Gynecological Endocrinology, 2012; 28(6): 451–454

© 2012 Informa UK, Ltd.

ISSN 0951-3590 print/ISSN 1473-0766 online
DOI: 10.3109/09513590.2011.634936

ENDOMETRIOSIS

A new oral contraceptive regimen for endometriosis management:

preliminary experience with 24/4-day drospirenone/ethinilestradiol
3 mg/20 mcg
Mohamed Mabrouk1,2, Serena Solfrini1, Clarissa Frascà1, Simona Del Forno1, Giulia Montanari1, Giulia Ferrini1,
Roberto Paradisi1 & Renato Seracchioli1
1The Minimally Invasive Gynaecological Surgery Unit, Gynaecology Department, S.Orsola-Malpighi Hospital, University of Bologna,

Bologna, Italy and 2Department of Obstetrics and Gynaecology, Alexandria University, Alexandria, Egypt
Gynecol Endocrinol Downloaded from informahealthcare.com by Michigan University on 10/31/14

pills followed by 4 days HFI), has been proposed for contracep-

We report our preliminary experience with the use of a low-dose
tion, showing reliable contraceptive efficacy, acceptable bleeding
oral contraceptive containing Drospirenone/Ethinylestradiol
pattern and satisfactory safety profile [7–13].
3 mg/20 mcg, both in cyclic and continuous regimen for endo-
It has been suggested that the short HFI of this new regimen
metriosis management. A total of 93 women were retrospec-
might provide a more homogenous hormonal milieu and a greater
tively included: 52 were treated by medical therapy (exclusive
ovarian suppression than the conventional 7-days HFI [14].
combined oral contraceptives (COC)-users), while 41 were
Furthermore, reduction in menstrual bleeding achieved with the
submitted to surgery followed by postoperative therapy (post-
24/4 regimen might give relief from menstruation-related symp-
operative COC-users). A clinical examination was performed
toms. All this data prompted us to evaluate the possible beneficial
at baseline and at 6-months follow-up. Presence and intensity
effects of Yaz® in patients with endometriosis.
of endometriosis-related symptoms were assessed by a visual
For personal use only.

analogue scale. Presence and dimension of endometriotic

lesions were evaluated by transvaginal ultrasonography.
Adverse effects and tolerability were analysed. In exclusive
COC-users, significant reductions in dysmenorrhoea and
dyspareunia scores and in endometrioma mean diameter were
observed at follow-up. In postoperative COC-users, anatomical
and symptom recurrence rates at follow-up were 4.9% and 17%,
respectively. The most frequent adverse effects were spotting
and headache. No difference between cyclic and continuous
regimen in terms of symptom relief, lesion progression and
tolerability was observed. From our preliminary experience,
Drospirenone/Ethinylestradiol 3 mg/20 mcg seems to be prom-
ising in endometriosis management.
Keywords: combined oral contraceptives, 24/4, continuous
regimen, endometriosis, dysmenorrhoea, drospirenone
Introduction
A positive effect of combined oral contraceptives (COC) on
endometriosis, in terms of pain relief and endometriotic lesions
control, has been observed in the last years [1–4]. Since hormonal
therapies should be administered for long time to be effective on
endometriosis, COC could represent a good therapeutic choice in
terms of safety, tolerability, metabolic effects and costs [1,2,5].
Oral contraceptives can be used in cyclic or continuous
regimen. The latter, avoiding the hormone free interval (HFI),
could be preferred when the cyclic administration is unable to
resolve painful symptoms related to monthly bleeding [4,6].
Recently, a low-dose COC containing Drospirenone/
®
Ethinylestradiol 3 mg/20 mcg (Yaz , Bayer Schering Pharma AG,
Berlin, Germany), administered in 24/4 regimen (24 days of active
Methods
We retrospectively reviewed clinical records of Endometriosis
Outpatient Clinic in Sant’Orsola University Hospital from January
2009 to October 2010. Women aged between 18 and 40 years,
with ultrasonographic diagnosis of uncomplicated endometriosis,
submitted to medical therapy with Drospirenone/Ethinylestradiol
®
3 mg/20 mcg (Yaz ) for at least 6 months were eligible for the
study. Patients who had been receiving hormonal therapy for at
®
least 3 months before Yaz prescription were excluded. All the
included patients reported endometriosis-related symptoms,
such as dysmenorrhoea, dyspareunia, chronic pelvic pain (CPP),
dyschezia and dysuria.
Both cyclic 24/4 and continuous regimens were considered
for this study. Patients are usually counselled in our centre about
different COC regimen options: COC therapy can provide pain
relief both in cyclic and continuous administration with no proven
difference between the two regimens in terms of side effects and
metabolic profile [6].
We retrospectively divided patients into two groups: exclusive
®
COC-users had received Yaz as exclusive treatment for endo-
metriosis, while postoperative COC-users had received it for
prophylaxis against endometriosis recurrence, after complete
surgical excision of endometriotic lesions. Patients had been
routinely asked to give their informed consent to anonymously
use their clinical data for medical research. The local ethics
committee approval was obtained.
Clinical examinations at the moment of Yaz prescription®
(baseline) and after 6 months of treatment (6-months follow-up)
were considered for the study. At each clinical control, trans-
vaginal ultrasonography was performed by expert examiners.
Presence, localization and diameter of endometriotic lesions,

