Accepted Manuscript Dienogest was Effective in Treating Hemorrhagic Ascites due to Endometriosis: a Case Report Ryoko Asano, M.D. Tsuneo Nakazawa, M.D., Ph.D. Fumiki Hirahara, M.D., Ph.D. Hideya Sakakibara, M.D., Ph.D. PII:
S1553-4650(14)00260-X
DOI:
10.1016/j.jmig.2014.04.014
Reference:
JMIG 2307
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 2 April 2014 Revised Date:
20 April 2014
Accepted Date: 21 April 2014
Please cite this article as: Asano R, Nakazawa T, Hirahara F, Sakakibara H, Dienogest was Effective in Treating Hemorrhagic Ascites due to Endometriosis: a Case Report, The Journal of Minimally Invasive Gynecology (2014), doi: 10.1016/j.jmig.2014.04.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
ASANO 1
Title Page:
Dienogest was Effective in Treating Hemorrhagic Ascites due to Endometriosis: a Case Report
RI PT
Authors: Ryoko Asano, M.D., Tsuneo Nakazawa, M.D., Ph.D., Fumiki Hirahara, M.D., Ph.D., Hideya Sakakibara, M.D., Ph.D.
Author Affiliations:
SC
Department of Obstetrics and Gynecology, Yokohama City University School of Medicine,
Corresponding Author: Ryoko Asano
M AN U
Yokohama, Japan
Yokohama City University, Department of Obstetrics, Gynecology and Molecular Reproductive Science
Address: 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan Email: [email protected]
Fax: (+81)457013536
TE D
Tel: (+81)457872690
AC C
EP
All the authors have no disclosures to report.
ACCEPTED MANUSCRIPT
ASANO 2
Title:
RI PT
Dienogest was Effective in Treating Hemorrhagic Ascites due to Endometriosis: a Case Report
Precis:
SC
A 35-year-old nulliparous Japanese woman with recurrent massive ascites associated with
M AN U
endometriosis was treated effectively by gonadotropin-releasing hormone agonist therapy followed
by dienogest.
Abstract:
TE D
Hemorrhagic ascites due to endometriosis is extremely rare, and its treatment is under discussion.
We report a case of recurrent endometriosis related ascites treated with dienogest (DNG).
EP
A 35-year-old nulliparous Japanese woman with a history of infertility presented with worsening
AC C
dysmenorrhea and abdominal distention caused by massive ascites. The patient underwent
exploratory laparotomy, and hemorrhagic ascites 5500ml was drained. She had a normal-sized uterus,
and the bilateral ovaries could not be observed due to extensive adhesion in the abdominal cavity.
Endometriosis was diagnosed by histopathological evaluation of the omentum biopsy and this was
considered to be the cause of ascites. After laparotomy she had recurrence of ascites. For the next 8
years, the patient was treated conservatively with gonadotropin-releasing hormone (GnRH) agonist
ACCEPTED MANUSCRIPT
ASANO 3
therapy and drainage during the intermittent periods, followed by DNG administration. She has been
treated continuously with DNG for 1 year with no recurrence of ascites.
RI PT
DNG could be an effective treatment for recurrent ascites associated with endometriosis, especially
SC
when surgical therapy is undesirable.
M AN U
Introduction:
Endometriosis is a chronic gynecological disorder caused by the presence of ectopic endometrial
tissue, especially in the peritoneal cavity. Dysmenorrhea, chronic pelvic pain and infertility are the
main symptoms of endometriosis, but it is asymptomatic in the majority of patients.
TE D
Hemorrhagic ascites due to endometriosis is extremely rare, and its etiology and progression are
poorly understood. It also mimicks ovarian malignancy, and its diagnosis and treatment have yet to
EP
be standardized. Ascites can be successfully treated with gonadotropin-releasing hormone (GnRH)
AC C
agonist therapy but reappears after treatment, and bilateral oophorectomy cures this condition
without recurrence (1). However, conservative therapy should be indicated for women of
child-bearing age.
Here we report a case of recurrent hemorrhagic ascites treated with GnRH agonist therapy followed
by dienogest (DNG), a selective progesterone receptor agonist, and full remission has been
maintained.
