1. Original Research
Effective Treatment of Heavy Menstrual
Bleeding With Estradiol Valerate and Dienogest
A Randomized Controlled Trial
Jeffrey T. Jensen, MD, MPH, Susanne Parke, MD, PhD, Uwe Mellinger, PhD, Andrea Machlitt, MD,
and Ian S. Fraser, MD
OBJECTIVE: To estimate the efficacy of a fixed estrogen from the last 90 days of treatment and the run-in phase
step-down and progestin step-up 28-day estradiol (E2) were compared. The primary variable was the “complete
valerate and dienogest oral contraceptive regimen in response” rate (complete resolution of qualifying abnormal
women with heavy menstrual bleeding, prolonged men- menstrual symptoms, including a 50% or greater reduction
strual bleeding, or heavy and prolonged menstrual bleed- in pretreatment menstrual blood loss volume in women
ing without organic pathology. with heavy menstrual bleeding). Secondary variables included
METHODS: This double-blind, placebo-controlled study objective changes in menstrual blood loss volume (alkaline
hematin methodology) and iron metabolism parameters.
randomized women aged 18 years or older with prolonged,
Overall, 180 women were needed to provide 90% power.
frequent, or heavy menstrual bleeding, objectively con-
firmed during a 90-day run-in phase, to treatment with E2 RESULTS: There were no marked differences in the char-
valerate and dienogest or placebo (2:1) for 196 days. Data acteristics of E2 valerate and dienogest (n 120) and
placebo (n 70) recipients. The proportion of “complete
responders” in the evaluable group was significantly
See related editorial on page 773. higher in E2 valerate and dienogest (35/80; 43.8%) com-
pared with placebo (2/48, 4.2%, P<.001) recipients. The
From the Department of Obstetrics and Gynecology, Oregon Health & Science mean [standard deviation] reduction in menstrual blood
University, Portland, Oregon; the Departments of Clinical Development, Clin- loss with E2 valerate and dienogest from the run-in phase
ical Statistics, and Global Medical Affairs Women’s Healthcare, Bayer Health-
Care Pharmaceuticals, Berlin, Germany; and the Department of Reproductive to the efficacy phase was substantial ( 353 mL [309 mL];
Medicine, University of Sydney, Sydney, New South Wales, Australia. mean 64.2%; median 70.6%) and significantly greater
Supported by Bayer HealthCare Pharmaceuticals. than that in placebo recipients ( 130 mL [338 mL]; mean
7.8%; median 18.7%; P<.001). Significant improve-
The authors thank Lyndal Staples and Phil Jones (inScience Communications,
a Wolters Kluwer business, Chester, United Kingdom) for medical writing ments in hemoglobin, hematocrit, and ferritin were seen
support during manuscript preparation. Funding for editorial assistance was with E2 valerate and dienogest, but not with placebo.
provided by Bayer HealthCare Pharmaceuticals.
CONCLUSION: Oral E2 valerate and dienogest was
Presented as an abstract and oral presentation at the 65th Annual Meeting of the highly effective compared with placebo in the treatment
American Society for Reproductive Medicine, October 17–21, 2009, Atlanta, Georgia.
of women with heavy menstrual bleeding, prolonged
Corresponding author: Jeffrey T. Jensen, Department of Obstetrics & Gynecology, menstrual bleeding, or heavy and prolonged menstrual
Oregon Health & Science University, 3181 SW Sam Jackson Park Road,
Portland 97239, OR; e-mail: jensenje@ohsu.edu.
bleeding without organic pathology.
Financial Disclosure CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,
Dr. Jensen is a consultant and speaker for Bayer HealthCare Pharmaceuticals Inc., www.clinicaltrials.gov, NCT00293059.
Wyeth Pharmaceuticals, and Schering Plough and has received research funding from (Obstet Gynecol 2011;117:777–87)
Bayer HealthCare Pharmaceuticals Inc, Wyeth Pharmaceuticals, Warner Chilcott, DOI: 10.1097/AOG.0b013e3182118ac3
the Population Council, and the National Institutes of Health (NIH); Dr. Parke, Dr.
Mellinger, and Dr. Machlitt are employees of Bayer HealthCare Pharmaceuticals. LEVEL OF EVIDENCE: I
Dr. Machlitt owns stock in Bayer HealthCare Pharmaceuticals. Dr. Fraser is a
consultant and speaker for Bayer HealthCare Pharmaceuticals, Schering Plough, and
A
Daiichi Sankyo Pharmaceuticals and has received research support from the NIH, the bnormal uterine bleeding describes a range of
Australian National Health and Medical Research Council, the Population Council,
Bayer HealthCare Pharmaceuticals, and Schering Plough.
menstrual bleeding symptoms, the most common
of which is heavy bleeding. The estimated worldwide
© 2011 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins. prevalence of subjective, self-defined abnormal uter-
ISSN: 0029-7844/11 ine bleeding varies greatly from 4% to 52%.1 Women
VOL. 117, NO. 4, APRIL 2011 OBSTETRICS & GYNECOLOGY 777

2. with abnormal bleeding have a reduced quality of life with the ethical principles of the Declaration of Hel-
compared with the general female population.1,2 sinki and the guidelines of the International Confer-
No common agreement has been reached on the ence on Harmonization on Good Clinical Practice.
classification of abnormal uterine bleeding symptoms; The study protocol was approved by each study site’s
however, symptom-oriented descriptive terminology Institutional Review Board before the start of the
such as heavy menstrual bleeding is generally pre- study. All participants provided written informed
ferred to poorly defined historical terms such as consent before entering the study.
menorrhagia.3 The study comprised a screening phase that
It is generally agreed that a normal bleeding lasted up to 28 days, a 90-day run-in interval, a
episode comprises a menstrual blood loss volume in 196-day treatment interval, and a 30-day follow-up
the range of 30 – 40 mL,4,5 with an upper limit of 80 phase. After the screening phase, participants entered
mL.6 The prevalence of objectively measured heavy the 90-day run-in interval during which the symptoms
menstrual bleeding (ie, a blood loss volume of 80 mL of heavy bleeding (at least two bleeding episodes with
or more per cycle as determined using the alkaline a measured menstrual blood loss volume of 80 mL or
hematin method to quantify hemoglobin extracted more), prolonged bleeding (at least two bleeding
from used sanitary items)6 has been reported to be episodes each lasting 8 days or more), or frequent
9 –14% in a review of epidemiologic studies.1 In the bleeding (more than five bleeding episodes with a
majority of women, the duration of menstruation is minimum of 20 bleeding days overall) or a combina-
3– 8 days.7 tion of any of the three were objectively confirmed by
Limited studies indicate that oral contraceptive the use of electronic diaries and quantification of
pills (OCPs) can reduce menstrual blood loss in menstrual blood loss by hemoglobin extraction from
women with heavy menstrual bleeding.8,9 The prop- collected sanitary protection.
