{"paper_id":"1e4beea7-276d-4b36-ac0f-b9e9880ef2fa","body_text":"www.ogscience.org 111\nOriginal Article\nObstet Gynecol Sci 2018;61(1):111-117\nhttps://doi.org/10.5468/ogs.2018.61.1.111\npISSN 2287-8572 · eISSN 2287-8580\nIntroduction\nThe pathology called “endometriosis is defined as presence \nof endometrial tissue (gland and stroma) outside the uterus”. \nIt is the leading cause of disability in women of reproductive \nage, and is also said to impair the quality of life [1,2]. Endo -\nmetriosis is estimated to affect 10% women in the reproduc-\ntive age group [3]. Ovarian endometriosis is one of the most \nfrequent manifestation of the disease, and previous studies \nindicate that 55% of women with ovarian endometriosis have \nendometriomas [4].\n \nEuropean Society of Human Reproduction \nand Embryology (ESHRE) guidelines state that surgical treat -\nClinical experience of long-term use of dienogest after \nsurgery for ovarian endometrioma\nAnjali Chandra\n1,2,*\n, A Mi Rho\n1,*\n, Kyungah Jeong\n1\n, Taeri Yu\n1\n, Ji Hyun Jeon\n1\n, So Yun Park\n1\n, Sa Ra Lee\n1\n,  \nHye-Sung Moon\n1\n, Hye Won Chung\n1\nDepartment of Obstetrics and Gynecology, \n1\nEwha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea, \n2\nDeen \nDayal Upadhyay Hospital, Delhi, India\nObjective \nEndometriosis is a common and recurring gynecologic disease which have afflicting females of reproductive age. We \ninvestigated the efficacy of long-term, post-operative use of dienogest for ovarian endometrioma.\nMethods\nWe studied 203 patients who had undergone laparoscopic or robotic surgery for ovarian endometrioma, and were \nadministrated dienogest 2 mg/day beginning in July of 2013, and continuing. We evaluated side effects of dienogest \nand ultrasonography was performed every 6 months to detect potential recurrence of endometrioma (2 cm) in these \npost-surgical patients.\nResults\nThe follow-up observation periods were 30.2±20.9 months from surgery. The mean age was 34.1±7.2 years old. The \nmean diameter of pre-operative endometrioma was 5.6±3.0 cm\n2\n. One hundred eighty-two (89.7%) women received \ndienogest continuously for 12.0±7.1 months. Of the subjects, 21 (10.3%) patients discontinued dienogest at 2.4±1.0 \nmonths. The most common side effect when dienogest was discontinued was abnormal uterine bleeding. The \noccurrence rate of vaginal bleeding was 15.8%, a number which did not differ significantly in patients with/without \npost-operative gonadotropin releasing hormone agonist administration. The other side effects were gastrointestinal \ntrouble including constipation, acne, headache, depression, hot flush, weight gain, and edema. However, no serious \nadverse events or side effects were documented and recurrent endometriomas were diagnosed in 3 patients (1.5%).\nConclusion\nThe data indicates that dienogest was both tolerable and safe for long-term use as prophylaxis in an effort to obviate \nthe recurrence of ovarian endometrioma post-operatively, as well as potential need for surgical re-intervention. \nKeywords: Dienogest; Endometriosis; Recurrence\nReceived: 2017.04.12.    Revised: 2017.08.04.   Accepted: 2017.08.10.\nCorresponding author: Kyungah Jeong\nDepartment of Obstetrics and Gynecology, Ewha Womans University \nMokdong Hospital, Ewha Womans University School of Medicine, 1071 \nAnyangcheon-ro, Y angcheon-gu, Seoul 07985, Korea \nE-mail: ogjeong@ewha.ac.kr\nhttp://orcid.org/0000-0002-9673-1152\n*These authors contributed equally to this work.\nArticles published in Obstet Gynecol Sci are open-access, distributed under the terms of \nthe Creative Commons Attribution Non-Commercial License (http://creativecommons.\norg/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, \nand reproduction in any medium, provided the original work is properly cited.\nCopyright © 2018 Korean Society of Obstetrics and Gynecology \n\nwww.ogscience.org112\nVol. 61, No. 1, 2018\nment would be warranted for ovarian endometriomas >3 cm. \nLaparoscopic stripping of the cyst wall is considered as the \n“Gold Standard” treatment of endometrioma as that proce-\ndure has been associated with reduced relapse rate, dimin -\nished signs and symptoms, improved intimate relations and \nalso, improves fertility by enhancing chances of spontaneous \nconception [5].\nHowever, recurrent endometrioma is a common dilemma \nand the condition can become a chronic problem. A pooled \nanalysis of 23 studies estimated recurrence rates of 21.5% at \n2 years and 40.0% to 50.0% at 5 years after primary surgery \n[6]. ESHRE does not offer specific guidelines for management \nof “recurrence of endometrioma”. In view of the foregoing, \nit is, in some cases, difficult to make a determination as to \nwhether conservative, office-based treatment modalities or \nsurgical re-intervention would represent the most informed, \npractical and best treatment option [7,8]. Consideration of \nsurgery must include consideration of potential, post-surgical \ndamage of ovarian function associated with diminished ovar-\nian reserve (DOR) has also been reported. In a pooled analysis \nof 237 patients, significant decrease in serum anti-Müllerian \nhormone (AMH) concentration was appreciated after an \novarian cystectomy, although antral follicle count (AFC) is not \nsignificantly affected after primary surgery (laparoscopic strip-\nping of endometrioma) [9]. Recent studies report that there is \nmarked decrease in ovarian reserve (evaluated by AFC) after a \nsurgery for recurrent endometrioma [10]. It is also concluded \nthat there is decrease in implantation rate, pregnancy rate \nand live birth rate in women with DOR caused by previous \ncystectomy for endometrioma. The success rate of in vitro fer-\ntilization (IVF) is decreased in such cases [11].