Contraception 78 (2008) 16 – 25

Original research article

Suppression of ovarian activity with a drospirenone-containing

oral contraceptive in a 24/4 regimen
Christine Klipping a , Ingrid Duijkers a , Dietmar Trummer b , Joachim Marr c,⁎
a
Dinox BV, 9713 GZ Groningen, The Netherlands
b
Clinical Statistics Europe, Bayer Schering Pharma AG, D-13342 Berlin, Germany
c
Clinical Development Gynecology and Andrology, Bayer Schering Pharma AG, D-13342 Berlin, Germany
Received 27 April 2007; revised 21 February 2008; accepted 22 February 2008

Abstract

Background: This study was conducted to compare ovarian activity of an oral contraceptive containing drospirenone (drsp) 3 mg plus
ethinylestradiol (EE) 20 mcg administered in 24/4 regimen compared with the conventional 21/7 regimen, during intended use and following
predefined dosing errors.
Study design: Women aged 18–35 years who ovulated or had a follicular diameter of ≥15 mm on or before Day 23 during a pretreatment
cycle were admitted into this double-blind, randomized study. Participants underwent 3 treatment cycles with drsp 3 mg/EE 20 mcg in a 24/4
(n=52) or a 21/7 (n=52) regimen. In the third treatment cycle, the initial three pills in both groups were replaced with placebos. Ovarian
activity was classified using the Hoogland scale during pretreatment and during Cycles 2 and 3.
Results: Suppression of ovarian activity was more pronounced with the 24/4 regimen — the odds ratio for a lower Hoogland score
(i.e., greater ovarian suppression) with the 24/4 regimen compared with the conventional 21/7 regimen were 6.01 (95% CI: 2.29–17.94) and
3.06 (95% CI: 1.44–6.65) for Cycles 2 and 3, respectively. More women in the 24/4 regimen group had no ovarian activity \ 87.8% vs.
56.0% during Cycle 2 and 55.1% vs. 30.0% during Cycle 3. The 24/4 regimen was associated with a more consistent suppression (less
fluctuation) of endogenous estradiol.
Conclusion: The drsp 3 mg/EE 20 mcg oral contraceptive in a 24/4 regimen was associated with greater ovarian suppression (despite
intentional dosing error), which results in decreased hormonal fluctuations, and may increase contraceptive efficacy with the low-dose
formulation.
© 2008 Published by Elsevier Inc.

Keywords: Combined oral contraceptives; Drospirenone; Ovulation inhibition; Ovarian activity; Ultrasound; 24/4 regimen

