Contraception 71 (2005) 1 – 7

Original research article

A comparative study of monophasic oral contraceptives containing either
drospirenone 3 mg or levonorgestrel 150 lg on premenstrual symptoms
Malinee Sangthawan*, Surasak Taneepanichskul
Faculty of Medicine, Reproductive Medicine Unit, Department of Obstetrics and Gynecology, King Chulalongkorn Memorial Hospital, Chulalongkorn
University, Bangkok 10330, Thailand
Received 6 February 2004; revised 19 July 2004; accepted 19 July 2004

Abstract
This open-label randomized study compared the effects of two combined oral contraceptives (OCs) containing 3 mg drospirenone
(DRSP)/30 lg ethinyl estradiol (EE) with 150 lg levonorgestrel (LNG)/30 lg EE on the prevalence and changes from baseline of
premenstrual symptoms after six cycles. The symptoms were measured using the Women’s Health Assessment Questionnaire. Subjects
receiving DRSP/EE had fewer prevalence of premenstrual symptoms than those receiving LNG/EE after six cycles. A significantly lower
score of negative affect category in the premenstrual phase was demonstrated in those receiving DRSP/EE more than LNG/EE. The DRSP/
EE group showed a greater improvement of mean scores from baseline in the premenstrual phase compared with those who received LNG/
EE on negative affect as seen in the items on anxiety, irritability, feeling sad or blue and weight gain in the category of water retention. In
conclusion, OCs containing DRSP have beneficial effects in reducing the prevalence of premenstrual symptoms especially the symptoms of
negative affect and weight gain, particularly when compared to LNG/EE. Hence, it should be recommended for women who are susceptible
to these adverse symptoms.
D 2005 Elsevier Inc. All rights reserved.
Keywords: Oral contraceptive; Drospirenone; Levonorgestrel; Premenstrual symptoms

1. Introduction Recently, an OC containing drospirenone 3 mg (DRSP) in

combination with ethinyl estradiol 30 lg (EE) was devel-
About 20–90% of women experience premenstrual symp-
oped. Drospirenone is different from other progestogens in
toms and 2–15% of them have severe symptoms [1– 4].
that it is an analogue of the aldosterone antagonist,
According to Moos [5,6], premenstrual symptoms comprise
spironolactone [14]. Spironolactone appears to be an effective
eight bcategories,Q negative affect, water retention, impaired
therapy for the negative mood change and somatic symptoms
concentration, pain, behavioral change, autonomic reaction,
of premenstrual symptoms [15–17]. The pharmacologic
arousal and control. Some women who used oral contra-
profile of drospirenone is more closely related to progester-
ceptives (OCs) to prevent pregnancy found these symptoms to
one than other synthetic progestogens in terms of antiminer-
be much milder [5,7]; on the other hand, some symptoms such
alocorticoid and antiandrogenic activities [14,18–20].
as water retention and mood swings might become worse. The
Studies of OCs containing DRSP on premenstrual symptoms
latter experiences have been important reasons for discontin-
showed benefits on premenstrual symptoms, that is, de-
uation of OCs [8–12]. Each progestogen has varying
creased negative affect and water retention symptoms and
androgenic, estrogenic and antiestrogenic activities, which
increased general well-being [2,21–24]. However, these
may cause unwanted adverse effects that could contribute to
effects did not reach the level of statistical significance when
premenstrual symptoms. Backstorm et al. [13] showed that
compared to the placebo group: patients who suffered from
monophasic desogestrel provoked less change in mood
premenstrual dysphoric disorder after three cycles of
parameters than monophasic and triphasic levonorgestrel
treatment [25].
(LNG).
There are few trials that compare OCs which have
antimineralocorticoid and antiandrogenic properties (i.e.,
* Corresponding author. Tel.: +66 2 256 4826; fax: +66 2 256 4829. OC containing DRSP) with other pills which do not have
E-mail address: msangthawan@hotmail.com (M. Sangthawan). these properties regarding premenstrual symptoms. In this
0010-7824/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.contraception.2004.07.010
2 M. Sangthawan, S. Taneepanichskul / Contraception 71 (2005) 1–7

