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Endocrine Care |
Contraceptive Development Network (A.B., D.T.B.), Centre for Reproductive Biology, University of Edinburgh, Edinburgh, EH3 9ET United Kingdom; and Shanghai Institute of Family Planning Technical Instruction (L.C., S.L.), International Peace Maternity and Child Health Hospital, China Welfare Institute, Shanghai 200030, People’s Republic of China
Address all correspondence and requests for reprints to: Prof. D. T. Baird, Contraceptive Development Network, Centre for Reproductive Biology, University of Edinburgh, 37 Chalmers Street, Edinburgh, EH3 9ET United Kingdom. E-mail: cdn{at}ed.ac.uk
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Abstract |
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Ninety-eight women (58 in Edinburgh and 40 in Shanghai) were randomized to receive either 2 or 5 mg mifepristone daily for 120 d. Ovarian activity was monitored by the weekly measurement of steroid metabolites in urine and of E2 and P in plasma every month. Endometrial function was assessed by menstrual records, and ultrasound measurement of endometrial thickness was assessed every month. Endometrial biopsy was collected on d 12 of the control cycle and after 60 and 120 d of treatment.
Ninety women (50 in Edinburgh and 40 in Shanghai) completed the study. Follicular activity continued during treatment with both doses in Edinburgh women, although ovulation was suppressed in the majority of cycles (90 and 95% of cycles in 2- and 5-mg groups, respectively). The women in Shanghai showed evidence of ovulation in only 3 of 160 months of treatment (2 in 2-mg group and 1 in 5-mg group). The majority of women in both centers were amenorrheic (65% in 2-mg group and 88% in 5-mg group in Edinburgh, and 90% in both dose groups in Shanghai). The endometrial thickness increased significantly in women in Edinburgh and decreased in Shanghai; histology showed either atrophic or cystic changes without evidence of hyperplasia. There was no pregnancy reported in the 200 months of exposure in 50 sexually active women who had used no other method of contraception during the study.
We conclude that mifepristone in low daily doses inhibits ovulation and induces amenorrhea in the majority of women and has the potential to be developed as a novel estrogen- free oral contraceptive pill.
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Introduction |
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Progesterone (P) is necessary for the establishment as well as the maintenance of pregnancy. Mifepristone and other antigestogens are now licensed for the termination of pregnancy in a number of countries worldwide (3, 4). However, the contraceptive potential of these compounds is much less explored (5, 6). It has been demonstrated previously that administration of mifepristone in daily doses as low as 2 mg will inhibit ovulation and prevent the formation of a secretory endometrium (7, 8, 9). Menstrual bleeding was delayed until the mifepristone was stopped after 30 d. Others have demonstrated that ovulation is delayed or inhibited when lower doses, e.g. 1 mg, are given for up to 5 months (10, 11). However, it is uncertain whether the minor effects that are observed on the endometrium would be incompatible with the establishment of pregnancy (12).
We have chosen to investigate the effect of the daily administration of mifepristone in a dose that would inhibit ovulation reproducibly. In this study, we report the effects of a double-blind randomized control trial comparing the effects of administration of 2 and 5 mg mifepristone per day for 120 d on ovulation and pattern of menstrual bleeding. We tested contraceptive efficacy in a subset of women who were exposed to the risk of pregnancy.
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Materials and Methods |
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Subjects were studied for one pretreatment cycle, for four cycles of treatment (120 d), and for one posttreatment cycle. Subjects were randomly allocated to receive 2 or 5 mg mifepristone daily for the 120 treatment days. The randomization was achieved from a table of random numbers and stratified by dose in groups of 10. The daily doses were issued in prepackaged identical bottles containing either 2x 1 mg mifepristone plus placebo or 1x 5 mg plus two placebos. The investigators and subjects were unaware of the dose that each subject was taking.
All subjects in Shanghai used this method as the sole method of contraception for the 4 months of treatment. In the Edinburgh center, 10 women used the method as the sole contraceptive, the remainder being surgically sterilized, not sexually active, or using barrier contraceptives.
Assessment of ovarian function
Ovarian function was monitored by measurement of ovarian steroids in urine and plasma and by transvaginal sonography. All subjects collected a weekly sample of early morning urine during the pretreatment cycle, starting in the early follicular phase (d 1–5), during the four cycles of treatment, and during the posttreatment cycle. Aliquots were frozen and stored at -20 C until assayed for estrone glucuronide (E1G), pregnanediol glucuronide, and creatinine (Cr). Blood samples were collected before treatment, after 30, 60, 90, and 120 d of treatment, and in the posttreatment cycle, and were assayed for E2 and P.
