The impact of electrocoagulation on ovarian reserve after laparoscopic excision of ovarian cysts: a prospective clinical study of 191 patients

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1 The impact of electrocoagulation on ovarian reserve after laparoscopic excision of ovarian s: a prospective clinical study of 191 patients Chang-Zhong Li, M.D., a Bo Liu, M.D., b Ze-Qing Wen, M.D., a and Qiang Sun, Ph.D. c a Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, b Department of Oncology, Shandong Tumor Hospital; and c School of Public Health, Shandong University, Jinan, People s Republic of China Objective: To investigate the impact of electrocoagulation on ovarian reserve after laparoscopic excision of ovarian s and the possible mechanisms. Design: A prospective study. Setting: Obstetrics and Gynecology Department of a university hospital. Patient(s): 191 patients with benign ovarian s undergoing ovarian ectomy. Intervention(s): Laparoscopic ovarian ectomy using bipolar or ultrasonic scalpel electrocoagulation and laparotomic ovarian ectomy using sutures after the excision of ovarian s. Main Outcome Measure(s): Follicle-stimulating hormone (FSH) assay and transvaginal ultrasound evaluating basal antral, mean ovarian diameter, and ovarian stromal blood flow velocity at day 3 of menstrual cycles 1, 3, 6, and 12 after surgery. Result(s): When comparing the bipolar group and ultrasonic scalpel group with the suture group, a statistically significant increase of the mean FSH value was found in bilateral- patients at 1-, 3-, 6-, and 12-month follow-up evaluations and in unilateral- patients at the 1-month follow-up evaluation. Statistically significant decreases of basal antral and mean ovarian diameter were found during the 3-, 6-, 12-month follow-up evaluations as well as statistically significant decreases of peak systolic velocity at all of the follow-up evaluations. Conclusion(s): Electrocoagulation after laparoscopic excision of ovarian s is associated with a statistically significant reduction in ovarian reserve, which is partly a consequence of the damage to the ovarian vascular system. (Fertil Steril Ò 2009;92: Ó2009 by American Society for Reproductive Medicine.) Key Words: Ovarian s, laparoscopic ovarian ectomy, electrocoagulation, ovarian reserve Received June 30, 2008; revised August 5, 2008; accepted August 7, 2008; published online October 20, C-Z.L. has nothing to disclose. B.L. has nothing to disclose. Z-Q.W. has nothing to disclose. Q.S. has nothing to disclose. Reprint requests: Chang-Zhong Li, M.D., Department of Obstetrics and Gynecology, Shandong Provincial Hospital, 324 Jing Wu Lu, Jinan , People s Republic of China (FAX: ; lichangzhong@hotmail.com). Laparoscopic ovarian ectomy is currently considered the treatment of choice in women with benign ovarian s and has gained increasing acceptance among gynecologic surgeons (1). However, the safety of this technique in terms of ovarian damage to the operated gonad has recently been questioned. A great deal of evidence supports that the removal of ovarian s is associated with injury to the ovarian reserve (2 7). Many of these studies involved patients who required assisted reproduction (3 6), and they found that the number both of follicles and retrieved oocytes obtained in the operated gonad during ovarian hyperstimulation was markedly reduced when compared with the contralateral intact ovary. However, most of these studies applied ovarian response to gonadotropin hyperstimulation to measure the ovarian reserve. It has been argued that these patients are not representative of all patients undergoing laparoscopic ovarian ectomy in terms of ovarian damage because these data were acquired from aggressive gonadotropin stimulation, which is thought to be different from a natural menstrual cycle (7). On the other hand, because ovarian reserve cannot be measured directly, the evaluation of ovarian reserve is difficult to carry out. The induction of ovarian hyperstimulation in an unselected population of surgical patients for the purpose of evaluating ovarian reserve is obviously ethically untenable. The serum level of follicle-stimulating hormone (FSH) is a predictor of functional ovarian reserve (8), but its usefulness is limited considering that the vast majority of patients undergo monolateral excision of a and the contralateral intact gonad may completely substitute for reduced function of the operated ovary (9). Given the well-established role of ultrasound