erties of an OCP combining estradiol (E2) valerate The study recruited women aged at least 18 years
(which circulates as E2) and dienogest (a progestin who had heavy menstrual bleeding, prolonged men-
with high endometrial potency) in an estrogen step- strual bleeding, frequent menstrual bleeding, or any
down and progestin step-up regimen was hypothe- combination thereof and who fulfilled the additional
sized to be beneficial in this setting. A phase III criteria for inclusion. To satisfy these criteria, individ-
clinical study showed that the cycle control and uals had to be willing to use a barrier method of
bleeding pattern achieved with E2 valerate and dieno- contraception and to use (and collect) all sanitary
gest was comparable to that of a monophasic OCP protection items (pads and tampons) provided to
containing ethinyl E2 20 micrograms and levonorg- them for use during the study. Participants also
estrel 100 micrograms.10 Moreover, E2 valerate and needed to have a normal endometrial biopsy or, at
dienogest was associated with shorter (median dura- most, mild simple endometrial hyperplasia during the
tion 4 compared with 5 days), lighter (rated signifi- 6 months before study entry. Women older than 40
cantly more often as only spotting or of light intensity) years had to have follicle-stimulating hormone level
menstrual bleeding, or more often absent (P .001).10 of less than 40 milli-international units/mL. Women
As such, we undertook this phase III study in North were excluded if, at screening before study entry, they
America to determine the efficacy and explore safety had an abnormal transvaginal ultrasonogram (defined
of E2 valerate and dienogest in women with con- as the presence of uterine pathology, eg, fibroids or
firmed heavy menstrual bleeding, prolonged men- polyps whose size or localization would be associated
strual bleeding, or heavy and prolonged menstrual with heavy menstrual bleeding) or clinically signifi-
bleeding without organic cause. cant abnormal values for any laboratory examination,
or if they had undergone in the 2 months before the
MATERIALS AND METHODS study endometrial ablation or dilatation and curet-
This was a phase III, randomized, double-blind, tage. Women were also excluded if they had organic
placebo-controlled study that was conducted to inves- pathology (including von Willebrand disease, chronic
tigate the efficacy and safety of E2 valerate and endometritis, adenomyosis, endometriosis, endome-
dienogest for the treatment of confirmed heavy men- trial polyps, significant leiomyomas, or uterine malig-
strual bleeding, prolonged menstrual bleeding, or heavy nancy). Exclusion criteria also included the use of
and prolonged menstrual bleeding (ClinicalTrials.gov agents intended for the treatment of symptoms of ab-
identifier: NCT00293059). The study was conducted normal uterine bleeding (eg, tranexamic acid, nonsteroi-
at 47 centers in the United States and Canada be- dal antiinflammatory drugs, and sex steroids); a body
tween December 2005 and May 2008 in accordance mass index (calculated as weight (kg)/[height (m)]2) of
778 Jensen et al Estradiol Valerate and Dienogest for Menstrual Bleeding OBSTETRICS & GYNECOLOGY

3. more than 32; smoking more than 10 cigarettes per day days of run-in phase were compared. The efficacy
(in women older than 35 years); and criteria consistent interval had to start on the first day of a treatment
with contraindications for the use of combined OCPs. cycle. For participants who completed up to day 6 of
For ethical reasons in this placebo-controlled trial, use of treatment cycle 7, the efficacy phase started on the
iron supplementation was allowed if the attending phy- first day of treatment cycle 4. For participants who
sician considered it necessary. prematurely discontinued or who had incomplete
After the run-in, participants with at least one data, the 90-day efficacy phase was shifted backward.
qualifying symptom were randomized (2:1) to E2 valer- A “complete response” was rigorously defined as a
ate and dienogest (NATAZIA, QLAIRA) or matching composite of the absence of all qualifying conditions:
placebo for 196 days (seven cycles) according to a no bleeding episodes that lasted more than 7 days; no
permuted-block, computer-generated (RANDO SAS more than four bleeding episodes overall; no bleeding
Macro, Version 9.1 for Windows) schedule generated episodes that involved a blood loss volume of 80 mL
by the study sponsor using blocks of six. Eligible or more; no more than one bleeding episode increase
individuals were given study drug according to the from baseline; no more than 24 days of bleeding
randomization code. The randomization number was overall; and no increase from baseline in an individ-
found on the label of the blister card. Randomization ual participant’s total number of bleeding days. For
achieved balanced treatment allocation in each block. individuals with prolonged bleeding, the decrease in
The E2 valerate and dienogest regimen com- the maximum duration of a bleeding episode between
prised E2 valerate 3 mg on days 1–2 (1 mg of E2 the run-in and efficacy phases had to be at least 2
valerate is equivalent to 0.76 mg of E2), E2 valerate 2 days. Similarly, for participants with heavy bleeding,
mg and dienogest 2 mg on days 3–7, E2 valerate 2 mg the blood loss volume for each episode had to be less
and dienogest 3 mg on days 8 –24, E2 valerate 1 mg than 80 mL and had to represent a decrease of at least
on days 25–26, and placebo on days 27–28. E2 50% from the average of the qualifying bleeding
valerate and dienogest was packaged in blister cards, episodes (ie, those episodes with a blood loss volume
each containing 28 tablets. Participants and investiga- of at least 80 mL during the run-in phase). The
tors were blinded to treatment. For this reason, the primary efficacy outcome was a responder analysis
placebo and E2 valerate and dienogest blister cards conducted in the intention-to-treat population (ie, all
were identical in appearance. All participants com- randomized participants). Participants were categorized
pleted an electronic diary on a daily basis throughout as complete responders (no abnormal bleeding symp-
the study (including during the run-in interval) to toms and achievement of all relevant criteria during the
document drug intake (during the treatment interval), 90-day efficacy interval); partial or nonresponders
the number of items of sanitary protection used, and (missed at least one of the relevant criteria for a com-
their perception of menstrual bleeding. Participants plete response during the efficacy phase [for participants
rated their daily bleeding intensity as none, spotting, enrolled with heavy bleeding this included the achieve-
or bleeding (light, normal, or heavy). Spotting was ment of a reduction in menstrual blood loss volume of
defined as bleeding that was lighter than the partici- 50% or more]); or as participants with missing data
pant’s normal experience during menstruation, with (received no study medication, did not complete the
no need for sanitary protection other than panty minimum 90 days of treatment [early drop-outs], or had
liners. In addition, participants were carefully in- too many missing bleeding data to define a valid 90-day
structed on how to collect all used sanitary protection efficacy phase [ie, more than 1 day in sequence with
(pads and tampons) and blood “clots” so that men- missing bleeding information or more than 9 noncon-
strual blood loss volume could be objectively assessed secutive days in a 90-day interval with missing bleeding
using a modification of the alkaline hematin method information]). The primary efficacy outcome was also
to quantify hemoglobin in menstrual fluid after Triton assessed in those participants with an evaluable response
X detergent extraction.11 Care was taken to counsel (ie, excluding individuals with missing data). The pri-
participants about ways of maximizing the collection mary efficacy variable was analyzed by the difference in
of their total menstrual loss. All sanitary protection the proportions of responders in the two groups and the
items were processed and analyzed at a central labo- corresponding unconditional two-sided 95% confidence
ratory (Specialty Labs, Valencia, CA). interval (CI).12 This unconditional CI was calculated by
The primary outcome was the proportion of inverting two separate one-sided tests of half the nomi-
participants with a complete response to treatment (ie, nal significance level each.
