Ovarian response after laparoscopic ovarian cystectomy for endometriotic cysts in 132 monitored cycles

FERTILITY AND STERILITY VOL. 72, NO. 2, AUGUST 1999 Copyright 1999 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Ovarian response after laparoscopic ovarian cystectomy for endometriotic cysts in 132 monitored cycles Foo-Hoe Loh, M.R.C.O.G.,* Anna Tan Tan, M.D., Jothi Kumar, Ph.D.,* and Soon-Chye Ng, M.D.* Department of Obstetrics and Gynaecology, National University of Singapore, Singapore and University of Santo Tomas Hospital, Manila, Philippines Objective: To investigate the follicular response of ovaries after laparoscopic ovarian cystectomy for endometriotic cysts. Design: A retrospective, controlled study. Setting: Obstetrics and Gynaecology Department of a university hospital. Patient(s): Patients with history of infertility who had laparoscopic ovarian cystectomy for endometriotic cysts. Intervention(s): Laparoscopic ovarian cystectomy, transvaginal ultrasound monitoring of follicles in natural cycles, stimulated cycles using clomiphene citrate (CC), chronic low-dose FSH, and flare down regimen. Main Outcome Measure(s): Follicular response of postcystectomy and normal ovaries. Result(s): For women 35 years of age, the mean follicular response of postcystectomy ovaries was reduced significantly when compared with normal ovaries in natural cycles (0.30 versus 1.00 follicle per cycle) and in CC-stimulated cycles (0.87 versus 1.27 follicles per cycle). The mean follicular response was not statistically significantly different when the ovaries were stimulated with chronic low-dose FSH or with the flare down regimen. For women 35 years, postcystectomy ovaries responded with a comparable number of follicles as the normal ovaries in natural cycles and the three different ovarian stimulation regimens. Conclusion(s): Postcystectomy ovaries showed reduced follicular response in natural and CC-stimulated cycles for women 35 years of age. Postcystectomy ovaries produced a comparable number of follicles as normal ovaries when stimulated with gonadotropins. (Fertil Steril 1999;72:316 21. 1999 by American Society for Reproductive Medicine.) Key Words: Endometriotic cyst, laparoscopic ovarian cystectomy, ovarian follicular response Received December 3, 1998; revised and accepted March 2, 1999. Reprint requests: Foo-Hoe Loh, M.R.C.O.G., Department of Obstetrics and Gynaecology, National University Hospital, 5, Lower Kent Ridge Road, Singapore 119074 (FAX: 65-7794753; E-mail: obglohfh@nus.edu.sg). * Department of Obstetrics and Gynaecology, National University of Singapore. University of Santo Tomas Hospital. 0015-0282/99/$20.00 PII S0015-0282(99)00207-1 Laparoscopic surgery is the approach of choice in women with benign ovarian cysts (1) and has gained increasing acceptance among gynecological surgeons. Endometriotic cysts are among some of the more common ovarian cysts encountered at surgery. Often, these procedures are performed for women who have the concomitant problem of infertility. Residual ovarian function in terms of follicle development after such surgery is an important consideration. Of particular concern are the amount of ovarian tissue that may be removed inadvertently during cystectomy and the damage that may be inflicted on the ovarian stroma by electrosurgical coagulation during hemostasis. In this study, we report the follicular response of ovaries after laparoscopic ovarian cystectomy for endometriotic cysts under four different conditions according to clinical indications. They were natural cycles, stimulated cycles with clomiphene citrate (CC), chronic low-dose FSH regimen (2), and the flare down regimen using buserelin acetate (Hoechst, Frankfurt, Germany) for down-regulation followed by conventional doses of Metrodin HP (Serono, Aubonne, Switzerland) in IVF-ET cycles. These were compared with the response of normal uninvolved ovaries in the same group of patients. The number of follicles developed in each with average diameter 16 mm just before ovulation, or hcg injection, was the final outcome measure. 316

