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REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY
Recurrent endometrioma and ovarian reserve: biological connection or surgical paradox? Edgardo Somigliana, MD, PhD; Laura Benaglia, MD; Paolo Vercellini, MD; Alessio Paffoni, MSc; Guido Ragni, MD; Luigi Fedele, MD OBJECTIVE: Cumulative evidence supports the view that ovarian endo-
metriomas originate from ovulatory events and that the ovarian reserve is reduced following surgery. On these bases, we have hypothesized that the risk of recurrence may be related to the residual ovarian reserve of the operated ovary. STUDY DESIGN: We retrospectively selected 45 women scheduled for in vitro fertilization who previously underwent surgical excision of monolateral endometriomas and compared ovarian responsiveness in those who did (n ⫽ 24) and did not (n ⫽ 21) have a recurrent endometrioma.
RESULTS: In the intact ovaries, the mean ⫾ SD number of codominant
follicles in women with and without recurrences was 3.5 ⫾ 1.7 and 3.7 ⫾ 2.2, respectively (P ⫽ NS). In the affected ovaries, the mean ⫾ SD number of follicles in gonads with and without recurrences was 2.5 ⫾ 2.3 and 1.1 ⫾ 1.5, respectively (P ⬍ .05).
CONCLUSION: Ovarian responsiveness is higher in gonads that devel-
oped recurrent endometriomas. Key words: endometrioma, in vitro fertilization, ovulation, recurrence
Cite this article as: Somigliana E, Benaglia L, Vercellini P, et al. Recurrent endometrioma and ovarian reserve: biological connection or surgical paradox? Am J Obstet Gynecol 2011;204:529.e1-5.
T
he pathogenesis of ovarian endometriomas is still debated. The 3 main pathogenetic hypotheses are the following: (1) the metaplasia of the coelomic epithelium covering the ovary; (2) the inversion and progressive invagination of the ovarian cortex after the accumulation of menstrual debris derived from bleeding of superficial endometriotic implants, which are located on the ovarian surface and adherent to the peritoneum; and (3) the secondary involvement of functional ovarian cysts (follicles or corpora lutea) by endometrial implants located on the ovarian surface.1 This latter hypothesis has received renovate interest and support in recent From the Department of Obstetrics, Gynecology, and Neonatology, Fondazione Instituto di Ricovero e Cura a Carattere Scientifico Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy. Received Oct. 22, 2010; revised Jan. 19, 2011; accepted Jan. 24, 2011. Reprints: Edgardo Somigliana, PhD, Infertility Unit, Fondazione Instituto di Ricovero e Cura a Carattere Scientifico Cà Granda, Ospedale Maggiore Policlinico, Via M. Fanti 6, 20122 Milano, Italy.
[email protected]. 0002-9378/$36.00 © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.01.053
years based on 2 main scientific evidences. First, a direct transition from follicles or corpora lutea into ovarian endometriomas has been observed by 2 independent authors in 12 and 11 cases, respectively.2,3 Second, long-term postsurgical administration of oral contraceptives that typically suppress ovulation are highly effective in the prevention of recurrence of ovarian endometriomas. Combining the results from 3 recent studies on this topic, the common odds ratio for the recurrence of ovarian endometrioma in oral contraceptive users is 0.12 (95% confidence interval, 0.03– 0.42).4-6 To date, the most effective treatment of ovarian endometrioma is the laparoscopic surgical excision.7,8 A major concern in this field is that ovarian reserve may be damaged following surgery.9 In particular, the rate of spontaneous ovulation as well as the responsiveness to ovarian hyperstimulation are reduced in operated ovaries.9-14 Moreover, serum levels of anti-Mullerian hormone dropped following surgery, in particular in women with bilateral disease.15 The ovarian injury is obviously not a systematic effect. The magnitude of the damage varies widely, from nil to the complete ovarian failure.9,14,16,17 Reasons for differences in damage magni-
tude are presently unknown, but they presumably include some characteristics of the cyst (size, location, grade of fibrosis of the cystic wall), the specific type of surgery performed (puncture/aspiration, ablation, bipolar or laser, excision in 1 or 2 step surgery), and the surgical expertise. Of note, some evidence also supports the idea that the damage may at least in part precede surgery.12,18,19 An important concern for physicians facing women with endometriosis is the elevated risk of recurrences. Recently Guo20 estimated a disease relapse rate higher than 20% at 2 years and 40-50% at 5 years. Even when considering ovarian endometriomas specifically, most recent and large-series report a cumulative recurrence rate of 20-50% at 3-5 years.4,5,21-23 Some studies have investigated risk factors for recurrences but data are inconsistent.20-24 In this study, we have hypothesized that the risk of recurrence may be strictly related to the residual ovarian reserve of the operated ovary. Indeed, if endometriomas do arise from ovulatory events, one may speculate that a severely injured ovary, whose primordial follicle reserve is depleted, will not develop recurrences because ovulation cannot occur. Conversely, in case of an ovarian reserve not significantly injured, the ovary
