Hum. Reprod. Advance Access published August 18, 2010
Human Reproduction, Vol.0, No.0 pp. 1 – 5, 2010
ORIGINAL ARTICLE Infertility
Decreased pregnancy rate is linkedto abnormal uterine peristalsis causedby intramural ﬁbroids
O. Yoshino1,2,*, T. Hayashi3, Y. Osuga1, M. Orisaka4, H. Asada5,S. Okuda6, M. Hori7, M. Furuya5, H. Onuki2, Y. Sadoshima2, H. Hiroi1,
T. Fujiwara8, F. Kotsuji4, Y. Yoshimura5, O. Nishii2, and Y. Taketani1
1Department of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan 2Department of Obstetrics and Gynecology,Mizonokuchi Hospital, Teikyo University, Kanagawa 213-8507, Japan 3Department of Radiology, Mizonokuchi Hospital, Teikyo University,Kanagawa 213-8507, Japan 4Department of Obstetrics and Gynecology, University of Fukui, Fukui 913-1193, Japan 5Department ofObstetrics and Gynecology, Keio University, Tokyo 160-0016, Japan 6Department of Radiology, Keio University, Tokyo 160-0016, Japan7Department of Radiology, Juntendo University, Tokyo 113-8431, Japan 8Reproduction Center, Sanno Hospital, Tokyo 107-0052, Japan
*Correspondence address. Tel: +81-3-3815-5411; Fax: +81-3-3816-2017; E-mail: [email protected]
Submitted on March 31, 2010; resubmitted on June 7, 2010; accepted on June 11, 2010
background: The relationship between ﬁbroids and infertility remains an unsolved question, and management of intramural ﬁbroids iscontroversial. During the implantation phase, uterine peristalsis is dramatically reduced, which is thought to facilitate embryo implantation.
Our aims were to evaluate (i) the occurrence and frequency of uterine peristalsis in infertile women with intramural ﬁbroids and (ii) whetherthe presence of uterine peristalsis decreases the pregnancy rate.
methods: Ninety-ﬁve infertile patients with uterine ﬁbroids were examined using magnetic resonance imaging (MRI). Inclusion criteriawere as follows: (i) presence of intramural ﬁbroids, excluding submucosal type; (ii) no other signiﬁcant infertility factors (excluding endome-
triosis); and (iii) regular menstrual cycles, and MRI performed at the time of implantation (luteal phase day 5 – 9). The frequency of junctionalzone movement was evaluated using cine-mode-display MRI. After MRI, patients underwent infertility treatment for up to 4 months, and thepregnancy rate was evaluated prospectively.
results: Fifty-one patients fulﬁlled the inclusion criteria, and 29 (57%) and 22 (43%) patients were assigned to the low (0 or 1 time/3 min) or high frequency (≥2 times/3 min) uterine peristalsis group, respectively. Endometriosis incidence was the same in both groups.
Ten out of the 29 patients (34%) in the low-frequency group achieved pregnancy, compared with none of the 22 patients (0%) in thehigh-frequency group (P , 0.005). Comparing pregnant and non-pregnant cases, 4 of 10 patients (40%) and 9 of 41 patients (22%), respect-ively, had endometriosis (not signiﬁcant).
conclusions: A higher frequency of uterine peristalsis during the mid-luteal phase might be one of the causes of infertility associatedwith intramural-type ﬁbroids.
