REVIEW URRENT C OPINION
Impact of endometriomas and their removal on ovarian reserve Baris Ata a and Gurkan Uncu b
Purpose of review The effect of endometrioma on ovulatory function and ovarian reserve was unclear. Conflicting opinions exist regarding effect of endometrioma excision on ovarian reserve. Recent findings Endometriomas do not seem to affect ovulatory function. Women with endometrioma have lower antral follicle count and serum anti-Mu¨llerian hormone levels than age-matched healthy controls. There is highquality evidence suggesting a significant decline in serum anti-Mu¨llerian hormone levels following endometrioma excision. However, a similarly significant decline in antral follicle count is not demonstrated. Cauterization seems to be a contributing factor to ovarian damage and suturing the cyst bed could perhaps be a better alternative. Summary It seems prudent to warn patients regarding loss of ovarian reserve following endometrioma excision. Surgeons should cautiously limit the use of cauterization following stripping of endometrioma. Well designed studies comparing effect of various haemostatic measures on ovarian reserve are needed. Keywords anti-Mu¨llerian hormone, antral follicle count, endometrioma, endometriosis, ovarian reserve
INTRODUCTION In the western world, endometriosis affects 0.8–2% of reproductive aged women [1–5] and approximately one-third of women with endometriosis have (an) endometrioma(s) [6–8]. Subfertility is the presenting symptom for 30–50% of women with endometriosis and endometriomas are frequently encountered during investigation of infertility. Whether endometriomas affect ovulatory function and ovarian reserve and whether subfertile women benefit from surgical excision of endometrioma have remained controversial. Herein, we will review effect of endometrioma and its excision on ovarian reserve.
ENDOMETRIOMA AND OVULATORY FUNCTION Two studies involving a total of 98 women with unilateral endometriomas reported strikingly similar rate of ovulation from the affected ovary of 31 and 34%, which was significantly decreased compared with the unaffected gonad [9,10]. However, in a recent study involving ultrasound monitoring of 1199 menstrual cycles in 244 women,
the incidence of ovulation from the affected and unaffected ovary was found to be similar (49.7 vs. 50.3%, P ¼ 0.92) [11 ]. Given the above findings and the fact that most women with endometriosis having regular ovulatory cycles, we think that the presence of an endometrioma is very unlikely to affect ovulation. &
ENDOMETRIOMA AND OVARIAN RESERVE The term ‘ovarian reserve’ refers to the quantity of follicles present in the ovaries at a given time. There is no currently available method of assessing ovarian reserve per se, but several proxy measures are available to estimate the size of follicular pool [12]. These include endocrine and ultrasound a
Department of Obstetrics and Gynecology, Koc University School of Medicine, Istanbul and bDepartment of Obstetrics and Gynecology, Uludag University School of Medicine, Bursa, Turkey Correspondence to Gurkan Uncu, Department of Obstetrics and Gynecology, Uludag University School of Medicine, Gorukle, 16059 Bursa, Turkey. Tel: +90 224 2952500; e-mail: [email protected] Curr Opin Obstet Gynecol 2015, 27:235–241 DOI:10.1097/GCO.0000000000000165
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KEY POINTS Endometrioma does not affect ovulatory function. Endometrioma is likely to cause a decline in ovarian reserve. Surgical excision of endometrioma leads to a decline in ovarian reserve. Cautiously limiting the use of bipolar cauterization could decrease the harm on ovarian reserve.
¨ llerian markers. Recently, serum levels of anti-Mu hormone (AMH) have become the endocrine marker of choice, as it has less inter-cycle and intra-cycle variation than follicle-stimulating hormone (FSH) [12–15]. Antral follicle count (AFC) is a reliable and commonly used ultrasound marker of ovarian reserve [12]. Although AMH is a systemic marker of ovarian reserve, it is suggested that AFC could allow assessment of individual ovaries. However, inter-cycle variation of AFC in individual ovaries remains to be determined and performance of AFC as an ovarian reserve test in the presence of cysts such as endometrioma is questionable [16 ,17]. Although the effect of endometrioma excision on ovarian reserve is investigated in several studies and meta-analyses, whether the presence of an endometrioma per se negatively affects ovarian reserve is less well studied. We prospectively compared AMH and AFC between reproductive aged women with and without endometrioma [18 ]. There were 30 women with regular menstrual periods in each group, and none of them had prior ovarian surgery. Women with endometrioma had significantly decreased total AFC (AFC in both ovaries), 14.7 4.11 vs. 9.73 4.77, P < 0.01. Although this finding could be ascribed to some extent to possible decreased visibility of antral follicles in affected gonads, serum AMH levels were also significantly lower in women with endometrioma, 4.20 2.26 vs. 2.81 2.15, P ¼ 0.02 [18 ]. Other studies indirectly evaluated the effect of endometrioma on ovarian reserve, that is compared the number of oocytes collected between endometrioma containing ovaries and contralateral normal ovaries following ovarian stimulation for in-vitro fertilization (IVF) cycles [19–21]. Somigliana et al. [19] retrospectively analysed records of 36 women with unilateral endometriomas and reported that the number of codominant follicles was not significantly decreased in ovaries containing an endometrioma (4.1 2.2 vs. 3.2 2.0, P ¼ 0.09). When successive stimulation cycles of the same patients were included in the analyses, there were &
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statistically significant differences in both the numbers of codominant follicles and the numbers of collected oocytes, the latter only in women with more than five oocytes [19]. However, not only can these be false-positive findings due to multiplicity in subgroup analyses, but clinical significance of the observed differences of approximately one follicle and one oocyte is also questionable. Almog et al. [20] retrospectively analysed 81 women with unilateral endometriomas and reported similar number of oocytes being collected from ovaries containing endometriomas and normal ovaries (6.0 0.4 vs. 6.1 0.5, P ¼ 0.8). Moreover, in the same study, compared with 162 age-matched women without endometriomas, undergoing IVF at the same centre during the same period, women with unilateral endometrioma had similar numbers of oocytes collected, 11.9 0.8 vs. 11.4 0.5, P ¼ 0.3 [20]. Most recently, Esinler et al. [21] reported similar observations in another retrospective study including 19 women with unilateral endometriomas measuring less than 3 cm in diameter. Even though endometriomas do not seem to affect oocyte yield in the IVF setting, we think that the presence of endometrioma per se has the potential to negatively affect ovarian reserve and more studies are needed to determine reproducibility of our observation of decreased AMH levels and AFC in the presence of endometrioma, the natural course of ovarian reserve in the presence of endometrioma under different scenarios, for example under hormonal suppression of ovulation or expectant management, and prospectively compare number of oocytes collected between women with and without endometrioma.
