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Hemostasis by Bipolar Coagulation Versus Suture After Surgical Stripping of Bilateral Ovarian Endometriomas: A Randomized Controlled Trial
Original Article
Hemostasis by Bipolar Coagulation Versus Suture After Surgical Stripping of Bilateral Ovarian Endometriomas: A Randomized Controlled Trial Simone Ferrero, PhD*, Pier Luigi Venturini, MD, David John Gillott, PhD, Valentino Remorgida, MD, and Umberto Leone Roberti Maggiore, MD From the Department of Obstetrics and Gynecology, San Martino Hospital and University of Genoa, Genoa, Italy (Drs. Ferrero, Venturini, Remorgida, and Leone Roberti Maggiore), and St. Bartholomew’s School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom (Dr. Gillott).
ABSTRACT Study objective: To estimate whether the suture of the ovary is superior to bipolar coagulation in preserving ovarian reserve in infertile women undergoing laparoscopic stripping of bilateral endometriomas. Design: Randomized controlled trial (Canadian Task Force classification I). Setting: University teaching hospital. Patients: 100 patients with bilateral endometriomas. Interventions: Patients underwent stripping of bilateral endometriomas and were randomized to undergo hemostasis by use of either laparoscopic suturing (LS group) or bipolar coagulation (BC group). Changes in ovarian reserve were investigated by measuring the levels of anti-Mullerian hormone (AMH) and basal follicle-stimulating hormone (FSH) before surgery and at 3, 6 and 12 months from surgery. Measurements and Main Results: At 3-month, 6-month, and 12-month follow-up, in both study groups, postsurgical AMH levels were significantly lower and basal FSH levels were significantly higher than before surgery. There was no significant difference in the mean percentage decrease of AMH levels in the BC group and LS group at 3-, 6-, and 12-month follow-up. The mean percentage increase in basal FSH was higher in the BC group than in the LS group at both 3-month (p 5 .023) and 6-month follow-up (p 5 .029), but not at 12-month follow-up. Pregnancy rate, time to conception, and rate of endometrioma recurrence was similar in the 2 study groups. Conclusion: Laparoscopic stripping of ovarian endometriotic cyst significantly decreases serum AMH levels and increases basal FSH levels independent from the method used to obtain hemostasis on the ovarian tissue. Journal of Minimally Invasive Gynecology (2012) 19, 722–730 Ó 2012 AAGL. All rights reserved. Keywords:
DISCUSS
AMH level; Bipolar coagulation; Endometrioma; FSH level; Stripping
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Laparoscopic cystectomy is currently used for the surgical treatment of ovarian endometriomas. However, several studies have indicated that the laparoscopic exciThe authors declare that they have no conflict of interest. Corresponding author: Simone Ferrero, MD, PhD, Department of Obstetrics and Gynecology, San Martino Hospital, Largo R. Benzi 1, 16132 Genoa, Italy. E-mail: [email protected] Submitted February 9, 2012. Accepted for publication August 2, 2012. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2012 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2012.08.001
sion of ovarian endometriomas might reduce ovarian reserve [1–4] and decrease the response of the ovaries to hormonal stimulation for assisted reproductive technologies [5–7]. Several mechanisms may contribute to damage of the ovary during surgery including the removal of healthy ovarian tissue [8] and thermal destruction of ovarian follicles by excessive use of bipolar coagulation for hemostasis purposes. In line with these hypotheses, some cases of premature ovarian failure have been reported after surgical treatment of bilateral endometriomas [9–11].
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Although the stripping technique is still widely used for the treatment of ovarian endometriomas, few studies investigated whether the use of bipolar coagulation or laparoscopic suturing to obtain hemostasis could affect ovarian reserve. One nonrandomized study compared bipolar coagulation and laparoscopic suture of the ovary in 46 patients with unilateral endometriomas, which had previous contralateral oophorectomy [12]. This study suggested that patients undergoing laparoscopic suturing of the ovary have lower postoperative follicle-stimulating hormone (FSH) levels when compared with patients undergoing bipolar coagulation of the ovary. A more recent trial assessed ovarian reserve in 45 patients undergoing laparoscopic stripping of unilateral endometriomas, which were randomized for treatment by either suturing or bipolar coagulation [4]. In the 3 postoperative menstrual cycles, the reduction in antral follicle count was significantly lower in sutured ovaries than in those that were coagulated. Ovarian endometriomas are more frequently bilateral than nonendometriotic cysts [13], and therefore the treatment of bilateral disease may significantly affect ovarian reserve [11,14]. This prospective randomized study aims to estimate whether the suture of the ovary is superior to bipolar coagulation in preserving ovarian reserve in infertile women undergoing laparoscopic stripping of bilateral endometriomas.
metriotic ovarian cysts; suspicion of malignant ovarian disease; use of hormonal therapies in the 4 months before inclusion in the study; desire of the patients to use hormonal therapies after surgery. Patients were recruited and underwent surgery between June 2007 and September 2010. The study was approved by the local research ethics committee. Patients enrolled in the study signed a written consent form.
Materials and Methods
Ultrasonographic evaluation of the endometriotic cyst was performed on the day of surgery. The number of endometriotic cysts in each ovary was recorded. The mean diameter of each endometriotic cyst was calculated by measuring the 3 perpendicular dimensions of the cyst. In each patient, the total endometrioma diameter was defined as the sum of the mean diameter of each endometrioma in both the ovaries.
This study included women of reproductive age with bilateral endometriomas with largest diameter R3 cm. All the patients had tried to conceive for at least 1 year before enrollment in the study; male partners had normal semen parameters according to criteria from the World Health Organization for sperm analysis (a sperm concentration of R20 ! 106/mL R50% motility and R30% novel structure, R75% viability with %1 ! 106/mL white blood cells) [15]; and patients wished to spontaneously conceive after surgery. The primary aim of the study was to estimate whether, in infertile women undergoing surgical excision of bilateral endometriomas, the suture of the ovary is superior to bipolar coagulation in preserving ovarian reserve as assessed by use of serum anti-Mullerian hormone (AMH) levels. Secondary aims of the study were to estimate the effects of surgery on basal FSH levels, to assess whether there is a correlation between the size of the endometriomas and ovarian reserve markers (AMH and basal FSH), and to evaluate the pregnancy rate and the rate of endometriomas recurrence at 1-year from surgery. Exclusion criteria for the study were as follow: age R40 years; previous ovarian surgery; previous surgery for endometriosis; evidence of polycystic ovary syndrome (according to the Rotterdam criteria), premature ovarian failure, and any other endocrine diseases (such as thyroid dysfunction, hyperprolactinemia or Cushing’s syndrome); bilateral tubal occlusion (demonstrated before surgery by hysterosalpingography); uterine malformations; presence of nonendo-
Assessment of Ovarian Reserve Venous blood samples were drawn within three months before surgery and after 3, 6, and 12 months from surgery. Ovarian reserve was estimated by measuring the levels of AMH and the levels of FSH on day 2–3 of the menstrual cycle. AMH was assayed with a commercial enzyme-linked immunosorbent assay (Diagnostic Systems Laboratories, Webster, TX). The AMH assay has a sensitivity of 0.006 ng/mL; the intraassay and interassay coefficients of variation were 9.4% and 7.2%. FSH levels were analyzed with the the Immulite 2000 immunoassay system (Diagnostic Products, Los Angeles, CA). The FSH assay has a sensitivity of 0.1 mIU/mL; the intraassay and interassay coefficients of variation were 4.6% and 6.3%, respectively. Ultrasonographic Evaluation of the Endometriotic Cyst
Randomization and Surgical Procedures Randomization was performed by a statistician who used the Random Allocation software version 1.00 (Isfahan University of Medical Sciences, Isfahan, Iran) and who had no other role in the study. A blocked randomization technique was used to ensure that the number of subjects assigned to each group was equally distributed; block size varied randomly to reduce the likelihood of foreknowledge of intervention assignment. Allocation was sealed in consecutively numbered opaque envelopes. Surgical procedures were performed by a team of surgeons with extensive experience in the treatment of endometriosis. During laparoscopy, on commencing the removal of the endometriotic cysts, patients were randomized to undergo hemostasis by use of either laparoscopic suturing or bipolar coagulation. The sealed opaque envelopes were opened by a surgical nurse. Laparoscopy was performed by use of a 10-cm sheath for the camera and three 5-mm ports for the operative instruments. The severity of endometriosis was classified
