Follicular growth during contraceptive pill or vaginal ring treatment depends on the day of ovulation in the pretreatment cycle

Ingrid J.M. Duijkers1,3, Carole H.J. Verhoeven2, Thom O.M. Dieben2 and Christine Klipping1

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: iduijkers{at}dinoxgroup.com


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: The aim of this study was to investigate whether the day of ovulation and the duration of a pretreatment cycle were related to the degree of follicular growth during subsequent contraceptive treatment. METHODS: This randomized, open-label study was performed in 40 healthy female volunteers, who were randomized by a computer-generated list after stratification for the ovulation day in a pretreatment cycle. They received two cycles of NuvaRing (21 subjects) or a combined oral contraceptive (COC) containing 30 µg ethinylestradiol and 150 µg levonorgestrel (19 subjects). Follicular diameter and serum hormone concentrations (FSH, LH, 17{beta}-estradiol, progesterone) were measured every third day. Data from treatment day 20 onwards were used for analysis. RESULTS: In the NuvaRing users, subjects with short cycles and early ovulations in the pretreatment cycle developed larger follicles during treatment than subjects with longer cycles and late ovulations. In the COC users, subjects with early ovulations in the pretreatment cycle developed larger follicles during treatment. CONCLUSIONS: The degree of follicular growth during treatment with a combined hormonal contraceptive is influenced by the duration of the pretreatment cycle and particularly by the duration of the follicular phase.

Key words: follicular growth/oral contraceptive/pill-free interval/vaginal ring


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The primary mechanism of action of combined contraceptives is the suppression of pituitary gonadotrophins, resulting in inhibition of follicular growth and ovulation. The currently marketed oral contraceptive pills and the combined contraceptive vaginal ring NuvaRing® appear to be very effective in this respect. In most regimens a treatment period of 21 days is followed by a 7 day treatment-free period. In the 7 day interval the hypothalamic–pituitary–ovarian axis resumes its activity, and follicular growth can be observed (Molloy et al., 1985Go; Van der Does and Exalto, 1995Go; Elomaa et al., 1998Go; van Heusden and Fauser, 1999, 2002Go). Missing pills in the days before and after the pill-free period may be hazardous because escape ovulation could occur (Chowdhury et al., 1980Go; Landgren and Diczfalusy, 1984Go; Landgren and Csemiczky, 1991Go; Korver et al., 1995Go; Rosenberg et al., 1995Go; van Heusden and Fauser, 2002Go).

There is a large variation in the degree of follicular growth in the treatment-free period (Killick, 1989Go; van der Does et al., 1995Go; Elomaa et al., 1998Go; van Heusden and Fauser, 2002Go). Follicular growth varies between different contraceptive preparations (Elomaa et al., 1998Go; van Heusden and Fauser, 1999Go; Creinin et al., 2002Go; van Heusden and Fauser 2002Go), and may also depend on inter-individual differences in pharmacokinetics (Fotherby et al., 1981Go; Jung-Hoffmann and Kuhl, 1990Go; Korver et al., 1995Go; van Heusden and Fauser, 2002Go). The individual duration of the follicular phase will probably also influence the rapidity of follicular growth in the treatment-free interval. We performed a study to investigate whether the day of ovulation and the duration of a pretreatment cycle were related to the degree of follicular growth during subsequent contraceptive treatment.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A single centre, open-label, randomized, comparative pharmacodynamic trial with NuvaRing versus a combined oral contraceptive (COC) was performed in healthy female volunteers. The study was conducted in a clinical research centre (Dinox Medical Investigations) in Nijmegen, The Netherlands. Comparative pharmacodynamic data on ovarian function will be reported separately.

Subjects
All subjects who participated 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 between 18 and 40 years, menstrual cycles with a usual length of between 24 and 35 days and an intra-individual variation of±3 days; body mass index between 18 and 29 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 into 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.

Study design
In the first study cycle, the screening cycle, the subjects did not use hormonal contraceptives. Cycle day 1 was the first day the subject menstruated before 10:00. From cycle day 6 (±1) onwards, the subjects visited the study centre every third (±1) day for transvaginal ultrasonography and blood sampling until ovulation was observed. The margin of 1 day was not allowed for the visit on day 12. Three (±1) and 6 (±1) days after ovulation, the subjects visited the centre again for ultrasonography and blood sampling. The criteria for ovulation were the disappearance of a dominant follicle or a significant decrease in the diameter associated by changes in the contour and/or content of the dominant follicle. At the visit when ovulation was detected ultrasonographically as well as at the next visit, serum progesterone levels were determined to confirm ovulation before the randomization procedure. The randomization procedure was performed 6 days after ovulation, using a computer-generated randomization list. Subjects received either the COC or NuvaRing. Only subjects who had shown an ovulation on or before day 21 (±1) were randomized; the other subjects were excluded from the study. Eligible subjects were stratified according to the day of ovulation in the screening cycle (before or after day 12), to obtain a reasonably balanced distribution of the subjects with short and long follicular phase lengths over the treatment groups.