EFFECT OF ENDOMETRIOMA EXCISION ON OVARIAN RESERVE Although indications for surgical treatment are controversial, it is frequently undertaken for removal/ ablation of an endometrioma [22–24]. Excisional surgery with the stripping technique is associated with better clinical outcome, including lower recurrence rates compared with drainage and ablation and thus is the commonly preferred approach [24–26]. However, two systematic reviews clearly demonstrated that endometrioma excision by the stripping technique leads to a decline in ovarian reserve as assessed by serum AMH concentrations [27,28]. The systematic review by Raffi et al. [27] included eight studies and reported a statistically significant decrease of 1.13 ng/ml [95% confidence interval (95% CI) 1.88 to 0.37 ng/ml] in serum AMH levels following surgical excision [27,29–36]. Volume 27 Number 3 June 2015
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Impact of endometriomas and their removal on ovarian reserve Ata and Uncu
It should be noted that follow-up was limited to 3 months in six of the eight studies. Subgroup analyses based on preoperative AMH levels, laterality of endometriomas (unilateral or bilateral) and patient age revealed categorically similar results, that is a significant decrease in AMH following endometrioma excision [27]. However, when analysis was limited with three higher quality studies according to the Newcastle–Ottawa scale, the difference was short of statistical significance, despite a strong trend (1.02 ng/ml, 95% CI 0.4 to 2.44). It should be noted that, despite similar categorical results, observations and estimates in individual studies demonstrated high heterogeneity. The systematic review by Somigliana et al. [28] was published the same year and included three additional studies to those in the systematic review by Raffi et al. [27,37–39]. Somigliana et al. [28] did not pool results in the form of a meta-analysis, possibly due to the above-mentioned heterogeneity issue. They presented a categorical evaluation of published studies. It is noteworthy that the only two studies that reported unchanged AMH levels were conducted by the same group [30,31], while the remaining nine of the 11 studies reported significant decrease in AMH levels following surgery. Again, the duration of follow-up was limited and only three studies reported AMH values measured more than 3 months after surgery. Age, laterality, cyst size, preoperative AMH levels and the presence of normal ovarian tissue on the enucleated cyst wall were evaluated as factors determining the rate of reduction in AMH level. However, findings varied across studies. Although the results of the two systematic reviews consistently demonstrated a significant decline in AMH levels following endometrioma excision, they also identified two important gaps in knowledge, whether the decline in AMH levels was permanent and which factors determined the rate of loss. Our groups conducted two prospective studies addressing the identified gaps in knowledge [18 ,40]. &
Is the decline in anti-Mu¨llerian hormone permanent? Our first study included 25 women undergoing unilateral endometriomas excision. Serum AMH levels were monitored up to 6 months postoperatively [40]. Endometrioma excision was associated with an immediate decline of 24% of the preoperative AMH level at the first postoperative month and this decline was sustained at postoperative sixth month, that is from 3.4 2.1 ng/ml preoperatively to 2.6 1.8 and 2.6 1.8 ng/ml at postoperative first and sixth months, respectively [40]. Our second
study included 30 women undergoing endometrioma excision who were also monitored for 6 months [18 ]. Even though the initial decline of 26% at the first postoperative month was similar to the decline observed in the former study, here, it was short of statistical significance, from 2.8 2.2 to 2.1 1.5 ng/ml (P ¼ 0.18). However, AMH level was significantly decreased at the sixth postoperative month control compared with baseline, 1.8 1.3 ng/ ml (P ¼ 0.02) [18 ]. In a more recent study including 193 women, Alborzi et al. [41 ] reported similar findings over 9 months of follow-up. AMH level declined from 3.9 3.6 ng/ml preoperatively to 1.8 1.8 ng/ ml at 9 months after surgery. These findings are consistent with the results of previous three studies, which had long follow-up periods of 6–9 months and were included in the systematic reviews. These results collectively suggest that endometrioma excision with the stripping technique is associated with a significant and persistent decline in serum AMH levels in the long term [18 ,29,36,38,40,41 ]. &
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Which factors determine the extent of reduction in serum anti-Mu¨llerian hormone? Age, laterality, preoperative AMH level, cyst size, inadvertent removal of normal ovarian tissue during surgery and the choice of haemostatic method were analysed as factors that could possibly affect the rate of decline in AMH following endometrioma excision. Age does not seem to be a factor determining AMH decline. Younger and older women seem to be affected similarly. However, preoperative AMH level was found to be positively correlated with the rate of decline in our study and the study by Celik et al. [18 ,38]. Women with higher preoperative AMH values experience a relatively higher drop in AMH levels. However, clinical significance of this finding is questionable, as they can still end up with a reasonably high AMH level. Although women with bilateral endometriomas were found to experience significantly greater decline in AMH than women with unilateral endometriomas in the studies by Hirokawa et al. [32] and Alborzi et al. [41 ], we and Celik et al. [38] failed to demonstrate a statistically significantly higher decline in women with bilateral endometriomas [18 ]. However, the absolute decline in AMH was consistently higher following bilateral endometrioma excision in both our study and the study by Celik et al. [38], and the failure to demonstrate statistical significance could be due to limited sample sizes in subgroup analyses. Inadvertent removal of normal ovarian tissue is almost inevitable during endometrioma excision. &
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We observed primordial follicles in 62 and 85% of surgical specimens in our two studies [18 ,40]. However, none of the studies, including ours, which investigated an association between the number of primordial follicles on the surgical specimen and the rate of decline in AMH, were able to demonstrate a significant correlation between the two [18 ,32,38]. Likewise, cyst size was not found be related with the rate of decline in AMH levels in any study. When all the above-mentioned findings are considered all together, some of the negative and contradictory findings, for example lack of an association between inadvertently removed follicles and a decline in AMH levels, or laterality affecting rate of decline in some studies but not in others, are likely false negatives due to one or more statistical limitations, that is difficulty of demonstrating statistically significant changes when one already starts with low values such as in the presence of large or bilateral cysts, or advanced age. This view is supported by consistent demonstration of a statistically significant positive correlation between preoperative AMH level and the rate of decline after surgery; the higher the preoperative AMH, the higher the rate of decline. This correlation would also credit the notion that the more inadvertent follicles removed the higher the rate of decline. However, inadvertent removal of healthy follicles surrounding the cyst wall is unlikely to be the only mechanism harming the remaining ovarian tissue. Thermal damage inflicted by dessication of bleeders following stripping could be a major factor leading to loss of ovarian reserve. It is noteworthy that bipolar cauterization was used to achieve haemostasis in all of the abovementioned studies. Suturing the cyst bed and application of haemostatic sealants without bipolar cauterization are alternative haemostatic methods. These are expected to decrease the adverse affect of surgery on ovarian reserve and they have been compared with bipolar cauterization in several studies. We recently published a systematic review and meta-analysis comparing the effect of haemostatic measures on ovarian reserve as measured by serum AMH levels [42 ]. We identified six studies including three randomized controlled trials and a prospective cohort study. Qualitatively, all but one of the six studies that were included reported significantly greater decline in AMH levels with bipolar cauterization, or a strong trend in the same direction. Four of the six studies were included in the meta-analysis and alternative haemostatic methods were found to be associated with a significantly lesser decline in ovarian reserve than bipolar cauterization. The mean decline in serum AMH &
