Uterine relaxation by sacral surface electrical stimulation on the day of embryo transfer
2007; Elsevier BV; Volume: 90; Issue: 4 Linguagem: Inglês
10.1016/j.fertnstert.2007.08.059
ISSN1556-5653
AutoresOsamu Fujii, Takashi Murakami, Haruo Murakawa, Yukihiro Terada, Takahide Ogura, Nobuo Yaegashi,
Tópico(s)Ectopic Pregnancy Diagnosis and Management
ResumoThe peak power of uterine peristalses after sacral surface electrical stimulation (ssES) treatment decreased markedly in comparison with that measured before ssES on the day of embryo transfer (ET). This suppression effect of uterine peristalses was stronger on day 5 of ET than on day 3. Because the uterus at the time of ET is sensitive to ssES, this electrical neuromodulation may be an effective method to induce uterine relaxation for ET. The peak power of uterine peristalses after sacral surface electrical stimulation (ssES) treatment decreased markedly in comparison with that measured before ssES on the day of embryo transfer (ET). This suppression effect of uterine peristalses was stronger on day 5 of ET than on day 3. Because the uterus at the time of ET is sensitive to ssES, this electrical neuromodulation may be an effective method to induce uterine relaxation for ET. Physiologic uterine contractions occurring throughout the menstrual cycle can be detected by transvaginal ultrasonography or magnetic resonance imaging (1Lyons E.A. Taylor P.J. Zheng X.H. Ballard G. Levi C.S. Kredentser J.V. Characterization of subendometrial myometrial contractions throughout the menstrual cycle in normal fertile women.Fertil Steril. 1991; 55: 771-774Abstract Full Text PDF PubMed Scopus (229) Google Scholar, 2Fujiwara T. Togashi K. Yamaoka T. Nakai A. Kido A. Nishio S. et al.Kinematics of the uterus: cine mode MR imaging.Radiographics. 2004; 24: e19Crossref PubMed Scopus (38) Google Scholar, 3van Gestel I. Ijland M.M. Hoogland H.J. Evers J.L. Endometrial wave-like activity in the non-pregnant uterus.Hum Reprod Update. 2003; 9: 131-138Crossref PubMed Scopus (76) Google Scholar). The direction and frequency of peristalses match the purposes of uterine functions at specific time points in the menstrual cycle. Uterine contractility is associated with fecundity during spontaneous cycles (4Ijland M.M. Evers J.L. Dunselman G.A. Volovics L. Hoogland H.J. Relation between endometrial wavelike activity and fecundability in spontaneous cycles.Fertil Steril. 1997; 67: 492-496Abstract Full Text PDF PubMed Scopus (112) Google Scholar) and influences fertility in assisted reproductive technology (ART) cycles (5Ijland M.M. Hoogland H.J. Dunselman G.A. Lo C.R. Evers J.L. Endometrial wave direction switch and the outcome of in vitro fertilization.Fertil Steril. 1999; 71: 476-481Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). In in vitro fertilization and embryo transfer (IVF-ET) treatment, gentle and meticulous manipulation during transcervical ET is recommended to optimize pregnancy and implantation rates (6Schoolcraft W.B. Surrey E.S. Gardner D.K. Embryo transfer: techniques and variables affecting success.Fertil Steril. 2001; 76: 863-870Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 7Mansour R.T. Aboulghar M.A. Optimizing the embryo transfer technique.Hum Reprod. 2002; 17: 1149-1153Crossref PubMed Scopus (140) Google Scholar). Avoidance of excessive uterine contractions by ET process is required.It was recently demonstrated that uterine peristalsis during menstruation can be suppressed by sacral surface electrical stimulation (ssES), the application of electrical stimulation to the skin above the second and fourth posterior sacral foramen (8Ogura T. Murakami T. Ozawa Y. Seki K. Handa Y. Magnetic resonance imaging of morphological and functional changes of the uterus induced by sacral surface electrical stimulation.Tohoku J Exp Med. 2006; 208: 65-73Crossref PubMed Scopus (3) Google Scholar). Our study investigated the effect of ssES on uterine relaxation on the day of ET.Fifteen women who had experienced one or more IVF-ET treatment failures participated in the study. These women received repeated IVF-ET