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may still display ovulatory events, thus being exposed to the risk of recurrences. In other words, the more severe the damage is to the ovary, the lower would be the risk of recurrence, with severely compromised ovaries markedly protected from recurrences. To support our hypothesis, we planned to demonstrate that the ovarian reserve of operated ovaries is less damaged in gonads with recurrences compared with those without. To this aim, we designed a retrospective study selecting women scheduled for in vitro fertilization (IVF) who had previously undergone unilateral excision of endometriotic cysts. Specifically, we compared responsiveness to hyperstimulation in operated ovaries with and without recurrences. If our hypothesis is valid, responsiveness should be greater in ovaries with recurrences compared with those without recurrences.
M ATERIALS AND M ETHODS Data from IVF–intracytoplasmic sperm injection (ICSI) cycles performed at the Infertility Unit of the Department of Obstetrics and Gynecology of the Fondazione Cà Granda, Ospedale Maggiore Policlinico, between January 2005 and December 2008 were reviewed. Inclusion criteria were as follows: (1) previous laparoscopic excision of 1 or more unilateral endometriotic ovarian cysts in our Institute (women operated twice because of recurrences were excluded), (2) no other adnexal interventions, (3) age 40 years or less at the time of ovarian stimulation, (4) contralateral nonoperated ovary unremarkable at the time of IVF (no endometrioma), (5) absence of nonendometriotic ovarian cysts in both gonads, (6) a noncanceled cycle prior to human chorionic gonadotropin (hCG) administration. Assumption of oral contraceptives, progestins, and gonadotropin-releasing hormone (GnRH) analogs during the interval between surgery and IVF was an exclusion criteria. Among selected women, we subsequently identified 2 different groups: (1) women with endometrioma recurrence on the operated ovary (recurrent group) and (2) women without recurrences after at least 3 years from surgery. This lat529.e2
ter criterion was decided to identify cases with a low, if any, residual risk to develop recurrence. Given the elevated rate of recurrences of the disease, the inclusion of all nonrecurrent cases would have exposed our results to a consistent risk of underestimation of the differences. Approval for the study was obtained by the local institutional review board. All patients referred to our unit gave their informed consent to the use of their clinical data for research purposes. This was a chart review. Only 1 cycle per patient was considered. Specifically, data exclusively refer to the first cycle performed after surgery. Information regarding surgical technique as well as dimension and histology of the cyst were obtained from surgical, ecographic, and pathological records. All laparoscopic operations were performed using stripping technique. The pharmacological regimen for controlled ovarian hyperstimulation used was the long protocol with a daily 0.1 mg GnRH agonist (triptoreline, Decapeptyl; Ipsen Pharma, Pavia, Italy) combined with the use of recombinant follicle-stimulating hormone (FSH; Gonal-F, Serono Laboratories, Inc, Rome, Italy). Dosage of recombinant FSH prescribed was decided based on age, hormonal tests, ultrasound characteristics of the ovaries, and results from previous pharmacological ovarian hyperstimulation cycles. In all cases, follicular growth was monitored by serial transvaginal ultrasonography. Ovulation was triggered administering 250 g of recombinant hCG (Ovitrelle; Serono Laboratories, Inc, Rome, Italy) when 2 or more leading follicles had mean diameter 18 mm or greater. On the day of hCG administration, a detailed transvaginal ultrasound scan was performed to record number and diameter of all the follicles. This information was recorded separately for the 2 ovaries. Transvaginal oocyte retrieval was performed 36 hours after hCG administration and transfer of the embryos 2-3 days later. Conservative surgery at laparoscopy was performed using mechanical instruments and electrosurgery only as previously described.4 Adhesions were sectioned with microscissors; the ovaries
