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• W2095367047 abstract "Local injury to the endometrium prior to controlled ovarian stimulation may considerably improve implantation rates and pregnancy outcomes in intracytoplasmic sperm injection patients with high-order implantation failure (≥4 IVF trials and ≥12 transferred embryos). Local injury to the endometrium prior to controlled ovarian stimulation may considerably improve implantation rates and pregnancy outcomes in intracytoplasmic sperm injection patients with high-order implantation failure (≥4 IVF trials and ≥12 transferred embryos). In vitro fertilization is the only available solution for many couples with various forms of infertility. The embryo implantation step in the IVF procedure is a complex multistage process whose failure represents the primary obstacle to successful IVF in a substantial number of patients (1Cross J.C. Werb Z. Fisher S.J. Implantation and the placenta: key pieces of the development puzzle.Science. 1994; 266: 1508-1518Crossref PubMed Scopus (1171) Google Scholar). Implantation failure can be defined as the repeated transfer of good morphology embryos to a normal uterus without achieving successful implantation and pregnancy. Several approaches have been implemented to improve implantation rates, including thinning of the embryo’s zona pellucida (i.e., assisted hatching) by means of mechanical, chemical, or laser methodologies (2Germond M. Primi M.P. Senn A. Hatching: how to select the clinical indications.Ann NY Acad Sci. 2004; : 1034145-1034151Google Scholar), the use of various types of media to enhance the adhesiveness of the blastocyst (e.g., fibrin sealant and hyaluronic acid) (3Bar-Hava I. Krissi H. Ashkenazi J. Orvieto R. Shelef M. Ben-Rafael Z. Fibrin glue improves pregnancy rates in women of advanced reproductive age and in patients in whom in vitro fertilization attempts repeatedly fail.Fertil Steril. 1999; 71: 821-824Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 4Simon A. Safran A. Revel A. Alzenman E. Reubinoff B. Porat-Katz A. et al.Hyaluronic acid can successfully replace albumin as the sole acromolecule in a human embryo transfer medium.Fertil Steril. 2003; 79: 1434-1438Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar), and changes in the implantation milieu by laparoscopic placement of zygotes in the fallopian tubes (ZIFT) (5Aslan D. Elizur S.E. Levron J. Shulman A. Lerner-Geva L. Bider D. et al.Comparison of zygote intrafallopian tube transfer and transcervical uterine embryo transfer in patients with repeated implantation failure.Eur J Obstet Gynecol Reprod Biol. 2005; 122: 191-194Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). The actual efficacy of all these procedures in improving implantation rates and pregnancy outcomes remains controversial (6Urman B. Recurrent implantation failure in assisted reproduction: how to counsel and manage A. General considerations and treatment options that may benefit the couple. B. Treatment options that have not been proven to benefit the couple.RBM Online. 2005; 11: 371-391Scopus (80) Google Scholar). The only reported clinical study on endometrial injury and its impact on pregnancy rate (PR) resulted in more than double the number of pregnancies in a group of 45 out of 134 patients who failed to conceive during one or more cycles of IVF-ET (7Barash A. Dekel N. Fieldust S. Segal I. Schechtman E. Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization.Fertil Steril. 2003; 79: 1317-1322Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar). By transferring a similar number of embryos in the study and control groups, the authors achieved an implantation rate of 28% versus 14%, a clinical PR of 67% versus 30%, and a live-birth rate per ET of 49% versus 23%, respectively. They hypothesized that this procedure has the potential to reduce the number of IVF attempts and minimize the risks of hyperstimulation, and to do so with obvious clinical and economic benefits (7Barash A. Dekel N. Fieldust S. Segal I. Schechtman E. Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization.Fertil Steril. 2003; 79: 1317-1322Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar). We evaluated the influence of local injury to the endometrium in a selected group of ICSI patients with high-order implantation failure. From June 2003 to June 2005, 120 couples with high-order implantation failure in ICSI were referred for counseling for further treatments. High-order implantation failure was defined as ≥4 unsuccessful ETs of “fresh” embryos and the cumulative transfer of at least 12 “fresh” embryos per patient without the achievement of a clinical pregnancy. Workup of repeated implantation failures included a search for intrauterine pathology (intrauterine adhesions, submucous myomas, or other uterine anomalies) by diagnostic hysteroscopy, an autoimmune serology profile, and a thrombophilia assessment. Cytologic examination was offered to all couples, but was performed in only 65 couples due to financial restrictions (8Raziel A. Friedler S. Schachter M. Kasterstein E. Strassburger D. Ron-El R. Increased frequency of female partner chromosomal abnormalities in patients with high-order implantation failure after in vitro fertilization.Fertil Steril. 