at either Tohoku University Hospital or Suzuki Memorial Hospital.Before fresh ETs, we initiated human menopausal gonadotropin (hMG) therapy (hMG-Fuji; Fuji Pharmaceuticals, Tokyo, Japan) at a dose of 225 IU/day for the first 8 days of ovarian stimulation. Additional hMG doses and their timing (hCG-Mochida; Mochida Pharmaceuticals, Tokyo, Japan; 10,000 IU, intramuscular) were adjusted according to follicular maturation criteria determined by ultrasonography and serum estradiol levels. For frozen-thawed ET, we administered intramuscular estrogen (Estolmon Depot; Fuji Pharmaceuticals; 10 mg) and progesterone (Progeston Depot; Fuji Pharmaceuticals; 125 mg) replacement therapy. For both patient populations, we gave luteal support with Progeston Depot every fifth day, beginning on the day of oocyte aspiration and continuing to the day of testing pregnancy or until week 12.We performed ssES before the ET procedure using a portable electrical stimulator (Nodoka; Lintec, Tokyo, Japan) and a 5 × 10 cm surface electrode (Lintec). The details of ssES have been described previously elsewhere (8Ogura T. Murakami T. Ozawa Y. Seki K. Handa Y. Magnetic resonance imaging of morphological and functional changes of the uterus induced by sacral surface electrical stimulation.Tohoku J Exp Med. 2006; 208: 65-73Crossref PubMed Scopus (3) Google Scholar). We recorded images obtained by transvaginal ultrasonographic imaging before and after ssES for 3 minutes, after which a physician performed the ET.Image analysis was performed using Ogura's method with modifications (8Ogura T. Murakami T. Ozawa Y. Seki K. Handa Y. Magnetic resonance imaging of morphological and functional changes of the uterus induced by sacral surface electrical stimulation.Tohoku J Exp Med. 2006; 208: 65-73Crossref PubMed Scopus (3) Google Scholar). The region of interest (ROI), which did not exceed the uterine diameter, was fixed at the center of the uterine body adjacent to the internal cervical os. In transvaginal ultrasonographic images, the uterine wall is visualized as two layers, the myometrium and the endometrium; the ultrasonographic brightness value of the myometrium is lower in intensity than that of the endometrium. Cyclic movement of the myometrium within the ROI could be seen as sequential changes in brightness over the ROI in ultrasonography. Fast Fourier transform of the brightness change was then performed, determining that the power spectrum of the brightness changes corresponded with uterine peristalsis.A 1-minute ultrasonographic animation was converted into 175 still pictures. The total image pickup time was 60 seconds. As transvaginal ultrasonography imaging was done at 2.92 f/second, the frequency resolution of Fourier transform was calculated to be 0.00268 Hz.This study was approved by the institutional review boards at the Tohoku University Graduate School of Medicine and Suzuki Memorial Hospital. Written informed consent was obtained from each patient.Our patients' ages ranged from 29 to 47 years old (38.2 ± 5.2 years, mean ± SD). Six women received fresh embryos in controlled ovarian hyperstimulation (COH) cycles, and nine received frozen-thawed ET during hormone replacement cycles. The ET was performed on day 3 in six patients and on day 5 in nine. No one dropped out halfway through the electrostimulation, and no patients had cutaneous manifestations or any other symptoms. Three patients were able to conceive, all of whom were in the day-5 ET group.As a measure of peristalsis, we measured the average power spectrum and the peak frequency of the changes in ROI brightness before and after ssES treatment in all 15 patients. Overall, the maximum power at peak frequency was statistically significantly decreased from 0.121 ± 0.083 before ssES to 0.067 ± 0.050 after ssES (P<.05, paired t-test). The peak frequency decreased from 0.0089 ± 0.0064 Hz (0.53 ± 0.38 times/minute) to 0.0070 ± 0.0022 Hz (0.41 ± 0.13 times/minute) after ssES, although this difference was not statistically significant (P=.28, paired t-test).We did not observe any statistically significant correlation