November 26, 2004
Gamete Intra-Fallopian Transfer or Intrauterine Insemination After Controlled Ovarian Hyperstimulation for Treatment of Infertility Due to Endometriosis
Key words: ENl)OMETRIOSIS, GIFT, INFERTILITY, IUI
ABSTRACTWe compared the effectiveness of gamete intm-Fallopian transfer (GIFT) and intrauterine insemination (IUI) after controlled ovarian hyperstimulation (COH) in the treatment of infertility due to cndometriosis. This was a retrospective study carried out at a tertiary teaching medical center. A total of 127 consecutive patients with endomettiosis were treated with GIFT or IUI after COH between June 1990 and December 1998. Patients were divided into two groups. Group 1 (n = 97) included patients with stages 1 and 2 endometriosis, and group 2 (n-30) included patients with stages 3 and 4 endometriosis. Laparoscopic conservative surgery for endometriosis was performed prior to IUI for patients in both group 1 and group 2. In group 1, 55 patients underwent 95 cycles of IUI after COH and 42 patients underwent 57 cycles of GIFT. In group 2, 14 patients underwent 16 cycles of IUI after COH, while 16patients underwent 22 cycles of GIFT. The stimulation protocol for both GIFT and IUI was mid-luteal pituitary down-regulation with a gonadotropin releasing hormone agonist (GnRH-a) followed by gonaciotmpins. In group 1, the pregnancy rates (GIFT = 50.9%, IUI = 29.4%) and the delivery rates (GIFT = 28.1%, IUI = 14.7%) per cycle were significantly higher in GIFT compared to IUI (p = 0.009 and p = 0.05, respectively). There was no significant differences in the pregnancy rate (GIFT 69%, IUI 50.9%, respectively) or the delivery rate (GIFT 38.1%, IUI 25.5%) per patient. In group 2, there was no significant difference in the pregnancy rate (GIFT 54.5%, IUI 31.3%) or the delivery rate (GIFT 40.9%, IUI 12.5%) per cycle, but the difference in the pregnancy rate (GIFT 75%, IUI 35.7%) and the delivery rate (GIFT 56.3%, IUI 14.3%) per patient was significantly higher in GIFT compared to IUI (p = 0.04 and p = 0.02, respectively). We conclude that, when the same stimulation protocol is used in the early stages of endometriosis, a few cycles of IUI can achieve similar results to GIFT, and therefore should be used first. In advanced stages of endometriosis GIFT appears to be more effective.
Endometriosis - The very word evokes images of pelvic adhesions, infertility and hopelessness. Endometriosis and its association with infertility is partly due to pelvic adhesions. When adhesions involve the tube and ovaries, they may interfere with tubal motility and ovum pickup by the fallopian tube1. With this in mind, clinicians have sought different modalities to help couples with infertility secondary to endometriosis. The techniques most commonly employed include: superovulation with intrauterine insemination (IUI), gamete intra-Fallopian transfer (GIFT), in vitro fertilization and embryo transfer (IVF-ET) or surgery followed by natural intercourse or ovulation induction. Since the beginning of our assisted reproductive technology (ART) unit in 1990, we have observed a significantly higher pregnancy rate after the GIFT procedure for non-tubal infertility compared to IVF-ET (unpublished data). Therefore, whenever ART was indicated for treatment of endometriosis-related infertility, we preferred GIFT over IVF-ET, providing one Fallopian tube was patent. In this study, we compare the effectiveness of two modalities of treatment: GIFT and IUI after controlled ovarian hyperstimulation (COH) in the treatment of infertility due to endometriosis. Our hypothesis was that GIFT would be more effective than IUI after COH in the treatment of endometriosis-related infertility.
