Evaluation of an ultra-low-dose oral

contraceptive for dysmenorrhea:

a placebo-controlled, double-blind,
randomized trial
Tasuku Harada, M.D.a and Mikio Momoeda, M.D.b
a
Department of Obstetrics and Gynecology, Tottori University School of Medicine, Tottori; and b Department of Integrated
Women's Health, St. Luke's International Hospital, Tokyo, Japan

Objective: To evaluate the efficacy and safety of an ultra-low-dose oral contraceptive (NPC-01; 0.02 mg ethinyl estradiol and 1 mg
norethisterone) in subjects with dysmenorrhea.
Design: Placebo-controlled, double-blind, randomized trial.
Setting: Clinical trial sites.
Patient(s): Two hundred fifteen subjects with dysmenorrhea.
Intervention(s): Subjects were randomly assigned to receive NPC-01, placebo, or IKH-01 (0.035 mg ethinyl estradiol and 1 mg
norethisterone) for four cycles.
Main Outcome Measure(s): Total dysmenorrhea score (verbal rating scale) assessing pain on the basis of limited ability to work and
need for analgesics.
Result(s): The reductions of total dysmenorrhea score and visual analog scale score after the treatment were significantly higher in the
NPC-01 group than in the placebo group. Furthermore, the efficacy of NPC-01 was comparable to that of IKH-01. The overall incidence
of side effects was significantly higher in the NPC-01 group than in the placebo group. All side effects that occurred in the NPC-01 group
were previously reported in patients receiving IKH-01. No serious side effects occurred.
Conclusion(s): The ultra-low-dose contraceptive NPC-01 relieved dysmenorrhea as effectively as IKH-01. Thus, NPC-01 could
represent a new option for long-term treatment of dysmenorrhea.
Clinical Trial Identification Number: NCT01129102. (Fertil SterilÒ 2016;106:1807–14. Ó2016 by American Society for Reproductive
Medicine.)
Key Words: Ultra-low-dose oral contraceptives, dysmenorrhea, placebo-controlled randomized trial
Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-
fertility-and-sterility/posts/11680-evaluation-of-an-ultra-low-dose-oral-contraceptive-for-dysmenorrhea-a-placebo-controlled-
double-blind-randomized-trial

D
ysmenorrhea is the term used (1). We previously conducted a ran- Ethinyl estradiol, which is con-
for describing painful men- domized, controlled trial (RCT) with a tained in OC pills, reduces irregular
strual cramps. It is a common placebo comparator that showed the ef- uterine bleeding, a side effect of admin-
gynecologic problem that can affect ficacy of an oral contraceptive (OC), istration of progestin (4). However, EE
as many as 50% of women. Approxi- IKH-01 (0.035 mg ethinyl estradiol increases the risk of venous thrombo-
mately 15% of these women suffer [EE] and 1 mg norethisterone [NET]), embolism (VTE), a serious although
from pain severe enough to temporarily for dysmenorrhea associated with relatively rare disease. In a large-scale
render them incapacitated, which re- endometriosis and for primary national cohort study on the associa-
sults in absences from work or school dysmenorrhea (2, 3). tion between OC pills and the risk of
VTE in Denmark from 1995 to 2005, Li-
Received March 23, 2016; revised and accepted August 31, 2016; published online October 4, 2016.
degaard et al. (5) found that the risk of
T.H. reports personal fees from Nobelpharma. M.M. reports personal fees from Nobelpharma. VTE depends on doses of the estrogen
Funded by Nobelpharma, Tokyo, Japan. and types of progestin. These results
Reprint requests: Tasuku Harada, M.D., Tottori University School of Medicine, Department of
Obstetrics and Gynecology, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan (E-mail: tasuku@ were corroborated by the study of van
grape.med.tottori-u.ac.jp). Hylckama Vlieg et al. (6), who exam-
Fertility and Sterility® Vol. 106, No. 7, December 2016 0015-0282/$36.00
ined the association between OC pills
Copyright ©2016 American Society for Reproductive Medicine, Published by Elsevier Inc. and the risk of VTE in The Netherlands.
http://dx.doi.org/10.1016/j.fertnstert.2016.08.051

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ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY

FIGURE 1

245 subjects screened

215 subjects randomized 30 subjects excluded

NPC-01 Placebo IKH-01

110 assigned 55 assigned 50 assigned

2 withdrew 1 withdrew 3 withdrew

Received NPC-01 Received placebo Received IKH-01

Dysmenorrhea (n = 108) Dysmenorrhea (n = 54) Dysmenorrhea (n = 47)

Primary (n = 56) Primary (n = 28) Primary (n = 0)

Secondary (n = 52) Secondary (n = 26) Secondary (n = 47)

6 withdrew 6 withdrew 3 withdrew

Analyzed Analyzed Analyzed

n=105 n=54 n=47

Flow diagram of the randomized, controlled trial.