Correspondence: Dr. Renato Seracchioli, M.D., Head of Minimally Invasive Gynecological Surgery Unit, Gynaecology Department, S.Orsola Hospital,
University of Bologna, Via Massarenti, 13 (40138), Bologna, Italy. Tel: 0039.051.6363944. Fax: 0039.051.6363944. E-mail: renato.seracchioli@aosp.bo.it
451
 452 M. Mabrouk et al.
both ovarian and deep infiltrating endometriosis (DIE), were
reported in clinical records. Mean lesion’s diameter was obtained
by calculating the average of the three dimensions diameters.
Furthermore, patients had been asked to grade the severity of
pain by using a 10-points visual analogue scale (VAS [15]).
At 6-months follow-up, women were asked to rank their
satisfaction about medical treatment (very satisfied, satisfied,
neither satisfied nor dissatisfied, dissatisfied, very dissatis-
fied) and their physical and emotional well-being (improved,
unchanged or worsened) as it was part of another ongoing
study [9,10].
In all postoperative COC-users, surgical reports described the
complete excision of endometriotic lesions and histopathological
examination reports confirmed their endometriotic nature. Pain
recurrence was defined as pain graded ≥4 on the VAS scale [16].
We considered as endometrioma recurrence any lesion of diam-
eter >15 mm with typical ultrasonographic features and as DIE
recurrence tender lesions with the characteristic hypoechogenic
Gynecol Endocrinol Downloaded from informahealthcare.com by Michigan University on 10/31/14
Exclusive COC-users
Significant reductions in dysmenorrhoea and dyspareunia
VAS scores (P = 0.006 and P = 0.012, respectively) and in
endometrioma mean diameter (P = 0.021) were observed at
follow-up (Table II).
Postoperative COC-users
Among postoperative COC-users, seven patients (17%) reported
at least one symptom recurrence at follow-up (one dysmenorrea,
one CPP, five dyspareunia, two dyschezia and one dysuria).
Endometrioma recurrences were observed in two patients (4.9%),
while no DIE recurrence was observed.
Tolerability
Adverse effects reported are described in Table III. The most
frequent were spotting and headache. Concerning the discon-
tinuation profile, at follow-up, eight women (8.6%) expressed

the intention of interrupting the therapy: four (4.3%) because of

avascular pattern [4,17–19]. adverse effects (headache, vaginal dryness, nausea and spotting),
The main outcome measures were: variations in VAS score
and in lesions mean diameter between baseline and follow-up Table I. Characteristics of study population at descriptive analysis
for exclusive COC-users, symptoms and lesions recurrence rates (continuous variables are presented as mean ± SD).
at follow-up for postoperative COC-users. Percentage of adverse Postoperative
effects, discontinuation of the therapy, patients’ satisfaction and Overall Exclusive COC- COC-users
Characteristics (n = 93) users (n = 52) (n = 41) P
well-being were also evaluated. Difference between cyclic and
continuous administrations was analysed for all the variables Age (years) 34.2 ± 5.3 33.2 ± 6.8 36.4 ± 2.5 0.23
considered. BMI (kg/m2) 21.5 ± 2.8 20.8 ± 4.1 21.9 ± 3.7 0.21
Cyclic users (%) 56 (60.2) 34 (65.4) 22 (53.6) 0.18
Statistical analysis Continuous users (%) 37(39.8) 18 (34.6) 19 (46.4) 0.12
For personal use only.