2002; 78: 515-519Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Couples in whom there was no evidence of pathology received an offer to undergo endometrial sampling shortly before their next assisted reproduction procedure. Patients >40 years of age and those with a body mass index (BMI) >29 kg/m2 or <18 kg/m2 were excluded, as were poor responders (defined as day 3 serum FSH level >12 IU/L or <4 follicles on the hCG day in previous IVF cycles). Other exclusion criteria were possible causes for impaired implantation, such as a systemic disease, uterine malformations, presence of endometriomas, or ultrasonographic evidence of hydrosalpinx. Patients gave written informed consent to undergo endometrial sampling. They were instructed to use nonhormonal means of contraception during the current cycle. Possible complications related to the sampling procedure, such as infection or persistent bleeding, were documented. The women who opted for IVF without a biopsy comprised the control group. Endometrial biopsy was done with a biopsy catheter (Pipelle; de Cornier, Prodimed, Neuilly-en-Thelle, France) as follows: the Pipelle was inserted through the cervical os and advanced gently until resistance was felt. The inner piston of the device was then withdrawn to create suction, and the endometrial sample was obtained by moving the Pipelle up and down approximately 2–3 cm within the uterine cavity, but not beyond the cervical os. This procedure was repeated at least four times, and the device was rotated 360° to ensure adequate coverage of the area. Endometrial biopsy was performed on days 21 and 26 of the spontaneous cycle, when GnRH agonist use begun. In five anovulatory patients, a combination of 11 tablets of 2 mg E2 valerate only and 10 tablets of 2 mg E2 valerate with 0.5 mg Norgestrel (Progyluton; Schering, AG/Berlin, Germany), was administered to mimic a spontaneous cycle, and biopsies were performed on days 14 and 19. Controlled ovarian hyperstimulation was performed by the daily luteal subcutaneous administration of 0.1 mg triptorelin (Decapeptyl; Ferring, Malmö, Sweden) 600 μg intranasal napharelin (Synarel; Delpharm, France), 2 weeks prior to individualized administration of hMG (Menogon; Ferring, Mannheim, Germany) or recombinant preparations (Gonal F; Serono, Aubans, Switzerland, and Puregon; Organon, Lausanne, Switzerland). Oocyte retrieval was performed by the vaginal route guided by ultrasound, with the patient under general anesthesia. The morphology of each aspirated oocyte was noted after denudation with hyaluronidase. Intracytoplasmic sperm injection was performed in all cycles, in an effort to maximize the number of available embryos for transfer according to the methodology of Van Steirteghem et al. (9Van Steirteghem A.C. Nagy Z. Joris H. High fertilization and implantation rates after intracytoplasmic sperm injection.Hum Reprod. 1993; 8: 1061-1066Crossref PubMed Scopus (1128) Google Scholar). Embryos were considered suitable for transfer and introduced into the uterine cavity 48–72 hours after the ICSI procedure. Embryo transfer was performed with a Wallace catheter (Simcare, Lancing, United Kingdom). The PR was calculated solely by clinical pregnancies. Early abortion was defined as a pregnancy loss that took place before 12 weeks of gestation, and late abortion as a pregnancy loss that took place between 12–20 weeks of gestation. Three of 63 biopsy-treated couples with repeated implantation failure were excluded because they did not reach the stage of ET. All 57 controls reached the stage of ET, yielding a total of 117 patients for study. Satellite chromosomes were found in 2 of 65 cases in which cytologic examination was carried out: 46,XX 21ps+, 22ps+ and 46,XX 1qh+, 15ps+. The former patient’s husband’s karyotype was, surprisingly, 46,XY 22ps+. One patient displayed hyperchromatic chromosomes, i.e., 46,XX 9(q12–q13). These findings were interpreted by the genetic team as normal variants frequently found in our population. Patient characteristics were similar between the biopsy-treated group and controls (Table 1). The mean number of treatment cycles per patient and total number of transferred embryos prior to IVF were, however, significantly higher in the study group compared with controls (Table 1). A relatively high number of embryos were transferred in the study and control women (Table 1). No associated complications were reported among the 126 endometrial biopsies. No pathology other than “secretory endometrium” was found in the pathological examination of the biopsies (all 60 cases).TABLE 1Characteristics, controlled ovarian hyperstimulation, and