Harada. Ultra-low-dose oral contraceptive for dysmenorrhea. Fertil Steril 2016.

Dysmenorrhea is categorized into two types, primary and of endometrial-like tissues outside the uterus, which affects
secondary. Primary dysmenorrhea refers to menstrual pain 10% of women of reproductive age (7). The main clinical
without underlying pathology. The most common cause of symptoms are dysmenorrhea, chronic pelvic pain, and infer-
secondary dysmenorrhea is endometriosis, ectopic growth tility. Treatment of endometriosis may be surgical,

1808 VOL. 106 NO. 7 / DECEMBER 2016


conservative, or a combination of both. Although surgical
treatment, especially laparoscopic surgery, is the most effi-
cient in eliminating pain, the high recurrence rate represents
a serious clinical problem (8–10). Recent evidence suggests
that postsurgical medical treatment is mandatory for
preventing unwanted recurrence, in particular for avoiding
repeated surgery in patients operated for ovarian chocolate
cysts (11, 12). Therefore, long-term medical management
with OCs or progestin is highly recommended (13), especially
for young women (14). This necessitates the development of
safer OCs suitable for long-term use.
We conducted an RCT with a placebo comparator to
verify the efficacy of the OC NPC-01, which contains less
EE (0.02 mg) than IKH-01, for dysmenorrhea. In addition,
we compared the efficacy and side effects of NPC-01 and
IKH-01 for secondary dysmenorrhea.
MATERIALS AND METHODS
Study Design
The RCT was conducted between May 2010 and April 2011
and included 215 subjects with dysmenorrhea at 18 centers
in Japan. The range of the subject numbers among centers
is 1–21 (median 12.5, 25%–75% interquartile range 7.75–
14.5). The patients were enrolled as encountered casually in
private practices. The protocol was approved by the institu-
tional review board at each study center (protocol number
NPC–16–2), and the trial was conducted in compliance with
the regulations governing good clinical practice. Monitors
visited all the centers regularly during the trial to ensure the
adherence to trial procedures. After giving informed consent,
the subjects with primary dysmenorrhea were randomized at
a ratio of 2:1 to receive NPC-01 (0.02 mg EE and 1 mg NET) or
placebo. The subjects with secondary dysmenorrhea were ran-
domized at a ratio of 2:1:2 to receive NPC-01, placebo, and
IKH-01 (0.035 mg EE and 1 mg NET). Although the regulatory
authority (Pharmaceuticals and Medical Devices Agency) re-
quested to use IKH-01 as a reference arm for the study, we
used IKH-01 as a reference arm only for secondary dysmen-
orrhea owing to funding considerations.
The treatment was initiated on the third day (
2 days) of
the menstrual cycle for 21 days, followed by 7 days free of any
medication and continued for four cycles. NPC-01, placebo,
and IKH-01 were prepared by the manufacturer (Nobel-
pharma) in 21-day blister packs that had identical appear-
ance. The use of analgesic agents customarily used by the
patients was allowed. Other hormonal treatments for pain
were prohibited.
Study Population
After screening 245 subjects with dysmenorrhea, 215 were ran-
domized and received the trial drug (Fig. 1). The inclusion
criteria were [1] age R16 years; [2] regular menstrual cycle
(28
2 days); and [3] diagnosis of secondary or primary
dysmenorrhea (secondary dysmenorrhea was diagnosed
when laparoscopy, laparotomy, or two transvaginal ultraso-
nography examinations revealed endometriosis, myoma, or
adenomyosis; primary dysmenorrhea was diagnosed after
VOL. 106 NO. 7 / DECEMBER 2016
Fertility and Sterility®
considering medical history, results of pelvic examination,
and findings of two transvaginal ultrasonography examina-
tions); and [4] the presence of moderate or severe dysmenor-
rhea, based on a total dysmenorrhea score of 3–6 (2, 3). The
exclusion criteria were a history of medical or surgical
treatment of dysmenorrhea within 8 weeks of entry into the
study, including hormonal agents such as OCs, or concurrent
use of medications that affect the metabolism of OCs.
Randomization and Blinding
Randomization was performed by the company that was
engaged by Nobelpharma, using the permuted block method.
In the case of subjects with primary dysmenorrhea, one block,
which consisted of six sets of drugs (four NPC-01 and two pla-
cebo), was allocated to each of the 18 centers. In the case of
subjects with secondary dysmenorrhea, one block, which
consisted of 10 sets of drugs (four NPC-01, two placebo,
and four IKH-01), was allocated to each of the 18 centers.
Allocation concealment was accomplished centrally by the
company and not broken until after all data were collected.
Both the subjects and doctors were blinded to the type of
medication.
Study Evaluation
Efficacy. The subjects were requested to visit at pretreatment,
menstrual period (five times), and after treatment, resulting in
a total of seven visits. The initial baseline score was obtained
at pretreatment visit. The primary outcome measure was the
total dysmenorrhea score (verbal rating scale), which evalu-
ates pain on the basis of limited ability to work (pain score)
and the need for analgesics, expressed by the number of
days the subjects took analgesics (drug score), as originally
developed by Harada et al. (2, 3).
The pain score and drug score were determined using the
following 4-grade scales. Pain score: None (score 0), none;
Mild (1), some loss of work (or study) efficiency; Moderate
(2), want to take some rest in bed, loss of work (or study);
and Severe (3), in bed for more than 1 day. Drug score:
None (0), none; Mild (1), take analgesics for 1 day; Moderate
(2), take analgesics for 2 days; and Severe (3), take analgesics
for R3 days.
In addition, the degree of dysmenorrhea was evaluated
using a visual analog scale (VAS) as a secondary outcome
measure. The primary endpoint was the mean difference in
the total dysmenorrhea score before and after the treatment,
and the secondary endpoints were [1] the mean changes in
VAS score before and after the treatment; and [2] the mean
changes in the total dysmenorrhea score and VAS score at
each cycle, with the pretreatment cycle considered as the
baseline cycle and changes evaluated throughout the treat-
ment (until cycle 5).
Safety. Side effects reported by subjects and observed by doc-
tors at the trial centers, excluding those present before the
initiation of the treatment, were documented throughout
the trial period. Vital signs (blood pressure and body weight)
were measured at each cycle; clinical laboratory tests (hema-
tologic and serum chemistry examinations) and transvaginal
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ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY

