Accepted Manuscript Ovarian endometrioma: What the patient needs G. Alabiso, L. Alio, S. Arena, A. Barbasetti di Prun, V. Bergamini, N. Berlanda, G. Biliotti, M. Busacca, M. Candiani, G. Centini, A. Di Cello, C. Exacoustos, L. Fedele, L. Lazzeri, S. Luisi, A. Maiorana, F. Maneschi, A. Mattei, L. Muzii, S. Pinzauti, V. Remorgida, R. Seracchioli, C. Tosti, R. Venturella, P. Vercellini, P. Vigano’, M. Vignali, F. Zullo, E. Zupi

PII:

S1553-4650(14)00041-7

DOI:

10.1016/j.jmig.2014.01.011

Reference:

JMIG 2233

To appear in:

The Journal of Minimally Invasive Gynecology

Received Date: 10 January 2014 Accepted Date: 12 January 2014

Please cite this article as: Alabiso G, Alio L, Arena S, Barbasetti di Prun A, Bergamini V, Berlanda N, Biliotti G, Busacca M, Candiani M, Centini G, Di Cello A, Exacoustos C, Fedele L, Lazzeri L, Luisi S, Maiorana A, Maneschi F, Mattei A, Muzii L, Pinzauti S, Remorgida V, Seracchioli R, Tosti C, Venturella R, Vercellini P, Vigano’ P, Vignali M, Zullo F, Zupi E, Ovarian endometrioma: What the patient needs, The Journal of Minimally Invasive Gynecology (2014), doi: 10.1016/j.jmig.2014.01.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Ovarian endometrioma: What the patient needs

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ETIC, Endometriosis Treatment Italian Club

4 ETIC members: Alabiso G, Alio L, Arena S, Barbasetti di Prun A, Bergamini V, Berlanda N, Biliotti G, Busacca M, Candiani M, Centini G, Di Cello A, Exacoustos C, Fedele L, Lazzeri L, Luisi S, Maiorana A, Maneschi F, Mattei A, Muzii L, Pinzauti S, Remorgida V, Seracchioli R, Tosti C, Venturella R, Vercellini P, Vigano’ P, Vignali M, Zullo F, Zupi E

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Corresponding Author: Ludovico Muzii, MD, Department of Obstetrics and Gynecology,

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“Sapienza” University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. Fax: +39-06-

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49973128. Email: [email protected]

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Precis

38 A panel of 29 experts in the field of endometriosis express their opinion on management options for

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a 35 years old patient with bilateral endometriomas.

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Abstract

42 A panel of 29 experts in the field of endometriosis express their opinion on management options

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regarding a 35 years old patient, currently not desiring pregnancy, with moderate pelvic pain, and

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with an ultrasonographic diagnosis of bilateral endometriomas. Many questions that this

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paradigmatic patient may pose to the clinician are addressed, and all clinical scenarios are

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discussed. A decision algorithm derived from this discussion is also proposed.

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Introduction

49 The number of scientific papers on endometriosis increased exponentially over recent decades,

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creating some problems of quality of the published evidence.

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Evidence-based medicine, which aims to apply the best available evidences gained from scientific

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methods, has the tendency to consider everything that is not proven as untrue, thus disregarding

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valuable observational information.

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Since endometriosis is a highly variable disease, and may present with many different clinical

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scenarios, often it may not be encompassed in inclusion and exclusion criteria of most randomized

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clinical trials (RCT).

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“ETIC” (Endometriosis Treatment Italian Club) includes a panel of Italian experts on endometriosis

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and pelvic pain disorders. It represents a scientific community with one of the highest cumulative

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Impact Factor worldwide, related to the published peer reviewed papers on endometriosis, being

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able to give authority bases statements in this field.

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The major goal of this Club, starting always from the patient desire, is to clarify as much as possible

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the controversies in the practical management of patients suffering for endometriosis.

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The aim of the present study is to answer all the potential questions coming from a paradigmatic 35

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years old patient, currently not desiring pregnancy, with moderate pelvic pain, and an

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ultrasonographic diagnosis of bilateral endometriomas (5 and 2 cm, respectively on the left and

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right ovary).

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68 Preoperative diagnosis

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The patient presents with a presumptive diagnosis of bilateral endometriomas at transvaginal

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ultrasonography (Figure 1). A correct diagnosis of an endometrioma is important, because there

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is an association between endometrioma, chronic pelvic pain (CPP) and subfertility, and also

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because it has to be differentiated from other benign and malignant ovarian lesions.

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Several studies have described the ultrasound characteristics of endometriomas in the attempt to

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define their typical ultrasound features (1-3). The “typical” endometrioma is a unilocular or

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multilocular (less than 5 locules) cyst with homogeneous low level of echogenicity, ground glass

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echogenicity, of the cyst fluid. Being endometriomas less vascularized a good accuracy could be

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obtained by associating conventional ultrasound with color or power Doppler. The algorithm of

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Guerriero (4) defined an endometrioma as either a unilocular cyst with ground glass echogenicity

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and no/moderate vascularization (“typical” endometrioma), or as a unilocular cyst with ground

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glass echogenicity and papillary projections, and any flow inside the papillary projection

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ACCEPTED MANUSCRIPT (“atypical” endometrioma). According to the algorithm of Guerriero (4), a unilocular cyst with

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ground glass echogenicity and strong vascularization or a unilocular-solid cyst with ground glass

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echogenicity and a papillary projection with detectable flow or strong vascularization are

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classified as non-endometriomas.

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Almost 50% of the endometriomas have ultrasound characteristics other than the typical

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unilocular cyst. The rule “premenopausal status, ground glass echogenicity, one to four locules

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and no papillations with detectable blood flow” describes endometriomas in the correct way, but

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it does not add more than a subjective evaluation.