ACCEPTED MANUSCRIPT
ASANO 4
Case Report:
RI PT
A 35-year-old nulliparous Japanese woman with a history of infertility presented with worsening
dysmenorrhea and abdominal distention. Her menstrual cycle was 28 days, and she did not have
SC
hypermenorrhea. She had received fertility therapy 3 years previously, with 11 cycles of oral
M AN U
clomiphene citrate and human chorionic gonadotropin (hCG) as luteal support. She also underwent
combination therapy with 1 cycle of human menopausal gonadotropin (hMG) and hCG, but did not
conceive. Physical examination revealed an otherwise healthy woman with distended abdomen. She
had gained 5 kg in the previous few months without change in her eating habits. Her vital signs were
TE D
normal. Abdominal ultrasonography and magnetic resonance imaging revealed massive ascites, with
uterus with small leiomyomata and normal-sized ovaries, from which we suspected normal-sized
EP
ovary carcinoma syndrome (Fig. 1). The serum CA125 level was 22 U/ml, and CEA was 0.5 ng/ml.
AC C
She had anemia with hemoglobin 10.0 g/dl.
She underwent exploratory laparotomy for suspected ovarian cancer. Intraoperative findings were
hemorrhagic ascites of 5500 ml, extensive adhesion, and small brown nodules on the omentum
which were determined to be endometriosis by frozen sections during the operation. She had a
normal-sized uterus, and the bilateral ovaries could not be observed due to extensive adhesion in the
abdominal cavity. There was no dissemination of cancer observed and the pouch of Douglas was
ACCEPTED MANUSCRIPT
ASANO 5
completely obliterated. In order to avoid injury to the intestines, only biopsy of the omentum could
be performed.
RI PT
Endometriosis was diagnosed by postoperative histopathology of the omentum and malignancy was
ruled out (Fig. 2). The final histopathology was endometriosis staged as Stage
Ⅳr-ASRM
SC
classification (score 98). The cytology of the endometrium and the ascites showed no malignant
M AN U
cells.
After laparotomy she had recurrences of ascites. For the next 8 years, the patient was treated
conservatively with GnRH agonist (leuprorelin acetate 1.88mg or buserelin acetate 1.80mg,
subcutaneous injection, every 4 weeks) and drainage during the intermittent periods (Fig. 3). She
TE D
underwent drainage a total of 13 times when she had a sense of distention and presence of ascites
was determined by ultrasound. As the patient had recurrent abdominal pain and elevated CRP levels
EP
as high as 28mg/dl resulting from the abdominal inflammation caused by endometriosis, GnRH
AC C
agonist therapy could not be terminated for a total of 29 months before initiating DNG. She had hot
flushes and bone mineral density was decreased by the side effect of GnRH agonist. The laboratory
test before DNG administration showed LH 0.3 mIU/ml and estradiol 11.5 pg/ml. Since switching
from GnRH agonist therapy to 2mg daily DNG taken orally, she has experienced no recurrence of
ascites or signs of inflammation, and no side-effects. She has been successfully treated with DNG
for over 1 year.
ACCEPTED MANUSCRIPT
ASANO 6
Discussion:
RI PT
Massive ascites associated with endometriosis is extremely rare. It was first reported in 1954 by
Brews, and to date only 76 cases have been reported in the literature (including 7 cases in the
SC
Japanese literature) (2). The majority of patients have been Black or Asian, and nulliparous (3). The
M AN U
pathogenesis is believed to be caused by rupture of an endometrioma or by exudation from pelvic
endometriosis, but the etiology is still not completely understood (4).
Gungor et al reviewed 63 cases of endometriosis presenting with ascites reported up to 2011 (1).
The most common symptoms were found to be abdominal distention, weight loss, and abdominal
TE D
pain. Surgical management such as salpingo-oophorectomy with or without total abdominal
hysterectomy, or biopsy was performed in 88.9% of cases. This high frequency of surgery might be
EP
due to the severity of symptoms and mimicking of malignancy. A definitive diagnosis of
AC C
endometriosis is usually made during or after surgery. Medical treatment such as GnRH agonist
therapy, danazol, progestins, and/or oral contraceptives are also administered with many patients (1,
3).
The treatment for ascites caused by endometriosis is controversial, but it can be considered to be
similar to that for endometriosis. Bilateral oophorectomy with or without hysterectomy usually cures
this condition. Radiotherapy was selected and was effective in 2 cases reported in 1954 and 1957 (2,
ACCEPTED MANUSCRIPT
ASANO 7
5). Following the development of progestins in the 1930s and GnRH agonists in the 1980s, hormonal
therapy in general gradually became common and therefore recent cases of endometriosis associated
RI PT
with ascites have been treated hormonally, except in cases treated surgically. The first case treated
with progestin only was reported in 1976, and to date 9 cases have been treated with progestin only,
SC
and 7 cases with danazol and progestin (4).