Key words: uterine ﬁbroma / cine magnetic resonance imaging / uterine peristalsis / infertility / intramural ﬁbroids
is an important factor in determining the treatment plan ). If the ﬁbroids are of the submucosal type, they
Uterine ﬁbroids are the most common solid pelvic tumors found in
can be effectively resected with a hysteroscope, which is a less invasive
women, and are estimated to occur in 20 – 50% of women, with
surgical technique. On the contrary, intramural or subserosal lesions
increased frequency during the late reproductive years
should be treated by laparotomy or laparoscopy (
). Despite this impressive epidemiological burden, the majority
However, in some cases myomectomy leads to surgical
of ﬁbroids are asymptomatic and do not require treatment (
complications and adhesion formation. In the case of intramural
ﬁbroids, patients are required to cease fertility treatment for several
In fertility treatment, it is generally accepted that the anatomical
months following surgery to allow the uterine scars to heal.
location of a uterine ﬁbroid (submucosal, intramural or subserosal),
However, even with these precautions, scarring has been known to
& The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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Yoshino et al.
cause uterine rupture during labor or pregnancy
temperature of at least 0.28C above the preceding 6 days (and occurring
Moreover, whereas meta-analyses consistently showed a detri-
in ,48 h) which is sustained for at least 11 days would indicate that ovu-
mental effect of submucosal but not subserosal ﬁbroids on treatment
lation had occurred ). All patients included
outcomes, conclusions regarding intramural lesions have been conﬂict-
in this study showed unequivocal biphasic cycles in their BBT chart. Wedesignated the day showing an elevated temperature at least 0.28C as
ing ; ). Therefore,
luteal phase day 1. The implantation window (luteal phase day 5 – 9)
management of intramural ﬁbroids continues to be difﬁcult and discor-
was judged retrospectively using the BBT chart (judged by gynecologists
dant. To address this problem, we decided to examine the mechan-
O.Y., M.O., H.O., H.A.).
isms through which ﬁbroids may inﬂuence fertility.
By routine MRI study, the information retrieved included the location,
Although the mechanism by which ﬁbroids may reduce fertility is
number and size of ﬁbroids. Also the presence of endometriosis and a dis-
uncertain, it is believed that ﬁbroids might interfere with embryo
torted uterine cavity was examined. The conditions for cine MRI have
implantation (). This detrimental effect on implan-
been described elsewhere ). MRI studies were per-
tation may be mediated by the occurrence of abnormal uterine con-
formed using a 1.5-T magnet unit (MRI machine from Siemens Medical
tractility (; ), but as far as
Systems at Takinogawa clinic or from GE Healthcare at Teikyo University,
we know there have been no comprehensive studies regarding intra-
Keio University and Fukui University) with a six channel array coil. Under
mural ﬁbroids, infertility and uterine contractility.
quiet respiration, a total of 30 serial images were obtained by single-shotfast spin-echo sequence [repetition time (TR)/echo time (TE) ¼ 6000/
During the implantation phase, it is well known that uterine peristal-
78 ms, ﬁeld of view ¼ 240 mm, slice thickness ¼ 10 mm, matrix ¼
sis is dramatically reduced, which is thought to aid in implantation of
256 × 256], every 6 s for 3 min in the mid-sagittal plane of the
the embryo in the endometrium (
uterus. All images in one study were summated into one image and
Recent major changes in ultrafast
displayed sequentially on the cine mode display at 250 ms intervals.
magnetic resonance imaging (MRI) techniques have enabled acquisition
Subsequently, conventional axial and sagittal T2 weighted images
of serial images, at intervals of only a few seconds. The cine mode
(T2WIs, TR/TE ¼ 4000 – 4720/90 – 111 ms) and axial T1WIs (TR/TE ¼
display (cine MRI) of these sequential images enables direct visualiza-
400 – 550/7.0 – 8.5 ms) were obtained using fast spin-echo techniques to
tion of uterine contractility (). Using a cine MRI display,
detect endometriosis and uterine ﬁbroids. One radiologist (T.H.) inter-
we have conﬁrmed that no uterine corporal peristalsis was noted in
preted the images, without knowledge of the patients' menstrual cycle.
