Aspiration of ovarian endometriomas before intracytoplasmic sperm injection

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1 FERTILITY AND STERILITY VOL. 82, NO. 3, SEPTEMBER 2004 Copyright 2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Aspiration of ovarian s before intracytoplasmic sperm injection Recai Pabuccu, M.D., a Gogsen Onalan, M.D., b Umit Goktolga, M.D., a Tansu Kucuk, M.D. a Esat Orhon, M.D., a and Temel Ceyhan, M.D. a Gulhane School of Medicine, Ankara, Turkey Received October 8, 2003; revised and accepted February 2, Presented in part at the Annual Meeting of the European Society of Human Reproduction, Madrid, Spain, June 29 July 2, Reprint requests: Recai Pabuccu, M.D., Department of Obstetrics and Gynecology, Gulhane School of Medicine, 06018, Etlik, Ankara, Turkey (FAX: ; gogsenonalan@yahoo.com). a Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Gulhane School of Medicine. b Ankara Training and Research Hospital, Obstetrics and Gynecology Clinic, Ankara, Turkey /04/$30.00 doi: /j.fertnstert Objective: To investigate whether aspiration of ovarian s before controlled ovarian stimulation (COH) improves intracytoplasmic sperm injection (ICSI) outcomes. Design: Prospective study. Setting: University hospital. Patient(s): A prospective analysis of 171 patients with ovarian endometriosis and tubal factor infertility were divided into four groups: aspiration of s at the beginning of COH in patients with ovarian s and no history of previous surgery (n 41) (group 1); nonaspirated s (n 40) (group 2); history of ovarian surgery for s in patients without ovarian s at the beginning of COH (n 44) (group 3); and tubal factor infertility (n 46) (control group 4). Intervention(s): Aspiration of s. Main Outcome Measure(s): Clinical parameters, characteristics of COH, and ICSI results were analyzed. Result(s): We observed higher levels of E 2 on the day of hcg injection after aspiration of s compared with nonaspirated s. When we compared all s and tubal factor (control) groups, we observed a lower number of total follicles ( 17 mm) and metaphase II (MII) oocytes in nonaspirated and resected groups and a longer duration of COH in the nonaspirated group compared with the tubal factor group. Implantation and clinical pregnancy rates were similar among all groups. Conclusion(s): In the current study, all patients with s had significantly lower numbers of MII oocytes compared with those in patients with tubal factor infertility. We propose that aspiration of s before COH neither reduces the amount of gonadotropins nor increases the number of follicles 17 mm, the number of MII oocytes retrieved, the implantation rates, or the clinical pregnancy rates. Resection of small s (1 6 cm) may not present any additional benefits to the IVF-ICSI cycle outcomes. (Fertil Steril 2004;82: by American Society for Reproductive Medicine.) Key Words: Endometrioma, aspiration, IVF-ICSI outcomes Endometriosis is a challenging disease that is encountered in one-third of infertile women; however, the association between endometriosis and infertility is complex and controversial, especially in mild and moderate forms (1). Using IVF, considerable recent evidence suggests four principal factors likely to contribute to endometriosis-associated infertility. These etiologies include impaired folliculogenesis, decreased fertilization, immunologic factors, and implantation defects. Ovarian s may also be a risk factor for the ovarian reserve (2). The effects of these etiologies can be overcome by the use of assisted reproductive techniques. In vitro fertilization has been reported to yield better conception rates in endometriosis-associated infertility (3, 4). However, some studies report equal pregnancy rates but lower fertilization (5) and implantation rates in endometriosis compared with tubal factor or unexplained infertility (6). During intracytoplasmic sperm injection (ICSI) for male factor infertility, endometriosis leads to a decreased number of retrieved oocytes, while the fertilization, implantation, and pregnancy rates remain unaffected compared with cases without endometriosis (7, 8). Such data indirectly suggest that ICSI may be a useful technique by which to overcome fertilization defects in selected women with endometriosis (2). There are few data reported in the literature about the management of endometriosis during 705