1. Introduction Until recently, progestin developmental trends were based

Since their introduction in the 1960s, combined oral
contraceptives have undergone substantial changes. These
changes have focused on the progressive reduction of the
ethinylestradiol (EE) dose and development of new proges-
tins with favorable properties. More recent developments
have included phasing the level of hormonal exposure
through the treatment cycle and extending the duration of
active treatment.
⁎ Corresponding author. Global Medical Development Gynecology and
Andrology, Bayer Schering Pharma AG, D-13342 Berlin, Germany.
Tel.: +49 0 30 468 17617; fax: +49 0 30 468 15348.
E-mail address: joachim.marr@bayerhealthcare.com (J. Marr).
0010-7824/$ – see front matter © 2008 Published by Elsevier Inc.
doi:10.1016/j.contraception.2008.02.019
on 19-nortestosterone or 17α-hydroxyprogesterone deriva-
tives. The development of the progestin drospirenone (drsp),
a spironolactone analog with antimineralocorticoid and
antiandrogenic activity, represents an advance from the
development trends and previously available progestins.
Clinical experience with the first drsp-containing combined
oral contraceptive, comprising drsp 3 mg/EE 30 mcg
(Yasmin®) in a traditional 21/7 regimen, showed it to be
an effective and well-tolerated contraceptive with good cycle
control [1–3].
Consistent with the continual development of new
combined oral contraceptives, a new low-dose, estrogen-
containing formulation with drsp (comprising pills contain-
ing drsp 3 mg/EE 20 mcg, YAZ®) was developed to
 C. Klipping et al. / Contraception 78 (2008) 16–25
provide 24 days of hormonal treatment followed by a
shortened 4-day placebo interval (24/4 regimen). This new
combined oral contraceptive has been demonstrated to have
a high degree of contraceptive efficacy, a good safety
profile and an acceptable bleeding pattern [4,5]. In placebo-
controlled randomized trials, it has also been clinically
proven to be effective in alleviating the emotional and
physical symptoms associated with premenstrual dysphoric
disorder (PMDD) [6,7].
An additional investigation was undertaken to determine
the effects on ovarian activity of the drsp 3 mg/EE 20 mcg
combined oral contraceptive administered in a 24/4
regimen compared with the conventional 21/7 regimen
during intended specified use and following predefined
dosing errors.
2. Methods
2.1. Design and ethical approval
This was a randomized, double-blind, parallel group,
comparison study conducted at a single center in The
Netherlands. The study was approved by an independent
ethics committee and was conducted in accordance with the
ethical principles established by the Declaration of Helsinki
and the International Conference on Harmonization–Good
Clinical Practice Guidelines. Written informed consent was
obtained from all participating women before enrolment into
the study.
2.2. Subjects
A total of 128 healthy women aged 18–35 years
(maximum age of 30 years for smokers) were screened for
participation into the study. The exclusion criteria were
consistent with the usual contraindications for combined oral
contraceptive use and included substantial obesity (body
mass index N30kg/m2), pregnancy or lactation (within
3 cycles before the study) and unwillingness to use a
nonhormonal method of contraception during the study. A
complete medical, gynecological and obstetric history was
obtained from all women at screening. In addition, the
women underwent physical and gynecological examinations,