MATERIALS AND METHODS
This was a retrospective study of 127 consecutive patients with endometriosis who were treated with GIFT or IUI after COH between June 1990 and December 1998. Patients were classified into two groups based on the stage of endometriosis according to the modified classification of the American Fertility Society. Group 1 (n = 97) were patients with stage I (minimal) or stage II (mild) endometriosis. Group 2 (n = 30) were patients with stage III (moderate) or stage IV (severe) endometriosis. Prior to surgery all patients had a standard infertility work-up, which included a full semen analysis, post-coital testing, documentation of ovulation, hysterosalpingograni and Chlamydia trachomatis antibody titer (IgG and IgM). Day 3 serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured whenever indicated, while serum thyroid stimulating hormone (TSH) and serum prolactin levels were assessed in all patients. Laparoscopic conservative surgery for endometriosis was performed prior to IUI in patients in both group 1 and group 2. When suspicious areas of endometriosis were found, argon beam coagulation (ConMed Corporation, Utica, New York, USA) at 40 W and a 4-1 flow rate was used to coagulate these areas. If endometriosis was found on the pelvic sidewall near the ureter, on the bladder or the bowels, carbon dioxide laser was used, if available; otherwise, argon beam coagulation was used with caution. Other conservative operations performed, if indicated, included salpingo-ovariolysis, excision of endometriomas, fimbrioplasty and salpingostomy. Following surgery, patients with stage I or II endometriosis tried to achieve pregnancy spontaneously or with Clomid treatment (Serono Laboratories, Inc., Randolph, ME, USA) for 3-6 months. If they failed to conceive, had an ovulatory disorder not responding to Clomid, or if there was an element of mild male factor infertility, they were offered IUI after controlled ovarian hyperstimulation or the GIFT procedure. There were a total of 95 cycles in the IUI group of group 1, and 1.6 cycles in the IUI group of group 2. There were a total of 57 cycles in the GIFT group of group 1 and 22 cycles in the GIFT group of group 2. The ovarian stimulation protocol was the same before both IUI and GIFT procedures. Controlled ovarian hyperstimulation was achieved following the pituitary down-regulation protocol using leuprolide acetate (Lupron; Tap Pharmaceuticals, North Chicago, IL, USA) and human menopausal gonadotropin (hMG) (Pergonal; Serono Laboratories, Inc., Randolph, ME, USA) and/or pure FSH (Metrodin; Serono Laboratories, Inc., Randolph Maine, USA) 2. The dosage of gonadotropin was adjusted according to the follicular response as determined by ultrasound scans and serum estradiol levels. When at least three dominant follicles of ≤ 17 mm were seen, human chorionic gonadotropin (hCG) 10000 IU (Profasi, Serono Laboratories, Inc., Randolph ME, USA) was administered 36 h before transvaginal ultrasound-guided oocyte retrieval under modified general anesthesia for the GIFT procedure. Intrauterine insemination was performed using the Kremer catheter (Fertility Technologies, Natick, MA, USA) 42 h after hCG administration and confirmation of ovulation by ultrasound scan. Gamete intra-Fallopian transfer was performed under general anesthesia at the conclusion of the oocytc retrieval. Three or four oocytc complexes, in which the cumulus was trimmed and any excess blood washed off, were introduced along with 200 000 motile sperm into a GIFT transfer catheter (Embryon GIFT Rocket Gcn-X International, Madison, GT, USA)3. This complex was then transferred into the ampullary portion of a preexamined Fallopian tube, approximately 4 cm into the tube. All values were reported as means standard deviations. A χ^sup 2^ test and Student's f test were used where appropriate. A probability value of
Table 1 illustrates demographic and clinical characteristics of patients in both group 1 and group 2. There was no significant difference in age, duration of infertility, percentage of patients with primary infertility, serum estradiol levels or number of ovarian follicles of ≥ 16 mm on day of hCG administration between patients undergoing GIFT or IUI in both groups. Number of follicles ovulated prior to IUI was determined by follicular collapse observed on transvaginal ultrasound that was performed 42 h after hCG administration. Table 1 also illustrates the number of oocytes retrieved and number of oocytes transferred into the Fallopian tubes.