2 ICSI cycles. The aim of this study is to investigate whether aspiration of ovarian s before controlled ovarian stimulation improves the prognosis of ICSI cycles. MATERIALS AND METHODS Between January 1999 and August 2002, 171 patients went through 171 ICSI cycles with ejaculated sperm at the Assisted Reproduction Unit of the Gulhane School of Medicine Department of Obstetrics and Gynecology. These patients were divided into four groups: aspiration of s at the beginning of controlled ovarian hyperstimulation (COH) in patients with ovarian s and no history of previous surgery (n 41) (group 1); nonaspirated s (n 40) (group 2); history of ovarian surgery for s in patients without ovarian s at the beginning of COH (n 44) (group 3); and tubal factor infertility (n 46) (control group 4). The study was approved by the Ethics Committee of the Gulhane School of Medicine. Patients were randomized into aspiration and nonaspiration groups according to the randomization list, which was generated by computer in blocks of 10. Written informed consent was obtained from all patients, and personal clinical information was concealed. Group 1 patients underwent transvaginal aspiration of s. They were invited to our IVF unit on day 3 of the menstrual cycle (starting day for COH). After vaginal cleansing by povidone iodine solution and paracervical local anesthetic injection, we performed aspiration of endometriotic cysts (thick, chocolate-colored fluid content) transvaginally by ultrasound-guided puncture. We flushed the cyst several times using 0.9% saline solution and terminated the procedure when the cyst was totally aspirated. A single dose of ceftazidime 2 g was injected IM after the aspiration. Aspirated material was sent for cytopathologic examination (9, 10). Blood samples for CA125 were taken from group 2 patients on day 3 of the menstrual cycle to confirm the diagnosis of s. Group 3 patients had a history of resection of ovarian s by laparoscopy or laparotomy no more than 4 years before the treatment cycles (with an operative report consistent with biopsy-proven endometriosis: bilateral, n 21; and unilateral, n 23). Endometriomas were resected twice in 11 women and once in 33 women. According to the revised American Society for Reproductive Medicine classification, 36 women had stage III and the rest stage IV endometriosis. No patient in the control group had endometriosis as documented by laparoscopy or laparotomy performed no more than 5 years before the treatment cycle. Patients with hydrosalpinx, documented tuberculosis, or a history of ovarian surgery were excluded from the control group. All patients had a normal uterine cavity documented by either hysterosalpingography and/or hysteroscopy no more than 1 year before the ICSI procedure. All patients had the same pituitary down-regulation, ovarian stimulation, oocyte retrieval, embryo transfer (ET), implantation, and luteal support protocols. All couples went through the ICSI procedure with ejaculated sperm using the same media and semen preparation methods. Thaw cycles were excluded from the study. Pituitary desensitization was performed as a long protocol. Triptrolein 100 g (decapeptyl daily 0.1) was injected in all patients SC in the arm starting on day 21 of the previous cycle. On the third day of the menstrual cycle, the triptrolein dose was decreased to 50 g. Group 1 patients underwent transvaginal aspiration on the day that the GnRH-a dose was decreased by half. Controlled ovarian hyperstimulation was also started with recombinant FSH (rec-fhs; Gonal F, Serono, Aubonne, Switzerland) 300 IU on the third day of the menstrual cycle. After the observation of at least three follicles larger than 11 mm and serum E 2 levels higher than 450 pg/ml, the FSH dose was decreased according to the step-down regimen. After the development of at least three follicles larger than 17 mm and serum E 2 levels higher than 500 pg/ml, 10,000 IU hcg (Profasi; Serono) was injected. Oocyte retrieval was performed 35 hours after hcg injection. An oocyte pick-up set with a 17 guage needle was used for oocyte retrieval under local anesthesia. Oocyte-corona complexes were denuded, the ICSI procedure was performed after 2 hours of incubation, and ET was done on day 3 or 5. All cycles included fresh transfers. The ET policy largely depended on the female age, number and quality of embryos developed, and history of prior assisted conception attempts. Overall, if the female age was 30 years, up to two topquality embryos were transferred. If the female age was between 30 and 36 years, up to three embryos were transferred. The transfer protocol was individualized for each of the above-mentioned age groups in the presence of poorgrade embryos and history of prior unsuccessful assisted conception attempts. In our assisted conception unit, methylprednisolone (16 mg/day) and doxycycline (100 mg b.i.d.) were administered to all patients as a routine protocol for 4 days, starting on the day of oocyte retrieval, to support implantation. All patients had luteal support with micronized vaginal P after ET. Clinical pregnancy was defined as the presence of at least one gestational sac with detectable fetal cardiac activity by transvaginal ultrasound. The implantation rate was calculated as the total number of gestational sacs divided by the total number of embryos transferred for each group analyzed. Data were presented as mean SD. Kruskal-Wallis and Mann-Whitney U-tests were used where appropriate. P.05 was considered statistically significant. 706 Pabuccu et al. Endometriomas and ICSI outcome Vol. 82, No. 3, September 2004