of age with either the peak frequency or the maximum power before or after ssES (data not shown). Hormone status based on the type of cycle, COH, or frozen-thawed ET did not statistically significantly affect uterine peristalsis before or after ssES (Table 1). The time of ssES application, however, did statistically significantly influence uterine contractility by ssES (see Table 1). Although the maximum power before ssES was not statistically significantly different between in the day five ET group and in the day-3 ET group, the maximum power after ssES in the former group was statistically significantly smaller than in the latter group (P<.05, unpaired t-test). As for the peak frequency, both groups showed no statistically significant differences either before or after ssES.Table 1Stratified analysis of uterine peristalsis.Parameter (case no.)Maximum power (mean ± SD)P valueaUnpaired t-test.Peak frequency (Hz)(mean ± SD)P valueaUnpaired t-test.Before ssESCOH cycle (6)0.122 ± 0.1130.0107 ± 0.0106vs..96.57FET cycle (9)0.120 ± 0.0640.0080 ± 0.0037Day-3 ET (6)0.138 ± 0.0610.0116 ± 0.0046vs..50.70Day-5 ET (9)0.110 ± 0.0440.0102 ± 0.0037After ssESCOH cycle (6)0.078 ± 0.0480.0078 ± 0.0062vs..90.46FET cycle (9)0.072 ± 0.0560.0071 ± 0.0049Day-3 ET (6)0.106 ± 0.0610.0071 ± 0.0013vs.<.05.70Day-5 ET (9)0.041 ± 0.0110.0068 ± 0.0027Note: COH, controlled ovarian hyperstimulation; FET, frozen-thawed embryo transfer; ssES, sacral surface electrical stimulation.a Unpaired t-test. Open table in a new tab This study confirms the ability of ssES to induce uterine relaxation at the day of ET. We observed that ssES suppressed the intensity of uterine peristalses on the day of ET although ssES could not statistically significantly decrease the frequency. After ssES, the maximum power of peristalsis in the day-5 ET group showed a statistically significant decrease from the levels observed in the day-3 group. Thus, the sensitivity to electromodulation by ssES may be higher in the day-5 uterus than the day-3 uterus.In this small and preliminary study, the patients were not controlled for age or for the number and quality of embryos transferred. In addition, ssES was performed before the ET procedure. The suppression of uterine peristalses by neuromodulation may not continue after stimulation of the uterus by artificial intrauterine catheterization. Consequently, this study did not stress a statistically significant improvement in pregnancy rates after ssES treatment. However, our preliminary results suggest that the combination of ET with ssES treatment may improve outcomes in ART, especially for day-5 ET. Our next concern is to evaluate the effectiveness of ssES treatment in supporting effective ET. A well-designed prospective randomized control study has been planned. Physiologic uterine contractions occurring throughout the menstrual cycle can be detected by transvaginal ultrasonography or magnetic resonance imaging (1Lyons E.A. Taylor P.J. Zheng X.H. Ballard G. Levi C.S. Kredentser J.V. Characterization of subendometrial myometrial contractions throughout the menstrual cycle in normal fertile women.Fertil Steril. 1991; 55: 771-774Abstract Full Text PDF PubMed Scopus (229) Google Scholar, 2Fujiwara T. Togashi K. Yamaoka T. Nakai A. Kido A. Nishio S. et al.Kinematics of the uterus: cine mode MR imaging.Radiographics. 2004; 24: e19Crossref PubMed Scopus (38) Google Scholar, 3van Gestel I. Ijland M.M. Hoogland H.J. Evers J.L. Endometrial wave-like activity in the non-pregnant uterus.Hum Reprod Update. 2003; 9: 131-138Crossref PubMed Scopus (76) Google Scholar). The direction and frequency of peristalses match the purposes of uterine functions at specific time points in the menstrual cycle. Uterine contractility is associated with fecundity during spontaneous cycles (4Ijland M.M. Evers J.L. Dunselman G.A. Volovics L. Hoogland H.J. Relation between endometrial wavelike activity and fecundability in spontaneous cycles.Fertil Steril. 