TABLE 1

Demographic characteristics and effect of pain treatment (entire study cohort).

Characteristic NPC-01 Placebo IKH-01 P value
Entire cohort
N 105 54 47
Age (y) 32.4 (7.29) 30.4 (7.41) 34.0 (6.93)
Weight (kg) 52.94 (6.908) 54.92 (10.918) 50.40 (5.766)
BMI (kg/m2) 20.89 (2.597) 21.72 (4.183) 20.15 (2.144)
Parity, n (%)
Nulliparous 72 (68.6) 43 (79.6) 30 (63.8)
Parous 33 (31.4) 11 (20.4) 17 (36.2)
Age of menarche (y) 12.3 (1.22) 12.2 (1.37) 12.2 (1.40)
Age of first menstrual pain (y) 17.9 (5.95) 17.7 (5.93) 18.5 (6.28)
Patients with dysmenorrhea
n 105 54
Dysmenorrhea score
Pretreatment 4.1 (1.00) 4.2 (0.95) < .001a
End of treatment 1.8 (1.57) 2.9 (1.55)
VAS
Pretreatment 51.8 (20.57) 48.6 (20.15) < .001a
End of treatment 21.2 (20.18) 35.6 (21.74)
Patients with primary dysmenorrhea
n 55 28
Dysmenorrhea score
Pretreatment 3.9 (0.92) 4.3 (0.90) .321a
End of treatment 1.6 (1.44) 2.4 (1.69)
VAS score
Pretreatment 53.0 (21.40) 54.2 (17.39) .063a
End of treatment 20.6 (18.86) 32.4 (24.20)
Patients with secondary dysmenorrhea
n 50 26 47
Dysmenorrhea score < .001a
Pretreatment 4.3 (1.05) 4.1 (0.99) 4.0 (0.87) .230b
End of treatment 2.0 (1.70) 3.4 (1.21) 2.1 (1.59) .002c
VAS score < .001a
Pretreatment 50.6 (19.76) 42.7 (21.50) 46.1 (21.73) .252b
End of treatment 21.8 (21.71) 39.1 (18.55) 23.7 (21.55) .004c
Note: Values are presented as mean (
SD) unless otherwise noted. All comparisons were made between pretreatment and end of treatment.
a
Two-sample t test comparison between the NPC-01 and the placebo.
b
Two-sample t test comparison between the NPC-01 and the IKH-01.
c
Two-sample t test comparison between the IKH-01 and the placebo.
Harada. Ultra-low-dose oral contraceptive for dysmenorrhea. Fertil Steril 2016.