including a cervical smear (waived if they had a normal
result in the last 6 months before screening). The women
were required to use nonhormonal methods of contraception
throughout the study period and during follow-up.
All eligible (n=105) women screened underwent a
pretreatment cycle, which started on the first day of
menstruation following screening. During the pretreatment
cycle, ovarian activity was monitored (on Menstrual Cycle
Days 7, 11, 15, 19, 23, 27 and 31, with assessments on Days
27 and 31 omitted if menstruation had already started) by
transvaginal ultrasonography [Toshiba Eccocee SSA-340A
device, with a 6 MHz vaginal transducer (PVF-621VT)] and
serum hormone levels [17-β estradiol (E2), progesterone,
luteinizing hormone (LH) and follicle-stimulating hormone
17
(FSH)] were determined by Roche E170 technology. Only
those women who ovulated (collapse of dominant ovarian
follicle determined by means of ultrasound) or showed a
follicle-like structure (FLS) of ≥15 mm on or before Day 23
of the pretreatment cycle (or during a second pretreatment
cycle) were randomized and admitted to the treatment phase:
eligible (n=105) women were allocated study medication
according to a randomization code using randomization
numbers (numbers were distributed equally between the two
groups) assigned by the Sponsor in chronological order,
based on the date of randomization.
2.3. Treatments
The participants received the drsp 3 mg/EE 20 mcg
combined oral contraceptive (Bayer Schering Pharma,
Berlin, Germany) either as a 24/4 or conventional 21/7
regimen — the pills in the two regimens were indistinguish-
able so as to maintain blinding (participants received placebo
pills during the hormone-free interval). The first study pill
was taken on the first day of menses and continued over three
treatment cycles. All participants recorded pill intake daily
on diary cards. At the beginning of the third treatment cycle,
the first three hormone-containing pills in each regimen were
replaced by placebo pills before resumption of the allocated
active treatment. Compliance to the regimen was assessed by
analyzing patient recordings of pill intake on diary cards
along with the return of used, partially used or unused
treatment packs. In addition, blood samples were also
collected (see below) for drsp assessment as an additional
means to check treatment compliance in some participants.
2.4. Assessments
No clinic visits or assessment were scheduled during the
first treatment cycle. Transvaginal ultrasound was performed
regularly at every on-treatment visit [Days 3 (or Day 2 for
cycle 3), 5, 8, 11, 14, 17, 20, 23, 26 of the cycle] to determine
the diameter [2 measurements were made (transverse and
longitudinal) and the average diameter calculated] of the
largest FLS per ovary. The double-wall endometrial thick-
ness was also determined at all clinic visits. Blood samples
(5 mL per sample) were obtained at each visit to assess E2,
progesterone, LH and FSH levels. Transvaginal ultrasound
examinations and blood sampling for E2 and progesterone
were performed every third day (±1 day).
Table 1
Summary of Hoogland scores
Score Activity Diameter of Progesterone Estradiol
FLS (mm) (nmol/L) (nmol/L)
1 No activity ≤10 – –
2 Potential activity N10 – –
3 Nonactive FLS N13 – ≤0.1
4 Active FLS N13 ≤5 N0.1
5 LUF N13, persisting N5 N0.1
6 Ovulation N13, ruptured N5 N0.1
LUF, luteinized unruptured follicle.
18 C. Klipping et al. / Contraception 78 (2008) 16–25