1997; 67: 492-496Abstract Full Text PDF PubMed Scopus (112) Google Scholar) and influences fertility in assisted reproductive technology (ART) cycles (5Ijland M.M. Hoogland H.J. Dunselman G.A. Lo C.R. Evers J.L. Endometrial wave direction switch and the outcome of in vitro fertilization.Fertil Steril. 1999; 71: 476-481Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). In in vitro fertilization and embryo transfer (IVF-ET) treatment, gentle and meticulous manipulation during transcervical ET is recommended to optimize pregnancy and implantation rates (6Schoolcraft W.B. Surrey E.S. Gardner D.K. Embryo transfer: techniques and variables affecting success.Fertil Steril. 2001; 76: 863-870Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 7Mansour R.T. Aboulghar M.A. Optimizing the embryo transfer technique.Hum Reprod. 2002; 17: 1149-1153Crossref PubMed Scopus (140) Google Scholar). Avoidance of excessive uterine contractions by ET process is required. It was recently demonstrated that uterine peristalsis during menstruation can be suppressed by sacral surface electrical stimulation (ssES), the application of electrical stimulation to the skin above the second and fourth posterior sacral foramen (8Ogura T. Murakami T. Ozawa Y. Seki K. Handa Y. Magnetic resonance imaging of morphological and functional changes of the uterus induced by sacral surface electrical stimulation.Tohoku J Exp Med. 2006; 208: 65-73Crossref PubMed Scopus (3) Google Scholar). Our study investigated the effect of ssES on uterine relaxation on the day of ET. Fifteen women who had experienced one or more IVF-ET treatment failures participated in the study. These women received repeated IVF-ET at either Tohoku University Hospital or Suzuki Memorial Hospital. Before fresh ETs, we initiated human menopausal gonadotropin (hMG) therapy (hMG-Fuji; Fuji Pharmaceuticals, Tokyo, Japan) at a dose of 225 IU/day for the first 8 days of ovarian stimulation. Additional hMG doses and their timing (hCG-Mochida; Mochida Pharmaceuticals, Tokyo, Japan; 10,000 IU, intramuscular) were adjusted according to follicular maturation criteria determined by ultrasonography and serum estradiol levels. For frozen-thawed ET, we administered intramuscular estrogen (Estolmon Depot; Fuji Pharmaceuticals; 10 mg) and progesterone (Progeston Depot; Fuji Pharmaceuticals; 125 mg) replacement therapy. For both patient populations, we gave luteal support with Progeston Depot every fifth day, beginning on the day of oocyte aspiration and continuing to the day of testing pregnancy or until week 12. We performed ssES before the ET procedure using a portable electrical stimulator (Nodoka; Lintec, Tokyo, Japan) and a 5 × 10 cm surface electrode (Lintec). The details of ssES have been described previously elsewhere (8Ogura T. Murakami T. Ozawa Y. Seki K. Handa Y. Magnetic resonance imaging of morphological and functional changes of the uterus induced by sacral surface electrical stimulation.Tohoku J Exp Med. 2006; 208: 65-73Crossref PubMed Scopus (3) Google Scholar). We recorded images obtained by transvaginal ultrasonographic imaging before and after ssES for 3 minutes, after which a physician performed the ET. Image analysis was performed using Ogura's method with modifications (8Ogura T. Murakami T. Ozawa Y. Seki K. Handa Y. Magnetic resonance imaging of morphological and functional changes of the uterus induced by sacral surface electrical stimulation.Tohoku J Exp Med. 2006; 208: 65-73Crossref PubMed Scopus (3) Google Scholar). The region of interest (ROI), which did not exceed the uterine diameter, was fixed at the center of the uterine body adjacent to the internal cervical os. In transvaginal ultrasonographic images, the uterine wall is visualized as two layers, the myometrium and the endometrium; the ultrasonographic brightness value of the myometrium is lower in intensity than that of the endometrium. Cyclic movement of the myometrium within the ROI could be seen as sequential changes in brightness over the ROI in ultrasonography. Fast Fourier transform of the brightness change was then performed, determining that the power spectrum of the brightness changes corresponded with uterine peristalsis. A 1-minute ultrasonographic animation