Outcome of in vitro fertilization/intracytoplasmic sperm injection after laparoscopic cystectomy for endometriomas

Outcome of in vitro fertilization/intracytoplasmic sperm injection after laparoscopic cystectomy for endometriomas Ibrahim Esinler, M.D.,a Gurkan Bozdag, M.D.,a Funda Aybar, M.D.,b Ulku Bayar, M.D.,c and Hakan Yarali, M.D.a a Department of Obstetrics and Gynecology, Hacettepe University Faculty of Medicine and b Anatolia Women and IVF Health Center, Ankara; and c Department of Obstetrics and Gynecology, Zonguldak Karaelmas University Faculty of Medicine, Zonguldak, Turkey

Objective: To assess the impact of prior unilateral or bilateral endometrioma cystectomy on controlled ovarian hyperstimulation (COH) and intracytoplasmic sperm injection (ICSI) outcome. Design: Retrospective case-control study. Setting: Department of Obstetrics and Gynecology, School of Medicine, Hacettepe University, Ankara, Turkey. Patient(s): Fifty-seven consecutive infertile patients were enrolled who had previously undergone unilateral (n ⫽ 34) or bilateral (n ⫽ 23) laparoscopic cystectomy for endometriomas more than 3 cm in diameter and underwent ICSI. The control group consisted of 99 patients with tubal factor infertility. Intervention(s): Controlled ovarian hyperstimulation and ICSI. Main Outcome Measure(s): Cycle cancellation rate, number of oocytes, fertilization rate, embryo quality, clinical pregnancy rate (PR), and implantation rate. Result(s): The mean number of oocytes, metaphase II oocytes, and two-pronucleated oocytes were significantly lower in the bilateral cystectomy group compared to the unilateral cystectomy and control groups. However, all other parameters, including fertilization rate, the mean number of embryos transferred, the mean number of grade 1 embryos transferred, the clinical PR per embryo transfer, and implantation rate, were comparable among the three groups. Within the unilateral cystectomy group, the mean number of oocyte retrieved from the operated site was significantly less than in the contralateral nonoperated site. Conclusion(s): Laparoscopic endometrioma cystectomy does reduce the ovarian reserve. However, diminished ovarian reserve does not translate into impaired pregnancy outcome. (Fertil Steril威 2006;85:1730 –5. ©2006 by American Society for Reproductive Medicine.) Key Words: Endometriosis, endometrioma, cystectomy, ovarian reserve, assisted reproductive technologies, intracytoplasmic sperm injection, pregnancy

Endometriomas affect 17%– 44% of women with endometriosis (1–3). The impact of ovarian endometriomas on the outcome of assisted reproductive technologies (ART) is controversial (4). There is ongoing debate on how to manage endometriomas, especially for those larger than 3 cm in diameter, before ART. Management options include no intervention, aspiration, cystectomy, fenestration, and ablation of the cyst wall (5). There is currently no consensus on which approach is most favorable in terms of preservation of ovarian reserve and subsequent ART outcome.

to COH after cystectomy has been reported in other studies (9 –13). Such decreased ovarian reserve might result from surgery (9 –11) or endometriosis itself (14 –17). If at least some of the detrimental effect on ovarian reserve originates from the surgery, one would expect more diminished response to COH after bilateral endometrioma cystectomy compared to unilateral cystectomy. To our knowledge, none of the published studies evaluated the COH response and ART outcome by group analysis in the patients who had undergone unilateral or bilateral cystectomy.

Cystectomy is commonly used for endometriomas more than 3 cm in diameter before ART (6). No detrimental effect of endometrioma cystectomy was reported on controlled ovarian hyperstimulation (COH) and ART outcomes in retrospective case-control studies, where patients with tubal factor infertility served as controls (7, 8). Reduced response

The aim of this study is to determine whether unilateral or bilateral cystectomy for endometriomas more than 3 cm in diameter before ART has any deleterious effect on COH and pregnancy outcome; patients with tubal factor infertility served as controls.

Received July 14, 2005; revised and accepted October 31, 2005. Reprint requests: Hakan Yarali, M.D., Hacettepe University, School of Medicine, Department of Obstetrics and Gynecology, Hafta sokak, No 23/4, G.O.P. 06700, Ankara, Turkey (FAX: 90-312-3052315; E-mail: [email protected]).

