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The study investigated the length of the first menstrual cycle after stopping oral contraceptive (OC) use, compared to non-OC users and subsequent cycles after stopping. It found:
1) The median length of the first cycle after OC discontinuation (30 days) was not significantly different from the second cycle (29 days) or cycles in non-OC users (29 days for both first and second).
2) When divided by age, those aged 18-24 had a significantly longer first post-treatment cycle, while those aged 25-29 had a shorter one, with no differences in older groups.
3) The ethinyl estradiol dose in the OC did not influence cycle length results.
The study investigated the length of the first menstrual cycle after stopping oral contraceptive (OC) use, compared to non-OC users and subsequent cycles after stopping. It found:
1) The median length of the first cycle after OC discontinuation (30 days) was not significantly different from the second cycle (29 days) or cycles in non-OC users (29 days for both first and second).
2) When divided by age, those aged 18-24 had a significantly longer first post-treatment cycle, while those aged 25-29 had a shorter one, with no differences in older groups.
3) The ethinyl estradiol dose in the OC did not influence cycle length results.
The study investigated the length of the first menstrual cycle after stopping oral contraceptive (OC) use, compared to non-OC users and subsequent cycles after stopping. It found:
1) The median length of the first cycle after OC discontinuation (30 days) was not significantly different from the second cycle (29 days) or cycles in non-OC users (29 days for both first and second).
2) When divided by age, those aged 18-24 had a significantly longer first post-treatment cycle, while those aged 25-29 had a shorter one, with no differences in older groups.
3) The ethinyl estradiol dose in the OC did not influence cycle length results.
Length of the menstrual cycle after discontinuation of oral contraceptives
INGRID J. M. DUIJKERS, LONNEKE ENGELS, & CHRISTINE KLIPPING Dinox Medical Investigations, Nijmengen, The Netherlands Abstract Objective To investigate whether the rst cycle after stopping oral contraceptive (OC) intake had a normal duration. Methods A retrospective study was performed in 680 women, 300 non-OC users and 380 women discontinuing OC intake. The length of one or two menstrual cycles was recorded. Results In the non-user group, the median duration of both the rst and second cycle was 29 days (range 1897 and 2056 days, respectively). In the OC user group the median duration from withdrawal bleeding until next menstruation was 30 (15 82) days. The second cycle lasted 29 (17122) days. The duration of the rst post-treatment cycle was not signicantly different from the next cycle or the cycle length in non-users. When the subjects were divided into different age categories, a signicantly longer rst posttreatment cycle was observed in the group aged 1824 years, but a shorter rst post-treatment cycle in the group aged 2529 years. No differences were seen in the higher age groups. The ethinyl estradiol dose of the OC preparation did not inuence the results. Conclusions The rst cycle after OC discontinuation had a normal duration. Keywords: Cycle length, cycle duration, discontinuation, oral contraceptive Introduction Many clinicians assume that the rst cycle after stopping combined oral contraceptive (OC) intake is not completely normal and has a longer duration than the next menstrual cycles [1,2]. Surprisingly, hardly any literature appears to exist on this subject. In the past a few studies were done to investigate the cycle length after discontinuation of high-dose combination OCs [36], most of them reporting an increased duration of the rst post-pill cycle. In more recent studies with lower-dose OCs a rapid return of ovulation after cessation of OC intake was reported, but data on the day of ovulation or the next menstruation were not given [79] or only the duration until the rst ovulation was investigated [10,11]. Recently, a large pro- spective study reported the characteristics of multiple cycles after discontinuation of OCs in 175 women, in comparison with a control group of 284 non-OC users [12]. In the post-pill group the cycle length was signicantly prolonged up to the ninth cycle. We performed a study to increase our knowledge on the subject. We investigated the length of the rst menstrual cycles after stopping the intake of a combination OC in healthy female volunteers, in comparison with the cycle length of women who did not use an OC. Since the degree of pituitary suppression depends on the dose of ethinyl estradiol (EE) in the OC preparation, the duration until restoration of pituitary and ovarian function may differ with different preparations [13,14]. Therefore, the cycle lengths after discontinuation of OCs with different doses of EE were compared. Furthermore, a comparison was made of cycle lengths in