ORIGINAL ARTICLE: ENDOMETRIOSIS

Ovarian damage after laparoscopicendometrioma excision might berelated to the size of cyst

Yan Tang,M.D., M.Sc., Shi-Ling Chen, M.D., Ph.D., Xin Chen, M.D., M.Sc., Yu-Xia He, M.D., De-Sheng Ye, M.D.,Wei Guo, M.D., Hai-Yan Zheng, M.D., Ph.D., and Xin-Hong Yang, M.D.

Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern MedicalUniversity, Guangzhou, People's Republic of China

Objective: To investigate the relationship between the size of an excised endometrioma and themagnitude of damage to the ovary afterthe surgery.Design: A retrospective, controlled study.Setting: A university hospital.Patient(s): Eighty-five women with a history of laparoscopic excision of unilateral endometrioma who underwent in vitro fertilization(IVF).Intervention(s): IVF-embryo transfer procedures.Main OutcomeMeasure(s): Antral follicle counts (AFC),numberofdominant follicles (folliclesR15mm), andnumberof oocytes retrieved.Result(s): In the group with cyst diameters ofR4 cm and group with cyst diameters of<4 cm, the AFC, number of dominant follicles,and number of oocytes retrieved were decreased in the operated ovaries when compared with those in intact ovaries; in the formergroup, a statistically significant reduction was observed. The differences of AFC, number of dominant follicles, and number of oocytesretrieved from both ovaries were further compared among the two groups: the decrease in the group with cyst diameters ofR4 cm washigher than in the group with cyst diameters of<4 cm. After adjusting for age and AFC in intact ovaries, similar results were obtained,although AFC only showed a tendency. In addition, the receiver operating characteristic curve analysis revealed a statisticallysignificant, positive correlation between the size of excised cysts and the incidence of fewer than four oocytes retrieved from anoperated ovary.

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Conclusion(s): The magnitude of the ovarian damage after laparoscopic endometriomaexcision might be related to the size of cyst; the damage to ovaries is more severe when anendometrioma R4 cm is excised. (Fertil Steril� 2013;100:464–9. �2013 by American Societyfor Reproductive Medicine.)Key Words: Endometrioma, excision, IVF, laparoscopy, retrieved oocytes

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I n recent years, laparoscopy has beenconsidered as the gold standard,first-line treatment for women

with endometriomas (1, 2). Severallaparoscopic techniques have been

Received December 7, 2012; revised March 19, 2013;12, 2013.

Y.T. has nothing to disclose. S.-L.C. has nothing to dnothing to disclose. D.-S.Y. has nothing to discloing to disclose. X.-H.Y. has nothing to disclose.

Supported by Comprehensive Strategic Sciences CoChinese Academy (20100908), Guangzhou Sc(11C22120737), National Key Basic Research(2007CB948104), National Natural Science Foun

Reprint requests: Shi-Ling Chen, M.D., Ph.D., DepartReproductive Medicine, Nanfang Hospital, SouPeople's Republic of China (E-mail: chensl_92@1

Fertility and Sterility® Vol. 100, No. 2, August 2013 0Copyright ©2013 American Society for Reproductivehttp://dx.doi.org/10.1016/j.fertnstert.2013.03.033

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described, in which excision isgenerally recommended for a lowerrecurrence rate of endometrioma anda higher subsequent spontaneouspregnancy rate (3). However, the

accepted March 21, 2013; published online April

isclose. X.C. has nothing to disclose. Y.-X.H. hasse.W.G. has nothing to disclose. H.-Y.Z. has noth-

operation Projects of Guangdong Province andience and Technology Program key projectsDevelopment Plan of China (973 Program)dation of China (81170574).ment of Gynecology and Obstetrics, Center forthern Medical University, Guangzhou 510515,63.com).

015-0282/$36.00Medicine, Published by Elsevier Inc.

literature has shown that residualovarian function after this surgicaltreatment may be impaired (4–6), andsome cases of severe ovarian damage,even premature ovarian failure (POF),have been reported after surgery (7, 8).Nevertheless, several aspects remain tobe elucidated—in particular, identifyingthe factors related to the magnitude ofdamage is an important, neglectedissue. This aspect may be of clinicalrelevance because it can shed light onthe pathogenetic mechanisms causingthe damage, so we believe this datarequires in-depth reflection. We per-formed a retrospective study on womenwho had been referred to our center for

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IVF techniques and who had undergone previous laparoscopicexcision of a unilateral endometrioma. We investigated therelationship between the size of an excised endometriomaand the magnitude of damage to the ovary after the surgery.