All blood samples were stored frozen and sent to a central
laboratory for analysis as appropriate. The blood samples
were analyzed in a single batch to minimize intra-assay
variation.
Ovarian activity was classified according to the Hoogland
scoring system, which combines data on follicular activity
obtained from transvaginal ultrasonography and serum
hormone determinations (Table 1) [8]. Combining data on
the growth pattern of FLSs with hormone measurement, as in
the Hoogland scoring system, differentiates between cystic
structures and the various stages of ovarian activity, allowing
comparisons between cycles and/or subjects. The Hoogland
scoring system is comprised of six points, differentiated by
FLS, progesterone and E2 measures. The highest hormones
levels and the largest diameter of the follicles measured in
each cycle were used to calculate the Hoogland score. A
Hoogland score of 1 is indicative of low ovarian activity
while a score of 6 indicates high levels of ovulation.
Safety assessments included monitoring for the occur-
rence of adverse events throughout the study and for changes
in laboratory values for blood chemistry, hematological and
urinalysis variables at screening, on Day 25 of cycle 3 and at
final examination. Adverse events were classified by the
study investigators as to their likely relationship to the study
medication as none, unlikely, possible, probable or definite
and coded using the Hoechst Adverse Reactions Terminol-
ogy System, version 2.3.
2.5. Statistical analyses
The sample size of 100 participants (50 per group) was
chosen without biometrical consideration and is more than

Fig. 1. Flow of participants through the study.

 C. Klipping et al. / Contraception 78 (2008) 16–25 19

Table 2
Baseline characteristics of the FAS
24/4 regimen 21/7 regimen
(n=52) (n=52)
Age, years 25.6 (4.1) 25.6 (4.4)
Height, cm 170.4 (5.8) 169.1 (6.9)
Weight, kg 64.4 (7.3) 66.0 (9.5)
Body mass index, kg/m2 22.2 (2.5) 23.0 (2.7)
Nulliparous, n (%) 46 (88.5) 43 (82.7)
Current smokers, n (%) 18 (34.6) 16 (30.8)
Contraceptive method at screening, 28 (53.8) 15 (28.8)
n (%)
Oral contraceptive 12 (23.1) 17 (32.7)
Condoms 0 1 (1.9)
Intrauterine device 11 (21.2) 13 (25.0)
Other 1 (1.9) 6 (11.5)
None
Fig. 2. Summary of ovarian activity (data presented for the PPS).
Continuous variables are presented as mean (standard deviation).
The proportional odds model used assumed that the odds
sufficient compared with sample sizes used in other similar, ratio was independent of the Hoogland score. The validity of
comparative, ovulation inhibition studies [9,10]. the proportional odds assumptions (i.e., that the indepen-
The primary efficacy variables were the Hoogland dence of odds ratio from the Hoogland score is adequate)
scores in Cycle 2 (following intended dosing regimen) was checked by the chi-square score test. In addition, the
and Cycle 3 (following three intentionally missed pills at proportion of volunteers with Hoogland scores of 1 or 2 in
the beginning of the cycle). The per-protocol set (PPS) was cycles 2 and 3 along with the associated two-sided 90% CIs
regarded as the primary analysis set and included women were calculated using normal approximations.
from the full analysis set (FAS, all randomized participants
who took at least one dose of study medication) without
major protocol violations that may affect the primary 3. Results
efficacy variable. 3.1. Participant characteristics
All analyses were conducted using SAS software (version
8). Descriptive statistics for the variables of interest were Of the 128 women screened, 105 met the criteria for
calculated for both groups. Frequency tables for ovarian inclusion and randomization [i.e., ovulated or showed a FLS
activity as classified by the Hoogland scores were con- of ≥15 mm on or before Day 23 of the pretreatment cycle(s)]
structed for treatment Cycles 2 and 3. A proportional odds and were randomized to treatment: 52 women to the drsp 3
model was used to predict the odds of having a lower mg/EE 20 mcg 24/4 regimen and 53 to the conventional 21/7
Hoogland score in the drsp 3 mg/EE 20 mcg 24/4 regimen regimen (Fig. 1). One woman in the conventional 21/7
group than in the conventional 21/7 regimen group. The odds regimen group withdrew consent before taking any medica-
ratio is a useful way of expressing how much higher the odds tion. The characteristics of the participants at baseline in the
for a certain event are in one group compared to the other FAS are summarized in Table 2. There was about twofold
group (in this case, the event has a lower Hoogland score). greater proportion of oral contraceptive users in the drsp
An odds ratio N1 implies that the event is more likely in the 3 mg/EE 20 mcg 24/4 regimen group at baseline compared
first group (drsp 3 mg/EE 20 mcg 24/4 regimen), and an odds with the conventional 21/7 regimen group \ otherwise, no
ratio b1 implies that the event is less likely in the first group. important differences were observed between treatment