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Subjective impression as other rules can misclassify malignancies as endometriomas in 0.2-0.9%

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of the cases. Borderline ovarian tumors and ovarian carcinomas (endometrioid or clear cell

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carcinoma) arising from endometrioid cysts show a vascularized solid component at ultrasound

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examination. Benign endometrioid cysts, and malignancies and borderline ovarian tumors arising

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from endometriosis might not represent a specifically difficult category of ovarian masses for

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assessment by an expert ultrasound examiner compared with the general population of ovarian

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masses (5). This seems not to be valid for ovarian cyst during pregnancy, where the

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differentiation between borderline ovarian tumors and decidualized endometriotic cyst can be

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difficult (6). Serum CA-125 levels are mostly not useful to distinguish endometriomas from other

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benign tumors and malignancies (7), whereas it can be used in differentiating endometriomas

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from other benign ovarian lesions (1).

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An endometrioma can be often associated with the presence of pelvic adhesions, hydrosalpinx

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and deep infiltrating endometriosis. Normally, the uterus and ovaries are mobile and not adherent

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to the surrounding tissues by palpation with the probe and/or by abdominal palpation with the

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hand, and these organ movements can be seen at ultrasound (“sliding sign”) (8-10).

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Endometriomas are usally fixed posteriorly to the uterus, in the pouch of Douglas, especially in

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case of bilateral endometriomas (“kissing ovaries”).

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In the presence of an endometrioma, frequently also the ipsilateral tube is involved by the disease,

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in terms of adhesions that alter the normal tubal course and occlude the tube, or by endometriotic

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foci affecting the tubal walls. As a consequence, a hydrosalpinx can be observed near the

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endometrioma.

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Rarely it happens that the normal architecture of one or both the ovaries and tubes can not be

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recognized anymore, with formation of a conglomerate of endometriotic cysts in which neither the

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ovary nor the tube can be separately identified.

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Ovarian endometriomas are frequently associated with other endometriotic lesions as deep

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infiltrating endometriosis (DIE) (11). Patients with suspected endometriomas associated with DIE,

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in particular those with a frozen pelvis or rectovaginal or bladder nodules, should be referred to an

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expert and dedicated sonographer in order to evaluate the extension of the disease. Underestimation

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of deep endometriosis or of extensive adhesions prior to surgery in patients with endometriomas is

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one of the main reasons explaining why surgery is sometimes incomplete (11), often leading to

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repetitive operative procedures.

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Ovarian endometrioma, among the three subtypes of endometriosis (superficial, deep and

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endometrioma) has the most controversial and debated relationship with pelvic pain (12). Since

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ovarian endometriomas are often an occasional ultrasonographic finding, it is very important to

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carefully evaluate the severity and the pathogenetic correlations of the associated pelvic pain, before

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opting for a surgical indication (11,13,14).

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This evaluation is of prominent relevance because all visceral pain must be managed as early as

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possible to avoid severe chronicization (15,16). Moreover, an early indication to surgery involves a

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high risk of recurrence. Nowadays it is clear that at the time of the second surgery for ovarian

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endometriosis the reproductive chances for such a patient decreases to less than a half (17,18).

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A reliable nonsurgical diagnosis (19) is extremely useful to start early a medical management of

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pain, and then postpone the laparoscopic treatment as close as possible to reproductive desire (20).

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Experiences with an ex adiuvantibus strategy in confirming the diagnosis by depot GnRH analogs

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(GnRH-a) have been reported (19,21), obtaining at the same time a very early and effective

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reduction of inflammation and pain coming from the superficial lesions often associated to

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endometrioma (22-24).

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The ex adiuvantibus approach allows also to discriminate those situations in which the associated

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visceral pain by irritable bowel syndrome (IBS) or interstitial cystitis/painful bladder syndrome are

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predominant, and whose management could be different (25,26).

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If the endometriomas are associated with DIE, with severe, site specific, and catamenial pain and

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bleeding, in those patients in which a medical approach does not solve the symptomatology, surgery

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often remains the most effective treatment (27,28).

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In conclusion, a superficial evaluation of pelvic pain associated with ovarian endometriosis and an

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“easy” indication to surgery does not guarantee an effective treatment of pain and exposes the

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patient to significant reproductive risks. On the contrary, a careful assessment of pain and its

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correlation both to endometriosis subtypes and to IBS and interstitial cystitis/painful bladder

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syndrome, altogether with a reliable no laparoscopic diagnosis, allow an early and effective medical

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treatment of the pain syndrome and a proper timing of laparoscopic surgery close to reproductive

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desire.

151 Infertility as an indication to surgery

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Although the patient is not currently seeking pregnancy, she will nonetheless enquire about the

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association between endometriosis and infertility, and about her reproductive potential with the

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pathology, or following the possible treatments.

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Endometriosis may lead to infertility through different paths, from distorted pelvic anatomy to the

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reduction of ovarian function, from changes in the quality of the peritoneal environment to poor

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oocyte quality (20,29).

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It is estimated that 25-30% of infertile women suffer from endometriosis, while a 30-50% of those

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women with endometriosis demonstrate infertility (20). The problem is even underestimated as the

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indication of endometriosis represented only 3.9% of 95625 in vitro fertilization (IVF) cycles in the

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United States in 2010 (30). A normal couple’s fecundity rate is 0.15 – 0.20 per month. In untreated

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women with endometriosis and infertility the fecundity rate falls to 0.02 – 0.10 per month. The

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fecundity rate in women with stage III-IV endometriosis is 2-10%, compared to 15-25% of controls

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(31).

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The best therapeutic choice emerges from the guidelines provided by the European Society of

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Human Reproduction and Embryology (ESHRE) (32) and the American Society of Reproductive

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Medicine (ASRM) (20).