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by use of the classification of the American Society for Reproductive Medicine [16]. In each patient, the same hemostatic technique was used for all the endometriomas. In both study groups, ovarian endometriomas were excised by using the stripping technique. Adhesiolysis was performed to release the ovaries from the surrounding structures if required. If the ovarian cysts remained unruptured despite manipulation, they were punctured to drain and aspirate the chocolate content of the cyst. The cyst wall was stripped from the healthy surrounding ovary by traction and countertraction, which was achieved by use of 2 or 3 atraumatic grasping forceps. In patients randomized to receive hemostasis by bipolar coagulation, when the cleavage became difficult, the red fibrotic tissue on the surface of the cyst wall was coagulated with bipolar forceps (20 W–30 W current) and cut as previously described by other authors [17]. After the removal of the cyst, bipolar coagulation was used as minimally as possible, only to control significant bleeding. In patients randomized to receive hemostasis by laparoscopic suturing (LS) group, no bipolar coagulation was performed during or after the stripping of the cyst. The suture was performed with intraovarian knots by use of 1 or 2 absorbable sutures (2-0 Vicryl; Ethicon Inc., Somerville, NJ). Follow-up Follow-up was performed at 3, 6, and 12 months after surgery. Although AMH levels are not affected by the use of hormonal therapies [18], patients requesting hormonal therapies during the follow-up were excluded from the study. Pregnancy was defined as a positive serum b–human chorionic growth hormone (b-hCG) test result with ultrasound evidence of a gestational sac and fetal heart. Power Calculation The primary aim of this study was to estimate whether the suture of the ovary is superior to bipolar coagulation in preserving ovarian reserve after surgical excision of endometriomas. Serum AMH levels were chosen as the best marker for evaluating the impact of laparoscopic cystectomy on ovarian reserve. At the time of the study design, because of the lack of publications describing the changes of ovarian reserve markers after surgical excision of bilateral ovarian endometriomas, a pilot study was conducted to define the sample size needed. AMH levels were measured before surgery and at 12 months from surgery in 15 women who underwent laparoscopic stripping of bilateral ovarian endometriomas and hemostasis by bipolar coagulation (mean change 6 SD, 1.52 6 0.72 ng/mL). It was hypothesized that a 30% difference in AMH levels between the 2 surgical techniques could be considered clinically relevant. To have an 80% chance of detecting such a difference at an overall statistical significance level of 5%, 31 patients per group were required (1-sided test). A 1-sided test was used in the power calculation because pre-
vious studies suggested that bipolar coagulation for hemostasis purposes may decrease ovarian reserve [9–11]; in contrast, there is no evidence that the suture of the ovary may affect ovarian reserve. Previous studies showed that up to 50% of the patients undergoing surgery for endometriomas might spontaneously conceive after laparoscopy [19–23]. Allowing for conceptions and dropouts, the aim of this study was to recruit about 50 patients in each study group. Statistical Analysis Chi-square test and Fisher’s exact test were used to compare the proportions. The Kolmogorov-Smirnov test was used to assess the normality of distribution of continuous variables. Friedman repeated measures analysis of variance on ranks (followed by Tukey testing when appropriate) was used to compare the changes in AMH and basal FSH before surgery and at follow-up. The Student t test and the MannWhitney rank sum test were used to compare the percentage changes in the levels of AMH and basal FSH between the 2 study groups. Spearman’s rank correlation coefficient was used to investigate whether there was a correlation between the total endometrioma diameter and the changes in AMH and basal FSH levels. Analysis was performed according to the intention to treat principle. Data were analyzed with the Sigma Stat software version 3.5 and the SPSS software version 13.0 (SPSS Science, Chicago, IL). A p value ,.05 was considered statistically significant. Results Of 121 women eligible for the study, 100 patients agreed to participate. Fifty were included in the BC group and 50 in the LS group. All the procedures were completed by laparoscopy. In 1 patient included in the LS group, bipolar coagulation was required to control ovarian bleeding. The diagrammatic flow of the participants is given in Figure 1. Table 1 shows the characteristics of the study population, the mean age of the patients and the mean diameter of the larger endometriotic cyst being similar in the 2 study groups. All procedures were completed by laparoscopy; no patient had development of postoperative bleeding requiring further surgery. The level of preoperative AMH was also similar in the two study groups (median, range: 2.7 ng/ml, 0.68–10.5 ng/ mL in the LS group and 2.3 ng/mL, 0.63–9.45 in the BC group; p 5 .441). In both the LS group and the BC group, the Friedman repeated measures analysis of variance on ranks showed that AMH levels were significantly different before surgery, at 3-month, 6-month, and 12-month follow-up (p , .001). The post-hoc Tukey test revealed that AMH levels were significantly lower at 3-month, 6-month, and 12-month follow-up when compared with preoperative levels (p , .05; Fig. 2). The level of preoperative basal FSH was similar in the 2 study groups (median, range: 6.4 mIU/mL, 3.8– 11.6 mIU/mL in the LS group, and 6.3 mIU/mL,
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Fig. 1 Flow chart shows recruitment and women’s progress through the study.
3.7–11.3 mIU/mL in the BC group; p 5 .780). In the LS group, the Friedman repeated measures analysis of variance on ranks showed that basal FSH levels were significantly different before surgery, at 3-, 6-, and 12-month follow-up (p , .001). The post-hoc Tukey test revealed that basal FSH levels were significantly higher at 3-month and 12-month follow-up when compared with preoperative levels (p , .05). In the BC group, the Friedman repeated measures analysis of variance on ranks showed that basal FSH levels were significantly different before surgery, at 3-month, 6-month, and 12-month follow-up (p , .001). The post-hoc Tukey test revealed that basal
FSH levels were significantly higher at 3-month, 6-month, and 12-month follow-up when compared with preoperative levels (p , .05; Fig. 3). No significant difference was observed in the mean percentage decrease of AMH levels between BC and LS groups at 3-month follow-up (p 5 .173, Mann-Whitney rank sum test), at 6-month follow-up (p 5 .892), and at 12-month follow-up (p 5 .834). The mean percentage increase in basal FSH was higher in the BC group than in the LS group at both 3-month (p 5 .023) and 6-month follow-up (p 5 .029). At 12-month follow-up, there was no significant difference in the mean percentage increase
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Table 1 Characteristics of the study population
Age (years, mean 6 SD; 95% CI) Patients with previous live birth (n [%; 95% CI]) ASRM points (median [range]) [16] Number of endometriotic cysts (n [median, range]) Diameter of the larger endometriotic cyst (cm, mean 6 SD [95% CI]) Total endometrioma diameter (cm, mean 6 SD [95% CI]) Side of the larger endometriotic cyst (n [%; 95% CI]) Left Right
BC group (n 5 50) 31.9 6 4.0 (30.7–33.0) 8 (16.0%; 7.2%–29.1%) 62.5 (45–121) 2 (2–3) 7.4 6 2.9 (6.6–8.2) 12.7 6 5.7 (14.3–11.0)
LS group (n 5 50) 32.1 6 3.7 (31.0–33.1) 6 (12.0%; 4.5%–24.3%) 66 (49–128) 2 (2–3) 7.5 6 2.4 (6.8–7.5) 12.3 6 3.7 (13.3–11.2)
30 (60.0%; 45.2%–73.6%) 20 (40.0%; 26.4%–54.8%)
34 (68.0%; 53.3%–80.5%) 16 (32.0%; 19.5%–46.7%)
p value .777* .773 .271y .758 .926* .791* .532
* Normally distributed data analyzed by use of the Student t test. y Nonparametric data analyzed by use of the Mann-Whitney rank sum test.
in serum FSH in BC group when compared with LS group (p 5 .133) (Fig. 4). At 3- and 12-month follow-up, total endometrioma diameter was correlated with the percentage change in AMH levels in both study groups. At 6-month follow-up, total endometrioma diameter was correlated with the percentage change in AMH levels only in the BC group. No correlation was observed between total endometrioma diameter and the percentage change in basal FSH levels in the BC group. At 6- and 12-month follow-up, total endometrioma diameter was correlated with the percentage change of basal FSH (Table 2).