MATERIALS AND METHODS Procedure From January 1994 to December 1997, 188 patients with endometriotic cysts had laparoscopic ovarian cystectomy performed in the Department of Obstetrics and Gynaecology, National University of Singapore. Only patients with histologic specimens that confirmed the diagnosis of endometriotic cysts were included in this series. Laparoscopic ovarian cystectomy was performed as previously described (3). The endometriotic cyst was decompressed electively, and the cyst wall was stripped off the. Hemostasis was achieved with bipolar electrocautery. No suture was placed in the after ovarian cystectomy. The study methodology has received local institutional review board approval. Patients Of the 188 patients with laparoscopic ovarian cystectomy for endometriotic cysts, 40 patients were seen for the problem of infertility and had undergone subsequent transvaginal ultrasound follicular monitoring. The average age of these 40 patients was 32.8 years (range, 22 43 years). The mean American Fertility Society (AFS) score was 51.2 (range, 21 128). Thirteen (32.5%) had moderate disease, whereas 27 (67.5%) had severe disease. Twenty-seven (67.5%) had unilateral endometriotic cysts, whereas 13 (32.5%) had bilateral cysts. One patient had an endometriotic cyst in the sole surviving after a previous oophorectomy for dermoid cyst. The mean size of the endometriotic cysts excised was 4.23 2.2 cm (range, 1 15 cm). Fifteen (37.5%) of the patients had anovulatory cycles, whereas 25 (62.5%) had documented ovulatory cycles. All patients had preoperative transvaginal ultrasound evaluation of the ovaries. Contralateral normal ovaries of patients with unilateral endometriotic cysts, based on ultrasound findings and further confirmation at laparoscopy, were used as controls. The responses of 53 postcystectomy ovaries and 26 normal ovaries (controls) over 132 monitored cycles (a total of 258 ovarian responses) were available for analysis. Ovarian Stimulation Each patient had a mean of 2.73 monitored cycles (range, 1 8). Of the 132 monitored cycles, 21 (15.9%) were spontaneous cycles, 77 (58.3%) were CC-stimulated cycles, 9 (6.8%) had induction of ovulation using chronic low-dose FSH, and 25 (19%) were cycles using the flare down regimen. Clomiphene citrate was given in doses ranging from 50 to 100 mg/d from day 2 to day 6 of the menstrual cycle. Ultrasound follicular monitoring was performed from day 12 of each cycle until spontaneous ovulation or hcg injection. Chronic low-dose FSH for induction of ovulation has been described previously (2). The stimulation regimen for IVF-ET cycles used in our department was the flare down regimen, starting with downregulation by subcutaneous buserelin acetate (Hoescht), 0.5 ml given daily for 2 weeks, from day 21 of the preceding cycle. On confirmation of sufficient down-regulation, three ampules (225 IU) of Metrodin HP (Serono) were given daily, whereas the buserelin acetate dose was adjusted to 0.2 ml/d. Follicular monitoring and estradiol measurements began on the 5th day after the start of Metrodin HP injections, and doses were adjusted according to the response. Ovarian Follicular Monitoring Ovulation was monitored with transvaginal ultrasound scans. Ovarian follicles were measured in two dimensions, and the average diameter was calculated. The number of follicles with average diameter 16 mm developed in each just before ovulation or hcg injection was noted. We analyzed the follicular responses of postcystectomy ovaries and compared them with responses of contralateral normal ovaries (controls) in the group of patients with unilateral cysts. Statistical Analysis The 132 monitored cycles were analyzed in two phases. For the first analysis, the total study population of patients (n 40 patients; 132 monitored cycles) with both unilateral and bilateral cysts was studied, comparing the responses of postcystectomy ovaries and normal ovaries. A second analysis was made for the subset of patients with unilateral cysts (n 27 patients; 67 monitored cycles), whereby a paired comparison was made between the endometriotic cyst and