a return to complete menstrual normality). Data from Secondary efficacy variables included changes in
the last 90 days of treatment (efficacy period) and 90 menstrual blood loss volume; the number of sanitary
VOL. 117, NO. 4, APRIL 2011 Jensen et al Estradiol Valerate and Dienogest for Menstrual Bleeding 779

4. protection items used; changes in the number of Safety assessments included measurement of vital
bleeding days and episodes; the proportion of partic- signs and physical and gynecologic examinations.
ipants cured of individual symptoms; and changes in Data relating to adverse events were gathered by
iron metabolism parameters. Other secondary end allowing participants to spontaneously volunteer in-
points included the proportion of participants with an formation rather than by direct questioning. Adverse
improvement in menstrual bleeding symptoms as- events were coded using MedDRA 10.0; as such, cate-
sessed by investigators using a global assessment scale gories were mandated by standard adverse event report-
and by individuals using a patient’s overall assessment ing requirements. Safety outcomes were assessed in all
scale. Both assessment scales were administered on randomized participants who took at least one dose of
days 84 and 196 (when investigators and participants study medication (the safety analysis population).
were still blinded to treatment). Each seven-category It was estimated that the success rate (based on
scale ranged from very much improved to very much the complete response rate) for the E2 valerate and
worse compared with symptoms at study admission. dienogest and placebo groups would be 50% and
Secondary efficacy outcomes were analyzed using the 20%, respectively, and that the overall dropout rate
intention-to-treat population, irrespective of re- would be 30%. Using these assumptions, it was calcu-
sponder status. If a 90-day efficacy interval could not lated that 120 participants would be required for the
be defined for a given woman (ie, if she had missing E2 valerate and dienogest group and 60 for the
data), she was excluded from any analyses that com- placebo group (180 in total) to provide 90% power to
pared data from the 90-day run-in interval with the test the null hypothesis (ie, that the two treatment
90-day efficacy interval. Such participants, however, groups would have an equal rate of success) at a 5%
were included in any analyses that referred to per- significance level. All variables were analyzed de-
cycle data. Continuous secondary efficacy variables scriptively. Numbers, means, standard deviations,
were analyzed using an analysis of variance or an minima, quartiles, medians, and maxima were calcu-
analysis of covariance model. Noncontinuous second- lated for metric data. Frequency tables were gener-
ary efficacy variables were analyzed by differences of ated for categorical data. Statistical analyses were
proportions and the corresponding CIs. performed using SAS for Windows.
Screened Excluded: n=887
N=1,077 Consent withdrawn: 138
Inclusion/exclusion criteria
not met: 604
Randomized (2:1 ratio) Patient lost to follow-up: 88
n=190 Other: 57
Randomized to estradiol Randomized to placebo
valerate and dienogest (intention-to-treat population)
(intention-to-treat population) n=70
n=120
Medication administered Medication administered
(safety population) (safety population)
n=119 n=66
Did not complete study Did not complete study
medication: n=35 medication: n=15
Discontinued study Discontinued study
medication: 31 medication: 13
Unknown: 4 Unknown: 2
Completed study course Completed study course
n=85 n=51
Fig. 1. Flow of participants through
the study.
Completed study medication Completed study medication
Jensen. Estradiol Valerate and Dienogest
n=84 n=51 for Menstrual Bleeding. Obstet Gynecol
2011.
780 Jensen et al Estradiol Valerate and Dienogest for Menstrual Bleeding OBSTETRICS & GYNECOLOGY

5. Table 1. Demographic and Baseline RESULTS
Characteristics of Participants Assigned The flow of participants through the study is shown in
to Estradiol Valerate and Dienogest or Figure 1. A total of 1,077 women were screened; of
Placebo (Intention-to-Treat Population)
these, 190 were randomized to treatment and com-
E2 Valerate and prised the intention-to-treat population: 120 were
Dienogest Placebo randomized to E2 valerate and dienogest and 70 to
(n 120) (n 70)
placebo. The most common reason for not being
Age (y) 36.9 7.5 37.0 6.7 randomized to treatment was failure to meet the strict
Ethnicity inclusion or exclusion criteria (n 604).
White 71 (59.2) 46 (65.7) The demographic and baseline characteristics of
Black 38 (31.7) 14 (20.0)
Hispanic 8 (6.7) 6 (8.6)
participants are shown in Table 1. Participants in the
Weight (kg) 71.3 11.1 69.5 11.8 two treatment groups were generally well matched in
2
Body mass index (kg/m ) 26.3 3.6 25.8 3.6 terms of age and body mass index. The most common
Bleeding symptoms* menstrual bleeding symptom at baseline was heavy
Prolonged bleeding 26 (21.7) 12 (17.1) bleeding (75.8 – 85.7%), followed by prolonged bleed-
Frequent bleeding 4 (3.3) 2 (2.9)
Heavy bleeding 91 (75.8) 60 (85.7)
ing (17.1–21.7%). The proportion of frequent bleeders
in both treatment groups was very low. Only one
E2, estradiol.