ICSI outcome of patients with implantation failure: comparison between patients who underwent endometrial biopsy prior to treatment and controls.CharacteristicBiopsy-treated patients (n = 60)aPatients with endometrial biopsy before controlled ovarian hyperstimulation for ICSI.Control patients (n = 57)bPatients with no procedure before controlled ovarian hyperstimulation for ICSI.P valuecStudent’s t-test.Mean age (y)33.1 ± 4.931.9 ± 4.2NSWeight (kg)63.6 ± 16.367.4 ± 14.0NSBMI24.6 ± 1.825.7 ± 1.7NSFSH (mIU/mL)6.0 ± 2.65.9 ± 1.8NSLH (mIU/mL)5.5 ± 3.34.7 ± 2.7NSInfertility duration (y)4.9 ± 2.95.5 ± 3.0NSTotal no. of previously transferred embryos21.5 ± 8.916 ± 4.9<.001Total no. of previous ICSI treatment cycles7.0 ± 1.95.7 ± 1.0<.003Gonadotropin ampoules36.7 ± 11.236.2 ± 17.0NSGonadotropin days11.0 ± 1.611.5 ± 2.8NSE2 on hCG day (pg/mL)2,072 ± 1,0932,041 ± 1,139NSP4 on hCG day (ng/mL)1.3 ± 0.61.4 ± 0.6NSNo. of follicles12.7 ± 5.812.4 ± 4.6NSNo. of oocytes11.5 ± 5.511.0 ± 4.9NSNo. of fertilizations7.2 ± 3.96.0 ± 3.1NSNo. of all embryos6.9 ± 4.05.8 ± 3.0NSNo. of embryos per transfer3.3 ± 0.93.8 ± 0.6NSNote: Values are mean ± SE. NS = not significant.Raziel. Endometrial injury to improve implantation. Fertil Steril 2007.a Patients with endometrial biopsy before controlled ovarian hyperstimulation for ICSI.b Patients with no procedure before controlled ovarian hyperstimulation for ICSI.c Student’s t-test. Open table in a new tab Note: Values are mean ± SE. NS = not significant. Raziel. Endometrial injury to improve implantation. Fertil Steril 2007. The distribution in the percentage of “good,” “fair,” and “poor” quality embryos (according to the classification by Plachot et al. [10Plachot M. Junca A.M. Mandelbaum J. Cohen J. Salat-Baroux J. Dalge C. Timing of in vitro fertilization of cumulus-free and cumulus-enclosed human oocytes.Hum Reprod. 1986; 1: 237-240PubMed Google Scholar]) among study patients and controls was comparable: 56%, 42%, and 2% in the biopsy-treated patients, compared with 48%, 48%, and 4% in the control group, respectively. The reproductive performance of the 60 ICSI patients with implantation failure and prior biopsies was significantly more favorable statistically, but not clinically, compared with that of the controls: the respective rates were 11% versus 4% (P=.02) for implantation, 30% versus 12% (P=.02) for pregnancy, and 22% versus 8% (P=.07) for ongoing pregnancies. The abortion rate was 28% for each group. We evaluated the pregnancy outcome of 117 ICSI patients with repeated failure. Endometrial scratching was performed twice, in the luteal phase, preceded by ovarian stimulation for ICSI in 63 patients. We found significantly higher rates of implantation and ongoing pregnancies among the patients with endometrial scratching compared with those who did not undergo the procedure prior to ovarian stimulation. We considered the 30% PR in such a group with a characteristically poor prognosis (mean number of 7 previous unsuccessful IVF trials, and a mean total number of 22 transferred embryos in previous treatment cycles) as an impressive finding. The association between scratching of the endometrium and the improvement of implantation is based on old evidence coming from animal studies that showed decidualization and subsequently improved receptivity of the uterus induced by local injury to the endometrium (11Loeb L. Über die experimentelle Erzeugung von Knoten von Deciduagewebe in dem Uterus des Meerschweinchens nach stattgefundener Copulation [The experimental proof changes in the uterine decidua of guinea pig after mating].Zentralbl Allg Pathol. 1907; 18: 563-565Google Scholar). Another form of trauma to the endometrium, intrauterine injections of oil, was reported in rats (12Humphrey K.W. Interaction between estrogen-17β and progesterone on the induction of deciduomata in ovariectomized mice.Aust J Biol Sci. 1969; 22: 689-699PubMed Google Scholar). Experiments in rats emphasized the possible involvement of histamine secreted by the uterus in response to trauma (13Finn C.A. Martin L. Endocrine control of the timing of endometrial sensitivity to a decidual stimulus.Biol Reprod. 1972; 7: 82-86Crossref PubMed Scopus (132) Google Scholar), and it was suggested that antihistamine treatment in rats may inhibit such a decidual response induced by a local injury (14Shelesnyak M.C. Marcus G.J. The study of nidation.in: Shelesnyak M.C. Marcus G.J. Ovum implantation, its hormonal, biochemical, neurophysiological and immunological bases. Science Publishers, Gordon and Breach, New York1967: 3-30Google Scholar). Another mechanism for increased receptivity of the endometrium is the wound-healing effect caused by endometrial sampling (15Sharkey A. Cytokines and implantation.Rev Reprod. 