486 also increases uterine sensitivity to a PGE analogue given orally, two investigative approaches were used in the present study: 1) direct registration of uterine contractions before and after administration of 9-methylene PGE2 in untreated and RU-486-treated early pregnant women; and 2) an efficacy trial involving treatment of pregnant women (amenorrhea of 49 days or less) with 25 mg RU 486 twice daily for three or four days followed by 2.5, 5.0 or 10 mg 9-methylene PGE2, or 600 mg RU486 followed by 10 mg 9-methylene PGE2 administered on day 3 and 4. The results showed that oral 9-methylene PGE2 had a clear stimulatory effect on uterine contractility which was further increased by pretreatment with RU 486. Following 2.5, 5.0 or 10.0 mg 9-methylene PGE2, the frequency of complete abortion was the same, or approximately 80%. The success rate is higher than that generally reported for RU 486 treatment alone. If 600 mg RU 486 was complemented with 10 mg 9-methylene PGE2 administered on both days 3 and 4, the frequency of complete abortion increased to 95%. Side effects were of a mild nature and generally occurred following administration of 9-methylene PGE2. The results of the present study indicate that a combined treatment based on oral administration of both the antiprogestin and the prostaglandin analogue can be developed into a highly effective and simple method to terminate early pregnancy.

Vascular changes in the human endometrium following the administration of the progesterone antagonist RU 486.

Eleven healthy women were assigned to one of two groups. They received 50 mg RU 486 orally per day either on cycle days 7 to 10 (preovulatory group n = 5) or on cycle days 20 to 23 (postovulatory group, n = 6). An endometrial biopsy was taken on the fourth day of the RU-treatment in the preovulatory group and on the second (n = 2) or fourth (n = 4) treatment day in the postovulatory group. Biopsies from 34 untreated women representing matched samples from early and mid preovulatory phase (n = 10) and mid and late postovulatory phase (n = 24) were used as control. The ultrastructure of the endometrial capillaries was investigated by morphometric methods. The administration of RU 486 during the preovulatory phase did not modify the vascular structure. However, when given in the postovulatory phase, necrosis occurred in the capillary endothelial cells with and without regressive changes of the adjacent stroma. The area and diameter of the capillary lumen and the area of the adventitia was smaller than in the control material (p less than 0.01). The result of the study suggests that RU 486, when administered in the postovulatory phase, directly affects the capillary vessels of the endometrium.

Plasma levels of antiprogestin RU 486 following oral administration to non-pregnant and early pregnant women.

RU 486 is a synthetic steroid which acts as an antiprogestin at the receptor level. The clinical usefulness of the compound for menstrual regulation and termination of early pregnancy is currently being evaluated. The aim of the present study was to determine the plasma levels of RU 486 following the oral administration of the compound to 42 pregnant and 10 non-pregnant women. The levels of RU 486 were measured by a radioimmunoassay method which uses chromatography on Sephadex LH 20 columns. The identity of the compound assayed as RU 486 was confirmed, but the presence of small amounts of two highly cross-reacting metabolites (monodemethyl and didemethyl RU 486) in the analyzed fractions could not be excluded. Following the ingestion of a single tablet containing 25 and 50 mg of the compound, a peak plasma value of approximately 3.5 to 4.0 mumol/l in both the pregnant and non-pregnant subjects was reached one to two hours later. The half-lives of elimination were about 20 hours in both the pregnant and the non-pregnant women. Following the repeated oral administration of 50, 100 or 200 mg of RU 486 daily for four days, maximum plasma levels of 2.9, 4.5 and 5.4 mumol/l, respectively, were found. Thus, the increase in plasma levels was not directly proportional to the increase in the dose. No accumulation of RU 486 in the plasma was found, even when the duration of treatment was prolonged to six days. The data partly explain the reported lack of relation between ingested dose and frequency of induced abortion and they may be useful for designing future studies on the use of compound to prevent implantation, induce menstruation or terminate an early pregnancy.

Termination of very early pregnancy by RU 486--an antiprogestational compound.