3 TABLE 1 Clinical details of the 171 patients in the study. Aspirated (n 41) Non-aspirated (n 40) History of (n 44) Tubal factor infertility (n 46) P Age (y) Duration of infertility (y) Body mass index (kg/m 2 ) Day 2 FSH (IU/mL) Day2E 2 (pg/ml) No. of antral follicles Diameter (mm) Bilateral (%) Note: Values are means SD. RESULTS Patients in all study groups were similar with respect to age, duration of infertility, FSH and E 2 levels on day 2, number of antral follicles, and body mass index (Table 1). The characteristics of COH in the four groups are shown in Table 2. A significantly longer duration of COH was observed in patients with nonaspirated s ( days) compared with women in the tubal factor infertility group ( days) (P.01). The number of follicles 17 mm was significantly lower in patients with nonaspirated s and resected s ( , , respectively) compared with those in the tubal factor infertility group ( ) (P.05). Estradiol levels on the day of hcg injection were significantly higher in patients with aspirated s (1, pg/ml) compared with those with nonaspirated s ( pg/ml) (P.01). All groups except the aspirated group (1, pg/ml) had significantly lower E 2 levels on the day of hcg injection compared with the tubal factor group (1, pg/ml) (nonaspirated group, pg/ml; resected group, 1, pg/ml; P.05). The rest of the characteristics for COH were similar in all four groups. The results of ICSI-ET cycles in the four groups are summarized in Table 3. Patients with tubal factor infertility had more metaphase II oocytes ( ) compared with all patients with s (P.01) (aspirated, ; nonaspirated, ; resected, ). Clinical pregnancy rates were similar in all groups: 24%, 20%, 27% in aspirated, nonaspirated, and resected groups, respectively, and 30% in the tubal factor infertility group (Fig. 1). Implantation rates were also similar among the study groups; 13%, 13%, 18%, and 14% in the aspirated, nonaspirated, resected, and tubal factor infertility groups, respectively (Fig. 2). In all study groups, women who became pregnant had higher numbers of antral follicles ( vs ), higher levels of E 2 on the day of hcg injection (1, TABLE 2 Characteristics of controlled ovarian hyperstimulation in the four groups with ICSI cycles. Aspirated (n 41) Non-aspirated (n 40) Resected (n 44) Tubal factor infertility (n 46) Duration of ovarian stimulation (d) a a Total rec-fsh ampules used per cycle Total follicle no. ( 17 mm) a b a,b E 2 level on hcg day (pg/ml) 1, c a,b 1, c 1, a,c a P.05, nonaspirated group vs. tubal factor infertility group. b P.05, resected group vs. tubal factor infertility group. c P.05, aspirated group vs. nonaspirated group. FERTILITY & STERILITY 707

4 TABLE 3 Results of ICSI-ET cycles among all four groups. Aspirated infertility (n 41) Nonaspirated (n 40) Resected (n 44) Tubal factor infertility (n 46) Mean fertilization rate (%) Metaphase II oocytes a b c b Implantation rate (%) Clinical pregnancy (%) Spontaneous abortion (%) a P.05, aspirated group vs. tubal factor infertility group. b P.05, nonaspirated group vs. tubal factor infertility group. c P.05, resected group vs. tubal factor infertility group. vs. 1, pg/ml), lower duration of infertility (4.4 3 vs years), and younger age ( vs years) compared with those who were not able to conceive (P.05). The rest of the study characteristics were similar among all four groups (Table 4). DISCUSSION Various alterations within the immunologic milieu of the peritoneal cavity create a hostile environment in endometriosis for successful gamete interaction and early embryo development (11, 12). Several approaches have been used to achieve conception in this group of patients, including expectant management, surgical resection, medical therapy, COH, and assisted reproductive technologies. Surgical resection of s, either by laparotomy or laparoscopy, is equally effective in eradicating endometriosis; however, if resection of s is not sufficiently radical, the risk of recurrence is high (13, 14). On the other hand, the radical approach may result in diminished ovarian reserves with a poor response to gonadotropins and a fewer number of oocytes. Clinicians should be more conservative in preserving the oocyte content of ovaries. The increased interest in safe and cost-effective outpatient therapy of s makes ultrasound-guided aspiration of this entity an attractive option to improve reproductive outcome before ovulation induction (15). FIGURE 1 Clinical pregnancy rate in all groups with ICSI cycles. Bars represent the clinical pregnancy rate (%). 1: Patients with aspiration of s at the beginning of COH (n 41); 2: patients with nonaspirated s (n 40); 3: women with a history of ovarian surgery for s with no ovarian s at the start of treatment (n 44); 4: women with tubal factor infertility as a control group (n 46). FIGURE 2 Implantation rate in all groups with ICSI cycles. Bars represent implantation rates (the total number of gestational sacs divided by the total number of embryos transferred for each group analyzed) (%). 1: Patients with aspiration of s at the beginning of COH (n 41); 2: patients with nonaspirated s (n 40); 3: women with a history of ovarian surgery for s with no ovarian s at the start of treatment (n 44); 4: women with tubal factor infertility as a control group (n 46). 708 Pabuccu et al. Endometriomas and ICSI outcome Vol. 82, No. 3, September 2004