M AN U
DNG is a novel synthetic progestin used to treat endometriosis, which was introduced in 2008 in
Japan. It is a selective progesterone receptor agonist as it activates progesterone receptors and has
antagonistic activity on androgen receptors (6). DNG has a dose dependent antiovulatory effect by
reducing serum estrogen levels in vivo (7), and a direct antiproliferative effect on human endometrial
TE D
stromal cells in vitro (8). DNG is as effective as GnRH agonist for relieving the pain symptoms
associated with endometriosis, with significantly lower reduction of bone mineral density, and fewer
EP
hot flushes, which are the typical side-effects of GnRH agonists (7). On the other hand, irregular
AC C
genital bleeding occurs more frequently with DNG compared to GnRH agonists (7).
In the present case, the ascites could not be cured by surgical treatment, as oophorectomy was
considered to be difficult because of extensive adhesion, and only a biopsy of the omentum could be
performed. We could not discontinue GnRH agonist, as the ascites was recurrent with menstrual
activity. With the introduction of DNG, full remission has been maintained without GnRH agonist
therapy.
ACCEPTED MANUSCRIPT
ASANO 8
To our knowledge this is the first case report of massive ascites treated with DNG. DNG could be
an effective treatment for recurrent ascites associated with endometriosis, especially for women
RI PT
desiring future fertility or when surgical therapy should be avoided. DNG may also be useful to
M AN U
SC
replace long-term GnRH agonist therapy.
References:
1. Gungor T, Kanat-Pektas M, Ozat M, Zayifoglu Karaca M. A systematic review: endometriosis
presenting with ascites. Arch Gynecol Obstet 2011;283:513-8.
Roy Soc Med 1954;47:461.
TE D
2. Brews A. Endometriosis including endometriosis of the diaphragm and Meigs' syndrome. Proc
EP
3. Ussia A, Betsas G, Corona R, De Cicco C, Koninckx PR. Pathophysiology of cyclic hemorrhagic
AC C
ascites and endometriosis. J Minim Invasive Gynecol 2008;15:677-81.
4. Bernstein JS, Perlow V, Brenner JJ. Massive ascites due to endometriosis. Am J Dig Dis
1961;6:1-7.
5. Charles D. Endometriosis and hemorrhagic pleural effusion. Obstet Gynecol 1957;10:309-312.
6. Sasagawa S, Shimizu Y, Nagaoka T, Tokado H, Imada K, Mizuguchi K. Dienogest, a selective
progestin, reduces plasma estradiol level through induction of apoptosis of granulosa cells in the
ACCEPTED MANUSCRIPT
ASANO 9
ovarian dominant follicle without follicle-stimulating hormone suppression in monkeys. J
Endocrinol Invest 2008;31:636-41.
RI PT
7. Harada T, Momoeda M, Taketani Y, Aso T, Fukunaga M, Hagino H, Terakawa N. Dienogest is as
effective as intranasal buserelin acetate for the relief of pain symptoms associated with
randomized,
double-blind,
multicenter,
controlled
trial.
Fertil
Steril
SC
endometriosis--a
M AN U
2009;91:675-81.
8. Okada H, Nakajima T, Yoshimura T, Yasuda K, Kanzaki H. The inhibitory effect of dienogest, a
synthetic steroid, on the growth of human endometrial stromal cells in vitro. Mol Hum Reprod
TE D
2001;7:341-7.
Figure Legends:
EP
Figure 1
AC C
T2-weighted magnetic resonance imaging demonstrating massive ascites in the peritoneal cavity (A).
Pouch of Douglas is totally closed due to extensive adhesion (B). Leiomyomata of the uterus can
also be observed (C).
Figure 2
Hematoxylin and eosin staining of the omentum biopsy specimen. Ectopic endometrial glands and
ACCEPTED MANUSCRIPT
ASANO 10
stroma can be observed (arrow).