Table 1 Background details
Table 2 shows the pregnancy outcome in group 1 according to the procedure performed (IUI vs. GIFT). Fifty-five patients in group 1 underwent 95 cycles of ItJI with or without COH and 28 patients conceived. The pregnancy rate per cycle and per patient was 29.4% and 50.9%, respectively. The delivery rate per cycle and per patient was 14.7% and 25.5%, respectively. The miscarriage rate, ectopic pregnancy rate and multiple pregnancy rate was 46.4%, 3.8% and 40.9%, respectively. Forty-two patients in group 1 underwent 57 cycles of GIFT and 29 patients conceived. The pregnancy rate per cycle and per patient was 50.9% and 69%, respectively. The delivery rate per cycle and per patient was 28.1% and 38.1%, respectively. The miscarriage rate, ectopic pregnancy rate, and multiple pregnancy rates were 41.3%, 3.4% and 44.8%, respectively. The pregnancy rate and delivery rate per cycle were significantly higher in GIFT compared to IUI (p = 0.009 and p = 0.05, respectively). However, there were no differences in the pregnancy rate or delivery rate per patient between GIFT \and IUI in group 1.
Table 3 shows the pregnancy outcome in group 2 according to the procedure performed (IUI vs. GIFT). Fourteen patients underwent 16 cycles of IUI and five patients conceived. The pregnancy rate per cycle and per patient was 31.3% and 35.7%, respectively. The delivery rate per cycle and per patient was 12.5% and 14.3%, respectively. Miscarnage rate, ectopic pregnancy rate and multiple pregnancy rate was 40%, 20% and 20%, respectively. Sixteen patients underwent 22 cycles of GIFT and 12 patients conceived. The pregnancy rate per cycle and per patient was 54.5% and 75%, respectively. The delivery rate per cycle and per patient was 40.9% and 56.3%, respectively. The miscarriage rate, ectopic pregnancy rate and multiple pregnancy rate was 25%, 0% and 33.3%, respectively. There was no significant difference in the pregnancy rate (p = 0.16) and delivery rate (p = 0.06) per cycle, but the pregnancy rate and the delivery rate per patient were significantly higher in GIFT compared to IUI in group 2 (p = 0.04 and p = 0.02, respectively).
Table 2 Endometriosis stage 1 and stage II
Table 3 Endometriosis - stage III and stage IV
Infertility was once thought of as the end result of cndometriosis. The causes for endometriosis-associated infertility that were postulated were several: pelvic adhesions, disturbed fblliculogenesis, ovulatory dysfunction, accelerated ovum transport, sperm phagocytosis, fertilization impairment, embryotoxicity, defective implantation and inmiunological alterations . Today, with all the advancements made in ART, there are many options available to couples with even advanced stages of endometriosis. During COH there is an increase in the number of preovulatory follicles and an increase in ovarian size, which may bring the ovary into close proximity to the fimbria5. In addition, hyperstimulation may have an effect on tubal vascularity and motility, which may enhance the ovum pick-up mechanism. Furthermore, COH may correct subtle ovulatory disorders that may not be detected by standard investigations, e.g. a luteinized unruptured follicle5. When COH is combined with IUI, the pregnancy rate is increased6. Blumenfeld and Nahhas determined that treatment of sperm prior to insemination enhanced fertilization capacity7, and Alien and colleagues determined that IUI increased the number of sperm reaching the distal oviduct8. In fact, the advantage to insemination over natural intercourse is that, with the swim-up protocol of washing sperm, the motihty of sperm is improved, and with insemination sperm are introduced closer to the oocytes9. In our study, the IUI groups achieved a pregnancy rate of 29.4% for group 1 and 31.3% for group 2. These values were similar to the rate of 19-27% per cycle, quoted by Serhal and co-workers in 1988(10), and later confirmed by Crosignam and co-workers in 1991(11) and Mills and colleagues in 1992(12). It is imperative to indicate that all of our patients in both group 1 and group 2 underwent conservative surgery for endometriosis prior to IUI and COH. Therefore, our results in this study represent the effect of surgical intervention in addition to the effects of IUI and COH. The therapeutic value of laparoscopic conservative surgery for treatment of infertility due to early stages of endometriosis was reported by Marcoux and colleagues in 1997(13). In that randomized controlled trial it was concluded that laparoscopic resection or ablation of minimal or mild endometriosis enhanced fecundity in infertile women13. However, it is important to note that although the fecundity rate increased from 2.4 in the no-treatment group to 4.7 in the surgically treated group, the fecundity rate remained low. Therefore, we believe that, following laparoscopic surgery for infertility-related endometriosis, couples should be encouraged to achieve pregnancy spontaneously for a period of 3-6 months. Thereafter, IUI and COH should be tried to enhance the fecundity rate per cycle. Tummori and associates, in a randomized controlled trial for treatment of infertility associated with early stages of endometriosis, concluded that IUI plus COH was associated with a superior outcome assessed by both crude live-birth rates and proportional hazard analysis14.