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levels was 6.95% less with alternative haemostatic methods than bipolar cauterization (95% CI –13.0 to –0.9, P ¼ 0.02) 3 months after surgery. However, the difference was not significant in subgroup analyses comparing bipolar cauterization with suture (8.29%, 95% CI 17.14 to 0.56) or with haemostatic sealants (5.77%, 95% CI 14.07 to 2.53) separately [42 ]. It should be noted that haemostatic sealants are costly and they can be associated with serious side effects such as intravasation and thromboembolism as well as small bowel obstruction [42 ]. We do not think that their routine use to preserve ovarian reserve following endometrioma excision is justified at the moment. A more recent study that compared the rate of decline in AMH with suturing or bipolar cauterization after endometrioma excision reported significantly less harm on ovarian reserve with suturing [43]. Although 62 women in the bipolar cauterization group experienced a median decline of 42% in AMH level at the third postoperative month, 63 women in the suture group had only 24.6% decline (P ¼ 0.001) [43]. Once our meta-analysis is updated with this new study, we have no doubt that suturing will appear significantly better than bipolar cauterization in terms of preserving ovarian reserve. Unfortunately, the quality of currently available evidence supporting alternative haemostatic methods is modest at best. Therefore we cannot strongly recommend abandoning bipolar cauterization in favour of suturing at the moment, but we do think that surgeons should strive to limit the use of bipolar cauterization during laparoscopic endometrioma excision in order to preserve ovarian reserve. Although suturing is an inexpensive alternative to bipolar cauterization, it is an advanced endoscopic skill. However, it can be mastered under proper guidance and adequate practice. The importance of proper identification of the cleavage plane before stripping cannot be overestimated. It is our distinct opinion that bleeding is minimal when the cyst is stripped off in the correct plane. This not only diminishes the need for haemostasis regardless of the method but could also help minimizing the damage on ovarian circulation. &
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Effect of endometrioma excision on ovarian reserve as assessed by antral follicle count In view of the recent discussions regarding sample stability issues of AMH during storage of sera for later analysis and its being a systemic marker of ovarian reserve rather than enabling assessment of each gonad separately, Muzii et al. [44 ] claimed that previous systematic reviews assessing ovarian reserve with AMH could be misleading. They conducted &
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another systematic review and meta-analysis, which included 13 studies that reported AFC before and after endometrioma excision. AFC was not found to be significantly decreased in the operated ovary compared with preoperative count; mean difference was 0.1 with a 95% CI between 1.45 and 1.65 [44 ]. However, we and others expressed concerns regarding this approach [16 ,17]. Although handling and storage conditions of the sample at room temperature or 208C before analysis can lead to systematic variations in AMH readings, it is unlikely that a systematic error would be introduced in pre and postoperative comparisons in the studies included in the previous AMH-based systematic reviews [27,28,45]. This is simply because all samples would be handled similarly, that is the same assay and storage conditions, in a particular centre. Hence, pre and postoperative readings would be similarly affected. Moreover, only one of the eight studies included in the meta-analysis by Raffi et al. [27] reported storing samples at 208C [29], whereas samples were either analysed directly without cryostorage [33,36] or were stored at 708C or –808C before actual measurements in the remaining seven studies [30–32,34,35]. AMH levels are expected to remain stable at the latter temperatures [45]. When we repeated the calculations in the meta-analysis by Raffi et al. [27] after exclusion of the study in which samples were stored at 208C, the conclusion was essentially unchanged [16 ,29]. Serum AMH levels were still significantly decreased by an average of 0.9 ng/ml following endometrioma excision (Fig. 1) [16 ]. Second, when compared with AFC, AMH, despite its limitations, has similar correlation with primordial follicle count and similar capacity for predicting ovarian response to stimulation [46–48]. Moreover, inter-cycle and intra-individual variation of AMH was found to be significantly less &
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than that of AFC in several studies [49]. But above all, reliability of AFC is questionable in the presence of an endometrioma, as visualization of antral follicles may be obscured by the cyst that occupies a substantial portion of the ovary. This could lead to underestimation of preoperative AFC, and obscure a decrease in the postoperative period, when antral follicles can be more easily detected following cyst excision [16 ,17]. Although Muzii et al. [44 ] suggested that AFC in the affected gonad could better reflect the effect of surgery on ovarian reserve than AMH, this was neglected in their meta-analysis. Studies which reported the total AFC for both ovaries, even for patients who had a unilateral endometrioma, were included [18 ,36,38,40,41 ]. When the meta-analysis is limited to studies which compared AFC in the affected gonad before and after surgery, the results are somewhat changed, demonstrating a strong trend towards decreased AFC following surgery, –1.1, 95% CI 2.78 to 0.6 (Fig. 2) [29,31,50,51]. &
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CONCLUSION Endometriomas do not seem to affect ovulatory function; however, there is some evidence suggesting that they are associated with a decrease in ovarian reserve. There is high-quality evidence showing endometrioma excision leads to a further decrease in ovarian reserve as assessed by AMH. Although the postoperative decrease in AFC is short of statistical significance, the trend seems to parallel change in AMH levels. Due to technical limitations, AFC may not be a reliable marker of ovarian reserve in the presence of endometrioma. Cauterization per se seems a contributing factor to the decline in ovarian reserve following endometrioma excision. It will be prudent to warn patients regarding the decline in ovarian reserve following surgery and
Preoperative Postoperative Mean difference Study or subgroup Mean SD Total Mean SD Total Weight IV, random, 95% CI Biacchiardi 2011 Ercan 2010 Ercan 2011
3 1.62 2.03
0.4 1.09 0.41
43 47 36
1.3 1.39 1.95
0.3 1.16 0.62
43 47 36
19.3% 20.9%
Hirokawa 2011 Hwu 2011 Kitajima 2011 Lee 2010 Tsolakidis 2009
3.9 3.95 4.27 4.69 3.9
2.5 2.34 3 2.25 1.26
38 2.1 31 2.01 19 3.024 13 3.29 10 2.9
1.6 1.17 2.48 2.11 0.63