the healthy volunteers during the mid- and late-luteal phases
Evaluated points included (i) perception of movement of the junctional
However, in the pilot study, we have also
zone on the cine mode display, (ii) frequency of that movement, if percei-
revealed that three out of ﬁve patients who have intramural ﬁbroids
vable, (iii) the presence or absence of endometriosis and (iv) the locationand number of uterine ﬁbroids. Patients were divided into two groups
showed uterine peristalsis during the time period of the implantation
based on the frequency of uterine peristalsis; ,2 times/3 min (low-
window (luteal phase day 5 – 9) ). The aims of
frequency group) and ≥2 times/3 min (high-frequency group), as
this study are to evaluate the following: (i) the occurrence and fre-
described After receiving MRI, the patients underwent
quency of uterine peristalsis in infertile women with intramural
treatment for infertility at each hospital for up to 4 months. Brieﬂy, ovu-
uterine ﬁbroids; and (ii) whether the presence of uterine peristalsis
lation induction was performed without use of drugs (natural cycle), or
decreases the pregnancy rate.
with clomiphene citrate or hMG for 2 – 3 courses, respectively. Clomi-phene citrate (50 – 100 mg) was started on cycle day 5 for 5 days. HMG(75 – 150 mIU) was administered on cycle day 3 and continued according
Materials and Methods
to the ovarian response. Depending on the previous ovarian response orthe treatment history at a previous hospital, an appropriate treatment was
A total of 95 patients with uterine ﬁbroids who desire pregnancy were
chosen. The size of follicles was checked frequently using transvaginal
examined by MRI between September 2008 and October 2009 at four
ultrasound until the diameter of the leading follicle reached 18 mm or
hospitals (Teikyo University Mizonokuchi hospital, Keio University, Fukui
greater, and the timing of ovulation was estimated. In some cases, hCG
University and Takinogawa clinic) after obtaining approvals from the
at a dose of 5000 IU was administered. Intrauterine insemination (IUI)
ethics committee at each institute. Among 95 subjects, 51 fulﬁlled the fol-
was performed when motile sperm concentration was ,20 × 106/ml.
lowing inclusion criteria: (i) they had intramural ﬁbroids without submuco-
Luteal phase support was not provided.
sal type; (ii) in advance of the MRI test, all patients underwent screening
Data for age, period of infertility, number of ﬁbroids and maximum
for infertility factors at each hospital; (iii) MRI was performed during the
diameter of ﬁbroids in different groups were expressed as median with
time of the implantation window (luteal phase day 5 – 9).
minimum – maximum range and compared using the Mann – Whitney
Patients had no other signiﬁcant infertility factors (excluding endome-
U-test (Statcel software). Additional patient information and results
triosis) in the screening test, i.e. anovulation, corpus luteum insufﬁciency,
were analyzed by 2 × 2 contingency table analysis. Statistical signiﬁcance
tubal disease or abnormal semen analysis of the partner. In detail, patients
was set at P , 0.05.
had regular menstrual cycles of about 28 days and basal levels of serumFSH, LH and prolactin on menstrual cycle day 3 – 5 were within thenormal range (criteria: FSH 3.5 – 12.5 mIU/ml, LH 2.4 – 12.6 mIU/mland prolactin 4.9 – 29.3 ng/ml). Serum estradiol and progesterone concen-
trations in the mid-luteal phase were above 100 pg/ml and 10 ng/ml,
The distribution of patients, as categorized by peristalsis frequency, is
respectively. Patients showed no tubal obstruction in the hysterosalpingo-graphy test. Sperm concentration of the partner was above 20 × 106/ml
shown in Table . Among 51 infertility patients harboring intramural
). After the screening tests, the func-
ﬁbroids, 29 (57%) and 22 (43%) patients were assigned to the
tional status of the ovaries was monitored using a basal body temperature
low- and high-frequency group of uterine peristalsis, respectively.
(BBT) chart. An analysis of BBT graphs was carried out, where a rise in
Clinical characteristics of patients in both groups are presented in
Pregnancy rate and intramural ﬁbroids
Table I The distribution of women with infertility
Table III Patients with intramural-type ﬁbroids were
categorized by frequency of uterine peristalsis ( per
divided into two groups, based on the frequency of
uterine peristalsis; <2 times/3 min (low-frequencygroup) and ≥2 times/3 min (high-frequency group).
