E.M. Belsey

Termination of pregnancy with reduced doses of mifepristone

OBJECTIVES To compare the abortifacient efficacy and side effects of three doses of the antiprogestin mifepristone plus prostaglandin for termination of early pregnancy. DESIGN Randomised, double blind multicentre trial. SETTING 11 departments of obstetrics and gynaecology and of family planning, mostly in university hospitals, in seven countries. SUBJECTS 1182 women with an early pregnancy (menstrual delay of 7-28 days) requesting abortion. INTERVENTIONS Single doses of 200 mg, 400 mg, or 600 mg mifepristone followed, 48 hours later, by vaginal pessary of 1 mg of the prostaglandin E1 analogue gemeprost. MAIN OUTCOME MEASURES Outcome of treatment; duration and subjective amount of menstrual bleeding; side effects and complications; and concentrations of haemoglobin. RESULTS Outcome was similar with the three doses of mifepristone. Of the 1151 women with known outcome, 95.5% had a complete abortion (364 (93.8%) of those given 200 mg mifepristone, 368 (94.1%) of those given 400 mg, and 367 (94.3%) of those given 600 mg), 3.7% had an incomplete abortion (14 (3.6%), 15 (3.8%), and 14 (3.6%)), 0.3% had a missed abortion (three (0.8%), one (0.3%), and none), and 0.4% had a continuing live pregnancy (two (0.5%), two (0.5%), and one (0.3%)). Of the 43 women who had incomplete abortion, 23 underwent emergency uterine curettage (usually for haemostatic purposes) and three of these women were given a blood transfusion. The numbers of reported complaints, bleeding patterns, and changes in blood pressure and haemoglobin concentrations were similar with the three treatments. CONCLUSIONS For termination of early pregnancy a single dose of 200 mg mifepristone is as effective as the currently recommended dose of 600 mg when used in combination with a vaginal pessary of 1 mg gemeprost.

Menstrual bleeding patterns in untreated women

Abstract Menstrual histories recorded by more than 1000 healthy, untreated women have been analyzed using the reference period method. Results were obtained for each year of age from 15 to 49. Between menarche and age 19, the most important feature of menstrual patterns is their variability. Within-woman mean segment (cycle) length then decreases slowly but steadily, from 29.0 days at age 20 to 26.7 days at age 40. The range of segment lengths over a year also falls, to a minimum of 7 days at age 38. During the 40s, mean segment length rises to 29 days at age 49, and there is a sharp increase in the range, to 28 days. The length and variability of bleeding episodes, however, changes little between the ages of 19 and 49. Modifications to the World Health Organization definitions of ‘clinically important’ bleeding patterns are proposed.

Consequences of uterine blood loss caused by various intrauterine contraceptive devices in South American women

Increased menstrual blood loss (MBL) associated with intrauterine device (IUD) use may precipitate or aggravate iron deficiency anaemia, adversely affecting the health of women particularly those from developing countries. Studies were conducted to define the association of MBL and iron status in South American women; to determine the level of MBL induced by IUD use which would result in iron depletion, the length of time for this depletion to occur and, comparing various IUDS, to determine if any currently tested IUDs are suited to long-term use in South American women. A total of 395 women received one of 5 types of IUDs in Santiago, Chile, and Juiz de Fora, Brazil: Lippes Loop, Multiload-250 and Multiload-375 were used in both centres; in Santiago some subjects received the Copper-7 or ProgestasertR devices and in Juiz de Fora, the TCu 200 and the T-Chloroquin IUDs were also tested. MBL and haemoglobin (HGB) were measured for 3 menstrual cycles before insertion, and following insertion, at one, two, four, six, nine, twelve, eighteen and twenty-four months in the majority of cases. Serum ferritin was measured before insertion and at intervals of six months. Mean values of MBL prior to IUD insertion in both centres varied from 21-30 ml. As with previous publications, the use of the Lippes Loop was associated with the greatest increase in MBL which was sustained throughout the 24 months of observation. Women who had one of the two types of Multiload devices inserted also had increased MBL and reduced ferritin for at least 12 months of use. TCu 200 and Copper-7 IUD users had an initial increase in MBL of 1 to 17 ml in the first six months of observation returning to normal levels beyond six months. Serum ferritin levels were lower for one year and then returned to admission values. ProgestasertR users confirmed previous reports of a reduction of 40-50% in MBL and an increase in serum ferritin. Few significant changes in haemoglobin (HGB) concentrations were found. Serum ferritin levels on admission ranged from 7.1 to 16.4 ng/ml in Santiago and from 15.8 to 23.2 ng/ml in Juiz de Fora. Many women were in a marginal state of iron balance as evidenced by lower serum ferritin values. Changes in serum ferritin were very closely related to those in MBL.(ABSTRACT TRUNCATED AT 400 WORDS)

Morphometric study of the human endometrium following continuous exposure to levonorgestrel released from vaginal rings during 90 days.