Table 3
Ovarian activity graded by the Hoogland scale; n (%) a
1. No activity 2. Potential activity 3.Non-active 4. Active FLS 5. LUF 6. Ovulation b
FLS
24/4 21/7 24/4 21/7 24/4 21/7 24/4 21/7 24/4 21/7 24/4 21/7
Pre-treatment cycle 0 0 2 (4.1) 0 0 0 7 (14.3) 4 (8) 0 0 40 (81.6) 46 (92.0)
Cycle 2 43 (87.8) 28 (56.0) 5 (10.2) 11 (22.0) 0 0 1 (2.0) 9 (18.0) 0 1 (2.0) 0 1 (2.0)
Cycle 3 27 (55.1) 15 (30.0) 8 (16.3) 7 (14.0) 0 0 13 (26.5) 24 (48.0) 0 0 1 (2.0) 4 (8.0)
a
Data presented for the PPS.
b
Overall, 5 women ovulated during the study: one woman in the conventional 21/7 regimen group ovulated during both treatment cycles 2 and 3. All these
women were compliant based on diary card entries for pill intake and drsp blood levels. However, one patient in the conventional 21/7 regimen group took
antibiotics for 10 days during cycle 3 to treat scarlet fever.
20 C. Klipping et al. / Contraception 78 (2008) 16–25
Fig. 3. Maximum follicle size in the PPS with the drsp 3 mg/EE 20 mcg 24/4 regimen (─) and with the conventional 21/7 regimen (
(Q1-Q3).
groups. Overall, 49 women in the drsp 3 mg/EE 20 mcg 24/4
regimen group, and 50 in the conventional 21/7 regimen
group completed the study as planned and were included in
the per-protocol analysis.
3.2. Ovarian activity
Table 3 summarizes ovarian activity for both groups
during the pretreatment cycle and treatment Cycles 2 and 3
based on the Hoogland scoring system. Ovarian activity was
suppressed completely in more women in the drsp 3 mg/EE
20 mcg 24/4 regimen group compared with the conventional
21/7 regimen group [43 (87.8%) vs. 28 (56.0%) during Cycle
2 and 27 (55.1%) vs. 15 (30.0%) during cycle 3]; conversely,
a high proportion of women had ovarian activity (Hoogland
score 2–6) in the latter group (6 [12.2%] vs. 22 [44.0%]
during cycle 2 vs. 22 [44.8%] vs. 35 [70.0%] during cycle 3)
(Fig. 2). In the conventional 21/7 regimen group, one woman
ovulated and another had a luteinized unruptured follicle
during correct intended dosing (cycle 2) \ neither of these
events occurred in the drsp 3 mg/EE 20 mcg 24/4 regimen
group. One woman ovulated in the drsp 3 mg/EE 20 mcg 24/4
regimen group following a predefined dosing error compared
with 4 women in the conventional 21/7 regimen group.
During correct intended dosing in Cycle 2, the proportion
of subjects with low Hoogland scores of 1 or 2 was higher in
Fig. 4. Maximum endometrial thickness in the PPS with the drsp 3 mg/EE 20 mcg 24/4 regimen (─) and with the conventional 21/7 regimen (
median (Q1–Q3).
\). Data shown as median
the drsp 3 mg/EE 20 mcg 24/4 regimen group (n=48; 98.0%,
90% CI 94.6–100) compared with the conventional 21/7
regimen group (n=36; 78.0%, 90% CI 68.4–87.6), suggest-
ing greater suppression of follicular development with the
drsp 3 mg/EE 20 mcg 24/4 regimen. Similarly, during
treatment in Cycle 3 (where three pills were intentionally
replaced with placebo at the start of the cycle), the proportion
of subjects with low Hoogland scores of 1 (no activity) or 2
(potential activity) was higher in the drsp 3 mg/EE 20 mcg
24/4 regimen group (n=35; 71.4%, 90% CI 60.8–82.0)
compared with the conventional 21/7 regimen group (n=22;
44.0%, 90% CI 32.5%–55.6%).
Overall, in Cycle 2, the odds of a lower Hoogland score in
the drsp 3 mg/EE 20 mcg 24/4 regimen group was 6.01-fold
greater (95% CI: 2.29–17.94) than in the conventional 21/7
regimen group, confirming the greater suppression of
ovarian activity with the drsp 3 mg/EE 20 mcg 24/4 regimen
during correct intended use. The score test for the
proportional odds assumption was insignificant (p=.79)
indicating that the assumptions in the model hold true (i.e.,
the odds ratio is independent from the Hoogland score).
The odds of a lower Hoogland score during cycle 3 in the
drsp 3 mg/EE 20 mcg 24/4 regimen group following
intentional dosing error was 3.06-fold greater (95% CI:
1.44–6.65) than in the conventional 21/7 regimen group,
also confirming the greater suppression of ovarian activity
\). Data shown as
 C. Klipping et al. / Contraception 78 (2008) 16–25
Fig. 5. Serum concentrations of E2 with the drsp 3 mg/EE 20 mcg 24/4 regimen (A) and with the conventional 21/7 regimen (B). Data shown as median (Q1–Q3)
for the PPS.
with the drsp 3 mg/EE 20 mcg 24/4 regimen. The score test
for the proportional odds assumption was again insignificant
(p=.92).
3.3. Effects on follicular structures
The median diameters (with Q1 and Q3) of the largest
FLSs in both treatment groups are shown in Fig. 3. The