Peristalsis frequency (/3 min)
Number of Patients (total 51)
Endometriosis (number of patients)
Deformed uterine cavity (number of patients)
Table II Patients with intramural-type ﬁbroids weredivided into two groups, based on the frequency of
uterine peristalsis; <2 times/3 min (low-frequency
group) and ≥2 times/3 min (high-frequency group).
Magnetic resonance imaging (MRI) ﬁndings and pregnancy rates within 4 months after
MRI study are shown.
N.S., not signiﬁcant.
Median (min –max range)N.S.
Ten out of 29 patients (34%) achieved pregnancy in the low-
frequency group within 4 months, while none of the 22 patients
(0%) in the high-frequency group achieved pregnancy (P , 0.005)
Infertility (number of patients)
during the same 4-month period. All conceptions were achieved
with non-IVF techniques. As shown in Table seven and three
patients achieved pregnancy with natural cycle and clomiphene
History of IVF (number of patients)
citrate treatment, respectively. One out of 10 pregnant cases utilized
IUI, and others became pregnant with timed natural intercourse.
Clinical characteristics of both groups are shown.
N.S., not signiﬁcant.
It is well described that the direction and frequency of uterine peristal-sis signiﬁcantly varies during the cycle phases (). Uterine peristalsis is active during the periovulatory and men-
Table : the data are comparable for age, gravida, infertility period and
strual phase, and the direction is cervix to fundus during the periovu-
the ratio of patients undergoing IVF treatment.
latory phase and fundus to cervix during the menstrual phase.
The MRI study showed that the endometriosis morbidity, the
However, during the luteal phase, uterine peristalsis is barely observed
number of ﬁbroids, the maximum diameter of ﬁbroids and ratio of
(; ). These results
patients having a distorted uterine cavity were the same in both
support the concept that uterine peristalsis is related to uterine func-
groups (Table ). Uterine ﬁbroids were located only in the corpus
tion, namely such activities as sperm transport, embryo implantation
uteri and fundus uteri. There was no case of isthmic and cervical
and discharge of menstrual blood
With ultrasonography, Fanchin et al. examined the uterine peristalsis
After receiving MRI, 6 out of 29 patients in the low peristalsis group
of infertile patients who do not have uterine abnormalities
and 6 out of 22 in the high peristalsis group underwent hMG treat-
) and demonstrated a negative
ment, while others had natural cycles (timed intercourse or IUI) or
correlation between the frequency of uterine peristalsis on the day of
clomiphene citrate treatment (Table ). IUI was performed in 9
embryo transfer and pregnancy outcome. Although they recorded
out of 29 patients and 4 out of 22 patients in the low and high peri-
uterine peristalsis on luteal phase day 2, not the implantation
stalsis groups, respectively.
window (luteal phase day 5 – 9), they did show that high-frequency
Yoshino et al.
found in the number of ﬁbroids, the maximum diameter of the ﬁbroids
Table IV The distribution of fertility treatment and
and the incidence of a deformed uterine cavity (data not shown).
pregnancy outcome in 51 patients: ovulation induction
The relationship between abnormal peristalsis and ﬁbroids (i.e.
was performed without drugs (natural cycle), and with
deformation of uterine cavity, number and size) has been unclear.
clomiphene citrate or hMG.
As estrogen induces peristalsis ), aromataseexpression in ﬁbroids (), which might result in elev-
ated tissue estrogen concentration, could be a contributory factor.
Further study is needed to examine this hypothesis.