different age groups, since menstrual cycle length declines with increasing age [15]. Materials and methods Retrospective anonymized data from ten clinical drug trials were collected. The healthy female volunteers participating in these trials were not allowed to use an OC during one or two cycles before the intake of study medication. At the screening visit, before a subject entered a clinical trial, the menstrual history was obtained, the date of last menstruation was registered and, if applicable, the date of discontinuation of the OC, the type of OC and the rst day of the last withdrawal bleeding. During the pretreatment phase of the trial starting dates of the next menstruations were registered. The clinical drug trials were approved by an independent ethical committee. All subjects gave their written informed consent. Correspondence: I. J. M. Duijkers, Dinox Medical Investigations, Groenewoudseweg 317, 6524 TX Nijmegen, The Netherlands. Tel: +31-24-3224445. Fax: +31-24-3888953. E-mail: iduijkers@dinoxgroup.com Gynecological Endocrinology, February 2005; 20(2): 74 79 ISSN 0951-3590 print/ISSN 1473-0766 online # 2005 Taylor & Francis Group Ltd DOI: 10.1080/09513590400021011 G y n e c o l
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o n l y . Data from 680 women, aged between 18 and 40 years, were collected. The data were divided into two subsets. One group of 300 women did not use an OC in the 3 months prior to the clinical trial (non-users). Of all 300 women, the duration of one menstrual cycle was known and from the majority (194 women) also the duration of a second cycle. The second group of 380 women discontinued the intake of a combination OC to be able to participate in the clinical drug trial (OCusers). The exact date of OCdiscontinuation was known in 379 women, the start date of withdrawal bleeding in 278 women. The date of the rst spontaneous menstruationwas recordedinall women, the date of the second menstruation in 287 women. The start of the rst post-treatment cycle was dened as the rst day of withdrawal bleeding. When the cycle length was calculated, the rst day of bleeding was included but not the rst day of the next menstruation. A comparison was made between the lengths of the rst and the second menstrual cycle after OC discontinuation, and also between the cycle length in women who discontinued OC use and the cycle length in non-OC users. Furthermore, the cycle lengths after discontinuation of OCs with different doses of EE were compared (20 mg, 30 mg, 35 mg, 50 mg and triphasic OCs with 30/40/30 mg EE, respectively). In addition, a comparison was made of cycle lengths in different age groups. The two-sided Student t test was used to compare age in the two study groups (non-users and OC users). The difference between rst and second cycle length in the OC user group was analyzed by the two-sided Wilcoxon rank sum test for paired data, whereas the difference in rst cycle length of non-users and OC users was analyzed by the two- sided Wilcoxon rank sum test for independent data. The KruskalWallis test was used when three or more groups were compared. Statistical signicance was taken at the probability level of 5% or less (p 40.05). Results The distribution across different age categories of the non-users and OC users is shown in Table I. The distribution was somewhat different in the two study groups: in the lower age categories more subjects were OC users, whereas in the higher age groups more subjects did not use an OC. The mean age ( +stan- dard deviation (SD)), was 25.3 +5.2 years in the non-user group and 23.7 +4.5 years in the OC user group. This difference was statistically signicant. Of the women who discontinued OC use, 46 women (12%) used an OC containing 20 mg EE, 243 women (64%) used a 30 mg EE pill, 37 women (10%) used a pill with 35 mg EE, four (1%) used a pill with 37.5 mg EE, nine (2%) used a 50 mg EE pill and 41(11%) used a triphasic OC with 30/40/30 mg EE. The mean duration ( +SD) from the intake of the last OC tablet until the start of withdrawal bleeding was 3.5 +1.0 days. The duration until withdrawal bleeding was comparable after discontinuation of OCs with different EE doses (mean duration 3.3, 3.5, 4.0, 3.3 and 3.3 days in the 20, 30, 35, 50 and 30/40/30 mg group, respectively; not statistically signicant). The median lengths of the rst and second registered menstrual cycle in the non-user group, as well as the median lengths of the rst and second cycle after OC discontinuation, are depicted in Table II and Figure 1. When the duration from withdrawal bleeding until next menstruation was compared with the second cycle after OC discontinuation, the difference was not statistically signicant. The dura- tion from withdrawal bleeding until next menstruation was also not statistically signicantly different from the rst registered cycle in non-users. The numbers of rst and second cycles with a duration of 35 days or shorter, of 3670 days, or longer than 70 days in the non-user