scanning in the diagnosis and follow-up of ovarian s, Frattarelli et al. (10) and Candiani et al. (7) reported that basal antral and mean ovarian diameter could be used as indicators of ovarian reserve. Engmann et al. (11) found that the value of ovarian stromal blood flow velocity was an initial marker of ovarian reserve before the change of FSH level and ovarian volume. With the combined use of serum hormonal evaluation and ultrasound examination, we prospectively investigated the ovarian reserve of 191 patients after the excision of benign ovarian s. The damage to ovarian reserve was evaluated during through a 12-month follow-up period after the 1428 Fertility and Sterility â Vol. 92, No. 4, October /09/$36.00 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 application of bipolar, ultrasonic scalpel electrocoagulation or suture for ovarian ectomy. MATERIALS AND METHODS Patients This study was conducted from November 2003 to May 2007 at the Department of Obstetrics and Gynecology of Shandong Provincial Hospital of China, and the study was approved by the institutional review board of Shandong Provincial Hospital. Before enrollment, every patient who received a diagnosis of ovarian s was instructed to observe at least two menstrual cycles, at which point repeated day-3 ultrasound examinations were performed to determine whether the size remained the same or became bigger. No oral contraceptives or other treatments were applied to the ovarian s. Inclusion criteria were as follows: [1] age 18 to 40 years; [2] uni/bilateral ovarian (s) without clinical and sonographic suspicion of ovarian cancer; [3] regular menstrual cycles defined as a cycle length between 25 and 35 days in the 6 months before surgery; and [4] agreement to be enrolled in the study. Exclusion criteria were as follows: [1] prior ovarian surgery; [2] surgical necessity to perform adnexectomy; [3] known endocrine disease; [4] postoperative pathologic diagnosis that was not benign ovarian ; and [5] oral contraceptive use before surgery. Written informed consent from all patients was obtained. Procedures The serum FSH level of all the patients enrolled in this study was determined by radioimmunoassay (Diagnostic Products Corporation, Co., Tianjin, China) on day 3 of the cycle before the surgical procedure. A transvaginal ultrasound (Aloka SSD-1000 with multifrequency convex endovaginal transducer UST ; Aloka Co., Tokyo, Japan) examination was systematically performed before surgery to confirm the diagnosis of ovarian and precisely record the dimensions of the. All patients were informed about alternative therapeutical approaches, and the patients chose between laparoscopy or a transabdominal open procedure to remove the (s). Patients who agreed to laparoscopic surgery were prospectively randomized into the bipolar group or the ultrasonic scalpel group by means of a computer-generated randomized allocation schedule provided by the study s statistician. Laparoscopic ovarian ectomy was performed with 10-mm laparoscope (Richard Wolf GmBH, Knittlingen, Germany). After initial diagnostic evaluation of the pelvis and abdomen and washing, every effort was made to excise the without spilling its contents, especially when the ultrasound diagnosis had revealed a dermoid. When the was ruptured during the surgery, the contents were aspirated and the inner wall of the was checked for possible vegetations. Removal of the was carried out carefully by identifying the wall and removing it from the ovarian cortex by traction with grasping forceps. For patients in the bipolar group, the bed was treated by careful desiccation of all bleeding sources using a Wolf bipolar forceps (Richard Wolf) at a power of 40 Watt for coagulation. For the patients in ultrasonic scalpel group, an ultrasonic harmonic scalpel (Ultracision G220; Johnson & Johnson/Ethicon, Cincinnati, OH) with coagulation mode at power level 3 was applied gently for hemostasis when necessary. No sutures were used for reapproximation of the ovarian edges. For patients who did not want to undergo laparoscopic surgery, conventional laparotomic ovarian ectomy was applied. After peritoneal cytology and inspection of the peritoneal cavity, the was freed and then carefully excised. We applied 3-0 absorbable sutures (Ethicon Inc. New Jersey) to reapproximate the edges of the ovary and to achieve a satisfying hemostasis. No electrocoagulation was used for hemostasis. Both laparoscopic and open procedures for removal were performed