38 31 19 13 10
14.3% 14.5% 7.8% 8.2% 15.0%
0.08 [0.16, 0.32] 1.80 [0.86, 2.74] 1.94 [1.02, 2.86] 1.25 [–50, 3.00] 1.40 [0.28, 3.08] 1.00 [0.13, 1.87]
194 100.0%
0.96 [0.35, 1.57]
Total 95% CI
194
Mean difference IV, random, 95% CI
Not estimable 0.23 [–0.23, 0.69]
Heterogeneity Tau2 = 0.45; Chi2 = 30.18, df = 6 (P < 0.0001); I 2 = 80% Test for overall effect: Z = 3.08 (P = 0.002)
–4
-2
–4
Postoperative higher
2
4
Preoperative higher
FIGURE 1. Mean difference in serum anti-Mu¨llerian hormone after laparoscopic endometrioma excision. Data represent reanalysis of studies included in the study by Raffi et al. [27], with the exclusion of serum samples stored at 208C until analysis. Reprinted with permission from Ata and Urman [16 ]. &
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Study or subgroup
Preoperative Postoperative Mean difference Mean SDTotal Mean SDTotal Weight IV, random, 95% CI 33 36 48 61
20.6% 25.7% 27.5% 26.1%
–2.70 [–4.58, –0.82] 0.80 [–0.15, 1.75] 1.90 [1.44, 2.36] 3.60 [2.75, 4.45]
Total 95% CI 178 178 100.0% Heterogeneity :Tau2 = 2.57; Chi2 = 43.34, df = 3 (P < 0.00001); I 2 = 93% Test for overall effect: Z = 1.31 (P = 0.19)
1.11 [–0.55, 2.78]
Biacchiardi 2011 Ercan 2011 Var 2011 Zaitoun 2013
3.3 4.5 5.6 6.6
3.2 2 1.1 2.3
6 3.7 3.7 3
4.5 2.1 1.2 2.5
33 36 48 61
–10
Mean difference IV, random, 95% CI
–5 0 5 Higher after surgery Higher before surgery
10
FIGURE 2. Antral follicle counts in the same ovary before and after excision of endometrioma. Data represent reanalysis of studies included in Muzii et al. [44 ], with the exclusion of studies involving nonoperated gonad in antral follicle count. Reprinted with permission from Ata and Urman [16 ]. &
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to cautiously limit cauterization to the possible extent. Well designed studies comparing effect of bipolar cauterization and suturing on ovarian reserve are needed. Inclusion of an untreated control group would enable comparing the results against the natural decline in ovarian reserve over time. It should also be noted that endometriosis per se, even in the absence of endometrioma, could possibly affect ovarian reserve through mechanisms to be determined [52,53]. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Moen MH, Schei B. Epidemiology of endometriosis in a Norwegian county. Acta Obstet Gynecol Scand 1997; 76:559–562. 2. Abbas S, Ihle P, Koster I, Schubert I. Prevalence and incidence of diagnosed endometriosis and risk of endometriosis in patients with endometriosisrelated symptoms: findings from a statutory health insurance-based cohort in Germany. Eur J Obstet Gynecol Reprod Biol 2012; 160:79–83. 3. Gylfason JT, Kristjansson KA, Sverrisdottir G, et al. Pelvic endometriosis diagnosed in an entire nation over 20 years. Am J Epidemiol 2010; 172:237– 243. 4. Ballard KD, Seaman HE, de Vries CS, Wright JT. Can symptomatology help in the diagnosis of endometriosis? Findings from a national case-control study: Part 1. BJOG 2008; 115:1382–1391. 5. Leibson CL, Good AE, Hass SL, et al. Incidence and characterization of diagnosed endometriosis in a geographically defined population. Fertil Steril 2004; 82:314–321. 6. Vercellini P, Chapron C, De Giorgi O, et al. Coagulation or excision of ovarian endometriomas? Am J Obstet Gynecol 2003; 188:606–610. 7. Jenkins S, Olive DL, Haney AF. Endometriosis: pathogenetic implications of the anatomic distribution. Obstet Gynecol 1986; 67:335–338. 8. Redwine DB. Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease. Fertil Steril 1999; 72:310–315. 9. 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; 25:239–244.
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10. Benaglia L, Somigliana E, Vercellini P, et al. Endometriotic ovarian cysts negatively affect the rate of spontaneous ovulation. Hum Reprod 2009; 24:2183–2186. 11. Leone Roberti Maggiore U, Scala C, Venturini PL, et al. Endometriotic ovarian & cysts do not negatively affect the rate of spontaneous ovulation. Hum Reprod 2015; 30:299–307. This is the largest study examining affect of endometrioma on ovulation. It seems to provide a definitively convincing answer. 12. Domingues TS, Rocha AM, Serafini PC. Tests for ovarian reserve: reliability and utility. Curr Opin Obstet Gynecol 2010; 22:271–276. 13. La Marca A, Stabile G, Artenisio AC, Volpe A. Serum anti-Mullerian hormone throughout the human menstrual cycle. Hum Reprod 2006; 21:3103– 3107. 14. La Marca A, Giulini S, Tirelli A, et al. Anti-Mullerian hormone measurement on any day of the menstrual cycle strongly predicts ovarian response in assisted reproductive technology. Hum Reprod 2007; 22:766–771. 15. Broer SL, Broekmans FJ, Laven JS, Fauser BC. Anti-Mullerian hormone: ovarian reserve testing and its potential clinical implications. Hum Reprod Update 2014; 20:688–701. 16. Ata B, Urman B. Endometrioma excision and ovarian reserve: do assessments & by antral follicle count and anti-Mullerian hormone yield contradictory results? Hum Reprod 2014; 29:2852–2854. This letter provides a detailed discussion on possible limitations and relevance of AMH and AFC as markers of ovarian reserve in women with endometrioma. 17. Lima ML, Nastri CO, Coelho Neto MA, et al. Antral follicle count might be underestimated in the presence of an ovarian endometrioma. Hum Reprod 2015; 30:250. 18. Uncu G, Kasapoglu I, Ozerkan K, et al. Prospective assessment of the impact & of endometriomas and their removal on ovarian reserve and determinants of the rate of decline in ovarian reserve. Hum Reprod 2013; 28:2140– 2145. This study prospectively compared ovarian reserve markers between women with endometrioma and age-matched healthy controls. Women with endometrioma have significantly lower AMH and AFC. 19. Somigliana E, Infantino M, Benedetti F, et al. The presence of ovarian endometriomas is associated with a reduced responsiveness to gonadotropins. Fertil Ster 2006; 86:192–196. 20. Almog B, Shehata F, Sheizaf B, et al. Effects of ovarian endometrioma on the number of oocytes retrieved for in vitro fertilization. Fertil Steril 2011; 95:525–527. 21. Esinler I, Bozdag G, Arikan I, et al. Endometrioma
Impact of endometriomas and their removal on ovarian reserve Baris Ata a and Gurkan Uncu b
Purpose of review The effect of endometrioma on ovulatory function and ovarian reserve was unclear. Conflicting opinions exist regarding effect of endometrioma excision on ovarian reserve. Recent findings Endometriomas do not seem to affect ovulatory function. Women with endometrioma have lower antral follicle count and serum anti-Mu¨llerian hormone levels than age-matched healthy controls. There is highquality evidence suggesting a significant decline in serum anti-Mu¨llerian hormone levels following endometrioma excision. However, a similarly significant decline in antral follicle count is not demonstrated. Cauterization seems to be a contributing factor to ovarian damage and suturing the cyst bed could perhaps be a better alternative. Summary It seems prudent to warn patients regarding loss of ovarian reserve following endometrioma excision. Surgeons should cautiously limit the use of cauterization following stripping of endometrioma. Well designed studies comparing effect of various haemostatic measures on ovarian reserve are needed. Keywords anti-Mu¨llerian hormone, antral follicle count, endometrioma, endometriosis, ovarian reserve
INTRODUCTION In the western world, endometriosis affects 0.8–2% of reproductive aged women [1–5] and approximately one-third of women with endometriosis have (an) endometrioma(s) [6–8]. Subfertility is the presenting symptom for 30–50% of women with endometriosis and endometriomas are frequently encountered during investigation of infertility. Whether endometriomas affect ovulatory function and ovarian reserve and whether subfertile women benefit from surgical excision of endometrioma have remained controversial. Herein, we will review effect of endometrioma and its excision on ovarian reserve.