Ovarian follicular activity during treatment was compared with that in the follicular phase of the pretreatment cycle. The baseline ovarian function was taken to be the mean of the two samples collected in the follicular phase of the pretreatment cycle, and the activity during treatment was scored according to the following criteria: 1) totally suppressed, E1G throughout treatment is less than 50% above the mean baseline; 2) partially suppressed, E1G is raised at least 50% above the mean baseline on one or two consecutive weeks (i.e. one episode of follicular activity); 3) continued follicular activity, E1G raised at least 50% above the mean baseline on at least two separate occasions (i.e. separated by at least 2 wk). Ovulation was deemed to have occurred if the excretion of pregnanediol glucuronide exceeded 0.5 mmol/mol Cr and was at least 3-fold higher than that in the preceding week (13).
Each subject attended for transvaginal sonography on d 12 of the pretreatment cycle, after 30, 60, 90, and 120 d of treatment, and in the posttreatment cycle, when ovarian dimensions, follicular number and diameter, and any ovarian cysts were measured.
Assessment of endometrial development
Endometrial thickness was measured by transvaginal sonography on d 12 of the control cycle, after 30, 60, 90, and 120 d treatment, and in the posttreatment cycle. Measurement was performed in the sagittal plane, from one basal layer to the other; the diameter of any luminal fluid present was subtracted from the measurement. Endometrial biopsies were collected by Pipelle biopsy, fixed in normal buffered formalin, and embedded in paraffin. Samples were collected on d 12 of the pretreatment cycle and after 60 and 120 d of treatment. Sections were stained with hematoxylin-eosin, and endometrial histology was assessed by two observers who were blind to sample timing and dose group.
Assessment of menstrual bleeding pattern
Each subject was required to keep a menstrual bleeding diary for the duration of the study. Each day was classified as no bleeding, spotting, normal bleeding, or heavy bleeding.
Assay methods
All assays were performed in the laboratory of the center using similar methods. Pregnanediol glucuronide was measured using a direct enzyme immunoassay (working range, 0.25–32 µM/liter), whereas direct immunoassay was used to measure E1G (working range, 8.4–2140 nM/liter). In Edinburgh, the primary antibodies were rabbit E-3-G BSA and anti P-3-G BSA for E1G and pregnanediol glucuronide, respectively, obtained from the MRC/AFRC Comparative Physiology Research Group (London, UK) and used as described previously (14, 15) from our laboratory. In Shanghai, kits using similar reagents were obtained from Immunometrics Ltd. (London, UK). Intra- and interassay coefficients of variation were 6 and 9% for E1G, and 10 and 13% for pregnanediol glucuronide in Edinburgh; and 7.5 and 9.1% for E1G, and 8.9 and 10.3% for pregnanediol glucuronide in Shanghai. Geometric means of daily replicates were divided by the respective daily Cr concentration to correct for variations in the dilution of the urine specimen.
E2 and P in plasma were measured by RIA. In Edinburgh, E2 was assayed after ether extraction using I125 E2 3-carboxymethyl as label and sheep antiserum (BW/26/9/90). P was measured by direct immunoassay using I125-11
progesterone glucuronide (Amersham International, Bucks, UK) as label, and rabbit antiprogesterone 11-hemisuccinate BSA antiserum. In Shanghai, E2 and P were assayed directly using commercially available ELIZA kits (Biosource Technologies, Inc., Nivelles, Belgium). In Edinburgh, intra- and interassay coefficients of variation were 8 and 11% for E2, and 8 and 10% for P (9), whereas in Shanghai the corresponding values were 4.4 and 7.6% for E2 and 6.8 and 7.4% for P.
Fifty samples that were assayed for E2 in both Shanghai and Edinburgh gave comparable values over the range measured (correlation coefficient, 0.89)
Safety parameters
Each subject was reviewed in the pretreatment cycle, after 30, 60, 90, and 120 d of treatment, and in the posttreatment cycle. At each visit, blood pressure and pulse were measured, and blood was taken for full blood count, urea and electrolytes, liver function tests, glucose, lipids, PRL, and cortisol. In addition, each subject was asked to report any health problems or adverse events that had occurred since the last visit.
