{"paper_id":"f89f1983-426c-44df-9add-fab75f7e936c","body_text":"ENDOMETRIOSIS (PA STRA TTON, SECTION EDITOR)\nEffect of Long-Term Use of Hormones on Endometriomas\nNicola Berlanda & Martina Morini & Dhouha Dridi &\nLucrezia de Braud & Benedetta Bracco & Paolo Vercellini\nPublished online: 12 July 2013\n# Springer Science+Business Media New Y ork 2013\nAbstract Surgery remains the standard treatment for endome-\ntriomas larger than 3 cm. Three to six months of hormonal\ntreatment administered preoperatively does not facilitate surge-\nry; additionally, treatment taken postoperatively delays but does\nnot prevent endometrioma recurrence and thus does not offer\nsubstantial long-term advantages. Nevertheless, postoperative\nlong-term continuous use of oral contraceptives results in a\n90 % reduction in cyst recurrence compared with no treatment.\nThe possible mechanisms of action of oral contraceptives in\npreventing endometrioma recurrence include hypomenorrhea,\novulation inhibition and improvement of progesterone resis-\ntance. Further studies are needed to assess whether long-term\nuse of oral contraceptives mightbe effective in the treatment and\nprevention of endometriomas without surgery.\nKeywords Endometrioma . Ovarian cysts . Laparoscopic\nsurgery . Medical treatment of endometriosis . Oral\ncontraceptives . Infertility . Pelvic pain\nIntroduction\nDuring the last decades, the debate regarding the clinical\nmanagement of endometriomas has focused more on surgical\nrather than medical treatment. During this period, the surgical\napproach has been modified from laparotomy to laparoscopy, a\nminimally invasive approach. Subsequently, laparoscopic\ntechniques have been developed to reduce the surgical trauma\nto the healthy ovary. In this scenario, hormonal medical treat-\nment has been administered either pre- or post- operatively for\nlimited periods of time, i.e., 3 or 6 months, with the aim of\nimproving surgical outcome. Unfortunately, however, these\nperioperative medical treatment regimens do not add any clin-\nical advantages compared to surgical treatment alone. In 2004,\nin fact, a Cochrane review concluded that“there is no evidence\nof benefit associated with post-surgical medical therapy and\ninsufficient evidence to determine whether there is a benefit\nfrom pre-surgical medical therapy” of endometriosis [1].\nRecently, however, there has been a growing body of evi-\ndence suggesting that long-term hormonal treatment could play\na central role in the postoperative management of patients with\novarian endometriotic cysts. The transition from 3 to 6 months\nto a long-term hormonal treatment for endometriomas is not\nonly a practical matter of prolonging the time of drug adminis-\ntration, but it implies a conceptual change in the overall strategy\nfor the management of this condition.\nIn the present paper, we review the available evidence on\nthe hormonal treatment of endometriomas, with the aim of\nN. Berlanda : M. Morini : D. Dridi : L. de Braud : B. Bracco :\nP . V ercellini\n“Luigi Mangiagalli” Department of Obstetrics and Gynecology,\nUniversità degli Studi di Milano and Fondazione IRCCS Ca ’\nGranda Ospedale Maggiore Policlinico, Via della Commenda 12,\nMilan, italy\nM. Morini\ne-mail: martina.morini19@gmail.com\nD. Dridi\ne-mail: dh.dridi2@gmail.com\nL. de Braud\ne-mail: ludebraud@hotmail.it\nB. Bracco\ne-mail: benedetta.bracco@studenti.unimi.it\nP . V ercellini\ne-mail: paolo.vercellini@unimi.it\nP . V ercellini\nCenter for Research in Obstetrics and Gynecology (C.R.O.G.),\nViale Caldara 39, 20122 Milano, Italy\nN. Berlanda ( *)\nClinica Ostetrica e Ginecologica “Luigi Mangiagalli”, Università\ndegli Studi di Milano and Fondazione IRCCS Ca’ Granda Ospedale\nMaggiore Policlinico, Via della Commenda 12, 20122 Milan, Italy\ne-mail: nicola.berlanda@gmail.com\nCurr Obstet Gynecol Rep (2013) 2:178 –185\nDOI 10.1007/s13669-013-0053-8\n\ndescribing previous indications, the current treatment stan-\ndard, and the possible future trends.