ENDOMETRIOMA AND OVULATORY FUNCTION Two studies involving a total of 98 women with unilateral endometriomas reported strikingly similar rate of ovulation from the affected ovary of 31 and 34%, which was significantly decreased compared with the unaffected gonad [9,10]. However, in a recent study involving ultrasound monitoring of 1199 menstrual cycles in 244 women,
the incidence of ovulation from the affected and unaffected ovary was found to be similar (49.7 vs. 50.3%, P ¼ 0.92) [11 ]. Given the above findings and the fact that most women with endometriosis having regular ovulatory cycles, we think that the presence of an endometrioma is very unlikely to affect ovulation. &
ENDOMETRIOMA AND OVARIAN RESERVE The term ‘ovarian reserve’ refers to the quantity of follicles present in the ovaries at a given time. There is no currently available method of assessing ovarian reserve per se, but several proxy measures are available to estimate the size of follicular pool [12]. These include endocrine and ultrasound a
Department of Obstetrics and Gynecology, Koc University School of Medicine, Istanbul and bDepartment of Obstetrics and Gynecology, Uludag University School of Medicine, Bursa, Turkey Correspondence to Gurkan Uncu, Department of Obstetrics and Gynecology, Uludag University School of Medicine, Gorukle, 16059 Bursa, Turkey. Tel: +90 224 2952500; e-mail: [email protected] Curr Opin Obstet Gynecol 2015, 27:235–241 DOI:10.1097/GCO.0000000000000165
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Fertility, IVF and reproductive genetics
KEY POINTS Endometrioma does not affect ovulatory function. Endometrioma is likely to cause a decline in ovarian reserve. Surgical excision of endometrioma leads to a decline in ovarian reserve. Cautiously limiting the use of bipolar cauterization could decrease the harm on ovarian reserve.
¨ llerian markers. Recently, serum levels of anti-Mu hormone (AMH) have become the endocrine marker of choice, as it has less inter-cycle and intra-cycle variation than follicle-stimulating hormone (FSH) [12–15]. Antral follicle count (AFC) is a reliable and commonly used ultrasound marker of ovarian reserve [12]. Although AMH is a systemic marker of ovarian reserve, it is suggested that AFC could allow assessment of individual ovaries. However, inter-cycle variation of AFC in individual ovaries remains to be determined and performance of AFC as an ovarian reserve test in the presence of cysts such as endometrioma is questionable [16 ,17]. Although the effect of endometrioma excision on ovarian reserve is investigated in several studies and meta-analyses, whether the presence of an endometrioma per se negatively affects ovarian reserve is less well studied. We prospectively compared AMH and AFC between reproductive aged women with and without endometrioma [18 ]. There were 30 women with regular menstrual periods in each group, and none of them had prior ovarian surgery. Women with endometrioma had significantly decreased total AFC (AFC in both ovaries), 14.7 4.11 vs. 9.73 4.77, P < 0.01. Although this finding could be ascribed to some extent to possible decreased visibility of antral follicles in affected gonads, serum AMH levels were also significantly lower in women with endometrioma, 4.20 2.26 vs. 2.81 2.15, P ¼ 0.02 [18 ]. Other studies indirectly evaluated the effect of endometrioma on ovarian reserve, that is compared the number of oocytes collected between endometrioma containing ovaries and contralateral normal ovaries following ovarian stimulation for in-vitro fertilization (IVF) cycles [19–21]. Somigliana et al. [19] retrospectively analysed records of 36 women with unilateral endometriomas and reported that the number of codominant follicles was not significantly decreased in ovaries containing an endometrioma (4.1 2.2 vs. 3.2 2.0, P ¼ 0.09). When successive stimulation cycles of the same patients were included in the analyses, there were &
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statistically significant differences in both the numbers of codominant follicles and the numbers of collected oocytes, the latter only in women with more than five oocytes [19]. However, not only can these be false-positive findings due to multiplicity in subgroup analyses, but clinical significance of the observed differences of approximately one follicle and one oocyte is also questionable. Almog et al. [20] retrospectively analysed 81 women with unilateral endometriomas and reported similar number of oocytes being collected from ovaries containing endometriomas and normal ovaries (6.0 0.4 vs. 6.1 0.5, P ¼ 0.8). Moreover, in the same study, compared with 162 age-matched women without endometriomas, undergoing IVF at the same centre during the same period, women with unilateral endometrioma had similar numbers of oocytes collected, 11.9 0.8 vs. 11.4 0.5, P ¼ 0.3 [20]. Most recently, Esinler et al. [21] reported similar observations in another retrospective study including 19 women with unilateral endometriomas measuring less than 3 cm in diameter. Even though endometriomas do not seem to affect oocyte yield in the IVF setting, we think that the presence of endometrioma per se has the potential to negatively affect ovarian reserve and more studies are needed to determine reproducibility of our observation of decreased AMH levels and AFC in the presence of endometrioma, the natural course of ovarian reserve in the presence of endometrioma under different scenarios, for example under hormonal suppression of ovulation or expectant management, and prospectively compare number of oocytes collected between women with and without endometrioma.