by the same skilled surgical team. Frozen sections were obtained, and the diagnosis was confirmed histologically for every patient. Follow-up All patients were asked to return on day 3 of menstrual cycles 1, 3, 6, and 12 after their surgery, at which point an FSH assay was performed. The interassay and intra-assay coefficients of variation for FSH were 6.6% and 5.4%, respectively. Transvaginal ultrasound examinations were performed by two senior radiologists, each of whom has more than 10 years of experience. The operators were blinded as to the side of previous surgery. The Aloka SSD-1000 with multi frequency convex endovaginal transducer UST is capable of measuring 3-mm antral follicles in diameter. All ovarian follicles measuring 3 mm to 10 mm on both ovaries were counted. Using the largest crosssectional sagittal view of the ovary, the averaged ovarian diameters for each patient were calculated by measuring two perpendicular diameters. The stromal blood flow of the ovary was assessed by color Doppler ultrasound. Flow velocity waveforms were obtained from stromal blood vessels away from the ovarian capsule and the utero-ovarian ligament. The gate of the Doppler was positioned when a vessel with good color signals was identified on the screen. The peak systolic velocity of stromal vessels was calculated electronically when at least three similar, consecutive waveforms of good quality were obtained. Statistical Analysis Statistical analyses were performed with Statistics Package for Social Sciences software (SPSS, Inc., Chicago, IL) version 11.5 for windows. Qualitative data were expressed as number and compared using chi-squared test. Quantitative data were expressed as the mean standard deviation Fertility and Sterility â 1429

3 TABLE 1 Characteristics of patients. Bipolar Ultrasonic scalpel Suture Characteristic s s s P value Number Pregnancy b NS Dropout c NS Age NS Cyst size (cm) NS Blood loss (ml) <.05 a Cyst type Endometrioma NS Others NS Notes: Data are presented as mean standard deviation or number. NS ¼ not statistically significant. a Suture group versus bipolar group or ultrasonic scalpel group. b Pregnancies occurred in four patients after postoperative menstrual cycle 3 and in another seven patients after the postoperative menstrual cycle 6. c A total of 14 patients dropped out for unknown reasons. (SD), and analysis of variance (ANOVA) with Newman- Keuls follow-up test was used for multiple comparisons between means. P<.05 was considered statistically significant. RESULTS Characteristics of Patients According to the inclusion criteria, a total of 192 patients enrolled in this study. One patient who underwent laparotomy was excluded after a diagnosis of ovarian carcinoma by frozen section, and she was treated accordingly. During the study period, 191 patients were found to be eligible. There were no intraoperative or postoperative complications and no blood loss more than 200 ml. The general patient characteristics are presented in Table 1. There was no significant difference for any of the variables considered except the suture group experience greater blood loss. Pregnancies occurred in four patients after the third postoperative menstrual cycle and in seven patients after the sixth postoperative menstrual cycle; those patients were no longer followed for the study. Fourteen patients dropped out during the follow-up period, so the number of patients varied for every follow-up interval (Table 2). The data from before pregnancy or dropout were also included in the statistics. FSH Assay Because of the damage to the ovary is different for unilateral and bilateral s, the patients were subdivided accordingly when analyzing their FSH values before surgery and during the 12-month follow-up period. All patients had normal FSH values preoperatively. The curves of the FSH value before surgery and during the 12-month follow-up period are shown in Figure 1. Comparing the suture group with the bipolar group and the ultrasonic scalpel group, a statistically significant difference of the mean FSH value was seen in the bilateral- patients during all the 12-month follow-up period and in the unilateral- patients only at the 1-month follow-up visit. Transvaginal Ultrasound Examinations For the unilateral- patients, as shown in Table 2, no difference was detected for the quantitative data of the intact ovary among the three groups. At the 1-month follow-up visit, the peak systolic velocity of the operated group decreased