1 Shanghai Institute of Family Planning Technical Instruction, International Peace Maternity and Child Health Hospital, 2 Jiaxing Reproduction Health Care Centre, Shanghai, People's Republic of China and 3 University of Edinburgh, Department of Obstetrics and Gynaecology, Edinburgh, UK
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Abstract |
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Key words: bleeding/contraception/implants/mifepristone/progestin-only
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Introduction |
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Although the mechanisms underlying menstrual disturbance are not completely understood (Fraser et al., 1997; Hickey et al., 1999a
,b
) a variety of approaches have been tested to reduce irregular bleeding in association with progestin-only contraception and thereby to improve continuation rates (Fraser, 1983
).
It has been demonstrated that the addition of an antiprogesterone to progestin-only contraception reduces the incidence of unscheduled bleeding in monkeys (Williams et al., 1997). In a small pilot study among women using Norplant®, we have demonstrated that a single dose of mifepristone 200 mg induces changes in endometrial progesterone and oestrogen receptors which are consistent with the functional inhibition of progesterone. There was a suggestion that anti-progesterone treatment might improve bleeding patterns, either by a direct effect on the endometrium or by inducing ovulation (Wang et al., 1997
). In an attempt to see whether the monthly administration of a single dose of anti-progesterone might confer a clinically significant improvement in bleeding patterns, we undertook a double-blind randomized trial of once a month administration of mifepristone to women using the Chinese levonorgestrel-releasing implant (Sino-implant).
None of the authors has any vested interests of a commercial nature relevant to this study.
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Materials and methods |
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Women were randomized (50 in each group), using random number tables, in blocks of eight attending each clinic, to receive either 50 mg mifespristone (two tablets of 25 mg each) or two placebo tablets (both placebo and mifepristone were provided by the Shanghai Hualian Pharmaceutical Co. Ltd, Shanghai, PR China). Treatment was administered in a double-blind manner.
All women were instructed to keep a daily diary of bleeding and spotting. Spotting was defined as vaginal blood loss not requiring sanitary protection. After being enrolled in the study, a record of bleeding was kept for 90 days prior to starting treatment. After completion of 90 days of record-keeping, women were instructed to attend the family planning clinic for the first treatment on the third day after the start of a bleeding/spotting episode. After the first treatment women were given a date to return to the clinic once every 28 days for 5 months (a total of six treatments in all). Treatment was always given at the family planning clinic, where pill taking was observed by a doctor after urinary ß-human chorionic gonadotrophin (HCG) had been measured to exclude pregnancy. At this visit the bleeding diary was checked. Bleeding diaries were continued for a further 90 days after completion of the last cycle of treatment.
Urinary HCG was measured using a kit (SurestepTM HCG; Applied Biotech Inc., San Diego, CA, USA), the lower level of sensitivity of which was 25 IU/l.
Statistical analysis
Since we had no meaningful data on which to base power calculations the sample size was chosen to give sufficient power to detect as significant a mean difference of 0.6 standard deviations. Menstrual diaries were analysed using the MDS Menstrual Diary Analysis Programme (World Health Organization, Special Program of Research, Development and Research Training in Human Reproduction, Statistics and Data Processing Unit, Version 3.0. 1993) (WHO, 1996).
Bleeding patterns were analysed in blocks of 90 days (reference periods) (Figure 1). For each reference period the number of days of bleeding and spotting, the number of episodes of bleeding and spotting; the mean duration of spotting and bleeding episodes and the number of `dry days' (free of bleeding and spotting) were calculated. Thus reference period 1 includes 90 days before the first treatment (mifepristone or placebo). Reference periods 2 and 3 cover a total of 180 days from the first treatment and together include 6 treatment months and the first 12 days of month 7. Reference period 4 started 39 days after the last treatment and ended 90 days later (Figure 1
).
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Results |
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The effect of treatment on bleeding patterns is shown in Figure 2. There were no statistically significant differences between subjects and controls in any of the parameters assessed during the 90 day period before treatment was started. Women in both groups tended to show a similar decrease in the number of bleeding days (and therefore an increase in the number of dry days) with time (Figure 2A
). Women treated with mifepristone bled for a mean of 48 ± 15 days (range 2188) during the first 90 days, falling to 29 days in reference period 2 (P < 0.0002) with a further decrease to 23 days during reference period 3. Women treated with placebo recorded a mean of 51 ± 15 days (range 2789) of bleeding in reference period 1, falling to 33 days (P < 0.0002) during reference period 2. By reference period 4 (after treatment), there were no significant differences between subjects and controls in any of the bleeding parameters measured. The mean number of bleeding and spotting episodes also fell with time (Figure 2B
), with no significant difference between women treated with mifepristone and controls. The most marked difference between the two groups was in the average duration of bleeding episodes (Figure 2B
) which, among the subjects, fell from a mean of 14 days before treatment to 6.5 days after the first 90 days of treatment (P < 0.00001). Among controls, the mean duration of bleeding episodes also fell significantly with time from 15 days during the 90 days before treatment to 11.1 days at the end of the first 90 days of treatment (P = 0.0003) and 8.2 days after the completion of all six treatment cycles. The mean duration of bleeding episodes almost halved for both groups of women when the number during the pre-treatment period was compared with that post-treatment, regardless of whether they had been treated with placebo or mifepristone.
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Discussion |
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While these results may seem somewhat disappointing, the women clearly found mifepristone to be of benefit. It hardly needs scientific methodology to confirm that a bleeding episode of shorter duration has to be more acceptable than one that continues for days on end.
Levonorgestrel contraceptive implants act mainly by changing the quality of cervical mucus and inhibiting normal sperm penetration (Croxatto et al., 1987). Abnormal endometrial development will prevent implantation, should fertilization occur. Any intervention designed to improve bleeding patterns which `inhibits' the action of the progestogen might theoretically jeopardize contraception. Reassuringly, no woman conceived during 300 `cycles' of use of mifepristone in combination with the Sino-implant. In the event that administration of an anti-progesterone might reverse the contraceptive effects of the progestogen, mifepristone itself at a dose of 50 mg has both contraceptive and abortifacient effects and the risk of pregnancy may in fact be reduced still further.
The results of this study suggest that the once a month administration of mifepristone may be an effective and acceptable way to ameliorate bleeding irregularities and `tide women over' until bleeding patterns improve with time as a consequence of an increasing frequency of ovulatory cycles. It is possible to achieve a similar effect with the combined oral contraceptive pill (Diaz et al., 1990), but most women find the idea of using two hormonal contraceptives simultaneously hard to understand and many have chosen a long-acting implant because they do not like or cannot remember to take a pill every day. Further, and more detailed, studies of the mechanism of action of this regimen are warranted.
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Notes |
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References |
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Submitted on December 20, 1999; accepted on May 23, 2000.