ORAL CONTRACEPTIVES

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
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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
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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.
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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
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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.
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