Statistical methods
The power calculation was based on the numbers required to show a significant difference in ovulation rates, which was assumed to be 25% for 2 mg and 5% for 5 mg (7, 8, 9). It was calculated that 92 women would be required to demonstrate with 80% power a significant difference (P < 0.05) between doses.
Statistical analysis was carried out using SPSS (SPSS, Inc., Chicago, IL). Wilcox signed rank test and paired t test were used to compare plasma E2, urinary estrone, and endometrial thickness before and at various time points throughout treatment. Analysis of covariance was used to compare the dose effect on plasma E2 levels and on endometrial thickness.
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Results |
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).
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Ovarian function
There was considerable variation in the pattern of excretion of E1G, with some women showing cyclical fluctuations representing growth and regression of ovarian follicles (Fig. 1A). In others, the level remained consistently low (Fig. 1C).
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). There was a small but statistically insignificant fall in E1G excretion in the 2-mg group (P = 0.06). The mean E1G level during the 4 months of treatment was similar to that found during the follicular phase of the pretreatment cycle in both groups (P > 0.1). There was no significant change in the mean level of E2 in samples collected monthly in either dose (Fig. 3) (mean ± SE; 2 mg, 478.1 ± 60.7 vs. 408.5 ± 28.8 pmol/liter, P = 0.26; 5 mg, 452.1 ± 42.6 vs. 435.7 ± 50.9 pmol/liter, P = 0.83).
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). Fewer women in the higher dose group (5 mg) than in the 2-mg group (19 vs. 38%) ovulated once during treatment, and there were fewer ovulatory cycles (10 of 104 vs. 5 of 96, respectively). Transvaginal sonography identified eight fluid-filled ovarian cysts (30–63 mm) in the Edinburgh group, four in each dose group. All were asymptomatic and resolved spontaneously during treatment.
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). The concentration of E2 was significantly (P < 0.001) lower in both treatment groups by the end of the first month (Fig. 5), and this depression was sustained throughout treatment (mean ± SE, 2 mg, 210.2 ± 9.4 vs. 124.0 ± 3.4 pmol/liter; 5 mg, 221.4 ± 14.8 vs. 124.4 ± 2.3 pmol/liter; P < 0.001).
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). Consistent with a profound degree of ovarian suppression was the fact that no ovarian cysts were detected during the monthly examination by transvaginal ultrasound. Within 30 d of stopping treatment, ovulatory cycles returned in all women in both Edinburgh and Shanghai.
Menstrual bleeding pattern
In Edinburgh, 17 of the 26 women (65%) treated with 2 mg mifepristone and 21 of 24 women (88%) given 5 mg were amenorrheic throughout the treatment phase. In Shanghai, 18 of the 20 women (90%) in each dose group were amenorrheic during treatment.
In Edinburgh, the mean number of days of bleeding during treatment was 4.4 d for the 2-mg group and 0.6 d for the 5-mg group. In Shanghai the mean number of days of bleeding was 0.4 and 0.7 d for the 2- and 5-mg groups, respectively. These differences in mean number of days of bleeding are largely due to two women in the Edinburgh 2-mg group who reported 24 and 53 d of bleeding during treatment. Analysis by Mann-Whitney U test did not show any statistically significant treatment difference in mean number of days of bleeding during treatment.
Of those 15 women in Edinburgh (10 in the 2-mg group and 5 in the 5-mg group) who showed biochemical evidence of ovulation, only 4 (3 in the 2-mg group and 1 in the 5-mg group) reported a menstrual bleed subsequent to the rise in pregnanediol excretion, suggesting asynchrony between the ovarian and endometrial cycles. Of the Shanghai women who showed biochemical evidence of ovulation, the two women in the 2-mg group reported a subsequent menstrual bleed, but the woman who ovulated on 5 mg daily did not (Fig. 1D).
All subjects reported a menstrual bleed within 3 wk of stopping mifepristone treatment. There was a trend in both Edinburgh and Shanghai for this posttreatment bleeding to be longer than the normal pretreatment menses (Table 3). However, the only difference that reached significance was the increase in the number of days of bleeding post treatment in the Edinburgh group treated with 2 mg (5.2 vs. 10 d; P < 0.05; Mann-Whitney U test).