RI PT
Figure 3
Treatment timeline. Since the first operation, the patient has been repeatedly treated with GnRH
SC
agonist therapy and drainage. Due to recurrent abdominal pain and elevated CRP levels caused by
AC C
EP
TE D
M AN U
endometriosis, GnRH agonist therapy could not be discontinued for 29 months before starting DNG.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
http://www.AAGL.org/jmig-21-5-JMIG-D-14-00173
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
http://www.AAGL.org/jmig-21-5-JMIG-D-14-00173
S1553-4650(14)00260-X
DOI:
10.1016/j.jmig.2014.04.014
Reference:
JMIG 2307
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 2 April 2014 Revised Date:
20 April 2014
Accepted Date: 21 April 2014
Please cite this article as: Asano R, Nakazawa T, Hirahara F, Sakakibara H, Dienogest was Effective in Treating Hemorrhagic Ascites due to Endometriosis: a Case Report, The Journal of Minimally Invasive Gynecology (2014), doi: 10.1016/j.jmig.2014.04.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
ASANO 1
Title Page:
Dienogest was Effective in Treating Hemorrhagic Ascites due to Endometriosis: a Case Report
RI PT
Authors: Ryoko Asano, M.D., Tsuneo Nakazawa, M.D., Ph.D., Fumiki Hirahara, M.D., Ph.D., Hideya Sakakibara, M.D., Ph.D.
Author Affiliations:
SC
Department of Obstetrics and Gynecology, Yokohama City University School of Medicine,
Corresponding Author: Ryoko Asano
M AN U
Yokohama, Japan
Yokohama City University, Department of Obstetrics, Gynecology and Molecular Reproductive Science
Address: 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan Email: [email protected]
Fax: (+81)457013536
TE D
Tel: (+81)457872690
AC C
EP
All the authors have no disclosures to report.
ACCEPTED MANUSCRIPT
ASANO 2
Title:
RI PT
Dienogest was Effective in Treating Hemorrhagic Ascites due to Endometriosis: a Case Report
Precis:
SC
A 35-year-old nulliparous Japanese woman with recurrent massive ascites associated with
M AN U
endometriosis was treated effectively by gonadotropin-releasing hormone agonist therapy followed
by dienogest.
Abstract:
TE D
Hemorrhagic ascites due to endometriosis is extremely rare, and its treatment is under discussion.
We report a case of recurrent endometriosis related ascites treated with dienogest (DNG).
EP
A 35-year-old nulliparous Japanese woman with a history of infertility presented with worsening
AC C
dysmenorrhea and abdominal distention caused by massive ascites. The patient underwent
exploratory laparotomy, and hemorrhagic ascites 5500ml was drained. She had a normal-sized uterus,
and the bilateral ovaries could not be observed due to extensive adhesion in the abdominal cavity.
Endometriosis was diagnosed by histopathological evaluation of the omentum biopsy and this was
considered to be the cause of ascites. After laparotomy she had recurrence of ascites. For the next 8
years, the patient was treated conservatively with gonadotropin-releasing hormone (GnRH) agonist
ACCEPTED MANUSCRIPT
ASANO 3
therapy and drainage during the intermittent periods, followed by DNG administration. She has been
treated continuously with DNG for 1 year with no recurrence of ascites.
RI PT
DNG could be an effective treatment for recurrent ascites associated with endometriosis, especially
SC
when surgical therapy is undesirable.
M AN U
Introduction:
Endometriosis is a chronic gynecological disorder caused by the presence of ectopic endometrial
tissue, especially in the peritoneal cavity. Dysmenorrhea, chronic pelvic pain and infertility are the
main symptoms of endometriosis, but it is asymptomatic in the majority of patients.
TE D
Hemorrhagic ascites due to endometriosis is extremely rare, and its etiology and progression are
poorly understood. It also mimicks ovarian malignancy, and its diagnosis and treatment have yet to
EP
be standardized. Ascites can be successfully treated with gonadotropin-releasing hormone (GnRH)
AC C
agonist therapy but reappears after treatment, and bilateral oophorectomy cures this condition
without recurrence (1). However, conservative therapy should be indicated for women of
child-bearing age.
Here we report a case of recurrent hemorrhagic ascites treated with GnRH agonist therapy followed
by dienogest (DNG), a selective progesterone receptor agonist, and full remission has been
maintained.