\nEpidemiological and Clinical Characteristics\nof Endometriomas\nEndometriosis affects up to 10 % of women of reproductive age\n[2]. The ovary is involved in more than half of the cases [3]. An\novarian endometrioma is a pseudocyst lined by endometrioid\nmucosa that contains a typical tarry, thick, chocolate-like fluid\nas the result of accumulation of hemorrhagic blood. Due to\nhemolysis of entrapped blood, chocolate fluid contains a very\nhigh iron concentration which creates an environment of a\ncytotoxic oxidative stress. Local high oxidative stress could\nbe, at least in part, the mechanism of cellular toxicity responsible\nfor either the reduction of the number of ovarian follicles, which\nmay cause subfertility, or DNA damage, which may predispose\nto epithelial ovarian cancer [4, 5]. Indeed epidemiologic studies\ndemonstrated, in women with ovarian endometrioma, a higher\nincidence of endometrioid and clear cell carcinoma as compared\nto the general population, with an increased relative risk ranging\nbetween 1.3 and 2 [6].\nAt ultrasonography, chocolate fluid content has a typical\nhomogeneous low echogenic pattern and therefore the sono-\ngraphic diagnosis of endometriomas is highly reliable. Ovarian\nendometriotic cysts range in size from less than 1 cm up to 15\nto 20 cm. They may be asymptomatic or associated with pelvic\npain. Endometriomas are unilateral in 70 % and bilateral in\n30 % of cases; the left ovary is significantly more frequently\naffected than the right ovary with a 60 %:40 % ratio [ 7].\nPathogenesis of Endometriomas\nThree different pathogenic theories for endometriomas have\nbeen proposed [8]: 1) inversion and progressive invagination\nof the ovarian cortex after accumulation of menstrual debris\nderiving from bleeding of superficial endometriotic implants\n[9–11]; 2) secondary involvement of functional ovarian cysts\nby endometriotic implants located on the ovarian surface\n[12]; and 3) metaplasia of the coelomic epithelium covering\nthe ovary [ 13]. The left-lateral predisposition of ovarian\nendometriotic cysts seems to support the first two “retro-\ngrade menstruation or transplantation ” theories rather than\nthe third “metaplasia” theory. In fact, the process of coelomic\nepithelium metaplasia would not be influenced by the pelvic\nanatomy. In contrast, the probability of peritoneal and ovar-\nian implantation of endometrial cells refluxed through the\nfallopian tubes during menstruation may be higher in the left\nhemipelvis due to the presence of the sigmoid colon, which\nmay create an anatomical shelter favouring the stasis of such\ncells and preventing them from being cleared by the circu-\nlating peritoneal fluid [ 7, 14].\nAmong the two “transplantation” theories, the former one\nreferring to an invagination of the ovarian cortex has been\nsuggested on the basis of the histological finding that in 90 %\nof cases the endometriotic wall consists of ovarian cortex,\ndemonstrated by the presence of primordial follicles [ 11].\nScurry et al. [15] have subsequently confirmed these findings;\nat histological evaluation of the endometrioma capsule, they\nidentified two types of endometriotic cysts: one with endome-\ntrial lining, fibrosis, and ovarian cortical tissue, i.e. the cortical\ninvagination endometrioma, in 42 % of cases, and one with\nonly endometrial lining and fibrosis in 58 % of cases. These\nestimates are consistent with those reported in another study\non the histology of the endometrioma wall [ 16], in which\nendometriosis, fibrosis, and ovarian cortical tissue were pres-\nent in 46 % of the specimens, whereas endometriosis and\nfibrosis were found in 54 % of the specimens.\nThe second “implantation”\ntheory postulates that an endo-\nmetrioma develops from a functional ovarian cyst that un-\ndergoes invasion with endometriotic cells; in turn, these cells\nbleed inside the cyst and, eventually, the functional wall of the\ncyst gradually changes to become an endometrioma. Although\na definitive histologic confirmation of this theory, i.e. a cyst\nwith continuity between a func tional cyst and endometrial\nlining, has never been observed [17], this theory regarding the\norigin of an endometrioma from a physiologic cyst is supported\nby ultrasonographic evidence; using serial transvaginal ultraso-\nnographic evaluations, an endometrioma has been observed to\ndevelop from either an ovarian follicle [18] or a corpus luteum\n[19]( F i g .1). Moreover, both surgical and histological evi-\ndence suggests that hemorrhagic functional cysts may play a\nrole in the genesis of endometriosis-related chocolate cysts:\nfirst, chocolate-coloured fluid in absence of active endometri-\nosis tissue has been laparoscopically demonstrated in the\novary, three months after drainage of an endometrioma in\nthe same location followed by administration of GnRH ago-\nnist therapy [20]; and second, of 42 chocolate cysts diagnosed\nas endometrioma at the time of laparoscopy, only 68 % were\nconfirmed by pathology, with the other cases diagnosed as\ncorpora lutea (27 %) or follicular cysts (5 %) [ 21].