group and in the group who discontinued OC use are listed in Table III. Most of the subjects with long cycles reported normal menstrual cycle lengths before OC use. In the majority of these cases the other registered cycle had a normal duration. Since the non-user and OC user groups had a different distribution across the age categories, cycle lengths were compared in the different age groups. Figure 2 shows the median length of the rst and second menstrual cycles in the non-user and the OC user groups, in different age cate- gories. In the group aged from 1824 years, the rst cycle in OC users was signicantly longer than the second cycle and the cycle length in non-users. In the age group 2529 years, the rst cycle after OC discontinuation was signicantly shorter than the second cycle and not signicantly different from the cycle length in non-users. In the two highest age groups, the length of the rst cycle after OC discontinuation was not statistically signicantly different from the second cycle and the cycle of non-users. Figure 3 depicts the median lengths of the rst and second cycles after OC discontinuation, comparing OCs with different doses of EE. Although the rst cycle duration tended to increase with increasing EE Table I. Age distribution in the group of non-users of oral contraceptives (OCs) and the group of women who discontinued OC use. Age (years) Non-users OC users Total 1824 158 (23.2) 252 (37.1) 410 (60.3) 2529 70 (10.3) 84 (12.4) 154 (22.6) 3034 58 (8.5) 33 (4.9) 91 (13.4) 3540 14 (2.1) 11 (1.6) 25 (3.7) Total 300 (44.1) 380 (55.9) 680 (100) Data are expressed as number of subjects with the percentage of the total number of subjects in parentheses. Cycle length after OC discontinuation 75 G y n e c o l
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o n l y . dose, the length of the rst and second cycle did not differ signicantly between the groups. Discussion It is generally assumed that the length of the rst menstrual cycle after discontinuation of the use of an OC is increased compared with the regular cycle length. The present study was performed to investi- gate the cycle lengths of the rst and second menstrual cycles after discontinuation of OC use, and to compare them with normal cycle length. The results of the present study showed that the median duration from last OC intake until with- drawal bleeding was 3.5 days. The duration from withdrawal bleeding until next menstruation was similar to the second cycle duration and the cycle length in non-users. Apparently, a few days after stopping OC intake ovarian function was already restored. The terminal half-life of ethinyl estradiol is approximately 10 h, and of progestogens, 824 h [16,17]. As soon as these steroids were largely cleared from the body, as indicated by the start of withdrawal bleeding, follicular growth must have started again. This nding is supported by several other studies. Changes in gonadotropin and 17b- estradiol (E 2 ) levels in the pill-free period in OC users were determined [18], in some studies in combination with ultrasound measurements of folli- cular growth [11,13,19,20]. When these parameters in the pill-free period are compared with the early Figure 1. Median length of the rst and the second menstrual cycles in non-users of oral contraceptives (OCs) and subjects who discontinued OC use. Table III. Number of cycles (and percentage) with a duration shorter than 35 days, between 36 and 70 days and longer than 70 days in the non-user group and the group who discontinued oral contraceptive (OC) use. Cycle length (days) 1st cycle non-users 2nd cycle non-users 1st cycle after OC 2nd cycle after OC 435 261 (87.0) 185 (95.3) 235 (85.5) 242 (84.3) 3670 36 (12.0) 9 (4.6) 38 (13.8) 43 (15.0) 470 3 (1.0) 0 (0) 2 (0.7) 2 (0.7) Table II. Median duration (with range) and mean duration (+standard deviation (SD)) of the rst and second menstrual cycle in non-users of oral contraceptives (OCs) and women who discontinued OC use. After OC discontinuation, both the duration from the last OC intake and from the start of withdrawal bleeding until the next menstruation are listed. [Duration (days)] [First cycle] [Second cycle] Median (range) Mean (+SD) n Median (range) Mean (+SD) n Non-users 29 (1897) 30.5 (+8.2) 300 29 (2056) 29.1 (+4.7) 194 OC users From last OC until next menstruation 33 (1889) 33.9 (+7.1) 379 From start of bleeding until next menstruation 30 (1582) 30.8 (+7.0) 275 29 (17122) 31.1 (+9.3) 287 Figure 2. Median length of the rst and second menstrual cycles in non-users of oral contraceptives (OCs) and subjects who discontinued OC use, comparing different age categories. The numbers of non-users and OC users were 158 and 252 in the 18 24 year age group, 70 and 84 in the 2529 year, 58 and 33 in the 3034 year and 14 and 11 in the 3540 year age group, respectively. Signicant differences (p 40.05) are indicated by an asterix. Figure 3. Median cycle length of the rst and second cycles after discontinuation of oral contraceptives (OCs) comparing OCs with different doses of ethinyl estrradiol (EE). 76 I. J. M. Duijkers et al. G y n e c o l