contralateral normal of the same patient. Appropriate statistical methods were used to compare each group, including the Mann-Whitney U-test, which was used for nonparametric analysis. For the subgroup of paired data, Wilcoxon rank-signed test was used to test for statistical significance. RESULTS Aggregate Results of 132 Monitored Cycles Because age is an important determinant in ovarian response (4) and decline in fecundity begins to accelerate after the age of 35 years (5), the 132 cycles with 258 ovarian responses were stratified according to age groups of 35 or 35 years (Table 1). Considering the group of younger women 35 years of age, the mean follicular response of postcystectomy ovaries was reduced significantly compared with normal ovaries in both natural cycles and CC-stimulated cycles. Although there appeared to be a large difference in the ovarian responses of the low-dose FSH group, the difference was not statistically significant because of the small number of cycles in this category. Postcystectomy and normal ovaries re- FERTILITY & STERILITY 317

TABLE 1 Mean number of follicles produced by postcystectomy ovaries and normal ovaries per cycle, stratified according to age group of patient. Cycle Normal Postcystectomy P value Normal Postcystectomy P value Natural cycle Mean no. of follicles SD 1.00 0.0 0.30 0.47.011 0.57 0.53 0.45 0.52 NS (No. of patients/ovarian responses) (4/4) (11/20) (2/7) (5/11) Clomiphene citrate Mean no. of follicles SD 1.27 0.96 0.87 0.81.044 0.44 0.53 0.80 0.65 NS (No. of patients/ovarian responses) (12/26) (21/92) (4/9) (8/25) Low-dose FSH Mean no. of follicles SD 1.33 0.58 0.56 0.53 NS 0.50 0.71 0.50 0.71 NS (No. of patients/ovarian responses) (3/3) (5/9) (1/2) (1/2) Flare down regimen Mean no. of follicles SD 7.00 6.16 5.12 4.21 NS 1.88 2.42 3.00 3.56 NS (No. of patients/ovarian responses) (4/4) (10/26) (4/8) (5/10) Note: NS not significant. sponded in a comparable manner when undergoing the flare down regimen. For the older patients 35 years of age, even the normal ovaries showed poorer response, and there was no statistically significant difference between the ovarian responses of postcystectomy ovaries and normal ovaries in all the four different categories of ovarian cycles. Among normal ovaries, the effect of age on ovarian response in natural cycles appeared to be large (1.00 versus 0.57 follicles per per cycle), but the difference was not statistically significant because of the small number of cycles involved. For CC-stimulated cycles, age was a significant factor in response of normal ovaries (P.021). In the flare down regimen, the difference in ovarian response approached but did not reach statistical significance (P.059). Among postcystectomy ovaries, the age difference was blunted, and there was no difference between responses of ovaries from women 35 or 35 years of age. Size of Cyst Within the respective age groups, size of the endometriotic cysts did not influence the subsequent ovarian follicular response of postcystectomy ovaries (Table 2). TABLE 2 Mean number of follicles produced by postcystectomy ovaries per monitored cycle, stratified according to age group of patient and size of endometriotic cysts. Cycle Natural cycle 0.50 0.55 0.21 0.43 0.44 0.53 0.50 0.71 (No. of patients/ovarian responses) (4/6) (7/14) (4/9) (1/2) Clomiphene citrate 0.81 0.67 0.94 0.91 0.89 0.60 0.75 0.68 (No. of patients/ovarian responses) (7/36) (14/56) (5/9) (3/16) Low-dose FSH 0.75 0.50 0.40 0.55 0.50 0.71 No case (No. of patients/ovarian responses) (2/4) (3/5) (1/2) Flare down regimen 5.57 3.51 4.95 4.52 3.13 4.02 2.50 0.71 (No. of patients/ovarian responses) (3/7) (7/19) (3/8) (2/2) Note: Values are means ( SD) of follicles per per cycle. All P values are.05. 318 Loh et al. Ovarian response after cystectomy Vol. 72, No. 2, August 1999