The effects of vaginal devices releasing levonorgestrel (LNG) at a constant rate of approximately 20 micrograms/24 hrs on the human endometrium were studied in a group of 69 normally menstruating women during a period of 90 days of continuous use. Peripheral blood samples were withdrawn three times weekly starting at day 10 of a pretreatment (control) cycle and then three times weekly from day 60 to 90 of the treatment period. The levels of LNG, estradiol, progesterone and sex hormone binding globulin (SHBG) were analyzed by radioimmunoassay techniques. Endometrial biopsies were obtained in the luteal phase of the pretreatment cycle and on day 84-87 of the treatment period. Increased bleeding occurred in most subjects exposed to the LNG-releasing device; the mean number of bleeding and spotting days was 26.4 +/- 8.9 S.D. which exceeded that found in their control cycle. Morphometric analyses of the endometrial biopsies using 9 quantitative indices, revealed highly significant changes in glands and stroma following the use of the LNG-releasing vaginal device. Irrespective of the circulating steroid levels, the administration of LNG significantly diminished the glandular diameter (p less than 0.001), reduced the volume density of the glands (p less than 0.001) and of the glandular epithelium (p less than 0.001). and modified the ratio glandular epithelium: glands (p less than 0.001). It is concluded that levonorgestrel released at a rate of 20 micrograms/24 hrs, induces characteristic changes in the histologic structure of the human endometrium. Although no simple correlation has been found between any of the endometrial indices and the numbers of bleeding/spotting days or bleeding days, the changes as such may represent biochemical alterations which could be predisposing factors for intermenstrual bleeding and spotting. To prove a causal relationship between morphological and biochemical changes and changes in bleeding patterns, further in-depth studies may be required.

Prostaglandin production in human endometrium following continuous exposure to low-dose levonorgestrel released from a vaginal ring

Arachidonic acid metabolites produced by primary cultures of human endometrial cells derived from biopsies obtained before and after exposure to 20 micrograms/day levonorgestrel for 84 +/- 1 days were analysed by reverse phase HPLC. This revealed a significant increase in PGF1 alpha and an epoxide metabolite upon levonorgestrel stimulation. The proportion of epoxide metabolite, PGF1 alpha and PGE2 were positively correlated with serum levonorgestrel levels while HETES, PGE2 and epoxide were similarly correlated with serum oestradiol. The extent of intermenstrual bleeding during exposure to levonorgestrel was correlated with the proportion of epoxide and HETES products in vitro which is discussed in relation to their physiological function.

The effect of the contraceptive pill on blood pressure: a randomized controlled trial of three progestogen-oestrogen combinations in Szeged, Hungary.

As part of an international multicentered investigation a double-blind comparative clinical trial was conducted at the Department of Obstetrics and Gynecology, University Medical School, Szeged, Hungary, in order to study the effect of different combined oral contraceptives on blood pressure. Healthy, normotensive women were randomly allocated to either of the following oral contraceptives: 250 micrograms levonorgestrel + 50 micrograms ethinyloestradiol (LN 250 + EE 50), 250 micrograms levonorgestrel + 30 micrograms ethinyloestradiol (LN 250 + EE 30), 1 mg norethisterone acetate + 50 micrograms ethinyloestradiol (NA 1 + EE 50). Standardized blood pressure measurements were carried out at admission and 3, 6, 9, and 12 months after admission. Blood pressure change from admission to subsequent visits was analysed in subjects who were seen by the same observer both at admission and the follow-up under consideration. The systolic blood pressure slightly but not significantly increased in groups LN 250 + EE 50 and NA 1 + EE 50, whereas the diastolic pressure showed a minimal decrease. In group LN 250 + EE 30 both systolic and diastolic blood pressure increased significantly (+5.58 and +3.20 mm Hg, respectively) at the 12-month follow-up. The study supports previous findings that combined oral contraceptive use is associated with a moderate rise in blood pressure. The progestogen-to-oestrogen ratio in the pill may be as important in this context as the dose of either component itself.