American Journal of Obstetrics & Gynecology JUNE 2011
www.AJOG.org were completely mobilized; and endometriomas were evacuated, rinsed with normal saline, and excised by means of countertraction applied to the pseudocapsule and normal gonadal cortex with atraumatic microforceps. Hemostasis was achieved by selective application of bipolar current. All interventions were performed by 3 different expert surgeons. The presence of a recurrent endometrioma was diagnosed when a roundshaped cystic mass with a minimum diameter of 10 mm, with thick walls, regular margins, and homogeneous low echogenic fluid content with scattered internal echoes and without papillary proliferations was observed.25 The presence of the lesion had to be confirmed at least twice at 2 months’ interval. Diameter of follicles was calculated as the mean of 3 perpendicular diameters. Clinical pregnancy was defined as the ultrasonographic demonstration of an intrauterine gestational sac 4 weeks after embryo transfer. The main outcome of the study was the number of codominant follicles (diameter greater than 15 mm) at the time of hCG administration. Analysis of the data was performed using the Statistics Package for Social Sciences (SPSS 16.0; SPSS, Inc, Chicago, IL). Baseline variables were compared using Student t test or Fisher’s exact test, as appropriate. Number of follicles per ovaries was compared using unpaired Student t test and confirmed using nonparametric MannWhitney test for unpaired data. P ⬍ .05 was considered statistically significant.
R ESULTS Forty-five women were selected. Twentyfour had a recurrent endometrioma (recurrence group), whereas the remainder was free of recurrences (recurrence-free group, n ⫽ 21). In the recurrence group, 1 endometrioma was present in 20 cases (83%), whereas the remaining 4 women had 2 cysts (n ⫽ 4, 17%). The mean ⫾ SD of the diameter of the endometriomas was 21 ⫾ 7 mm. Baseline characteristics of the 2 study groups are shown in Table 1. As expected, the time between surgery and IVF significantly differed.
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TABLE 1
Baseline clinical characteristics of the 2 study groups Characteristics
Recurrence group (n ⴝ 24)
Recurrence-free group (n ⴝ 21)
P value
At the time of surgery
.....................................................................................................................................................................................................................................
Age, y
31.4 ⫾ 3.6
29.4 ⫾ 4.2
.10
Diameter of the excised cyst, mm
44 ⫾ 14
51 ⫾ 23
.31
..................................................................................................................................................................................................................................... a ..............................................................................................................................................................................................................................................
At the time of IVF
.....................................................................................................................................................................................................................................
34.8 ⫾ 3.0
34.8 ⫾ 3.9
.98
Previous pregnancies
5 (21%)
2 (10%)
.42
Time since ovarian surgery, y
3.4 ⫾ 1.9
5.3 ⫾ 2.7
.008
Age, y
..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................
Duration of infertility, y
3.6 ⫾ 1.8
4.1 ⫾ 3.7
.58
21.9 ⫾ 2.3
21.8 ⫾ 3.1
.98
9.0 ⫾ 5.1
9.3 ⫾ 4.0
.84
..................................................................................................................................................................................................................................... 2
BMI, kg/m
.....................................................................................................................................................................................................................................
Day 3 serum FSH, IU/mL
..............................................................................................................................................................................................................................................
BMI, body mass index; FSH, follicle-stimulating hormone; IVF, in vitro fertilization. a
One per patient per group was excised 2 endometriomas in the same ovary. The diameter included in the analysis corresponded to the bigger one.