5 TABLE 4 Characteristics of pregnant and nonpregnant patients. Pregnant patients (n 43) Nonpregnant patients (n 128) Age (y) a a Duration of infertility (y) a a Day 2 FSH (IU/mL) Day2E 2 (IU/mL) Body mass index (kg/m 2 ) No. of antral follicles a a Duration of ovarian stimulation (d) Total rec-fsh ampules used per cycle Total follicle no. 17 mm E 2 level on hcg day (pg/ml) 1, a 1, a Metaphase II oocytes Fertilization rate (%) Diameter of (mm) Bilateral (%) a P.05. According to our data, all studied parameters related to ovarian stimulation in groups, except E 2 levels on the day of hcg injection, are similar to those in women without ovarian s. Estradiol levels on the day of hcg injection are significantly higher in patients going through aspiration of s compared with those without aspiration. Nonaspirated and resected groups have significantly lower levels of E 2 compared with those in the tubal group. Studies with in vitro cultures of granulosa cells demonstrate decreased E 2 synthesis in women with endometriosis (16). However, there are also contradictory results including unaffected E 2 levels and surprisingly more favorable E 2 /T ratios in patients with endometriosis (17). In the current study, higher levels of E 2 in the aspiration group may be explained by the loss of unhealthy tissue, which may affect the intraovarian mechanism of follicle selection and oocyte maturation (18, 19). Furthermore, it can be argued that ultrasound-guided aspiration of s decompresses the mass effect of biochemically inactive end-stage disease with an increase in the intraovarian vascularization and relieves the deleterious paracrine effect of s on oocyte maturation. Assisted reproductive technologies, mainly IVF, should theoretically maximize fertility rates by removing gametes and zygotes from the hostile peritoneal environment and bypassing the abnormal pelvic anatomy associated with endometriosis. Numerous studies compared IVF outcomes in women with endometriosis with other diagnostics entities (3 6, 20). The impact of s on IVF outcomes has been addressed in several studies (18, 21 23). Al-Azemi et al. (18) described reduced ovarian response, which required higher doses of gonadotropin treatment in patients with s. In the current study, we observed a longer COH duration without higher gonadotropin doses in patients with nonaspirated s compared with those in the tubal factor infertility group. Yanushpolsky et al. (21) reported a higher incidence of pregnancy loss and adverse effects on the number of oocytes retrieved with transvaginal ultrasound guided techniques and on the embryo quality in patients with endometriosis. Cumulative pregnancy and live birth rates were unaffected in endometriosis cases. In contrast, Olivennes et al. (22) were not able to demonstrate any effect of persistent s on COH and IVF. A recent study by Suganuma et al. (23) is the only published study to analyze the impact of pretreatment ovarian endometrial cyst aspiration on IVF and ICSI outcomes. Using a prospective study design, infertile women with s who underwent IVF-ICSI were divided into three groups as follows: [1] 62 IVF and 25 ICSI cycles in 36 patients who underwent laparotomy or laparoscopy (surgery group); [2] 35 IVF and 18 ICSI cycles in 23 patients for whom the content was aspirated under transvaginal ultrasound imaging and treated with or without alcohol fixation (cyst aspirated group); and [3] 30 IVF and 18 ICSI cycles in 20 patients who did not undergo pretreatment and who had confirmed ovarian endometriosis at oocyte retrieval (no treatment group). They found that pretreatment for ovarian endometrial cyst reduces the number of retrieved oocytes. Although oocyte quality as a measure of mature oocytes was not affected by the presence of s, the fertilization rate was improved by cyst aspiration. However, differences between the IVF and ICSI outcomes were not mentioned. Unfortunately, none of these investigators correlated size with outcome. In the present study, we observed patients with nonaspirated s to have lower levels of E 2 on the day of hcg injection and lower numbers of follicles ( 17mm) and metaphase II oocytes compared with those with tubal factor infertility. We did not observe any negative impact of s on implantation and clinical pregnancy rates. Surrey et al. (24) propose that it may be difficult to differentiate the impact of an isolated per se on the cycle outcome because patients with these lesions may have concomitant peritoneal disease as a confounding variable. They suggest that it may be logical to make every effort to avoid aspiration of an during the oocyte retrieval procedures to prevent rupture and inadvertent exposure. Surgical resection of s before IVF has been evaluated by several studies in the literature. Canis et al. (25) reported outcomes in a series of 41 patients who underwent FERTILITY & STERILITY 709