\nIndications and Limitations of Surgical Treatment\nof Endometriomas\nFor infertile women, laparoscopic ovarian cystectomy some-\ntimes may be recommended for endometriomas larger than\n3 cm in diameter, because endometrioma fluid may damage\nthe ovary and complications like peritonitis can arise in wom-\nen with endometriomas undergoing ART [ 22]. Additional\nindications for surgery include the coexistence of unbearable\nCurr Obstet Gynecol Rep (2013) 2:178 –185 179\n\nchronic pelvic pain, a rapid growth in endometrioma size, and\nthe uncertainty regarding the precise nature of the cyst [ 23].\nThe standard surgical technique for endometrioma re-\nmoval is laparoscopic stripping, that is, the gentle traction\nand countertraction of the pseudocystic wall (ovarian cortex\nsurrounding so-called chocolate fluid) and the residual ovar-\nian parenchyma by means of atraumatic forceps. Hemostasis\nof the pseudocystic bed is then achieved by pinpoint bipolar\nelectrocoagulation [23]. An alternative technique consists of\nthe fenestration and drainage of the endometrioma followed\nby laser vaporization (or bipolar coagulation) of the internal\nendometriotic foci. The results of a randomized, controlled\ntrial (RCT) demonstrated a less severe effect on ovarian\nreserve, as defined by less diminished serum anti-Müllerian\nhormone levels in women who underwent the fenestration-\nvaporization technique as compared with the stripping tech-\nnique [24]. However, data from two RCTs documented a sub-\nstantial advantage of stripping over fenestration-vaporization in\nterms of spontaneous pregnancy rate and risk of endometrioma\nrecurrence [25, 26].\nIn recent years, several studies have demonstrated that\nsurgical excision of endometriomas is associated with a high\nrate of postoperative recurrences, ranging from 30 % to 50 %\nafter 2 to 5 years [ 27–29]. Moreover, ultrasonographic eval-\nuation of 93 ovaries in women undergoing IVF after the\nstripping of a unilateral endometrioma has shown that, de-\nspite the use of microsurgical and minimally invasive tech-\nniques, approximately 50 % of operated ovaries show a\nreduced responsiveness to ovarian stimulation, and in ap-\nproximately 13 % of ovaries, a complete absence of follicular\ngrowth is observed, confirming severe impairment of ovar-\nian reserve [ 30].\nRationale and Available Compounds for the Hormonal\nTreatment of Endometriomas\nBecause peritoneal and ovarian endometriosis is believed to\narise from the implantation of regurgitated endometrial cells,\nthe medical treatment strategies include the creation of a\nhypoestrogenic hormonal milieu to induce atrophy of both\neutopic and ectopic endometrium, and to reduce or eliminate\nmenstrual bleeding.\nIn light of the possible relat ionship between hemorrhagic\nfunctional ovarian cysts and the formation of endometriomas,\nsuppression of ovulation might be particularly effective in the\nprevention of ovarian endometriosis [ 19]. Thus, whereas\nanovulation would act indirectly on endometriotic peritoneal\nimplants, through the induction of a hypoestrogenic state and\nthe reduction of menstrual bleeding, anovulation would directly\ninhibit the formation of functional cyst-related endometriomas.\nIn endometriosis, the eutopic and ectopic endometrium may\nnot respond normally to progesterone and is considered by\nsome investigators to be progesterone-resistant, which could\ncontribute to proliferation and survival of implants [ 31]. One\ntheory is that progesterone resistance in patients with endome-\ntriosis may be due to the over-expression of progesterone\nreceptor A (PR-A) and the downregulation of progesterone\nreceptor B (PR-B). In a recent paper, endometrioma samples\nobtained from patients treated with the progestin dienogest\nshowed a significantly higher expression of PR-B compared\nwith that observed in the control endometrioma samples.