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 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 days 20 and 24 in both cycles. 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.

Treatment
Each tablet contains 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 with an outer diameter of 54 mm and a cross-sectional diameter of 4.0 mm. The total content of hormones is 2.7 mg EE and 11.7 mg etonogestrel, the active metabolite of desogestrel. NuvaRing releases EE and etonogestrel at a daily average amount of 15 µg and 120 µg respectively, 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 was assessed at each visit. Serum levels of FSH, LH, 17{beta}-estradiol (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 1.9 to 6.4%. The intra-assay precision varied from 0.9 to 6.5%. The lower detection limit of E2 was 49.9 pmol/l.

Analysis
Data from treatment day 20 in cycle 1 onwards were used for the analysis in view of the different starting procedures for COC and NuvaRing treatment. Median values were only calculated if at least two individual values were available. Differences in maximum follicular diameters during treatment in relation to the pretreatment cycle duration and pretreatment day of ovulation were analysed by the Kruskal–Wallis test. P≤0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects were recruited in September and October 2002; the last assessment was done in January 2003. A total of 52 subjects was screened. Four subjects did not meet the inclusion criteria (three of whom did not ovulate on or before day 21 in the pretreatment cycle), one subject withdrew her consent, seven were not included for other reasons (in five cases because a sufficient number of subjects was randomized). Forty subjects were randomized, 21 of which received NuvaRing (three with an early and 18 with a late ovulation in the screening cycle), 19 received the COC (two with an early and 17 with a late ovulation). All randomized subjects were treated and used the study medication according to the compliance criteria, and were included in the analysis.

The mean age of the NuvaRing users was 28.6 (SD 6.0) years, in the COC users 28.0 (SD 5.8) years. Mean body mass index was 22.4 (SD 2.5) kg/m2 and 23.2 (SD 3.0) kg/m2 in the NuvaRing and the COC users respectively.

The distribution of cycle duration and day of ovulation in the pretreatment cycle in the two treatment groups is listed in Table I.


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Table I. Distribution of cycle duration and day of ovulation in the pretreatment cycle in the NuvaRing and the combined oral contraceptive (COC) users, and median maximum follicular diameter during treatment in relation to pretreatment cycle duration and pretreatment day of ovulation

 
Median values of the maximum follicular diameter on different days in the pretreatment and the treatment cycles are shown in Figures 1 and 2. Figure 1 shows the results when the subjects in each treatment group were divided into three subgroups according to the duration of the pretreatment cycle: one group with a cycle duration between 22 and 25 days (Cy 22–25), one group with a cycle between 26 and 30 days (Cy 26–30) and a group with a cycle between 31 and 35 days (Cy 31–35). In the NuvaRing users, an association was present between the pretreatment cycle duration and follicular growth in the pretreatment cycle: follicular growth started later with increasing cycle duration. At the end of the first treatment period, a relatively large median follicular diameter (15 mm) was seen in the Cy 22–25 group, which decreased initially during the ring-free period. At the end of the ring-free interval, increasing follicular diameters were observed in the Cy 22–25 and the Cy 26–30 groups. Maximum values were reached on treatment day 30 in the Cy 22–25 group (13 mm) and on treatment day 33 in the Cy 26–30 group (12 mm). In the Cy 31–35 group, only minimal follicular growth was seen in the ring-free period. After 2 weeks of treatment in the second cycle, the median follicular diameter was suppressed to early follicular values in all subgroups.



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Figure 1. Median values of the maximum follicular diameter on each study day in subjects with a pretreatment cycle duration of 22–25, 26–30 and 31–35 days respectively, in the NuvaRing users (A) and the combined oral contraceptive users (B). In the left part of the figure the results in the pretreatment cycle are shown, in the right part the results during treatment. The vertical lines indicate the treatment and treatment-free periods respectively.

 


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Figure 2. Median values of the maximum follicular diameter on each study day in subjects who ovulated between cycle days 9–12, 12–15, 15–18 and 18–21 respectively, during the pretreatment cycle. Results are shown from the NuvaRing users (A) and the combined oral contraceptive users (B). In the left part of the figure the results in the pretreatment cycle are shown, in the right part the results during treatment. The vertical lines indicate the treatment and treatment-free periods respectively.