Endometriosis is one of the most important factors of infertility (
In the present study, when comparing pregnant (n ¼
10) and non-pregnant cases (n ¼ 41), 4 out of 10 patients (40%) and 9
out of 41 patients (22%) had endometriosis, respectively, and the differ-
ence was not signiﬁcant. Meanwhile, the endometriosis morbidity was
comparable between low and high peristalsis groups (Table ). This
ﬁnding implies that endometriosis has little or no impact on uterine peri-stalsis at the time of the implantation window, whereas others have
found that uterine peristalsis was suppressed during the periovulatory
phase in patients with endometriosis ).
We utilized MRI technology to detect uterine peristalsis. With ultra-
sonography, it is difﬁcult to clearly detect the endometrium because of
deformation caused by ﬁbroids. Furthermore, pressing the uterus with
a transvaginal transducer may induce uterine contraction
Thus, the cine MRI method is favorable for evaluating patients
In the present study, we demonstrate that abnormal uterine peristal-
sis in the presence of intramural ﬁbroids could be one of the reasons for
a decreased pregnancy rate in these patients. Studies are warranted to
investigate if myomectomy for patients in the high peristalsis group is aconstructive method to normalize uterine peristalsis.
When motile sperm concentration was ,20 × 106/ml, intrauterine insemination
(IUI) was performed. Data are shown as the number of patients in the low (,2
times/3 min) and high (≥2 times/3 min) frequency uterine peristalsis groups.
O.Y., T.H., M.O., H.A., S.O., M.H., H.H., T.F. contributed to thestudy design, O.Y., T.H., M.O., H.A., S.O., M.F., H.O., Y.S., O.N. exe-cuted the study, O.Y., Y.O. performed the analysis, O.Y., Y.O., M.O.,
endometrial waves on the day of embryo transfer appear to affect the
S.O. contributed toward drafting the manuscript and H.A., M.H., F.K.,
IVF-embryo transfer outcome in a negative manner, perhaps by expel-
Y.Y., Y.T. involved in critical discussion.
ling embryos from the uterine cavity (). In a pre-vious study using cine MRI, we found that during the time of the
implantation window, although no corporal contractions were noted
We thank Dr Heather M. Martinez for her helpful discussion and criti-
in healthy volunteers, some patients with intramural-type ﬁbroids
cal reading of the manuscript. We thank Dr Yasufumi Shimizu,
exhibited uterine peristalsis ).
Dr Hiroshi Motoyama and Dr Toshihiro Kawamura (Denentoshi
A critical and still unsolved question is the relationship between
ladies' clinic), Dr Kenichi Tatsumi (Umegaoka women's clinic), Dr
ﬁbroids and infertility. Management of the intramural-type ﬁbroid is
Susumu Tokuoka (Tokuoka women's clinic), Dr Ryo Matsuoka
very controversial in the ﬁeld of reproductive medicine (
(Tokyo Hitachi hospital) and Dr Ryukichi Ogawa (Ogawa clinic) for
; Here, we focused on the occur-
their supporting our study. We also thank Mr Ryuji Nojiri and Mr
rence of abnormal uterine contractility caused by intramural ﬁbroids,
Yoshitsugu Funatsu (Takinogawa clinic) and Mr Mitsuru Harako
and examined whether this has a detrimental effect on the pregnancy
(Teikyo University Mizonokuchi hospital) for their technical assistance.
rate in infertility patients. We found that less than half of the patientswith intramural ﬁbroids exhibited abnormal uterine peristalsis during
Conﬂict of interest statement: none declared.
the mid-luteal phase. Interestingly, in the high-frequency peristalsisgroup, no patients achieved pregnancy, while one-third of the patients
in the low peristalsis group achieved pregnancy. Comparing the low-and high-frequency peristalsis groups, there is no difference in the
This work was supported by Health and Labor Sciences Research
number of ﬁbroids, the maximum diameter of the ﬁbroids and the inci-
Grants from the Ministry of Health, Labor and Welfare of Japan and
dence of a deformed uterine cavity (Table Also, when comparing
Grant-in-Aid for Scientiﬁc Research from the Ministry of Education,
pregnant (n ¼ 10) and non-pregnant cases (n ¼ 41), no difference was
Culture, Sports, Science and Technology.
