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Evidence-based management of endometrioma

Published:December 03, 2010DOI:https://doi.org/10.1016/j.rbmo.2010.11.013

      Abstract

      Endometrioma is commonly seen in women of reproductive age who may wish to preserve their ovarian function. Surgical treatment is associated with a high recurrence rate and its employment for women undergoing assisted conception has recently been challenged. Medical treatment has not been shown to be effective in controlling symptoms or improving fertility potential. The results of retrospective and non-randomized studies have been inconsistent and created an ongoing debate between gynaecologists and fertility specialists. This manuscript reviews and critically appraises the evidence for management of endometrioma in women of reproductive age. In asymptomatic women, surgical treatment is usually recommended for women above the age of 40 and for large endometriomas. Except for pelvic clearance, there is insufficient evidence to suggest that surgical treatment of endometrioma is better than medical treatment with respect to the long-term relief of symptoms and quality of life. Laparoscopic excision of ovarian endometrioma prior to IVF does not offer any additional benefit over expectant management. A large, well-designed, adequately powered randomized controlled study that compares the effects of surgical removal versus expectant management of endometrioma on ovarian performance and pregnancy outcomes in women undergoing IVF is warranted.
      Endometrioma is commonly seen in women of reproductive age who may wish to preserve their ovarian function. Surgical treatment is associated with a high recurrence rate and its employment for women undergoing assisted conception has recently been challenged. Medical treatment has not been shown to be effective in controlling symptoms or improving fertility potential. The results of retrospective and non-randomized studies have been inconsistent and created an ongoing debate between gynaecologists and fertility specialists. In this manuscript we have reviewed and critically appraised the evidence for management of endometrioma in women of reproductive age. In asymptomatic women, surgical treatment is usually recommended for women above the age of 40 and for large endometriomas. Except for pelvic clearance, there is no evidence to suggest that surgical treatment of endometrioma is better than medical treatment with respect to the long-term relief of symptoms and quality of life. Laparoscopic excision of ovarian endometrioma prior to IVF does not offer any additional benefit over expectant management. A large, well-designed, adequately powered randomized controlled study that compares the effects of surgical removal versus expectant management of endometrioma on ovarian performance and pregnancy outcomes in women undergoing IVF is warranted.

      Keywords

      Introduction

      Endometrioma is best defined as an ovarian pseudocyst arising from growth of ectopic endometrial tissue, which progressively invaginates the ovarian cortex (
      • Hachisuga T.
      • Kawarabayashi T.
      Histopathological analysis of laparoscopically treated ovarian endometriotic cysts with special reference to loss of follicles.
      ). It is commonly seen in women of reproductive age who may complain of pelvic pain, dyspareunia and/or subfertility; some others may be asymptomatic. Around 17–44% of women with endometriosis also have endometriomas (
      • Jenkins S.
      • Olive D.L.
      • Haney A.F.
      Endometriosis: pathogenetic implications of the anatomic distribution.
      ,
      • Redwine D.B.
      Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease.
      ). The incidence of endometriosis varies according to the population studied, with an average of 10–15% (
      • Fauconnier A.
      • Chapron C.
      Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications.
      ). Whereas detection of peritoneal endometriosis and adhesions typically requires laparoscopic assessment of the pelvis, endometriomas can be reliably diagnosed by transvaginal ultrasound scan (
      • Eskenazi B.
      • Warner M.
      • Bonsignore L.
      • Olive D.
      • Samuels S.
      • Vercellini P.
      Validation study of nonsurgical diagnosis of endometriosis.
      ).
      Although there is some evidence to suggest that untreated endometriosis may resolve spontaneously in up to a third of women (
      • Petta C.A.
      • Ferriani R.A.
      • Abrao M.S.
      • Hassan D.
      • Rosa E.
      • Silva J.C.
      • Podgaec S.
      • Bahamondes L.
      Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis.
      ,
      • Vercellini P.
      • Frontino G.
      • De Giorgi O.
      • Aimi G.
      • Zaina B.
      • Crosignani P.G.
      Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study.
      ), the natural course of endometrioma is unknown. This is because of the lack of follow-up studies involving untreated women with endometrioma.
      The pain-free interval and the quality of life are important key performance indicators of the treatment of endometriosis. As endometrioma is commonly associated with periovarian adhesions or deeply infiltrating endometriosis, it is not always possible to relate the woman’s symptoms to the endometrioma per se (
      • Fauconnier A.
      • Chapron C.
      Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications.
      ). Surgical treatment of endometrioma is associated with a high recurrence rate (
      • Busacca M.
      • Marana R.
      • Caruana P.
      • Candiani M.
      • Muzii L.
      • Calia C.
      Recurrence of ovarian endometrioma after laparoscopic excision.
      ,
      • Koga K.
      • Takemura Y.
      • Osuga Y.
      • Yoshino O.
      • Hirota Y.
      • Hirata T.
      • Morimoto C.
      • Harada M.
      • Yano T.
      • Taketani Y.
      Recurrence of ovarian endometrioma after laparoscopic excision.
      ,
      • Saleh A.
      • Tulandi T.
      Reoperation after laparoscopic treatment of ovarian endometriomas by excision and by fenestration.
      ) and its employment for women undergoing IVF has been recently challenged (
      • Garcia-Velasco J.A.
      • Somigliana E.
      Management of endometriomas in women requiring IVF: to touch or not to touch.
      ,
      • Tsoumpou I.
      • Kyrgiou M.
      • Gelbaya T.A.
      • Nardo L.G.
      The effect of surgical treatment for endometrioma on in vitro fertilization outcomes: a systematic review and meta-analysis.
      ), though definite conclusions remain a matter of debate (
      • Nama V.
      • Kalu E.
      Management of endometrioma in women embarking on IVF: paucity of good quality evidence.
      ). Endometriomas associated with severe endometriosis and multifocal disease (
      • Chapron C.
      • Pietin-Vialle C.
      • Borghese B.
      • Davy C.
      • Foulot H.
      • Chopin N.
      Associated ovarian endometrioma is a marker for greater severity of deeply infiltrating endometriosis.
      ) require a multidisciplinary management approach. Surgery is usually recommended for large symptomatic endometriomas and for subfertile women (
      • Jones K.D.
      • Sutton C.
      Patient satisfaction and changes in pain scores after ablative laparoscopic surgery for stage III–IV endometriosis and endometriotic cysts.
      ).
      The results of retrospective and non-randomized studies have been inconsistent and created an ongoing debate between gynaecologists and fertility specialists. This manuscript reviews and critically appraises the evidence for management of endometrioma in women of reproductive age.

      Materials and methods

      MEDLINE, EMBASE and Cochrane library were searched from 1974 to February 2010 in full text for relevant publications. The search strategy used terms such as ‘endometrioma’, ‘endometriosis’, ‘cystectomy’, ‘dysmenorrhoea’, ‘dyspareunia’, ‘pelvic pain’, ‘IVF’, ‘ICSI’ and ‘assisted conception’. The references of retrieved articles and relevant reviews were hand-searched to identify other potentially eligible studies missed by the initial search. Articles with inappropriate design were rejected from the review.

