Mifepristone: a novel estrogen-free daily contraceptive pill
Introduction
The introduction of the combined oral contraceptive (COC) pill by Pincus, Rock and Chang in the early 1960s was a major breakthrough in contraceptive technology [1]. The concept was based on the observation that when the secretion of progesterone is persistently high during pregnancy, ovulation is suppressed. Modification of the steroid nucleus resulted in synthetic orally active gestogens such as norethisterone which are contraceptive by suppressing ovulation. The addition of a synthetic estrogen such as ethinyl estradiol further enhanced suppression of ovarian function and resulted in much less irregular bleeding. The regimen of 21-days treatment followed by 7 pill-free days was chosen so that the pattern of menstruation would be similar to that which occurs during a spontaneous menstrual cycle and has remained virtually unchanged for the last 40 years [2]. However, many women “manipulate” their menses by extending the period of pill taking to more than 21 days [3]. One of the reasons for the continuing popularity of COC is this highly predictable and controlled pattern of menses.
Some of the rare but more serious side effects associated with COC, e.g. venous thromboembolism, and breast cancer, are thought to be due mainly to the estrogen component [4], [5]. For women with contraindications to COC, gestogen-only contraception offers a highly effective alternative in the form of pills (POP), depot injections or implants [6]. However, all gestogen-only contraceptives suffer from the disadvantage of a high incidence of menstrual irregularities which are the cause of a relatively low continuation rate. About 30% of women discontinue POP after 1 year because of unpredictable breakthrough bleeding or amenorrhoea. Although the latter is now considered by some women as desirable it is virtually impossible to predict the ultimate pattern of menstruation.
The last 10 years has seen the publication of a number of studies which challenge the dogma that women would not use a method of contraception which resulted in amenorrhoea. A survey of women in the Netherlands in 1994 found that a significant minority of women would welcome a method of contraception which would abolish periods [7]. The acceptance was age related with an increasing proportion of older women wanting a method which consistently produced amenorrhoea. More recently, we have further explored the attitudes of women towards amenorrhoea in a range of countries world wide [8]: 200 women attending family planning clinics in Shanghai, Hong Kong, Cape Town, Sagamu (Nigeria) and Edinburgh were given a short questionnaire asking whether they would use a method of contraception which inhibited periods (menses). The percentage of women who liked to have periods ranged from only 20% in Edinburgh to 70% in Sagamu. The latter result was surprising because in Sagamu a significant number of women had experience of depo-medroxyprogesterone acetate which frequently results in amenorrhoea. Many women in this setting thought that periods were a sign of fertility and were good for them because “they got rid of bad blood”. These positive attitudes to menstruation are presumably socially ingrained because there are no medical advantages of periodic blood loss per se. In contrast, particularly in societies with a high incidence of anaemia, the health benefits of amenorrhoea are obvious.
In our early investigations into the effects of the antigestogen mifepristone on the ovarian cycle, we noticed that at a dose of 5 mg per day the menses were delayed until some days after stopping the treatment [9], [10]. Although ovulation was inhibited, follicular development continued and the levels of estrogen maintained within the range found in the mid-follicular phase of the cycle. We postulated that this might provide a novel estrogen-free method of contraception which would result in a more acceptable pattern of menstrual bleeding than experienced with the POP. In this paper, we will briefly review our experience with low-dose mifepristone as a daily contraceptive pill.
Section snippets
History
The contraceptive potential of compounds which antagonized the action of progesterone was realised many years before the discovery of mifepristone [11]. In the original clinical publication, it was reported that menstrual bleeding was provoked after giving mifepristone at a dose of 50 mg per day in the mid-luteal phase of the cycle [12]. The effects of mifepristone on the ovarian and endometrial cycle are dependent on the dose and timing of administration. In general, higher doses suppress
Once-a-month pill
Relatively large single doses (50–600 mg) of mifepristone inhibit ovulation and implantation, when given in the mid-late follicular, and early- or mid-luteal phase, respectively. This approach is highly effective as an emergency contraceptive but results in disruption of the menstrual cycle in a significant proportion of women [14]. However, if given in the early luteal phase (day of LH surge to LH+3), the formation of a secretory endometrium is retarded and menses occurs at the appropriate time
Once-per-week pill
It was originally suggested by Hodgen and coworkers that mifepristone had potential as a once-per-week contraceptive pill by repeatedly disrupting development of follicles [23]. However, in a dose of 50 mg, the inhibition of ovulation is inconsistent [24]. In lower doses of 2.5–10 mg per week, ovulation is not inhibited although the follicular phase may be prolonged (Table 1; [25], [26], [27]). Although the endometrium is disrupted, the pregnancy rate is disappointingly high.
In summary,
Continuous daily pill
The effect of daily mifepristone on the ovarian and endometrial cycles depends on the dose (Table 2). In doses of 10 mg per day or more, follicular development is inhibited and the ovarian secretion of estradiol minimal. The hypoestrogenic state has therapeutic advantage for the treatment of endometriosis or fibromyomata [28], [29]. In doses above 50 mg, there is a significant rise in the secretion of cortisol and ACTH due to the antiglucocorticoid action of mifepristone [29], [30]. For both
The effect on the endometrium
Antigestogens have a direct as well as indirect effect on the endometrium. Because ovulation is inhibited, the endometrium biopsied after 21 days of 2 mg mifepristone per day shows persistent proliferative changes with increased expression of the cell proliferative marker Ki67 in glands and stroma [37]. Surprisingly, there is a marked reduction in mitosis as compared to persistent proliferative endometrium suggesting a block in the mitotic cell cycle. Even in cycles where there was biochemical
Effect on menstrual cycle
Approximately 90% of women taking daily 5 mg mifepristone remained amenorrhoeic throughout our study [38]. Overall, there was a marked reduction in the number of days of bleeding. In Edinburgh, 2 of the 26 women who took 2 mg per day had episodes of prolonged bleeding lasting 24 and 53 days. Although the bleeding was not heavy, and there was no significant reduction in haemoglobin concentration, menstrual disturbance such as this is a considerable disadvantage. Approximately 90% of women who took
Contraceptive efficacy
In spite of these profound effects of mifepristone on ovarian and endometrial function, there is very little data on contraceptive efficacy (Table 2). In one study in which 0.5 mg mifepristone was given to 32 women for a total of 141 cycles, five pregnancies occurred [32]. The majority of cycles were regular, although some were prolonged for up to 69 days. Although this study demonstrated a significant reduction in pregnancy rate as compared to that which would have been expected if no
Conclusions
Mifepristone and other progesterone antagonist have great potential as antifertility agents. Mifepristone together with a suitable prostaglandin has already an established clinical role as a method of inducing abortion in early pregnancy. Its effectiveness as an emergency contraceptive has been demonstrated in a number of Phase III trials although only in China is it registered for this indication. Research is needed to explore its use as regular method of contraception in the form of a
Acknowledgements
We are grateful to Mrs. Teresa Henderson for immunocytochemistry, and Mrs. Meg Anderson for typing the manuscript.
This work was supported by a Grant to the Contraceptive Development Network from Medical Research Council/Department for International Development, UK. Grant No. G9523250.
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