TABLE 3 Mean number of follicles produced by ovaries with recurrent endometriotic cysts undergoing repeat ovarian cystectomy. Cycle once twice once twice Natural cycle 0.28 0.46 0.50 0.71 0.45 0.50 No case (No. of patients/ovarian responses) (7/18) (1/2) (3/11) Clomiphene citrate 0.89 0.85 0.78 0.65 0.80 0.65 No case (No. of patients/ovarian responses) (11/74) (3/18) (4/25) Low-dose FSH 0.67 0.52 0.33 0.58 No case 0.50 0.71 (No. of patients/ovarian responses) (2/6) (3/3) (1/2) Flare down regimen 4.96 3.97 7.00 8.49 3.00 3.56 No case (No. of patients/ovarian responses) (5/24) (1/2) (5/10) Note: Values are mean number ( SD) of follicles per per cycle. All P values are.05. Ovaries With Recurrent Cysts and Repeat Cystectomy Seven of the ovaries had a repeat cystectomy for a recurrence of cyst at the index surgery. Twenty-seven ovarian responses from ovaries with repeat cystectomies were available for comparison with 168 responses from ovaries operated once. The mean follicular response of ovaries that had repeat cystectomy was comparable with ovaries undergoing the first cystectomy in all the four different types of ovarian cycles in patients 35 years of age (Table 3). Ovulatory and Anovulatory Cycles Whether the patient had previously documented ovulatory or anovulatory cycles did not influence ovarian follicular responses of both normal and postcystectomy ovaries in all the four different types of ovarian cycles. Paired Comparison for Unilateral Cysts We further analyzed a subgroup of patients with unilateral cysts (Fig. 1) with the contralateral normal as control for paired analysis. There was a total of 67 cycles: 11 unstimulated cycles, 39 CC-stimulated cycles, 5 cycles with low-dose FSH, and 12 cycles with the flare down regimen. The overall results showed similar differences between the responses of postcystectomy and the normal as in the aggregate analysis (Fig. 1). After stratification for age, the difference between postcystectomy and normal ovaries was seen mainly in patients 35 years of age. For this group of younger women, postcystectomy ovaries had significantly reduced mean follicular response compared with normal ovaries in unstimulated cycles (0.0 versus 1.0 follicles per cycle, P.046) and in CC-stimulated cycles (0.61 versus 1.26 follicles per cycle, P.011). There was little difference when the ovaries were stimulated with gonadotropins, whether using the low-dose FSH regimen or the flare down regimen. For women 35 years of age, the responses of postcystectomy ovaries were comparable in all four different categories of ovarian cycles. Size of Cyst The size of the endometriotic cysts did not make a difference with respect to the ovarian follicular response of postcystectomy ovaries within their respective age groups. FIGURE 1 Ovarian response of postcystectomy and normal ovaries in patients with unilateral endometriotic cysts: a paired comparison., normal ;, postcystectomy. FERTILITY & STERILITY 319

Pregnancy Rate Fifteen (37.5%) of the 40 patients conceived during the study period. Life-table analysis showed the median time to pregnancy was 29 months (95% confidence interval, 16 42 months). In vitro fertilization-embryo transfer contributed to 4 (26.7%) of these pregnancies. DISCUSSION There is considerable controversy with respect to the most appropriate type of surgical intervention for endometriotic cyst of the. Hughesdon (6) suggested that the endometrioma originated from progressive invagination of the ovarian cortex caused by progression of endometriotic implants on the surface of the trapped by surrounding adhesions. Donnez et al. (7) and Nisolle and Donnez (8) proposed an alternative theory that endometrioma originates from metaplastic change of mesothelium that has invaginated into the ovarian cortex. It is not unusual to find oocytes in the vicinity of the endometrial stroma in biopsies of the endometriotic cyst wall. If either of the above two theories is correct, excising the cyst wall of the endometrioma may be removing part of the ovarian cortex and precious primordial follicles along with it. Another major concern with laparoscopic ovarian cystectomy is that electrosurgical energy used to achieve hemostasis may cause significant damage to the. Drainage of the endometriotic cyst alone is ineffective, and rapid recurrence of the cyst invariably occurs (9). An alternative of vaporizing the cyst