 
In the COC users, follicular growth in the pretreatment cycle started earliest in the Cy 26–30 group. The relatively late follicular growth in the Cy 22–25 group was due to two subjects in this subgroup who had an ovulation between days 15 and 18 followed by a short luteal phase. At the end of the first treatment period, follicular growth was suppressed in all subgroups. Only a small increase in follicular diameter was seen during and after the pill-free interval. The largest follicular diameter (median 9 mm) was seen on treatment days 30 and 33 in the Cy 26–30 group.

Figure 2 shows the results when the day of ovulation in the pretreatment cycle was taken into account. In each treatment group, the subjects were divided into four subgroups: one group with ovulation between cycle days 9 and 12 (Ov 9–12), ovulation between days 12 and 15 (Ov 12–15), ovulation between days 15 and 18 (Ov 15–18), and a group ovulating between cycle days 18 and 21 (Ov 18–21). In the NuvaRing users, follicular activity was suppressed in all subgroups at the end of the first treatment period, but in the ring-free periods follicles started to grow. There was an inverse relationship between the day of ovulation in the pretreatment cycle and the maximum follicular diameter during treatment: subjects with early ovulations developed larger follicles during treatment. In the Ov 9–12 group, the maximum follicular diameter was 18 mm (median) on treatment day 36. At the end of the second treatment period, follicular activity was suppressed again in all subgroups.

In the COC users follicular activity was suppressed at the end of the first treatment period and follicular growth started in the pill-free interval. The maximum follicular diameter was largest in the Ov 9–12 group. In this subgroup, follicular growth was not completely suppressed during the entire second treatment cycle. The largest follicular diameter (median 17 mm) was seen on treatment day 42.

Table I shows median values of the individual maximum follicular diameters during treatment in relation to the pretreatment cycle duration and the pretreatment day of ovulation. In the NuvaRing users, differences in maximum follicular diameters between the subgroups were statistically significant when comparing pretreatment cycle durations, but not when comparing days of ovulation. The differences in the COC users were not statistically significant.

None of the subjects ovulated during the treatment cycles. Median serum progesterone concentrations were <2 nmol/l. The maximum progesterone concentration during treatment was 6.23 nmol/l. This value was measured in a NuvaRing user. Median serum FSH and LH concentrations increased in the ring- and pill-free periods and gradually decreased during treatment. Figure 3 shows median serum E2 concentrations, comparing subgroups with different days of ovulation in the pretreatment cycle. In the NuvaRing users, E2 levels were suppressed to values around the detection limit of the assay at the end of the first treatment period. In the ring-free interval, E2 concentrations increased. The largest median E2 concentration (569 pmol/l) was seen on treatment day 30 in the Ov 9–12 group. With the continuation of treatment, E2 levels declined again to very low values. Also in the COC users, E2 concentrations were around the detection limit of the assay at the end of the first treatment cycle. In the Ov 9–12 group, E2 concentrations were elevated during the second cycle, reaching a maximum of 366 pmol/l on treatment day 33. At the end of the second treatment period, E2 levels were again suppressed. Only a small increase of E2 levels in the pill-free interval was seen in the groups with pretreatment ovulation after day 12.



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Figure 3. Median values of the serum 17{beta}-estradiol concentration on each study day in subjects who ovulated between cycle days 9–12, 12–15, 15–18 and 18–21 respectively, during the pretreatment cycle. Results are shown from the NuvaRing users (A) and the combined oral contraceptive users (B). In the left part of the figure the results in the pretreatment cycle are shown, in the right part the results during treatment. The vertical lines indicate the treatment and treatment-free periods respectively.

 
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.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
To our knowledge, this is the first study investigating the relationship between the day of ovulation and the duration of a pretreatment cycle on the one hand, and follicular growth during subsequent treatment with a combination contraceptive on the other hand. Two different contraceptives were used in the present study: a combined contraceptive vaginal ring (NuvaRing) and a COC.

When the subjects within each treatment group were divided into subgroups according to duration of the pretreatment cycle, some trends could be observed. In the NuvaRing users, a relationship was present between the pretreatment cycle duration and follicular growth in the pretreatment cycle: follicular growth started later with increasing cycle duration. Also during NuvaRing treatment, a relationship could be observed between the pretreatment cycle duration and the degree of follicular growth in the ring-free interval and the subsequent treatment period. Follicular growth was most pronounced in the subgroups with the shortest cycle duration. In the COC users, there was no such relationship. The subgroup which ovulated between cycle days 26 and 30 showed the earliest follicular growth in the pretreatment cycle. During treatment the largest follicles were seen in the same subgroup. Apparently, in the COC users a short cycle duration did not correlate with rapid follicular growth. This can be explained by the fact that two of the three subjects in this subgroup had a relatively late ovulation with a short luteal phase in the pretreatment cycle. This observation indicates that the cycle duration is less important than the duration of the follicular phase and the day of ovulation.