MATERIALS AND METHODSPatients

Our study reviewed the medical records of 85 women who hadhad laparoscopic excision of a unilateral single ovarianendometrioma followed by IVF treatment at Center forReproductive Medicine of Obstetrics and GynecologyDepartment of Nanfang Hospital between September 2006and January 2012. All patients fulfilled the following criteria:[1] availability of a detailed description of surgical interven-tion, including the dimensions and histology of the cyst; [2]no other adnexal interventions; and [3] age %40 years atthe time of ovarian stimulation. Patients were selectedregardless of the delay between the surgery and IVFcycle. Some patients received 3 months of treatment withgonadotropin-releasing hormone (GnRH) analogues immedi-ately after surgery.

Women who underwent two surgeries for recurrentendometrioma were excluded, but the presence of a recurrentendometrioma—diagnosed by the presence of a round-shapedcystic mass with a minimum diameter of 10 mm, with thickwalls, regular margins, and homogeneous low echogenic fluidcontent with scattered internal echoes and without papillaryproliferations (7)—was not an exclusion criterion. Recurrentcysts were identified and aspirated transvaginally byultrasound-guided puncture before controlled ovarianstimulation (COS). Excision of the cyst involved the incisionof the endometrioma either with or without the use ofelectrosurgical or laser energy, followed by excision of thewall of endometrioma using a combination of scissors(or monopolar hook) and grasping forceps. The study protocolwas approved by the institutional ethics committee ofNanfang Hospital, and informed consent for their clinicaldata to be used for research purposes was obtained from allparticipants.

IVF Treatment

A transvaginal ultrasound scan to determine the antralfollicle count (AFC) was performed on day 2 or 3 of themenstrual cycle before the IVF cycle, and the antral follicleswere classified as those follicles measuring 2–9 mm in size.All the follicles were measured in two dimensions, and theaverage diameter was calculated. All ultrasound examina-tions were performed by a single experienced operator (X.C.).

A tailored protocol was developed based on the age,baseline sex hormone levels, AFC, body mass index (BMI),and economic condition of each patient. Follicular growthwas monitored by serial transvaginal ultrasonography. Finaloocyte maturation was triggered by administering humanchorionic gonadotropin (hCG) when at least one leadingfollicle had reached 17 mm and two other follicles hadreached 16 mm in mean diameter. Oocyte retrieval wasperformed under the guidance by transvaginal ultrasound34 to 36 hours after the hCG injection, and the number of

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oocytes was recorded. On day 2 or 3 after oocyte retrieval,embryo transfer was performed. Of note, all data wererecorded separately for the two ovaries. Clinical pregnancywas defined as ultrasonographic demonstration of anintrauterine gestational sac 4 weeks after embryo transfer.

Statistical Analysis

Patients were divided into two groups according to thediameter of the excised cyst:<4 cm andR4 cm. The diameterof the excised cyst was calculated as the mean of the heightand width of the cyst, which was obtained from surgical,echographic, or pathologic records. The AFC, number ofdominant follicles (folliclesR15 mm), and number of oocytesretrieved were the main study outcome measures.

Appropriate statistical tests were used for comparison,including the chi-square test, independent-samples t test,paired-samples t test, and Mann-Whitney U-test. Analysisof covariance (ANCOVA) was performed to exclude thepotential effects of some covariates. The receiver operatingcharacteristic (ROC) curve method was used to analyze theassociation between the size of the excised cyst and theincidence of fewer than four oocytes retrieved from an oper-ated ovary. The statistical analysis was performed with theStatistical Package for Social Sciences (SPSS, version 16.0for Windows). P< .05 was considered statistically significant.

RESULTSA total of 85 patients fulfilled the criteria. 35 patients with51 cycles were recruited in the group with cyst diameters of<4 cm, and 50 patients with 63 cycles were in the groupwith cyst diameters of R4 cm. The baseline characteristicsof the patients and cycles of two groups were compared,and except for the diameter of the excised cyst (2.6 � 0.8vs. 5.3� 1.3, P< .001), the other parameters were comparablebetween the two groups (Table 1).