Somigliana. Recurrent endometrioma and ovarian reserve. Am J Obstet Gynecol 2011.
The remaining characteristics resulted conversely similar. The IVF outcome is illustrated in Table 2. None of the reported variables was significantly different between the 2 study groups. In the intact ovary, the number of codominant follicles was similar in the 2 study groups. The mean ⫾ SD number of follicles in women with and without recurrences was indeed 3.5 ⫾ 1.7 and 3.7 ⫾ 2.2, respectively (Student t test, P ⫽ 0.72; Mann-Whitney test, P ⫽ .90). In contrast, a statistically significant difference emerged when considering the affected ovaries. Specifically, the mean ⫾ SD number of follicles in gonads with and without
recurrences was 2.5 ⫾ 2.3 and 1.1 ⫾ 1.5, respectively (Student t test, P ⫽ .023; Mann-Whitney test, P ⫽ .04). This result is illustrated in the Figure.
C OMMENT The results of this study support our original hypothesis. Ovarian responsiveness was more pronounced in gonads that developed recurrent endometriomas compared with those that did not. This presumably reflects a more intact ovarian reserve.26 The study has some strengths and some limits that have to be considered.
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First of all, the study is retrospective and it is based on chart review. However, the decision to focus exclusively on the codominant follicles should have protected our results from inaccuracies. In our unit, the dimension and number of follicles are systematically recorded the day of hCG administration, and all ultrasound scans are performed by expert physicians who are unlikely to miss large follicles. A prospective study aimed at disentangling this point would be more appropriate, but it would also require an important and prolonged effort with, in our view, no substantial benefits. Noteworthy, the strict selection criteria used has inevitably limited the number of eligible women. Although more than 1000 IVF-ICSI cycles per year are performed in our unit, only 45 women over a 4 year period fulfilled the inclusion criteria. In this regard, it has to be recognized that the limited sample size represents a further limit of the study. In fact, our results, although statistically significant, need to be confirmed in larger studies. Second, we focused on a highly selected study group. All women were infertile and had received ineffective surgery. Inferences to the entire population of women with endometrioma cannot be definitely drawn and further evidence is thus required. On the other hand, it is wise to note that IVF is a model without equal to assess the endometrioma-related impact on ovarian reserve. Indeed, responsiveness to ovarian hyperstimula-
TABLE 2
IVF cycle outcome in the 2 study groups Characteristics
Recurrence group (n ⴝ 24)
Recurrence-free group (n ⴝ 21)
P value
Duration of stimulation, d
11.3 ⫾ 1.9
10.2 ⫾ 2.1
.10
Total number of rFSH, IU
3341 ⫾ 1188
2988 ⫾ 1523
.41
Number of oocytes retrieved
5.3 ⫾ 2.2
6.2 ⫾ 4.4
.36
Number of embryos transferred
2.3 ⫾ 0.8
1.9 ⫾ 0.7
.39
Number of transfers not performed, n (%)
3 (12)
7 (33)
.15
Number of clinical pregnancies and PR per transfer, n (%)
4 (17)
5 (24)
.71
Number of implanted embryos and implantation rate, n (%)
5 (10)
5 (18)
.48
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
FSH, follicle-stimulating hormone; IVF, in vitro fertilization; rFSH, recombinant FSH. Somigliana. Recurrent endometrioma and ovarian reserve. Am J Obstet Gynecol 2011.
