1 Department of Woman and Child Health, Division for Obstetrics and Gynaecology, Karolinska Hospital/Institute, Stockholm, Sweden, 2 Department of Obstetrics and Gynecology, Dijkzigt University Hospital, Rotterdam, The Netherlands, 3 Department of Gynecology, The Princess Royal Hospital, Hull, UK, 4 Instituto Chileno de Medicina Reproductiva, Santiago de Chile, Chile, 5 Service d'Endocrinologie, Hopital Saint-Antoine, Paris, France and 6 Department of Obstetrics and Gynecology, University of Edinburgh, Edinburgh, UK
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Abstract |
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Key words: anti-progestogens/cycle control/progestogen-only pill
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Introduction |
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Daily administration of 75 µg desogestrel (Cerazette; Organon, Oss, The Netherlands) has been shown to be a safe and reliable contraceptive method with an efficacy comparable with low-dose combined oral contraceptives (Collaborative Study Group on the Desogestrel-Containing Progestogen-Only Pill, 1998). However, irregular bleeding remains a major clinical problem and satisfaction and long-term compliance may improve if these bleeding problems can be reduced.
Org 31710 is a synthetic 19-nor steroid possessing strong anti-progestogenic and weak androgenic/anti-androgenic activity. It has less anti-glucocorticoid activity than, for example, mifepristone. Org 31710 did not show any agonistic progestogenic activity in the Clauberg test, even in doses 4- to 8-fold higher than the progestogen norethisterone (Kloosterboer et al., 1988, 1994
). If administered during the mid-luteal phase of the menstrual cycle at sufficiently high dosages, Org 31710 will, as with other anti-progestogens, induce bleeding and shedding of the endometrium (Kloosterboer et al., 1988
; Swahn et al., 1988
). Org 31710 appeared to be more potent than mifepristone for induction of menses in monkeys, since the monkeys started to bleed 12 days earlier than following mifepristone (Kloosterboer et al., 1988
). In an earlier study it was shown that a single dose of 150 mg Org 31710 was the lowest dose that would induce a bleeding within 2428 h after ingestion (data on file, Organon).
It has been demonstrated that the addition of an anti-progesterone to progesterone-only contraception reduces the incidence of unscheduled bleeding in monkeys, and that the supplementary administration of an anti-progestogen to a POP regimen may improve cycle control, possibly as a result of blocking progesterone receptors in the endometrium (Hodgen et al., 1994; Heikinheimo et al., 1996
). Once a month administration of mifepristone improves bleeding patterns in women using subdermal contraceptive implants releasing levonorgestrel (Norplant) (Cheng et al., 2000
). The improvement in bleeding pattern could be either by a direct effect of anti-progestin on the endometrium, as suggested by the effect on steroid receptor expression, or by inducing ovulation (Glasier et al., 2002
). An increased ovulation rate may jeopardise contraception; however, no pregnancies occurred when mifepristone was administered to Norplant users (Cheng et al., 2000
)
This study was designed to determine if the addition of the new anti-progestogen, Org 31710, at regular 28 day intervals to a POP regimen of 75 µg desogestrel daily would improve cycle control in women using this form of contraception. As part of this study the effect on endocrine parameters was studied. These data have been published separately (Van Heusden et al., 2000)
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Subjects and methods |
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Eligible subjects were given a continuous POP regimen consisting of 75 µg desogestrel daily and then randomized by computer code to receive in addition either a single dose of 150 mg (three tablets containing 50 mg each) of the anti-progestogen, Org 31710, or visually indistinguishable placebo tablets once every 28 days in a double-blind fashion. The first desogestrel and Org 31710/placebo tablets were both given on the first day of menstruation and therapy continued for between 16 and 28 weeks (four to seven cycles of 28 days). Therefore, Org 31710/placebo tablets were given on a maximum of seven occasions (mean 5.8) on days 1, 28, 56, 84, 112, 140 and 168.
Subjects
Women were eligible for participation in the study if they were healthy, 1845 years old, had normal menstrual cycles with a mean length of 2435 days (with an intra-individual variation of ±3 days) and a body mass index between 18 and 29 kg/m2. The menstrual history was asked for in detail at the screening visit. The volunteers were advised to use barrier methods of contraception during the whole treatment period unless they had undergone sterilization. Women who had taken recent steroid contraceptive therapy (orally 1 month, parental 6 months), who were lactating, had abnormal haematological or biochemical values at screening, hypertension, PAP smear class III or higher and undiagnosed vaginal bleeding were excluded from participation.