In the group with cyst diameters of <4 cm, themean � standard deviation (SD) AFC, number of dominantfollicles, and number of oocytes retrieved in the operatedovaries were 4.9 � 2.7, 2.6 � 2.2, and 4.6 � 3.6, respectively;in the intact ovaries, the values were 5.6� 3.0, 3.4� 2.3, and5.5 � 4.1, respectively. A decrease was observed in theoperated ovaries, but no statistically significant differenceswere shown between the operated and intact ovaries.However, in the group with cyst diameters ofR4 cm, all thoseparameters (the mean � SD AFC, number of dominantfollicles, and number of oocytes retrieved) in the operatedovaries showed statistically significant decreases whencompared with the values in the intact ovaries (4.9 � 3.2 vs.7.3 � 3.8, P< .001; 2.1 � 2.2 vs. 4.0 � 2.7, P< .001; and2.8 � 2.5 vs. 6.2 � 3.7, P< .001, respectively). These resultsare shown in Table 2.

Furthermore, the differences of AFC, number of dominantfollicles, and number of oocytes retrieved from the twoovaries—calculated as: Number in the intact ovary � Numberin the operated ovary—were compared between two groups. Inthe group with cyst diameters ofR4 cm, all these parameterswere statistically significantly higher when comparedwith those in the group with cyst diameters of <4 cm

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TABLE 1

Characteristics of patients and cycles in the groups with an excised cyst <4 cm or R4 cm in diameter.

Characteristic

Cyst diameter

P value<4 cm R4 cm

No. of patients 35 50At the time of surgery

Age (y)a 30.4 � 3.9 28.7 � 4.0 .053c

Diameter of the excised cyst (cm)a 2.6 � 0.8 5.3 � 1.3 < .001c

Ovarian side .897d

Leftb 17 (48.6) 25 (50.0)Rightb 18 (51.4) 25 (50.0)

Type of infertility .322d

Primary infertilityb 24 (68.6) 29 (58.0)Secondary infertilityb 11 (31.4) 21 (42.0)

Postoperative medical treatmentb 11 (31.4) 20 (40.0) .419d

At the time of ovarian stimulationAge (y)a 32.2 � 3.7 30.9 � 3.5 .056c

Duration of infertility (y)a 4.1 � 2.5 4.1 � 2.5 .924c

Delay between surgery and IVF (y)a 1.4 � 1.6 1.9 � 2.0 .212c

Recurrence of endometriomab 9 (25.7) 13 (26.0) .976d

Total AFC (two ovaries)a 10.5 � 5.1 12.2 � 5.8 .087c

No. of cycles 51 63Stimulation protocol .728d

Long protocolb 33 (64.7) 46 (73.0)Prolonged protocolb 9 (17.6) 10 (15.9)GnRH antagonist protocolb 6 (11.8) 5 (7.9)High-dose Gn for ovarian stimulation

without down-regulationb2 (3.9) 2 (3.2)

Short GnRH agonist protocolb 1 (2.0) 0 (0.0)Total dose of gonadotropin (IU)a 3,275.5 � 1,163.9 2,846.2 � 1,117.2 .051c

Total no. of oocytes retrieved (two ovaries)a 10.1 � 6.0 9.0 � 5.2 .295c

No. of embryos transferreda 1. 8 � 0.9 1. 8 � 0.9 .568c

Clinical pregnancies per transferb 19 (37.3) 24 (38.1) .927d

No. of implanted embryosb 27 (28.7) 32 (29.1) .954d

a Values are mean � standard deviation (SD).b Values in the parentheses are percentages.c Independent-samples t test was used for the analysis. P< .05 was considered statistically significant.d Chi-square test was used for the analysis. P< .05 was considered statistically significant.

Tang. Ovarian damage and endometrioma size. Fertil Steril 2013.

ORIGINAL ARTICLE: ENDOMETRIOSIS

(2.5 � 3.9 vs. 0.7 � 2.7, P¼ .011; 1.9 � 2.9 vs. 0.8 � 2.7,P¼ .039; and 3.3 � 3.6 vs. 0.9 � 4.9, P¼ .006, respectively)(Table 3). Age and AFC in the intact ovaries at the time ofovarian stimulation may potentially have affected the results,so ANCOVA also was performed. After adjustment, the valuesof the mean � standard error (SE) for AFC, number of domi-nant follicles, and number of oocytes retrieved in the operatedovaries were compared between the two groups. Statisticallysignificant differences were still observed in the number ofdominant follicles and the number of oocytes retrieved

TABLE 2

Comparison of antral follicle count (AFC), number of dominant follicles, aovaries in two groups.