      Management of endometrioma in subfertile women

      The pathogenesis of infertility in women with endometriosis has not been clearly understood except in cases of distorted pelvic anatomy. Even in women undergoing IVF, pregnancy rates were found to be lower in patients with endometriosis compared with those with tubal factor infertility (
      • Barnhart K.
      • Dunsmoor-Su R.
      • Coutifaris C.
      Effect of endometriosis on in vitro fertilization.
      ). The cumulative live birth rate after 1–4 cycles of IVF appears to be lower in stage III–IV endometriosis compared with stage I–II endometriosis or in women with tubal factor infertility (
      • Kuivasaari P.
      • Hippeläinen M.
      • Anttila M.
      • Heinonen S.
      Effect of endometriosis on IVF/ICSI outcome: stage III/IV endometriosis worsens cumulative pregnancy and live-born rates.
      ).
      Different causes have been postulated including impaired folliculogenesis, toxic effect of cytokines on oocyte or embryo quality and disordered fertilization and embryo implantation (
      • Garcia-Velasco J.A.
      • Arici A.
      Is the endometrium or oocyte/embryo affected in endometriosis?.
      ,
      • Garrido N.
      • Navarro J.
      • García-Velasco J.
      • Remoh J.
      • Pellice A.
      • Simón C.
      The endometrium versus embryonic quality in endometriosis-related infertility.
      ,
      • Harada T.
      • Iwabe T.
      • Terakawa N.
      Role of cytokines in endometriosis.
      ,
      • Jha P.
      • Farooq A.
      • Agrawal N.
      • Buckshee K.
      In vitro sperm phagocytosis by human peritoneal macrophage in endometriosis-associated infertility.
      ,
      • Pellicer A.
      • Valbuena D.
      • Bauset C.
      • Albert C.
      • Bonilla- Musoles F.
      • Remohi J.
      • Simon C.
      The follicular endocrine environment in stimulated cycles of women with endometriosis: steroid levels and embryo quality.
      ). The effect of endometrioma per se on fertility has not been adequately investigated as it is rare to find isolated endometrioma without surrounding peritoneal disease. Indeed even minimal endometriosis is known to be associated with subfertility (
      • Pritts E.A.
      • Taylor R.N.
      An evidence-based evaluation of endometriosis-associated infertility.
      ) and its treatment has been demonstrated to improve fertility outcome (
      • Jacobson T.Z.
      • Barlow D.H.
      • Koninckx P.R.
      • Olive D.
      • Farquhar C.
      Laparoscopic surgery for subfertility associated with endometriosis.
      ). Although there is some evidence to suggest disturbance of the physiological mechanisms leading to ovulation in ovaries with endometriomas (
      • Benaglia L.
      • Somigliana E.
      • Vighi V.
      • Nicolosi A.E.
      • Iemmello R.
      • Ragni G.
      Is the dimension of ovarian endometriomas significantly modified by IVF–ICSI cycles?.
      ,
      • Kaplan C.R.
      • Eddy C.A.
      • Olive D.L.
      • Schenken R.S.
      Effect of ovarian endometriosis on ovulation in rabbits.
      ), the exact causes are unknown. It may be speculated that the inflammatory reaction typically associated with the presence of endometriosis may play a role. Alternatively, the expanding ovarian cyst may cause pressure atrophy of the ovarian tissue or affect the normal vascularization of the ovary.
      • Nakahara K.
      • Saito H.
      • Saito T.
      • Ito M.
      • Ohta M.
      • Takahasi T.
      • Hiroi M.
      Ovarian fecundity in patients with endometriosis can be estimated by the incidence of apoptotic bodies.
      found a higher incidence of apoptotic bodies in the ovarian membrana granulosa of patients with endometriosis than that of a control (male factor infertility) group. The incidence of apoptotic bodies correlated with the stage of endometriosis but was significantly higher in women with endometrioma, who in turn had lower numbers of developed follicles and retrieved oocytes after ovarian stimulation compared with the control group (
      • Nakahara K.
      • Saito H.
      • Saito T.
      • Ito M.
      • Ohta M.
      • Takahasi T.
      • Hiroi M.
      Ovarian fecundity in patients with endometriosis can be estimated by the incidence of apoptotic bodies.
      ). It has also been suggested by some investigators that oocyte quality may be affected by ovarian endometriosis (
      • Pal L.
      • Shrifren J.L.
      • Isaacson K.B.
      • Chang Y.
      • Leykin L.
      • Toth T.L.
      Impact of varying stages of endometriosis on the outcome of in vitro fertilization–embryo transfer.
      ,
      • Simon C.
      • Gutierrez A.
      • Vidal A.
      • de los Santos M.J.
      • Tarrin J.J.
      • Remohi J.
      • Pellicer A.
      Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation.
      ,
      • Yanushpolsky E.H.
      • Best C.L.
      • Jackson K.V.
      • Clarke R.N.
      • Barbieri R.L.
      • Homstein M.D.
      Effects of endometriomas on oocyte quality, and pregnancy rates in in vitro fertilization cycles: a prospective, case-controlled study.
      ).
      Currently, there is insufficient data to clarify whether the endometrioma-related damage to ovarian reserve precedes or follows surgery. It has been shown that ovaries with endometriotic cysts already exhibited reduced number of follicles and vascular activity compared with other types of benign cysts (
      • Maneschi F.
      • Marasa L.
      • Incadela S.
      • Mazzarese M.
      • Zupi E.
      Ovarian cortex surrounding benign neoplasms: a histologic study.
      ). A retrospective analysis of 168 IVF cycles for normoresponder women with ovarian cysts (
      • Kumbak B.
      • Kahraman S.
      • Karlikaya G.
      • Lacin S.
      • Guney A.
      In vitro fertilization in normoresponder patients with endometriomas: comparison with basal simple ovarian cysts.
      ) reported higher gonadotrophin consumption and lower oocyte yield in women with endometrioma compared with non-endometriotic simple cysts. Although the number of transferred grade-I embryos and the implantation rate were found to be higher in women with non-endometriotic cysts, there was no significant difference in pregnancy and ongoing pregnancy rates between the two groups.
      • Somigliana E.
      • Infantino M.
      • Benedetti F.
      • Arnoldi M.
      • Calanna G.
      • Ragni G.
      The presence of ovarian endometriomas is associated with a reduced responsiveness to gonadotropins.
      evaluated 36 unoperated women with monolateral endometriomas who were selected for IVF. Significantly higher numbers of dominant follicles were seen in the unaffected gonads compared with the contralateral ones. This difference corresponded to a mean reduction of 25% (95% CI 6–44) in the affected ovaries. The deleterious effect was more evident in women with larger cysts, in those with more than one cyst and in those who were more responsive to ovarian stimulation (
      • Somigliana E.
      • Infantino M.
      • Benedetti F.
      • Arnoldi M.
      • Calanna G.
      • Ragni G.
      The presence of ovarian endometriomas is associated with a reduced responsiveness to gonadotropins.
      ). On the contrary, a small retrospective study (
      • Wong B.C.
      • Gillman N.C.
      • Oehninger S.
      • Gibbons W.E.
      • Stadtmauer L.A.
      Results of in vitro fertilization in patients with endometriomas: is surgical removal beneficial?.
      ) failed to show a significant difference in IVF pregnancy rate between women with untreated endometrioma and those who had peritoneal endometriosis without endometrioma.
      Of note, the ovulation rate has been repeatedly shown to be reduced in ovaries operated on for endometrioma compared with contralateral intact ovaries (
      • Candiani M.
      • Barbieri M.
      • Bottani B.
      • Bertulessi C .
      • Vignali M.
      • Agnoli B.
      • Somigliana E.
      • Busacca M.
      Ovarian recovery after laparoscopic enucleation of ovarian cysts: insights from echographic short-term postsurgical follow-up.
      ,
      • Horikawa T.
      • Nakagawa K.
      • Ohgi S.
      • Kojima R.
      • Nakashima A.
      • Ito M.
      • Takahashi Y.
      • Saito H.
      The frequency of ovulation from the affected ovary decreases following laparoscopic cystectomy in infertile women with unilateral endometrioma during a natural cycle.
      ,
      • Loh F.H.
      • Tan A.T.
      • Kumar J.
      • Ng S.C.
      Ovarian response after laparoscopic ovarian cystectomy for endometriotic cysts in132 monitored cycles.
      ). There is insufficient evidence from randomized controlled trials (RCT) to support any treatment approach for subfertile women with endometrioma including those undergoing IVF.

