1 Dinox Medical Investigations, Groenewoudseweg 317, 6524 TX Nijmegen and 2 NV Organon, P.O.Box 20, 5340 BH Oss, The Netherlands
3 To whom correspondence should be addressed. Email: thom.dieben{at}organon.com
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Abstract |
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Key words: NuvaRing/oral contraceptive/ovarian function/ovulation inhibition/vaginal ring
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Introduction |
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NuvaRing®, a contraceptive vaginal ring releasing 15 µg ethinylestradiol (EE) and 120 µg etonogestrel per day, recently became available. It has a monthly regimen, comprising 3 weeks of ring use followed by a 1 week ring-free period. The vaginal route of hormone administration avoids gastrointestinal absorption and hepatic first-pass metabolism. Hormone release remains constant over the 3 week period of use and daily fluctuations do not occur (Timmer and Mulders, 2000). Vaginal delivery enables the achievement of adequate contraceptive efficacy and good cycle control with lower dosing than that given with oral preparations. Furthermore, the ring can easily be inserted and removed by the user herself. Previous studies have demonstrated that NuvaRing is an effective contraceptive with excellent cycle control, which is well tolerated and accepted by users (Dieben et al., 2002
; Novák et al., 2003
).
The effect of NuvaRing treatment on ovarian function has been studied previously (Mulders and Dieben, 2001; Mulders et al., 2002
). In these trials, ovarian suppression and ovulation inhibition was observed in all subjects. It was shown that follicular growth and hormonal levels after 3 weeks of NuvaRing treatment were similar to those after 3 weeks intake of a COC containing 30 µg EE and 150 µg desogestrel (Mulders and Dieben, 2001
). However, an actual comparative pharmacodynamic trial, comparing NuvaRing with a COC, has not been performed before. The aim of the present study was to examine the effect on ovarian function of NuvaRing treatment in comparison with that of a COC containing 30 µg EE and 150 µg levonorgestrel. According to the instructions for use in the package inserts, when NuvaRing is used for the first time it should be inserted between cycle days 1 and 5, whereas COC treatment should be started on cycle day 1. The day 15 start for NuvaRing is to give women the option of avoiding insertion of the first ring during their period, with treatment starting on cycle day 5 being the latest day allowed. This difference in starting procedures was taken into account when the pharmacodynamic effects of both treatments were compared.
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Materials and methods |
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Subjects
All subjects participating in this trial gave their written informed consent and the study was approved by an independent ethical committee (Foundation of Therapeutic Evaluation of Drugs (STEG), Duivendrecht, The Netherlands). Main inclusion criteria were: age 1840 years, menstrual cycle length of 2435 days with an intra-individual variation of±3 days; body mass index 1829 kg/m2; good physical and mental health. Exclusion criteria were: contraindications for contraceptive steroids, abnormal cervical smear diagnosed in the screening phase; clinically relevant abnormal laboratory results; use of the following drugs: hydantoins, barbiturates, primidone, carbamazepine, oxcarbazepine, topiramate, felbamate, rifampicin, rifabutin, griseofulvin, sex steroids and herbal remedies containing St John's wort, use of an injectable hormonal method of contraception within a period of 6 months, breastfeeding in the last 2 months, status post-partum or post-abortion in the last 2 months, administration of investigational drugs in the last 2 months, a history (within 12 months) of alcohol or drug abuse.
Before inclusion in the study, all subjects underwent a general physical and gynaecological examination, including transvaginal ultrasonography and cervical smear. Haematological and clinical chemical blood parameters were determined.
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Study design |
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Treatment was started at the next menstruation and administered for two cycles of 28 days. The COC was used from cycle day 1 onwards, i.e. the first day the subject menstruated before 10:00 (treatment day 1). Tablets were taken once daily for 21 days, followed by a 7 day pill-free period. NuvaRing was inserted vaginally on cycle day 5 (treatment day 1) and kept in situ for 21 days, followed by a ring-free period of 7 days. According to the instructions for use in the package insert, NuvaRing treatment should be started between cycle days 1 and 5, and the worst case (day 5) was chosen. Transvaginal ultrasonography and blood sampling were performed every third day during both treatment cycles from treatment day 2 onwards, except for a 4 day interval between treatment days 20 and 24 in each cycle. For each assessment, a margin of±1 day was allowed. Body weight, blood pressure and haematological and clinical chemical blood parameters were measured at the last visit. The subjects recorded tablet intake or hours of ring use and the occurrence of vaginal bleeding on a daily basis in a diary booklet.