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Surgical treatment, although its results are sometimes overestimated, can improve pregnancy rates

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regardless of the stage of the disease (29,33). Women who undergo surgical treatment for

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endometriosis have a 50% higher chance of conceiving spontaneously within 1-2 years after

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surgery.

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Surgery is mandatory when starting to attempt pregnancy, while its value is questionable in the

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context of assisted reproductive technology. An incorrect surgical procedure adversely affects the

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patient's ovarian reserve, with repercussions on responsiveness to ovarian hyperstimulation and

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anti-Mullerian hormone levels (34).

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According to ESHRE and currently accepted guidelines, surgical treatment of endometriomas >3

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cm in diameter improves fertility more than the simple drainage and coagulation of the cyst. The

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conservative treatment of the cyst pseudocapsule (fenestration and coagulation/ablation of the cyst

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wall) is not only less effective in improving the chances of pregnancy, but also exposes the patient

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to a significant risk of recurrence (32).

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This is in our opinion the key point of the clinical pathway that leads from the diagnosis of

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endometriosis to a possible pregnancy. The quality of surgical treatment is the critical factor to

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tissue and is likely to improve the chances for pregnancy in the future.

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The correct timing of surgery is not clearly detailed in international guidelines. Patients with

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bilateral ovarian endometriomas are particularly challenging with respect to the possible damage to

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the ovarian reserve due to the disease or the surgery. In these cases, however, it is widely agreed

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that surgery may be an option, as the disease affects responsiveness to stimulation (34). Surgical

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treatment should always be mandatory, but only when performed by expert hands, capable of

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avoiding more damage with surgery than from the disease itself.

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The timing of surgery should also take account of future pregnancies. Endometriosis is a recurrent

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disease. A correct timing allows reducing the number of repeated surgeries, in light of the

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deterioration of oocyte quality after each surgical procedure. A second surgery will have the

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paradoxical effect of reducing the patients’ success rates. In these cases, assisted reproductive

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technology should be considered as the treatment of choice.

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Oncological risk for the endometrioma

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Endometriosis is a risk factor for epithelial ovarian cancer (35). However, estimates on the strength

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of the association vary widely, with reported relative risks (RR) ranging from 1.3 to 8.9 (36). Pearce

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et al. (37) pooled and analyzed individual data from 13 case-control studies including 7911 women

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with invasive ovarian cancer and 13226 controls. Self-reported endometriosis was associated with a

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significantly increased risk of clear cell (odds ratio OR 3.05; 95% confidence interval CI, 2.43-

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3.84), low-grade serous (OR 2.11; 95% CI 1.39-3.20), and endometrioid (OR 2.04; 95% CI, 1.67-

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2.48) invasive ovarian cancer. Available evidence suggests that most endometrioid and clear-cell

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ovarian cancers derive from endometriosis (38-40).

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It has been suggested that women with endometriosis-associated ovarian cancer have a

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longer-disease-free as well as overall survival compared with those affected by cancers of the same

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histotype but without endometriosis. However, the differences vanish after controlling for stage at

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surgery (41-43). This has been interpreted in terms of earlier diagnosis in women with

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endometriosis owing to more aggressive evaluation for pelvic pain symptoms or more strict

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surveillance aimed at timely identification of disease recurrences.

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Endometriosis in general has been indicated as the putative precursor lesion of clear-cell and

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endometriotic ovarian cancers, but only atypical endometriosis should be regarded as a definite

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preneoplastic lesion (44). Atypical endometriosis has been reported to be present in 2-3% of excised

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ovarian endometriomas (45). Although endometriotic implants are distributed all over the pelvis,

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endometriosis-associated ovarian cancers develop almost exclusively in the ovaries. This strongly

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derailment (46).

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Only limited data are available to evaluate the effect of medical and surgical preventive

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interventions. Modugno et al. (47) pooled information on the self-reported history of endometriosis

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from four population-based case-control studies of incident epithelial ovarian cancer. The use of

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combination oral contraceptive (COC) was associated with a substantial reduction in risk among

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women with endometriosis. The effect was related to duration of use, reaching an 80% reduction in

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risk for >10 years of use.

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Only two studies evaluated the effect of conservative surgery or salpingo-oophorectomy for

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endometriosis on the risk of epithelial ovarian cancer. Rossing et al. (48) assessed the risk of

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ovarian malignancy associated with a prior diagnosis of, and ovarian surgery following, ovarian

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cysts and endometriosis. Compared with women without history of endometriosis, the OR was 1.6

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(95% CI, 1.1 - 2.3) among those with endometriosis but no surgery, and it was 1.2 (95% CI, 0.5 -

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2.5) among women with endometriosis and surgery. The reduction in risk was more evident in

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women who had undergone a unilateral oophorectomy than in those who reported cystectomy.

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Melin et al. (49) identified all Swedish women with a first time diagnosis of endometriosis between

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1969 and 2007 and, by linkage to the National Swedish Cancer Register, all women diagnosed with

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epithelial ovarian cancer at least one year after the endometriosis diagnosis. A protective effect was

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observed for both, one-sided oophorectomy (OR 0.19; 95% CI, 0.08 - 0.46), as well as radical

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excision of all visible endometriosis (OR 0.30; 95% CI, 0.12 - 0.74).

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Based on international guidelines, surgery is indicated anyway when large endometriomas are

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present. The doubt is what to do when small endometriomas are identified in women not wanting

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children or that have completed their family. The wisest approach should be based on a balance

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between risks, benefits, and patient preference after detailed information.