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MATERIALS AND METHODS Fifty-seven consecutive infertile patients who had previously undergone unilateral or bilateral laparoscopic endometrioma cystectomy were enrolled retrospectively through our computerized IVF database system. Inclusion criteria were: [1]

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first intracytoplasmic sperm injection (ICSI) cycle; [2] women aged less than 40 years; [3] a history of unilateral or bilateral laparoscopic cystectomy for endometriomas more than 3 cm; and [4] histopathologically confirmed diagnosis of endometrioma. Endometriomas less than 3 cm in diameter were excluded, as we do not perform surgery before ART in such cases. Patients who had undergone repeated surgery for recurrence of endometrioma or other ovarian cysts at the same or contralateral site were also excluded. Unilateral and bilateral cystectomies were performed in 34 and 23 patients, respectively. The control group consisted of 99 patients with laparoscopically proven tubal factor infertility without hydrosalpinx, endometriosis, and prior history of ovarian surgery. All patients in the three groups had severe male factor infertility necessitating ICSI. The first ICSI cycle was included for all patients in the three groups. All cystectomies were performed by laparoscopy at our department by two experienced senior endoscopists. Initial, complete adhesiolysis and mobilization of the ovaries were performed if necessary. After injection of saline between the ovarian cortex and the cyst wall to facilitate the dissection of the cyst wall, an incision was made at the antimesenteric site of the ovary with a sharp-tipped unipolar cautery. The cyst was drained and the cyst capsule was totally removed by traction and countertraction with two atraumatic 5-mm grasping forceps. The bleeders were then cauterized with a 5-mm microbipolar forceps to ensure proper hemostasis. Unnecessary thermal damage to the ovarian cortex was avoided so ovarian reserve was not decreased. All patients underwent COH using luteal-long leuprolide acetate (LA; Lucrin; Abbott, Cedex, Istanbul, Turkey) and recombinant FSH (Gonal-F; Serono, Istanbul, Turkey) using the step-down protocol (18). The starting dose of gonadotropin was determined based on the woman’s age, body mass index (BMI), antral follicle count at baseline transvaginal ultrasonography, and day 3 FSH and E2 levels. Ovarian response was monitored with frequent serum E2 measurements and transvaginal ultrasonography, as described previously (18). The criterion for hCG (Profasi; Serono, Istanbul, Turkey) administration was the presence of three or more follicles exceeding 17 mm in diameter. Oocyte retrieval was carried out under local anesthesia using vaginal ultrasound-guided puncture of follicles 36 hours after hCG administration. Standard procedures were carried out for gamete– embryo handling and day 3 embryo transfer was performed in all cases using the Wallace catheter. Luteal phase was supported by daily vaginal P suppositories (Crinone; Serono, Istanbul, Turkey) starting 1 day after oocyte retrieval. Cycle cancellation due to poor ovarian response was undertaken when less than three follicles more than 17 mm in diameter developed. Embryos were graded on day 3 according to a 1 to 4 scoring system (with 1 being the best), which was based on Fertility and Sterility姞

fragmentation, cell symmetry, and blastomere number (19). The embryos with even blastomeres and no fragmentation were graded as grade 1, the embryos with even blastomeres and ⬍20% fragmentation as grade 2a, the embryos with uneven blastomeres and no fragmentation as grade 2b, the embryos with uneven blastomeres and ⬍20% fragmentation as grade 2ab. The embryos with 30%–50% fragmentation and ⬎50% fragmentation were graded as grade 3 and 4 embryos, respectively. Grades 1–3 were considered as transferable embryos. Clinical pregnancy was defined as the presence of an intrauterine gestational sac at transvaginal ultrasonography. The statistical analyses were performed using Statistics Package for Social Sciences version 13.0 (SPSS Inc., Chicago, IL). Normally distributed parametric variables confirmed by Kolmogorov-Smirnov and Shapiro-Wilk tests were tested by analysis of variance (ANOVA) with Bonferroni test for post hoc analysis. Non-normally distributed metric variables were analyzed by Kruskal-Wallis test and Mann-Whitney U-test. The ␹2 test and Fisher’s exact test were used to analyze nominal variables in form of frequency tables. The comparison of the number of oocyte– cumulus complexes retrieved in the operated ovary and contralateral normal ovary was performed by use of paired sample t-test. Taking the total number of oocytes retrieved as the main outcome measure, the power analysis of the comparisons among the three groups was calculated with “t-test for two independent samples with common variance” using Power and Precision software release 2.0, 2000. P values of ⬍.05 or less were considered statistically significant. Values were expressed as mean ⫾SD, unless stated otherwise. RESULTS The three groups were comparable regarding women’s mean age, BMI, and duration of infertility (Table 1). Three cycles (8.8%) in the unilateral, five cycles (21.7%) in the bilateral, and nine cycles (9.1%) in the control group were canceled due to poor ovarian response (P⬎.05). The mean number of antral follicles on day 3 was significantly lower in the bilateral group when compared to those of the unilateral and control groups (Table 1). The bilateral cystectomy group required significantly higher does of FSH compared to the unilateral and control groups (Table 1). However, the duration of stimulation and the mean E2 level on the day of hCG administration was comparable in the three groups. The mean number of oocyte– cumulus complexes, metaphase II oocytes, and two-pronucleated oocytes were significantly lower in the bilateral cystectomy group compared to the unilateral cystectomy and control groups (Table 2). However, all other parameters, including fertilization rate, mean number of embryos transferred, mean number of grade 1 embryos transferred, clinical pregnancy rate (PR) per embryo transfer, implantation rate, multiple pregnancies, and miscarriage rates, were comparable among the three groups (Table 2). 1731