      Management of endometrioma prior to IVF

      IVF is the mainstay of treatment for endometriosis-related subfertility (
      • Kodama H.
      • Fukuda J.
      • Karube H.
      • Matsui T.
      • Shimizu Y.
      • Tanaka T.
      Benefit of in vitro fertilization treatment of endometriosis associated infertility.
      ,
      • Pal L.
      • Shrifren J.L.
      • Isaacson K.B.
      • Chang Y.
      • Leykin L.
      • Toth T.L.
      Impact of varying stages of endometriosis on the outcome of in vitro fertilization–embryo transfer.
      ). Some gynaecologists would offer surgical removal of endometrioma prior to commencing ovarian stimulation for IVF. The effects of surgical removal of endometrioma on ovarian reserve and ovarian response to gonadotrophin stimulation have been the focus of much studies. A potential deleterious effect of surgery is the accidental removal or damage of normal ovarian tissue. Conservative laparoscopic surgery of ovarian cysts with well-defined ovarian capsules (e.g., teratomas and benign cystadenomas) rarely results in healthy ovarian tissue being removed (
      • Hachisuga T.
      • Kawarabayashi T.
      Histopathological analysis of laparoscopically treated ovarian endometriotic cysts with special reference to loss of follicles.
      ,
      • Muzii L.
      • Bianchi A.
      • Crocè C.
      • Manci N.
      • Panici P.B.
      Laparoscopic excision of ovarian cysts: is the stripping technique a tissue-sparing procedure?.
      ). Conversely, in more than 50% of the endometriomas removed, primordial follicles were seen histologically close to the cyst wall, probably due to the technical difficulties encountered in removing the cyst (
      • Hachisuga T.
      • Kawarabayashi T.
      Histopathological analysis of laparoscopically treated ovarian endometriotic cysts with special reference to loss of follicles.
      ,
      • Muzii L.
      • Bianchi A.
      • Crocè C.
      • Manci N.
      • Panici P.B.
      Laparoscopic excision of ovarian cysts: is the stripping technique a tissue-sparing procedure?.
      ). Stripping the endometriotic cyst wall is technically more difficult than non-endometriotic ovarian cysts, resulting in the inevitable removal of normal ovarian tissue (
      • Exacoustos C.
      • Zupi E.
      • Amadio A.
      • Szabolcs B.
      • De Vivo B.
      • Marconi D.
      • Elisabetta Romanini M.
      • Arduini D.
      Laparoscopic removal of endometriomas: sonographic evaluation of residual functioning ovarian tissue.
      ,
      • Muzii L.
      • Bellati F.
      • Bianchi A.
      • Palaia I.
      • Manci N.
      • Zullo M.A.
      • Angioli R.
      • Panici P.B.
      Laparoscopic stripping of endometriomas: a randomized trial on different surgical techniques: Part II.
      ,
      • Tsolakidis D.
      • Pados G.
      • Vavilis D.
      • Athanatos D.
      • Tsalikis T.
      • Giannakou A.
      • Tarlatzis B.C.
      The impact on ovarian reserve after laparoscopic ovarian cystectomy versus three-stage management in patients with endometriomas: a prospective randomized study.
      ). Drainage and coagulation of the cyst wall carries a risk of damage to the ovarian cortex. Both surgical techniques have been associated with reduced ovarian reserve and premature ovarian failure (
      • Busacca M.
      • Riparini J.
      • Somigliana E.
      • Oggioni G.
      • Izzo S.
      • Vignali M.
      • Candiani M.
      Postsurgical ovarian failure after laparoscopic excision of bilateral endometriomas.
      ,
      • Horikawa T.
      • Nakagawa K.
      • Ohgi S.
      • Kojima R.
      • Nakashima A.
      • Ito M.
      • Takahashi Y.
      • Saito H.
      The frequency of ovulation from the affected ovary decreases following laparoscopic cystectomy in infertile women with unilateral endometrioma during a natural cycle.
      ). It has been reported that the risk of premature ovarian failure after laparoscopic removal of bilateral endometrioma is 2.4% (
      • Busacca M.
      • Riparini J.
      • Somigliana E.
      • Oggioni G.
      • Izzo S.
      • Vignali M.
      • Candiani M.
      Postsurgical ovarian failure after laparoscopic excision of bilateral endometriomas.
      ).
      The treatment options for women with endometrioma who are about to undergo IVF treatment include surgery, expectant management and medical treatment. The results of studies that compared surgical treatment with no treatment of endometrioma were conflicting (
      • Garcia-Velasco J.A.
      • Mahutte N.G.
      • Corona J.
      • Zuniga V.
      • Giles J.
      • Arici A.
      • Pellicer A.
      Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case-control study.
      ,
      • Pabuccu R.
      • Onalan G.
      • Goktolga U.
      • Kucuk T.
      • Orhon E.
      • Ceyhan T.
      Aspiration of ovarian endometriomas before intracytoplasmic sperm injection.
      ,
      • Suganuma N.
      • Wakahara Y.
      • Ishida D.
      • Asano M.
      • Kitagawa T.
      • Katsumata Y.
      • Moriwaki T.
      • Furuhashi M.
      Pretreatment for ovarian endometrial cyst before in vitro fertilization.
      ,
      • Tinkanen H.
      • Kujansuu E.
      In vitro fertilization in patients with ovarian endometriomas.
      ,
      • Wong B.C.
      • Gillman N.C.
      • Oehninger S.
      • Gibbons W.E.
      • Stadtmauer L.A.
      Results of in vitro fertilization in patients with endometriomas: is surgical removal beneficial?.
      ). In addition, those studies were retrospective and included a small number of women. A systematic review and meta-analysis concluded that surgical treatment of endometrioma has no significant effect on IVF pregnancy rates and ovarian response to stimulation compared with no treatment (
      • Tsoumpou I.
      • Kyrgiou M.
      • Gelbaya T.A.
      • Nardo L.G.
      The effect of surgical treatment for endometrioma on in vitro fertilization outcomes: a systematic review and meta-analysis.
      ).
      The evidence from studies that have compared ovarian response in surgically removed endometrioma with the contralateral normal ovary is less convincing. Nevertheless, out of the six published studies (
      • Duru N.K.
      • Dede M.
      • Acikel C.H.
      • Keskin U.
      • Fidan U.
      • Baser I.
      Outcome of in vitro fertilization and ovarian response after endometrioma stripping at laparoscopy and laparotomy.
      ,
      • Ho H.Y.
      • Lee R.K.
      • Hwu Y.M.
      • Lin M.H.
      • Su J.T.
      • Tsai Y.C.
      Poor response of ovaries with endometrioma previously treated with cystectomy to controlled ovarian hyperstimulation.
      ,
      • Loh F.H.
      • Tan A.T.
      • Kumar J.
      • Ng S.C.
      Ovarian response after laparoscopic ovarian cystectomy for endometriotic cysts in132 monitored cycles.
      ,
      • Ragni G.
      • Somigliana E.
      • Benedetti F.
      • Paffoni A.
      • Vegetti W.
      • Restelli L.
      • Crosignani P.G.
      Damage to ovarian reserve associated with laparoscopic excision of endometriomas: a quantitative rather than a qualitative injury.
      ,
      • Somigliana E.
      • Ragni G.
      • Benedetti F.
      • Borroni R.
      • Vegetti W.
      • Crosignani P.G.
      Does laparoscopic excision of endometriotic ovarian cysts significantly affect ovarian reserve? Insights from IVF cycles.
      ,
      • Wyns C.
      • Donnez J.
      Laser vaporization of ovarian endometriomas: the impact on the response to gonadotrophin stimulation.
      ) all except one (
      • Loh F.H.
      • Tan A.T.
      • Kumar J.
      • Ng S.C.
      Ovarian response after laparoscopic ovarian cystectomy for endometriotic cysts in132 monitored cycles.
      ) showed a higher number of follicles whilst three studies (
      • Ho H.Y.
      • Lee R.K.
      • Hwu Y.M.
      • Lin M.H.
      • Su J.T.
      • Tsai Y.C.
      Poor response of ovaries with endometrioma previously treated with cystectomy to controlled ovarian hyperstimulation.
      ,
      • Ragni G.
      • Somigliana E.
      • Benedetti F.
      • Paffoni A.
      • Vegetti W.
      • Restelli L.
      • Crosignani P.G.
      Damage to ovarian reserve associated with laparoscopic excision of endometriomas: a quantitative rather than a qualitative injury.
      ,
      • Wyns C.
      • Donnez J.
      Laser vaporization of ovarian endometriomas: the impact on the response to gonadotrophin stimulation.
      ) reported a higher number of oocytes retrieved in the contralateral normal ovary compared with surgically removed endometrioma. Although the majority of the studies have suggested a negative effect of surgery on ovarian response to gonadotrophin stimulation, the retrospective nature and the small sample size lessen the conclusion of those studies. Only one RCT (
      • Demirol A.
      • Guven S.
      • Baykal C.
      • Gurgan T.
      Effect of endometrioma cystectomy on IVF outcome: a prospective randomized study.
      ) investigating the effect of surgical treatment of endometrioma on IVF outcome was found. The study showed some evidence of reduced ovarian response after surgical excision of endometrioma compared with drainage at the time of oocyte retrieval as evidenced by longer duration of stimulation, higher dose of gonadotrophins used, lower peak oestradiol concentrations and lower number of oocytes retrieved. Although the authors of this RCT did not find a difference in pregnancy rate between the two groups, they did not comment on the quality of the embryos and provided no data on the incidence of ovarian or pelvic infection.
      In the absence of properly designed and powered RCT, the management of endometrioma prior to IVF remains controversial. Operating on an endometrioma >3 cm may interfere with follicle tracking and oocyte retrieval; nevertheless, some clinicians believe that excision of endometrioma prior to IVF improves ovarian response to gonadotrophin stimulation and live birth rates. The European Society of Human Reproduction and Embryology (ESHRE) recommend laparoscopic ovarian cystectomy if the endometrioma is ⩾4 cm in diameter in order to confirm the diagnosis histologically, to reduce the risk of infection, to improve access to follicles and possibly to improve ovarian response. The authors advise that women should be counselled regarding the risks of reduced ovarian function after surgery and that the decision should be reconsidered if a woman has had previous ovarian surgery (
      • Kennedy S.
      • Bergqvist A.
      • Chapron C.
      • D’Hooghe T.
      • Dunselman G .
      • Greb R.
      • Hummelshoj L.
      • Prentice A.
      • Saridogan E.
      ESHREguideline for the diagnosis and treatment of endometriosis.
      ). An ESHRE-sponsored survey has been conducted (