Treatment
Each tablet contained 150 µg levonorgestrel and 30 µg EE (Microgynon 30; Schering AG, Germany). NuvaRing (NV Organon, The Netherlands) is a flexible, soft, transparent ethylene vinylacetate copolymer ring that releases a daily average of 15 µg EE and 120 µg etonogestrel, over a period of 3 weeks.
Measurements
Transvaginal ultrasonography was performed using an Eccocee device (Toshiba) with a 6 MHz vaginal probe. The mean diameter of the bi-directional measurement of the largest follicle in each ovary and double-layer endometrial thickness were assessed at each visit.
Serum levels of FSH, LH, 17-oestradiol (E2) and progesterone were determined in each blood sample. Blood samples were processed to serum and stored at 20°C until assays were performed. FSH, LH, E2 and progesterone levels in serum were determined by time-resolved fluoroimmunoassay (AutoDelfia®; Wallac Oy, Finland). The inter-assay precision for FSH, LH, E2 and progesterone varied from 1.4 to 3.6%. The intra-assay precision varied from 0.8 to 3.8%. The lower detection limit of E2 was 49.9 pmol/l.
Analysis
The primary efficacy variable was the maximum follicular diameter (maxFD), which was defined as the largest follicular diameter measured during a treatment cycle. After logarithmic transformation, the maxFD for each of the two treatment cycles was analysed by means of an analysis of variance (ANOVA) model with factors cycle, treatment, their interaction and the stratification factor for timing of ovulation in the screening cycle ( or > cycle day 12). Using this ANOVA model, point estimates with 95% confidence intervals (CI) were calculated for the ratio of geometric (least-squares) means for NuvaRing over COC for each of the two treatment cycles.
Several secondary analyses were performed. Per subject and treatment cycle, the maxFD was determined for the ring/pill period and the ring-free/pill-free period separately. Furthermore, because of the difference in starting day for the ring and the COC treatment (cycle day 5 versus 1), the first week of the treatment cycle was ignored to determine the maxFD values per subject. Finally, the maxFD was determined per subject for both treatment cycles combined. For each of these secondary analyses, a similar ANOVA model was used to determine the ratio of geometric means of maxFD values of NuvaRing over COC and corresponding 95% CI.
Summary statistics (median with interquartile ranges) were calculated for the serum hormone levels and endometrial thickness. Statistical testing was not done for these parameters.
The results of a previous pharmacodynamic NuvaRing study (Mulders and Dieben, 2001) showed a coefficient of variation of the maxFD values for NuvaRing of 30%, which was expected to be a bit higher for the COC group. With a planned number of 20 subjects per group, upper limits of the 95% CI of the maxFD ratio of 1.321.60 mm could be obtained for both treatment cycles, with 80% power and an expected maxFD ratio of 1.
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Results |
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For none of the ANOVA analyses could it be concluded that the treatment effect on the maxFD differed significantly between the subjects with an early and a late ovulation (P>0.10 for interaction between treatment and timing of ovulation at screening). Therefore this interaction term was excluded from the ANOVA models.
Summary statistics for the maxFD and ANOVA results are presented in Table I and median maxFD values during the study period are shown in Figure 1. In the screening cycle (cycle 0), the maxFD was comparable between the groups. At the start of the first treatment cycle, the ovarian activity was higher in the NuvaRing group compared with the COC group. On treatment day 2 the median maxFD was 9 mm in the NuvaRing group compared with 6 mm in the COC group. The median maxFD were low in both treatment groups, <7 mm, during the second and third week of the first cycle, increasing in the treatment-free period and reaching their maximum on the second day of the second treatment cycle (11 mm in the NuvaRing and 9 mm in the COC group). With the continuation of treatment in the second cycle, in both groups the median maxFD decreased. In 12 subjects of the NuvaRing group and in three subjects of the COC group, the maximum follicular diameter reached a value 13 mm during one or both treatment cycles. In most of these subjects the follicular diameter decreased during the ring/pill period. Two subjects in each group had large follicles that persisted until the next ring-free/pill-free period. One subject in the COC group developed a follicle with a maxFD of 39 mm in the second treatment cycle.
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Both NuvaRing and the COC were well tolerated. No serious adverse events occurred and none of the subjects discontinued use due to an adverse event. No clinically relevant abnormalities or changes were observed in laboratory and vital signs assessments.
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Discussion |
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The results from this study showed that ovarian function was adequately suppressed in both treatment groups. Ovulations did not occur. The largest median value of the maximum follicular diameter was measured on the second day after the ring-free/pill-free period and was 11 mm. During the treatment periods, median maxFD levels decreased to values <7 mm in the NuvaRing and in the COC group. Median serum E2 concentrations were profoundly suppressed during the treatment period in both groups.