study, we chose an OC containing LNG which is widely cycles by using the Women’s Health Assessment Question-
used in Thailand to compare to an OC containing DRSP naire (WHAQ), which was a subset of items selected from
regarding premenstrual symptoms. the Menstrual Distress Questionnaire [2,5,6]. The WHAQ
The primary objective of this study was to compare the was translated from English to Thai and tested for reliability
prevalence of premenstrual symptoms at six cycles in those with a Cronbach’s a of .80. This self-report questionnaire
who used EE 30 lg and DRSP 3 mg (DRSP/EE) with EE 30 included six categories that contained a total of 23 items.
lg and levonorgestrel 150 lg (LNG/EE) as a contraceptive The six categories composed of three main categories, that
method. is, negative affect, water retention, impaired concentration,
The secondary objective was to compare the effect of and another three additional categories, that is, increased
both preparations on premenstrual symptoms at six cycles appetite, feelings of well-being, and undesirable hair
after treatment. changes. The negative affect category contained eight items,
the water retention category contained four items and the
impaired concentration category contained eight items, as
2. Materials and methods shown in Table 1. Each item was graded using a five-point
2.1. Study design and population scale from 0 to 4 (0 = absent, 1= mild, 2 = moderate,
3 = strong, 4= severe/very strong). The WHAQ assessed
This study was an open-label, randomized, comparative the patient symptoms at three different phases of menstru-
study performed at the family planning clinic of King ation, premenstrual (4 days before menstrual flow), men-
Chulalongkorn Memorial Hospital, Bangkok, Thailand, strual (during menstrual flow), and postmenstrual (the
from February to September 2003. The study protocol was remainder of the cycle) phases.
approved by the Ethics Committee of the Faculty of The primary measured outcome was the prevalence of
Medicine, Chulalongkorn University. premenstrual symptoms at cycle 6, which was determined by
One-hundred and four women who were willing to take subjects who had symptoms in the premenstrual phase which
oral OC pills for contraception were randomly assigned to disappeared during their menstrual and postmenstrual
two groups: one used the preparation of EE 30 lg and phases. Secondary measured outcomes were the mean scores
DRSP 3 mg, and the other used the preparation of EE 30 lg and the mean score changes from baseline of WHAQ
and LNG 150 lg. categories (mean of the difference between the score at
The inclusion criteria included women who were of baseline and at cycle 6) between the two OC preparations.
child-bearing age (18–35 years), who requested OCs for at
least six cycles (both new users and switchers) and had 2.3. Statistical analysis
regular menstrual cycles lasting between 21 and 35 days, as Descriptive statistics (mean, SD, percentage) were used
well as had not used an injectable hormonal contraceptive to analyze the demographic data. The prevalence of
within 6 months or an OC within 3 months before the study. premenstrual symptoms at cycle 6 between each preparation
Women who previously used implantable contraceptives or was compared by chi-square test. We compared mean
intrauterine devices had to have three consecutive normal WHAQ scores and mean WHAQ score changes from
menstrual cycles after these contraceptives were removed. baseline after using either preparation at cycle 6 by
Post-abortion and postpartum patients were eligible if they
had had three consecutive menstrual cycles before the study.
The exclusion criteria included women who were Table 1
pregnant or suspected of being pregnant, who were breast- WHAQ (six categories, total 23 items)
feeding, who smoked and who were contraindicated for Negative Water Impaired Three
using OCs according to WHO categories 2, 3 and 4 [26]. affect (8) retention (4) concentration (8) additional
All subjects were required to sign written informed categories
consent forms before being recruited into the study. Loneliness Weight gain Insomnia Increased
appetite
2.2. Study protocol and data collection Anxiety Painful or Forgetfulness Feelings of
tender breasts well-being
Subjects who met the study criteria were randomly given Mood swings Breast and Confusion Undesirable
a blister pack which contained 21 tablets of either 3 mg abdominal hair changes
DRSP/30 lg EE or 150 lg LNG/30 lg EE for six cycles. swelling
They were instructed to take one tablet a day from the first Crying Skin blemishes Poor judgment
or disorders
day of their menstruation for 21 consecutive days followed
Irritability Difficulty
by a 7-day pill-free interval. The recommended dosing concentrating
interval was not longer than 24 h. Compliance was assessed Tension Distractibility
by pill count from the blister packs. Feeling sad Poor motor
Both groups of subjects were evaluated on the premen- or blue coordination
Restlessness Minor accidents
strual symptoms at baseline and at the end of six menstrual
 M. Sangthawan, S. Taneepanichskul / Contraception 71 (2005) 1–7 3