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The concept that all endometriosis forms are precursor lesions of most type I epithelial ovarian

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cancers would imply the need for strict surveillance, serial screening, and systematic surgical

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exploration of doubtful conditions. Considering the high prevalence of endometriosis, the limited

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incidence of clear-cell and endometrioid ovarian cancers, and the modest increase (~50%) in the

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relatively limited lifetime risk of all invasive forms (~1%), the enormous organizational efforts

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would possibly result in a limited reduction of mortality at the price of undefined morbidity and

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high costs, with probable inappropriate investment of the limited healthcare resources.

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Based on current knowledge, only patients with atypical endometriosis should be considered at high

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risk, otherwise the frightening information of harboring a pre-malignant condition may induce

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many low-risk patients to request unnecessary extirpative surgery. The psychological consequences

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Patients with endometriosis may still be reassured that, in the worst scenario, they have around 98%

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life-time probability of not developing invasive ovarian cancer compared with 99% of the general

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female population. Finally, the 'chemoprophylactic', long-term use of oral COC, which has been

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demonstrated to dramatically reduce the risk of ovarian cancer also in women with endometriosis,

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should be fostered.

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258 Evaluation of ovarian reserve

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It has to be underlined that both the excision of ovarian endometriomas and the presence of

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endometriomas per se are demonstrated to be associated with a decrease in ovarian reserve: during

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the surgical procedure, ovarian tissue is inadvertently excised together with the cyst wall (50,51).

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A therapeutic option for the 35-years-old-patient with bilateral ovarian endometriomas could

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obviously be laparoscopic surgery. Since this patient has a potential desire of future pregnancies,

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she should be informed that an increase of pregnancy rates after surgical treatment of

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endometriomas has been demonstrated.

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There is a general agreement that pregnancy rates observed after laparoscopic excision of ovarian

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endometriomas are increased, varying from 30% to 67%, with an average value of about 50% (52).

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The effects of surgical endometrioma excision on ovarian reserve have been evaluated in several of

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studies (50, 53-56). The authors compared ovarian volume and vascularization (Pulsatility and

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Resistance indexes), antral follicle count, and anti-Mullerian hormone levels before and after

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surgery. As expected, decreased ovarian volume and antral follicle count, and lower pulsatility and

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resistance indexes, were reported in the ovaries surgically treated by endometrioma excision

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compared with non-operated controlateral ovaries or preoperative measures (57).

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In some studies a significantly higher antral follicle count was reported after endometrioma

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excision, even in presence of significantly lower levels of anti-Mullerian hormone (54,58,59).

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However, this finding may be inaccurate, either due to a post-surgical reactive response of ovarian

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parenchyma, or due to the presence of endometrioma itself, which did not allow the precise

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preoperative evaluation of antral follicle count (54,59).

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To date, the evaluation of anti-Mullerian hormone levels before and after surgery is widely used to

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investigate the effects of surgical excision of ovarian endometriomas on ovarian reserve (56).

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Studies serially evaluating serum anti-Mullerian hormone concentrations documented a reduction

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usually occurring early after the intervention already evident in the first week following surgery

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(53,60,61).

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Postoperative anti-Mullerian hormone decrease appears more significant in patients treated for

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The presence of bilateral endometriomas is a variable that could orient our decision towards

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expectant management, in absence of other signs whose could make the intervention necessary,

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such as pain symptoms or sonographic features of malignancies. In fact, patients who have been

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operated for bilateral endometriomas have a low and definite risk of postsurgical premature ovarian

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failure (62).

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Expectant management should also be considered if our patient has already undergone surgery for

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ovarian endometriosis, and has an evidence of already damaged ovarian reserve. In this case, a

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second intervention could cause a further impairment of her future fertility.

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Finally, because of the well known age-related decrease of both anti-Mullerian hormone and antral

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follicle count (63), patients’ age should be taken in consideration.

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A multimodal diagnostic evaluation of ovarian reserve, designing a new algorithm able to predict

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ovarian age in terms of both reproductive prognosis and distance to menopause could be very useful

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in decision making. A lot of factors should be evaluated, such as 3D- imaging, hormonal profile,

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antral follicle count, ovarian volume, and vascularization.

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301 Surgical technique

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The surgical approach to an ovarian endometrioma can be either by complete excision of the cyst

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wall, or by fenestration and subsequent ablation or coagulation of the cyst wall. In a Cochrane meta-

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analysis (64), based on two RCT (65,66), the laparoscopic excision of the ovarian endometrioma

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has been demonstrated to yield better results in terms of subsequent pregnancy rates compared to

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fenestration and coagulation or ablation of the cyst wall. More recently, a third RCT by Carmona et

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al (67) confirmed the superiority of the stripping technique compared to fenestration and laser

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ablation with a long-term follow-up.

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Recently, Tsolakidis (58) and Pados (68) performed a RCT comparing the stripping technique to a

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so-called “three-stage” technique, in which the three stages are a first operative laparoscopy, where

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only fenestration and drainage of the endometrioma are performed, a subsequent “second-stage”,

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consisting of a 3-month GnRH-a treatment, and a second laparoscopy, representing the “third

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stage”, where CO2 laser ablation of the cyst wall is performed. A higher antral follicle count at 6-

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month follow-up is reported for the ovaries operated with the three-stage technique, with similar

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ovarian volumes (68), and a significantly lower reduction of anti-Mullerian hormone levels (58).

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This study has however some drawback, such as the small sample size (10 patients per arm) and the

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higher recurrence rate in the three-stage arm (20% versus 0% in the excision arm) that do not

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support, in our opinion, the three-stage technique as a yet validated technique for the surgical

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ACCEPTED MANUSCRIPT treatment of the endometrioma. Also, the need for a repeat surgical procedure, and the use of

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expensive medical treatment in between the two laparoscopies, render this approach not

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cost/effective.

