| BackgroundThe introduction of the combined oral contraceptive (COC) in the early 1960s was a major breakthrough in contraceptive technology. Some of the rare but more serious side effects associated with COC, e.g. venous thromboembolism, and breast cancer, are though to be due mainly to the estrogen component. For women with contraindications to COC, gestogen-only contraception offers a highly effective alternative in the form of pills (POP), depot injections or implants. 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 unpredictablebreakthrough bleeding or amenorrhoea. It is essential to find an ideal contraceptive drug.Progesterone secreted by the corpus luteum and placenta is necessary for establishment and maintenance of pregnancy. In the latter half of the menstrual cycle, progesterone induces secretory differentiation of the endometrium, with glandular changes, stromal decidualization and spiral artery differentiation. These changes are thought to be essential for the subsequent implantation and nourishment of a blastocyst. Mifepriston is a synthetic 19-norsteroid that has potent antiglucocorticoid and antigestagenic properties. It acts by blocking the action of progesterone at the receptor level, and thushas multiple potential antifertility actions.The combination of mifepristone and prostaglandin in the medical induction of abortion is now well established, a single dose as low as 10 mg is highly effective as an emergency contraceptive. Clinical experience of the potential use of antigestogens as contraceptives is confined almost exclusively to mifepristone. Mifepristone can be used to: (a) inhibit ovulation, (b)prevent implantation or (c) induce menses by disrupting implantation. These modes of action have all been utilized in attempts to develop a daily, weekly or monthly pill.Gemzell-Danielsson et al carried out a contraceptive efficacy pilot study using a single dose of mifepristone 200mg given in the early luteal phase (day LH+2). There was only 1 pregnancy out of 124 "at risk" cycles, giving a probability of pregnancy of 0.008. There was no upset to the timing of the subsequent menstrual cycle. Hapangama et al also treated subjects with 200mg of mifepristone on day LH+2, and reported two pregnancies out of a total of 178 cycles, giving a probability of pregnancy of 0.01. A second approach of inducing menses by giving mifepristone with or without misoprostol just before or at the time of expected menses results in too many failures to be used as a regular contraceptive pill.It was originally suggested by Hodgen and coworkers that mifepristone hand potential as a once-per-week contraceptive pill by repeatedly disrupting development of follicles. However, in a dose of 50mg, the inhibition of ovulation is inconsistent. In lower dose of 2.5-10mg per week, ovulation is not inhibited although the follicular phase may be prolonged. Although the endometrium is disrupted, the pregnancy rate is disappointingly high.The effect of daily mifepristone on the ovarian and endometrial cycles depends on the dose. In dose of 10mg per day or more, follicular development is inhibited andthe ovarian secretion of estradiol minimal. At dose below 2mg, ovulation continues although the follicular phase is prolonged in some cycles. Minor asynchronous changes in the endometrium have been described which are likely to interfere with implantation. However, a contraceptive efficacy trial of 0.5mg mifepristone per day was stopped prematurely because although demonstrating a reduction in fertility there were too many pregnancies to be acceptable as a regular method of contraception. In one study using 2 or 5mg per day, ovulation is suppressed in over 90% of cycles. There were no pregnancies in the 50 women who chose to use daily mifepristone as their sole method of contraception for a total 200 cycles.Currrent researches suggest that mifepristone might be a novel estrogen-free method of contraception, it will be necessary to demonstrate not only high efficacy but also minimal side effects. In particular, it will be more acceptable. If given in the early luteal phase (day of LH+2), the formation of a secretory endometrium is retarded and menses occurs at the appropriate time. Although two studies have demonstrated high contraceptive efficacy, the difficulties in timing the administration of mifepristone make it unlikely that this approach is practical for use as a egular once-a-month pill. A low-dose mifepristone (2 or 5mg) have been demonstrated high contraceptive efficacy and minimal side effects, the amenorrhoea which results from a continuous regimen would not be popular with many women.Scheme of administration need to be further studied before mifepristone can be recommended for routine contraceptive pill. Therefore, we decided to test the effect of low dose mifepristone administration in the latter half of the menstrual cycle on ovarian function and endometrial development.Materials and MethodsTen subjects were recruited to the study, and gave written informed consent. All subjects had regular menstrual cycles (26-31 days), had not used hormonal or intrauterine contraception for at least 3 months prior to the study and were willing to use reliable barrier contraception for the duration of the study. All women were screened before entering the study, included routine physical and pelvic examination. Blood samples were collected for measurement of full blood count, urea and electrolytes, liver function tests, glucose and lipids. All subjects were asked to keep daily records on any side-effects and bleeding. The study included one control cycle,three treatment cycles and a follow-up cycle. Ten women were randomly allocated to group A (n=5) and group B (n=5). During the first treatment cycle, women took mifepristone 5mg qd×14d starting on menstrual cycle day 15, then stopping 14d in group A. Women took mifepristone 5mg qod×14d starting on menstrual cycle day 15 in group B. All were repeated 3 cycles. During study, a blood sample was obtained for measurement of E2, P Once weekly. All subjects determined the LH peak in urine sample every day by using a rapid self-test and attended for transvaginal sonography starting on menstrual cycle day 10, when follicular number and diameter were measured. Endometrial biopsy was taken in control and third treatment cycle on days LH+7d according to the LH self-test. The biopsy material was immediately fixed in normal buffered formalin and after embedding in paraffin was stained with hematoxylin and eosin for light microscopy, and immuno-histochemistry of progesterone receptors (PR), and leukemia inhibitory factory (LIF).One-way ANOVA test was used for statistical analysis. Two-tailed test with P < 0.05 were considered significant. All data were managed with SPSS 10.0 for windows.Results1. In group A, menstrual cycle length was prolonged after the treatment with mifepristone, the follicular phase prolonged significantly. There was significant difference compared with control cycles (P<0.05). In group B, 1 woman got amenorrhea in the treatment cycle, and the other 4 women experienced no change in menstrual cycle length compared with control cycles. Analysis did not show any statistically significant difference (P>0.05). All subjects reported normal menstrual cycles in the follow-up cycle.2. In the treatment cycle, women's blood count, liver and kidney function, fat metabolism, serum glucose level were normal. No severe side effect occured.3. Ovarian follicular activity continued in 30 treatment cycles. 3 ovulating cycles was inhibited in group A and group B.4. There was no statistically significant difference of E2 , P values in blood between control cycle and treatment cycle in group A and B (P>0.05). During the treatment cycle, comparing group A with group B, there was no significant difference of E2, P values in blood (P>0.05).5. Optical microscopy observations indicated that the endometrium in control cycle display the character of middle secretory phase, The endometrium in third treatment cycle show the character of early secretory phase.6. Glandular epithelium PR staining was significantly more pronounced after mifepristone treatment, while there was a reduction in the LIF staining.Conclusions1. Oral low dose mifepristone in the latter half of the menstrual cycle is harmless to women's blood count, liver and kidney function, fat metabolism, serum glucose level. No severe side effect.2. Oral 5mg/qd mifepristone in the latter half of the menstrual cycle can postpone ovulation and prolong menstrual cycle length, not effect the E2, P values in blood. Oral 5mg/qod mifepristone in the latter half of the menstrual cycle do not affect ovulation and menstrual cycle.3. Oral low dose mifepristone in the latter half of the menstrual cycle can obstruct endometrial development. |
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