Table 2 subjects were allocated to either treatment protocol, 99

Baseline demographic data (95.2%) of them completed the study and 5 subjects
DRSP/EE group LNG/EE group withdrew prematurely; three cases in the LNG/EE group:
(n=50) (n=49) one was lost to follow up, one switched to an implantable
Mean age (years)FSDa 27.5F4.2 26.0F4.7 contraceptive and the other withdrew due to adverse side
Mean height (cm)FSDa 154.7F5.7 153.0F5.5
effects (nausea, vomiting and dizziness); two cases in the
Mean weight (kg)FSDa 53.2F8.3 52.0F8.7
Mean BMI (kg/m2)FSDa 22.2F3.3 22.7F3.3 DRSP/EE group lost to follow-up.
Mean parityFSDa 1.0F0.5 1.1F0.5 The prevalence of premenstrual symptoms at baseline in
Education level (%)a the DRSP/EE group and the LNG/EE group were 58% and
Primary 16 32 59.2%, respectively, which was not significantly different.
Secondary 70 62
At cycle 6, the prevalence of premenstrual symptoms in the
Postsecondary 14 6
a
DRSP/EE group was significantly lower than that of the
No significant difference.
LNG/EE group (32% vs. 61.2%; p =.005) (Table 3).
Mean WHAQ scores in the premenstrual, menstrual
Table 3 and postmenstrual phases are shown in Table 4. At cycle
Prevalence of premenstrual symptoms at baseline and cycle 6 6, only the negative affect score in the premenstrual phase
DRSP/EE group [n (%)] LNG/EE group [n (%)] was significantly lower in the DRSP/EE group than in the
Baseline 29/50 (58.0) 29/49 (59.2) LNG/EE group (2.5F3.3 vs. 4.2F4.9; p =.046; 95% CI,
Cycle 6a 16/50 (32.0) 30/49 (61.2) 3.39, 0.03). The remaining five out of six categories
a
Statistically significant difference, p =.005. in the premenstrual phase (water retention, impaired
concentration, feelings of well-being, increased appetite
independent t test. The level of significance was considered and undesirable hair changes) were not significantly
at 95% confidence interval and p b.05. different. All categories of the menstrual and postmen-
Statistical Package for Social Sciences for Windows strual phases were also not significantly different between
Version 11.5 was used for all statistical analyses. each group.
The DRSP/EE group showed a greater magnitude of
change from baseline on negative affect during the
3. Results
premenstrual phase than the LNG/EE group ( p=.035; 95%
The demographic data were not significantly different CI, 3.15, 0.12). There were no significant differences in
between the two groups as shown in Table 2. A total of 104 the mean score changes from baseline of all categories

Table 4
Mean WHAQ scores of premenstrual, menstrual and postmenstrual phases at baseline and cycle 6
Categories Baseline Cycle 6
DRSP/EE LNG/EE p-value 95% CI DRSP/EE LNG/EE p-value 95% CI
Premenstrual phase
Negative affecta 4.5F4.7 4.5F3.8 .926 1.80, 1.64 2.5F3.3 4.2F4.9 .046a 3.39, 0.03
Water retention 2.8F2.7 3.0F2.2 .722 1.16, 0.81 1.9F2.3 2.1F2.0 .551 1.13, 0.60
Impaired concentration 3.3F4.3 4.0F4.0 .404 2.38, 0.96 1.9F3.2 3.2F4.1 .083 2.78, 0.17
Well-being 1.4F0.8 1.7F1.1 .129 0.70, 0.09 1.8F0.9 2.0F1.0 .335 0.60, 0.20
Increased appetite 1.3F1.2 1.2F1.0 .636 0.34, 0.55 1.2F1.2 1.2F1.2 .779 0.55, 0.41
Undesirable hair change 0.2F0.5 0.2F0.6 .807 0.27, 0.21 0.3F0.8 0.5F1.0 .287 0.56, 0.17