ultrasonography were performed before the treatment and at
cycles 3 and 5. Presence of uterine bleeding was assessed ac-
cording to diaries filled by the patients throughout the trial
period.
Statistical Methods
For the entire study cohort, mean changes of the total dysmen-
orrhea and VAS scores from the baseline cycle until the final
evaluation at the end of the treatment period were assessed us-
ing Student's t test, because the primary study outcome is the
comparison of NPC-01 with placebo for dysmenorrhea. Sample
size calculation was conducted with reference to previous re-
ports (2, 3). For the comparative study, the needed sample
size was determined to be 144 (NPC-01: 96; placebo: 48) on
the basis of the following assumptions: a difference in total
dysmenorrhea score between NCP-01 and placebo of 1.2–1.4;
a common standard deviation of 1.5, 2:1 ratio to NPC-01
and placebo group; a two-sided significance level of a ¼
5%; and a power of 90% for the t test of the hypothesis that
NPC-01 is better than placebo. Repeated-measures analysis us-
ing a mixed model was performed to evaluate the transitional
effect of the treatment, and the F test was used to compare the
difference between treatment groups by time points. Statistical
significance was set at P< .05.
For reported or observed side effects, Fisher's exact test
was used to compare proportions of subjects experiencing
the event. For vital signs and clinical laboratory data, mean
changes from the results before the treatment initiation
were determined at visits during cycles 3 and 5 using a t test.
RESULTS
Demographic Characteristics and Disposition
Subjects in the NPC-01, placebo, and IKH-01 groups had
similar demographic characteristics (Table 1).
The workflow of subjects allocation after screening is
shown in Figure 1. Of the 245 subjects with dysmenorrhea
screened in the trial, 30 subjects were excluded before
randomization. The remaining 215 subjects were randomized
to achieve the following group sizes: n ¼ 110 for NPC-01, n ¼
55 for placebo, and n ¼ 50 for IKH-01. Two subjects in the

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 Fertility and Sterility®

FIGURE 2

Changes in the mean (
SE) dysmenorrhea and VAS scores from the pretreatment cycle to cycle 5 in the patients with (A) dysmenorrhea, (B) primary
dysmenorrhea, and (C) secondary dysmenorrhea. *P<.05, **P<.01 for NPC-01 vs. placebo.
Harada. Ultra-low-dose oral contraceptive for dysmenorrhea. Fertil Steril 2016.