was converted into 175 still pictures. The total image pickup time was 60 seconds. As transvaginal ultrasonography imaging was done at 2.92 f/second, the frequency resolution of Fourier transform was calculated to be 0.00268 Hz. This study was approved by the institutional review boards at the Tohoku University Graduate School of Medicine and Suzuki Memorial Hospital. Written informed consent was obtained from each patient. Our patients' ages ranged from 29 to 47 years old (38.2 ± 5.2 years, mean ± SD). Six women received fresh embryos in controlled ovarian hyperstimulation (COH) cycles, and nine received frozen-thawed ET during hormone replacement cycles. The ET was performed on day 3 in six patients and on day 5 in nine. No one dropped out halfway through the electrostimulation, and no patients had cutaneous manifestations or any other symptoms. Three patients were able to conceive, all of whom were in the day-5 ET group. As a measure of peristalsis, we measured the average power spectrum and the peak frequency of the changes in ROI brightness before and after ssES treatment in all 15 patients. Overall, the maximum power at peak frequency was statistically significantly decreased from 0.121 ± 0.083 before ssES to 0.067 ± 0.050 after ssES (P<.05, paired t-test). The peak frequency decreased from 0.0089 ± 0.0064 Hz (0.53 ± 0.38 times/minute) to 0.0070 ± 0.0022 Hz (0.41 ± 0.13 times/minute) after ssES, although this difference was not statistically significant (P=.28, paired t-test). We did not observe any statistically significant correlation of age with either the peak frequency or the maximum power before or after ssES (data not shown). Hormone status based on the type of cycle, COH, or frozen-thawed ET did not statistically significantly affect uterine peristalsis before or after ssES (Table 1). The time of ssES application, however, did statistically significantly influence uterine contractility by ssES (see Table 1). Although the maximum power before ssES was not statistically significantly different between in the day five ET group and in the day-3 ET group, the maximum power after ssES in the former group was statistically significantly smaller than in the latter group (P<.05, unpaired t-test). As for the peak frequency, both groups showed no statistically significant differences either before or after ssES. Note: COH, controlled ovarian hyperstimulation; FET, frozen-thawed embryo transfer; ssES, sacral surface electrical stimulation. This study confirms the ability of ssES to induce uterine relaxation at the day of ET. We observed that ssES suppressed the intensity of uterine peristalses on the day of ET although ssES could not statistically significantly decrease the frequency. After ssES, the maximum power of peristalsis in the day-5 ET group showed a statistically significant decrease from the levels observed in the day-3 group. Thus, the sensitivity to electromodulation by ssES may be higher in the day-5 uterus than the day-3 uterus. In this small and preliminary study, the patients were not controlled for age or for the number and quality of embryos transferred. In addition, ssES was performed before the ET procedure. The suppression of uterine peristalses by neuromodulation may not continue after stimulation of the uterus by artificial intrauterine catheterization. Consequently, this study did not stress a statistically significant improvement in pregnancy rates after ssES treatment. However, our preliminary results suggest that the combination of ET with ssES treatment may improve outcomes in ART, especially for day-5 ET. Our next concern is to evaluate the effectiveness of ssES treatment in supporting effective ET. A well-designed prospective randomized control study has been planned. The authors thank Dr. Yasunobu Handa, who collaborated in the design and implementation of the study, Dr. Masakuni Suzuki, who welcomed and facilitated this study, and Mr. Ikuo Tachibana, who provided excellent technical assistance. We also thank the women who participated in this study.
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