Menstrual phase
Negative affect 3.7F4.0 4.8F3.9 .147 2.76, 0.42 2.6F3.5 3.8F4.9 .175 2.87, 0.53
Water retention 2.0F1.9 2.5F2.0 .241 1.26, 0.32 1.8F2.2 1.6F1.6 .619 0.56, 0.95
Impaired concentration 2.9F3.5 4.1F3.3 .108 2.49, 0.25 2.2F2.9 3.2F4.1 .153 2.45, 0.38
Well-being 1.3F0.9 1.6F1.1 .081 0.76, 0.04 1.9F1.0 2.2F1.1 .155 0.72, 0.11
Increased appetite 0.9F0.9 1.0F0.9 .406 0.54, 0.22 0.9F1.0 1.1F1.6 .347 0.80, 0.28
Undesirable hair change 0.3F0.5 0.2F0.5 .666 0.18, 0.28 0.3F0.7 0.4F1.0 .395 0.52, 0.20

Postmenstrual phase
Negative affect 1.9F3.0 2.8F3.3 .115 2.28, 0.25 1.6F2.7 2.2F3.7 .296 1.95, 0.61
Water retention 1.0F1.8 1.7F2.2 .062 1.55, 0.04 1.2F2.0 1.3F1.5 .886 0.76, 0.65
Impaired concentration 2.0F2.5 3.2F3.7 .052 2.46, 0.01 1.4F2.4 2.2F3.4 .172 1.98, 0.36
Well-being 1.8F0.9 2.0F1.2 .410 0.59, 0.24 2.2F1.1 2.6F1.1 .077 0.83, 0.04
Increased appetite 0.5F0.7 0.7F0.9 .070 0.64, 0.03 0.7F1.0 0.8F1.0 .675 0.50, 0.32
Undesirable hair change 0.2F0.5 0.3F0.7 .390 0.36, 0.15 0.2F0.7 0.5F1.0 .150 0.60, 0.09
a
Statistically significant difference at cycle 6.
4 M. Sangthawan, S. Taneepanichskul / Contraception 71 (2005) 1–7

during the menstrual and postmenstrual phases between

each group (Fig. 1).
Mean score changes from baseline in the premenstrual
phase of each item was analyzed. The DRSP/EE group
showed significant decrease of negative affect compared to
the LNG/EE group on anxiety (p=.045; 95% CI, 0.66,
0.008), irritability (p =.006; 95% CI, 0.74, 0.13) and
feeling sad or blue (p=.006; 95% CI, 0.65, 0.11), as
shown in Fig. 2. Fig. 3 revealed that weight gain in the
DRSP group had a significant change from baseline in score
than LNG (p=.022; 95% CI, 0.75, 0.06). In the DRSP/
EE group, weight gain scores decreased while the result was
converse in the LNG/EE group, wherein weight gain scores
increased after six cycles. There were no significant

Fig. 2. Mean score changes from baseline in items of negative affect

category of premenstrual phase.

differences between groups in changes from baseline of

items in categories of impaired concentration, feelings of
well-being, increased appetite and undesirable hair change
(data shown in Figs. 4 and 5).

4. Discussion
The prevalence of premenstrual symptoms at baseline of
both groups was about 60%, this is in corroboration with
previous studies [1– 4]. This study demonstrated that DRSP/
EE OC reduced the prevalence of premenstrual symptoms
by half whereas LNG/EE OC did not alter the prevalence of
premenstrual symptoms at cycle 6. Foidart et al. [27] studied

