1 Clinical Development Department, NV Organon, Oss, The Netherlands and 2 Centre for Reproductive Medicine, Academic Hospital V.U.B., Laarbeeklaan 101, B-1090 Brussels, Belgium
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Abstract |
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Key words: compliance/etonogestrel/ovarian function/vaginal ring
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Introduction |
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The pharmacokinetics and pharmacodynamicsi.e. interference with follicle development and inhibition of ovulationof NuvaRing have been studied during normal and prolonged use, where the ring was left in place for an additional 2 weeks. This study showed controlled release concentrationtime profiles for ENG and EE (Timmer and Mulders, 2000). Using NuvaRing for the recommended period of use resulted in complete inhibition of ovulation, as assessed by vaginal ultrasound and serum concentrations of FSH, 17ß-estradiol (E2), LH and progesterone. Inhibition of ovulation was maintained during the additional 2 week period of NuvaRing use (Mulders and Dieben, 2001
).
As with any contraceptive method, compliance with the prescribed regimen is essential to maintain reliability. The aim of the present study was to test the robustness of this novel form of contraception if the usage schedule was deviated from. This was done by evaluating ovarian function with NuvaRing in women who were instructed either to adhere to, or to deviate from, the recommended regimen of use.
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Materials and methods |
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Study population
Fifty-one women, aged 1835 years, in good physical and mental health and with a body mass index (BMI) between 18 and 29 kg/m2 were enrolled into the study. All subjects were required to have good visibility of both ovaries by vaginal ultrasound and good venous accessibility. Subjects were excluded if they had any contraindications to contraceptive steroids. Other exclusion criteria specific to vaginal ring use comprised: the presence at screening of a cervicitis, vaginitis or a bleeding cervical erosion; diagnosis at screening of a Papanicolaou (PAP) Class III, IV or V cervical smear result; cystocele, rectocele or prolapse of uterine cervix; severe or chronic constipation; dyspareunia or other coital problems.
Study design
All trial medication was supplied by NV Organon, Oss, The Netherlands. All subjects received at least one pretreatment cycle of a combined oral contraceptive (COC) containing 150 µg desogestrel and 30 µg EE (Marvelon®; NV Organon). Following the usual 7 day pill-free period, all women were randomly allocated to one of three treatment groups, AC (Figure 1). The women were assigned to one of the groups and given a subject code number according to a randomization list. Forty-five women used NuvaRing according to the recommended regimen of use (3 weeks of continuous ring use followed by a 1 week ring-free interval) for the first cycle. The second cycle differed depending on the treatment group (15 women per group). Six randomized subjects did not receive NuvaRing treatment but were held in reserve in case there were drop-outs.
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Before the start of the first treatment cycle, women were instructed how to insert and remove the ring. Temporary ring removal was not allowed and condoms were used as additional protection against pregnancy if follicles with a diameter 13 mm were observed during the vaginal ultrasound assessments.
Study assessments
At screening, all subjects provided a medical and gynaecological history and underwent a medical and gynaecological examination. Immediately before insertion of the first vaginal ring, a home pregnancy test was performed. NuvaRing treatment was only started if this test was negative.
Vaginal ultrasonography was performed and blood samples were collected for assay of serum hormones according to the following schedule. (i) Group A (3 week cycle): on day 21 of the second cycle and daily thereafter until the detection of ovulation by vaginal ultrasound. Maximal follow-up period was 28 days following ring removal. After ovulation, daily blood sampling continued for an additional period of 7 days, but never beyond the maximum period of follow-up. (ii) Group B (3 day cycle): on the first, second (ultrasound only), and third day of the second cycle (3 day cycle), and daily thereafter until the detection of ovulation by vaginal ultrasound. Maximal follow-up period was 28 days following ring removal. After ovulation, daily blood sampling continued for an additional period of 7 days, but never beyond the maximum period of follow-up. (iii) Group C (13 mm follicle): on day 21 of the first cycle and daily thereafter up to and including the day of removal of the second vaginal ring.
Vaginal ultrasonography was performed using a Toshiba Capasse SSA-220A with a 5 MHz transvaginal transducer. Follicle size was determined based on the measurement of follicular diameters (measured in the longitudinal and transverse planes). The mean of the two axes was to be recorded. Only follicles with a diameter 5 mm were recorded. Endometrial thickness was measured by vaginal ultrasound of the sagittal plane of the uterus and calculated by measuring the sum of both endometrial layers.