6 laparoscopic resection of large ( 3 cm in diameter) (s) (unilateral in 30 patients and bilateral in 11 patients) before IVF cycles in comparison with 139 endometriosis cases without s and 59 patients with tubal factor infertility. Despite extensive ovarian surgery, they did not observe any significant change in the number of oocytes or embryos. On the contrary, in a retrospective study of 40 patients undergoing resection of ovarian s (mean diameter, cm) before IVF, Loh et al. (26) reported reduced follicular response in natural and clomiphene-stimulated cycles without any change in ovarian response after gonadotropin stimulation. More recently, Donnez et al. (27) reported 85 patients (187 cycles) who underwent laparoscopic cyst wall vaporization of ovarian s before IVF. The investigators compared these patients with 289 tubal factor infertility patients (633 cycles). The response to stimulation and clinical pregnancy rates were similar between the two groups. Resection of large lesions clearly enhances access to follicles within underlying normal ovarian tissue and eliminates the potential for rupture during oocyte aspiration. Meticulous surgical techniques avoiding compromise of ovarian blood supply and healthy ovarian tissue are mandatory (24). In the current study, we observed lower E 2 levels on the day of hcg injection and lower numbers of total follicles ( 17 mm) and metaphase II oocytes in patients with resected s compared with those with tubal factor infertility. However, resection of s had no negative impact on implantation and clinical pregnancy rates. A considerable body of evidence suggests that endometriosis-associated infertility patients going through assisted reproductive techniques have compromised follicular development (19, 28). If endometriosisassociated infertility is a result of oocyte-related factors, this may be overcome by using ICSI. Results of endometriosis cases going through ICSI cycles are rarely reported in the literature. Two studies analyzed the impact of endometriosis on ICSI outcomes; there was no reduction in fertilization, cleavage, or implantation rates, similar to our data in the present study (7, 8). It has been hypothesized that some of the altered factor(s) involved in the process of oocyte activation in endometriosis patients could be overcome by ICSI procedure and that similar fertilization, implantation, and clinical pregnancy rates could be obtained in patients with s (8). However it should be stressed that most of the studies evaluating the impact of endometriosis on IVF and ICSI cycle outcomes are retrospective. Therefore well-designed prospective clinical studies are warranted to investigate any impact of endometriosis on the outcomes of IVF or ICSI cycles. In the current study, all patients with s had significantly lower numbers of metaphase II oocytes compared with those in patients with tubal factor infertility. We propose that aspiration of s before COH neither reduces the amount of gonadotropins nor increases the number of total follicles ( 17 mm), the number of retrieved metaphase II oocytes, implantation rates, or clinical pregnancy rates. In conclusion, resection of small s (1 6 cm) may not present any additional benefits to the IVF-ICSI cycle outcomes. References 1. Janssen RPS, Russell P. Nonpigmented endometriosis: clinical laparoscopic and pathologic definition. Am J Obstet Gynecol 1987;155: Mahutte NG, Arici A. New advances in the understanding of endometriosis related infertility. J Reprod Immunol 2002;55: Komada H, Fukuda J, Karube H, Matsui T, Shimizu Y, Tanaka T. Benefit of in vitro fertilization treatment for endometriosis associated infertility. 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7 24. Surrey ES, Schoolcraft WB. Management of endometriosis-associated infertility. Obstet Gynecol Clin N Am 2003; Canis M, Pouly JL, Tamburro S, Mage G, Wattiez A, Bruhat MA. Ovarian response during IVF embryo transfer cycles after laparoscopic ovarian cystectomy for endometriotic cysts of 3 cm in diameter. Hum Reprod 2001;12: Loh FH, Tan AT, Kumar J, Ng S-C. Ovarian response after laparo scopic ovarian cystectomy for endometriotic cysts in 132 monitored cycles. Fertil Steril 1999;72: Donnez J, Wyns C, Nisolle M. Does ovarian surgery for s impair the ovarian response to gonadotropin? Fertil Steril 2001;76: Cahill DJ. What is the optimal medical management of infertility and minor endometriosis. Analysis and future prospects. Debate Hum Reprod 2002;17: FERTILITY & STERILITY 711