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Transvaginal sonography
In the Edinburgh women, there was a trend during treatment for the endometrial thickness to increase relative to the baseline measurement on d 12 of the pretreatment cycle (Fig. 3). This increase in thickness was significant after 3 months of treatment in the 2-mg group (P = 0.020) and after 2 months of treatment in the 5-mg group (P = 0.015). Analysis of covariance did not show any treatment difference at any of the time points in the Edinburgh women.
In contrast, the Shanghai women showed a significant reduction in endometrial thickness in both dose groups (2 mg, P = 0.003; 5 mg, P < 0.001) by the end of the first month of treatment (Fig. 5). This significant thinning of endometrium was maintained in the Shanghai women throughout the 4 months of treatment. Analysis of covariance showed a treatment difference in the Shanghai women after 1 month of treatment (P = 0.034), but not at any other point.
Endometrial histology
Normal endometrium was confirmed on all pretreatment biopsies. In the Edinburgh women, the endometrial appearances were similar after both 60 and 120 d of treatment, with the majority of subjects showing either simple proliferative or inactive endometrium with some cystic dilatation (Fig. 6). One subject in the 5-mg group showed secretory changes in the endometrium collected after 120 d of treatment. This correlated with biochemical evidence of preceding ovulation. Two subjects in the 2-mg group were in the luteal phase following an episode of ovulation when the endometrium was collected. Neither of these samples showed secretory changes. One Edinburgh subject in the 5-mg group showed features of complex hyperplasia after 60 d of treatment, but after 120 d this subject’s endometrium had become inactive. No cases showed any evidence of cytological atypia.
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Safety parameters and adverse events
There were no changes in mean blood pressure and pulse during treatment with either dose of mifepristone. Likewise, monitoring of full blood count, serum biochemistry, and lipids did not show any significant changes during the 4 months of treatment. There were no changes in the levels of PRL and cortisol.
In the Edinburgh group, three subjects showed an elevation of alanine transaminase during treatment. The other markers of liver function (
glutamyl transferase, bilirubin, and alkaline phosphatase) remained within the normal ranges. In two subjects (2 and 5 mg), the alanine transaminase single elevated value was associated with a flu-like illness and returned to within the normal range while treatment continued. In the third subject (5 mg), who was asymptomatic, the level rose from 34 U/liter before treatment to 111 U/liter at the end of 120 d and fell to 39 U/liter 2 months after stopping treatment.
In the Edinburgh group, six subjects reported hot flushes during treatment. In all subjects, the plasma E2 level was within the normal range, and the flushes resolved once the study medication stopped. No hot flushes were reported in the Shanghai group.
Contraceptive efficacy
All 40 women in Shanghai and 10 of the Edinburgh women used no other method of contraception during the 4 months of treatment, giving a total of 200 months exposure to pregnancy risk. No pregnancies occurred.
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Discussion |
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In Shanghai, ovarian activity was more profoundly suppressed with both doses of mifepristone than in Edinburgh. Levels of urinary E1G and plasma E2 were suppressed during treatment to those found during the follicular phase of the cycle. Moreover, fewer women ovulated, and the endometrium was thinner than in Edinburgh women. The possible reasons for these differences include ethnic, dietary, and body composition. The Chinese women were significantly lighter than the women from Edinburgh and had a lower body mass index. It is possible that the difference in diet may alter the enterohepatic circulation, which is known to influence metabolism of steroids (16). The concentration of E2 in the control cycle was significantly lower in women in Shanghai than those in Edinburgh. However, in Shanghai the samples were collected in the early follicular phase of the cycle, whereas those in Edinburgh included women at mid-cycle and the luteal phase. The values from women in the follicular phase in both centers are similar, so we think it is unlikely that differences are due to the differences in assays, which correlated very well. Previous investigations have reported lower levels of E2 and estrone sulfate in Chinese compared with Caucasian women (17) as well as differences in urinary metabolites (18).
There were differences in other parameters of ovarian activity between the two groups of women. No ovarian cysts were detected in the Chinese women, in keeping with consistent suppression of ovarian activity. In contrast to the women in Edinburgh, there was a significant decline in the thickness of the endometrium in Chinese women in both dose groups. Taken together with the suppression of ovarian steroids, these observations all suggest that ovarian activity is more easily suppressed by mifepristone in women in Shanghai than those in Edinburgh.