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o n l y . follicular phase of a spontaneous menstrual cycle, follicle-stimulating hormone concentrations showed a similar increase, but in the pill-free period a delay of approximately 4 days was seen [11,20,21]. Also E 2 concentrations and follicular diameter increased similarly, but with a delay of several days. This delay equals the period until withdrawal bleeding starts. A small number of subjects had an extended duration of the rst cycle after OC discontinuation, although most of these subjects reported normal menstrual cycle lengths before OC use. In the majority of these cases the second cycle had a normal duration. This prolonged rst cycle duration may have been caused by the OC. However, the number of second cycles after OC discontinuation with prolonged duration was comparable to the number of long rst cycles. In the non-user group, the number of rst cycles with long duration was also comparable to the number in the OC user group. These results indicate that prolonged rst cycle duration after stopping OC intake is probably coincidental and not caused by the OC. In the past, a few studies were performed to investigate the cycle length after discontinuation of high-dose combination OCs containing either 50 mg EE or 50150 mg mestranol. Two studies comprised only a very small number of subjects [3,4]. In a study in 516 women three cycles after OC discontinuation were investigated [6]. In the group of women who had regular menstrual cycles before OC use (432 women), the mean duration of the rst post-treatment cycle was 36.0 days, that of the second cycle 29.9 days and of the third cycle 29.6 days. The duration of the rst post-treatment cycle was 35 days or less in 50.3%, 3670 days in 48.2% and more than 70 days in 1.8% of the women in this group. Another study comprised 163 women using different types of high-dose combination or sequential OCs [5]. The length of the rst post- treatment cycle was generally prolonged. In the groups using combination regimens the majority of cycles (52.8%) were 35 days or less, 41.6% were 3670 days and 5.6% were 70390 days long. In the group using the sequential regimen, the comparable values were 76.5%, 21.0% and 2.5%, respectively. Compared with these previous studies, in our study a smaller percentage of post-treatment cycles had a duration of more than 35 days. In two studies the return of ovulation after discontinuation of a lower-dose combination OC was investigated. Elstein and colleagues [10] per- formed a study in three women who discontinued the use of an OC containing 30 mg EE and 150 mg D- norgestrel. Ovulation occurred within 20 days after cessation of the OC. In another study the return of ovulation was investigated in 25 women after discontinuation of a triphasic combination OC, containing 3040 mg EE and 50100 mg gestodene [11]. Ovulation occurred on average 19 days after the last tablet intake. Although the start of the next menstruation was not mentioned in these studies, and we do not have data on the date of ovulation in our study, these results seem to be in agreement with ours, taking into account a luteal phase length of approximately 14 days. In two previous studies the cycle duration after discontinuation of lower-dose contraceptives was investigated. One study comprised only eight women using a daily oral contraceptive containing 35 mg EE and 0.625 mg norethisterone [22]. The subjects in this group were aged between 38 and 45 years. Menstruation started 63.4 days (mean, range 5195) after the start of the last pack of daily OCs. It was not mentioned how many tablets were included in a pack but, assuming it contained 21 tablets, menstruation started on average 42.4 days after the last tablet intake. In our study, menstruation started 33 days after the last OC intake, which is considerably earlier. Gnoth and associates [12] performed a large prospective study on the use of natural family planning. Characteristics of 3048 cycles in 175 women who discontinued OC use were compared with those of 6251 control cycles in 284 women who had never taken OCs. Participating women recorded menstrual bleeding, body temperature and cervical mucus aspects on cycle charts, from which cycle characteristics were derived. Of the post-pill women, 74% used xed combination OCs with 3037 mg EE, 2% used OCs with 50 mg EE, 6% used 20 mg EE pills and 18% used other preparations (sequential or unknown). The mean cycle duration was signicantly longer in the post-pill group up to the ninth cycle after pill discontinuation. Mean cycle duration decreased gradually from 34.95 days in the rst post-treatment cycle to 31.48 days in the ninth cycle, whereas in the control group the mean cycle duration remained between 29.31 and 29.89 days. However, the median cycle duration was 30 days in both groups and did not decrease during the observation