Fig. 2 Changes in AMH levels during follow-up in the 2 study groups.
The pregnancy rate was 30.0% (15/50; 95% CI, 17.9%– 44.6%) in the LS group and 36.0% (18/50; 95% CI, 22.9%–50.8%) in the BC group (p 5 .671). The time between surgery and conception was similar in the 2 study groups (median, range: 5 months, 2–11 months in the LS group and 5 months, 2–11 months in the BC group; p 5 .853). Patients who conceived during follow-up (n 5 33) had significantly higher preoperative AMH levels (median, range: 3.2 ng/mL, 0.9–10.5 ng/mL) than those who did not conceive (median, range: 2.1 ng/mL, 0.6–9.5 ng/mL; p 5 .010). Similarly, patients who conceived during
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Fig. 3 Changes in basal FSH levels during follow-up in the 2 study groups.
follow-up had significantly lower preoperative basal FSH levels (median, range: 5.4 mIU/mL, 3.8–9.2 mIU/mL) than those who did not conceive (median, range: 6.6 mIU/ml, 3.7–11.6 mIU/mL; p , .001). Nine women conceived before the first postoperative measurement of ovarian reserve
markers at 3-month follow-up. Patients who conceived after the 3 month follow-up (n 5 24) had significantly higher AMH levels at 3-month follow-up (median, range: 2.5 ng/mL, 0.8–10.1 ng/mL) than those who did not conceive (median, range: 1.9 ng/ml, 0.3–8.2 ng/mL; p 5 .033).
Fig. 4 Percentage changes of AMH and basal FSH during follow-up in the 2 study groups.
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Table 2 Correlation between total endometrioma diameter and percentage change in ovarian reserve markers
AMH 3 months 6 months 12 months Basal FSH 3 months 6 months 12 months
BC group
LS group
rs 5 20.450; p 5 .01 rs 5 20.559; p 5 .01 rs 5 20.648; p 5 .01
rs 5 20.301; p 5 .05 rs 5 20.171; p 5 .305 rs 5 20.369; p 5 .05
rs 5 0.110; p 5 .473 rs 5 0.004; p 5 .980 rs 5 0.109; p 5 .566
rs 5 0.207; p 5 .167 rs 5 0.339; p 5 .05 rs 5 0.008; p 5 .01
rs 5 Spearman correlation coefficient.
Similarly, patients who conceived after the 3-month followup had significantly lower basal FSH level at 3-month follow-up (median, range: 6.1 mIU/mL, 4.3–10.3 mIU/ mL) than those who did not conceive (median, range: 7.2 mIU/ml, 3.5–16.2 mIU/mL; p 5 .011). At 12-month follow-up, 64 patients had not conceived or used hormonal therapies. Recurrence of endometrioma was observed in 3 patients (6.0%; 95% CI, 1.3%–16.5%) in the LS group and in 1 patient (3.2%; 95% CI, 0.1%–10.6%) in the BC group (p 5 .617). Discussion Few previous studies investigated the effects of excision of ovarian bilateral endometriomas on ovarian reserve. One study including 14 patients reported that laparoscopic stripping of bilateral endometriomas combined with bipolar coagulation does not significantly decrease postoperative AMH levels measured 32.5 days after surgery [24]. In contrast, a more recent study including 13 women with bilateral endometriomas treated by stripping of the cyst and bipolar coagulation showed a significant postoperative decrease in the AMH levels at 1 month after surgery [25]. However, decreased serum AMH levels observed at 1 month after surgery may recover at longer follow-up, although the degree of recovery is decreased in patients treated for bilateral disease [14]. In this investigation, AMH levels were measured at 3 months from surgery when it is likely that a complete recovery of ovarian function is obtained. Our data clearly demonstrate that the laparoscopic stripping of bilateral ovarian endometriotic cyst significantly decreases serum AMH levels (Fig. 2) and increases basal FSH level (Fig. 3) independent from the method used to obtain hemostasis on the ovarian tissue. These observations are in line with the findings of a recent retrospective study demonstrating that at more than 6 months from surgery, patients treated with stripping of bilateral ovarian endometriomas (n 5 66) have serum AMH levels significantly lower than patients treated for unilateral endometriomas (n 5 81) [11].
When the technique used to perform the hemostasis was considered, patients treated with either laparoscopic suturing or bipolar coagulation had no significant difference in the percentage change of AMH levels at 3-, 6-, and 12-month follow-up. The percentage increase in basal FSH levels was significantly higher in patients treated with bipolar coagulation than in those treated with laparoscopic suturing at 3- and 6-month follow-up; however, this difference was not observed at 12-month follow-up. These results suggest that the accurate use of bipolar coagulation to achieve hemostasis after stripping of ovarian endometriomas does not have a major detrimental effect on ovarian reserve. This observation is in contrast with the findings of a recent randomized trial by Coric et al [4] reporting lower antral follicle count in patients treated with bipolar coagulation of the ovary than in those treated with suturing of the ovary after laparoscopic stripping of unilateral endometriomas. These different results are even more surprising considering that their study included patients with unilateral endometriomas and mean diameter of about 4 cm, whereas our study included patients with bilateral endometriomas and a mean diameter of about 7 cm. However, in the study by Coric et al [4], bipolar coagulation was performed after the completion of the stripping of the ovarian cyst. By contrast, in our investigation, bipolar coagulation was used when the cleavage plane of the cyst became difficult as previously described by Canis et al [17]. The use of bipolar coagulation during stripping of the cyst may not only reduce the ovarian bleeding but may also facilitate the stripping of the cyst. In addition, during the stripping of the cyst the identification of normal ovarian tissue and endometrioma might be difficult for the surgeon; therefore we cannot exclude the possibility that surgical experience influenced the postoperative ovarian reserve. A retrospective study including patients undergoing laparoscopic stripping of endometriomas combined with bipolar coagulation demonstrated that the postoperative antral follicle count is significantly lower when inexperienced surgeons perform the laparoscopic procedure [26]. Alternatively, it is possible that, in our study, the laparoscopic suture induced ischemic damage to the ovary, thus reducing ovarian reserve in this study group. A limitation of this study is that we did not record the time required to perform ovarian surgery or to perform the hemostasis on the ovary. Therefore we cannot estimate whether achieving hemostasis by laparoscopic suturing requires more time than use of bipolar coagulation. However, we could perform adequate ovarian hemostasis in most of the patients and in a reasonable amount of time. Although analyzing the association of decreased AMH levels with reproductive outcome was not our main objective, no significant difference was observed in the pregnancy rate and time to conceive between patients included in the 2 study groups. However, because of the study design, we cannot exclude the possibility that the study was underpowered to detect a significant difference in reproductive outcome of the 2 groups. The 12-month cumulative pregnancy rates observed
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Hemostasis Versus Suture after Surgical Stripping of Bilateral Ovarian Endometriomas