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An alternative surgical technique, that combines the advantages of the two techniques, stripping and

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fenestration with coagulation/ablation, avoiding the disadvantages of both, has been recently

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proposed (69,70). The excision technique is associated with better results in terms of subsequent

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fertility and pain recurrence, and this technique is therefore performed for most of the surgical

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procedure. When approaching the hilus, where excision has been demonstrated to be dangerous for

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the ovary, the coagulation/ablation technique is performed, in order to avoid damage to the tissue.

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The two studies reporting on the combined technique have demonstrated the feasibility of the new

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technique in a prospective study design, where the operated ovary has been compared to the

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contralateral, no operated ovary, with similar ovarian volumes and antral follicle count. The

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combined technique could be used in cases where the risk of damage to the ovarian reserve is

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higher, as in the patient with bilateral endometriomas discussed here. As of today, however, there is

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insufficient evidence to recommend the combined technique instead of the complete excision as the

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procedure of choice for the surgical treatment of endometriomas.

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Whichever the technique used, surgery should however be performed by experienced operators,

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since it has been demonstrated that the damage to the remaining ovary is inversely correlated with

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the experience of the surgeon (71). When performing surgery using the stripping technique, the

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correct plane of cleavage should always be identified and followed, and maximal effort to avoid

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damage to the normal ovary should be exerted in the area of the hilus, where the cyst wall and the

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ovarian tissue are densely adherent to each another (72).

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Postsurgical management

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A crucial issue in the management of endometriosis is the possibility of preventing recurrences after

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conservative surgery (73).

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Excisional surgery is the treatment of choice, as it significantly reduces painful symptoms and

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improves quality of life in 67–80% of patients (74). A frustrating aspect of conservative surgery,

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however, is the recurrence of endometriotic implants and painful symptoms at a long-term follow-

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up. A cumulative rate of endometrioma recurrence of 12–30% after 2–5years of follow-up has been

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reported (75). Recurrence or worsening of pain has been observed in 7–30% of patients within 3

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years of surgery, increasing to 40–50% after 5 years (76). As endometriotic tissue is hormonally

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sensitive, hormonal therapies could be effective in post-operative management of endometriosis to

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reduce the recurrence rate.

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ACCEPTED MANUSCRIPT It must be stressed, however, that hormones are not curative and endometriosis usually relapses at

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treatment suspension, and for this reason therapies need to be administered for long time (77).

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Witt and Barad suggested the use of low-dose oral contraceptive therapy to prevent recurrence of

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endometriotic lesions. In a prospective cohort study, Vercellini showed that regular post-operative

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use of an estrogen – progestin combination prevented endometrioma recurrence in one out of two

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patients 3 years after surgery (78).

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More recently Seracchioli et al. published the results of a randomized controlled trial confirming the

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above findings (79).

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In a systematic review, Seracchioli (80) identified seven studies evaluating post-operative COC

363

treatment on prevention of endometriosis recurrence. Six studies were prospective trials: four were

364

RCT (80,81), one was a self-controlled clinical trial and one was a cohort study (78). One study was

365

retrospective (82). The results of this study showed that a reduction in anatomical relapse rate was

366

observed when COC therapy was administered for more than 1 year after conservative surgery.

367

Post-operative use of COC was associated with a reduction in frequency and intensity of

368

dysmenorrhoea recurrence. No association was found between COC therapy and dyspareunia

369

prevention, although the effect of COC on chronic pelvic pain was conflicting. Regarding chronic

370

pelvic pain, there was no agreement about the effects of post-operative COC (79,80).

371

Because of adverse effects of medical treatments currently available, new therapeutic options

372

including the levonorgestrel-releasing intrauterine system (LNG-IUS) are being investigated.

373

In a prospective, randomized, controlled study, Yesim Bayoglu Tekin in 2009 compared efficacy of

374

LNG-IUS with depot GnRH-a on endometriosis-related CPP in patients with severe endometriosis

375

during 12 months. This study showed that both treatment modalities have comparable effectiveness

376

in the treatment of endometriosis-related CPP. Although expected side effects occurred in both

377

treatment arms, patients in the GnRH-a group showed a higher rate of satisfaction (83).

378

Morelli et al. compared two postoperative medical approaches for pain control and reduction of

379

recurrences in patients undergoing surgery for endometriosis: estradiol valerate + dienogest (COC)

380

(group A) or LNG-IUS. In conclusion, in endometriosis patients, postoperative COC administration

381

was significantly more effective than LNG-IUS in reducing pelvic pain and more effective in terms

382

of reducing the rate of recurrence, although not significantly. LNG-IUS, however, had significantly

383

higher patient satisfaction (84).

384

Recently Vercellini et al. in a systematic review and meta-analysis on the relation between long-

385

term postoperative adjuvant therapy and

386

postoperative COC use dramatically decreased the risk of ovarian endometrioma recurrence,

387

especially in women who used COC regularly and for prolonged periods (85).

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13

risk

of endometrioma recurrence

concluded

that

ACCEPTED MANUSCRIPT The most recent ESHRE guidelines indicate that hormonal therapies after surgery for endometriosis

389

can be prescribed in two situations: postoperative adjunctive hormonal therapy within 6 months

390

after surgery (short-term treatment) can be prescribed with the aim of improving the outcome of

391

surgery for pain, and secondary prevention, which is defined as prevention of the recurrence of pain

392

symptoms or the recurrence of disease in the long-term (more than 6 months after surgery).

393

Postoperative hormonal therapy may not improve the outcome of surgery but is an important

394

adjunct to surgery to prolong the symptom-free interval and prevent recurrence of symptoms (86).

RI PT

388

395 Postponing first surgery

397

There are no clear indications or guidelines regarding the proper timing of intervention for the

398

endometriomas. Surgical treatment should be individualized according to many factors depending

399

not only on the patient’s priority but also on the disease itself.