Vaginal bleeding pattern
The occurrence of vaginal bleeding was documented on a daily basis on a diary card by the women themselves. Vaginal bleeding was indicated as spotting (requiring maximally one pad/tampon per day) or bleeding (requiring two or more pads/tampons per day). Analysis of bleeding patterns was performed, excluding women with major protocol violations, as a per protocol group, by cycle and reference period (RP). Major protocol violations were defined as serious non-compliance with the study drugs, missing data on the diary cards or deviations from inclusion/exclusion criteria (i.e. injectable hormonal contraception within 6 months or other hormonal contraception within 4 months prior to the start of the study).
For the cycle analysis, treatment cycles were defined as the days between Org 31710/placebo intake. Based on the hypothesis that Org 31710 induces a regular bleeding pattern, each cycle was subdivided in two sections: a first section of the first 7 days (day 17: period of expected bleeding) and the other section (day 828, when bleeding was not expected). The percentage of women with bleeding or spotting (B/S), the number of B/S days, and the occurrence of B/S episodes starting in a certain period of the cycle were calculated per woman, per cycle and per RP.
Reference period analysis was performed as described by the World Health Organization using 90 day RPs (Rodriguez et al., 1976; Belsey et al., 1986
; Belsey and Farley, 1988
). Bleeding was categorized in five bleeding pattern indices (amenorrhoea, infrequent bleeding, frequent bleeding, prolonged bleeding and irregular bleeding) following standard World Health Organization definitions (Belsey et al., 1986
), with a modification for infrequent bleeding.
Amenorrhoea was defined as no B/S throughout a RP; infrequent bleeding was defined as less than three B/S episodes starting within an RP excluding amenorrhoea; frequent bleeding was defined as more than five B/S episodes starting within a RP; prolonged bleeding was defined as at least one B/S episode starting within a RP and lasting >14 days, and irregular bleeding was defined as a range of the length of bleeding-free intervals <17 days. Bleeding patterns were analysed for a shifted RP which was defined as a period of 90 days, starting 28 days after the first day of treatment, i.e. day 29118. This period was chosen to exclude the bleeding episode at the start of the study, noted for all women since the study started on the first day of menses. This shifted RP was considered more useful in comparing bleeding patterns between treatment groups.
Safety
Evaluation of safety was performed at screening, 13 days after each Org 31710/placebo intake and 13 days after the last desogestrel POP intake. Safety evaluation included assessment of haematology parameters, biochemistry and enzymes, urinalysis and vital signs. The numbers and nature of adverse events were recorded throughout the study period. For safety variables, only descriptive statistics were used.
Data analysis
For the cycle analysis, treatment cycles were defined as the treatment period starting on the day of Org 31710/placebo intake and ending on the day before the next Org 31710/placebo intake. These cycles were subdivided into the first period of 7 days (expected bleeding) and the remaining part of the cycle (non-expected bleeding).
Variables (such as mean number of B/S days, occurrence of B/S episode) were calculated per subject, per cycle and per period. Treatment group comparison was performed using the Wilcoxon test stratified for centre. In addition, the variables were summarized for each subject across cycles 27. These intra-subject variables are presented and analysed using the Wilcoxon test, stratified for centre.
The RP analysis as described by the World Health Organization using 90 day RPs was performed with inter-group comparison using the Wilcoxon test, stratified for centre. Differences between the treatment groups in the number of subjects who discontinued the study were analysed using the CochranMantelHaenszel test.
For safety parameters, descriptive statistics were used. Results were considered statistically significant if P < 0.05.
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Results |
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Cycle analysis
The median percentages of days with recorded B/S per cycle (and period of the cycle) are presented in Table II for cycle 1, 3, 6 and for cycles 27 combined. B/S on cycle days 17 (period of expected bleeding) was more frequent in the Org 31710 group compared with the placebo group. In the second period of the cycle (days 828), significantly less B/S was reported by the Org 31710 group compared with placebo in the first three cycles, whereas in cycles 47 no clear difference was observed. Similarly, more women reporting B/S episodes starting in, or with a part in cycle days 17 were observed in the Org 31710 group compared with the placebo group (Table III
), except for cycle 7. The percentage of women reporting B/S episodes starting in the second period of a cycle (days 828) was comparable for both treatment groups.
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No clinically relevant changes from baseline were observed for any of the measured haematology, biochemistry and urinalysis parameters. A difference between the Org 31710 and placebo groups was observed for body weight: 10 women in the Org 31710 group (19.2%) had an increase (n = 6) or decrease (n = 4) in body weight of >7% compared with one woman (2.0%) in the placebo group.