      Gelbaya, T.A., Gordts, S., D’Hooghe, T.M., Gergolet, M., Nardo, L.G., 2010. Management of endometrioma prior to in vitro fertilization: compliance with ESHRE guidelines. Reprod. Biomed. Online (Ahead of publication).

      ) to learn the strategies employed for the management of endometrioma (>3 cm) prior to IVF and to explore adherence to the ESHRE guidelines (
      • Kennedy S.
      • Bergqvist A.
      • Chapron C.
      • D’Hooghe T.
      • Dunselman G .
      • Greb R.
      • Hummelshoj L.
      • Prentice A.
      • Saridogan E.
      ESHREguideline for the diagnosis and treatment of endometriosis.
      ). An online questionnaire was sent to 396 members of the Special Interest Groups Reproductive Surgery and Endometriosis/Endometrium, with a response rate of 27%. Surgical management was the most common treatment (82.2%), with drainage and excision of the cyst wall being the preferred surgical approach (78.5%). The situation was different for women with previous ovarian surgery or recurrent endometrioma where surgical treatment was less commonly offered. It was reassuring that 47.7% of the responders offer expectant management of endometrioma before IVF in women with recurrent endometrioma or previous ovarian surgery.
      Women with endometrioma may include women with normal or poor ovarian reserve. In women with normal response, it may be useful to use a prolonged down-regulation protocol based on the evidence that this protocol may improve pregnancy rates in women with endometriosis (
      • Sallam H.N.
      • Garcia-Velasco J.A.
      • Dias S.
      • Arici A.
      Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis.
      ).
      Various treatment protocols have been devised to improve ovarian response and pregnancy outcome in women with predicted poor response to ovarian stimulation. Increasing the dose of gonadotrophins has not shown any benefit (
      • Klinkert E.R.
      • Broekmans F.J.M.
      • Looman C.W.N.
      • Habbema J.D.F.
      • te Velde E.R.
      Expected poor responders on the basis of an antral follicle count do not benefit from a higher starting dose of gonadotrophins in IVF treatment: a randomized controlled trial.
      ). There is insufficient evidence to support the routine use of the short gonadotrophin-releasing hormone (GnRH) agonist (co-flare) protocol in women with poor response (
      • Shanbhag S.
      • Aucott L.
      • Bhattacharya S.
      • Hamilton M.A.
      • McTavish A.R.
      Intervention for poor responders to controlled ovarian hyperstimulation in IVF.
      ). A previous RCT comparing the GnRH antagonist with co-flare protocols in poor responders women reported significantly higher ongoing pregnancy rate in women who received flexible GnRH-antagonist protocol (
      • Lainas T.G.
      • Sfontouris I.A.
      • Papanikolaou E.G.
      • Zorzovilas J.Z.
      • Petsas G.K.
      • Lainas G.T.
      • Kolibianakis E.M.
      Flexible GnRH antagonist versus flare-up GnRH agonist protocol in poor responders treated by IVF: a randomized controlled trial.
      ). In this study, women who had previously had one or two failed IVF treatments in which five or less oocytes were retrieved were included. In contrast,
      • Pabuccu R.
      • Onalan G.
      • Kaya C.
      GnRH agonist and antagonist protocols for stage I–II endometriosis and endometrioma in in vitro fertilization/intracytoplasmic sperm injection cycles.
      recruited three different groups of patients: women with mild-to-moderate endometriosis (n = 98), those who had ovarian surgery for endometrioma (n = 81) and those with endometrioma and no history of previous surgery (n = 67). The subjects in each group were randomized to ovarian stimulation with either GnRH agonist or antagonist protocol for intracytoplasmic sperm injection (ICSI). Ovarian stimulation protocol did not affect the implantation or clinical pregnancy rates in women with mild to moderate endometriosis or women with unoperated endometrioma. With regard to women who had previous ovarian surgery for endometrioma implantation and clinical pregnancy rates were higher with the GnRH-agonist protocol than with the GnRH-antagonist protocol (22.6% and 39% versus 15.9% and 27.5%, respectively). Further studies are needed to determine the best protocol for ovarian stimulation in poor-responder women with endometrioma.
      In summary, there is insufficient evidence to support routine surgical treatment of endometrioma in asymptomatic subfertile women. In line with the ESHRE guidelines, this review recommends expectant management if endometrioma is smaller than 4 cm and in cases of recurrent endometrioma. Women should be reassured that IVF does not influence the likelihood of endometriosis recurrence (
      • Benaglia L.
      • Somigliana E.
      • Vercellini P.
      • Benedetti F.
      • Iemmello R.
      • Vighi V.
      The impact of IVF procedures on endometriosis recurrence.
      ) or growth of endometrioma (
      • Benaglia L.
      • Somigliana E.
      • Vighi V.
      • Nicolosi A.E.
      • Iemmello R.
      • Ragni G.
      Is the dimension of ovarian endometriomas significantly modified by IVF–ICSI cycles?.
      ). Women who opt for surgical treatment of endometrioma prior to IVF should be offered ovarian reserve tests before surgery and those with reduced ovarian reserve should be discouraged from undergoing surgical treatment. Women undergoing ovarian surgery should be warned about the possible risk of surgery on ovarian function.