In the literature, treatment success at the 3rd month follow-up BMI, body mass index; COC, combined oral contraceptives.
after medical therapy was defined as 25% reduction of VAS scores
[20]. Having VAS score variation as a primary outcome measure, Table II. VAS scores of the five types of pain and endometriotic lesions
we retrospectively assumed that a 25% reduction in VAS pain mean diameter in exclusive COC-users at baseline and at 6-months
follow-up.
scores between the first and second examinations in COC-users
Baseline 6-months follow-up P
is clinically significant. The study was designed to have an 80%
power to detect a difference of 25% in VAS scores with 2-sided VAS score
α levels of 0.05. We calculated a required sample of 24 for each Dysmenorrea 5.2 ± 3.5 3.3 ± 3.7 0.006
group (total of 48 participants) to achieve this power. Being a Chronic pelvic pain 1.7 ± 3.3 1.3 ± 2.4 0.07
retrospective study, we included all eligible patients who fulfilled Dyspareunia 3.6 ± 3.6 2.3 ± 3.02 0.012
the inclusion criteria. Dyschezia 1.6 ± 2.9 1.2 ± 2.7 0.08
All continuous variables are expressed in terms of mean ± stan- Dysuria 0.06 ± 0.3 0.0 ± 0.0 0.061
dard deviation of the mean. All categorical variables are expressed Mean diameter (mm)
as proportion or percentage. The Kolmogorov–Smirnov test was Rectovaginal septum 11.4 ± 17.9 12.1 ± 18.1 0.23
used to check normality. The Fisher’s exact test (Two groups) or Recto-sigmoid 2.5 ± 6.9 3.7 ± 9.1 0.09
the Pearson χ-Square test (>2 groups) was used for categorical Ovary 12.9 ± 2.6 11.5 ± 4.8 0.021
data comparison. Paired t-test was used to test normally distrib- Urinary bladder 1.7 ± 3.5 1.7 ± 3.5 0.061
uted data and Wilcoxon non-parametric paired test was used to Variables are presented as mean ± SD.
test non-normally distributed data.
One-Way ANOVA was used to compare mean of different
groups in normally distributed homoschedastic data, the Table III. Adverse effects reported with Yaz® treatment at 6-months
Mann–Whitney U-test was used otherwise. Pearson correla- follow-up.
tion was used to test relationship between continuous variables. Overall Cyclic Continuous P cyclic
(n = 93) users (n = 56) users (n = 37) versus
Statistical analysis was carried out by means of the Statistical
Adverse effects n (%) n (%) n (%) continuous
Package for the Social Sciences Software (version 14.1; SPSS
Inc, Chicago, IL). Spotting 24 (25.8) 10 (17.) 14 (37.8) 0.37
Headache 18 (19.4) 13 (23.2) 5 (13.5) 0.09
Vaginal Dryness 5 (5.4) 3 (5.4) 2 (5.4) 0.06
Results Nausea 3 (2.8) 2 (3.6) 1 (2.7) 0.31
Out of 121 patients considered for the study, 28 were excluded Reduction of sexual 2 (1.9) 1 (1.8) 1 (2.7) 0.27
®
for receiving hormonal therapy before Yaz prescription. A total desire
of 93 women were therefore included: 52 (55.9%) were exclusive Bloating 1 (1.1) 1 (1.8) 0 0.62
COC-users and 41 (44.1%) were postoperative COC-users. The Breast Tenderness 1 (1.1) 1 (1.8) 0 0.53
characteristics of the study population are reported in Table I. Variables are presented as mean ± SD.