Data are mean standard deviation or n (%). enrolled participant (a 46-year-old woman, gravida 5
* Some participants presented with multiple symptoms. para 4, enrolled for heavy menstrual bleeding and
was randomly assigned to placebo) had an endome-
trial ablation (7 years before entering the study) in her
Bleeding intensity data from the diaries that were surgical history. An overview of the responder status
missed on nonconsecutive days were replaced using (and the reasons for a partial or nonresponse) in each
the highest intensity value for bleeding obtained on treatment group is shown in Table 2. The proportion
the bordering days. No more than 9 nonconsecutive of complete responders (ie, participants who met all of
days were replaced per 90-day interval. Consecutive the strict response criteria and who had a return to
days with missing bleeding intensity data were not menstrual normality) was significantly higher in the
replaced. E2 valerate and dienogest group than in the placebo
Table 2. Responder Status in Women Who Received Estradiol Valerate and Dienogest or Placebo
(Intention-to-Treat Population)
E2 Valerate and
Dienogest Placebo
(n 120) (n 70)
Complete responder 35 (29.2) 2 (2.9)
Partial or non-responder 45 (37.5) 46 (65.7)
Missing data 40 (33.3) 22 (31.4)
Patients classified as partial or nonresponders failed to meet the following criteria*
No bleeding episodes lasting more than 7 d 25 (20.8) 18 (25.7)
No more than four bleeding episodes overall 7 (5.8) 0 (0.0)
No bleeding episodes with a menstrual blood loss volume of 80 mL or more 30 (25.0) 42 (60.0)
No more than one bleeding episode increase from baseline 7 (5.8) 2 (2.6)
No more than 24 bleeding days overall 12 (10.0) 8 (11.4)
No increase from baseline in the total number of bleeding days 22 (18.3) 18 (25.7)
If enrolled with prolonged bleeding n 26 n 12
(Decrease of at least 2 d from the run-in phase to the efficacy 6 (23.1) 5 (41.7)
phase in the maximum duration of bleeding)
If enrolled with heavy bleeding n 91 n 60
(Menstrual blood loss associated with each episode less than 30 (33.0) 39 (65.0)
80 mL and decreased by at least 50% from the average of
the qualifying bleeding episodes during the run-in phase)
E2, estradiol.
Data are n (%).
* Women could have been classified as nonresponders for multiple reasons.
VOL. 117, NO. 4, APRIL 2011 Jensen et al Estradiol Valerate and Dienogest for Menstrual Bleeding 781

6. group; this was the case when results were analyzed in placebo group (51%, 17%, and 5%, respectively)
the intention-to-treat population and in the popula- achieved such reductions. An increase in menstrual
tion of participants with evaluable data. blood loss volume during treatment was observed by
Using the most conservative approach, that is, approximately 5% of E2 valerate and dienogest recip-
categorizing all randomized participants (intention-to- ients and more than 20% of placebo recipients.
treat population) with missing data as nonresponders, In a per-cycle analysis of menstrual blood loss,
35 of 120 individuals (29.2%) in the E2 valerate and individuals treated with E2 valerate and dienogest
dienogest group and 2 of 70 participants (2.9%) in the showed a marked reduction in menstrual blood loss
placebo group had a complete response to treatment volume from the second cycle of treatment onward,
(P .001). In an analysis of evaluable participants whereas menstrual blood loss volume remained rela-
according to the complete response criteria (ie, ex- tively stable and consistently higher in those women
cluding those individuals with missing data), the who received placebo (Fig. 3). Similar observations
complete response rate was 43.8% (35/80) in women were made in the per-cycle analysis of menstrual
who received E2 valerate and dienogest compared blood loss in women categorized as nonresponders or
with only 4.2% (2/48) in women who received pla- partial responders (Fig. 4).
cebo (P .001). For the complete responder analysis, menstrual
The majority of participants (ie, 91/120 [75.8%] bleeding outcomes during the 90-day run-in phase
treated with E2 valerate and dienogest and 60/70 and the 90-day efficacy phase in women treated with
[85.7%] with placebo) were recruited for heavy bleed- E2 valerate and dienogest or placebo are shown in
ing. If resolution of heavy bleeding (defined as less Table 3. Although there was no marked difference in
than 80 mL menstrual blood loss volume for each menstrual blood loss volume in E2 valerate and
episode) was considered the only response criterion dienogest and placebo recipients during the 90-day
required, 51 of 91 (56.0%) participants treated with E2 run-in interval, a substantial between-group differ-
valerate and dienogest and 16 of 60 (26.7%) with ence was seen during the 90-day efficacy interval
placebo would be defined as cured of heavy bleeding (Table 3). Participants who received E2 valerate and
at the end of study. dienogest showed a substantial (mean 64.2% [median
The percent reduction of menstrual blood loss 70.6%, range 49.3% to 100.0%]) reduction in men-
volume from baseline to end of study in the group of strual blood loss volume between the run-in and
participants defined as heavy bleeders is presented in efficacy intervals, which was greater than the reduc-
Figure 2. Overall, a 20%, 50%, and 80% reduction in tion (mean 7.8% [median 18.7%, range 324.9% to
menstrual blood loss volume was achieved by ap- 100.0%]) seen in participants who received placebo.
proximately 91%, 80%, and 45% of participants in the
E2 valerate and dienogest group, respectively; how-
Median menstrual blood loss volume (mL)
ever, much smaller proportions of participants in the
200
Estradiol valerate and dienogest
180 n=66 Placebo
100 160
Cumulative proportion of participants (%)
n=66 n=64
90 140 n=53
n=58 n=53
120 n=119 n=51 n=49
80
100
n=117
70 80
60 60
40
50
20 n=113 n=104 n=98 n=95 n=91
40 n=86
0
30 Baseline* 1 2 3 4 5 6 7
Cycle
20
Estradiol valerate and dienogest
Fig. 3. Median menstrual blood loss volume by cycle with
10
Placebo estradiol (E2) valerate and dienogest and placebo (inten-
0 tion-to-treat population). *For comparative purposes, base-
–100 –90 –80 –70 –60 –50 –40 –30 –20 –10 0 10 20 30 40
line was calculated as menstrual blood loss volume during
Change in menstrual blood loss volume (%)
the 90-day run-in period multiplied by 0.31 (ie, 28/90).