      Management of endometrioma in women with pelvic pain

      The relationship between chronic pelvic pain symptoms and endometrioma is not very clear. In studies using multivariate analysis, neither the presence of endometriomas nor any of their characteristics appears to correlate with painful symptoms (
      • Chapron C.
      • Fauconnier A.
      • Dubuisson J.B.
      • Barakat H.
      • Vieira M.
      • Breart G.
      Deep infiltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease.
      ,
      • Fauconnier A.
      • Chapron C.
      • Dubuisson J.B.
      • Vieira M.
      • Dousset B.
      • Breart G.
      Relation between pain symptoms and the anatomic location of deep infiltrating endometriosis.
      ,
      • Koninckx P.R.
      • Meuleman C.
      • Demeyere S.
      • Lesaffre E.
      • Cornillie F.J.
      Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain.
      ,
      • Porpora M.G.
      • Koninckx P.R.
      • Piazze J.
      • Natili M.
      • Colagrande S.
      • Cosmi E.V.
      Correlation between endometriosis and pelvic pain.
      ). In the majority of cases, it is not possible to relate the woman’s symptoms to endometrioma per se but to the periovarian adhesions or deeply infiltrating endometriosis, which should be treated simultaneously (
      • Fauconnier A.
      • Chapron C.
      Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications.
      ).
      Medical treatment is generally effective in relieving the endometriosis related pain. Hormonal compounds – combined oral contraceptives (COC), danazol, gestrinone, medroxyprogesterone acetate and GnRH agonist – have been found to be equally effective but the side-effect profiles vary (
      • Davis L.J.
      • Kennedy S.S.
      • Moore J.
      • Prentice A.
      Oral contraceptives for pain associated with endometriosis.
      ,
      • Prentice A.
      • Deary A.
      • Goldbeck-Wood S.
      • Farquhar C.
      • Smith S.
      Gonadotrophin-releasing hormone analogues for pain associated with endometriosis.
      ,
      • Prentice A.
      • Deary A.J.
      • Bland E.
      Progestagens and anti-progestagens for pain associated with endometriosis.
      ,
      • Selak V.
      • Farquhar C.
      • Prentice A.
      • Singla A.
      Danazol for pelvic pain associated with endometriosis.
      ). The painful symptoms usually recur after discontinuation of medical treatment (
      • Chapron C.
      • Fauconnier A.
      • Dubuisson J.B.
      • Barakat H.
      • Vieira M.
      • Breart G.
      Deep infiltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease.
      ). Several studies (
      • Buttram Jr., V.C.
      • Reiter R.C.
      • Ward S.
      Treatment of endometriosis with danazol: report of a 6 year prospective study.
      ,
      • Donnez J.
      • Nisolle M.
      • Casanas-Roux F.
      Endometriosis-associated infertility: evaluation of preoperative use of danazol, gestrinone and buserelin.
      ,
      • Nisolle-Pochet M.
      • Casanas-Roux F.
      • Donnez J.
      Histologic study of ovarian endometriosis after hormonal therapy.
      ,
      • Rana N.
      • Thomas S.
      • Rotman C.
      • Dmowski W.P.
      Decrease in the size of ovarian endometriomas during ovarian suppression in stage IV endometriosis. Role of preoperative medical treatment.
      ) showed reduction in the size of small endometriomas after ovarian suppression with danazol or GnRH agonist but large endometriomas are not going to be completely resolved. The decrease in the size of endometrioma varied from 14% to 89% with a mean of 51% (
      • Rana N.
      • Thomas S.
      • Rotman C.
      • Dmowski W.P.
      Decrease in the size of ovarian endometriomas during ovarian suppression in stage IV endometriosis. Role of preoperative medical treatment.
      ). As far as is known, there are no published studies investigating the effect of medical treatment, including hormonal suppression on pelvic pain in women with endometrioma. There is no reason why medical treatment cannot be offered to women with small symptomatic endometriomas, particularly for those women who wish to avoid surgery. In one study, hormonal suppression using GnRH agonist or danazol was found to be effective in reducing the size of endometrioma and in controlling pelvic pain and dysmenorrhoea (
      • Rana N.
      • Thomas S.
      • Rotman C.
      • Dmowski W.P.
      Decrease in the size of ovarian endometriomas during ovarian suppression in stage IV endometriosis. Role of preoperative medical treatment.
      ). There is inconclusive evidence to show that non-steroidal anti-inflammatory drugs are effective in managing pain caused by endometriosis (
      • Allen C.
      • Hopewell S.
      • Prentice A.
      • Gregory D.
      Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis.
      ).
      Surgical treatment of endometrioma is widely accepted as the first line management of symptomatic endometriomas, particularly for women who have completed their family (
      • Jones K.D.
      • Fan A.
      • Sutton C.J.G.
      The ovarian endometrioma: why is it so poorly managed? Indicators from anonymous survey.
      ). Surgical treatment include drainage with or without sclerotherapy, drainage with diathermy or laser vapourization of the cyst wall, drainage and stripping of the cyst wall (ovarian cystectomy) and radical treatment in the form of hysterectomy with or without oophorectomy. Uncontrolled studies reported significant relief of pain in a large proportion of cases after surgical treatment of endometrioma (
      • Jones K.D.
      • Sutton C.
      Patient satisfaction and changes in pain scores after ablative laparoscopic surgery for stage III–IV endometriosis and endometriotic cysts.
      ,
      • Sutton C.J.
      • Ewen S.P.
      • Jacobs S.A.
      • Whitelaw N.L.
      Laser laparoscopic surgery in the treatment of ovarian endometriomas.
      ). Of note, the recurrence rate of symptomatic endometriosis after surgical treatment is consistently high (
      • Fedele L.
      • Bianchi S.
      • Zanconato G.
      • Berlanda N.
      • Raffaelli R.
      • Fontana E.
      Laparoscopic excision of recurrent endometriomas: long-term outcome and comparison with primary surgery.
      ,
      • Koga K.
      • Takemura Y.
      • Osuga Y.
      • Yoshino O.
      • Hirota Y.
      • Hirata T.
      • Morimoto C.
      • Harada M.
      • Yano T.
      • Taketani Y.
      Recurrence of ovarian endometrioma after laparoscopic excision.
      ) and repeat surgery is not uncommon.
      There is a significant risk of visceral injury as endometriomas are usually associated with severe peritoneal endometriosis and multifocal disease (
      • Koninckx P.R.
      • Timmermans B.
      • Meuleman C.
      • Penninckx F.
      Complications of CO2-laser endoscopic excision of deep endometriosis.
      ,
      • Varol N.
      • Maher P.
      • Healey M.
      • Woods R.
      • Wood C.
      • Hill D.
      • Lolatgis N.
      • Tsaltas J.
      Rectal surgery for endometriosis-should we be aggressive?.
      ). Nevertheless, large endometriomas may be more susceptible to infection or rupture and should ideally be treated surgically.
      Surgical treatment of endometrioma can be performed via laparotomy or laparoscopy, with no significant differences in the risk of recurrence of the cyst or pelvic pain symptoms and fertility outcome (
      • Catalano G.F.
      • Marana R.
      • Caruana P.
      • Muzii L.
      • Mancuso S.
      Laparoscopy versus microsurgery by laparotomy for excision of ovarian cysts in patients with moderate or severe endometriosis.
      ,
      • Milingos S.
      • Loutradis D.
      • Kallipolitis G.l.
      • Liapi A.
      • Drakakis P.
      • Antsaklis A.
      • Michalas S.
      Comparison of laparoscopy with laparotomy for the treatment of extensive endometriosis with large endometriomata.
      ). It is recognized that laparotomy might be indicated in selected cases of severe endometriosis associated with dense extensive adhesions particularly in women who have had previous surgery. Recently, the authors of a UK survey on training in laparoscopic surgery found that 27% of trainees never performed a laparoscopy for the management of ectopic pregnancy and 52–62% never performed a laparoscopy for ovarian cyst or grade I–II endometriosis (
      • Majmudar T.
      • Slack M.
      Laparoscopy training for obstetrics and gynaecology trainees? A pilot study in the Easter Deanery, UK.
      ). Since surgery remains a widely used approach for treatment of endometrioma, bearing in mind the potential risk of iatrogenic premature ovarian failure, appropriate skills in laparoscopic surgery must constitute a core element of the subspecialty training in reproductive medicine.
      Laparoscopic or transvaginal ultrasound guided drainage of endometrioma is associated with a high and rapid recurrence rate (
      • Donnez J.
      • Nisolle M.
      • Gillerot S.
      • Anaf V.
      • Clerckx-Braun F.
      • Casanas-Roux F.
      Ovarian endometrial cysts: the role of gonadotropin-releasing hormone agonist and/or drainage.
      ,
      • Troiano R.N.
      • Taylor K.J.
      Sonographically guided therapeutic aspiration of benign-appearing ovarian cysts and endometriomas.
      ,
      • Vercellini P.
      • Vendola N.
      • Bocciolone L.
      • Colombo A.
      • Rognoni M.T.
      • Bolis G.
      Laparoscopic aspiration of ovarian endometriomata, effect with post operative gonadotropin releasing hormone agonist treatment.
      ,
      • Zanetta G.
      • Lissoni A.
      • Dalla Valle C.
      • Trio D.
      • Pittelli M.
      • Rangoni G.
      Ultrasound-guided aspiration of endometriomas: possible applications and limitations.
      ) and is rarely effective in alleviating the patient’s symptoms (
      • Chan L.Y.
      • So W.W.
      • Lao T.T.
      Rapid recurrence of endometrioma after transvaginal ultrasound-guided aspiration.
      ). It can be associated with a higher risk of pelvic infection (
      • Muzii L.
      • Marana R.
      • Caruana P.
      • Catalano G.F.
      • Mancuso S.
      Laparoscopic findings after transvaginal ultrasound-guided aspiration of ovarian endometriomas.