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FIGURE
Number of follicles in operated and contralateral intact gonads
Number of follicles in operated and contralateral intact gonads in women with (black bar ) and without (gray bar ) recurrences. Whereas the number of follicles in the unaffected gonads was similar in the 2 study groups, a statistically significant difference emerged for the affected ovaries (Student t test, P ⫽ .023; Mann-Whitney test, P ⫽ .04). Somigliana. Recurrent endometrioma and ovarian reserve. Am J Obstet Gynecol 2011.
tion is considered the best surrogate way to estimate ovarian reserve.26 Alternative tests such as day 3 serum FSH or antiMullerian hormone could not be used in the present study because they did not consent to differentiate the separate contribution of the 2 gonads. Antral follicle count may be an option because it allows the study of the gonads separately. Unfortunately, this variable was not systematically recorded in our unit and we are thus unable to add this information. Third, the 2 study groups may differ in their baseline characteristics. However, in this regard, it has to be underlined that recorded baseline characteristics did not differ between the study groups. The age at IVF, which is a critical variable when dealing with ovarian reserve, produced almost identical results. As expected, the unique exception was the time since surgery because this was an inclusion criteria for the nonrecurrence group. More importantly, the number of codominant follicles in the intact gonad was extremely similar, thus suggesting that the baseline ovarian reserve of the women in the 2 groups was also similar. This strongly supports the validity of the 529.e4
comparisons between the operated gonads of the 2 groups. Finally, it is noteworthy that the presence of an endometrioma may per se distort and damage the adjacent ovarian tissue. Evidence from pathological specimens clearly supports this possibility.18 Moreover, responsiveness to ovarian stimulation in unoperated ovaries carrying an endometrioma is partially reduced,12 and 2 recent studies documented a lower rate of spontaneous ovulation in unoperated ovaries carrying an endometrioma.13,19 Overall, however, the evidence that an endometrioma impairs ovarian function per se actually further supports the validity of our results. Indeed, given the design of the present study, this detrimental effect is expected to have diluted rather than inflated the differences between the 2 groups. Our results may thus be an underestimation of the real difference. The observation that the risk of recurrences is higher in ovaries whose ovarian reserve has been more spared by the disease or its surgical treatment is intriguing and may have some implications. First, it has to be viewed as a further confirmation of the role of ovulation in the pathogenesis of ovarian endometriomas. The less damaged the ovarian reserve, the higher the possibility of ovulation to occur and consequently the higher would be the risk of recurrence. There is also a second, more speculative implication for our results. The classical dogma supposing that a recurrence is indicative of an inappropriate first surgery may be herein inverted. For endometriomas’ surgery, the recurrence rate might represent an indicator of surgical expertise. The higher the rate of recurrences, the less traumatic has been the surgical intervention. Surgical expertise is, however, not the unique determinant of ovarian damage, and thus, this hypothesis, albeit intriguing, is mainly provocative. Moreover, it is noteworthy that there is also an alternative explanation for our findings. Because of the retrospective design of our study, we cannot rule out that recurrences were indeed persistences because of an incomplete surgery, at least for some cases. In these specific cases, sur-
American Journal of Obstetrics & Gynecology JUNE 2011
www.AJOG.org gery would have spared the ovarian reserve without solving the disease. In this regard, one may also consider that the type of endometrioma can affect the surgeon’s surgical confidence and ability to remove the cyst completely. For example, those stripped completely intact leave no question for residual disease, whereas those removed piecemeal because of scarred planes make residual disease a distinct possibility. Finally, it cannot be excluded that persistence may mirror the presence of a different type of cyst with, possibly, a different impact on ovarian reserve. The present study also emphasizes, once again, the importance of a comprehensive management of the patients. Even if a higher rate of recurrences would turn out to be a positive indicator