However, failure to conceive following ovarian hyperstimulation and IUI can be explained by defective fimbrial ovum pick-up, the luteinized unruptured follicle syndrome or oocytc entrapment, despite fbllicular rupture and failure of fertilization. GIFT is usually recommended after three failed attempts with IUI after COH. The aim of GIFT is to mimic nature by having the clinician place the oocytes and spermatozoa into the Fallopian tube and allowing the fertilized egg to reach the uterine cavity approximately 5 days after its release from the ovary15. In fact, it is thought that simply performing GIFT treats many of the causes of infertility in patients with endometriosis. Anovulation, the luteinized unruptured follicle syndrome, a deficient LH surge, absent ovum pick-up mechanism and macrophage phagocytosis of sperm are all by-passed by supcrovulation, aspiration and the direct introduction of gametes into the ampulla of the Fallopian tube where fertilization can occur. Therefore, GIFT is advocated by many groups as the method of assisted reproduction of choice when at least one normal Fallopian tube is present. In our study, patients who received GIFT achieved a 50% pregnancy rate if they had minimal to mild endometriosis and a 54.5% pregnancy rate with even moderate to severe endometriosis. Our data, therefore, suggest that the stage of endometriosis does not affect the pregnancy rate when GIFT is used for treatment of infertility. Reasonable success with GIFT was described by Mahmood and Templeton16, who reported a combined pregnancy rate of 23.7% (23/ 97) in their review of seven studies in which GIFT was used in patients with endometriosis. Guzick and colleagues postulated that the peritoneal fluid of women with endometriosis might contain mediators of infertility, which may account for low pregnancy outcome in women with endometriosis treated by the GIFT procedure17. Peritoneal fluid from endometriosis patients was found to result in lower sperm motility and velocity than the peritoneal fluid of the control group in their study. They also noted that peritoneal fluid of women with endometriosis may contain factors that interfere with sperm survival, egg capture, fertilization and embryo growth. At our unit, any peritoneal fluid is completely aspirated prior to the GIFT procedure. Fakih and Marshall suggested that, regardless of the stage of endometriosis, if a patient had tubal abnormalities (e.g. tubal convolutions, fimbrial agglutination, phimosis, tubal sacculations, diverticula or tubal adhesions) as a result of endometriosis, the success rate with GIFT was significantly reduced18. The pregnancy rates they reported were 33% for mild, 33% for moderate and 14% for severe endometriosis after the GIFT procedure.
Our miscarriage rate after GIFT in patients with early endometriosis was 41.3% and 25% in patients with moderate or severe endometriosis. In addition, our miscarriage rate after IUI in patients with early endometriosis was 46.4%), while in patients with advanced stages of endometriosis it was 40%. Similar higher miscarriage rates have been previously reported19. Yanushpolsky and colleagues reported a 47% miscarriage rate in women with endometriosis and endometriomas as compared to 14% in controls20. Based on retrospective studies, some authors have postulated a possible cause for increased miscarriage rates in endometriosis. They have suggested that the pregnancy rate after IVF is lower in women with endometriosis than in those without the disease, owing to reduced oocyte quality and decreased fertilization rate20. Pellicer and co-workers suggested a different possible cause: increased interleukin-6 levels in the follicular fluid of women with endometriosis. Their group noted reduced implantation rates in women with endometriosis as compared with controls21. Another possible theory for why patients with endometriosis have a lower birth rate as compared with controls was postulated by Dmowski and associates. They indicated that these particular patients may have autoantibodies that adversely affect the implantation of embryos22. They believe that these autoantibodies could be overcome by administering steroids. It was also suggested that advanced endometriosis might lead to an increased rate of spontaneous abortions. However, Matorras and colleagues, in their prospective analysis of 174 infertile women, showed that there was no correlation between the degree of endometriosis and the rate of spontaneous abortions23. Diaz and co-workers suggested the same: pregnancy, implantation and miscarriage rates were not affected by stage III and IV endometriosis when compared with controls. They believe that poor ART outcome in cases of advanced stages of endometriosis may be related to a reduced number of retrieved oocytes, leading to a reduced number of selected embryos available for transfer24.