Cyst diameter <4 cm (n [ 51

Operated ovary Intact ovary

AFC 4.9 � 2.7 5.6 � 3.0No. of dominant follicles 2.6 � 2.2 3.4 � 2.3No. of oocytes retrieved 4.6 � 3.6 5.5 � 4.1Note: Values are mean � standard deviation (SD). Paired-Samples t test was used for the analysis.

Tang. Ovarian damage and endometrioma size. Fertil Steril 2013.

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(group with cyst diameters of R4 cm vs. group with cystdiameters of <4 cm: 1.9 � 0.3 vs. 2.8 � 0.3, P¼ .026; and2.6� 0.4 vs. 4.9� 0.4, P< .001, respectively), but AFC merelyshowed a tendency (4.6 � 0.3 vs. 5.3 � 0.4).

In addition, the ROC curve analysis showed a positivecorrelation between the size of the excised cyst and theincidence of fewer than four oocytes retrieved in the operatedovary—the larger the cyst size, the more likely that fewer thanfour oocytes were retrieved from the operated ovary (P< .05)(Fig. 1).

nd number of oocytes retrieved between operated ovaries and intact

) Cyst diameter R4 cm (n [ 63)

P value Operated ovary Intact ovary P value

.078 4.9 � 3.2 7.3 � 3.8 < .001

.053 2.1 � 2.2 4.0 � 2.7 < .001

.196 2.8 � 2.5 6.2 � 3.7 < .001P< .05 was considered statistically significant.

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TABLE 3

Differences of antral follicle count (AFC), number of dominantfollicles, and number of oocytes retrieved from two ovariesbetween the groups with an excised cyst of <4 cm or R4 cmdiameter.

Difference

Cyst diameter

Pvalue

<4 cm(n [ 51)

R4 cm(n [ 63)

AFC 0.7 � 2.7 2.5 � 3.9 .011No. of dominant follicles 0.8 � 2.7 1.9 � 2.9 .039No. of oocytes retrieved 0.9 � 4.9 3.3 � 3.6 .006Note: Values are mean � standard deviation (SD). Mann-Whitney U-test was used for theanalysis. P< .05 was considered statistically significant.

Tang. Ovarian damage and endometrioma size. Fertil Steril 2013.

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DISCUSSIONMore and more studies are providing evidence that laparo-scopic endometrioma excision negatively affects ovarianfunction (9–13). However, most of these studies havefocused on whether this surgical treatment does or does notimpair ovarian function. In contrast, our study specificallysought to clarify whether the ovarian damage fromlaparoscopic endometrioma excision is related to the size ofendometrioma. We compared the AFC, number of dominantfollicles (follicles R15 mm), and number of oocytesretrieved between the operated ovary and the intact ovaryin two groups: those with cyst diameter R4 cm versus cystdiameter <4 cm.

FIGURE 1

Receiver operating characteristic (ROC) curve analysis demonstratesa positive correlation between the size of excised cyst and theincidence of fewer than four oocytes retrieved in the operatedovary. The area under the curve was 0.622 (95% confidenceinterval, 0.519–0.725).Tang. Ovarian damage and endometrioma size. Fertil Steril 2013.

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A reduction was observed in operated ovaries in bothgroups. In the group with cyst diameterR4 cm, a statisticallysignificant decrease was found. The difference in AFC,number of dominant follicles, and number of oocytesretrieved of two ovaries between the two groups were furthercompared, confirming that the decrease in the group with cystdiameter R4 cm was higher than that in the group with cystdiameter <4 cm. After adjusting for some covariates, weobtained similar results, except for with AFC, which merelyshowed a tendency. The results of our study show thatlaparoscopic ovarian excision of endometrioma is detrimentalto the ovarian reserve and to ovarian response; the damagewas more severe in the group with cyst R4 cm, especiallyin terms of the ovarian response to stimulation.

As the number of oocytes retrieved is a major outcome ofIVF treatment, we used ROC curve analysis to further explorethe potential association between the size of excised cyst andthe incidence of fewer than four oocytes retrieved from anoperated ovary. The result from the ROC curve analysisshowed that the larger the size of a cyst, the more likelythat fewer than four oocytes will be retrieved from anoperated ovary.