Fig. 2. Percent change in menstrual blood loss volume from P .001 for reduction in menstrual blood loss volume
baseline to end of study experienced by the proportion of between run-in and efficacy periods. In the first cycle of
participants defined as heavy bleeders (n 151) in the two treatment, the first dose of E2 valerate and dienogest and
treatment groups (see Table 1). placebo was taken on the first day of menstrual bleeding.
Jensen. Estradiol Valerate and Dienogest for Menstrual Bleeding. Jensen. Estradiol Valerate and Dienogest for Menstrual Bleeding.
Obstet Gynecol 2011. Obstet Gynecol 2011.
782 Jensen et al Estradiol Valerate and Dienogest for Menstrual Bleeding OBSTETRICS & GYNECOLOGY

7. participants treated with E2 valerate and dienogest
Median menstrual blood loss volume (mL)
200
Estradiol valerate and dienogest
(80.7%) than with placebo (41.9%; P .001). The
180 n=44 Placebo proportion of participants who assessed their bleeding
n=45
160 n=46
140
symptoms as being improved at study end was also
n=44 n=46 n=46 n=46
120 n=44
n=42 significantly larger in the E2 valerate and dienogest
n=46
100 group (81.2%) compared with the placebo group
80
60 n=45
(38.3%; P .001).
40 n=45 n=45 n=45 n=43 Tolerability and safety were assessed in 119 indi-
20 n=42 viduals who received E2 valerate and dienogest and
0
Baseline* 1 2 3 4 5 6 7
in 66 individuals who received placebo. A total of 80
Cycle (67.2%) participants in the E2 valerate and dienogest
Fig. 4. Median menstrual blood loss volume by cycle with group and 36 (54.5%) participants in the placebo
estradiol (E2) valerate and dienogest and placebo in partial group reported treatment-emergent adverse events. A
or nonresponders. *For comparative purposes, baseline was total of 15 participants (8.1%) prematurely discontin-
calculated as median menstrual blood loss volume during
the 90-day run-in period multiplied by 0.31 (ie, 28/90).
ued treatment because of treatment-emergent adverse
Nonresponders: women who did not fulfill all of the eight events: 11 (9.2%) were in the E2 valerate and dieno-
criteria for complete response. In the first cycle of treat- gest group and 4 (6.1%) were in the placebo group.
ment, the first dose of E2 valerate and dienogest and Treatment-emergent adverse events occurring in at
placebo was taken on the first day of menstrual bleeding. least 2% of participants in either treatment group are
Jensen. Estradiol Valerate and Dienogest for Menstrual Bleeding. detailed in Table 5. Overall, 34.5% of E2 valerate and
Obstet Gynecol 2011.
dienogest recipients and 15.2% of placebo recipients
experienced a treatment-emergent adverse event that
The mean adjusted between-treatment difference was was deemed to be possibly, probably, or definitely
252 mL (95% CI 339 to 165; P .001). Whereas related to treatment; those most frequently reported
the mean number of total sanitary protection items were acne (4.2%), breast pain (3.4%), breast tender-
used decreased from the 90-day run-in interval to the ness (2.5%), dysmenorrhea (2.5%), and headache
90-day efficacy interval in both treatment groups (2.5%) in the E2 valerate and dienogest group and
(Table 3), this decrease was greater in participants headache (6.1%) and nausea (3.0%) in the placebo
who received E2 valerate and dienogest, compared group. No deaths occurred during the study. Only
with placebo; the mean adjusted between-treatment two participants experienced serious treatment-emer-
difference over 90 days was 23 items (95% CI 39 gent adverse events: one occurred in an E2 valerate
to 8; P .001). and dienogest recipient (myocardial infarction) and
Improvements were seen in each measure of iron one occurred in a placebo recipient (hospitalization
metabolism (ferritin, hemoglobin, and hematocrit) for a suicide attempt). The myocardial infarction
in E2 valerate and dienogest recipients (Table 4). In (acute small non–ST-elevation infarct) occurred 2
contrast, little or no improvement was observed in days after the last dose of study medication in a
placebo recipients. Overall, concomitant use of med- 46-year-old woman who had a history of hyperlipid-
ications containing iron was reported in 16 of 120 emia and a family history of cardiovascular disease.
women (13.3%) in the E2 valerate and dienogest
group and in 12 of 70 women (17.1%) in the placebo DISCUSSION
group. An exploratory analysis of hemoglobin levels In this North American study of women with heavy
stratified according to iron supplement use showed menstrual bleeding, prolonged menstrual bleeding, or
that, in both treatment groups, hemoglobin levels heavy and prolonged menstrual bleeding, it was more
were higher in those individuals who received supple- difficult to recruit patients than in other studies with
ments compared with those who did not; however, E2 valerate and dienogest (eg, the prevention of
hemoglobin levels were increased to a greater extent pregnancy trials). This occurred largely because many
in participants who received E2 valerate and dieno- women with self-referred heavy menstrual bleeding,
gest compared with placebo, whether or not iron although interested in participation, did not meet the
supplements were used. strict inclusion criteria during the run-in period. In
The proportion of investigators who assessed the addition, some women were not willing to comply
change in their participants’ bleeding symptoms at with logistical requirements (such as collecting all
study end as improved (including much improved or sanitary products used during menstruation) or accept
very much improved) was significantly greater for the chance to be randomized to placebo. Nonetheless,
VOL. 117, NO. 4, APRIL 2011 Jensen et al Estradiol Valerate and Dienogest for Menstrual Bleeding 783

8. Table 3. Characteristics of Menstrual Bleeding During the 90-Day Run-In Phase and the 90-Day Efficacy
Phase in Women Treated With Estradiol Valerate and Dienogest or Placebo
E2 Valerate and Dienogest Placebo
Change Change
From 90-d From 90- P for
90-d Run-In to 90-d Day Run-In Between-
90-d Run- Efficacy 90-d Efficacy 90-d Run- Efficacy to 90-Day Group
In Phase Phase Phase In Phase Phase Efficacy Phase Difference
Menstrual blood (n 119) (n 80) (n 79) (n 66) (n 48) (n 46) .001
loss (mL) 518 382 196 267 353 309 618 432 444 306 130 338
Bleeding and (n 120) (n 80) (n 80) (n 70) (n 48) (n 48) Not available
spotting (d) 25.1 10.5 23.5 13.1 1.1 14.0 24.7 9.7 22.9 10.2 2.3 6.7
Bleeding only (d) (n 120) (n 80) (n 80) (n 70) (n 48) (n 48) .024
18.6 7.5 15.3 9.6 2.8 10.8 17.9 6.5 16.0 6.1 2.2 4.6
Spotting only (d) (n 120) (n 80) (n 80) (n 70) (n 48) (n 48) Not available
6.5 6.0 8.2 8.4 1.7 8.2 6.8 6.2 6.9 6.7 0.2 4.9
Bleeding episodes (n 119) (n 80) (n 79) (n 66) (n 48) (n 46) .080
3.5 0.8 3.0 1.2 0.5 1.5 3.5 0.8 3.2 0.7 0.30 0.9
Sanitary protection (n 119) (n 80) (n 79) (n 66) (n 48) (n 46) .001
(no. of items) 90 42 51 49 44 41 96 45 69 29 21 43
E2, estradiol.