EFFECT OF ENDOMETRIOMA EXCISION ON OVARIAN RESERVE Although indications for surgical treatment are controversial, it is frequently undertaken for removal/ ablation of an endometrioma [22–24]. Excisional surgery with the stripping technique is associated with better clinical outcome, including lower recurrence rates compared with drainage and ablation and thus is the commonly preferred approach [24–26]. However, two systematic reviews clearly demonstrated that endometrioma excision by the stripping technique leads to a decline in ovarian reserve as assessed by serum AMH concentrations [27,28]. The systematic review by Raffi et al. [27] included eight studies and reported a statistically significant decrease of 1.13 ng/ml [95% confidence interval (95% CI) 1.88 to 0.37 ng/ml] in serum AMH levels following surgical excision [27,29–36]. Volume 27 Number 3 June 2015
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Impact of endometriomas and their removal on ovarian reserve Ata and Uncu
It should be noted that follow-up was limited to 3 months in six of the eight studies. Subgroup analyses based on preoperative AMH levels, laterality of endometriomas (unilateral or bilateral) and patient age revealed categorically similar results, that is a significant decrease in AMH following endometrioma excision [27]. However, when analysis was limited with three higher quality studies according to the Newcastle–Ottawa scale, the difference was short of statistical significance, despite a strong trend (1.02 ng/ml, 95% CI 0.4 to 2.44). It should be noted that, despite similar categorical results, observations and estimates in individual studies demonstrated high heterogeneity. The systematic review by Somigliana et al. [28] was published the same year and included three additional studies to those in the systematic review by Raffi et al. [27,37–39]. Somigliana et al. [28] did not pool results in the form of a meta-analysis, possibly due to the above-mentioned heterogeneity issue. They presented a categorical evaluation of published studies. It is noteworthy that the only two studies that reported unchanged AMH levels were conducted by the same group [30,31], while the remaining nine of the 11 studies reported significant decrease in AMH levels following surgery. Again, the duration of follow-up was limited and only three studies reported AMH values measured more than 3 months after surgery. Age, laterality, cyst size, preoperative AMH levels and the presence of normal ovarian tissue on the enucleated cyst wall were evaluated as factors determining the rate of reduction in AMH level. However, findings varied across studies. Although the results of the two systematic reviews consistently demonstrated a significant decline in AMH levels following endometrioma excision, they also identified two important gaps in knowledge, whether the decline in AMH levels was permanent and which factors determined the rate of loss. Our groups conducted two prospective studies addressing the identified gaps in knowledge [18 ,40]. &
Is the decline in anti-Mu¨llerian hormone permanent? Our first study included 25 women undergoing unilateral endometriomas excision. Serum AMH levels were monitored up to 6 months postoperatively [40]. Endometrioma excision was associated with an immediate decline of 24% of the preoperative AMH level at the first postoperative month and this decline was sustained at postoperative sixth month, that is from 3.4 2.1 ng/ml preoperatively to 2.6 1.8 and 2.6 1.8 ng/ml at postoperative first and sixth months, respectively [40]. Our second
study included 30 women undergoing endometrioma excision who were also monitored for 6 months [18 ]. Even though the initial decline of 26% at the first postoperative month was similar to the decline observed in the former study, here, it was short of statistical significance, from 2.8 2.2 to 2.1 1.5 ng/ml (P ¼ 0.18). However, AMH level was significantly decreased at the sixth postoperative month control compared with baseline, 1.8 1.3 ng/ ml (P ¼ 0.02) [18 ]. In a more recent study including 193 women, Alborzi et al. [41 ] reported similar findings over 9 months of follow-up. AMH level declined from 3.9 3.6 ng/ml preoperatively to 1.8 1.8 ng/ ml at 9 months after surgery. These findings are consistent with the results of previous three studies, which had long follow-up periods of 6–9 months and were included in the systematic reviews. These results collectively suggest that endometrioma excision with the stripping technique is associated with a significant and persistent decline in serum AMH levels in the long term [18 ,29,36,38,40,41 ]. &
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Which factors determine the extent of reduction in serum anti-Mu¨llerian hormone? Age, laterality, preoperative AMH level, cyst size, inadvertent removal of normal ovarian tissue during surgery and the choice of haemostatic method were analysed as factors that could possibly affect the rate of decline in AMH following endometrioma excision. Age does not seem to be a factor determining AMH decline. Younger and older women seem to be affected similarly. However, preoperative AMH level was found to be positively correlated with the rate of decline in our study and the study by Celik et al. [18 ,38]. Women with higher preoperative AMH values experience a relatively higher drop in AMH levels. However, clinical significance of this finding is questionable, as they can still end up with a reasonably high AMH level. Although women with bilateral endometriomas were found to experience significantly greater decline in AMH than women with unilateral endometriomas in the studies by Hirokawa et al. [32] and Alborzi et al. [41 ], we and Celik et al. [38] failed to demonstrate a statistically significantly higher decline in women with bilateral endometriomas [18 ]. However, the absolute decline in AMH was consistently higher following bilateral endometrioma excision in both our study and the study by Celik et al. [38], and the failure to demonstrate statistical significance could be due to limited sample sizes in subgroup analyses. Inadvertent removal of normal ovarian tissue is almost inevitable during endometrioma excision. &
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We observed primordial follicles in 62 and 85% of surgical specimens in our two studies [18 ,40]. However, none of the studies, including ours, which investigated an association between the number of primordial follicles on the surgical specimen and the rate of decline in AMH, were able to demonstrate a significant correlation between the two [18 ,32,38]. Likewise, cyst size was not found be related with the rate of decline in AMH levels in any study. When all the above-mentioned findings are considered all together, some of the negative and contradictory findings, for example lack of an association between inadvertently removed follicles and a decline in AMH levels, or laterality affecting rate of decline in some studies but not in others, are likely false negatives due to one or more statistical limitations, that is difficulty of demonstrating statistically significant changes when one already starts with low values such as in the presence of large or bilateral cysts, or advanced age. This view is supported by consistent demonstration of a statistically significant positive correlation between preoperative AMH