of surgical expertise, it would remain a negative indicator of disease management. As previously mentioned, longterm administration of oral contraceptives is an extremely effective treatment in preventing recurrences and should be systematically proposed to women operated for endometriomas. In women seeking pregnancy, oral contraceptives obviously cannot be prescribed, but, given the possibility of alternative treatments such as IVF, a careful balance between the chances of spontaneous pregnancy and the risk of recurrences should be systematically considered. In our view, this balance may tip toward oral contraceptives and IVF after 1 year of fruitless attempts after surgery.27 Unfortunately, women operated for endometriosis who are seeking pregnancy rarely assume oral contraceptives. At least they do not until recurrence is diagnosed. As a consequence, only a small minority of women referring to our unit assume oral contraceptives after surgery and before recurrences develop. We were thus unable to design a study aimed at ascertaining the benefits of oral contraceptives in our unit. In conclusion, the present study supports the view that operated ovaries with a more intact remnant reserve are exposed to a higher risk of recurrences. Further evidence is required for a definite interpretation of this result. In particular, the role of the surgical technique needs to be eluci-
www.AJOG.org dated. Future studies should also aim to better clarify the origin of ovarian endometrioma. Ovulation is critical in the development but other pathogenetic mechanisms participate in their formation. The elucidation of this point may open new therapeutic scenarios and may possibly lead to some critical modifications of the surgical technique. f REFERENCES 1. Vigano P, Somigliana E, Gentilini D, Benaglia L, Vercellini P. Back to the original question in endometriosis: implantation or metaplasia? J Endometriosis 2009;1:1-8. 2. Jain S, Dalton ME. Chocolate cysts from ovarian follicles. Fertil Steril 1999;72:852-6. 3. Vercellini P, Somigliana E, Vigano P, Abbiati A, Barbara G, Fedele L. ’Blood on the tracks’ from corpora lutea to endometriomas. BJOG 2009;116:366-71. 4. Vercellini P, Somigliana E, Daguati R, Vigano P, Meroni F, Crosignani PG. Postoperative oral contraceptive exposure and risk of endometrioma recurrence. Am J Obstet Gynecol 2008; 198:504.e1-5. 5. Seracchioli R, Mabrouk M, Frascà C, et al. Long-term cyclic and continuous oral contraceptive therapy and endometrioma recurrence: a randomized controlled trial. Fertil Steril 2010;94:464-71. 6. Takamura M, Koga K, Osuga Y, et al. Postoperative oral contraceptive use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision. Hum Reprod 2009;24: 3042-8. 7. Alborzi S, Zarei A, Alborzi S, Alborzi M. Management of ovarian endometrioma. Clin Obstet Gynecol 2006;49:480-91.
Reproductive Endocrinology and Infertility 8. Chapron C, Vercellini P, Barakat H, Vieira M, Dubuisson JB. Management of ovarian endometriomas. Hum Reprod Update 2002;8:591-7. 9. Garcia-Velasco JA, Somigliana E. Management of endometriomas in women requiring IVF: to touch or not to touch. Hum Reprod 2009;24:496-501. 10. Loh FH, Tan AT, Kumar J, Ng SC. Ovarian response after laparoscopic ovarian cystectomy for endometriotic cysts in 132 monitored cycles. Fertil Steril 1999;72:316-21. 11. Candiani M, Barbieri M, Bottani B, et al. Ovarian recovery after laparoscopic enucleation of ovarian cysts: insights from echographic short-term postsurgical follow-up. J Minim Invasive Gynecol 2005;12:409-14. 12. Somigliana E, Infantino M, Benedetti F, Arnoldi M, Calanna G, Ragni G. The presence of ovarian endometriomas is associated with a reduced responsiveness to gonadotropins. Fertil Steril 2006;86:192-6. 13. Horikawa T, Nakagawa K, Ohgi S, et al. The frequency of ovulation from the affected ovary decreases following laparoscopic cystectomy in infertile women with unilateral endometrioma during a natural cycle. J Assist Reprod Genet 2008;25:239-44. 14. Benaglia L, Somigliana E, Vighi V, Ragni G, Vercellini P, Fedele L. Rate of severe ovarian damage following surgery for endometriomas. Hum Reprod 2010;25:678-82. 15. Chang HJ, Han SH, Lee JR, et al. Impact of laparoscopic cystectomy on ovarian reserve: serial changes of serum anti-Müllerian hormone levels. Fertil Steril 2009;94:343-9. 16. Busacca M, Riparini J, Somigliana E, et al. Postsurgical ovarian failure after laparoscopic excision of bilateral endomatriomas. Am J Obstet Gynecol 2006;195:421-5. 17. Di Prospero F, Micucci G. Is operative laparoscopy safe in ovarian endometriosis? Reprod Biomed Online 2009;18:167.
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