period. The differ- ence in mean cycle duration between the groups was probably caused by a signicantly larger percentage of cycles with a duration of more than 35 days in the post-pill group vs. the control group. This percentage was 22% and 9% in the rst cycle, respectively, and the difference was statistically signicant up to the sixth cycle. Also, the percentage of cycles of more than 90 days was signicantly larger in the post-pill group than in the control group up to the fth cycle. Comparing the results from this study with ours, median cycle lengths were comparable in both studies. However, we did not nd a difference in the mean cycle duration after OC discontinuation, because in our study the percentage of cycles longer than 35 days was not increased in the rst pill-free cycle. The percentage was comparable to that in the second pill-free cycle and also comparable with the rst study cycle in non-OCusers. It is unclear why the ndings in the two studies are different. The study populations were more or less comparable. Subjects with known cycle disturbances were not included in Cycle length after OC discontinuation 77 G y n e c o l
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o n l y . the study by Gnoth. There were only two minor differences between the study populations. In Gnoths study the percentage of subjects using a 20 mg EE pill was somewhat lower (6% vs. 12% in our study), but it seems unlikely that this small difference will have inuenced the results. Another difference is the mean age of the subjects. The mean age in the control group was equal in the two studies (25.3 years), but in the study by Gnoth the mean age in the OC group was signicantly higher (26.3 years) whereas in our study the mean age in the OC group was signicantly lower (23.7 years). Still, cycle length slightly declines with age, and this difference cannot explain why the mean cycle length in the study by Gnoth and co-workers was longer than that in our study. We compared cycle lengths within different age groups. In the group aged 1824 years, the duration of the rst cycle after OC discontinuation was signicantly longer than the second cycle and the rst cycle in non-users. Contrarily, in the group aged 2529 years the length of the rst post-treatment cycle was signicantly shorter than the second cycle. There were no statistically signicant differences in the other age groups. The fact that the rst post- treatment cycle was signicantly longer in the young- est age group could indicate that an effect of OC treatment on cycle duration was present in young women but disappeared with increasing age. This possibility cannot explain the difference between our results and those by Gnoth and colleagues [12], however, because the mean age of the OC users in that study was higher than in our study (26.3 vs. 23.7 years). The shorter duration of the rst post-pill cycle compared with the second cycle in the 2529-year group is unexpected and it is hard to give an explanation for this nding, especially since the results in the highest age groups were not in agreement with this result in the 2529-year group. However, too many conclusions should not be drawn from these age-specic results because the subject numbers per age category were relatively small, particularly in the higher age groups. Previous studies showed that ovarian recovery in the pill-free period was more rapid in women who used an OC containing 20 mg EE than in users of monophasic and triphasic preparations containing 530 mg EE [13,19]. This difference in ovarian recovery reects the degree of pituitary suppression, which depends on the EE dose in the OC preparation [14]. In our study a tendency towards increasing post- treatment cycle duration with increasing EE dose could be seen, but the differences were not statistically signicant, which may be due to the small numbers of subjects in some of the dose groups. The type of progestogen may also inuence the degree of suppres- sion and thus the recovery period. In our study different types of progestogens were used within each EE dose group but we did not compare cycle lengths after discontinuation of each type of OC, because the groups would be too small to draw any conclusions. In summary, the mean duration from the last OC intake until withdrawal bleeding was 3.5 days. The duration of the rst cycle after OC discontinuation, from withdrawal bleeding until next menstruation, was similar to that of the second post-pill cycle and the cycle length in women not using an OC. References 1. Fraser IS, Weisberg E. Fertility following discontinuation of different methods of fertility control. Contraception 1982;26: 389415. 2. Huggins GR, Cullins VE. Fertility after contraception or abortion. Fertil Steril 1990;54:559573. 3. Bell ET, Loraine JA. Urinary steroid and gonadotrophin excretion in women following long-term use of oral contra- ceptives. Lancet 1967;2:442444. 4. Klein TA, Mishell DR. 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