ACCEPTED MANUSCRIPT
ASANO 4
Case Report:
RI PT
A 35-year-old nulliparous Japanese woman with a history of infertility presented with worsening
dysmenorrhea and abdominal distention. Her menstrual cycle was 28 days, and she did not have
SC
hypermenorrhea. She had received fertility therapy 3 years previously, with 11 cycles of oral
M AN U
clomiphene citrate and human chorionic gonadotropin (hCG) as luteal support. She also underwent
combination therapy with 1 cycle of human menopausal gonadotropin (hMG) and hCG, but did not
conceive. Physical examination revealed an otherwise healthy woman with distended abdomen. She
had gained 5 kg in the previous few months without change in her eating habits. Her vital signs were
TE D
normal. Abdominal ultrasonography and magnetic resonance imaging revealed massive ascites, with
uterus with small leiomyomata and normal-sized ovaries, from which we suspected normal-sized
EP
ovary carcinoma syndrome (Fig. 1). The serum CA125 level was 22 U/ml, and CEA was 0.5 ng/ml.
AC C
She had anemia with hemoglobin 10.0 g/dl.
She underwent exploratory laparotomy for suspected ovarian cancer. Intraoperative findings were
hemorrhagic ascites of 5500 ml, extensive adhesion, and small brown nodules on the omentum
which were determined to be endometriosis by frozen sections during the operation. She had a
normal-sized uterus, and the bilateral ovaries could not be observed due to extensive adhesion in the
abdominal cavity. There was no dissemination of cancer observed and the pouch of Douglas was
ACCEPTED MANUSCRIPT
ASANO 5
completely obliterated. In order to avoid injury to the intestines, only biopsy of the omentum could
be performed.
RI PT
Endometriosis was diagnosed by postoperative histopathology of the omentum and malignancy was
ruled out (Fig. 2). The final histopathology was endometriosis staged as Stage
Ⅳr-ASRM
SC
classification (score 98). The cytology of the endometrium and the ascites showed no malignant
M AN U
cells.
After laparotomy she had recurrences of ascites. For the next 8 years, the patient was treated
conservatively with GnRH agonist (leuprorelin acetate 1.88mg or buserelin acetate 1.80mg,
subcutaneous injection, every 4 weeks) and drainage during the intermittent periods (Fig. 3). She
TE D
underwent drainage a total of 13 times when she had a sense of distention and presence of ascites
was determined by ultrasound. As the patient had recurrent abdominal pain and elevated CRP levels
EP
as high as 28mg/dl resulting from the abdominal inflammation caused by endometriosis, GnRH
AC C
agonist therapy could not be terminated for a total of 29 months before initiating DNG. She had hot
flushes and bone mineral density was decreased by the side effect of GnRH agonist. The laboratory
test before DNG administration showed LH 0.3 mIU/ml and estradiol 11.5 pg/ml. Since switching
from GnRH agonist therapy to 2mg daily DNG taken orally, she has experienced no recurrence of
ascites or signs of inflammation, and no side-effects. She has been successfully treated with DNG
for over 1 year.
ACCEPTED MANUSCRIPT
ASANO 6
Discussion:
RI PT
Massive ascites associated with endometriosis is extremely rare. It was first reported in 1954 by
Brews, and to date only 76 cases have been reported in the literature (including 7 cases in the
SC
Japanese literature) (2). The majority of patients have been Black or Asian, and nulliparous (3). The
M AN U
pathogenesis is believed to be caused by rupture of an endometrioma or by exudation from pelvic
endometriosis, but the etiology is still not completely understood (4).
Gungor et al reviewed 63 cases of endometriosis presenting with ascites reported up to 2011 (1).
The most common symptoms were found to be abdominal distention, weight loss, and abdominal
TE D
pain. Surgical management such as salpingo-oophorectomy with or without total abdominal
hysterectomy, or biopsy was performed in 88.9% of cases. This high frequency of surgery might be
EP
due to the severity of symptoms and mimicking of malignancy. A definitive diagnosis of
AC C
endometriosis is usually made during or after surgery. Medical treatment such as GnRH agonist
therapy, danazol, progestins, and/or oral contraceptives are also administered with many patients (1,
3).
The treatment for ascites caused by endometriosis is controversial, but it can be considered to be
similar to that for endometriosis. Bilateral oophorectomy with or without hysterectomy usually cures
this condition. Radiotherapy was selected and was effective in 2 cases reported in 1954 and 1957 (2,
ACCEPTED MANUSCRIPT
ASANO 7
5). Following the development of progestins in the 1930s and GnRH agonists in the 1980s, hormonal
therapy in general gradually became common and therefore recent cases of endometriosis associated
RI PT
with ascites have been treated hormonally, except in cases treated surgically. The first case treated
with progestin only was reported in 1976, and to date 9 cases have been treated with progestin only,
SC
and 7 cases with danazol and progestin (4).