in this study were 30% in the LS group and 36% in the BC groups. These pregnancy rates are apparently lower than those previously reported by other authors after laparoscopic cystectomy of endometriomas, which are higher than 50% [21,23]. However, this study included only infertile patients, whereas previous investigations included patients who underwent surgery because of pain, ovarian cyst, or infertility. Furthermore, this study included only patients with bilateral endometriomas, whereas most of the subjects of previous studies had unilateral disease. The differences in study design may justify the lower pregnancy rate observed in this study. In this investigation, patients who conceived had higher AMH levels and lower basal FSH levels than patients who did not conceive, both before surgery and at 3-month follow-up. These observations confirm the importance of determining the levels of ovarian reserve markers before surgery in patients undergoing laparoscopy for the treatment of bilateral ovarian endometriomas. This information allows provision of adequate counseling to the patients regarding the risk of poor post-operative ovarian function. In this respect, AMH may be preferred to other ovarian reserve markers (such as basal FSH and antral follicle count). In fact, AMH is a good indicator ovarian recruitable follicular pool and thus of ovarian reserve [27,28]. It has higher intercycle and intracycle reproducibility than other ovarian reserve markers. The levels of AMH are independent of the phase of the menstrual cycle [29], and they are not influenced by the administration of hormonal contraceptives [18], which are commonly used for treating endometriosis [30]. Several techniques have been proposed for preserving ovarian reserve in women requiring surgery for ovarian endometriomas. Two recent randomized trials compared the effects on ovarian reserve caused by cystectomy or by a 3-step procedure consisting of laparoscopic drainage of the cyst content, administration of GnRH agonist for 3 months and second laparoscopy to vaporize the internal wall of the cyst by use of CO2 laser [1,31]. One study including 20 patients with ovarian endometriomas showed that at 6 months after surgery, AMH levels were significantly less decreased in patients undergoing the 3-step procedure than in those undergoing cystectomy. Similarly, a nonsignificant trend for lower basal FSH values was observed in patients treated with the 3-step procedure than in those undergoing cystectomy [1]. A second investigation including 20 patients with endometriomas showed that at 6 months following surgery, antral follicle count was higher in patients treated with the 3-step procedure than in those who underwent cystectomy [31]. Previous studies that compared cystectomy with drainage and ablation by electrosurgery reported a more favorable outcome (response to ovarian stimulation and pregnancy rate) in patients treated with cystectomy [21,23,32,33]. However, these studies used bipolar coagulation instead of CO2 laser for the ablation, thus increasing the risk of thermal damage to the ovary. A mixed technique of excisional and ablative surgery has also been proposed for the treatment of
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endometriomas in a recent prospective study [34]. In 52 women with unilateral endometriomas, the stripping of the cyst was halted when approaching the ovarian hilus where the cleavage plane is usually not clearly visible, and CO2 laser was used to vaporize the remaining 10%–20% of the endometrioma. Six months after surgery the volume of the operated ovary and the antral follicle count were similar to the nonoperated ovaries [34]. Other techniques have been proposed to preserve ovarian reserve during the stripping of endometriotic cysts. A recent randomized prospective study including 15 women with single endometrioma suggested that the injection of vasopressin during laparoscopic excision of endometriomas reduces the use of coagulation and thus may protect ovarian reserve [35]. Other authors proposed the use of a gelantine-thrombin-matrix sealant (FloSeal; Baxter, Deerfield, IL) to control post-cystectomy ovarian wound bleeding [36]; however, the use of this hemostatic agent has been associated with small bowel obstruction in patients undergoing gynecologic surgery [37,38]. In conclusion, this study confirms that the surgical stripping of bilateral endometriomas causes a significant decrease in ovarian reserve independent from the method used for obtaining hemostasis on the ovary. The accurate use of bipolar coagulation during the stripping of bilateral endometriomas does not have a major detrimental effect on ovarian reserve. References 1. Tsolakidis D, Pados G, Vavilis D, et al. The impact on ovarian reserve after laparoscopic ovarian cystectomy versus three-stage management in patients with endometriomas: a prospective randomized study. Fertil Steril. 2010;94:71–77. 2. Hirokawa W, Iwase A, Goto M, et al. The post-operative decline in serum anti-Mullerian hormone correlates with the bilaterality and severity of endometriosis. Hum Reprod. 2011;26:904–910. 3. Var T, Batioglu S, Tonguc E, et al. The effect of laparoscopic ovarian cystectomy versus coagulation in bilateral endometriomas on ovarian reserve as determined by antral follicle count and ovarian volume: a prospective randomized study. Fertil Steril. 2011;95:2247–2250. 4. Coric M, Barisic D, Pavicic D, et al. Electrocoagulation versus suture after laparoscopic stripping of ovarian endometriomas assessed by antral follicle count: preliminary results of randomized clinical trial. Arch Gynecol Obstet. 2011;283:373–378. 5. Esinler I, Bozdag G, Aybar F, et al. Outcome of in vitro fertilization/intracytoplasmic sperm injection after laparoscopic cystectomy for endometriomas. Fertil Steril. 2006;85:1730–1735. 6. Benaglia L, Somigliana E, Vighi V, et al. Rate of severe ovarian damage following surgery for endometriomas. Hum Reprod. 2010;25:678–682. 7. Almog B, Sheizaf B, Shalom-Paz E, et al. Effects of excision of ovarian endometrioma on the antral follicle count and collected oocytes for in vitro fertilization. Fertil Steril. 2010;94:2340–2342. 8. Dogan E, Ulukus EC, Okyay E, et al. Retrospective analysis of follicle loss after laparoscopic excision of endometrioma compared with benign nonendometriotic ovarian cysts. Int J Gynaecol Obstet. 2011; 114:124–127. 9. Busacca M, Riparini J, Somigliana E, et al. Postsurgical ovarian failure after laparoscopic excision of bilateral endometriomas. Am J Obstet Gynecol. 2006;195:421–425. 10. Di Prospero F, Micucci G. Is operative laparoscopy safe in ovarian endometriosis? Reprod Biomed Online. 2009;18:167.
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11. Hwu YM, Wu FS, Li SH, et al. The impact of endometrioma and laparoscopic cystectomy on serum anti-M€ullerian hormone levels. Reprod Biol Endocrinol. 2011;9:80. 12. Fedele L, Bianchi S, Zanconato G, et al. Bipolar electrocoagulation versus suture of solitary ovary after laparoscopic excision of ovarian endometriomas. J Am Assoc Gynecol Laparosc. 2004;11:344–347. 13. Ferrero S, Ragni N, Fulcheri E. Lateral distribution of benign ovarian cysts. Int J Gynaecol Obstet. 2005;89:150–151. 14. Chang HJ, Han SH, Lee JR, et al. Impact of laparoscopic cystectomy on ovarian reserve: serial changes of serum anti-M€ullerian hormone levels. Fertil Steril. 2010;94:343–349. 15. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-cervical Mucus Interaction (1999). 4th edn. Cambridge: Cambridge University Press. 16. American Society for Reproductive Medicine: Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817–821. 17. Canis M, Pouly JL, Tamburro S, et al. Ovarian response during IVFembryo transfer cycles after laparoscopic ovarian cystectomy for endometriotic cysts of .3 cm in diameter. Hum Reprod. 2001;16: 2583–2586. 18. Li HW, Wong CY, Yeung WS, et al. Serum anti-m€ullerian hormone level is not altered in women using hormonal contraceptives. Contraception. 2011;83:582–585. 19. Donnez J, Nisolle M, Gillet N, et al. Large ovarian endometriomas. Hum Reprod. 1996;11:641–646. 20. Sutton CJG, Ewen SP, Jacobs SA, et al. Laser laparoscopic surgery in the treatment of ovarian endometrioma. J Am Assoc Gynecol Laparosc. 1997;4:319–323. 21. Beretta P, Franchi M, Ghezzi F, et al. Randomized clinical trial of two laparoscopic treatments of endometriomas: cystectomy versus drainage and coagulation. Fertil Steril. 1998;70:1176–1180. 22. Jones KD, Sutton CJ. Pregnancy rates following ablative laparoscopic surgery for endometriomas. Hum Reprod. 2002;17:782–785. 23. Alborzi S, Momtahan M, Parsanezhad ME, et al. A prospective, randomized study comparing laparoscopic ovarian cystectomy versus fenestration and coagulation in patients with endometriomas. Fertil Steril. 2004;82:1633–1637. 24. Ercan CM, Sakinci M, Duru NK, et al. Antimullerian hormone levels after laparoscopic endometrioma stripping surgery. Gynecol Endocrinol. 2010;26:468–472. 25. Iwase A, Hirokawa W, Goto M, et al. Serum anti-M€ullerian hormone level is a useful marker for evaluating the impact of laparoscopic cystectomy on ovarian reserve. Fertil Steril. 2010;94:2846–2849.