1998; 3: 52-61Crossref PubMed Scopus (154) Google Scholar). Various cytokines and growth factors that are secreted in the wound-healing process might have an additional favorable effect on uterine receptivity, and thus might improve the implantation of the blastocyst and PRs (16Basak S. Dubanchet S. Zourbas S. Chaouat G. Das C. Expression of pro-inflammatory cytokines in mouse blastocysts during implantation: modulation by steroid hormones.Am J Reprod Immunol. 2002; 47: 2-11Crossref PubMed Scopus (56) Google Scholar). Following these principles in humans, Barash et al. (7Barash A. Dekel N. Fieldust S. Segal I. Schechtman E. Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization.Fertil Steril. 2003; 79: 1317-1322Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar) reported a clinical PR of 67% and a live-birth rate of 49% in a group of 45 patients with repeated IVF failures who underwent endometrial sampling before stimulation for IVF. Their results are superior to ours, with a clinical PR of 30%, and 22% ongoing pregnancies. Since the mean age of their biopsied patients and ours (33.8 ± 5.8 vs. 33.1 ± 4.9 years, respectively) and their mean number of transferred embryos per patient and ours (3.4 ± 1.0 vs. 3.3 ± 0.9, respectively) were so similar, we assume that the difference lies in the previous history/performance of the studied patients. The number of failing cycles in Barash et al. (7Barash A. Dekel N. Fieldust S. Segal I. Schechtman E. Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization.Fertil Steril. 2003; 79: 1317-1322Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar) was 4.0 ± 2.0 (range, 1–10), compared with 7.0 ± 1.9 (range, 4–11) in our current study. Twenty-two embryos per patient (range, 13–42) were transferred before allocating the patients to endometrial biopsy. No data were provided on the total number of transferred embryos in their study. We assume that our study group represents a more selected group of “high-order” implantation failures with very low pregnancy potential compared with theirs, and thus a PR of 30%, induced by endometrial scratching, is highly encouraging. Between 6–8 cell embryos were transferred in 58% of the cases in Barash et al. (7Barash A. Dekel N. Fieldust S. Segal I. Schechtman E. Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization.Fertil Steril. 2003; 79: 1317-1322Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar), a blastocyst transfer was performed in 15%, and a double transfer was done in the remaining 27%. All embryos in our study group were within 48–72 hours from oocyte retrieval. We performed two luteal biopsies on days 21 and 26 of the cycle prior to ovarian hyperstimulation, while Barash et al. (7Barash A. Dekel N. Fieldust S. Segal I. Schechtman E. Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization.Fertil Steril. 2003; 79: 1317-1322Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar) performed four. The rationale for luteal biopsies was based on animal studies that showed the beneficial effect of injury-induced decidualization when the trauma to the endometrium was done in the luteal phase. The optimal number and exact timing for performing biopsies in patients with repeated failure in IVF await further studies. We are aware of the limitation of our study having been conducted on self-selected patients. Much has been written on the importance of the equal chance of patients being assigned to any group at time of selection (17Trout S.E. McDonough P.G. Need bulletproof randomization.Fertil Steril. 2003; 80: 1535-1536Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar), best accomplished by randomized computer selection. We could not withhold a change in the treatment protocol in patients with ≥4 prior IVF failures, especially when they were aware of the existence of a procedure, even an experimental one, that resulted in a 49% live-birth rate per embryo transfer elsewhere. There are still various unanswered questions concerning endometrial scratching in the setting of IVF. After one successful pregnancy and delivery, is there any need to perform a repeated endometrial biopsy before the next IVF treatment? Also, should the biopsy and ovarian stimulation be performed without any gap of time in between (as done in this study), or is there any disadvantage in waiting and, if so, for how long? We conclude that an embryo scratching preceded by ICSI seems to be an efficient and safe procedure that may improve the PR of ICSI patients with implantation failure. Our results are preliminary. If the same results are validated by a larger study on a randomized group of patients, the routine performance of endometrial sampling in similar patients should be considered. This procedure is easy to perform, and is apparently free of complications. The authors thank Ms. Esther Eshkol for editorial assistance." @default.
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• W2095367047 title "Favorable influence of local injury to the endometrium in intracytoplasmic sperm injection patients with high-order implantation failure" @default.
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