median diameter of the largest FLSs following intentional
dosing error in cycle 3 was smaller in the drsp 3 mg/EE 20 mcg
24/4 regimen group compared with the conventional 21/7
regimen group (10.2; Q1/Q3, 8.5/15.3 vs. 14.3; Q1/Q3, 10.2/
22.2; p=.001). The median diameter of the largest FLS
following intentional dosing error in the drsp 3 mg/EE 20 mcg
24/4 regimen group was similar to that achieved during
correct intended dosing in the conventional 21/7 regimen
group (10.2; Q1/Q3, 8.5/15.3 vs. 9.6; Q1/Q3, 7.9/12.5).
3.4. Effects on endometrial thickness and hormone levels
The maximum endometrial thickness reached during
treatment in both groups is shown in Fig. 4. Both treatment
regimens suppressed growth compared with pretreatment. In
addition, the maximum endometrial thickness following
21
intentional dosing error in the drsp 3 mg/EE 20 mcg 24/4
regimen group was similar to that achieved during correct
intended dosing in the conventional 21/7 regimen group.
The changes in serum levels of E2, FSH and LH are
shown in Figs. 5–7: overall, both regimens suppressed
production of E2 and LH during the treatment cycles
compared with the pretreatment cycle. Serum E2 concentra-
tion fluctuations were consistently suppressed at about a
median 10 pg/mL during correct intended use in cycle 2 with
the drsp 3 mg/EE 20 mcg 24/4 regimen but fluctuated
between 10–33 pg/mL with the conventional 21/7 regimen.
FSH levels were suppressed with active treatment in both
groups relative to the pretreatment cycle. Progesterone was
consistently suppressed compared to pretreatment and to a
similar extent with both treatment regimens during cycles 2
and 3 (data not shown). Moreover, with intentional dosing
errors during cycle 3, the longer the pill-free interval, the
greater the rise in serum E2 concentrations.
3.5. Safety
Both regimens were well tolerated, and few adverse
events were reported overall. Two serious adverse events
22 C. Klipping et al. / Contraception 78 (2008) 16–25
Fig. 6. Serum concentrations of FSH with the drsp 3 mg/EE 20 mcg 24/4 regimen (A) and with the conventional 21/7 regimen (B). Data shown as mean (±S.D.)
for the PPS.
(lymphangioma and ovarian cyst) were reported in two
women during the study (both in the conventional 21/7
regimen group) but were considered not related to treatment.
Treatment-related adverse effects were generally typical of
those associated with hormonal contraceptive use (Table 4).
Only one adverse effect (depressive mood) occurred during
the study (in the conventional 21/7 regimen group) that led to
discontinuation of study medication. General laboratory
parameters varied only slightly for both regimens and gave
no reasons for safety concerns.
4. Discussion
This study, one of the largest ovulation inhibition trials to
date, demonstrated that increasing the duration of active
hormone intake to 24 days and shortening the hormone-free
interval to 4 days with the drsp 3 mg/EE 20 mcg combined
oral contraceptive results in greater suppression of ovarian
activity compared with the conventional 21/7 regimen.
Moreover, the 24/4 regimen was associated with a more
consistent suppression of endogenous E2 and endogenous
hormonal fluctuations. There was a lower incidence of
escape ovulation (2.0% vs. 8.0%) with the shorter 4-day
hormone-free interval following predefined dosing errors at
the beginning of the treatment cycle (equivalent to extending
the hormone-free interval by 3 days) than with the
conventional 21/7 regimen. The suppression of ovarian
activity achieved in 24/4 regimen group following inten-
tional dosing errors was similar to that observed in
conventional 21/7 regimen group during intended use.
Overall, the results of this study are consistent with those
of other studies demonstrating that a reduction in the
hormone-free interval from 7 days to 3–5 days is associated
with better ovarian suppression (irrespective of EE dose) as
demonstrated by reduced follicular development [9–11].
Conversely, extending the hormone-free interval (i.e.,
missing pills at the beginning of a treatment cycle) may
reduce the inhibitory effects, allowing for greater ovarian
activity and increased risk of ovulation [12,13].
A minimum of 7 consecutive days of combined oral
contraceptive use at the beginning of a menstrual cycle is
deemed necessary to reliably suppress ovarian activity, with
the rest of the active treatment regimen needed to maintain
 C. Klipping et al. / Contraception 78 (2008) 16–25 23