TABLE 1 The baseline characteristics and controlled ovarian hyperstimulation response of the unilateral cystectomy, bilateral cystectomy, and control groups.

Characteristic No. of canceled cycles (n, %) Female age (y) Body mass index (kg/m2) Duration of infertility (mo) Time interval between cystectomy and ICSI (mo) Day 3 FSH level (mIU/mL) Day 3 antral follicle count Duration of stimulation (d) Total dose of FSH used (IU) E2 level on the day of hCG administration (pg/mL) Endometrial thickness at hCG administration (mm)

Unilateral cystectomy (n ⴝ 34)

Bilateral cystectomy (n ⴝ 23)

Control (n ⴝ 99)

P value

3 (8.8) 31.3 ⫾ 3.9 24.1 ⫾ 2.4 72.2 ⫾ 40.5 34.4 ⫾ 15.6

5 (21.7) 31.2 ⫾ 4.4 24.9 ⫾ 4.6 85.3 ⫾ 35 42.7 ⫾ 22.3

9 (9.1) 31.9 ⫾ 4.0 24.8 ⫾ 3.8 83.6 ⫾ 42 —

NS NS NS NS NS

7.1 ⫾ 2.2 10.0 ⫾ 4.1 11.3 ⫾ 3.1 2655.8 ⫾ 1449.1 2536.4 ⫾ 1514.7

8.1 ⫾ 2.5 7.1 ⫾ 2.6a 10.7 ⫾ 1.5 3423.4 ⫾ 1682.3a 1730.6 ⫾ 1060.8

7.3 ⫾ 3.3 11.3 ⫾ 3.9 10.3 ⫾ 2.1 2519.4 ⫾ 964.9 1949.4 ⫾ 1323.2

NS ⬍.05 NS ⬍.05 NS

9.9 ⫾ 2.1

NS

10.3 ⫾ 2.4

11.2 ⫾ 2.2

Note: Values are expressed as mean ⫾ SD or n (%). NS ⫽ not significant. a Statistically different from unilateral cystectomy and control groups. Esinler. ICSI outcome after endometrioma cystectomy. Fertil Steril 2006.

Of interest, within the unilateral cystectomy group, the mean number of oocyte– cumulus complexes retrieved from the operated site was significantly less than in the contralateral nonoperated site (4.5 ⫾ 4.0 and 6.6 ⫾ 3.5, P⬍.05). However, the mean number of oocytes collected per patient was comparable in the unilateral cystectomy and control groups. Considering the total number of oocytes retrieved as the main outcome measure, the power of the comparison between the bilateral and unilateral groups was 63%. The respective figure for comparison between the bilateral and control groups was 84%.

group, composed of patients with either tubal factor infertility (7, 8, 12, 13), early stage endometriosis without endometrioma (7), or nonoperated endometrioma (11, 20 –22) (Table 3). The second approach compares the COH response of the operated and nonoperated sites within the unilateral cystectomy patients (9, 10, 22, 23) (Table 3). There is paucity of data on the impact of bilateral endometrioma cystectomy on COH response and ART outcome compared to unilateral cystectomy and the controls.