Lysosomal-enzymes in the Human Endometrium - a Biochemical-study in Untreated and Levonorgestrel-treated Women

The activities of four lysosomal enzymes, i.e. N-acetyl-beta-hexosaminidase, acid phosphatase, alpha-D-mannosidase and alpha-L-fucosidase have been measured in extracts of endometrial biopsies from untreated and levonorgestrel-treated women of fertile age. Values were compared with protein and DNA content, as well as with lactate dehydrogenase activity, used as reference constituents. In parallel, organ cultures were established from the same endometrial specimens and the release of lysosomal enzymes into the medium was followed. The human endometrium possesses a rich lysosomal equipment, comparable to that found in the human liver. In the untreated cycles, the activities of lysosomal enzymes show a coordinate response to the hormonal changes, decreasing by about 40% from the proliferative to the mid-late secretory phase. Long-term levonorgestrel treatment causes a marked cytoplasmic atrophy, as shown by decreased protein content and lactate dehydrogenase activity, whereas DNA content remains unchanged. In contrast, N-acetyl-beta-hexosaminidase, one of the most active lysosomal enzymes studied, shows a higher specific activity upon levonorgestrel. In both untreated and treated endometria, the organ cultures provide biochemical evidence for a higher release of N-acetyl-beta-hexosaminidase than of lactate dehydrogenase, indicating active secretion of the lysosomal enzyme. During levonorgestrel treatment, there was no correlation between clinically recognized spotting-bleeding patterns and lysosomal enzyme content in, or release from, the endometrium.

Cervical ripening with mifepristone (RU 486) in late first trimester abortion

In order to further evaluate the usefulness of the antiprogestogen, mifepristone, as a cervical ripening agent, a double-blind multicentre study was undertaken of 230 primigravid women with 10-12 weeks amenorrhoea who were randomly assigned to receive either 0 (placebo) or 200 mg of mifepristone 36 hours before surgical pregnancy termination. Fifteen women who did not fulfil all of the selection criteria were excluded from analysis. In the mifepristone group (N = 105) 12 women experienced some pre-operative vaginal bleeding as compared with only one subject in the placebo group (N = 110), but only one of these 12 women described the bleeding as more than her usual menstrual flow. In mifepristone-treated women the cervix was about 1 mm more dilated at operation and further mechanical dilatation was needed less frequently than in placebo-treated controls. High resistance during further mechanical stretching was encountered significantly more often and at a smaller cervical diameter in the placebo group than in the women given mifepristone. Also, dilatation was reported by the operating surgeons to be easier in women given the antiprogestogen. Other significant differences included a shorter operation time, lower peroperative blood loss and less frequent use of analgesic drugs post-operatively in the mifepristone group. Post-operative complications, the duration of post-operative bleeding and the interval to the first menstruation were similar in both groups. The results confirm that the antiprogestogen, mifepristone, is an effective cervical ripening agent which deserves further study in comparison with the currently used methods, i.e. prostaglandins and osmotic dilators.

Regional and Individual Variation in Bleeding Patterns Associated with Steroid Contraception

The disturbance in menstrual bleeding induced by many methods of contraception is an important side-effect because of its potential impact on acceptability. Amenorrhea tends to be rejected because most women value menstruation as an assurance that they are not pregnant; it is also indicative of femininity, fertility and continuing youth, and widely viewed as important to general well-being1. Prolonged or unpredictable bleeding may, at best, be merely inconvenient or embarrassing, but in some cultures the taboos associated with menstruation can make any disruption to the normal pattern almost intolerable. As many as 25% of women recruited to trials of the long-acting injectable, depot medroxypro-gesterone acetate (DMPA), discontinue method use within a year because of bleeding problems.2,3 In recent studies of newer methods, the one-year cumulative discontinuation rates for bleeding irregularities have ranged from 9% among women using monthly injectables to 17% in a group using a vaginal ring.4,5

Menstrual blood loss with use of a vaginal ring releasing 20 μg levonorgestrel per day

Abstract Menstrual blood loss (MBL), haemoglobin and serum ferritin levels were studied in a total of 127 women from three developing country centres, using a vaginal ring releasing 20 μg levonorgestrel/day. The objective was to evaluate changes in MBL and body iron stores over one year of use. The discontinuation rate for bleeding problems varied between centres from 3 to 13% at one year, but these differences were not significant. There were no differences in MBL or iron status on admission between women who completed or discontinued from the study. Even though there was considerable variation in MBL and haemoglobin levels among the three centres before insertion of the ring, a decrease in MBL was observed in all centres after commencement of ring use. Conversely, an increase in haemoglobin levels was noted in all centres although the change reached significance only in Beijing. There were no alterations in serum ferritin levels. These results suggest that use of a vaginal ring releasing 20 μg levonorgestrel/day for one year will not significantly affect menstrual blood loss volume nor cause changes in body iron stores.