Blood samples were processed to serum and stored at 20°C until assays were performed. FSH, E2, LH, and progesterone levels in serum were determined by time-resolved fluoroimmunoassay (AutoDelfia®; Wallac Oy, Turku, Finland). Samples from one subject were analysed in one series (one batch) as much as possible. The inter-assay precision for FSH, E2, LH, and progesterone varied from 1.9 to 6.4%. The intra-assay precision varied from 0.9 to 6.5%.
During the whole study period, women recorded compliance to the NuvaRing treatment schedule on diary cards. Compliance was documented as the number of hours of ring use per day. Questioning regarding the occurrence of adverse events and use of concomitant medication took place throughout the trial. In addition to medications known to interfere with the effect of sex steroids, concomitant use of sex steroids other than the trial medication was prohibited. After completion of the study, women underwent a physical and gynaecological examination.
Statistical methods
The sample size of 15 subjects per treatment arm was justified by sufficiently narrow confidence intervals for the mean time to ovulation (groups A and B) and for the relative frequency of non-ovulating subjects (group C), taking into account a 20% discontinuation rate (i.e. three subjects) per treatment arm.
Summary statistics (median with interquartile ranges) were calculated for vaginal ultrasound measurements (follicular diameters and endometrial thickness) and serum hormone levels. The median values and ranges as presented apply to the diameters of the largest follicles or the highest serum hormone levels per subject per day. Summary statistics (mean, median, minimum and maximum) were also calculated for the time to ovulation and the time to detection of the largest follicle (in groups A and B), or the time needed to develop a follicle with a diameter of 13 mm (group C). The exposure data were summarized for each treatment group by listing the total hours of NuvaRing use. The tolerability analyses were restricted to descriptive statistics.
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Results |
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Ovarian function
The pattern of restoration of ovarian function after using NuvaRing according to the recommended regimen (group A) or for 3 consecutive days only (group B) is displayed in Figures 24.
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In group A, follicle growth started 3 days after ring removal, increasing from a median maximum follicular diameter 5 mm after ring removal to 18 mm at the time of the LH surge. In group B, follicle growth started 7 days after ring removal, increasing from a median maximum follicular diameter of 9 mm after ring removal to 19 mm at the time of the LH surge.
Concomitant with follicle growth, serum E2 levels started to rise 3 (group A) and 2 (group B) days after ring removal, with peak levels occurring around the time of LH surge. The endometrial thickness in women of group A decreased after removal of the ring (withdrawal bleeding), followed by growth from 2 mm on day 5 to 10 mm at the time of LH surge. The endometrial thickness in women of group B also increased from day 5 onwards.
Vaginal ultrasound assessments showed that post-treatment ovulation occurred, within the maximum period of follow-up of 28 days, in 27 of 29 women in groups A and B. In both groups, ovulation was confirmed by adequately high serum progesterone levels in the luteal phase. The median time to ovulation was 19 (group A) and 17 days (group B) after removing the ring (Table II), with the first ovulation occurring after 13 (group A) and 12 (group B) days.
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In group C (Figures 5 and 6), the pattern of ovarian function in the ring-free period of the first cycle resembled that of group A after removal of the second ring (Figures 24
). Ring removal resulted in a rise in FSH levels and accompanying stimulation of follicle growth, as evidenced by the increase in follicular diameters and serum E2 levels. Please note that (of course) in Figure 5
the sample size decreases over time.
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Insertion of NuvaRing after the extended ring-free period by women in group C interfered with ovarian function, as shown by the difference in patterns between Figure 6 (group C) and Figures 24
(group A). Follicle growth was disrupted as the median diameter of the largest follicle remained
1314 mm during days 111 of the second cycle, and serum E2 levels decreased after insertion of the second ring. Individually, an equal number of subjects showed an increase, a decrease or no change in the size of the largest follicle during the first week of the second cycle. The highest serum E2 levels were achieved during the extended ring-free period in all women except three with highest levels in the first week of the second cycle and one with the highest level on day 9 of the second cycle. These four women all had follicles that grew in the first half of the second cycle.