26. Yu HT, Huang HY, Soong YK, et al. Laparoscopic ovarian cystectomy of endometriomas: surgeons’ experience may affect ovarian reserve and live-born rate in infertile patients with in vitro fertilizationintracytoplasmic sperm injection. Eur J Obstet Gynecol Reprod Biol. 2010;152:172–175. 27. Fanchin R, Schon€auer LM, Righini C, et al. Serum anti-M€ullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod. 2003;18: 323–327. 28. Kwee J, Schats R, McDonnell J, et al. Evaluation of anti-M€ullerian hormone as a test for the prediction of ovarian reserve. Fertil Steril. 2008; 90:737–743. 29. Gruijters MJ, Visser JA, Durlinger AL, et al. Anti-M€ullerian hormone and its role in ovarian function. Mol Cell Endocrinol. 2003;211:85–90. 30. Ferrero S, Remorgida V, Venturini PL. Current pharmacotherapy for endometriosis. Expert Opin Pharmacother. 2010;11:1123–1134. 31. Pados G, Tsolakidis D, Assimakopoulos E, et al. Sonographic changes after laparoscopic cystectomy compared with three-stage management in patients with ovarian endometriomas: a prospective randomized study. Hum Reprod. 2010;25:672–677. 32. Alborzi S, Ravanbakhsh R, Parsanezhad ME, et al. A comparison of follicular response of ovaries to ovulation induction after laparoscopic ovarian cystectomy or fenestration and coagulation versus normal ovaries in patients with endometrioma. Fertil Steril. 2007;88:507–509. 33. Hart RJ, Hickey M, Maouris P, et al. Excisional surgery versus ablative surgery for ovarian endometriomata. Cochrane Database Syst Rev. 2008;2:CD004992. 34. Donnez J, Lousse JC, Jadoul P, et al. Laparoscopic management of endometriomas using a combined technique of excisional (cystectomy) and ablative surgery. Fertil Steril. 2010;94:28–32. 35. Saeki A, Matsumoto T, Ikuma K, et al. The vasopressin injection technique for laparoscopic excision of ovarian endometrioma: a technique to reduce the use of coagulation. J Minim Invasive Gynecol. 2010;17:176–179. 36. Ebert AD, Hollauer A, Fuhr N, et al. Laparoscopic ovarian cystectomy without bipolar coagulation or sutures using a gelantine-thrombin matrix sealant (FloSeal): first support of a promising technique. Arch Gynecol Obstet. 2009;280:161–165. 37. Hobday CD, Milam MR, Milam RA, et al. Postoperative small bowel obstruction associated with use of hemostatic agents. J Minim Invasive Gynecol. 2009;16:224–226. 38. Suzuki Y, Vellinga TT, Istre O, et al. Small bowel obstruction associated with use of a gelatin-thrombin matrix sealant (FloSeal) after laparoscopic gynecologic surgery. J Minim Invasive Gynecol. 2010;17: 641–645.
Hemostasis by Bipolar Coagulation Versus Suture After Surgical Stripping of Bilateral Ovarian Endometriomas: A Randomized Controlled Trial Simone Ferrero, PhD*, Pier Luigi Venturini, MD, David John Gillott, PhD, Valentino Remorgida, MD, and Umberto Leone Roberti Maggiore, MD From the Department of Obstetrics and Gynecology, San Martino Hospital and University of Genoa, Genoa, Italy (Drs. Ferrero, Venturini, Remorgida, and Leone Roberti Maggiore), and St. Bartholomew’s School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom (Dr. Gillott).
ABSTRACT Study objective: To estimate whether the suture of the ovary is superior to bipolar coagulation in preserving ovarian reserve in infertile women undergoing laparoscopic stripping of bilateral endometriomas. Design: Randomized controlled trial (Canadian Task Force classification I). Setting: University teaching hospital. Patients: 100 patients with bilateral endometriomas. Interventions: Patients underwent stripping of bilateral endometriomas and were randomized to undergo hemostasis by use of either laparoscopic suturing (LS group) or bipolar coagulation (BC group). Changes in ovarian reserve were investigated by measuring the levels of anti-Mullerian hormone (AMH) and basal follicle-stimulating hormone (FSH) before surgery and at 3, 6 and 12 months from surgery. Measurements and Main Results: At 3-month, 6-month, and 12-month follow-up, in both study groups, postsurgical AMH levels were significantly lower and basal FSH levels were significantly higher than before surgery. There was no significant difference in the mean percentage decrease of AMH levels in the BC group and LS group at 3-, 6-, and 12-month follow-up. The mean percentage increase in basal FSH was higher in the BC group than in the LS group at both 3-month (p 5 .023) and 6-month follow-up (p 5 .029), but not at 12-month follow-up. Pregnancy rate, time to conception, and rate of endometrioma recurrence was similar in the 2 study groups. Conclusion: Laparoscopic stripping of ovarian endometriotic cyst significantly decreases serum AMH levels and increases basal FSH levels independent from the method used to obtain hemostasis on the ovarian tissue. Journal of Minimally Invasive Gynecology (2012) 19, 722–730 Ó 2012 AAGL. All rights reserved. Keywords:
DISCUSS
AMH level; Bipolar coagulation; Endometrioma; FSH level; Stripping
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Laparoscopic cystectomy is currently used for the surgical treatment of ovarian endometriomas. However, several studies have indicated that the laparoscopic exciThe authors declare that they have no conflict of interest. Corresponding author: Simone Ferrero, MD, PhD, Department of Obstetrics and Gynecology, San Martino Hospital, Largo R. Benzi 1, 16132 Genoa, Italy. E-mail: [email protected] Submitted February 9, 2012. Accepted for publication August 2, 2012. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2012 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2012.08.001
sion of ovarian endometriomas might reduce ovarian reserve [1–4] and decrease the response of the ovaries to hormonal stimulation for assisted reproductive technologies [5–7]. Several mechanisms may contribute to damage of the ovary during surgery including the removal of healthy ovarian tissue [8] and thermal destruction of ovarian follicles by excessive use of bipolar coagulation for hemostasis purposes. In line with these hypotheses, some cases of premature ovarian failure have been reported after surgical treatment of bilateral endometriomas [9–11].
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Although the stripping technique is still widely used for the treatment of ovarian endometriomas, few studies investigated whether the use of bipolar coagulation or laparoscopic suturing to obtain hemostasis could affect ovarian reserve. One nonrandomized study compared bipolar coagulation and laparoscopic suture of the ovary in 46 patients with unilateral endometriomas, which had previous contralateral oophorectomy [12]. This study suggested that patients undergoing laparoscopic suturing of the ovary have lower postoperative follicle-stimulating hormone (FSH) levels when compared with patients undergoing bipolar coagulation of the ovary. A more recent trial assessed ovarian reserve in 45 patients undergoing laparoscopic stripping of unilateral endometriomas, which were randomized for treatment by either suturing or bipolar coagulation [4]. In the 3 postoperative menstrual cycles, the reduction in antral follicle count was significantly lower in sutured ovaries than in those that were coagulated. Ovarian endometriomas are more frequently bilateral than nonendometriotic cysts [13], and therefore the treatment of bilateral disease may significantly affect ovarian reserve [11,14]. This prospective randomized study aims to estimate whether the suture of the ovary is superior to bipolar coagulation in preserving ovarian reserve in infertile women undergoing laparoscopic stripping of bilateral endometriomas.
metriotic ovarian cysts; suspicion of malignant ovarian disease; use of hormonal therapies in the 4 months before inclusion in the study; desire of the patients to use hormonal therapies after surgery. Patients were recruited and underwent surgery between June 2007 and September 2010. The study was approved by the local research ethics committee. Patients enrolled in the study signed a written consent form.
Materials and Methods
Ultrasonographic evaluation of the endometriotic cyst was performed on the day of surgery. The number of endometriotic cysts in each ovary was recorded. The mean diameter of each endometriotic cyst was calculated by measuring the 3 perpendicular dimensions of the cyst. In each patient, the total endometrioma diameter was defined as the sum of the mean diameter of each endometrioma in both the ovaries.