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ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY
FIGURE 3
Changes in the incidence rate of irregular uterine bleeding (not spotting) from the first treatment cycle to the fourth treatment cycle.
Harada. Ultra-low-dose oral contraceptive for dysmenorrhea. Fertil Steril 2016.
NPC-01 group, 1 subject in the placebo group, and 3 subjects
in the IKH-01 group withdrew from this study before taking
the trial drug. Accordingly, 108 subjects were treated with
NPC-01, 54 with placebo, and 47 with IKH-01.
Fifteen subjects (NPC-01 group: 6; placebo group: 6; IKH-01
group: 3) discontinued the medication. In the NPC-01 group, the
reasons were subject's request (n ¼ 2), adverse events (n ¼ 2),
and loss to follow-up (n ¼ 2). In the placebo group, the reasons
were subject's request (n ¼ 3), adverse events (n ¼ 1), conflict
with the exclusion criteria (n ¼ 1), and pregnancy (n ¼ 1). In
the IKH-01 group, the reasons were adverse events (n ¼ 2)
and conflict with the exclusion criteria (n ¼ 1).
Efficacy
Three subjects in the NPC-01 group were excluded from effi-
cacy analysis because their data were unavailable.
All subjects with dysmenorrhea. The means (SD) of the total
dysmenorrhea score and VAS score in the subjects with
dysmenorrhea before and after treatment are shown in
Table 1. The reduction of total dysmenorrhea score was signif-
icantly higher in the NPC-01 group (2.3) than in the placebo
group (1.3) (P< .001). Similarly, the reduction of VAS score
was significantly higher in the NPC-01 group (30.6) than in
the placebo group (13.0) (P< .001). From cycle 2 to 5, the re-
1812
ductions of total dysmenorrhea score and VAS score were
significantly higher in the NPC-01 group than in the placebo
group (Fig. 2A).
Subjects with primary dysmenorrhea. The means (SD) of the
total dysmenorrhea score and VAS score in the subjects with
primary dysmenorrhea before and after treatment are shown
in Table 1. The reduction of total dysmenorrhea score was
higher in the NPC-01 group (2.3) than in the placebo group
(1.9). Similarly, the reduction of VAS score was higher in the
NPC-01 group (32.3) than in the placebo group (21.9).
Subjects with secondary dysmenorrhea. The means (SD) of
the total dysmenorrhea score and VAS score in the subjects
with secondary dysmenorrhea before and after treatment
are shown in Table 1. The reduction of total dysmenorrhea
score was higher in the NPC-01 group (2.3) and IKH-01
group (1.9) than in the placebo group (0.7). The reduction
of the VAS score was higher in the NPC-01 group (28.7) and
IKH-01 group (22.4) than in the placebo group (3.5). In the
NPC-01 group, from cycle 2 to 5, the reductions of total
dysmenorrhea score and VAS score in the subjects with sec-
ondary dysmenorrhea were similar to that in the subjects
with primary dysmenorrhea (Fig. 2B, C). In the subjects with
secondary dysmenorrhea, from cycle 2 to 5, the reductions
of total dysmenorrhea score and VAS score in the NPC-01
group were similar to those in the IKH-01 group (Fig. 2C).
VOL. 106 NO. 7 / DECEMBER 2016