400

For example if we consider the paradigmatic patient, aged 35, with bilateral endometriomas

401

measuring 5 and 2 cm, with moderate symptoms and a future desire of pregnancy, which factors

402

should be considered to manage her disease with a correct timing?

403

In reproductive age, one should take into account the associated pregnancy desire. Currently, there

404

is no general consensus regarding the proper management of women with an ovarian endometrioma

405

who wishes to conceive, because of the lack of randomized controlled trials. If the patient has an

406

actual desire of pregnancy, firstly we have to exclude other causes of infertility, such as male's

407

semen and sperm alterations. Once we ruled out other potential infertility factors, surgery should be

408

offered early because the primary benefit of surgery is to enhance the chances of natural conception

409

(20), which are higher shortly after surgery (87). Moreover, laparoscopic surgery offers the

410

possibility to perform an accurate evaluation of tubal status (88). On the contrary, if we find other

411

factors responsible of infertility, we should address our patient directly to IVF. Several studies

412

dealing with surgical removal of endometriomas prior to IVF underlined the lack of evidence of an

413

effect of surgery on reproductive outcomes (20). Previous or present ovarian endometriosis does not

414

impair success rates of IVF and ovarian surgery does not add any improvements in IVF outcomes

415

(20).

416

Today many women need to postpone their reproductive and familiar objectives due to their job

417

plans or because of social reasons. In these cases, we should discuss and plan with the patient the

418

correct timing for surgical treatment. We have to postpone the surgical treatment and propose a

419

medical therapy until the moment she desires to conceive to preserve as much as possible her

420

ovarian follicular reserve. Indeed, delaying conception after surgery is associated with a lower

421

pregnancy rate and a higher rate of recurrence (87). 14

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ACCEPTED MANUSCRIPT If she reports symptoms related to endometriomas, the first line treatment should be medical.

423

Usually hormonal therapy provides a substantial symptom control and restrains the increase of

424

endometriomas size (89). Only in rare cases of severe incapacitating pain not controlled by medical

425

therapy, surgical treatment of endometriomas is advised (90).

426

For what concerns the cyst characteristics, with a transvaginal ultrasonography performed by a

427

skilled gynecologist it is possible to estimate the likelihood of malignancy of an ovarian cyst with a

428

high level of accuracy. When there is a suspect of malignancy, surgery is the most appropriate

429

treatment. Regarding cyst dimension, the literature does not show any consensus about the

430

indication to surgery. The ESHRE guidelines edited in 2008 consider the size of 3 cm as the cut-off

431

in cyst diameter to indicate surgery. In our clinical everyday experience, the rapid growth of

432

endometrioma size more than the size itself is decisive for planning the surgical intervention.

433

Another consistent problem is the one of repeated surgery, because of the increasing number of

434

patients with endometriosis recurrence observed in clinical practice. Recent studies evidenced that

435

repeated surgeries for recurrent endometriosis have the same limitations as primary surgery, with

436

long-term cumulative recurrence rates ranging from 20 to 40% (18). Moreover, only 25% of women

437

conceive after a repeat conservative surgery for infertility, which is almost half the pregnancy rate

438

following primary surgery. Postponing surgery and proposing alternative management such as

439

medical therapy (89) or IVF constitute effective alternatives.

440

Finally, we have to inform the patient about the negative effects of surgery on ovarian parenchyma.

441

Undoubtedly healthy ovarian tissue is removed during excisional surgery moreover another

442

important issue to consider is the bilaterality of endometriomas, because patients who had been

443

operated for bilateral endometriomas have an increased risk of premature ovarian failure (62).

444

When we are discussing with the patient about the timing to perform a surgical treatment of an

445

endometrioma, we should consider the risk of endometrioma recurrence because it is a cause of

446

repeated surgical intervention whose may compromise ovarian function through the reduction of

447

ovarian tissue. Recurrence rate of ovarian endometrioma is 7-30% after 3 years, 40-50% after 5

448

years from surgery (76).

449

In conclusion, to answer the question “When surgical treatment is delayed and when is it

450

proposed?” we have first to talk to the woman we face, because only by listening and understanding

451

her objectives, her priorities, her needs, we will be able to individualize the timing of endometrioma

452

treatment.

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453 454

Nonsurgical alternatives

455

Current medical management of endometriosis is based on three major mechanism of action: 15

ACCEPTED MANUSCRIPT iatrogenic menopause, pseudopregnancy and antinflammatory action.

457

GnRH-a induce a reversible hypoestrogenic state by down regulation of GnRH receptors and

458

desensitization of pituitary. The dose of GnRH-a used for the treatment of endometriosis varies with

459

the specific compound and mode of delivery. The side effect profiles of the GnRH-a tend to produce

460

hypo-estrogenic symptoms (hot flushes, sleep disturbances, vaginal dryness, and decrease of

461

libido), and other no specific side effects such as joint pain, headache, and mood changes, may also

462

occur (91).

463

Low-dose regimens or vaginal administration of danazol are highly effective in the treatment of

464

painful symptoms associated with recurrent endometriosis, have no systemic side effects, and

465

improve quality of life. Vaginal danzol administration seems to be a valid alternative to repeated

466

surgery and in the treatment of infiltrating endometriosis pelvic pain and adenomyosis (92).

467

In recent studies, more than half of patients with chronic pelvic pain and mild to moderate

468

endometriosis were satisfied or very satisfied with LNG-IUS treatment. Advantages of the LNG-

469

IUS include that it provides continuous therapy for 5 years without the need of replacement, and

470

any problems with the system can be solved by removal. In addition there are high concentrations

471

of progestins in the pelvis and less into systemic circulation. The LNG-IUS may be an effective

472

therapy, reducing dysmenorrhea and non-menstrual pelvic pain as well as significantly reducing

473

dyspareunia and dyschezia (93).