When the two treatment groups were compared, a difference was observed in the maxFD levels in the first treatment cycle. According to the instructions in the package insert, COC treatment was started on cycle day 1, whereas NuvaRing treatment was started on cycle day 5, the latest day allowed, and therefore pharmacodynamically the worst case scenario. In many subjects, early follicular development had already commenced on cycle day 5. Therefore, the median maxFD was higher at the start of treatment in the NuvaRing group than in the COC group. During the second week of the first treatment cycle, the maxFD reached comparable levels in the two groups. The different starting procedures explain the higher estimated maxFD in the NuvaRing group in the first treatment cycle, and the difference disappeared after the first treatment cycle. In the ring-free/pill-free period and the second treatment cycle, the estimated maxFD were comparable in the two groups. When the two treatment cycles were combined, the estimated maxFD were also comparable in both groups.
Although the estimated maxFD were comparable in the two groups after the first treatment cycle, there was a tendency towards slightly higher maxFD levels in the NuvaRing group than in the COC group. Serum hormone concentrations showed the same pattern. Median FSH and LH levels tended to be somewhat higher in the NuvaRing group at the end of both treatment periods and in the treatment-free intervals. Serum E2 concentrations were profoundly suppressed during the treatment periods in both groups, but in the ring-free/pill-free periods E2 levels tended to be higher in the NuvaRing group than in the COC group. However, there was a large inter-individual variation and the observed difference could be due to chance.
A difference in ovarian suppression between the two groups could be expected when pharmacokinetic parameters of the preparations are considered. In a previous pharmacokinetic study, NuvaRing treatment (15 µg EE and 120 µg etonogestrel per day) was compared with a COC containing 30 µg EE and 150 µg desogestrel (Marvelon®) (Timmer and Mulders, 2000). The systemic exposure to EE with NuvaRing was
50% of that with Marvelon, while the exposure to etonogestrel (the active metabolite of desogestrel) was similar with both preparations. It is known that the EE dose of a COC preparation influences the degree of ovarian suppression (Spellacy et al., 1980
; van Heusden and Fauser, 1999
). Since the systemic exposure to EE with NuvaRing is lower than that with Marvelon, and probably also with Microgynon 30, a lower degree of ovarian suppression was to be expected with NuvaRing. But, despite the considerably lower EE exposure with NuvaRing compared with the COC, in the present study only minor differences in ovarian suppression were observed.
The small difference in endometrial thickness between the NuvaRing and the COC group in the first treatment cycle can also be explained by the different starting procedures. Nuva-Ring treatment was started at the end of menstruation, when endometrial proliferation had already commenced. Treatment with the COC was started at the first day of menstruation, thus preventing normal endometrial proliferation. After the withdrawal bleeding in the ring-free/pill-free period, endometrial thickness was comparable in the two groups.
In conclusion, ovarian activity was adequately suppressed with both NuvaRing and the COC treatment. Lower ovarian activity was observed in the COC group compared with the NuvaRing group during the first cycle, which is likely to be the result of the different starting procedures. The effect of NuvaRing and COC treatment on ovarian activity was comparable in the second treatment cycle.
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References |
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Mulders TMT and Dieben ThOM (2001) Use of the novel combined contraceptive vaginal ring NuvaRing for ovulation inhibition. Fertil Steril 75, 865870.[CrossRef][ISI][Medline]
Mulders TMT, Dieben ThOM and Coelingh Bennink HJT (2002) Ovarian function with a novel combined contraceptive vaginal ring. Hum Reprod 17, 25942599.
Novák A, de la Loge C, Abetz L and van der Meulen EA (2003) The combined contraceptive vaginal ring, NuvaRing®: an international study of user acceptability. Contraception 67, 187194.[CrossRef][ISI][Medline]
Spellacy WN, Kalra PS, Buhi W and Birk SA (1980) Pituitary and ovarian responsiveness to a graded gonadotropin releasing factor stimulation test in women using a low-estrogen or a regular type of oral contraceptive. Am J Obstet Gynecol 137, 109115.[ISI][Medline]
Timmer CJ and Mulders TMT (2000) Pharmacokinetics of etonogestrel and ethinyloestradiol released from a combined contraceptive vaginal ring. Contraception 59, 311318.[ISI]
Van Heusden AM and Fauser BCJM (1999) Activity of the pituitaryovarian axis in the pill-free interval during use of low-dose combined oral contraceptives. Contraception 59, 237243.[CrossRef][ISI][Medline]
Submitted on June 3, 2004; accepted on August 2, 2004.
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