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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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- Ovulation induction ated tissue estrogen concentration, could be a contributory factor.
Further study is needed to examine this hypothesis.
Low-frequency group Endometriosis is one of the most important factors of infertility ( In the present study, when comparing pregnant (n ¼ Timed intercourse 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- Clomiphene citrate ence was not significant. Meanwhile, the endometriosis morbidity was Timed intercourse 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 Timed intercourse phase in patients with endometriosis ).
We utilized MRI technology to detect uterine peristalsis. With ultra- High-frequency group sonography, it is difficult to clearly detect the endometrium because of deformation caused by fibroids. Furthermore, pressing the uterus with Timed intercourse a transvaginal transducer may induce uterine contraction Thus, the cine MRI method is favorable for evaluating patients Clomiphene citrate with fibroids.
Timed intercourse 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 Timed intercourse 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.
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