lining with CO 2 laser in a two-step procedure after drainage and pretreatment with GnRH analogues has been proposed (9). However, this is a two-step procedure that requires repeated anesthesia. Ovarian fenestration with bipolar electrocoagulation of the cyst wall lining has been reported to achieve comparable pregnancy rates and recurrence rates as ovarian cystectomy in one study (10). However, this conclusion was disputed by the results of the study by Beretta et al. (11), which demonstrated better pregnancy rates and reduced recurrence of pain in patients who had laparoscopic ovarian cystectomy as opposed to drainage and coagulation of the cyst wall in a prospective, randomized, controlled trial. Many gynecologists would still perform a formal ovarian cystectomy, by stripping the cyst wall off the, in view of the need for a more complete histology. Although the risk is small, there is always the theoretical concern of an associated endometrioid or clear cell carcinoma of the (12, 13). It is known that the ovarian response of ovaries with coexisting endometriotic cysts appear not to be compromised in patients undergoing IVF-ET cycles with gonadotropin stimulation (14). Our study suggests that postcystectomy ovaries when stimulated with gonadotropins, such as in the flare down regimen, were able to respond comparably with the normal. There are presently few available data that examined the follicular response of ovaries with coexisting endometriotic cysts in spontaneous cycles or CC-stimulated cycles. The results of this study suggest that the follicular responses of postcystectomy ovaries were significantly reduced in natural cycles and CC-stimulated cycles compared with the normal for women 35 years of age. The age of the patient remained an important factor in the response of normal ovaries. In contrast, the impact of age on the response of postcystectomy ovaries appeared to be minimal. Hence, differences between the respective ovarian responses were more apparent among the younger women. For the group of older women, the follicular response of normal ovaries already was diminished, and little difference was noted between the responses of normal ovaries and postcystectomy ovaries. One needs to be cautious in attributing the diminished response of the postcystectomy ovaries noted in this study as solely due to surgical injury to the. It has been shown, by pathological sections of ovaries containing benign ovarian cysts, that ovaries with endometriotic cysts already exhibited reduced number of follicles and vascular activity compared with other types of benign cyst (15). This is consistent with the finding of this study that the size of the cyst and repeat surgery of the for endometriotic cysts did not have much impact on the postcystectomy ovarian response; much of the damage may have been inflicted by the disease itself. In conclusion, ovaries after laparoscopic ovarian cystectomy for endometriotic cysts showed reduced follicular response compared with normal ovaries in natural and CCstimulated ovarian cycles for women 35 years of age. Postcystectomy ovaries responded well to aggressive gonadotropin stimulation, producing a comparable number of follicles as normal ovaries. Acknowledgments: The authors thank M. Mongelli, M.D., for his help with statistical analysis of the data and for his critical appraisal of the paper. References 1. Yuen PM, Yu KM, Yip SK, Lau WC, Rogers MS, Chang A. A randomized prospective study of laparoscopy and laparotomy in the management of benign adnexal masses. Am J Obstet Gynecol 1997; 177:109 14. 2. Yong EL, Ng SC, Chan CLK, Kumar J, Teo LS, Raman SS. Chronic low-dose follicle stimulating hormone compared with clomiphene/ human menopausal gonadotropin for induction of ovulation. Gynecol Endocrinol 1997;11:35 42. 3. Canis M, Boughizane S, Loh FH, Pouly JL, Wattiez A, Manhes H, et al. Techniques for ablation and excision of endometriosis. In: Shaw RD, ed. Endometriosis, current understanding and management. Oxford: Blackwell Science, 1995;13:248 63. 320 Loh et al. 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