statistically significantly in the bipolar group and the ultrasonic scalpel group compared with the suture group; however, no statistically significant difference of basal antral or mean ovarian diameter of the operated ovary was found among the three groups. At the 3-, 6-, 12-month follow-up visits, the basal antral, peak systolic velocity, and mean ovarian diameter of the operated ovary in the bipolar group and the ultrasonic scalpel group were statistically significantly decreased when compared with the suture group at the same time. For bilateral-s patients, comparing the suture group with the bipolar group and the ultrasonic scalpel group, statistically significant differences of basal antral and mean ovarian diameter were revealed during the 3-, 6-, 12-month follow-up evaluations; a statistically significant difference of peak systolic velocity was seen at all the follow-up visits (Table 3) Li et al. Electrocoagulation and ovary damage Vol. 92, No. 4, October 2009

4 Fertility and Sterility â 1431 TABLE 2 Ultrasound examination for unilateral- patients during the 12-month follow-up period. Time 1-month follow-up 3-month follow-up 6-month follow-up 12-month follow-up Characteristic Operated ovary with bipolar Operated ovary with ultrasonic scalpel Operated ovary with suture Intact ovary in bipolar group Intact ovary in ultrasonic scalpel group Intact ovary in suture group Number Peak systolic a Number follicle a number Peak systolic a a Number a Peak systolic a a Number a Peak systolic a a Note: Data are presented as mean standard deviation or number. a Comparing the operated ovaries in the bipolar group and ultrasonic scalpel group with those in the suture group, P<.05.

5 FIGURE 1 Mean follicle-stimulating hormone values before surgery and during the 12-month follow-up period. Values are presented as mean standard deviation. *Comparing the bipolar group and ultrasonic scalpel group with the suture group, P<.05. Ovarian Function after Ovarian Cystectomy at 12-month Follow-Up The data in Table 4 reveals that the percentage of patients with oligomenorrhea or FSH >10 IU/L in the bipolar group and the ultrasonic scalpel group after ovarian ectomy at the 12-month follow-up visit was statistically significantly higher than in the suture group. DISCUSSION Our study has demonstrated that bipolar or ultrasonic scalpel coagulation of the ovarian parenchyma during ectomy adversely affects ovarian reserve. With the development of laparoscopic technology, more and more gynecologists apply laparoscopy in their practices, especially for benign ovarian s. Many of them start their laparoscopic practices from laparoscopic ectomy with the help of electrocoagulation instruments such as monopolar, bipolar, or ultrasonic scalpels and lasers. Tulikangas et al. (12) reported that the average length of injury to the bladder with monopolar, bipolar, and ultrasonic scalpels was 2.1, 1.3, and 0.9 cm, respectively. Monopolar cautery appears to have the most lateral spread of thermal energy and is not recommended for use in ovarian ectomy. In fact, many gynecologists have observed patients with ovarian dysfunction or even ovarian failure after laparoscopic ovarian ectomy with electrocoagulation. Now bipolar and ultrasonic scalpels are being widely used in laparoscopic ovarian ectomy, but does that mean they are safe to the ovarian reserve? Several retrospective studies have reported reduced responses to gonadotropin after ectomy (13 16), and others reported a marked reduction in the number of both dominant follicles and retrieved oocytes in the operated ovary after ectomy (3, 4, 6). In contrast, some retrospective studies have not found adverse outcomes after ovarian ectomy compared with controls (tubal infertility) (17 20). Garcia-Velasco et al. (17) and Marconi et al. (20) reported that laparoscopic ectomy of ovarian endometriomas did not affect ovarian response to gonadotropin stimulation, although the gonadotropin dose was higher in the ectomy group. However, as previously mentioned, most studies on the topic of ovarian reserve after surgery are provided by infertility centers and are consequently limited by the selection of patients. We did not consider the woman s postsurgical fertility a proper criterion for evaluating the ovarian reserve. Fertility is not the result of ovarian function alone and depends on multiple factors. Moreover, not all of our patients desired to get pregnant during the study period. Furthermore, most of the above-mentioned