However, three related studies (12, 14, 15) that alsoinvestigated the relevance of the diameter of an excised cystto the subsequent ovarian follicular response of operatedovaries reported discordant results. There are at least threeexplanations for the discrepancies. To begin with, in one ofthose studies (14), the small sample size (12 cycles) wasinsufficient to investigate this issue. Moreover, theystratified the patients into different groups according to age,which made the sample size even smaller. Second, in theother studies (12, 15), a cutoff of 3 cm was chosen. Wespeculate that the smaller cutoff value may have led to lesssignificant differences; and the cutoff value recommendedby the European Society of Human Reproduction andEmbryology (ESHRE) guidelines is 4 cm (16). Additionally,the different surgical technologies employed may have beena factor. In our study, the surgical technologies employedwas endometrioma excision; in the study from Donnezet al. (15), the cyst wall vaporization technique wasemployed. It is known that the laparoscopic vaporizationtechnique is less deleterious to the ovarian reserve (17).

The reasons for the results can only be hypothesized.First, based on histologic studies, it has been reported thatthe ovarian tissue adjacent to the endometrioma wall differsmorphologically from normal ovarian tissue and may notfunction normally (18, 19). This could be related to theexcess oxidative stress in the normal ovarian cortexsurrounding endometrioma (20). It has been demonstratedthat oxidative stress can induce apoptosis and necrosis ofoocytes in vitro (21). All these studies suggest the functionaldisruption caused by endometrioma per se may be presentbefore surgery. It also cannot be excluded that, witha single endometriotic cyst, the larger the cyst, the moresevere the damage to the surrounding ovarian tissue.

Second, surgery may be a further responsible mechanism.Histologic analyses have clearly shown that surgery leads toa significant amount of follicles lost for the accidentalremoval of normal ovarian cortex which is adjacent to the

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ORIGINAL ARTICLE: ENDOMETRIOSIS

endometriotic cyst wall (19, 22, 23). More notably, two recentstudies have demonstrated that the adjacent ovarian tissueremoved is proportional to the cyst diameter—the larger thecyst diameter, the more tissue is removed (24, 25).

Third, for large endometrioma, coagulation is frequentlyused, which results in further damage to ovaries (26, 27).Large endometrioma are frequently multilocular and maycontain communicating or on-communicating corpus luteumor dysfunctional cysts, so coagulation with these large cysts,particularly the multilocular cysts, is difficult (17). In thesecases, extensive coagulation is required. The cyst lining alsois surrounded by fibrosis, and the remaining ovarian cortexsurrounding the large endometrioma is often thinner than5 mm (28), which makes the cleavage more difficult forsurgeons, even experienced laparoscopists (29). Such difficul-ties may lead to frequent tearing and severe bleeding and mayprovoke excessive use of coagulation, thus inducing irrevers-ibly severe damage to ovaries. This may explain why somepatients with a larger endometrioma excised have adverseIVF outcomes even when good ovarian reserve was present.

Our study had several limitations. Ourswas a retrospectivestudy, and most of the patients had already undergonesurgical excision of their endometriomas before presentingfor IVF treatment, so we could not compare their preoperativeand postoperative data. Second, the inclusion of severalprotocols may be another limitation. In our study, differencesbetween the intact ovary and the operated ovary wereconsidered to be damage caused by the surgery. However,for any single patient, both ovaries were in the sameenvironment and underwent the same controlled ovarianhyperstimulation protocol; thus, even though there areseveral protocols, our results are persuasive. Furthermore,our findings could not distinguish the injury inflicted by thesurgery per se from that caused by the endometriomas, andpresently there are no definite data available to clarify thatissue. Further prospective randomized controlled trials arerequired.

Our study has shown that laparoscopic ovarian excisionof endometrioma is detrimental to ovarian reserve andovarian response. The damage is more severe in ovariesfrom which an endometriomaR4 cm was excised, especiallyin respect to the ovarian response to stimulation. This impliesthe ovarian damage after laparoscopic endometriomaexcision may be related to the size of cyst. Further studiesare required to clarify this relationship. We believe that ourresults have important implications for the management ofendometriomas.

Acknowledgments: The authors thank all members inCenter for Reproduction of Obstetrics and GynecologyDepartment of Nanfang Hospital for their great help andvaluable suggestions.

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