Mifepristone: a novel estrogen-free daily contraceptive pill

Abstract

When the first synthetic progesterone antagonist (mifepristone) was synthesized over 20 years ago, it was clear that it had a potential as an antifertility agent. Research into the use of antiprogestogens for contraception have concentrated on three general approaches: (1) inhibition of ovulation, (2) inhibition of implantation and (3) disruption of implantation or “menstrual induction”. The effect of mifepristone on the ovarian and endometrial cycle depends on dose, timing and frequency of administration. Doses of 10 mg per day or more suppress follicular development and estradiol levels. Ovulatory cycles are maintained in the dose of less than 2 mg although there is increased variability in cycle length. The endometrium shows some minor asynchronous changes, although these are not sufficient to prevent pregnancy. We have chosen to investigate daily doses between 2 and 5 mg which inhibit ovulation and menstruation in over 90% of cycles while still maintaining follicular development and levels of estradiol within the range found during the follicular phase. The endometrium shows proliferative or cystic changes lined by a layer of inactive glandular epithelium set in densely packed stroma. There is, however, an absence of proliferative activity as reflected by a reduced mitotic index and Ki67 staining. These unusual histological appearances are associated with downregulation of PR but a massive upregulation of AR in particularly glandular epithelium. The antiproliferative effect of mifepristone is reassuring suggesting that the risk of atypical hyperplasia due to the effect of prolonged exposure to estrogen unopposed by progesterone is low. In a pilot study, there were no pregnancies in 200 months of exposure in 50 women who used this method as their sole method of contraception. Daily mifepristone could provide a novel contraceptive method which should be devoid of the risks associated with estrogen containing combined oral contraceptive (COC), e.g. venous thromboembolism. The health benefits of avoiding the morbidity associated with menstruation are considerable. Recent surveys suggest that amenorrhoea would be popular with many women.

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.