investigations were retrospective studies, and the patients who had been operated on were compared with those who had not been operated on, which can cause bias. Fedele et al. (2) reported that bipolar electrocoagulation of the ovarian parenchyma during laparoscopic removal of endometriotic ovarian s adversely affected ovarian function, but they only studied FSH levels of endometrioma patients, which does not rule out ovarian damage by endometriosis itself. Candiani et al. (7) studied the antral follicle count, ovarian volume, stromal blood flow, and side of ovulation in 31 patients after laparoscopic ectomy, but they failed to observe the reduction of stromal blood flow so they could not classify the possible mechanisms that caused gonad injury. In our study, serum FSH evaluation and ultrasound examination were performed to investigate the ovarian reserve for 191 patients after the excision of benign ovarian s. To ensure appropriate comparability and error reduction, the 1432 Li et al. Electrocoagulation and ovary damage Vol. 92, No. 4, October 2009

6 TABLE 3 Ultrasound examination for bilateral- patients during 12-month follow-up period. Time Characteristic Bipolar group Ultrasonic scalpel group Suture group 1-month follow-up Number Peak systolic a month follow-up Number a Peak systolic a a 6-month follow-up Number a Peak systolic a a 12-month follow-up Number a Peak systolic a a Note: Data are presented as mean standard deviation or number. a Comparing the bipolar group and ultrasonic scalpel group with the suture group, P<.05. patients were divided according to unilateral and bilateral s to analyze the ovarian reserve. Comparing the bipolar group and the ultrasonic scalpel group with the suture group, a statistically significant increase of mean FSH value (see Fig. 1) was seen in the bilateral- patients at all of the 12-month follow-up visits and in the unilateral- patients at the 1-month follow-up visit. Statistically significant decreases of basal antral and mean ovarian diameter during the 3-, 6-, 12-month follow-up evaluations and statistically significant decreases of peak systolic velocity during all follow-up evaluations also were found in the bipolar group and the ultrasonic scalpel group (see Tables 2 and 3). We followed up most of the patients for 12 months and found statistically significantly more patients with oligomenorrhea or FSH >10 IU/L in the bipolar group and the ultrasonic scalpel group (see Table 4). The FSH level is a predictor of functional ovarian reserve, and an increase in FSH level indicates a decrease in ovarian reserve (8). One might argue that a change in FSH may reflect a decreased FSH-responsive pool of oocytes. But with the application of ultrasound evaluation, we revealed the change in basal antral, peak systolic velocity, and mean ovarian diameter of the operated ovary at the same time. These data suggest a significant decrease of ovarian reserve in the bipolar group and the ultrasonic scalpel group compared with the suture group. Of course, the mechanisms underlying the reduction of ovarian reserve in an operated ovary have been poorly investigated. Several possible mechanisms can be hypothesized. First, the injury may precede surgery. The per se can negatively affect the surrounding ovarian tissue. Based on histologic analysis, it has been reported recently that the ovarian tissue surrounding the endometrioma wall is morphologically altered and possibly not functional, thus suggesting that a functional disruption may already be present before surgery (21). Histologic alterations involving endometriomas Fertility and Sterility â 1433

7 TABLE 4 Ovarian function after ovarian ectomy at 12 months. Bipolar Ultrasonic scalpel Suture Characteristic s s P value Patient number Regular cycles <.05 a Menses Menorrhagia Oligomenorrhea <.05 a FSH <10 IU/L <.05 a FSH FSH IU/L <.05 a FSH >20 IU/L Notes: Data are presented as number of patient. FSH ¼ follicle-stimulating hormone. a Bipolar group and ultrasonic scalpel group versus suture group. did not appear to be present when the ovarian cortex surrounding mature teratomas and oadenomas was studied (21, 22). Second, a consistent amount of ovarian tissue accidentally may be removed during the operation. It has been reported that the presence of recognizable ovarian tissue adjacent to the wall of the enucleated endometriotic appears in a consistent proportion of specimens (22, 23). Third, the lesion inflicted to the ovarian stroma and vascularization