Data are mean standard deviation unless otherwise specified.
Only those participants with evaluable data (ie, no missing data) were included in this analysis.
a sufficient number of women participated to demon- condition. To the authors’ knowledge, no other stud-
strate that E2 valerate and dienogest is an effective ies have used such strict criteria. Excluding individu-
and well-tolerated treatment for heavy menstrual als with missing data, the complete response rate with
bleeding, prolonged menstrual bleeding, or heavy E2 valerate and dienogest was 43.8%. Moreover, a
and prolonged menstrual bleeding. Participants using substantial reduction in menstrual blood loss per
E2 valerate and dienogest were significantly more cycle was observed in E2 valerate and dienogest–
likely to achieve a complete response, a novel pri- treated participants categorized as partial or nonre-
mary efficacy variable based on stringent criteria sponders and in participants with missing diary data.
developed in consultation with the U.S. Food and E2 valerate and dienogest recipients showed a
Drug Administration. Classification as a complete rapid, large, and sustained decrease in menstrual
responder required that participants fulfill a compos- blood loss volume. Furthermore, the proportion of
ite of up to eight individual criteria during a 90-day participants who experienced resolution of heavy
efficacy interval. Participants had to show an absence bleeding, that is, no bleeding episodes with a men-
of previous symptoms plus a defined improvement in strual blood loss of 80 mL or more, was much higher
Table 4. Levels of Hemoglobin, Hematocrit, and Ferritin at Baseline and Adjusted Mean Change From
Baseline in Participants Who Received Estradiol Valerate and Dienogest or Placebo
E2 Valerate and Dienogest Placebo
Adjusted Mean Change Adjusted Mean Change
Baseline From Baseline Baseline From Baseline
Hemoglobin (g/dL) (n 120) (n 108) (n 70) (n 59)
12.2 1.3 0.6* 12.0 1.4 0.1
Hematocrit (%) (n 120) (n 108) (n 70) (n 59)
†
37.3 3.6 1.4 37.0 3.8 0.05
Ferritin (ng/mL) (n 120) (n 112) (n 68) (n 59)
23.2 35.1 2.9‡ 21.2 18.6 0.4
E2, estradiol.
Baseline data are mean standard deviation.
* P .004 compared with change from baseline with placebo.
†
P .001 compared with change from baseline with placebo.
‡
P .011 compared with change from baseline with placebo.
784 Jensen et al Estradiol Valerate and Dienogest for Menstrual Bleeding OBSTETRICS & GYNECOLOGY

9. Table 5. Treatment-Emergent Adverse Events (in tection items than those treated with placebo; most
Alphabetical Order) That Occurred in (81.2%) reported themselves as improved at the end
2% or More of Participants Who of treatment, which was more than twice the rate
Received Estradiol Valerate and reported in placebo recipients.
Dienogest or Placebo (Safety Analysis The off-label use of OCPs as a treatment for
Population)
heavy menstrual bleeding is common, despite only
E2 Valerate and limited supportive clinical data based on objective
Dienogest Placebo quantification methods. The few studies that em-
Adverse Event (n 119) (n 66)
ployed objective menstrual blood loss quantification
Acne 6 (5.0) 0 methods suggest that OCPs reduced heavy bleeding
Anemia 2 (1.7) 4 (6.1) by a mean 43% and 35% at 2 and 12 months’ use,
Anxiety 1 (0.8) 3 (4.5) respectively.8,14 In two studies that used the subjective
Arthralgia 0 3 (4.5)
pictorial blood loss assessment chart to quantify men-
Back pain 3 (2.5) 3 (4.5)
Breast pain 5 (4.2) 0 strual blood loss, the mean reductions in heavy men-
Breast tenderness 4 (3.4) 1 (1.5) strual bleeding scores with OCPs were 2.5%14 and
Bronchitis 3 (2.5) 2 (3.0) 68%15 at 12 months’ use, respectively. However, the
Cervical dysplasia 3 (2.5) 2 (3.0) small sample sizes in these trials make the results less
Chest pain 1 (0.8) 2 (3.0)
robust than the data generated in the current study.
Depression 3 (2.5) 1 (1.5)
Diarrhea 3 (2.5) 2 (3.0) Moreover, the magnitude of the observed reduction
Dizziness 0 2 (3.0) in menstrual blood loss with E2 valerate and dieno-
Dysmenorrhea 3 (2.5) 2 (3.0) gest treatment in the current study is much greater
Dyspepsia 3 (2.5) 0 than the effects noted in these earlier studies.