Pregnancy rate and intramural ﬁbroids
tubal status and presence of endometriosis. J Reprod Med 2000;45:89 – 93.
Ayres-de-Campos D, Silva-Carvalho JL, Oliveira C, Martins-da-Silva I,
Mueller A, Siemer J, Schreiner S, Koesztner H, Hoffmann I, Binder H,
Silva-Carvalho J, Pereira-Leite L. Inter-observer agreement in analysis
Beckmann MW, Dittrich R. Role of estrogen and progesterone in the
of basal body temperature graphs from infertile women. Hum Reprod
regulation of uterine peristalsis: results from perfused non-pregnant
1995;10:2010 – 2016.
swine uteri. Hum Reprod 2006;21:1863 – 1868.
Bulun SE, Imir G, Utsunomiya H, Thung S, Gurates B, Tamura M, Lin Z.
Orisaka M, Kurokawa T, Shukunami K, Orisaka S, Fukuda MT,
Aromatase in endometriosis and uterine leiomyomata. J Steroid
Shinagawa A, Fukuda S, Ihara N, Yamada H, Itoh H et al. A
Biochem Mol Biol 2005;95:57 – 62.
comparison of uterine peristalsis in women with normal uteri and
Donnez J, Jadoul P. What are the implications of myomas on fertility? A
uterine leiomyoma by cine magnetic resonance imaging. Eur J Obstet
need for a debate? Hum Reprod 2002;17:1424 – 1430.
Gynecol Reprod Biol 2007;135:111 – 115.
Fanchin R, Ayoubi JM. Uterine dynamics: impact on the human
reproduction process. Reprod Biomed Online 2009;18(Suppl 2):
ﬁbromyomatous myometrium and its relationship to infertility. Hum
Reprod Update 1998;4:520 – 525.
Fanchin R, Righini C, Olivennes F, Taylor S, de Ziegler D, Frydman R.
Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O, Crosignani PG.
Uterine contractions at the time of embryo transfer alter pregnancy
Fibroids and female reproduction: a critical analysis of the evidence.
rates after in vitro fertilization. Hum Reprod 1998;13:1968 – 1974.
Hum Reprod Update 2007;13:465 – 476.
Fujiwara T, Togashi K, Yamaoka T, Nakai A, Kido A, Nishio S,
Togashi K. Uterine contractility evaluated on cine magnetic resonance
Yamamoto T, Kitagaki H, Fujii S. Kinematics of the uterus: cine mode
imaging. Ann N Y Acad Sci 2007;1101:62 – 71.
MR imaging. Radiographics 2004;24:e19.
Verkauf BS. Myomectomy for fertility enhancement and preservation. Fertil
Kido A, Togashi K, Nishino M, Miyake K, Koyama T, Fujimoto R,
Steril 1992;58:1 – 15.
Iwasaku K, Fujii S, Hayakawa K. Cine MR imaging of uterine peristalsis
World Health Organization (WHO). Laboratory Manual for the Examination
in patients with endometriosis. Eur Radiol 2007;17:1813 – 1819.
of Human Semen and Sperm-Cervical Mucus Interaction, 3rd edn.
Lesny P, Killick SR, Tetlow RL, Robinson J, Maguiness SD. Uterine
Cambridge: Cambridge University Press, 1992.
junctional zone contractions during assisted reproduction cycles. Hum
Zervomanolakis I, Ott HW, Hadziomerovic D, Mattle V, Seeber BE,
Reprod Update 1998;4:440 – 445.
Virgolini I, Heute D, Kissler S, Leyendecker G, Wildt L. Physiology of
Maruyama M, Osuga Y, Momoeda M, Yano T, Tsutsumi O, Taketani Y.
upward transport in the human female genital tract. Ann N Y Acad Sci
Pregnancy rates after laparoscopic treatment. Differences related to
2007;1101:1 – 20.
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