by electrosurgical coagulation during hemostasis may have a substantial impact (24). In our study, the patients in suture group, who were operated on with traditional laparotomy techniques, may have lost less ovarian tissue during ectomy than the patients in the bipolar and ultrasonic scalpel groups. But the damage could not be ascribed merely to the amount of ovarian tissue removed during surgery. The electrosurgical coagulation during hemostasis might, at least in part, be responsible for the injury. The vascular system of the gonad is important in terms of ovarian reserve. In our study, compared with the suture group, the peak systolic velocity in the bipolar group and the ultrasonic scalpel group showed a statistically significant decrease at the 1-, 3-, 6-, 12-month follow-up evaluations, but the significant reductions of mean ovarian diameter and basal antral appeared later at the 3-, 6-, 12-month followup visits (see Tables 2 and 3). We have speculated that local inflammation and thermal injury of electrocoagulation decreased the peak systolic velocity. The persistent low peak systolic velocity in the bipolar group and ultrasonic scalpel group indicates that the damage to the ovarian vascular system by electrocoagulation is nonreversible; at the same time, it may be one of the reasons for the reduction of mean ovarian diameter. This result was consistent with studies of Engmann et al. (11) and Zaidi et al. (25), which reported that the value of ovarian stromal blood flow velocity was an initial marker of ovarian reserve before the change of FSH level and ovarian volume. However, Candiani et al. (7) reported no ovarian stromal blood reduction after laparoscopic ectomy, which was concluded from 31 cases studied only for 3 months. But the investigators themselves noted that the small number of patients, short duration of the study, and high dropout rate (35%) may have influenced their results. Potential limitations in our study are as follows. First, we did not design a randomized clinical trial, and no power analysis was used in the design of the study. Without randomization, it is possible that the patients in the suture group had a more favorable ovarian reserve than the other group although the general characteristics of the three groups before surgery revealed no statistically significant difference. Patients were informed about alternative approaches and chose what kind of surgical technique they wanted to receive. Second, we did not compare the basal antral, peak systolic velocity, and mean ovarian diameter of the diseased ovary before surgery, so we cannot rule out the possibility of any difference. Third, a single sample of FSH was obtained preoperatively, so we cannot demonstrate that FSH levels were uniform and unchanging before the surgery. Thus, one could argue that the change of FSH merely represents variability in FSH values in these women secondary to some type of ovarian dysfunction. The purpose of this study was not to demonstrate that laparoscopic ectomy is a bad choice for benign ovarian s. In fact, laparoscopic ectomy has many advantages over conventional laparotomy, including reduced morbidity, shorter hospital stays, faster recovery time, and fewer postoperative adhesions (26). Ovarian s must be removed, but ovarian reserve is limited and nonreversible once damaged. The risks are clear the more important question is how to reduce the damage Li et al. Electrocoagulation and ovary damage Vol. 92, No. 4, October 2009

8 Our results should make laparoscopic surgeons aware of the potential damage that electrocoagulation may induce on healthy ovarian parenchyma. A minimally invasive approach should consider not only the size of incision, but also the potential damage to organ function. Gentle, careful electrocoagulation of the bleeders after stripping the capsule during ectomy is of paramount importance. Moreover, the surgeon should avoid electrocoagulation of the remaining ovarian stroma and the ovarian hilus (20). It is important to use some kind of cooling solution to minimize the thermal spread. In spite of the longer operative time and the need for proper training, synthesis of the ovary by suturing after removal of the wall seems a valid alternative in such cases (2). The results of our study support the following observations. First, the laparoscopic excision of ovarian s is associated with a statistically significant reduction in ovarian reserve. 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