M AN U
DNG is a novel synthetic progestin used to treat endometriosis, which was introduced in 2008 in
Japan. It is a selective progesterone receptor agonist as it activates progesterone receptors and has
antagonistic activity on androgen receptors (6). DNG has a dose dependent antiovulatory effect by
reducing serum estrogen levels in vivo (7), and a direct antiproliferative effect on human endometrial
TE D
stromal cells in vitro (8). DNG is as effective as GnRH agonist for relieving the pain symptoms
associated with endometriosis, with significantly lower reduction of bone mineral density, and fewer
EP
hot flushes, which are the typical side-effects of GnRH agonists (7). On the other hand, irregular
AC C
genital bleeding occurs more frequently with DNG compared to GnRH agonists (7).
In the present case, the ascites could not be cured by surgical treatment, as oophorectomy was
considered to be difficult because of extensive adhesion, and only a biopsy of the omentum could be
performed. We could not discontinue GnRH agonist, as the ascites was recurrent with menstrual
activity. With the introduction of DNG, full remission has been maintained without GnRH agonist
therapy.
ACCEPTED MANUSCRIPT
ASANO 8
To our knowledge this is the first case report of massive ascites treated with DNG. DNG could be
an effective treatment for recurrent ascites associated with endometriosis, especially for women
RI PT
desiring future fertility or when surgical therapy should be avoided. DNG may also be useful to
M AN U
SC
replace long-term GnRH agonist therapy.
References:
1. Gungor T, Kanat-Pektas M, Ozat M, Zayifoglu Karaca M. A systematic review: endometriosis
presenting with ascites. Arch Gynecol Obstet 2011;283:513-8.
Roy Soc Med 1954;47:461.
TE D
2. Brews A. Endometriosis including endometriosis of the diaphragm and Meigs' syndrome. Proc
EP
3. Ussia A, Betsas G, Corona R, De Cicco C, Koninckx PR. Pathophysiology of cyclic hemorrhagic
AC C
ascites and endometriosis. J Minim Invasive Gynecol 2008;15:677-81.
4. Bernstein JS, Perlow V, Brenner JJ. Massive ascites due to endometriosis. Am J Dig Dis
1961;6:1-7.
5. Charles D. Endometriosis and hemorrhagic pleural effusion. Obstet Gynecol 1957;10:309-312.
6. Sasagawa S, Shimizu Y, Nagaoka T, Tokado H, Imada K, Mizuguchi K. Dienogest, a selective
progestin, reduces plasma estradiol level through induction of apoptosis of granulosa cells in the
ACCEPTED MANUSCRIPT
ASANO 9
ovarian dominant follicle without follicle-stimulating hormone suppression in monkeys. J
Endocrinol Invest 2008;31:636-41.
RI PT
7. Harada T, Momoeda M, Taketani Y, Aso T, Fukunaga M, Hagino H, Terakawa N. Dienogest is as
effective as intranasal buserelin acetate for the relief of pain symptoms associated with
randomized,
double-blind,
multicenter,
controlled
trial.
Fertil
Steril
SC
endometriosis--a
M AN U
2009;91:675-81.
8. Okada H, Nakajima T, Yoshimura T, Yasuda K, Kanzaki H. The inhibitory effect of dienogest, a
synthetic steroid, on the growth of human endometrial stromal cells in vitro. Mol Hum Reprod
TE D
2001;7:341-7.
Figure Legends:
EP
Figure 1
AC C
T2-weighted magnetic resonance imaging demonstrating massive ascites in the peritoneal cavity (A).
Pouch of Douglas is totally closed due to extensive adhesion (B). Leiomyomata of the uterus can
also be observed (C).
Figure 2
Hematoxylin and eosin staining of the omentum biopsy specimen. Ectopic endometrial glands and
ACCEPTED MANUSCRIPT
ASANO 10
stroma can be observed (arrow).
RI PT
Figure 3
Treatment timeline. Since the first operation, the patient has been repeatedly treated with GnRH
SC
agonist therapy and drainage. Due to recurrent abdominal pain and elevated CRP levels caused by
AC C
EP
TE D
M AN U
endometriosis, GnRH agonist therapy could not be discontinued for 29 months before starting DNG.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
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EP
TE D
M AN U
SC
RI PT
http://www.AAGL.org/jmig-21-5-JMIG-D-14-00173
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
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http://www.AAGL.org/jmig-21-5-JMIG-D-14-00173