\nDienogest treatment did not alter the expression of PR-A and\nthus the PR-B/PR-A ratio was improved [32].\nThe compounds most widely used for the treatment of\nendometriosis include danazol, gonadotrophin releasing hor-\nmone analogues (GnRH-a), progestogens, and the oral con-\ntraceptive pill (OC). These medications, unlike surgical ex-\ncision, do not affect ovarian reserve.\nThe efficacy of these medications lasts only for as long as\nthey are administered and, at treatment suspension, ovulatory\nFig. 1 a Cystic corpus luteum with reticular appearance in a previously\nnormal ovary. b Same case as in 1A after 5 weeks. Progression of the\ncystic corpus luteum to an endometrioma, with homogeneous low\nechogenic fluid content\n180 Curr Obstet Gynecol Rep (2013) 2:178 –185\n\ncycles and menstrual bleeding are restored terminating the\npotential beneficial effects of treatment on endometriosis.\nTherefore, in order to maximize the preservation of ovarian\nreserve, long-term medical treatment, possibly until women\nseek conception, would be required.\nAmong the two most frequently used medications for the\ntreatment of endometriosis, GnRH and OC, neither used as\npostoperative medical therapy has been shown to be superior\nin reducing the recurrence of endometriomas [ 31]. However,\nsignificant side effects and high costs limit treatment with\nGnRH-a to no more than 6 months. By contrast, OCs, to-\ngether with progestins, offer a practical combination of ben-\nefits, risks, and costs [ 33–35], and based on the extensive\nepidemiologic information available, represent the safest\nmedical alternatives for long-term treatment of endometri-\nosis [36–38].\nEffects of Hormones on Endometriomas\nIn a previous study evaluating the effect of ovarian stimulation\non endometrioma size, 35 women with 45 endometriotic cysts\nunderwent transvaginal ultrasonography the month preceding\nan IVF attempt and 3 to 6 months after the cycle. The median\n(interquartile range) diameter of endometriomas before and\nafter the IVF cycle was unchanged: 20 (12 –27) mm and 20\n(17–27) mm, respectively, and new endometriomas were not\ndetected [39]. More data are needed to confirm that ovarian\nstimulation affects neither the size of existing endometriomas\nnor formation of new endometriotic cysts.\nThe effect of ovarian suppression on existing endome-\ntriomas has been reported in six studies, evaluating the possi-\nble benefits of 3 to 6 months of hormonal treatment before\nsurgical excision of the cysts. All six studies included a\nGnRH-a treatment group, which was compared to a no-\ntreatment group in four studies, to a danazol treatment group\nin one, and to both a no treatment and a danazol group in one.\nIn three studies, hormonal treatment was administered be-\ntween an initial surgical procedure consisting in laparoscopic\ncyst drainage and a second surgical procedure consisting in\nlaparoscopic or laparotomic second look/cyst excision. Two of\nthese three studies were randomized, parallel group trials [40,\n41]; in both of them, the second surgical evaluation document-\ned a significant reduction in endometrioma cyst size after 12-\nweeks of treatment with GnRH-a compared with no treatment.\nThe third study [ 42] demonstrated a 51 % reduction in\nendometrioma size after administration of either GnRH-a or\ndanazol for 6 months. In another study, follow-up evaluation\nwas performed by means of transvaginal ultrasonography. In\nthis study, two groups of women with endometriomas of mean\ndiameter 4.5 cm (range, 2–7) were given either GnRH-a ther-\napy for 3 months or no treatment after laparoscopic cyst drain-\nage. Six months after the initial surgery, transvaginal ultrasound\nshowed recurrent cysts in all women. There were no significant\ndifferences in mean endometrioma diameter between the two\ngroups or between pre-laparoscopic and 6-month ultrasound\nexaminations within each treatment group [43].