DISCUSSION In this study we noted that the COH response and pregnancy outcome of the unilateral cystectomy group was comparable to the tubal factor controls. Patients in the bilateral cystectomy group, however, required significantly more FSH, produced less oocyte– cumulus complexes, and metaphase II oocytes. However, the mean number of embryos transferred, embryo quality, and PR were comparable to those of the unilateral cystectomy and control groups.

Diminished ovarian response after endometrioma cystectomy has been reported in some retrospective studies (9 –13, 23). Loh et al. (23) reported that in women ⬍35 years of age, the mean number of follicles ⱖ16 mm in diameter developed from postcystectomy ovaries was diminished significantly when compared with contralateral nonoperated ovaries in non-ART natural (0.3 vs. 1.0) and clomiphene citrate (CC)stimulated cycles (0.9 vs. 1.3). Somigliana et al. (10), evaluated the impact of unilateral cystectomy on ART outcome in 32 patients (46 cycles). The mean number of follicles greater than 15 mm in diameter on the day of hCG administration was 53% reduced in the operated ovary compared to the contralateral site (4.2⫾2.5 vs 2.0⫾1.5, respectively; P⬍0.001).

There is controversy on the effect of endometrioma cystectomy on subsequent response to COH for ART. Two approaches have been used to assess the impact of ovarian surgery on ovarian reserve. The first approach compares COH response of the cystectomy group to that of the control

In concordance with the study by Somigliana et al. (10), Ho et al. (9), in 32 patients (38 cycles), noted significant reduction of oocytes in the operated ovaries compared to contralateral normal ovaries (2.9 ⫾ 2.6 vs. 6.1 ⫾ 4.1, respectively; P⬍.01). Wu et al. (12), in 22 patients, evaluated

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ICSI outcome after endometrioma cystectomy

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TABLE 2 The embryological data and pregnancy outcome of the unilateral cystectomy, bilateral cystectomy, and control groups.

Characteristic No. of oocyte-cumulus complexes No. of metaphase II oocytes Metaphase II oocytes/total oocytes (%) 2-pronuclei/metaphase II oocytes (%) No. of 2-pronucleated oocytes No. of transferred grade I embryosb No. of transferred grade I embryos/No. of embryos transferred (%) No. of transferred grade 2 embryosb No. of embryos transferred Clinical pregnancy/embryo transfer (%) Implantation rate (%) Multiple pregnancy rate (%) Twin (%) Triplet (%) Miscarriage rate (n, %)

Unilateral cystectomy (n ⴝ 34)

Bilateral cystectomy (n ⴝ 23)

Control (n ⴝ 99)

P value

10.8 ⫾ 6.2 8.1 ⫾ 5.4 76.4 71.9 6.6 ⫾ 3.1 0.6 ⫾ 0.2 22.1

7.1 ⫾ 4.4a 5.5 ⫾ 3.2a 79.7 68.6 3.9 ⫾ 2.3a 0.4 ⫾ 0.2 14.6

11.1 ⫾ 6.1 8.7 ⫾ 4.8 76.6 73.6 6.7 ⫾ 4.4 0.9 ⫾ 0.1 25.5

⬍.05 ⬍.05 NS NS ⬍.05 NS NS

2.0 ⫾ 0.2 2.9 ⫾ 1.3 45.2 23.2 36 29 7 2 (14.2)

2.1 ⫾ 0.3 2.7 ⫾ 1.2 44.4 27.0 38 26 12 1 (12.8)

1.9 ⫾ 0.1 3.0 ⫾ 1.3 47.8 19.1 38 31 7 6 (13.9)

NS NS NS NS NS NS NS NS

Note: Values are expressed as mean ⫾ SD, unless stated otherwise. NS ⫽ not significant. a Statistically different from unilateral cystectomy and control groups. b Mean ⫾ SEM. Esinler. ICSI outcome after endometrioma cystectomy. Fertil Steril 2006.