Gynecological Endocrinology

two (2.2%) because they desired to conceive and two (2.2%)
because of pain persistence. At follow-up, 74 women (79.5%)
were satisfied or very satisfied with the treatment and 13 women
(14%) expressed dissatisfaction. Emotional and physical well-
being was unchanged in 42 patients (45%) and improved in 44
(47.5%) compared with baseline.
No significant difference between cyclic and continuous users
was observed in terms of adverse effects, VAS score and lesions
diameter variations, symptoms and lesions recurrence.
Discussion
®
From our results, Yaz seems to have a positive effect in patients
with endometriosis. To the best of our knowledge, this is the
first study reporting the effect of a 24/4 COC regimen on
endometriosis.
Considering that endometriosis-related symptoms are
frequently coincident with menstrual bleeding, various experts
Gynecol Endocrinol Downloaded from informahealthcare.com by Michigan University on 10/31/14
recommend the elimination of the HFI in women with pain
resistant to cyclic therapy [6,16]. Continuous COC administra-
tion however, leads to amenorrhea, which some women do not
accept. The new 24/4 regimen, providing a short HFI, reduces but
doesn’t eliminate menstrual bleeding and might provide longer
relief from menstruation-related symptoms.
In the present study, a significant reduction in dysmenor-
rhoea and dyspareunia intensity was observed at follow-up,
both in cyclic and continuous regimen. Other authors have
observed a reduction in endometriosis-related symptoms in
patients treated by COC for at least 4 months, both in cyclic
For personal use only.
21/7 and continuous use [21–23]. It has been demonstrated
that continuous regimen can be successfully administered in
patients with dysmenorrhoea who do not respond to cyclic
COC [6]. In our study, a significant difference in symptoms
relief between continuous and 24/4 cyclic regimens was not
observed. This short HFI could provide a more homogenous
hormonal milieu and a greater ovarian suppression than the
conventional 7-days HFI [14]. It has been described that endo-
metriosis symptoms seem to be related to recurrent microb-
leeding within the endometriotic implants and the associated
inflammation. The ovarian inactivation and the endometrial
tissue atrophy induced by COC, leading to a reduction in
prostaglandins production and inflammation, seems to play a
central role in endometriosis symptoms control [1,24–26].
®
From the analysis of our data, Yaz seems to be associated with
reducing endometriomas dimensions. Our results are in agree-
ment with Harada et al., who demonstrated a significant reduction
of endometrioma volume after four cycles of COC assumption
[21]. The authors hypothesized that induced ovarian inactivation
and low estrogens concentration may down-regulate cell prolif-
eration and enhance apoptosis of the endometrium [27,28].
®
Regarding DIE, from our results Yaz seems to have a
role in restraining its progression. In the current literature,
data concerning COC therapy and DIE are very little. A study
evaluating the effect of continuous COC in women affected
by rectovaginal endometriosis showed lesions reduction after
12-months of therapy [23]. We cannot exclude that a longer dura-
tion of the treatment could have provided a significant reduction
of DIE lesions size in our series.
®
Postoperative administration of Yaz might have protec-
tive effects against symptoms recurrence. Pain recurrence rate
at follow-up was lower in the present series when compared
with percentages reported in a previous study evaluating symp-
toms recurrence in patients treated by postoperative COC [16].
© 2012 Informa UK, Ltd.
24/4-day COC in endometriosis 453
Furthermore, lesions’ recurrence rate observed in our study
seems acceptable, since it’s comparable with data from literature
at 6-months follow-up [4,29].
Since long-term hormonal administration is recommended for
effective medical management of endometriosis, its tolerability must
®
be an issue of concern. From our data, Yaz seems well tolerated,
with a low discontinuation rate and high patients’ satisfaction and
well-being. Concerning adverse effects, our findings do not differ
from those reported in literature with others COC [4,6,8,9]. Patients
included in our study had most frequently reported spotting. In
a prospective randomized study, Antilla et al. analysed the daily
bleeding pattern with Drospirenone/Ethinilestradiol 3 mg/20 mcg
over 7 treatment cycles: the occurrence of spotting and bleeding was
highest in the first treatment cycle and decreased throughout the
study [10]. It is possible that the high percentage of spotting reported
in our study might be related to the first treatment cycles. Moreover,
at follow-up only 4 women expressed the intention to interrupt the
treatment because of side effects and the vast majority of patients
reported satisfaction with the therapy and unchanged or improved
physical and emotional well-being. Our data are consistent with the
general trend reported in other studies considering safety, tolerability
®
and satisfaction with Yaz [8–13]. This tolerability profile may be
related to the shorter HFI of the 24/4 regimen, which might reduce
the hormone withdrawal effects and lead to a better premenstrual
symptoms control than cyclic 21/7 COC [10,11,14]. Moreover, the
®
fourth-generation progestin contained in Yaz , Drospirenone, has
antimineralcorticoid and antiandrogenic activity which can reduce
premenstrual dysphoric disorder and premenstrual symptoms like
bloating and breast tenderness [12,13].
In the present study, no difference between cyclic and contin-
uous administration in terms of symptoms and lesions control,
disease recurrence and tolerability was observed. The real innova-
®
tion of Yaz is its 24/4 regimen, which might induce a hormonal
status in the cyclic administration as much comparable as possible
to the continuous regimen.
The retrospective study design and the short follow-up could
be considered as limits of our study. Randomized controlled trials
are necessary to assess our findings.
®
Our results show that Yaz might provide a promising
regimen for the medical management of endometriosis in terms
of symptom relief and lesion control. Moreover, the equivalence
between cyclic 24/4 and continuous regimens permits a medical
treatment choice which considers patient’s preference.
Declaration of Interest: The authors report no conflicts of
interest.
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Gynecological Endocrinology