Fig. 1. Mean score changes from baseline of six categories in premenstrual, Fig. 3. Mean score changes from baseline in items of water retention
menstrual and postmenstrual phases. category of premenstrual phase.
 M. Sangthawan, S. Taneepanichskul / Contraception 71 (2005) 1–7
Fig. 4. Mean score changes from baseline in items of impaired concentration category of premenstrual phase.
the incidence of premenstrual symptoms by comparing
DRSP/EE with an OC containing desogestrel for 26 cycles
and reported that the incidence of premenstrual symptoms
prior to treatment was higher in the DRSP/EE group, but
became lower during treatment than OC containing des-
ogestrel (18% vs. 20%). These results showed the consistent
benefit of DRSP/EE OC over other second- or third-
Fig. 5. Mean score changes from baseline in categories of feelings of well-
being, increased appetite and undesirable hair change of premenstrual
phase.
5
generation progestogens such as LNG or desogestrel on
the decrement of premenstrual symptoms prevalence.
Significant improvements of mean scores and changes
from baseline scores were revealed with DRSP/EE com-
pared to LNG/EE only in negative affect during the
premenstrual phase, on items of anxiety, irritability and
feeling sad or blue. Numerous hypotheses have been
proposed to explain the mechanisms of mood, behavioral
or psychological changes in the premenstrual phase of the
cycle, as related to neurotransmitters (i.e., serotonin,
endogenous opioids, c-aminobutyric acid, cathecho-
lamines), fluctuation of female hormones, testosterone, etc.
[7,28 –32]. However, these mechanisms are not yet clear.
Progesterone is known to exert direct sedative effect on the
central nervous system, as reflected in slowing electroen-
cephalogram in humans and alteration of arousal threshold
stimuli in the hypothalamus of various animals [7,29]. Thus,
its deficiency would increase nervous excitability, irritabil-
ity, tension, anxiety and aggression. The possible reason on
the benefits to negative affect of DRSP may be due to the
similarity of DRSP to progesterone on these effects rather
than LNG. Some investigators have demonstrated abnor-
mally elevated plasma testosterone in women with premen-
strual symptoms and aggression [31,33]. Therefore, it was
possible that the improvement of negative affect in women
who were receiving DRSP compared to those receiving
LNG was related to the antiandrogenic property of DRSP.
Weight gain in the category of water retention was only
significantly decreased from baseline in DRSP/EE than
LNG/EE during the premenstrual phase while the effect that
6 M. Sangthawan, S. Taneepanichskul / Contraception 71 (2005) 1–7
appeared in the LNG/EE group was reversed. In the normal
menstrual cycle, plasma renin activity and concentration,
angiotensin II and aldosterone are also elevated in the
second half of the cycle [7,34]. There is evidence of
premenstrual weight gain and an increase in urinary
potassium/sodium (K+/ Na2+) ratio during the luteal phase
[7,35]; however, other studies have found different results
[34,36 –38]. Progesterone has a natriuretic effect by
competitively blocking aldosterone at the distal renal
tubules. Drospirenone is an analogue of the aldosterone
antagonist, spironolactone. The pharmacologic property of
DRSP is more likely related to that of progesterone,
especially with regard to antimineralocorticoid activity, than
LNG, which does not have such properties [14].
Apter et al. [24] reported on an open-label, multicenter,
uncontrolled study of DRSP/EE OC in women experiencing
psychological, behavioral and somatic premenstrual symp-
toms. The results showed a significant beneficial effect on
general well-being (anxiety, depressed mood, positive well-
being, self-control, general health, vitality) by cycle 3 which
was maintained to cycle 6. An open-label, multicenter,
uncontrolled study of DRSP/EE OC by Parsey and Pong
[23] reported that the symptoms of water retention and
negative affect significantly improved from baseline in all
three phases of the menstrual cycles at cycle 6 of treatment,
and also Borenstein et al. [39] reported the same results after
two cycles of treatment. Brown et al. [2] showed improve-
ment of water retention and negative affect symptoms only
in the premenstrual and menstrual phases after six cycles of
treatment. There were no significant differences in the
changes of scores from baseline between the groups in
impaired concentration, feelings of well-being, increased
appetite and undesirable hair change, which were consistent
with the previous studies [2,21,23].
Most previous studies of DRSP/EE OC on premenstrual
symptoms were uncontrolled, with only the study of
Freeman et al. [25] using a placebo group for comparison.
Freeman et al. compared DRSP/EE OC with a placebo for
three cycles of treatment using the Calendar of Premen-
strual Experiences (COPE) score inventory in patients with
premenstrual dysphoric disorder, which revealed only the
factors of acne, appetite and craving in the DRSP/EE
group were different from the placebo group, but found no
significant differences between the active drug and the
placebo on the other premenstrual symptoms. This
outcome was distinct from our study, perhaps because of
too short a duration to detect the differences between the
active drug and placebo treatments. In our study the
duration was six menstrual cycles; different outcomes may
appear after the first 3 months. The included subjects and
the outcome measurements were also distinct. Our study
not only included patients who suffered from premenstrual
dysphoric disorder as their study did, but also included
patients who required OCs regardless of premenstrual
symptoms prior to treatment. Our study used the WHAQ
instead of COPE scores in measuring these symptoms.
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