Safety
Overall, the incidence of side effects was significantly higher
in the NPC-01 group than in the placebo group (89.7% vs.
57.4%). The incidence of irregular uterine bleeding and poly-
menorrhea was significantly higher in the NPC-01 group than
in the placebo group (70.1% vs. 37.0% and 8.4% vs. 0.0%,
respectively). The side effects that occurred in the NPC-01
and IKH-01 groups were lower abdominal pain (10.3% and
2.1%), nausea (9.3% and 17.0%), headache (12.1% and
12.8%), hypermenorrhea (5.6% and 10.6%), atypical bleeding
(70.1% and 78.7%), oligomenorrhea (22.4% and 12.8%), and
polymenorrhea (8.4% and 10.6%).
There were no serious side effects in either group. No clin-
ically remarkable changes in the laboratory parameters or vi-
tal signs were observed in the NPC-01 group, although the
uterine volume decreased significantly at cycle 5 (pretreat-
ment, 73.87
76.731 cm3 vs. cycle 5, 71.06
77.941 cm3;
P¼ .015), whereas no significant decrease in the uterine vol-
ume was observed in the placebo group.
The comparison of changes in the incidence of uterine
bleeding (not spotting) between the NPC-01 and IKH-01
groups is shown in Figure 3. As shown in Figure 3, the inci-
dence of irregular uterine bleeding, excluding spotting, or
menstrual bleeding was high during the first treatment cycle
in the IKH-01 group but decreased starting from the second
treatment cycle. In contrast, although the overall trend was
similar during the first treatment cycle in the NPC-01 group,
the incidence of irregular uterine bleeding was significantly
higher than that in the IKH-01 group after the second treat-
ment cycle (Fig. 3). Although the rate of bleeding days
increased in the NPC-01 group after the second treatment cy-
cle, the incidence of bleeding during pill-free interval was
lower in the NPC-01 group than that in the IKH-01 group.
DISCUSSION
We conducted an RCT with a placebo comparator to verify the
efficacy of NPC-01 (0.02 mg EE and 1 mg NET), which con-
tains a reduced EE amount compared with IKH-01, for
dysmenorrhea. Because of the high postsurgery recurrence
rate, long-term maintenance treatment with OCs or progestin
is essential for modern management of endometriosis (13, 14).
NPC-01 may be a strong candidate for long-term usage.
The total dysmenorrhea score, which was the primary
outcome measure in the present study, is adjusted according
to the methods of Biberoglu et al. (15) and Andersch and Mil-
son (16), and its reproducibility and reliability have been
confirmed (2, 3). Compared with the placebo, NPC-01 signifi-
cantly reduced the total dysmenorrhea and VAS scores in sub-
jects with dysmenorrhea by the end of the treatment (Table 1)
and during the treatment period (cycle 2 to 5; Fig. 2). These re-
sults are similar to those of the previous RCT of IKH-01 in sub-
jects with dysmenorrhea associated with endometriosis (2)
and those with primary dysmenorrhea (3). Moreover, the
changes in the total dysmenorrhea and VAS scores in the pa-
tients with secondary dysmenorrhea (cycle 2 to 5) were similar
between the NPC-01 and IKH-01 groups (Fig. 2).
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Fertility and Sterility®
Ethinyl estradiol, a common component of OCs, increases
the risk of VTE, which, despite the low incidence, is a serious
disease (5, 6). To reduce the risk of VTE, NPC-01, a combina-
tion preparation, was designed to contain less EE than IKH-01
(0.02 mg vs. 0.035). Because EE contributes to reduction of
irregular uterine bleeding, a side effect of administration of
synthetic progestin, it was expected that the incidence of
irregular uterine bleeding would be higher for NPC-01 than
for IKH-01. A high incidence of irregular uterine bleeding
associated with administration of a combination preparation
containing a reduced dose of EE (0.15 mg desogestrel þ
0.03 mg EE; 0.15 mg desogestrel þ 0.02 mg EE) was previ-
ously reported by Akerlund et al. (4). In this study the inci-
dence of uterine bleeding was higher in the NPC-01 group
than that in the IKH-01 group after second treatment cycle
(Fig. 3). However, none of the subjects in the NPC-01 and
IKH-01 groups discontinued the treatment because of irreg-
ular uterine bleeding. Moreover, each of the side effects that
occurred in the NPC-01 group was previously reported in
the subjects taking IKH-01.
The present study is unique in that we evaluated the effi-
cacy of a lower-dose EE preparation compared with a higher-
dose EE preparation, in a combined OC containing the same
progestin component in both preparations. This allowed us
to examine the effect of the different doses of EE alone on
the primary outcome of secondary dysmenorrhea. Although
it is plausible that a lower dose of EE may be beneficial in
reducing the risk of VTE, the determination of the effect on
VTE would require huge numbers of study participants to
determine whether the lower-dose EE preparation actually re-
duces the risk of VTE.
The effectiveness of OC containing 0.02 mg EE or less has
been reported on both primary and secondary dysmenorrhea
(17, 18). Continuous use of OC, without the drug-free interval,
has been successfully used for alleviating recurrent dysmen-
orrhea that does not respond to a cyclic pill regimen (19). A
continuous regimen has also been reported to be useful for
managing postoperative pain control (20), bladder endometri-
osis (21), and colorectal endometriosis (22), suggesting that
continuous use may be more effective than conventional cy-
clic regimen.
In conclusion, this ultra-low-dose contraceptive could be
an attractive option for the treatment of dysmenorrhea.
Acknowledgments: The authors thank the following doc-
tors for participation in the study: Hitoshi Ohkubo (Sapporo
Maternity Women's Hospital), Masaki Hashimoto (Hashimoto
Clinic), Teruko Yasuda (Yoshio Clinic), Shinichi Tanaka
(Primo Women's Clinic), Soichiro Nagai (Kotoni Obstetrics
and Gynecology Clinic), Kengo Manase (Gorinbashi Obstet-
rics Gynecology and Pediatrics Hospital), Sayaka Dantuka
(Dantuka Clinic), Chisei Tei (Sei Women's Clinic), Yukari
Sumi (Toranomon Women's Clinic), Mika Sekine (Life Clinic
Ginza), Kiichiro Sumi (Sumi Ladies Clinic), Toyohiko Miya-
zaki (Akasakamituke Miyazaki Obstetrics and Gynecology
Clinic), Tsuneo Yokokura (Yokokura Clinic), Sumie Yukawa
(Yukawa Women's Clinic), Atsushi Sakai (Motomachi Ladies
Clinic), Kazuhisa Ideta (Chayamachi Ladies Clinic), Chisato
1813
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY
Kiuchi (Kiuchi Ladies Clinic), and Shingo Yamabe (Yamabe
Ladies Clinic).
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