      ,
      • Nargund G.
      • Parsons J.
      Infected endometriotic cysts secondary to oocyte aspiration for in-vitro fertilization.
      ,
      • Padilla S.L.
      Ovarian abscess following puncture of an endometrioma during ultrasound-guided oocyte retrieval.
      ,
      • Yaron Y.
      • Peyser M.R.
      • Samuel D.
      • Amit A.
      • Lessing J.B.
      Infected endometriotic cysts secondary to oocyte aspiration for in-vitro fertilization.
      ,
      • Zanetta G.
      • Lissoni A.
      • Dalla Valle C.
      • Trio D.
      • Pittelli M.
      • Rangoni G.
      Ultrasound-guided aspiration of endometriomas: possible applications and limitations.
      ) and pelvic adhesions (
      • Garvey T.S.
      • Kazer R.R.
      • Milad M.P.
      Severe pelvic adhesions following attempted ultrasound-guided drainage of bilateral ovarian endometriomas.
      ,
      • Muzii L.
      • Marana R.
      • Caruana P.
      • Catalano G.F.
      • Mancuso S.
      Laparoscopic findings after transvaginal ultrasound-guided aspiration of ovarian endometriomas.
      ). Evidence from one RCT (
      • Donnez J.
      • Nisolle M.
      • Gillerot S.
      • Anaf V.
      • Clerckx-Braun F.
      • Casanas-Roux F.
      Ovarian endometrial cysts: the role of gonadotropin-releasing hormone agonist and/or drainage.
      ) suggests that the administration of GnRH agonist for 3 months after drainage of endometrioma may reduce the revised American Fertility Society grading score for endometriosis by 20% and the mean cyst diameter by 52%. The authors of this trial also reported histological evidence of decreased glandular and mitotic activity in women who received GnRH agonist for 3 months after drainage of the endometrioma. This approach may be useful in women who are at high risk of surgical complications such as those with a history of previous multiple surgery or those with frozen pelvis. This review advises prophylactic preoperative antibiotics before drainage of endometrioma to reduce the risk of infection.
      Some investigators studied the effect of sclerotherapy on the recurrence of drained endometrioma by instillation of 95% ethanol (
      • Hsieh C.L.
      • Shiau C.S.
      • Lo L.M.
      • Hsieh T.T.
      • Chang M.Y.
      Effectiveness of ultrasound-guided aspiration and sclerotherapy with 95% ethanol for treatment of recurrent ovarian endometriomas.
      ,
      • Noma J.
      • Yoshida N.
      Efficacy of ethanol sclerotherapy for ovarian endometriomas.
      ,
      • Yazbeck C.
      • Madelenat P.
      • Ayel J.P.
      • Jacquesson L.
      • Bontoux L.M.
      • Solal P.
      • Hazout A.
      Ethanol sclerotherapy: a treatment option for ovarian endometriomas before ovarian stimulation.
      ), 1–5% tetracycline (
      • Aboulghar M.A.
      • Mansour R.T.
      • Serour G.I.
      • Sattar M.
      • Ramzy A.M.
      • Amin Y.M.
      Treatment of recurrent chocolate cysts by transvaginal aspiration and tetracycline sclerotherapy.
      ,
      • Fisch J.D.
      • Sher G.
      Sclerotherapy with 5% tetracycline is a simple alternative to potentially complex surgical treatment of ovarian endometriomas before in vitro fertilization.
      ), 600,000 IU interleukin-2 (
      • Acién P.
      • Quereda F.J.
      • Gómez-Torres M.J.
      • Bermejo R.
      • Gutierrez M.
      GnRH analogues, transvaginal ultrasound-guided drainage and intracystic injection of recombinant interleukin-2 in the treatment of endometriosis.
      ) or methotrexate (
      • Mesogitis S.
      • Antsaklis A.
      • Daskalakis G.
      • Papantoniou N.
      • Michalas S.
      Combined ultrasonographically guided drainage and methotrexate administration for treatment of endometriotic cysts.
      ) into the cyst wall. The recurrence rate of endometrioma was lower with ethanol (13–15%) and methotrexate (18%) than after tetracycline (25%) or interleukin-2 (30%). Further studies evaluating the dose and efficacy of different sclerotherapeutic agents are warranted before this technique can be recommended for routine clinical practice.
      Excision of endometrioma involves drainage followed by stripping of the cyst wall. Compared with drainage and coagulation, excision of endometrioma has the advantage of providing a tissue sample for histological diagnosis and exclusion of malignancy. In addition, the findings of two RCT (
      • Alborzi S.
      • Momtahan M.
      • Parsanezhad M.
      • Dehbashi S.
      • Zolghadri J.
      • Alborzi S.
      A prospective, randomized study comparing laparoscopic ovarian cystectomy versus fenestration and coagulation in patients with endometriomas.
      ,
      • Beretta P.
      • Franchi M.
      • Ghezzi F.
      • Busacca M.
      • Zupi E.
      • Bolis P.
      Randomized clinical trial of two laparoscopic treatments of endometriomas: cystectomy versus drainage and coagulation.
      ) and one Cochrane review (
      • Hart R.J.
      • Hickey M.
      • Maouris P.
      • Buckett W.
      • Garry R.
      Excisional surgery versus ablative surgery for ovarian endometriomata.
      ) involving a total of 164 women with symptomatic endometrioma clearly indicate that excisional surgery offers advantage over drainage and ablation with respect to the recurrence of endometrioma and the symptoms of dysmenorrhoea, deep dyspareunia and non-menstrual pelvic pain. After excision of endometrioma, haemostasis can be achieved by bipolar or laser coagulation, intraovarian suturing or the use of fibrin glue to approximate the ovarian capsule and cover serosal defects. A small RCT (
      • Pellicano M.
      • Bramante S.
      • Guida M.
      • Bifulco G.
      • Di Spiezio Sardo A.
      • Cirillo D.
      • Nappi C.
      Ovarian endometrioma: postoperative adhesions following bipolar coagulation and suture.
      ) involving 32 women with single endometrioma undergoing ovarian cystectomy observed significantly lower rate of post-surgical ovarian adhesions in the group who had intraovarian sutures than in the group who had bipolar coagulation for haemostasis (30.8% versus 57.1%). In another prospective controlled non-randomized study involving 30 women with endometrioma (
      • Takeuchi H.
      • Awaji M.
      • Hashimoto M.
      • Nakano Y.
      • Mitsuhashi N.
      • Kuwabara Y.
      Reduction of adhesions with fibrin glue after laparoscopic excision of large ovarian endometriomas.
      ), the use of fibrin gel to approximate the ovarian capsule after surgical removal of endometrioma was associated with a significant decrease in the adhesion score. The decrease was most marked in women with endometriomas measuring 5 cm or more in diameter and for those with a high pre-operative adhesion score.
      Excision of ovarian endometrioma is associated with a high recurrence rate.
      • Busacca M.
      • Marana R.
      • Caruana P.
      • Candiani M.
      • Muzii L.
      • Calia C.
      Recurrence of ovarian endometrioma after laparoscopic excision.
      prospectively evaluated 366 patients who underwent excision of endometrioma and followed them up for a minimum of 6 months post-operatively or 6 months after discontinuation of post-operative medical therapy. They observed a cumulative rate of ultrasonographic recurrence of 11.7% and a cumulative rate of a second surgery of 8.2% over 48 months. Ultrasonographic cyst recurrence was associated with pain recurrence in 73% of cases. Among the factors that were significantly associated with recurrence of endometrioma, the stage of the disease and a history of previous surgery for endometriosis were the most important. In another retrospective study involving 224 patients who were followed up for a minimum of 2 years after laparoscopic excision of endometrioma (
      • Koga K.
      • Takemura Y.
      • Osuga Y.
      • Yoshino O.
      • Hirota Y.
      • Hirata T.
      • Morimoto C.
      • Harada M.
      • Yano T.
      • Taketani Y.
      Recurrence of ovarian endometrioma after laparoscopic excision.
      ), the overall recurrence rate of endometrioma was 30.4%. A higher recurrence rate was observed in women who had received previous medical treatment for endometriosis and those with large endometrioma. In an attempt to compare the effect of primary versus repeat surgical treatment of endometrioma on the recurrence rate and ovarian function,
      • Fedele L.
      • Bianchi S.
      • Zanconato G.
      • Berlanda N.
      • Raffaelli R.
      • Fontana E.
      Laparoscopic excision of recurrent endometriomas: long-term outcome and comparison with primary surgery.
      conducted a retrospective analysis of 305 primary surgeries and 54 reoperations for recurrent endometrioma in the same ovary as the primary cyst. The 5-year cumulative rates were not significantly different in both groups with respect to recurrence of endometrioma, retreatment requirement or pregnancy rate. However, women who had repeat surgery were more likely to need assisted conception and reported more irregular menstrual cycles associated with FSH concentrations ⩾14 IU/ml.
      There is not enough evidence to support the use of hormonal suppression prior to surgical treatment of endometriosis or endometrioma. One study comparing pre-surgical medical therapy with surgery alone showed a significant improvement in American Fertility Society scores in the medical therapy group but this may or may not be associated with better outcomes for the patients (
      • Donnez J.
      • Nisolle M.
      • Gillerot S.
      • Anaf V.
      • Clerckx-Braun F.
      • Casanas-Roux F.
      Ovarian endometrial cysts: the role of gonadotropin-releasing hormone agonist and/or drainage.
      ). Although pre-operative hormonal therapy appears to reduce the size of endometrioma (
      • Rana N.
      • Thomas S.
      • Rotman C.
      • Dmowski W.P.
      Decrease in the size of ovarian endometriomas during ovarian suppression in stage IV endometriosis. Role of preoperative medical treatment.
      ,
      • Tsujioka H.
      • Inoue Y.
      • Emoto M.
      • Sadamori R.
      • Shirota K.
      • Hachisuga T.
      • Kawarabayashi T.
      The efficacy of preoperative hormonal therapy before laparoscopic cystectomy of ovarian endometriomas.