level and the rate of decline after surgery; the higher the preoperative AMH, the higher the rate of decline. This correlation would also credit the notion that the more inadvertent follicles removed the higher the rate of decline. However, inadvertent removal of healthy follicles surrounding the cyst wall is unlikely to be the only mechanism harming the remaining ovarian tissue. Thermal damage inflicted by dessication of bleeders following stripping could be a major factor leading to loss of ovarian reserve. It is noteworthy that bipolar cauterization was used to achieve haemostasis in all of the abovementioned studies. Suturing the cyst bed and application of haemostatic sealants without bipolar cauterization are alternative haemostatic methods. These are expected to decrease the adverse affect of surgery on ovarian reserve and they have been compared with bipolar cauterization in several studies. We recently published a systematic review and meta-analysis comparing the effect of haemostatic measures on ovarian reserve as measured by serum AMH levels [42 ]. We identified six studies including three randomized controlled trials and a prospective cohort study. Qualitatively, all but one of the six studies that were included reported significantly greater decline in AMH levels with bipolar cauterization, or a strong trend in the same direction. Four of the six studies were included in the meta-analysis and alternative haemostatic methods were found to be associated with a significantly lesser decline in ovarian reserve than bipolar cauterization. The mean decline in serum AMH &
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levels was 6.95% less with alternative haemostatic methods than bipolar cauterization (95% CI –13.0 to –0.9, P ¼ 0.02) 3 months after surgery. However, the difference was not significant in subgroup analyses comparing bipolar cauterization with suture (8.29%, 95% CI 17.14 to 0.56) or with haemostatic sealants (5.77%, 95% CI 14.07 to 2.53) separately [42 ]. It should be noted that haemostatic sealants are costly and they can be associated with serious side effects such as intravasation and thromboembolism as well as small bowel obstruction [42 ]. We do not think that their routine use to preserve ovarian reserve following endometrioma excision is justified at the moment. A more recent study that compared the rate of decline in AMH with suturing or bipolar cauterization after endometrioma excision reported significantly less harm on ovarian reserve with suturing [43]. Although 62 women in the bipolar cauterization group experienced a median decline of 42% in AMH level at the third postoperative month, 63 women in the suture group had only 24.6% decline (P ¼ 0.001) [43]. Once our meta-analysis is updated with this new study, we have no doubt that suturing will appear significantly better than bipolar cauterization in terms of preserving ovarian reserve. Unfortunately, the quality of currently available evidence supporting alternative haemostatic methods is modest at best. Therefore we cannot strongly recommend abandoning bipolar cauterization in favour of suturing at the moment, but we do think that surgeons should strive to limit the use of bipolar cauterization during laparoscopic endometrioma excision in order to preserve ovarian reserve. Although suturing is an inexpensive alternative to bipolar cauterization, it is an advanced endoscopic skill. However, it can be mastered under proper guidance and adequate practice. The importance of proper identification of the cleavage plane before stripping cannot be overestimated. It is our distinct opinion that bleeding is minimal when the cyst is stripped off in the correct plane. This not only diminishes the need for haemostasis regardless of the method but could also help minimizing the damage on ovarian circulation. &
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Effect of endometrioma excision on ovarian reserve as assessed by antral follicle count In view of the recent discussions regarding sample stability issues of AMH during storage of sera for later analysis and its being a systemic marker of ovarian reserve rather than enabling assessment of each gonad separately, Muzii et al. [44 ] claimed that previous systematic reviews assessing ovarian reserve with AMH could be misleading. They conducted &
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Impact of endometriomas and their removal on ovarian reserve Ata and Uncu
another systematic review and meta-analysis, which included 13 studies that reported AFC before and after endometrioma excision. AFC was not found to be significantly decreased in the operated ovary compared with preoperative count; mean difference was 0.1 with a 95% CI between 1.45 and 1.65 [44 ]. However, we and others expressed concerns regarding this approach [16 ,17]. Although handling and storage conditions of the sample at room temperature or 208C before analysis can lead to systematic variations in AMH readings, it is unlikely that a systematic error would be introduced in pre and postoperative comparisons in the studies included in the previous AMH-based systematic reviews [27,28,45]. This is simply because all samples would be handled similarly, that is the same assay and storage conditions, in a particular centre. Hence, pre and postoperative readings would be similarly affected. Moreover, only one of the eight studies included in the meta-analysis by Raffi et al. [27] reported storing samples at 208C [29], whereas samples were either analysed directly without cryostorage [33,36] or were stored at 708C or –808C before actual measurements in the remaining seven studies [30–32,34,35]. AMH levels are expected to remain stable at the latter temperatures [45]. When we repeated the calculations in the meta-analysis by Raffi et al. [27] after exclusion of the study in which samples were stored at 208C, the conclusion was essentially unchanged [16 ,29]. Serum AMH levels were still significantly decreased by an average of 0.9 ng/ml following endometrioma excision (Fig. 1) [16 ]. Second, when compared with AFC, AMH, despite its limitations, has similar correlation with primordial follicle count and similar capacity for predicting ovarian response to stimulation [46–48]. Moreover, inter-cycle and intra-individual variation of AMH was found to be significantly less &
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than that of AFC in several studies [49]. But above all, reliability of AFC is questionable in the presence of an endometrioma, as visualization of antral follicles may be obscured by the cyst that occupies a substantial portion of the ovary. This could lead to underestimation of preoperative AFC, and obscure a decrease in the postoperative period, when antral follicles can be more easily detected following cyst excision [16 ,17]. Although Muzii et al. [44 ] suggested that AFC in the affected gonad could better reflect the effect of surgery on ovarian reserve than AMH, this was neglected in their meta-analysis. Studies which reported the total AFC for both ovaries, even for patients who had a unilateral endometrioma, were included [18 ,36,38,40,41 ]. When the meta-analysis is limited to studies which compared AFC in the affected gonad before and after surgery, the results are somewhat changed, demonstrating a strong trend towards decreased AFC following surgery, –1.1, 95% CI 2.78 to 0.6 (Fig. 2) [29,31,50,51]. &