This study included women of reproductive age with bilateral endometriomas with largest diameter R3 cm. All the patients had tried to conceive for at least 1 year before enrollment in the study; male partners had normal semen parameters according to criteria from the World Health Organization for sperm analysis (a sperm concentration of R20 ! 106/mL R50% motility and R30% novel structure, R75% viability with %1 ! 106/mL white blood cells) [15]; and patients wished to spontaneously conceive after surgery. The primary aim of the study was to estimate whether, in infertile women undergoing surgical excision of bilateral endometriomas, the suture of the ovary is superior to bipolar coagulation in preserving ovarian reserve as assessed by use of serum anti-Mullerian hormone (AMH) levels. Secondary aims of the study were to estimate the effects of surgery on basal FSH levels, to assess whether there is a correlation between the size of the endometriomas and ovarian reserve markers (AMH and basal FSH), and to evaluate the pregnancy rate and the rate of endometriomas recurrence at 1-year from surgery. Exclusion criteria for the study were as follow: age R40 years; previous ovarian surgery; previous surgery for endometriosis; evidence of polycystic ovary syndrome (according to the Rotterdam criteria), premature ovarian failure, and any other endocrine diseases (such as thyroid dysfunction, hyperprolactinemia or Cushing’s syndrome); bilateral tubal occlusion (demonstrated before surgery by hysterosalpingography); uterine malformations; presence of nonendo-
Assessment of Ovarian Reserve Venous blood samples were drawn within three months before surgery and after 3, 6, and 12 months from surgery. Ovarian reserve was estimated by measuring the levels of AMH and the levels of FSH on day 2–3 of the menstrual cycle. AMH was assayed with a commercial enzyme-linked immunosorbent assay (Diagnostic Systems Laboratories, Webster, TX). The AMH assay has a sensitivity of 0.006 ng/mL; the intraassay and interassay coefficients of variation were 9.4% and 7.2%. FSH levels were analyzed with the the Immulite 2000 immunoassay system (Diagnostic Products, Los Angeles, CA). The FSH assay has a sensitivity of 0.1 mIU/mL; the intraassay and interassay coefficients of variation were 4.6% and 6.3%, respectively. Ultrasonographic Evaluation of the Endometriotic Cyst
Randomization and Surgical Procedures Randomization was performed by a statistician who used the Random Allocation software version 1.00 (Isfahan University of Medical Sciences, Isfahan, Iran) and who had no other role in the study. A blocked randomization technique was used to ensure that the number of subjects assigned to each group was equally distributed; block size varied randomly to reduce the likelihood of foreknowledge of intervention assignment. Allocation was sealed in consecutively numbered opaque envelopes. Surgical procedures were performed by a team of surgeons with extensive experience in the treatment of endometriosis. During laparoscopy, on commencing the removal of the endometriotic cysts, patients were randomized to undergo hemostasis by use of either laparoscopic suturing or bipolar coagulation. The sealed opaque envelopes were opened by a surgical nurse. Laparoscopy was performed by use of a 10-cm sheath for the camera and three 5-mm ports for the operative instruments. The severity of endometriosis was classified
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by use of the classification of the American Society for Reproductive Medicine [16]. In each patient, the same hemostatic technique was used for all the endometriomas. In both study groups, ovarian endometriomas were excised by using the stripping technique. Adhesiolysis was performed to release the ovaries from the surrounding structures if required. If the ovarian cysts remained unruptured despite manipulation, they were punctured to drain and aspirate the chocolate content of the cyst. The cyst wall was stripped from the healthy surrounding ovary by traction and countertraction, which was achieved by use of 2 or 3 atraumatic grasping forceps. In patients randomized to receive hemostasis by bipolar coagulation, when the cleavage became difficult, the red fibrotic tissue on the surface of the cyst wall was coagulated with bipolar forceps (20 W–30 W current) and cut as previously described by other authors [17]. After the removal of the cyst, bipolar coagulation was used as minimally as possible, only to control significant bleeding. In patients randomized to receive hemostasis by laparoscopic suturing (LS) group, no bipolar coagulation was performed during or after the stripping of the cyst. The suture was performed with intraovarian knots by use of 1 or 2 absorbable sutures (2-0 Vicryl; Ethicon Inc., Somerville, NJ). Follow-up Follow-up was performed at 3, 6, and 12 months after surgery. Although AMH levels are not affected by the use of hormonal therapies [18], patients requesting hormonal therapies during the follow-up were excluded from the study. Pregnancy was defined as a positive serum b–human chorionic growth hormone (b-hCG) test result with ultrasound evidence of a gestational sac and fetal heart. Power Calculation The primary aim of this study was to estimate whether the suture of the ovary is superior to bipolar coagulation in preserving ovarian reserve after surgical excision of endometriomas. Serum AMH levels were chosen as the best marker for evaluating the impact of laparoscopic cystectomy on ovarian reserve. At the time of the study design, because of the lack of publications describing the changes of ovarian reserve markers after surgical excision of bilateral ovarian endometriomas, a pilot study was conducted to define the sample size needed. AMH levels were measured before surgery and at 12 months from surgery in 15 women who underwent laparoscopic stripping of bilateral ovarian endometriomas and hemostasis by bipolar coagulation (mean change 6 SD, 1.52 6 0.72 ng/mL). It was hypothesized that a 30% difference in AMH levels between the 2 surgical techniques could be considered clinically relevant. To have an 80% chance of detecting such a difference at an overall statistical significance level of 5%, 31 patients per group were required (1-sided test). A 1-sided test was used in the power calculation because pre-
vious studies suggested that bipolar coagulation for hemostasis purposes may decrease ovarian reserve [9–11]; in contrast, there is no evidence that the suture of the ovary may affect ovarian reserve. Previous studies showed that up to 50% of the patients undergoing surgery for endometriomas might spontaneously conceive after laparoscopy [19–23]. Allowing for conceptions and dropouts, the aim of this study was to recruit about 50 patients in each study group. Statistical Analysis Chi-square test and Fisher’s exact test were used to compare the proportions. The Kolmogorov-Smirnov test was used to assess the normality of distribution of continuous variables. Friedman repeated measures analysis of variance on ranks (followed by Tukey testing when appropriate) was used to compare the changes in AMH and basal FSH before surgery and at follow-up. The Student t test and the MannWhitney rank sum test were used to compare the percentage changes in the levels of AMH and basal FSH between the 2 study groups. Spearman’s rank correlation coefficient was used to investigate whether there was a correlation between the total endometrioma diameter and the changes in AMH and basal FSH levels. Analysis was performed according to the intention to treat principle. Data were analyzed with the Sigma Stat software version 3.5 and the SPSS software version 13.0 (SPSS Science, Chicago, IL). A p value ,.05 was considered statistically significant. Results Of 121 women eligible for the study, 100 patients agreed to participate. Fifty were included in the BC group and 50 in the LS group. All the procedures were completed by laparoscopy. In 1 patient included in the LS group, bipolar coagulation was required to control ovarian bleeding. The diagrammatic flow of the participants is given in Figure 1. Table 1 shows the characteristics of the study population, the mean age of the patients and the mean diameter of the larger endometriotic cyst being similar in the 2 study groups. All procedures were completed by laparoscopy; no patient had development of postoperative bleeding requiring further surgery. The level of preoperative AMH was also similar in the two study groups (median, range: 2.7 ng/ml, 0.68–10.5 ng/ mL in the LS group and 2.3 ng/mL, 0.63–9.45 in the BC group; p 5 .441). In both the LS group and the BC group, the Friedman repeated measures analysis of variance on ranks showed that AMH levels were significantly different before surgery, at 3-month, 6-month, and 12-month follow-up (p , .001). The post-hoc Tukey test revealed that AMH levels were significantly lower at 3-month, 6-month, and 12-month follow-up when compared with preoperative levels (p , .05; Fig. 2). The level of preoperative basal FSH was similar in the 2 study groups (median, range: 6.4 mIU/mL, 3.8– 11.6 mIU/mL in the LS group, and 6.3 mIU/mL,
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Fig. 1 Flow chart shows recruitment and women’s progress through the study.