This is confirmed by the results obtained after dividing the subjects into subgroups according to the day of ovulation in the pretreatment cycle. Ultrasonography was performed every third day, so the exact ovulation day was not known but the day of ovulation was defined within a 3 day period. Both in the NuvaRing and in the COC users a correlation could be observed between the rapidity of follicular growth and the day of ovulation in the pretreatment cycle, and the degree of follicular growth during subsequent contraceptive treatment. Despite the fact that the number of subjects in some of the subgroups was very small, the results show a clear pattern. Subjects who ovulate early in spontaneous cycles have a greater risk of developing large follicles during contraceptive treatment than subjects with a late ovulation.

Follicular diameters and serum E2 concentrations showed a comparable pattern. Increases of follicular diameters and E2 concentrations occurred simultaneously in the ring-free/pill-free periods. However, the suppression of E2 levels which was observed when treatment was resumed occurred several days earlier than the decrease in follicular diameter. Apparently, the E2-producing capacity of the follicle had already diminished before it became smaller in size.

The results from this study have implications for clinical practice as well as for the design of ovulation inhibition studies in the development of new hormonal contraceptives. In clinical practice it is important to identify the subjects who are most likely to develop pre-ovulatory follicles during the use of hormonal contraceptives. These subjects are at risk of escape ovulation, especially when the treatment-free period is extended because of omitting tablets or forgetting to insert a vaginal ring (Chowdhury et al., 1980Go; Landgren and Diczfalusy, 1984Go; Hamilton and Hoogland, 1989Go; Killick, 1989Go; Landgren and Csemiczky, 1991Go; Elomaa and Lähteenmaäki, 1999Go; van Heusden and Fauser, 2002Go). This risk is probably higher when the steroid dose of the contraceptive is lower (Elomaa et al., 1998Go; van Heusden and Fauser, 1999Go, 2002Go; Creinin et al., 2002Go). Previous studies have shown that the risk of escape ovulation is rather low, but in none of these studies was the actual cycle duration or day of ovulation of the included subjects mentioned (Wang et al., 1982Go; Hamilton and Hoogland, 1989Go; Landgren and Csemicky, 1991Go; Elomaa et al., 1998Go). If escape ovulation does not occur, large follicles might develop into luteinized unruptured follicles or into functional cysts (Hamilton et al., 1985Go; Hamilton and Hoogland, 1989Go; Landgren and Csemiczky, 1991Go; Grimes et al., 1994Go; van der Does, 1995Go; Elomaa et al., 1998Go; Elomaa and Lähteenmäki, 1999Go; van Heusden and Fauser, 2002Go). If escape ovulation occurs, the risk of pregnancy is probably still low because of the additional effects of hormonal contraceptives on cervical mucus and endometrial histology (Chowdhury et al., 1980Go; Hamilton and Hoogland, 1989Go). However, to reduce the risk of pregnancies during hormonal contraceptive treatment, one could consider advising subjects with early ovulations, for instance before cycle day 12, to reduce the treatment-free period from 7 to 5 days or to skip the treatment-free interval. In clinical practice, one will generally not know the ovulation day, only the usual cycle duration will be known. Our results have shown that the day of ovulation is a better predictor for the degree of follicular growth than the cycle duration. In the case of a short luteal phase, subjects may be identified as being at risk when in fact they are not. However, some correlation with cycle duration does exist. Subjects with short menstrual cycles, for instance <26 days, might be given the same advice as subjects with early ovulations.

The results from the present study should be considered when an ovulation inhibition study is designed. One should pay attention to the definition of the inclusion criteria. If the usual cycle length is one of the criteria, the limits of acceptance determine the study population. Excluding subjects with short or long cycles will influence the results of the study. Furthermore, it seems important to identify the cycle characteristics of the subjects which will actually be included in the study. A spontaneous cycle should be monitored before the start of treatment, not only to investigate if the cycle is ovulatory but also to determine the day of ovulation. If the study population does not comprise subjects with an early ovulation, a new treatment may seem effective, but ovulations or pregnancies may occur during later clinical development of the product. If a relatively small number of subjects will be included in a study, one could consider stratification according to the day of ovulation. This will prevent an unbalanced distribution of subjects with early and late ovulations over the treatment groups which could influence the results. For a proof-of-concept study with a new hormonal contraceptive, one could consider including only a small number of subjects with early ovulations. If the treatment proves to be effective in this subject group, it will probably also be effective in subjects with late ovulations.

In conclusion, the degree of follicular growth during treatment with a combined hormonal contraceptive is influenced by the duration of the pretreatment cycle and particularly by the duration of the follicular phase. Subjects with early ovulations develop larger follicles during hormonal contraceptive treatment than subjects with late ovulations.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on June 3, 2004; accepted on August 2, 2004.





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