the impact of cystectomy for endometriomas more than 6 cm in diameter on ovarian stromal blood flow on the day of hCG administration. Twenty-six women with tubal factor infertility served as the control group. Ovarian stromal blood flow parameters (vascularization index, flow index, and vascularization flow index) were significantly decreased in the cystectomy group without any evident difference in total ovarian volume. The presence of primordial follicles at the cyst capsule may support a possible detrimental effect of surgery on ovarian reserve (24). Muzii et al. (24) performed histologic analyses of 26 endometrioma cystectomy specimens and noted that ovarian tissue was removed with the cyst capsule in 54% of the cases. In another recent study enrolling 48 patients, Muzii et al. (25) reported that recognizable ovarian tissue was inadvertently excised together with the endometrioma cyst wall in most cases. They assessed the quantity and nature of ovarian tissue inadvertently resected along with the endometriotic tissue in different parts of the cyst wall including the cyst adhesion site within the ovarian fossa, the intermediate part of the cyst wall, and ovarian hilus. At the initial adhesion site and at the intermediate part of the cyst wall, the ovarian tissue removed along with the endometrioma wall was mainly constituted of tissue with no follicles or only primordial follicles. Close to the ovarian hilus, the ovarian tissue removed along with the Fertility and Sterility姞

endometrioma wall mostly consisted of tissue that contained primary and secondary follicles. This study further supports that great caution should be undertaken to avoid ovarian damage while stripping the cyst capsule and hemostasis near the hilus. In other studies, however, no detrimental effect of prior cystectomy on ovarian reserve and response to COH has been reported (7, 8, 20, 21, 26). Garcia-Velasco et al. (21) recently compared ART outcome after cystectomy to no intervention in patients with endometriomas more than 3 cm in diameter. The total FSH level was significantly higher and the peak E2 level was significantly lower in the cystectomy group. However, the mean number of oocytes retrieved and the PR were comparable among the two groups. Canis et al. (7) evaluated the ART outcome of 41 patients who underwent cystectomy for endometriomas more than 3 cm in diameter. One hundred thirty-nine patients with endometriosis without ovarian endometrioma and 59 patients with tubal infertility served as controls. The number of oocytes and embryos obtained and the PR were comparable among the three groups. In a recently published retrospective cohort study, Wong et al. (22) reported that unilateral resection of endometriomas was not associated with a reduced number of oocyte yield (mean ⫾ SEM) when compared to contralateral normal ovaries (5.2 ⫾ 0.8 vs. 5.6 ⫾ 0.9, respectively). 1733

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TABLE 3 Literature review of the impact of endometrioma cystectomy on ART outcome.

ICSI outcome after endometrioma cystectomy

Study characteristics Cystectomy

References Pabuccu et al, 2004 (13) Wong et al, 2004 (22) Wong et al, 2004 (22) Garcin-Velasco et al, 2004 (21) Marconi et al, 2002 (8) M-H Wu et al, 2003 (12) Takuma et al, 2002 (20) Suganuma et al, 2002 (11) Canis et al, 2001 (7) Canis et al, 2001 (7) Tinkannen and Kujansu, 2000 (26) Ho et al, 2002 (9)

No. of patients (No. of cycles) 44 (44) NA (45) NA

Laterality Unilateral (n ⫽ 23) Bilateral (n ⫽ 21) NA Unilateral

133 (147) NA 39 (39) 22 (30) 36 (69)

NA NA NA

Control Mean diameter of endometrioma (cm) NA 2–5

d

2–5

d

36 (62)

NA

NA

39 (39)

Unilateral (n ⫽ 28) Bilateral (n ⫽ 11) Unilateral (n ⫽ 28) Bilateral (n ⫽ 11)

⬎3

55 (55)

Unilateral (n ⫽ 22) Bilateral (n ⫽ 33)

3

32 (38)

Unilateral

39 (39)

c

⬎6 4.2 ⫾ 2.0

⬎3

NA

FSH dose (IU or vials) (mean ⴞ SD) Patient characteristics

Cystectomy

c

Control

Tubalfactor 2490 ⫾ 622 IU 2392 ⫾ 562 IU infertility a,b NA (29) Not operated 37.2 ⫾ 2.1 vial 26.3 ⫾ 2.6 viala endometrioma NA Contralateral ovary 56 (63) Not operated 3880 ⫾ 129 IUa,b 3404 ⫾ 162 IUa endometrioma 39 (39) Tubal factor 49 ⫾ 17 vialb 36 ⫾ 18 vial infertility 26 (30) Tubal factor NA NA infertility 16 (43) Aspirated NA NA endometrioma 20 (30) Not operated NA NA endometrioma 59 (59) Tubal factor NA NA infertility NA NA 128 (128) Early stage endometriosis (Stage I–II) 45 (45) Patients without NA NA endometriomas 46 (46)

⬎3 4.8 ⫾ 2.3

No. of patients (No. of cycles)

32 (38)

Contralateral ovary

Note: NA ⫽ not available; OCC ⫽ oocyte– cumulus complexes; CP ⫽ clinical pregnancy; ET ⫽ embryo transfer. Values were expressed as mean ⫾ SEM. Statistically different from control group, P ⬍ .05. c Values were expressed as mean ⫾ SD. d Range. a

b

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Esinler. ICSI outcome after endometrioma cystectomy. Fertil Steril 2006.