3.7–11.3 mIU/mL in the BC group; p 5 .780). In the LS group, the Friedman repeated measures analysis of variance on ranks showed that basal FSH levels were significantly different before surgery, at 3-, 6-, and 12-month follow-up (p , .001). The post-hoc Tukey test revealed that basal FSH levels were significantly higher at 3-month and 12-month follow-up when compared with preoperative levels (p , .05). In the BC group, the Friedman repeated measures analysis of variance on ranks showed that basal FSH levels were significantly different before surgery, at 3-month, 6-month, and 12-month follow-up (p , .001). The post-hoc Tukey test revealed that basal
FSH levels were significantly higher at 3-month, 6-month, and 12-month follow-up when compared with preoperative levels (p , .05; Fig. 3). No significant difference was observed in the mean percentage decrease of AMH levels between BC and LS groups at 3-month follow-up (p 5 .173, Mann-Whitney rank sum test), at 6-month follow-up (p 5 .892), and at 12-month follow-up (p 5 .834). The mean percentage increase in basal FSH was higher in the BC group than in the LS group at both 3-month (p 5 .023) and 6-month follow-up (p 5 .029). At 12-month follow-up, there was no significant difference in the mean percentage increase
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Table 1 Characteristics of the study population
Age (years, mean 6 SD; 95% CI) Patients with previous live birth (n [%; 95% CI]) ASRM points (median [range]) [16] Number of endometriotic cysts (n [median, range]) Diameter of the larger endometriotic cyst (cm, mean 6 SD [95% CI]) Total endometrioma diameter (cm, mean 6 SD [95% CI]) Side of the larger endometriotic cyst (n [%; 95% CI]) Left Right
BC group (n 5 50) 31.9 6 4.0 (30.7–33.0) 8 (16.0%; 7.2%–29.1%) 62.5 (45–121) 2 (2–3) 7.4 6 2.9 (6.6–8.2) 12.7 6 5.7 (14.3–11.0)
LS group (n 5 50) 32.1 6 3.7 (31.0–33.1) 6 (12.0%; 4.5%–24.3%) 66 (49–128) 2 (2–3) 7.5 6 2.4 (6.8–7.5) 12.3 6 3.7 (13.3–11.2)
30 (60.0%; 45.2%–73.6%) 20 (40.0%; 26.4%–54.8%)
34 (68.0%; 53.3%–80.5%) 16 (32.0%; 19.5%–46.7%)
p value .777* .773 .271y .758 .926* .791* .532
* Normally distributed data analyzed by use of the Student t test. y Nonparametric data analyzed by use of the Mann-Whitney rank sum test.
in serum FSH in BC group when compared with LS group (p 5 .133) (Fig. 4). At 3- and 12-month follow-up, total endometrioma diameter was correlated with the percentage change in AMH levels in both study groups. At 6-month follow-up, total endometrioma diameter was correlated with the percentage change in AMH levels only in the BC group. No correlation was observed between total endometrioma diameter and the percentage change in basal FSH levels in the BC group. At 6- and 12-month follow-up, total endometrioma diameter was correlated with the percentage change of basal FSH (Table 2).
Fig. 2 Changes in AMH levels during follow-up in the 2 study groups.
The pregnancy rate was 30.0% (15/50; 95% CI, 17.9%– 44.6%) in the LS group and 36.0% (18/50; 95% CI, 22.9%–50.8%) in the BC group (p 5 .671). The time between surgery and conception was similar in the 2 study groups (median, range: 5 months, 2–11 months in the LS group and 5 months, 2–11 months in the BC group; p 5 .853). Patients who conceived during follow-up (n 5 33) had significantly higher preoperative AMH levels (median, range: 3.2 ng/mL, 0.9–10.5 ng/mL) than those who did not conceive (median, range: 2.1 ng/mL, 0.6–9.5 ng/mL; p 5 .010). Similarly, patients who conceived during
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Fig. 3 Changes in basal FSH levels during follow-up in the 2 study groups.
follow-up had significantly lower preoperative basal FSH levels (median, range: 5.4 mIU/mL, 3.8–9.2 mIU/mL) than those who did not conceive (median, range: 6.6 mIU/ml, 3.7–11.6 mIU/mL; p , .001). Nine women conceived before the first postoperative measurement of ovarian reserve
markers at 3-month follow-up. Patients who conceived after the 3 month follow-up (n 5 24) had significantly higher AMH levels at 3-month follow-up (median, range: 2.5 ng/mL, 0.8–10.1 ng/mL) than those who did not conceive (median, range: 1.9 ng/ml, 0.3–8.2 ng/mL; p 5 .033).
Fig. 4 Percentage changes of AMH and basal FSH during follow-up in the 2 study groups.
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Table 2 Correlation between total endometrioma diameter and percentage change in ovarian reserve markers
AMH 3 months 6 months 12 months Basal FSH 3 months 6 months 12 months
BC group
LS group
rs 5 20.450; p 5 .01 rs 5 20.559; p 5 .01 rs 5 20.648; p 5 .01
rs 5 20.301; p 5 .05 rs 5 20.171; p 5 .305 rs 5 20.369; p 5 .05
rs 5 0.110; p 5 .473 rs 5 0.004; p 5 .980 rs 5 0.109; p 5 .566
rs 5 0.207; p 5 .167 rs 5 0.339; p 5 .05 rs 5 0.008; p 5 .01
rs 5 Spearman correlation coefficient.
Similarly, patients who conceived after the 3-month followup had significantly lower basal FSH level at 3-month follow-up (median, range: 6.1 mIU/mL, 4.3–10.3 mIU/ mL) than those who did not conceive (median, range: 7.2 mIU/ml, 3.5–16.2 mIU/mL; p 5 .011). At 12-month follow-up, 64 patients had not conceived or used hormonal therapies. Recurrence of endometrioma was observed in 3 patients (6.0%; 95% CI, 1.3%–16.5%) in the LS group and in 1 patient (3.2%; 95% CI, 0.1%–10.6%) in the BC group (p 5 .617). Discussion Few previous studies investigated the effects of excision of ovarian bilateral endometriomas on ovarian reserve. One study including 14 patients reported that laparoscopic stripping of bilateral endometriomas combined with bipolar coagulation does not significantly decrease postoperative AMH levels measured 32.5 days after surgery [24]. In contrast, a more recent study including 13 women with bilateral endometriomas treated by stripping of the cyst and bipolar coagulation showed a significant postoperative decrease in the AMH levels at 1 month after surgery [25]. However, decreased serum AMH levels observed at 1 month after surgery may recover at longer follow-up, although the degree of recovery is decreased in patients treated for bilateral disease [14]. In this investigation, AMH levels were measured at 3 months from surgery when it is likely that a complete recovery of ovarian function is obtained. Our data clearly demonstrate that the laparoscopic stripping of bilateral ovarian endometriotic cyst significantly decreases serum AMH levels (Fig. 2) and increases basal FSH level (Fig. 3) independent from the method used to obtain hemostasis on the ovarian tissue. These observations are in line with the findings of a recent retrospective study demonstrating that at more than 6 months from surgery, patients treated with stripping of bilateral ovarian endometriomas (n 5 66) have serum AMH levels significantly lower than patients treated for unilateral endometriomas (n 5 81) [11].