\nTwo studies have compared the intraoperative and postop-\nerative outcome of the laparoscopic excision of ovarian\nendometriotic cysts with and without preoperative hormonal\ntreatment, without preliminary laparoscopic drainage. In one\nstudy, no significant difference was found between the two\ngroups in total operative time, c yst excision time, complexity\nof surgery, and recurrence rates among patients who received a\n3-month preoperative treatment with GnRH-a compared with a\nno-treatment group [44]. In the other study [ 45], patients with\novarian endometrioma undergoing a laparoscopic cystectomy\nwere divided into three groups: no preoperative hormonal\ntherapy; preoperative GnRH-a therapy for 3 to 6 months; and\npreoperative danazol therapy for 3 to 6 months. Mean diameter\nof endometriomas was reduced by preoperative hormonal ther-\napy in both the GnRH-a and danazol groups. Interestingly, this\nstudy considered the effect of preoperative hormonal therapy\non the histological characteristics of the endometrioma capsule.\nIn this study, the preoperative hormonal therapy groups showed\nfibrosis in a higher number of capsules, with a significantly\nlonger mean operation time compared with the no-therapy\ngroup; the loss of ovarian follicles was similar among the no\ntherapy and hormone groups. The authors concluded that pre-\noperative hormonal therapy caused severe fibrosis, which ham-\npered stripping the cyst wall from the ovary and resulted in\ninadvertent removal of normal ovarian stroma.\nThe same authors have previously suggested [46] that when\nthe endometrioma wall is attached to the ovarian stroma, the\nremoval of the capsule is easy for the surgeon, but it is\nassociated with damage to the ovarian stroma and loss of\nfollicles. In contrast, stripping the capsule from invaginated\ncortex (in endometriomas that arise that way) does not affect\nthe ovarian stroma or follicles. Similar considerations were\nreported by Nezhat et al. [ 9\n, 17], who proposed categorizing\nendometriomas based on their clinical characteristics arising\nfrom the corresponding purported pathogenic mechanism.\nAccording to them, type I endometriomas, i.e., the cortical\ninvagination endometriomas, usually are <5 cm in size, contain\na dark fluid, and have capsules that are difficult to remove\nbecause they are associated with dense fibrosis and adhesions.\nConversely, type II endometriomas, originating from function-\nal cysts that were invaded by plaques of endometriosis, are\nlarger in size and have a capsule that is more easily removed\nbecause of a clearer cleavage plane. More studies are needed to\ninvestigate the relationship among the different pathogenic,\nanatomical, and intraoperative characteristics of ovarian\nendometriotic cysts in relation to treatment paradigms in order\nto develop optimal approaches to treatment.\nIn conclusion, preoperative hormonal treatment of ovari-\nan endometriomas has been associated with conflicting\nCurr Obstet Gynecol Rep (2013) 2:178 –185 181\n\nresults. The most frequently reported effect has been a re-\nduction of the cyst size, but this effect did not facilitate\nsurgery nor did it improve surgical outcome; on the contrary,\none study reported increased fibrosis of the cystic capsule\nassociated with increased surgical difficulty.\nHowever, the reduction in size observed with three to six\nmonths of medical therapy makes it tempting to speculate that\na longer hormonal treatment might reduce endometrioma size\neven further. If this observation is valid, the use of primary\nhormonal treatment for small to medium-sized endometriomas\n(diameter ≤5 cm) could be investigated with periodic ultraso-\nnographic evaluation of the cyst size to confirm treatment\nbenefit. In young, asymptomatic patients who wish to delay\npregnancy for many years, postponing surgery until pregnancy\nis desired would be advantageous, to minimize the risks of\nsurgical compromise of ovarian reserve.\nEffect of Postoperative Hormonal Treatment\nConsidering the limitations of surgical excision of endome-\ntriomas, namely the high postoperative recurrence rate and\nthe potential detrimental effect on ovarian reserve, the efficacy\nof ovarian suppression in prolonging the recurrence-free inter-\nval after laparoscopic excision of ovarian endometriomas has\nbeen evaluated.