No. of OCC’s (mean ⴞ SD)

No. of M-2 oocytes (mean ⴞ SD)

Cystectomy

Control

Cystectomy

Control

NA

NA

5.7 ⫾ 1.3b

7.2 ⫾ 1.5

NA

a

NA NA 10.8 ⫾ 0.6 7.5 ⫾ 3.9

11.8 ⫾ 0.9

a

8.7 ⫾ 5.1 b

Control

25

30

46

32

Cystectomy 8.3

Control 10

9.6 ⫾ 1.1

5.2 ⫾ 0.8

a

5.6 ⫾ 0.9

a

8.7 ⫾ 0.6

a

8.4 ⫾ 0.8a

25.4

22.7

3.9

6.1

NA

38.4

33.3

NA

NA

NA

b

41

NA

NA

NA

6.0 ⫾ 0.8

11.3 ⫾ 1.1

NA

7.3 ⫾ 4.9

8.8 ⫾ 5.4

NA

b

Cystectomy

Miscarriage rate (%)

a

10.0 ⫾ 1.0

NA a

CP/ET (%)

b

15

22

11

NA

NA

NA

NA

NA

7.2 ⫾ 6.2

9.7 ⫾ 6.7

5.7 ⫾ 4.8

8.0 ⫾ 5.4

29.0

36.6

NA

NA

9.4 ⫾ 6.2

11.6 ⫾ 7.5

NA

NA

35.9

31.2

NA

NA

9.4 ⫾ 6.2

10.9 ⫾ 6.5

NA

NA

35.9

30.5

NA

NA

6.1

6.5

NA

NA

27

39

NA

NA

2.9 ⫾ 2.6b

6.1 ⫾ 4.1

NA

NA

The findings of our study suggest that laparoscopic endometrioma cystectomy does reduce the ovarian reserve, as reflected by significantly diminished number of oocytes collected in the operated side compared to the nonoperated side within the unilateral cystectomy group. Requirement of significantly more FSH, production of less oocyte– cumulus complexes, and metaphase II oocytes in the bilateral cystectomy group further support the detrimental effect of cystectomy on ovarian reserve. However, diminished ovarian reserve does not translate into impaired pregnancy outcome, as PR of the unilateral cystectomy, bilateral cystectomy, and control groups were comparable. REFERENCES 1. Busacca M, Vignali M. Ovarian endometriosis: from pathogenesis to surgical treatment. Curr Opin Obstet Gynecol 2003;15:321– 6. 2. Jenkins S, Olive DL, Haney AF. Endometriosis: pathogenetic implications of the anatomic distribution. Obstet Gynecol 1986;67:335– 8. 3. Redwine DB. Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease. Fertil Steril 1999;72:310 –5. 4. Isaacs JD Jr., Hines RS, Sopelak VM, Cowan BD. Ovarian endometriomas do not adversely affect pregnancy success following treatment with in vitro fertilization. J Assist Reprod Genet 1997;14:551–3. 5. Chapron C, Vercellini P, Barakat H, Vieira M, Dubuisson JB. Management of ovarian endometriomas. Hum Reprod Update 2002;8:591–7. 6. Beretta P, Franchi M, Ghezzi F, Busacca M, Zupi E, Bolis P. Randomized clinical trial of two laparoscopic treatments of endometriomas: cystectomy versus drainage and coagulation. Fertil Steril 1998;70: 1176 – 80. 7. 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;16:2583– 6. 8. Marconi G, Vilela M, Quintana R, Sueldo C. Laparoscopic ovarian cystectomy of endometriomas does not affect the ovarian response to gonadotropin stimulation. Fertil Steril 2002;78:876 – 8. 9. Ho HY, Lee RK, Hwu YM, Lin MH, Su JT, Tsai YC. Poor response of ovaries with endometrioma previously treated with cystectomy to controlled ovarian hyperstimulation. J Assist Reprod Genet 2002;19:507– 11. 10. Somigliana E, Ragni G, Benedetti F, Borroni R, Vegetti W, Crosignani PG. Does laparoscopic excision of endometriotic ovarian cysts significantly affect ovarian reserve? Insights from IVF cycles. Hum Reprod 2003;18:2450 –3. 11. Suganuma N, Wakahara Y, Ishida D, Asano M, Kitagawa T, Katsumata Y, et al. Pretreatment for ovarian endometrial cyst before in vitro fertilization. Gynecol Obstet Invest 2002;54 Suppl 1:36 – 42.