Fatigue 4 (3.4) 3 (4.5)
The type and frequency of most adverse events
Gastroenteritis 3 (2.5) 0
Headache 5 (4.2) 9 (13.6) were similar in recipients of E2 valerate and dienogest
Hypertension 2 (1.7) 2 (3.0) and placebo, with a few exceptions (eg, breast pain
Hypoesthesia 1 (0.8) 2 (3.0) and breast discomfort), which may have been hor-
Influenza 3 (2.5) 0 mone-related. However, percentage reporting of ad-
Insomnia 1 (0.8) 2 (3.0)
verse events is unreliable with small numbers. Other
Metrorrhagia 6 (5.0) 0
Migraine 3 (2.5) 0 adverse events such as headache and anxiety were
Nasopharyngitis 9 (7.6) 6 (9.1) uncommon in E2 valerate and dienogest recipients,
Nausea 6 (5.0) 5 (7.6) suggesting that the product was well tolerated. Over-
Sinusitis 4 (3.4) 1 (1.5) all, the safety profile of E2 valerate and dienogest
Tension headache 4 (3.4) 0
across its entire clinical development program (2,703
Upper respiratory tract 4 (3.4) 1 (1.5)
infection women with more than 30,000 treatment cycles’
Vaginal infection 3 (2.5) 0 experience) appears similar to other low-dose com-
Vaginitis bacterial 6 (5.0) 4 (6.1) bined OCPs. Although about one third of women
Vomiting 2 (1.7) 2 (3.0) enrolled in these studies were aged over 35 years
Vulvovaginal mycotic 4 (3.4) 3 (4.5)
(about two thirds in the current study), no relevant
infection
Weight increase 7 (5.9) 0 differences have been detected with regard to the
safety profile of E2 valerate and dienogest between
E2, estradiol.
Data are n (%). younger (18 –35 years) and older (36 –53 years)
women. One venous thromboembolism (deep vein
thrombosis) and two cases of arterial thromboembo-
with E2 valerate and dienogest (56.0%) than with lism (myocardial infarction in women with preexist-
placebo (26.7%). ing risk factors) were observed during the clinical
Measured menstrual blood loss represents a development of the E2 valerate and dienogest OCP,
meaningful clinical parameter, especially when peak one of which, a myocardial infarction, occurred in the
flow, in heavy bleeders, affects a woman’s ability to current study. It is generally accepted that the inci-
contain her blood loss. Furthermore, women with dence of cardiovascular events, including venous
heavy menstrual bleeding are more likely to experi- thromboembolism, myocardial infarction and stroke,
ence anemia than women with a lower menstrual increases as a function of age, independent of OCP
blood loss.13 Notably, women treated with E2 valerate use. At present, age alone is not a contraindication to
and dienogest used significantly fewer sanitary pro- the use of any OCP, and clinicians should base the
VOL. 117, NO. 4, APRIL 2011 Jensen et al Estradiol Valerate and Dienogest for Menstrual Bleeding 785

10. decision to prescribe on established criteria that eval- exaggerating the reduction in measured menstrual
uate potential medical contraindications.16 The risks blood loss. Nonetheless, the reduction in menstrual
of rare but serious adverse events with the E2 valerate blood loss observed in E2 valerate and dienogest
and dienogest pill are currently being assessed in a group was accompanied by significant improvement
large active surveillance postmarketing study, Inter- in iron metabolism parameters, but this was not the
national Active Surveillance Study–Safety of Contra- case in the placebo group.
ceptives: Role of Estrogens (INAS-SCORE). The unique dosing regimen (estrogen step-down
E2 valerate and dienogest may represent an and progestogen step-up) and the hormonal compo-
attractive alternative to current medical treatments for nents of this novel OCP may account for its ability to
heavy menstrual bleeding. The levonorgestrel-releas- reduce heavy menstrual bleeding. The regimen en-
ing intrauterine system is an effective, well-tolerated sures estrogen dominance in the first part of the cycle
medical therapy in women with heavy menstrual and progestogen dominance in the mid-to-late part of
bleeding, but is not suitable for or accepted by all the cycle.10 Furthermore, the treatment regimen in-
women.17 Although cyclical progestins administered corporates 22 days of continuous treatment with
during the luteal phase are much less effective than dienogest, a progestin with a pronounced endometrial
other treatments,18 extended regimens of high-dose activity,24 –26 followed by 6 progestogen-free days that
cyclical oral medroxyprogesterone acetate and nore- provide almost continuous E2 exposure,27 which is
thisterone have been shown to reduce menstrual thought to support endometrial stability.
blood loss volume.19,20 That said, these doses are not In conclusion, E2 valerate and dienogest is an
approved and may be associated with reduced toler- effective and well-tolerated treatment in women with
ability. Oral tranexamic acid (recently approved in heavy menstrual bleeding, prolonged menstrual
the United States for the treatment of heavy menstrual bleeding, or heavy and prolonged menstrual bleeding
bleeding) is associated with a reduction in menstrual without organic pathology. E2 valerate and dienogest
blood loss volume,21 but it is not a contraceptive and provides an important new oral, daily, self-adminis-
cannot regulate the menstrual cycle. In addition, in a tered noninvasive and fertility-sparing treatment op-
trial (that used the alkaline hematin method to quan- tion that is reversible and provides reliable contracep-
tify blood loss), a 40% reduction from baseline in tive efficacy.28
mean menstrual blood loss was observed with
tranexamic acid 3,900 mg/d,22 suggesting that E2 REFERENCES
valerate and dienogest may be more effective in 1. Fraser IS, Langham S, Uhl-Hochgraeber K. Health-related
restoring normal menstrual blood loss. Nonsteroidal quality of life and economic burden of abnormal uterine
antiinflammatory drugs approved for the treatment of bleeding. Exp Rev Obstet Gynecol 2009;4:179 – 89.
heavy menstrual bleeding (eg, mefenamic acid) may 2. Liu Z, Doan QV, Blumenthal P, Dubois RW. A systematic
review evaluating health-related quality of life, work impair-
alleviate accompanying dysmenorrhea; however, ment, and health-care costs and utilization in abnormal uterine
their ability to reduce heavy menstrual bleeding is bleeding. Value Health 2007;10:183–94.
limited.8,23 3. Fraser IS, Critchley HO, Munro MG, Broder M; Writing
This study has a number of limitations that have Group for This Menstrual Agreement Process. A process
designed to lead to international agreement on terminologies
to be considered when making generalizations rela- and definitions used to describe abnormalities of menstrual
tive to clinical practice. Women recruited to our bleeding. Fertil Steril 2007;87:466 –76.
study, with its stringent recruitment criteria, may not 4. Fraser IS, Weisberg E, Minehan E, Johansson ED. A detailed
be truly representative of those seeking treatment in analysis of menstrual blood loss in women using Norplant and
Nestorone progestogen-only contraceptive implants or vaginal
routine clinical practice. In addition, it is possible that rings. Contraception 2000;61:241–51.