\n“Short-Term” 3 to 6 Months Treatment\nIn three studies, the long-term recurrence rate of endometriomas\nwas assessed among women who received a 3 to 6 months\npostoperative hormonal treatment compared with women who\nreceived no treatment. In one study [47], patients were random-\nized after surgery into four groups: placebo versus GnRH-a,\ncontinuous OCs, or dietary therapy for 6 months. Dietary ther-\napy consisted of additional nutritional intake of vitamins (B6, A,\nC, E), mineral salts (Ca, Mg, Se, Zn, Fe), lactic ferments,\nomega-3, and omega-6 fatty acids (fish oil). No statistically\nsignificant difference in endometrioma recurrence rate, as\nassessed by transvaginal ultrasonography, was detected 18-\nmonths after surgery among any of the postoperative treatment\ngroups compared with the placebo group. In another study [48],\nat a follow-up evaluation 36 months after surgery, the postop-\nerative use of a GnRH agonist for 3 months delayed the time to\nrecurrence by 2 months, and its use for 4 or 6 months delayed\nrecurrence for approximately 5 months compared with the\nexpectant management group. Despite such delay, time to re-\ncurrence was not significantly different among treated and\nuntreated women. Similarly, a randomized, controlled trial re-\nported that postoperative administration of OC for 6 months did\nnot significantly affect the recurrence rate of endometriomas\nafter a mean follow-up of 22 months (range 12 –48) from\nsurgical treatment. However, in this trial, the mean time to\nrecurrence of endometriomas was delayed in the treatment\ngroup (18.2 months) compared with the control group (12.7-\nmonths) [49].\nOverall, in the former three studies, 137 women received\nGnRH-a and 134 received OC. Based on this limited amount\nof data, a 3- to 6-month course of postoperative hormonal\ntreatment with either GnRH-a or OC does not significantly\nreduce the long-term recurrence risk of endometriomas.\nLong-Term Treatment\nIn order to verify the hypothesis that the lack of efficacy of\nshort-term postoperative treatment in preventing long-term\nrecurrence of endometriomas could be caused by the rapid\nreturn to a regular follicular and hormonal activity after\ndiscontinuation of ovarian-suppressing hormones, some au-\nthors have evaluated the efficacy of a long-term treatment in\nreducing postoperative endometrioma recurrence.\nRecently, a systematic MEDLINE search was conducted\nto identify all comparative studies published between Janu-\nary 2000 and February 2012 in the English language on the\nrelationship between long-term postoperative adjuvant ther-\napy and risk of endometrioma recurrence [ 50]. Of the 12\narticles assessed in detail, 4 were selected based on surgery\nfor endometriotic cysts, postoperative medical treatment use\nfor ≥12 months versus expectant management, and ultraso-\nnographic and/or histological diagnosis of endometrioma\nrecurrence. A total of 965 women were enrolled, 726 of\nwhom were in three cohort studies [ 51–53] and 239 in one\nrandomized controlled trial [ 54]. Oral contraceptives (OCs)\nwere always used as the postoperative adjuvant treatment.\nThe characteristics and the results of the four selected studies\nare reported in Table 1. As shown, the duration of OC use\nvaried from 24 [ 52, 54] to 35 months [ 53]. Overall, an\nendometrioma recurrence was identified in 33 of 423 women\n(8 %; 95 % confidence interval (CI) 6–11 %) in the OC group\nand in 117 of 341 women (34 %; 95 % CI 29 –40 %) in the\nno-treatment group. The overall OR of the four studies was\n0.12 (95 % CI 0.05 –0.29), meaning that the risk of\nendometrioma recurrence after first line surgery is reduced\nby 88 % among OC users compared with non-OC users. In\naddition, among the three cohort studies, the endometrioma\nrecurrence rate was compared between the 275 women who\ntook the OC for the entire duration of follow-up, i.e., “al-\nways” users and the 179 women who took the OC discon-\ntinuously or for only part of the study period, i.e., “ever”\nusers. In the former group, 16 endometriotic cysts were\ndetected (6 %; 95 % CI 4 –9 %) compared with 48 in the\nlatter (27 %; 95 % CI 21 –34 %). The pooled OR was 0.21\n(95 % CI 0.11 –0.4). In other words, regular OC use begin-\nning immediately after surgery was associated with only\none-fifth of the risk of cyst recurrence observed in women\nwho have used OC for short periods of time. Finally, when\n182 Curr Obstet Gynecol Rep (2013) 2:178 –185\n\ncomparing ever users of OC with never users of OC, the\noverall OR of endometrioma recurrence after surgery was\n0.39, meaning that even irregular OC use was associated\nwith a 60 % reduction in risk compared with no OC use.