Our data may be helpful in counseling patients undergoing endoscopie surgery, followed by IUI plus COH, and patients undergoing ART for the treatment of infertility due to endometriosis. We believe that endoscopie surgery in patients with endometriosis is warranted to diagnose and conservatively treat infertility secondary to endometriosis. Following surgery, IUI plus COH may enhance the fecundity rate per cycle compared to sexual intercourse in natural cycles. Therefore, IUI plus COH should be offered to all patients with early stages and even some patients with advanced stages, especially in young women and in the absence of male factor infertility.
However, there are conflicting reports in the literature regarding the ovarian response to COH after laparoscopic ovarian cystectomy for en\dometrioma. Some reports suggested that, in experienced hands, laparoscopic cystectomy did not negatively affect the ovarian response to COH25-27.
Meanwhile, other reports suggested that potential gonadal damage could be caused by laparoscopic surgery for ovarian endometriosis. Ho and colleagues concluded that surgery for ovarian endometrioma may damage ovarian reserve and may result in poor ovarian response to COH28. In addition, Williams and colleagues reported better pregnancy rates in women with endometriomas during IVF-ET compared to those who had ovarian cystectomy29.
Furthermore, IVF-ET can achieve high pregnancy rates in patients with advanced stages of endometriosis30. The latter can be suspected by vaginal ultrasound scan findings of possible endometriomas in patients with a history of endometriosis.
Therefore, some authors suggest that, for infertile patients with endometriomas, IVF-ET without prior surgery might be a better option to avoid reduction of the ovarian response, especially in the presence of advanced female reproductive age31.
Finally, the data in this report should be interpreted with caution in view of the fact that it was a retrospective analysis. A prospective randomized study is needed to confirm the findings in our study.
Following conservative surgery for endometriosis, patients with early stages of endometriosis should be treated with IUI plus COH for up to three cycles. This protocol can achieve similar results to those of GIFT and therefore should be used first. However, in advanced stages of endometriosis, GIFT appears to be more effective.
The abstract of this paper was presented at the Vl World Congress on Endometriosis, Quebec City, Canada, 1998. Abstract no. P-316, p. 178. The authors would like to thank Cheryl Anderson, Carol Bowman, RN, and Lincla Rutherford for the preparation of this manuscript.
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S. Lodhi, A, Abdel Fattah*, T. Abozaid[dagger], J. Murphy[double dagger], E. Formantin[dagger], M. Sasy[dagger], K. Barber** and M. Abuzeid*,[dagger],,[dagger][dagger]
Department of Obstetrics and Gynecology, St Joseph Mercy- Oakland, Pontiac, MI; *IVF Michigan, Rochester Hills, MI; [dagger]Hurley Medical Center, Flint, MI; [double dagger]Department of Obstetrics and Gynecology, Genesys Regional Medical Center, Grand Blanc, MI; **McLaren Regional Medical Center, Flint, MI; [dagger][dagger]Department of Obstetrics and Gynecology and Reproductive Biology, Michigan State University, College of Human Medicine, East Lansing, MI, USA
Correspondence: Dr M. Abuzcid, Division of Reproductive Endocrinology, Hurley Medical Center, Two Hurley Plaza, Suite 209, Flint, MI 48503-5993, USA
Copyright CRC Press Sep 2004