474

Progesterone derivates (e.g. medroxyprogesterone, dydrogesterone and cyproterone acetate) or 19-

475

nortestosterone derivates (e.g. norethisterone, levonorgestrel, desogestrel, dienogest) are used for

476

the treatment of endometriosis (94,95).

477

There is a general consensus that estroprogestins represent a valuable option in the treatment of the

478

disease. They establish a steady hormonal environment that suppresses ectopic implants, reduces

479

inflammation, and prevents the formation of ovarian endometriomas by inhibiting ovulation. This

480

action translates into an improvement of pain symptoms and prevention of recurrences in a

481

consistent proportion of women (96). Estroprogestins keep the implants quiescent and improve pain

482

symptoms. COC treatment reduces the rate of post-operative endometrioma recurrence and should

483

now be considered an essential part of long-term therapeutic strategies in order to limit further

484

damage to future fertility (97).

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485 486

Evolution of the endometrioma

487

The natural history of endometriosis, as well as of ovarian endometriomas, is poorly understood

488

because few women will progress through their reproductive lifespan without attempt at effective

489

therapy. Therefore, we have very few information to predict untreated endometrioma evolution in 16

ACCEPTED MANUSCRIPT the medium and long term. A recent paper (98) reported the sonographic follow-up (median 48

491

months, range 7-119) of 72 asymptomatic patients with an ultrasound diagnosis of endometrioma

492

(mean diameter 2.8 + 1.1 cm, range 1.1-6.6). During the follow-up period, in 22 (31%) patients the

493

endometrioma disappeared after a mean time of 45 months (range 9-109), in 21 (29%) the

494

endometrioma persisted, and 17 (24%) the endometrioma underwent surgical excision. The main

495

limits of the study are its observational and monocentric study design, and the fact that the

496

diagnosis lacked hystologic confirmation, although sensitivity and specificity of transvaginal

497

ultrasound for the diagnosis of endometrial cyst have been reported to be 84-100% and 90-100%,

498

respectively (35,99). Nevertheless, the authors suggest that a significant number of lesions

499

diagnosed as endometrioma were actually hemorrhagic cysts. However, these data suggest that, in

500

asymptomatic women with small ovarian lesion having ultrasound appearance of endometrioma, the

501

wait-and-see may be a reasonable option.

502

When considering this option, the effect of the endometrioma on the ovarian cortex and function

503

must be considered. It has been shown that endometriomas exerts a negative influence on the

504

surrounding ovarian cortex. It has been shown that the ovarian cortex harvested from ovaries with

505

large endometriomas (mean diameter 6.5+2.3 cm) has a reduced number of mature follicles when

506

compared with other similar-sized ovarian cysts (100). Similar data have been reported more

507

recently in the ovarian cortex surrounding smaller endometriomas (mean diameter 2.7+1.0 cm)

508

(101). The authors

509

endometrioma than without, with an inverse correlation between follicular density and age,

510

although not significant. These data led the authors to suggest that surgical intervention, even at an

511

early stage of cyst development, may be beneficial to protect the ovarian reserve.

512

As regards the function of the ovary site of endometrioma, it has been reported that the presence of

513

an endometrioma, with a mean diameter of 3.1 + 1.6 cm, may have a detrimental impact on ovarian

514

physiology, with a rate of ovulation in healthy and affected ovaries of about 2:1 (102). The ovarian

515

reserve of women with (median diameter 42,5 mm, range 38,6-51,7) and without endometrioma

516

was evaluated by anti-Mullerian hormone level and antral follicle count on day 3-5 of the cycle.

517

Results showed a significantly lower anti-Mullerian hormone levels and total antral follicle count in

518

the endometrioma patients than in controls (50). Data on the response to ovulation induction of the

519

affected ovary, have been recently reported: in patients with unilateral endometrioma diameter < 3

520

cm, the total number of follicles and of co-dominant follicles seems to be unaffected by the

521

endometriotic cyst (103-105). Therefore, a single endometrioma < 3 cm in diameter per se did not

522

seem to have a deleterious effect on ovarian reserve.

523

Despite the complete comprehension of the close relationship between endometrioma and ovarian

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reported that follicular density was significantly lower in cortex with ovarian

17

ACCEPTED MANUSCRIPT 524

function is far to be reached, several data suggest that the presence of endometrioma seems to

525

damage ovarian cortex. As regards ovarian reserve, the endometrioma < 3 cm seems to have a

526

limited functional impact (102-105), although a reduction in follicular density has been reported

527

(101). Data on larger endometriotic cyst suggest a deterioration of the ovarian reserve from an

528

hystologic (100), serologic and ultrasonographic point of view (50).

RI PT

529 Endometrioma and pregnancy

531

One of the typical questions a patient with an ovarian endometrioma may ask during a consultation

532

is “what if I get pregnant without previous surgery? ”. The available data on this subject is scarce

533

and can be divided in two sections: endometriosis (in general) and endometrioma (in specific).

534

SC

530

Relationship between endometriosis and pregnancy

536

Data from retrospective studies suggest a possible association between endometriosis and the

537

possibility of preterm birth (106).

538

The causal link supposed to be responsible for this increased risk might be the same

539

hyperinflammatory state involved in endometriosis affecting decidua/trophoblast interaction and

540

activating preterm birth later in pregnancy (107).

541

The other possible complication reported in the literature is the development of severe

542

intraabdominal bleeding. This could secondary to rupture of blood vessels (108) or direct bleeding

543

form endometriotic implants (109).

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Relationship between endometrioma and pregnancy

546

The only study (although retrospective) presenting data on the natural history of endometriomas in

547

pregnancy showed development of complications in 20% of cases (110).

548

Complications included decidualization, abscess and rupture with hemoperitoneum (111).