\nThe protection against recurrence of endometrioma has\nbeen observed among patients receiving OC continuously,\ntherefore experiencing amenorrhea, as well as those with\nhypomenorrhea induced by cyclical OC use. The observation\nthat a comparable therapeutic effect is achieved independently\nof the presence or absence of OC-induced menstruations sug-\ngests that reducing endometrial reflux through the fallopian\ntubes might not be the only therapeutic mechanism of OC in\npreventing endometrioma recurrence. Additional or alternative\nmechanisms of action may include: 1) ovulation inhibition per\nse may constitute a protective factor, because it prevents the\nformation of endometriomas from functional ovarian cysts;\nand 2). OC administration might improve the progesterone\nresistance associated with endometriosis.\nBased on the results of this s ystematic review and meta-\nanalysis, OC use after conservative surgery for ovarian endome-\ntriotic cysts appeared to decrease the risk of endometrioma\nrecurrence dramatically compared with no treatment, especially\nin women who used the contraceptive pill regularly and for\nprolonged periods of time. After first-line surgery for ovarian\nendometriomas, women should be informed of the high risk of\ncyst recurrence if no further treatment is undertaken and, when-\never childbearing is deferred, regular OC use until pregnancy is\ndesired should be strongly considered.\nMedical Treatment for the Primary Prevention\nof Endometriomas\nBased upon the strong protective effect of OC on both endome-\ntrioma recurrence and the development of functional cysts\n[55–57], OC use might be a strategy for endometrioma\nprevention. Unfortunately, epidemiological data are not available\nto support this approach. However, in a population at higher risk\nof developing endometriomas, such as first-degree relatives of\nwomen with endometriosis and endometriomas, the pri-\nmary prevention of ovarian endometriotic cysts might\nprove cost-effective.\nEpidemiological data were recently systematically reviewed\nregarding the relationship between OC exposure and risk of\nendometriosis [58], suggesting a reduction in risk of endome-\ntriosis in current OC users and a trend towards an increased\nrisk in past OC users. However, the interpretation of these\nfindings is difficult because the definitive confirmation or\nexclusion of endometriosis requires surgery, therefore, the\nexact point in time that endometriosis has occurred is not\nknown. In particular, it is probable that the observed increase\nof endometriosis risk among past OC users simply reflects a\ndelayed diagnosis due to the recurrence of symptoms\nsuppressed by pill use with its discontinuation. In this regard,\na study specifically designed to assess the risk of ovarian\nendometriomas among OC users and non-OC users in a subset\nof women at increased risk of developing this condition could\novercome this limitation, as the ultrasonographic diagnosis of\novarian endometrioma is highly reliable.\nConclusions\nA limitation of conservative surgical treatment of ovarian\nendometriotic cysts is a high recurrence rate. This recurrence\nrate only partially reflects the surgeon’s ability and the surgical\ntechnique because of the intrinsic biology of endometriomas. In\nother words, because the pathogenesis of endometriosis is very\nlikely to be multifactorial, including biochemical, endocrine, and\ninflammatory factors, surgerycannot simultaneously affect all\nthese biological variables and therefore, importantly, surgical\neradication of all visible endometriotic lesions does not eradicate\nTable 1 Results of studies comparing the rate of recurrence of ovarian endometriotic cysts in women undergoing excision of endometriomas\nfollowed by oral contraceptive use for ≥2 years versus no postoperative long-term medical treatment. Literature data, 2008 –2010\nAuthors, year Type of\nstudy\nNumber of\nparticipants\nPostoperative\ntherapeutic scheme\nMonths of\nfollow-up\nAnalysis of\ndrop outs\nRecurrence in OC\ngroup; n (%)\nRecurrence in no\nPLTT group; n (%)\nV