      ), it may induce fibrosis of the capsule, thus increasing the difficulty in stripping the cyst wall without affecting the loss of ovarian follicles (
      • Tsujioka H.
      • Inoue Y.
      • Emoto M.
      • Sadamori R.
      • Shirota K.
      • Hachisuga T.
      • Kawarabayashi T.
      The efficacy of preoperative hormonal therapy before laparoscopic cystectomy of ovarian endometriomas.
      ).
      A Cochrane systematic review involving 11 RCT concluded that there is insufficient evidence from the studies identified to conclude that hormonal suppression in association with surgery for endometriosis is associated with a significant benefit with regard to any of the outcomes identified (
      • Yap C.
      • Furness S.
      • Farquhar C.
      • Rawal N.
      Pre and post operative medical therapy for endometriosis surgery.
      ).
      • Jee B.C.
      • Lee J.Y.
      • Suh C.S.
      • Kim S.H.
      • Choi Y.M.
      • Moon S.Y.
      Impact of GnRH agonist treatment on recurrence of ovarian endometriomas after conservative laparoscopic surgery.
      analysed the influence of post-operative GnRH-agonist treatment on disease recurrence after conservative laparoscopic surgery for ovarian endometriomas in 109 premenopausal women. The patients were divided into four treatment groups: expectant management (n = 37) and GnRH therapy for 3 (n = 28), 4 (n = 21) and 6 months (n = 23). The overall crude recurrence rate was 16.5% after follow-up for an average of 20 months. There was no significant difference in cumulative probabilities of disease recurrence at 24 and 36 months between the four groups. Similar findings were reported by
      • Marana R.
      • Costantini W.
      • Muzii L.
      • Uglietti A.
      • Caruana P.
      • Arnold M.
      Laparoscopic excision of ovarian endometriomas: does post-operative medical treatment prevent recurrence?.
      .
      The evidence regarding the use of COC after surgical treatment of endometriosis or endometrioma is conflicting. Post-operative treatment with a COC has not been shown to be effective after surgical treatment of endometriosis (
      • Muzii L.
      • Marana R.
      • Caruana P.
      • Catalano G.F.
      • Margutti F.
      • Panici P.B.
      Postoperative administration of monophasic combined oral contraceptives after laparoscopic treatment of ovarian endometriomas: a prospective, randomized trial.
      ). With respect to endometrioma, a retrospective study involving 87 patients with endometrioma reported a lower recurrence rate in women who used the COC post-operatively (
      • Takamura M.
      • Koga K.
      • Osuga Y.
      • Takemura Y.
      • Hamasaki K.
      • Hirota Y.
      • Yoshino O.
      • Taketani Y.
      Post-operative oral contraceptive use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision.
      ). The recurrence rate appeared to be related to the duration of COC use, being lower in women who continued the COC for 24 months than in women who discontinued the COC before the end of the study or those who never used the COC post-operatively. Similar findings from another retrospective study involving 277 patients with endometrioma were reported by
      • Vercellini P.
      • Somigliana E.
      • Daguati R.
      • Vigano P.
      • Meroni F.
      • Crosignani P.G.
      Postoperative oral contraceptive exposure and risk of endometrioma recurrence.
      . In agreement with the aforementioned studies, a RCT (
      • Seracchioli R.
      • Mabrouk M.
      • Frasca C.
      • Manuzzi L.
      • Montanari G.
      • Keramyda A.
      • Venturoli S.
      Long-term cyclic and continuous oral contraceptive therapy and endometrioma recurrence: a randomized controlled trial.
      ) of 239 women who underwent surgical excision of endometrioma reported a lower recurrence rate in women who used the COC either cyclically (14.7%) or continuously (8.2%) compared with non-users (29%). Two RCT (
      • Muzii L.
      • Marana R.
      • Caruana P.
      • Catalano G.F.
      • Margutti F.
      • Panici P.B.
      Postoperative administration of monophasic combined oral contraceptives after laparoscopic treatment of ovarian endometriomas: a prospective, randomized trial.
      ,
      • Sesti F.
      • Capozzolo T.
      • Pietropolli A.
      • Marziali M.
      • Bollea M.R.
      • Piccione E.
      Recurrence rate of endometrioma after laparoscopic cystectomy: a comparative randomized trial between post-operative hormonal suppression treatment or dietary therapy vs. placebo.
      ) did not find a benefit from post-operative use of COC. The first RCT (
      • Sesti F.
      • Capozzolo T.
      • Pietropolli A.
      • Marziali M.
      • Bollea M.R.
      • Piccione E.
      Recurrence rate of endometrioma after laparoscopic cystectomy: a comparative randomized trial between post-operative hormonal suppression treatment or dietary therapy vs. placebo.
      ) recruited 259 consecutive women who underwent laparoscopic unilateral/bilateral cystectomy for endometrioma. Patients were randomized to receive placebo (n = 65), GnRH agonist (n = 65), continuous low-dose monophasic oral contraceptives (n = 64) or dietary therapy (vitamins, mineral salts, lactic ferments, fish oil) (n = 65) for 6 months and were followed up for 18 months. There was no significant difference in the recurrence rate of endometrioma between women who received post-operative hormonal therapy (COC or GnRH agonist), dietary therapy or placebo. In the second RCT (
      • Muzii L.
      • Marana R.
      • Caruana P.
      • Catalano G.F.
      • Margutti F.
      • Panici P.B.
      Postoperative administration of monophasic combined oral contraceptives after laparoscopic treatment of ovarian endometriomas: a prospective, randomized trial.
      ) 70 patients were randomized to receive either low-dose cyclic COC post-operatively for 6 months or no treatment and were followed up for a mean duration of 22 months. The authors did not report a significant difference in the recurrence of endometrioma or moderate-to-severe pain or in the mean time to recurrence of symptoms or endometriomas between the study and the control group.
      Hysterectomy with or without salpingo-oophorectomy may be justified in women with advanced endometriosis who do not wish to preserve their fertility. There are currently no RCT that have investigated the role of oophorectomy in management of advanced endometriosis. A retrospective study of 240 women with advanced endometriosis (
      • Shakiba K.
      • Bena J.F.
      • McGill K.M.
      • Minger J.
      • Falcone T.
      Surgical treatment of endometriosis: a 7-year follow-up on the requirement for further surgery.
      ) reported that the lowest rates of re-operation for symptomatic endometriosis were in those women who had hysterectomy and bilateral oophorectomy as a primary procedure. In women who underwent local excision with ovarian preservation, the surgery-free percentages were 79.4%, 53.3% and 44.6% at 2, 5 and 7 years, respectively. In women who underwent hysterectomy with ovarian preservation, the 2-, 5- and 7-year re-operation-free percentages were 95.7%, 86.6% and 77.0%, respectively. In women who underwent hysterectomy without ovarian preservation, the percentages were 96.0%, 91.7% and 91.7%, respectively. In women between 30 and 39 years of age, removal of the ovaries did not significantly improve the surgery-free time. Since oophorectomy is associated with other significant disadvantages in terms of earlier menopause, the authors suggest that hysterectomy with ovarian conservation should be considered for advanced endometriosis in women younger than 40 years (
      • Shakiba K.
      • Bena J.F.
      • McGill K.M.
      • Minger J.
      • Falcone T.
      Surgical treatment of endometriosis: a 7-year follow-up on the requirement for further surgery.
      ).
      In another historical prospective study involving 138 women who had hysterectomy with or without ovarian tissue preservation for endometriosis (
      • Namnoum A.B.
      • Hickman T.N.
      • Goodman S.B.
      • Gehlbach D.L.
      • Rock J.A.
      Incidence of symptom recurrence after hysterectomy for endometriosis.
      ), patients who had ovarian conservation had six times greater risk of developing recurrent pain and eight times greater risk of re-operation. It is quite possible that the risk of re-operation may increase in cases of endometrioma due to the high rate of cyst recurrence. In addition, the risk of ovarian cancer is slightly increased in women with endometrioma (
      • Kobayashi H.
      • Sumimoto K.
      • Kitanaka T.
      • Yamada Y.
      • Sado T.
      • Sakata M.
      • Yoshida S.
      • Kawaguchi R.
      • Kanayama S.
      • Shigetomi H.
      • Haruta S.
      • Tsuji Y.
      • Ueda S.
      • Terao T.
      Ovarian endometrioma - risks factors of ovarian cancer development.
      ). There is no consensus about how menopausal symptoms should be managed following oophorectomy for endometriosis. Oestrogen-only hormone therapy has been associated with disease recurrence. This has lead to recommendations to use tibolone or combined oestrogen and progestogen following oophorectomy for endometriosis in an attempt to prevent oestrogenic proliferation (
      • Soliman N.F.
      • Hillard T.C.
      Hormone replacement therapy in women with past history of endometriosis.
      ). However, there is some evidence that long-term combined hormone therapy may increase the risk of post-menopausal breast cancer compared with oestrogen alone, at least in older populations (
      • Rossouw J.E.
      • Anderson G.L.
      • Prentice R.L.
      • La Croix A.Z.
      • Kooperberg C.
      • Stefanick M.L.
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      • Beresford S.A.
      • Howard B.V.
      • Johnson K.C.
      • Kotchen J.M.
      • Ockene J.
      Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.
      ). Evidence for the risks associated with combined hormone therapy in younger women is limited. The absolute risk of morbidity in these younger women is believed to be lower and thus the benefit/risk ratio may be higher than in older women (