549

In summary, due to the limited number of cases reported in the literature, one can state that

550

endometriotic patients (even with endometrioma) can expect to have an uneventful pregnancy.

551

However, both physicians and patients must be aware that complications may arise in pregnancy. In

552

this case, referral to very experienced units is highly recommended.

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553 554

Fertility preservation options

555

Fertility preservation in endometriosis has gained attention only recently. Obviously, this approach

556

would be indicated for patients with an ovarian involvement such as our patient, who is at risk to

557

undergo a reduction of the ovarian reserve related to the presence of endometrioma itself, to the 18

ACCEPTED MANUSCRIPT 558

surgical treatment of the disease, or to its recurrence (112-114). Patients with endometriosis may

559

presently preserve oocytes or ovarian tissue.

560 Oocyte cryopreservation

562

In describing a five years experience using oocyte vitrification to preserve fertility, Garcia Velasco

563

et al have recently reported that endometriosis was the reason for preserving in 38 patients out of

564

505 women (6.8%) who decided to cryopreserve gametes (115). Potential concerns associated with

565

the preservation of oocytes in endometriosis patients are the following:

566

i) The reduced number of oocytes that can be retrieved in this group of patients, both whether the

567

women have been already operated or not (34,116). This means that the women might undergo

568

more than one ovarian stimulation cycle to obtain and freeze an adequate number of oocytes

569

(117,118).

570

ii) Concerns related to the potential risk of progression of the disease as a consequence of ovarian

571

stimulation procedures, especially if repetitive. However, studies evaluating this possibility are

572

rather comforting (102,103).

573

iii) Concerns related to the risk of causing the infection of the endometrioma after oocyte retrieval,

574

although this risk is low (119).

575

Women with endometriomas, especially when bilateral, should be counselled to preserve their

576

oocytes. Due to the risk of ovarian failure associated with the laparoscopic intervention (62), oocyte

577

retrieval should be performed before the cyst removal. Unfortunately, the performance of oocyte

578

collection is not as efficient as in not affected women (34). Women with unilateral endometriomas

579

may better decide to preserve before the surgical intervention for the cyst excision but can also

580

decide to undergo oocyte retrieval after the operation.

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581

Ovarian tissue preservation

583

Ovarian tissue preservation would have the advantage that tissue collection might be performed

584

during the surgical intervention for the excision of the cyst. However, at present, this option should

585

be considered only when radical surgery for the treatment of severe endometriosis may be necessary

586

(120). Healthy ovarian cortex can be recovered during the oophorectomy procedure and freezed. An

587

alternative option in cases requiring unilateral oophorectomy is the reimplantation of fresh ovarian

588

cortex in the heterolateral orthotopic site (121). The survival of primordial follicles is, in these

589

cases, favoured by the absence of the freezing/thawing process.

590

In more conventional clinical situations such as the presence of unilaterial or bilateral cysts that

591

need to be excised, it should be considered that the quality of the cortex surrounding the

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582

19

ACCEPTED MANUSCRIPT endometrioma in terms of follicular density has been severely compromised (114). Therefore,

593

especially for bilateral ovarian endometriomas, the opportunity to collect and preserve an already

594

damaged ovarian tissue that will be subjected to further alterations during freezing and thawing

595

procedures is questionable. Future developments, such as the isolation of follicles from the tissue

596

and their maturation in vitro, may open new perspectives for ovarian tissue preservation in women

597

with endometriosis.

598

Although studies on cost effectiveness of the procedures need to be performed in light of the

599

potential consequent saving on clinical fertility procedures, fertility preservation should presently be

600

part of the gynecologic or preoperative counselling in reproductive age women with ovarian

601

endometriotic cysts with immediate or future desire for childbearing.

SC

RI PT

592

602 Conclusions

604

In this review, all possible questions that a 35 years old patient, currently not desiring pregnancy,

605

with moderate pelvic pain, and an ultrasonographic diagnosis of bilateral endometriomas (5 and 2

606

cm, respectively on the left and right ovary) may pose to the clinician are addressed, and all clinical

607

scenarios are discussed. A decision algorithm derived from this discussion is proposed in Figure 2.

608

Some of these decisions are not based on sound evidence from RCT, but on the opinion of a panel

609

of 29 experts in the field of endometriosis.

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ACCEPTED MANUSCRIPT References

614

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34. Benaglia L, Bermejo A, Somigliana E,et al. In vitro fertilization outcome in women with

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comprehensive review and a critical analysis of clinical and epidemiological evidence.

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36. Kobayashi H, Sumimoto K, Kitanaka T, et al. Ovarian endometrioma: risk factors of ovarian

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cancer development. Eur J Obstet Gynecol Reprod Biol. 2008; 138:187-93.

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37. Pearce CL, Templeman C, Rossing MA, et al. Association between endometriosis and risk of

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38. Viganò P, Somigliana E, Chiodo I, et al. Molecular mechanisms and biological plausibility

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39. Wei JJ, Williams J, Bulun S. Endometriosis and ovarian cancer: a review of clinical, pathologic,

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40. Worley MJ, Welch W, Berkowitz R, et al. Endometriosis-associated ovarian cancer: a review of

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pathogenesis. Int J Mol Science. 2013; 14:5367-79.

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41. Kumar S, Munkarah A, Arabi H, et al. Prognostic analysis of ovarian cancer associated with

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endometriosis. Am J Obstet Gynecol. 2011; 204:63 e 1-7.

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42. Cuff J, Longacre TA. Endometriosis does not confer improved prognosis in ovarian carcinoma

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of uniform cell type. Am J Surg Pathol. 2012; 36:688-95.

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ACCEPTED MANUSCRIPT 102. Benaglia L, Somigliana E, Vercellini P, et al. Endometriotic ovarian cysts negatively affect the

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