RU 486, a new antiprogestational compound, was given to 37 women seeking termination of pregnancy and with amenorrhea of 42 days or less. One patient was found at the second follow-up visit to have an extrauterine pregnancy. The patients received either 25 mg, 50 mg or 100 mg RU 486 twice daily for four days. All patients attended three follow-up visits, one, two and five to six weeks after the start of therapy. The start, duration and amount of bleeding as well as plasma progesterone, beta-hCG and cortisol concentrations were determined for each treatment day and at the follow-up visits. All patients but three started to bleed during treatment. Frequency of complete abortion was 61% (22 out of 36 patients). In only three patients was the pregnancy unaffected by treatment. The clinical efficacy of the treatment was not dose-dependent. Most of the patients experienced only minor side effects in terms of mild uterine pain, nausea and vomiting. However, two patients suffered from heavy bleeding requiring blood transfusion and curettage. In the patients with complete abortion, beta-hCG values decreased significantly but not until the first follow-up visit. The plasma progesterone also decreased. The decrease appeared earlier with the higher daily dose of RU 486. Cortisol concentrations increased during treatment with all 3 dosage regimens but the levels remained within the normal range. It is concluded that treatment with RU 486 may provide a novel therapy for "menstrual regulation" but the efficacy of the treatment needs to be improved to compete with alternatives such as vacuum aspiration.

PIP: RU 486, a new antiprogestational compound, was given to 37 women seeking termination of pregnancy and with amenorrhea of 42 days or less. 1 patient was found at the 2nd follow-up visit to have an extrauterine pregnancy. The patients received either 25 mg, 50 mg, or 100 mg RU 486 twice daily for 4 days. All patients attended 3 follow-up visits, 1, 2, and 5-6 weeks after the start of therapy. The start, duration, and amount of bleeding as well as plasma progesterone, beta-human chorionic gonadotropin (hCG) and cortisol concentrations were determined for each treatment day and at follow-up visits. All but 3 patients started to bleed during treatment. Frequency of complete abortion was 61% (22 of 36 patients). In only 3 patients was the pregnancy unaffected by treatment. The clinical efficacy of the treatment was not dose-dependent. Most of the patients experienced only minor dise effects in terms of mild uterine pain, nausea, and vomiting. However, 2 patients suffered from heavy bleeding requiring blood transfusion and curettage. In patients with complete abortion, beta-hCG values decreased significantly but not until the 1ft follow-up visit. The plasma progesterone also decreased. This decrease appeared earlier with the higher daily dose of RU 486. Cortisol concentrations increased during treatment with all 3 dosage regimens but the levels remained within the normal range. It is concluded the treatment with RU 486 may provide a novel therapy for menstrual regulation but the efficacy of it needs to be improved to compete with such alternatives as vacuum aspiration.

Effect of antihormones on endometrial receptors and protein secretion.

The antiestrogen tamoxifen and the antiprogestin RU 486 both interact with respective hormones at the receptor level, RU 486 as a pure antagonist which inhibits endometrial development, the downregulation of estrogen and progesterone receptors and the production of endometrial protein, such as PP14, during the secretory phase of the menstrual cycle. Tamoxifen, on the other hand, has both agonistic and antagonistic action.

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.

Prostaglandins and antiprogestins.

There is considerable interest in the development of a non-surgical method to terminate early pregnancy. During the three weeks immediately following the first missed menstrual period, several prostaglandin (PG) analogs such as sulprostone, gemeprost and 9-methylene PGE2 have been used to terminate the pregnancy. Prostaglandins, however, at the doses required to induce disruption of the conceptus cause gastrointestinal side effects and uterine pain which are more severe than those subsequent to vacuum aspiration. Treatment with the antiprogestin, mifepristone counteracts the effects of progesterone in pregnancy and thus prevents maintenance of the pregnancy. Mifepristone administered alone causes termination of the pregnancy in most, but not all, cases. In addition to removing the influence of progesterone, mifepristrone also induces regular uterine contractions and significantly increased the sensitivity of the uterus to PG analogs. Mifepristone (50 mg/day) followed by an intramuscular injection of a low dose, (0.25 mg), of sulprostone (approximately 1/6 of the dose of prostaglandin necessary to induce abortion if used alone) was highly effective in terminating early pregnancy, causing complete abortion in 94% of cases. Gastrointestinal side effects were rare and uterine pain significantly less common than if PG analogs were used alone. Subsequently the combination of mifepristone and vaginal administration of gemeprost (0.5-1.0 mg) has been shown to be equally effective Ideally, the PG analog would be administered orally rather than by injection or vaginal administration. Preliminary data indicate that 9-methylene PGE2 but not PEG2 may be suitable for this purpose in combination with mifepristone.(ABSTRACT TRUNCATED AT 250 WORDS)