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CONCLUSION Endometriomas do not seem to affect ovulatory function; however, there is some evidence suggesting that they are associated with a decrease in ovarian reserve. There is high-quality evidence showing endometrioma excision leads to a further decrease in ovarian reserve as assessed by AMH. Although the postoperative decrease in AFC is short of statistical significance, the trend seems to parallel change in AMH levels. Due to technical limitations, AFC may not be a reliable marker of ovarian reserve in the presence of endometrioma. Cauterization per se seems a contributing factor to the decline in ovarian reserve following endometrioma excision. It will be prudent to warn patients regarding the decline in ovarian reserve following surgery and
Preoperative Postoperative Mean difference Study or subgroup Mean SD Total Mean SD Total Weight IV, random, 95% CI Biacchiardi 2011 Ercan 2010 Ercan 2011
3 1.62 2.03
0.4 1.09 0.41
43 47 36
1.3 1.39 1.95
0.3 1.16 0.62
43 47 36
19.3% 20.9%
Hirokawa 2011 Hwu 2011 Kitajima 2011 Lee 2010 Tsolakidis 2009
3.9 3.95 4.27 4.69 3.9
2.5 2.34 3 2.25 1.26
38 2.1 31 2.01 19 3.024 13 3.29 10 2.9
1.6 1.17 2.48 2.11 0.63
38 31 19 13 10
14.3% 14.5% 7.8% 8.2% 15.0%
0.08 [0.16, 0.32] 1.80 [0.86, 2.74] 1.94 [1.02, 2.86] 1.25 [–50, 3.00] 1.40 [0.28, 3.08] 1.00 [0.13, 1.87]
194 100.0%
0.96 [0.35, 1.57]
Total 95% CI
194
Mean difference IV, random, 95% CI
Not estimable 0.23 [–0.23, 0.69]
Heterogeneity Tau2 = 0.45; Chi2 = 30.18, df = 6 (P < 0.0001); I 2 = 80% Test for overall effect: Z = 3.08 (P = 0.002)
–4
-2
–4
Postoperative higher
2
4
Preoperative higher
FIGURE 1. Mean difference in serum anti-Mu¨llerian hormone after laparoscopic endometrioma excision. Data represent reanalysis of studies included in the study by Raffi et al. [27], with the exclusion of serum samples stored at 208C until analysis. Reprinted with permission from Ata and Urman [16 ]. &
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Study or subgroup
Preoperative Postoperative Mean difference Mean SDTotal Mean SDTotal Weight IV, random, 95% CI 33 36 48 61
20.6% 25.7% 27.5% 26.1%
–2.70 [–4.58, –0.82] 0.80 [–0.15, 1.75] 1.90 [1.44, 2.36] 3.60 [2.75, 4.45]
Total 95% CI 178 178 100.0% Heterogeneity :Tau2 = 2.57; Chi2 = 43.34, df = 3 (P < 0.00001); I 2 = 93% Test for overall effect: Z = 1.31 (P = 0.19)
1.11 [–0.55, 2.78]
Biacchiardi 2011 Ercan 2011 Var 2011 Zaitoun 2013
3.3 4.5 5.6 6.6
3.2 2 1.1 2.3
6 3.7 3.7 3
4.5 2.1 1.2 2.5
33 36 48 61
–10
Mean difference IV, random, 95% CI
–5 0 5 Higher after surgery Higher before surgery
10
FIGURE 2. Antral follicle counts in the same ovary before and after excision of endometrioma. Data represent reanalysis of studies included in Muzii et al. [44 ], with the exclusion of studies involving nonoperated gonad in antral follicle count. Reprinted with permission from Ata and Urman [16 ]. &
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to cautiously limit cauterization to the possible extent. Well designed studies comparing effect of bipolar cauterization and suturing on ovarian reserve are needed. Inclusion of an untreated control group would enable comparing the results against the natural decline in ovarian reserve over time. It should also be noted that endometriosis per se, even in the absence of endometrioma, could possibly affect ovarian reserve through mechanisms to be determined [52,53]. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Moen MH, Schei B. Epidemiology of endometriosis in a Norwegian county. Acta Obstet Gynecol Scand 1997; 76:559–562. 2. Abbas S, Ihle P, Koster I, Schubert I. Prevalence and incidence of diagnosed endometriosis and risk of endometriosis in patients with endometriosisrelated symptoms: findings from a statutory health insurance-based cohort in Germany. Eur J Obstet Gynecol Reprod Biol 2012; 160:79–83. 3. Gylfason JT, Kristjansson KA, Sverrisdottir G, et al. Pelvic endometriosis diagnosed in an entire nation over 20 years. Am J Epidemiol 2010; 172:237– 243. 4. Ballard KD, Seaman HE, de Vries CS, Wright JT. Can symptomatology help in the diagnosis of endometriosis? Findings from a national case-control study: Part 1. BJOG 2008; 115:1382–1391. 5. Leibson CL, Good AE, Hass SL, et al. Incidence and characterization of diagnosed endometriosis in a geographically defined population. Fertil Steril 2004; 82:314–321. 6. Vercellini P, Chapron C, De Giorgi O, et al. Coagulation or excision of ovarian endometriomas? Am J Obstet Gynecol 2003; 188:606–610. 7. Jenkins S, Olive DL, Haney AF. Endometriosis: pathogenetic implications of the anatomic distribution. Obstet Gynecol 1986; 67:335–338. 8. Redwine DB. Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease. Fertil Steril 1999; 72:310–315. 9. 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; 25:239–244.
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10. Benaglia L, Somigliana E, Vercellini P, et al. Endometriotic ovarian cysts negatively affect the rate of spontaneous ovulation. Hum Reprod 2009; 24:2183–2186. 11. Leone Roberti Maggiore U, Scala C, Venturini PL, et al. Endometriotic ovarian & cysts do not negatively affect the rate of spontaneous ovulation. Hum Reprod 2015; 30:299–307. This is the largest study examining affect of endometrioma on ovulation. It seems to provide a definitively convincing answer. 12. Domingues TS, Rocha AM, Serafini PC. Tests for ovarian reserve: reliability and utility. Curr Opin Obstet Gynecol 2010; 22:271–276. 13. La Marca A, Stabile G, Artenisio AC, Volpe A. Serum anti-Mullerian hormone throughout the human menstrual cycle. Hum Reprod 2006; 21:3103– 3107. 14. La Marca A, Giulini S, Tirelli A, et al. Anti-Mullerian hormone measurement on any day of the menstrual cycle strongly predicts ovarian response in assisted reproductive technology. Hum Reprod 2007; 22:766–771. 15. Broer SL, Broekmans FJ, Laven JS, Fauser BC. Anti-Mullerian hormone: ovarian reserve testing and its potential clinical implications. Hum Reprod Update 2014; 20:688–701. 16. Ata B, Urman B. Endometrioma excision and ovarian reserve: do assessments & by antral follicle count and anti-Mullerian hormone yield contradictory results? Hum Reprod 2014; 29:2852–2854. This letter provides a detailed discussion on possible limitations and relevance of AMH and AFC as markers of ovarian reserve in women with endometrioma. 17. Lima ML, Nastri CO, Coelho Neto MA, et al. Antral follicle count might be underestimated in the presence of an ovarian endometrioma. Hum Reprod 2015; 30:250. 18. Uncu G, Kasapoglu I, Ozerkan K, et al. Prospective assessment of the impact & of endometriomas and their removal on ovarian reserve and determinants of the rate of decline in ovarian reserve. Hum Reprod 2013; 28:2140– 2145. This study prospectively compared ovarian reserve markers between women with endometrioma and age-matched healthy controls. Women with endometrioma have significantly lower AMH and AFC. 19. Somigliana E, Infantino M, Benedetti F, et al. The presence of ovarian endometriomas is associated with a reduced responsiveness to gonadotropins. Fertil Ster 2006; 86:192–196. 20. Almog B, Shehata F, Sheizaf B, et al. Effects of ovarian endometrioma on the number of oocytes retrieved for in vitro fertilization. Fertil Steril 2011; 95:525–527. 21. Esinler I, Bozdag G, Arikan I, et al. Endometrioma