the laborious process of collecting used sanitary items 5. Hale GE, Manconi F, Luscombe G, Fraser IS. Quantitative
may have resulted in some women not collecting all measurements of menstrual blood loss in ovulatory and anovu-
items used, particularly overtime, and therefore, re- latory cycles in middle- and late-reproductive age and the
menopausal transition. Obstet Gynecol 2010;115(2 pt
sult in otherwise greater reductions in measured 1):249 –56.
blood loss than would otherwise be expected as a
6. Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood
result of fewer sanitary items collected. However, the loss–a population study. Variation at different ages and
willingness to continue to comply with collection of attempts to define normality. Acta Obstet Gynecol Scand
sanitary items would more likely be an issue if the 1966;45:320 –51.
patient perceived that her medication was not work- 7. National Institute for Health and Clinical Excellence. Clin-
ical guideline: heavy menstrual bleeding. January 2007.
ing. Therefore participants in the placebo group may Available from: http://www.nice.org.uk/nicemedia/pdf/
have had less incentive to persist with study protocols, CG44FullGuideline.pdf. Accessed February 15, 2011.
786 Jensen et al Estradiol Valerate and Dienogest for Menstrual Bleeding OBSTETRICS & GYNECOLOGY

11. 8. Fraser IS, McCarron G. Randomized trial of 2 hormonal and atic Reviews 2008, Issue 1. Art. No.: CD001016. DOI:
2 prostaglandin-inhibiting agents in women with a complaint 10.1002/14651858.CD001016.pub2.
of menorrhagia. Aust N Z J Obstet Gynaecol 1991;31:66 –70. 19. Fraser IS. Treatment of ovulatory and anovulatory dysfunc-
9. Nilsson L, Rybo G. Treatment of menorrhagia. Am J Obstet tional uterine bleeding with oral progestogens. Aust N Z J
Gynecol 1971;110:713–20. Obstet Gynaecol 1990;30:353– 6.
10. Ahrendt HJ, Makalova D, Parke S, Mellinger U, Mansour D. 20. Irvine GA, Campbell-Brown MB, Lumsden MA, Heikkila A,
Bleeding pattern and cycle control with an estradiol-based oral Walker JJ, Cameron IT. Randomised comparative trial of the
contraceptive: a seven-cycle, randomized comparative trial of levonorgestrel intrauterine system and norethisterone for treat-
estradiol valerate/dienogest and ethinyl estradiol/levonorg- ment of idiopathic menorrhagia. Br J Obstet Gynaecol 1998;
estrel. Contraception 2009;80:436 – 44. 105:592– 8.
11. Shaw ST Jr, Aaronson DE, Moyer DL. Quantitation of men- 21. Wellington K, Wagstaff AJ. Tranexamic acid: a review of its
use in the management of menorrhagia. Drugs 2003;63:
strual blood loss–further evaluation of the alkaline hematin
1417–33.
method. Contraception 1972;5:497–513.
22. Lukes AS, Moore KA, Muse KN, Gersten JK, Hecht BR,
12. Chan IS, Zhang Z. Test-based exact confidence intervals for Edlund M, et al. Tranexamic acid treatment for heavy men-
the difference of two binomial proportions. Biometrics 1999; strual bleeding: a randomized controlled trial. Obstet Gynecol.
55:1201–9. 2010;116:865–75.
13. Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood 23. Reid PC, Virtanen-Kari S. Randomised comparative trial of
loss and iron deficiency. Acta Med Scand 1966;180:639 –50. the levonorgestrel intrauterine system and mefenamic acid for
14. Shabaan MM, Zakherah MS, El-Nashar SA, Sayed GA. the treatment of idiopathic menorrhagia: a multiple analysis
Levonorgestrel-releasing intrauterine system compared to low using total menstrual fluid loss, menstrual blood loss and
dose combined oral contraceptive pills for idiopathic menor- pictorial blood loss assessment charts. BJOG 2005;112:1121–5.
rhagia: a randomized clinical trial. Contraception 2011;83: 24. Oettel M, Breitbarth H, Elger W, Graser T, Hubler D,
¨ ¨
48 –54. Kaufmann G, et al. The pharmacological profile of dienogest.
15. Endrikat J, Shapiro H, Lukkari-Lax E, Kunz M, Schmidt W, Eur J Contracept Reprod Health Care 1999;4(suppl 1):2–13.
Fortier M. A Canadian, multicentre study comparing the 25. Oettel M, Graser T, Hoffmann H, Moore C, Zimmermann H,
¨
efficacy of a levonorgestrel-releasing intrauterine system to an Zimmermann T. The preclinical and clinical profile of dieno-
oral contraceptive in women with idiopathic menorrhagia. gest: a short overview. Drugs Today 1999;35(suppl C):3–12.
J Obstet Gynaecol Can 2009;31:340 –7.
26. Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Imada K,
16. Peterson HB, Curtis KM, Jamieson D, Lehnherr J, March- et al. Dienogest is a selective progesterone receptor agonist in
banks P. U S. Medical Eligibility Criteria for Contraceptive transactivation analysis with potent oral endometrial activity
Use, 2010: adapted from the World Health Organization due to its efficient pharmacokinetic profile. Steroids 2008;73:
Medical Eligibility Criteria for Contraceptive Use, 4th edition. 222–31.
MMWR Recomm Rep 2010;59(RR-4): 1– 86. 27. Zeun S, Lu M, Uddin A, Zeiler B, Morrison D, Blode H.
17. Lethaby AE, Cooke I, Rees M. Progesterone or progestogen- Pharmacokinetics of an oral contraceptive containing oestra-
releasing intrauterine systems for heavy menstrual bleeding. diol valerate and dienogest. Eur J Contracept Reprod Health
The Cochrane Database of Systematic Reviews 2005, Issue 4. Care 2009;14:221–32.
Art. No.: CD002126. DOI: 10.1002/14651858.CD002126. 28. Palacios S, Wildt L, Parke S, Machlitt A, Romer T, Bitzer J.
pub2. Efficacy and safety of a novel oral contraceptive based on
18. Lethaby A, Irvine G, Cameron I. Cyclical progestogens for oestradiol (oestradiol valerate/dienogest): a Phase III trial. Eur
heavy menstrual bleeding. The Cochrane Database of System- J Obstet Gynecol Reprod Biol 2010;149:57– 62.
VOL. 117, NO. 4, APRIL 2011 Jensen et al Estradiol Valerate and Dienogest for Menstrual Bleeding 787