      MHRA [Internet]. Hormone Replacement Therapy: Update Advice. Drug Safety Update, 2007 September; 1 (2). <http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON2032234/> (cited 01.18.10).

      ).
      In summary, treatment options for symptomatic endometrioma should take into account several factors including the woman’s chronological age and her desire for fertility including any reproductive plans, previous surgery, concerns about increased risks of surgical complications or long term effects of medical therapy and the patient’s preference. Medical treatment should be offered to symptomatic women with small endometrioma who wish to avoid surgery. Conservative surgical treatment is generally preferred for premenopausal women who wish to preserve their ovarian function. Excision of endometrioma offers advantage over drainage and ablation with respect to the recurrence of endometrioma and pelvic pain. Radical treatment is best reserved for older women who have completed their family.

      Management of women with asymptomatic endometrioma

      There is a wide variation in the reported incidence of endometriosis in asymptomatic women, ranging from 2% to 50% (
      • Fauconnier A.
      • Chapron C.
      Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications.
      ), while there is a lack of population-based studies reporting on the incidence of asymptomatic endometrioma in the general population. Although endometrioma is commonly associated with severe endometriosis (
      • Chapron C.
      • Pietin-Vialle C.
      • Borghese B.
      • Davy C.
      • Foulot H.
      • Chopin N.
      Associated ovarian endometrioma is a marker for greater severity of deeply infiltrating endometriosis.
      ), there is no correlation between the stage of endometriosis and the severity of pelvic pain symptoms (
      • Szendei G.
      • Hernádi Z.
      • Dévényi N.
      • Csapó Z.
      Is there any correlation between stages of endometriosis and severity of chronic pelvic pain? Possibilities of treatment.
      ). Management of asymptomatic endometrioma should take several factors into account including the accuracy of the diagnosis, the size of the cyst, the woman’s age and her wish to preserve fertility and ovarian function. The local guidelines for management of suspected ovarian malignancy should be followed in cases of ovarian endometrioma. Ultrasound scanning and serum cancer antigen 125 (CA-125) may help to identify rare instances of ovarian cancer. However, CA-125 concentrations can be elevated in the presence of endometrioma (
      • Kennedy S.
      • Bergqvist A.
      • Chapron C.
      • D’Hooghe T.
      • Dunselman G .
      • Greb R.
      • Hummelshoj L.
      • Prentice A.
      • Saridogan E.
      ESHREguideline for the diagnosis and treatment of endometriosis.
      ). Due to the increased risk of ovarian cancer, surgical treatment is usually recommended for women above the age of 40 and for large endometriomas (
      • Kobayashi H.
      • Sumimoto K.
      • Kitanaka T.
      • Yamada Y.
      • Sado T.
      • Sakata M.
      • Yoshida S.
      • Kawaguchi R.
      • Kanayama S.
      • Shigetomi H.
      • Haruta S.
      • Tsuji Y.
      • Ueda S.
      • Terao T.
      Ovarian endometrioma - risks factors of ovarian cancer development.
      ). Expectant management is appropriate for younger women and for smaller endometriomas. It is prudent to follow-up women who opt for expectant management by annual ultrasound scan and serum CA-125.

      Conclusions

      Endometriomas are commonly seen in women of reproductive age who may wish to preserve their ovarian function and/or fertility. There is insufficient evidence to suggest that surgical treatment of endometrioma is better than medical treatment with respect to the long-term relief of symptoms and quality of life. Treatment of symptomatic women should be individualized according to the woman’s age and her desire for fertility, previous surgery, long-term effects of medical therapy and the patient’s preference. Although the evidence is insufficient, drainage and sclerotherapy of endometrioma, possibly followed by post-operative ovarian suppression for 3 months, may be valid for women with a history of previous multiple surgery or those with frozen pelvis who wish to preserve their ovaries. Laparoscopic excision of ovarian endometrioma prior to IVF does not offer any additional benefit over expectant management in terms of ovarian response to gonadotrophin stimulation or pregnancy outcome. A large, well-designed, adequately powered RCT that compares the effects of surgical removal versus expectant management of endometrioma on ovarian performance and pregnancy outcomes in women undergoing IVF is warranted. Until such a trial is conducted and definite conclusions can be drawn, the management of women with endometrioma prior to IVF should be individualized to maximize the chances of success and minimize the risks. All therapeutic options including conservative, medical or surgical treatment as well as the advantages and disadvantages should be fully discussed with the patient. Any decision for surgery should be carefully considered and balanced against the risks, especially in women who have had ovarian surgery or those with suboptimal ovarian reserve. If the patient opts for surgical treatment, she should be appropriately counselled about the potential risk of premature ovarian failure and the remote possibility of oophorectomy. Surgical treatment can be justified for women with concomitant pelvic pain not responding to medical treatment, when the cyst is larger than 4 cm or when malignancy cannot be reliably excluded.

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