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12. Wu MH, Tsai SJ, Pan HA, Hsia KY, Chang FM. Three-dimensional power Doppler imaging of ovarian stromal blood flow in women with endometriosis undergoing in vitro fertilization. Ultrasound Obstet Gynecol 2003;21:480 –5. 13. Pabuccu R, Onalan G, Goktolga U, Kucuk T, Orhon E, Ceyhan T. Aspiration of ovarian endometriomas before intracytoplasmic sperm injection. Fertil Steril 2004;82:705–11. 14. Bergendal A, Naffah S, Nagy C, Bergqvist A, Sjoblom P, Hillensjo T. Outcome of IVF in patients with endometriosis in comparison with tubal-factor infertility. J Assist Reprod Genet 1998;15:530 – 4. 15. Azem F, Lessing JB, Geva E, Shahar A, Lerner-Geva L, Yovel I, et al. Patients with stages III and IV endometriosis have a poorer outcome of in vitro fertilization-embryo transfer than patients with tubal infertility. Fertil Steril 1999;72:1107–9. 16. Arici A, Oral E, Bukulmez O, Duleba A, Olive DL, Jones EE. The effect of endometriosis on implantation: results from the Yale University in vitro fertilization and embryo transfer program. Fertil Steril 1996;65:603–7. 17. Yanushpolsky EH, Best CL, Jackson KV, Clarke RN, Barbieri RL, Hornstein MD. Effects of endometriomas on ooccyte quality, embryo quality, and pregnancy rates in in vitro fertilization cycles: a prospective, case-controlled study. J Assist Reprod Genet 1998;15:193–7. 18. Bukulmez O, Yarali H, Yucel A, Sari T, Gurgan T. Intracytoplasmic sperm injection versus in vitro fertilization for patients with a tubal factor as their sole cause of infertility: a prospective, randomized trial. Fertil Steril 2000;73:38 – 42. 19. Hardarson T, Hanson C, Sjogren A, Lundin K. Human embryos with unevenly sized blastomeres have lower pregnancy and implantation rates: indications for aneuploidy and multinucleation. Hum Reprod 2001;16:313– 8. 20. Takuma N, Sengoku K, Pan B, Wada K, Yamauchi T, Miyamoto T, et al. Laparoscopic treatment of endometrioma-associated infertility and pregnancy outcome. Gynecol Obstet Invest 2002;54 Suppl 1:30 –5. 21. Garcia-Velasco JA, Mahutte NG, Corona J, Zuniga V, Giles J, Arici A, et al. Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case-control study. Fertil Steril 2004;81:1194 –7. 22. Wong BC, Gillman NC, Oehninger S, Gibbons WE, Stadtmauer LA. Results of in vitro fertilization in patients with endometriomas: is surgical removal beneficial? Am J Obstet Gynecol 2004;191:597– 607. 23. Loh FH, Tan AT, Kumar J, Ng SC. Ovarian response after laparoscopic ovarian cystectomy for endometriotic cysts in 132 monitored cycles. Fertil Steril 1999;72:316 –21. 24. Muzii L, Bianchi A, Croce C, Manci N, Panici PB. Laparoscopic excision of ovarian cysts: is the stripping technique a tissue-sparing procedure? Fertil Steril 2002;77:609 –14. 25. Muzii L, Bellati F, Bianchi A, Palaia I, Manci N, Zullo MA. Laparoscopic stripping of endometriomas: a randomized trial on different surgical techniques. Part II: pathological results. Hum Reprod 2005;20: 1987–92. 26. Tinkanen H, Kujansuu E. In vitro fertilization in patients with ovarian endometriomas. Acta Obstet Gynecol Scand 2000;79:119 –22.

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