Fig. 7. Serum concentrations of LH with the drsp 3 mg/EE 20 μg 24/4 regimen (A) and with the conventional 21/7 regimen (B). Data shown as mean (±S.D.) for
the PPS.

anovulation [14]. On the other hand, 7 consecutive hormone- the administration of the drsp 3 mg/EE 20 mcg combined
free days (as with the conventional 21/7 regimen) can be oral contraceptive in cycles of 24/4 or 21/7 regimens
undertaken without loss of contraceptive efficacy \ provides similar contraceptive efficacy, both with good
although residual follicular activity may be evident during bleeding and safety profiles [4,5,15,16].
the hormone-free interval, escape ovulation does not usually Missing pills at the beginning of a treatment cycle
occur [13]. Moreover, the available evidence suggests that represents the most likely scenario where the residual
ovarian activity seen during the hormone-free interval may
Table 4
more likely escalate to allow escape ovulation than for pills
Treatment-related adverse events (possible, probable or definite) reported by missed at other times during the cycle. Consequently, the
N5% of women in any group design of this study would more than likely be an adequate
Adverse event 24/4 regimen (n=52) 21/7 regimen (n=52) representation of missed pills at other times during the
treatment cycle.
Headache 8 (15.4%) 14 (26.9%)
Abdominal pain 5 (9.6%) 10 (19.2%) This study, with intentional dosing error days in Cycle 3
Emotional lability 7 (13.5%) 8 (15.4%) (equivalent to missed pill days), is also a reasonable
Breast pain 5 (9.6%) 10 (19.2%) representation of current practice for a number of women
Intermenstrual bleeding 5 (9.6%) 9 (16.3%) [17,18]. In a prospective US study comparing the consis-
Nausea 6 (11.5%) 7 (13.4%)
tency of self-reported pill-taking with data from an electronic
Metrorrhagia 6 (11.5%) 4 (7.7%)
Dysmenorrhea 3 (5.8%) 5 (9.6%) device measuring compliance, the proportion of women who
Acne 3 (5.8%) 5 (9.6%) reported not missing any pills ranged between 53–59% over
Vaginal hemorrhage 4 (7.7%) 4 (7.7%) 3 months compared with 19–33% recorded by the device
Leukorrhea 2 (3.8%) 3 (5.8%) [17]. Moreover, the proportion of women missing at least 3
Pruritus 3 (5.8%) 1 (1.9%)
pills recorded by the device was about threefold greater than
24 C. Klipping et al. / Contraception 78 (2008) 16–25
that reported by the women (30–51% vs 10–14%). In a
secondary analysis of the prospective US study, a common
reason cited for missing pills (on consecutive days) was “no
new pack,” which would suggest that a significant number of
women extended the hormone-free interval beyond that
recommended [19]. Consequently, shortening the hormone-
free interval should reduce the risk of escape ovulation when
pills are omitted or missed in clinical practice and may result
in an increase in the contraceptive safety margin [20].
Reduced fluctuations in E2 levels with the 24/4 regimen
study compared with the conventional 21/7 regimen were
observed in this study. This observation, coupled with the
long elimination half-life of drsp (30.9–32.5 h) [21], which
does not lead to the complete elimination of drsp (nor to the
complete diminution of its beneficial antimineralocorticoid
and antiandrogenic effects) from the systemic circulation
before initiation of the next treatment cycle, may, in part,
account for the benefits of the drsp 3 mg/EE 20 mcg
combined oral contraceptive in the treatment of the
emotional and physical symptoms associated with PMDD
[6,7]. No difference was observed between the 24/4 regimen
and the conventional 21/7 regimen in progesterone levels in
this study, even after intentional dosing errors at the
beginning of the treatment cycle. Generally, both FSH and
LH levels were suppressed to a greater extent by the 24/4
regimen than the conventional 21/7 regimen compared with
pretreatment. The greater suppression of LH with the 24/4
regimen was maintained following intentional induced
dosing errors, but not for FSH levels (which rose during
the hormone-free interval to levels comparable with pre-
treatment). Overall, these results are consistent with greater
suppression of ovarian activity with the 24/4 regimen.
Both drsp 3 mg/EE 20 mcg regimens demonstrated good
safety and tolerability profiles. Moreover, the incidence and
types of adverse events reported in this study were
comparable with those reported with other low-dose
combined oral contraceptives. Interestingly, there was a
general trend towards fewer adverse events with the 24/4
regimen including those typically associated with hormone
withdrawal such as headache and breast tenderness [22].
In summary, both regimens demonstrated reliable sup-
pression of ovarian activity as indicated by low Hoogland
scores. However, the 24/4 regimen was associated with
greater ovarian suppression, and lower and less variable
serum hormone concentrations and fluctuations in general,
than the conventional 21/7 regimen. The shorter hormone-
free interval with the drsp 3 mg/EE 20 mcg combined oral
contraceptive taken in a 24/4 regimen may increase the
contraceptive safety margin in clinical practice compared
with the conventional 21/7 regimen.
Acknowledgments
Funding for this study (protocol no. 308382) was
provided by Bayer Schering Pharma AG, Berlin, Germany.
Joachim Marr and Dietmar Trummer are employees of Bayer
Schering Pharma. Christine Klipping and Ingrid Duijkers are
employees of the Contract Research Organisation, Dinox
Medical Investigations, who were contracted to perform the
study. The authors would like to thank Richard Glover for his
editorial assistance.
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