The inhibition of ovulation in group C demonstrated by vaginal ultrasound was confirmed by the absence of an LH surge and by low progesterone levels, during both the extended ring-free period of the first cycle and the normal ring-use period of the second cycle.
Tolerability
Twenty of the 45 subjects had drug-related adverse events (AEs). Most of these were classified as female reproductive disorders and within this group leukorrhoea and dysmenorrhoea were most frequently reported. All cases of leukorrhoea concerned increased vaginal discharge. All reported adverse events were of mild-to-moderate intensity.
Results of the physical and gynaecological examinations and the haematology and blood biochemistry analyses performed at baseline and at the end of the study were comparable (data not shown).
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Discussion |
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Irrespective of whether the length of the second NuvaRing treatment period was 3 days or the normal 3 weeks, ovulation required a similar time period after removal of the ring. The median time to ovulation after 3 days or 3 weeks NuvaRing use was 17 and 19 days respectively; the time for the first women to ovulate was also similar for these groups (12 and 13 days respectively). Although as a result of the different period of ovarian suppression the size of the follicles on the removal day was larger after 3 days compared with 3 weeks of NuvaRing exposure, the similarity in the time to ovulation in the two treatment groups shows that women in both groups needed to recruit a new cohort of follicles. Therefore, this study indicates that as little as 3 days of NuvaRing use is sufficient to suppress the hypothalamicpituitaryovarian axis, in contrast to the generally acknowledged requirement of 7 days with combined oral contraceptives (Guillebaud, 1987; Korver et al., 1995
).
The median time needed for the development of a 13 mm follicle was 11 days, meaning that the standard ring-free period had to be extended by 4 days to achieve this diameter in 50% of the women. The most rapid development of a 13 mm follicle required an extension of the ring-free period by only 1 day, whereas the slowest required a ring-free period of 21 days for the development of such a follicle. Since none of these women ovulated after inserting the second ring, these data indicate that ovulation of follicles with a size up to 13mm can be blocked by NuvaRing treatment.
The NuvaRing data (on extension of the ring-free period, group C) are in agreement with results from studies with several COC. Extension of the pill-free period by 34 days was associated with a large inter-individual variation in follicle growth, combined with a low risk of ovulation (Killick, 1989; Killick et al., 1990
; Landgren and Csemiczky, 1991
; Hedon et al., 1992
; Elomaa et al., 1998
). In one study (Killick 1989
), the pill-free period was extended until follicles reached a diameter of 12 mm. The median pill-free period needed for development of such a follicle was 11 days (range: 716 days). Despite resumption of COC intake, most follicles continued to grow, and even responded to hCG administration by both rupture and luteinization. These data show that dominant follicles maintain the capacity to ovulate after exposure to contraceptive steroids. It is most likely that ovulation does not occur due to prevention of the LH surge by the combined contraceptive.
In a similar study (Elomaa and Lähteenmäki, 1999), follicles were allowed to continue to grow to a diameter of 16 mm before the start of the next pill cycle. As expected, the median time for the development of 16 mm follicles was greater (18 days; range: 1426 days) than that for a 12 or 13 mm follicle. However, the ovulatory potential of a 16 mm functional follicle was not inhibited by the resumption of pill intake. This illustrates that only a substantial extension of the pill-free period may reduce the efficacy of combined contraceptives.
In conclusion, this study demonstrates that ovulation, at least until the stage of a 13 mm dominant follicle, is prevented and 3 consecutive days of NuvaRing use already interfered with follicle growth. In the meantime, large efficacy studies have demonstrated that NuvaRing (standard usage regimen of 3 weeks of continuous use followed by a 1 week ring-free period) is a highly effective, reversible method of hormonal contraception (Roumen et al., 2001). The results of the current study support this and show that NuvaRing remained a robustly effective method of contraception after some deliberate deviations from the standard usage regimen, provided that users adhered to the recommended regimen in the previous or subsequent cycle.
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Acknowledgements |
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Notes |
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References |
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Roumen, F.J.M.E., Apter, D., Mulders, T.M.T. and Dieben, T.O.M. (2001) Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl estradiol. Hum. Reprod., 16, 469475.
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Submitted on October 5, 2001; resubmitted on February 22, 2002; accepted on May 14, 2002.