Concern has been expressed previously that long-term exposure to antigestagen compounds will carry a risk of endometrial hyperplasia and possible malignancy by allowing the endometrium continuous exposure to estrogen unopposed by P (19). A previous study reporting on daily treatment with 1 mg mifepristone over five cycles did not find any cases of endometrial hyperplasia, although a number of subjects were found to have a thickened endometrium on ultrasonography (11). Our study has confirmed that there were no cases of endometrial hyperplasia in 90 women after 4 months of exposure to daily low-dose mifepristone. One subject showed hyperplastic change after 2 months of exposure, but this had resolved to inactive endometrium by the end of 4 months of treatment.
In the group of women treated in Edinburgh, endometrial thickness was found to increase throughout the treatment period, although it remained within the range found in the luteal phase of the cycle. However, this thickening did not appear to reflect exposure to unopposed estrogen because even the cases with thicker endometrium did not show evidence of hyperplasia. In monkeys, antiprogestogen induces a dose-dependent decrease in endometrial thickness and proliferation despite up-regulation of estrogen receptors (20, 21). A number of women showed inactive but dilated glands, and it may be that a thickening apparent on ultrasonography reflects the collection of fluid within the glandular lumen rather than true thickening. In contrast, the women treated in Shanghai did not follow this pattern. Indeed, there was progressive reduction in endometrial thickness in the Chinese women during the 4 months of treatment, and the endometrium of the Chinese women did not show the cystic dilatation that was frequently observed in the Edinburgh tissue. The mechanism by which mifepristone prevents hyperplasia of the endometrium in the presence of unopposed estrogen is not clear but has been observed with other antigestogens (21, 22).
Edinburgh women showed more ovarian activity and had higher plasma E2 levels during treatment than those in Shanghai, and it may be that these differences result in varying endometrial exposure to circulating E2. Conversely, although there was less ovarian activity in the Shanghai women, there were more cases showing secretory change. Previous work using 1 mg mifepristone daily also identified cases of endometrial secretory change without a preceding ovulation and luteal phase (11). It has been postulated that mifepristone can have agonist effects on the endometrium, particularly when endogenous P levels are very low (21). It may be that the endometrial appearances in the Shanghai women reflect this agonist activity that becomes manifest as a result of the ovarian suppression and lack of endogenous P.
The major advantage of the combined oral contraceptive (COC) is high efficacy combined with predictable pattern of bleeding. Many of the more serious side effects associated with COCs, e.g. venous thromboembolism, are largely due to the estrogen component (1). Progestogen-only contraceptive pills are less effective than COCs and are associated with considerable upset in the pattern of menstrual bleeding. A published study using 1 mg mifepristone per day demonstrated that more than half the women showed irregular bleeding or amenorrhea (11). Regular menses are maintained when the dose is reduced to 0.5 mg/d, but unfortunately the contraceptive efficacy is insufficient (12). The fact that the majority of women in our study have amenorrhea or a markedly reduced number of days of bleeding suggests that it would be a popular option at least in some European countries (23). Suppression of ovulation combined with disruption in the formation of a secretory endometrium makes it very likely that it would be a particularly effective contraceptive, as suggested by our preliminary findings.
The results of this study confirm that a daily dose of 2 or 5 mg mifepristone has antifertility effects. There were no pregnancies in the 50 sexually active women who were exposed to the risk of pregnancy for a total of 200 months. However, it is not possible to assess the contraceptive efficacy accurately from these preliminary data, particularly because the majority of women exposed to the risk of pregnancy (40) were Chinese in whom ovarian activity was suppressed more effectively than in women in Edinburgh. The 2-mg dose allows more ovulatory episodes and has a less predictable bleeding pattern. The 5-mg daily dose has a more predictable pattern of amenorrhea and may therefore have greater acceptability in practice. Longer term studies are required to further assess the endometrial safety of daily low-dose mifepristone and to confirm the contraceptive efficacy.
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Acknowledgments |
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Footnotes |
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Abbreviations: COC, Combined oral contraceptive; Cr, creatinine; E1G, estrone glucuronide; P, progesterone.
Received July 18, 2001.
Accepted September 19, 2001.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
, Menses. A, Persistent follicular activity but no ovulation in a woman in Edinburgh on 2 mg/d. B, Single ovulatory episode in Edinburgh woman on 2 mg/d. C, Complete suppression of ovarian activity in Edinburgh women on 5 mg/d. D, single ovulatory cycle in woman in Shanghai on 5 mg/d.