ercellini et al.,\n2008 [51]\nCohort 277 Cyclic OC vs. no PLTT 28 Yes 9/ 102* (9) 26/ 46 (56)\nTakamura et al.,\n2009 [52]\nCohort 87 Cyclic OC vs. no PLTT 24 Yes 1/ 34* (3) 17/ 39 (44)\nSeracchioli\net al., 2010\n[54]\nRCT 239 Cyclic and continuous OC\nvs. no PLTT\n24 No 17/ 148 † (11) 20/ 69 (29)\nLee et al., 2010\n[53]\nCohort 362 GnRH-a followed by OC\nShort-term GnRH-a only\n35 Yes 6/ 139* (4) 54/ 187 (29)\nOC, oral contraceptive; PLTT, postoperative long-term treatment; RCT, randomised control trial; GnRHa, gonadotropin-releasing hormone analog\n*Only “always OC users ” are considered. †Cyclic and continuous OC users are considered together\nModified from: V ercellini et al. Acta Obstet Gynecol Scand 2013;92:8 –16\nCurr Obstet Gynecol Rep (2013) 2:178 –185 183\n\nthe disease. Another limitation of conservative surgical treatment\nof ovarian endometriotic cysts is the possible association with\nfollicle loss, which might diminish the fertility potential of\noperated women. As a consequence the therapeutic approach,\nespecially with regards to recurrent cysts, must be extremely\ncautious because, obviously, repeat surgery is more likely to\nincrease gonadal damage than a single procedure.\nSimilar to surgical treatment, hormonal therapy of endo-\nmetriosis, although it allows suppression of the activity of\nendometriotic implants, is not able to eradicate the disease.\nIndeed, until a drug with the ability to selectively destroy\nectopic endometrial cells and preserve the eutopic endome-\ntrium is available, which does not seem to be probable in the\nnear future, medical treatment of endometriosis necessarily\nwill continue to imply the survival of ectopic implants.\nAccordingly, reappearance of symptoms at drug discontinu-\nation is expected and must not be considered as a demon-\nstration of inefficacy of therapy.\nGiven the potential intrinsic limitations of both surgical and\nmedical treatment of endometriosis and the fact that endome-\ntriosis should be viewed as a chronic disease that requires a\nlifelong management, the adequate approach to the disease is\nto maximize the use of medical treatment and avoid repeated\nsurgical procedures [59]. In more practical terms, maximizing\nthe use of medical treatment means that hormones may be\nadministered for years, and therefore the first choice treatment\nis OCs, which are effective, safe, and well tolerated. At present,\nthe available evidence strongly support the fact that long-term\npostoperative OC use should be considered a real therapeutic\nadvance for patients operated for endometriomas.\nAdditional RCTs would be useful to determine the precise\nprotective effect of adjuvant OC use definitively. However,\ngiven the impressive effect consistently observed in all the\ncomparative studies considered, planning further trials including\na no-treatment group would pose major ethical problems. Future\nstudies designed to evaluate possible additional indications for\nOC treatment in the management of endometriomas are needed.\nOf particular interest would be the long term administration of\nOC in: 1) asymptomatic young women with ultrasonographic\ndiagnosis of small to medium-sized endometriomas, i.e., with a\nmaximal diameter≤5 cm, to determine whether cyst size may be\nreduced and surgical treatment postponed until pregnancy is\ndesired, thus minimizing the risk of recurrence, as long as\nultrasonographic follow-up assessments are performed regular-\nly during treatment, and 2) women without the diagnosis of\nendometrioma, who are at increased risk of developing an\nendometrioma due to family history or other factors, to evaluate\na possible role of OC in endometriotic cyst prevention.\nCompliance with Ethics Guidelines\nConflict of Interest Paolo V ercellini received travel/accommodations\nexpenses covered or reimbursed from ASRM.\nNicola Berlanda, Martina Morini, Dhouha Dridi, Lucrezia de Braud,\nand Benedetta Bracco declare that they have no conflict of interest.\nHuman and Animal Rights and Informed Consent This article\ndoes not contain any studies with human or animal subjects performed\nby any of the authors.\nReferences\nPapers of particular interest, published recently, have been\nhighlighted as:\n Of importance\n1. 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