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Discussion |
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In the present study, we showed that the bleeding pattern of women using the 75 µg desogestrel POP was significantly improved by the administration of 150 mg Org 31710 once every 28 days. A cyclic bleeding pattern was observed in the Org 31710 treatment group with a bleeding-free period in all subjects and in all treatment cycles following the addition of Org 31710. The incidence of B/S was significantly higher during day 17 (period of expected bleeding) in the Org 31710 group compared with the control group, accompanied by a significantly lower incidence of B/S in the remaining part of the cycle (day 828, period of unscheduled bleeding). These differences were clearly observed in the initial treatment cycles, but were somewhat less pronounced during the later cycles of the treatment period. Thus, cycle control in the Org 31710 group was not yet optimal, as also evidenced by the relatively high incidence of B/S episodes starting in the second period of the cycle. The seemingly better cycle control in the initial treatment cycles could reflect a decrease in effect over time, but such a trend needs to be confirmed in larger studies.
A similar improvement in bleeding pattern has been reported (Cheng et al., 2000) in women using a levonorgestrel-releasing subdermal contraceptive implant in whom 50 mg mifepristone was given once every 4 weeks.
The mechanism behind the improvement in bleeding pattern is not known. As part of this study, the effect of the treatment on pituitaryovarian activity was also studied (Van Heusden et al., 2000). The results further support the previously published finding that 75 µg desogestrel daily in contrast to 30 µg levonorgestrel daily (Collaborative Study Group on the Desogestrel-Containing Progestogen-Only Pill, 1998
) completely inhibited ovulation. When Org 31710 was added to the desogestrel POP treatment, increased serum progesterone level (>10 nmol/l), indicating ovulation, was found in 29% of the subjects. However, changes in serum FSH, estradiol and progesterone levels could not predict ovulation and none of the measured parameters could be related to the observed bleeding pattern. Endometrial thickness as assessed by transvaginal sonography was also greater on cycle days 713 and 19 in the Org 31710-treated group (Van Heusden et al., 2000
).
If sufficient doses of different anti-progestogens, including Org 31710, are administered during the mid-luteal phase, shedding of the endometrium and vaginal bleeding will occur (Swahn et al., 1988; Kloosterboer et al., 1994
; Cameron et al., 1996
). It is likely that this effect is due to a direct effect on the endometrium since it is not associated with a decrease in ovarian steroid concentration and can be induced even when progesterone levels are artificially elevated by exogenous hCG administration (Croxatto et al., 1985
). However, when given at the end of the secretory phase a luteolytic effect may also be of importance, which is the case with mifepristone (Swahn et al., 1988
). The reason for the improved cycle control with an Org 31710POP regimen is not clear. Since more subjects bled during the first days following Org 31710 treatment, this indicates that shedding of the endometrium could be one explanation. Another possibility is an increased frequency in ovulatory cycles with Org 31710POP treatment in comparison with POP alone (Van Heusden et al., 2000
). In these subjects, a luteolytic effect of Org 31710 cannot be excluded.
It has previously been demonstrated that in ovariectomized cynomolgus monkeys in the presence of progesterone, mifepristone is antagonistic, but in its absence mifepristone exhibits endometrial progestational effects at low doses and an anti-proliferative (anti-estrogenic) effect at higher doses (Wolf et al., 1989; Chwalisz et al., 1991
). Further results indicate that the anti-proliferative effect of the anti-progestogen is not due to a decrease in estrogen receptor concentration as occurs during progesterone treatment. On the contrary, both estrogen and progesterone receptor concentration increased significantly and to supra normal levels in ovariectomized monkeys on estradiol replacement therapy when treated with mifepristone. A possible explanation is that the over-expressed estrogen receptor might not activate the post-receptor mechanism responsible for endometrial tissue growth (Neulen et al., 1996
). These effects support the suggestion that the action of anti-progestogen on the bleeding pattern with desogestrel POP is mainly due to an effect on the endometrium and the progesterone receptor (Heikinheimo et al., 1996
).
The contraceptive mode of action of the desogestrel POP depends on the suppression of ovulation and the mid-cycle peaks of LH, as well as on effects on cervical mucus, Fallopian tube motility and endometrium (McCann and Potter, 1994). Since the addition of Org 31710 to the desogestrel treatment increases the rate of ovulation, a possible drawback may be an increased risk of contraceptive failure. However, the frequency of ovulation was similar to that observed with 30 µg/day levonorgestrel (Collaborative Study Group on the Desogestrel-Containing Progestogen-Only Pill, 1998
) and in the study by Cheng et al. (Cheng et al., 2000
), and in these studies, no pregnancy occurred.
In light of an improved but not yet optimal bleeding pattern associated with this regimen and the possible decreased contraceptive efficacy with Org 31710 added to POP, further investigations will be necessary for the clinical development of an optimal Org 31710POP regimen.
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Acknowledgements |
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Notes |
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References |
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Submitted on June 4, 2001; resubmitted on April 18, 2002; accepted on June 20, 2002.