When the technique used to perform the hemostasis was considered, patients treated with either laparoscopic suturing or bipolar coagulation had no significant difference in the percentage change of AMH levels at 3-, 6-, and 12-month follow-up. The percentage increase in basal FSH levels was significantly higher in patients treated with bipolar coagulation than in those treated with laparoscopic suturing at 3- and 6-month follow-up; however, this difference was not observed at 12-month follow-up. These results suggest that the accurate use of bipolar coagulation to achieve hemostasis after stripping of ovarian endometriomas does not have a major detrimental effect on ovarian reserve. This observation is in contrast with the findings of a recent randomized trial by Coric et al [4] reporting lower antral follicle count in patients treated with bipolar coagulation of the ovary than in those treated with suturing of the ovary after laparoscopic stripping of unilateral endometriomas. These different results are even more surprising considering that their study included patients with unilateral endometriomas and mean diameter of about 4 cm, whereas our study included patients with bilateral endometriomas and a mean diameter of about 7 cm. However, in the study by Coric et al [4], bipolar coagulation was performed after the completion of the stripping of the ovarian cyst. By contrast, in our investigation, bipolar coagulation was used when the cleavage plane of the cyst became difficult as previously described by Canis et al [17]. The use of bipolar coagulation during stripping of the cyst may not only reduce the ovarian bleeding but may also facilitate the stripping of the cyst. In addition, during the stripping of the cyst the identification of normal ovarian tissue and endometrioma might be difficult for the surgeon; therefore we cannot exclude the possibility that surgical experience influenced the postoperative ovarian reserve. A retrospective study including patients undergoing laparoscopic stripping of endometriomas combined with bipolar coagulation demonstrated that the postoperative antral follicle count is significantly lower when inexperienced surgeons perform the laparoscopic procedure [26]. Alternatively, it is possible that, in our study, the laparoscopic suture induced ischemic damage to the ovary, thus reducing ovarian reserve in this study group. A limitation of this study is that we did not record the time required to perform ovarian surgery or to perform the hemostasis on the ovary. Therefore we cannot estimate whether achieving hemostasis by laparoscopic suturing requires more time than use of bipolar coagulation. However, we could perform adequate ovarian hemostasis in most of the patients and in a reasonable amount of time. Although analyzing the association of decreased AMH levels with reproductive outcome was not our main objective, no significant difference was observed in the pregnancy rate and time to conceive between patients included in the 2 study groups. However, because of the study design, we cannot exclude the possibility that the study was underpowered to detect a significant difference in reproductive outcome of the 2 groups. The 12-month cumulative pregnancy rates observed
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in this study were 30% in the LS group and 36% in the BC groups. These pregnancy rates are apparently lower than those previously reported by other authors after laparoscopic cystectomy of endometriomas, which are higher than 50% [21,23]. However, this study included only infertile patients, whereas previous investigations included patients who underwent surgery because of pain, ovarian cyst, or infertility. Furthermore, this study included only patients with bilateral endometriomas, whereas most of the subjects of previous studies had unilateral disease. The differences in study design may justify the lower pregnancy rate observed in this study. In this investigation, patients who conceived had higher AMH levels and lower basal FSH levels than patients who did not conceive, both before surgery and at 3-month follow-up. These observations confirm the importance of determining the levels of ovarian reserve markers before surgery in patients undergoing laparoscopy for the treatment of bilateral ovarian endometriomas. This information allows provision of adequate counseling to the patients regarding the risk of poor post-operative ovarian function. In this respect, AMH may be preferred to other ovarian reserve markers (such as basal FSH and antral follicle count). In fact, AMH is a good indicator ovarian recruitable follicular pool and thus of ovarian reserve [27,28]. It has higher intercycle and intracycle reproducibility than other ovarian reserve markers. The levels of AMH are independent of the phase of the menstrual cycle [29], and they are not influenced by the administration of hormonal contraceptives [18], which are commonly used for treating endometriosis [30]. Several techniques have been proposed for preserving ovarian reserve in women requiring surgery for ovarian endometriomas. Two recent randomized trials compared the effects on ovarian reserve caused by cystectomy or by a 3-step procedure consisting of laparoscopic drainage of the cyst content, administration of GnRH agonist for 3 months and second laparoscopy to vaporize the internal wall of the cyst by use of CO2 laser [1,31]. One study including 20 patients with ovarian endometriomas showed that at 6 months after surgery, AMH levels were significantly less decreased in patients undergoing the 3-step procedure than in those undergoing cystectomy. Similarly, a nonsignificant trend for lower basal FSH values was observed in patients treated with the 3-step procedure than in those undergoing cystectomy [1]. A second investigation including 20 patients with endometriomas showed that at 6 months following surgery, antral follicle count was higher in patients treated with the 3-step procedure than in those who underwent cystectomy [31]. Previous studies that compared cystectomy with drainage and ablation by electrosurgery reported a more favorable outcome (response to ovarian stimulation and pregnancy rate) in patients treated with cystectomy [21,23,32,33]. However, these studies used bipolar coagulation instead of CO2 laser for the ablation, thus increasing the risk of thermal damage to the ovary. A mixed technique of excisional and ablative surgery has also been proposed for the treatment of
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endometriomas in a recent prospective study [34]. In 52 women with unilateral endometriomas, the stripping of the cyst was halted when approaching the ovarian hilus where the cleavage plane is usually not clearly visible, and CO2 laser was used to vaporize the remaining 10%–20% of the endometrioma. Six months after surgery the volume of the operated ovary and the antral follicle count were similar to the nonoperated ovaries [34]. Other techniques have been proposed to preserve ovarian reserve during the stripping of endometriotic cysts. A recent randomized prospective study including 15 women with single endometrioma suggested that the injection of vasopressin during laparoscopic excision of endometriomas reduces the use of coagulation and thus may protect ovarian reserve [35]. Other authors proposed the use of a gelantine-thrombin-matrix sealant (FloSeal; Baxter, Deerfield, IL) to control post-cystectomy ovarian wound bleeding [36]; however, the use of this hemostatic agent has been associated with small bowel obstruction in patients undergoing gynecologic surgery [37,38]. In conclusion, this study confirms that the surgical stripping of bilateral endometriomas causes a significant decrease in ovarian reserve independent from the method used for obtaining hemostasis on the ovary. The accurate use of bipolar coagulation during the stripping of bilateral endometriomas does not have a major detrimental effect on ovarian reserve. References 1. Tsolakidis D, Pados G, Vavilis D, et al. The impact on ovarian reserve after laparoscopic ovarian cystectomy versus three-stage management in patients with endometriomas: a prospective randomized study. Fertil Steril. 2010;94:71–77. 2. Hirokawa W, Iwase A, Goto M, et al. The post-operative decline in serum anti-Mullerian hormone correlates with the bilaterality and severity of endometriosis. Hum Reprod. 2011;26:904–910. 3. Var T, Batioglu S, Tonguc E, et al. The effect of laparoscopic ovarian cystectomy versus coagulation in bilateral endometriomas on ovarian reserve as determined by antral follicle count and ovarian volume: a prospective randomized study. Fertil Steril. 2011;95:2247–2250. 4. Coric M, Barisic D, Pavicic D, et al. Electrocoagulation versus suture after laparoscopic stripping of ovarian endometriomas assessed by antral follicle count: preliminary results of randomized clinical trial. Arch Gynecol Obstet. 2011;283:373–378. 5. Esinler I, Bozdag G, Aybar F, et al. Outcome of in vitro fertilization/intracytoplasmic sperm injection after laparoscopic cystectomy for endometriomas. Fertil Steril. 2006;85:1730–1735. 6. Benaglia L, Somigliana E, Vighi V, et al. Rate of severe ovarian damage following surgery for endometriomas. Hum Reprod. 2010;25:678–682. 7. Almog B, Sheizaf B, Shalom-Paz E, et al. Effects of excision of ovarian endometrioma on the antral follicle count and collected oocytes for in vitro fertilization. Fertil Steril. 2010;94:2340–2342. 8. Dogan E, Ulukus EC, Okyay E, et al. Retrospective analysis of follicle loss after laparoscopic excision of endometrioma compared with benign nonendometriotic ovarian cysts. Int J Gynaecol Obstet. 2011; 114:124–127. 9. Busacca M, Riparini J, Somigliana E, et al. Postsurgical ovarian failure after laparoscopic excision of bilateral endometriomas. Am J Obstet Gynecol. 2006;195:421–425. 10. Di Prospero F, Micucci G. Is operative laparoscopy safe in ovarian endometriosis? Reprod Biomed Online. 2009;18:167.
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