\nRepeated surgery for recurrent endometriomas is associated \nwith evidence of a higher loss of ovarian tissue and is more \nharmful to the ovarian reserve evaluated by AFC and ovarian \nvolume, if compared with endometriomas operated for the \nfirst time [12]. Surgical re-intervention should be considered \nonly after more conservative therapies have been implement-\ned, and then shown to be ineffective, or the cyst formation \nis expanding so rapidly that there is suspected malignancy. \nBefore the second surgery for recurrent endometrioma is rec-\nommended, the patient should be informed about the poten-\ntial risk of ovarian failure. In cases of persistent infertility, IVF \nshould be considered after primary surgery [12].\nDue to increased incidence of recurrent endometrioma \npostoperatively and other surgery related complications, it is \nnecessary to consider the strategy for prophylaxis, or preven-\ntion. According to ESHRE revised guidelines in 2014, it has \nbeen recommended that all clinicians prescribe, to their post-\noperative patients, hormone-based contraceptives within \nthe 6-month period following surgery, in an effort to obviate \nrecurrence of the signs and symptoms of recurrent endome-\ntrioma [13].\nAlthough dienogest (2 mg once daily), a fourth-generation \nprogestin, has been implemented and thought to be useful \nby clinical trial for its long-term use (up to 65 weeks) in the \ntreatment of endometriosis [14,15], there is still lack support-\nive evidence to approve the safety, efficacy, higher compliance \nand lower withdrawal rate for long-term use of dienogest.\nTherefore, the present study was conducted to investigate \nthe clinical experience of long-term use of dienogest after \nsurgery for ovarian endometrioma.\nMaterials and methods\nThis study was conducted retrospectively on 203 patients who \nunderwent laparoscopic or robotic surgery for ovarian endo-\nmetrioma and subsequent treatment with dienogest (2 mg/\nday) at the Department of Obstetrics and Gynecology, Ewha \nWomans University Mokdong Hospital. The surgeries were \nperformed by 4 experienced gynecologic surgeons. The en -\nrolled study population had been prescribed dienogest from \nJuly 2013 through February 2016.\nAll patients were reproductive-aged women with regular \nmenstruation and did not want to get pregnant promptly af-\nter surgery. The size of the ovarian endometriomas were var-\nied, and when there were multiple ovarian endometriomas, \nthe mean diameter was measured with the largest and total \ndiameter of cysts by ultrasonography. All ovarian endometrio-\nmas seen during surgery were removed and combined pelvic \nadhesions were dissected. The stage of endometriosis was \ndefined by revised American Society for Reproduction Medi -\ncine (rASRM) classification during operation and the diagnosis \nwas confirmed by final histopathology. The patients who \nwere tolerable for gonadotropin releasing hormone (GnRH) \nagonist were injected it monthly for the time as possible up to \n6 months before administration of dienogest.\nBaseline characteristics of patients were analyzed and \nthe patients prescribed dienogest (2 mg/day) were seen tri-\nmonthly thereafter, to evaluate for possible side effects. Ad -\n\nwww.ogscience.org 113\nAnjali Chandra, et al. Long-term use of dienogest after surgery\nverse events were investigated at all visits at the discretion of \nher doctor during and after treatment of dienogest.\nClinical characteristics of patients were compared be -\ntween continued dienogest group and discontinued dieno -\ngest group. The long-term use was defined treatment for 6 \nmonths and more, otherwise, the discontinued group was \ndiscriminated a group that stopped before 6 months of start-\ning medication.\nTransvaginal or transrectal ultrasound obtained every 6 \nmonths, to detect recurrence of endometrioma (≥2 cm). The \nvisualization of round-shaped homogeneous hypoechoic cyst \nof low-level echoes within the ovary was defined as charac -\nteristic ultrasonographic finding of endometrioma.\nStatistical analysis was performed using IBM SPSS Statistics \nversion 20 (SPSS Japan Inc., Tokyo, Japan). A Student’s t-test \nand an χ\n2\n test were used and 2-tailed P-values of <0.05 were \nconsidered to be significant.\nThis study was approved by the Institutional Review Board \nof Ewha Womans University Mokdong Hospital.\nResults\nThe follow-up observation periods were 30.2±20.9 months \nfrom surgery for ovarian endometrioma. The mean age was \n34.1±7.2 years old (range, 18 to 53 years) and body mass in-\ndex was 20.8±3.0 kg/m\n2\n. One sixty-one (79.3%) of patients \nwere nulliparous women. The mean diameter of pre-operative \nendometrioma was 5.6±3.0 cm\n2\n. Before surgery, serum cancer \nantigen (CA) 125, CA 19-9, and AMH levels were measured \n113.4±428.6 U/mL, 44.1±116.3 U/mL, and 4.4±3.4 ng/mL, \nrespectively. Sixty-nine point five percent of patients had uni-\nlocular type of endometrioma and 30.5% were multilocular \novarian cysts. Fifty-three point seven percent were unilateral \nendometrioma and 46.3% of patients had bilateral cysts. Sixty-\nnine percent of patients had documented presence of deep \ninfiltrating endometriosis (DIE) according operation finding.\nOf the total, 182 (89.7%) of the women received dienogest \ncontinuously for 12.0±7.1 months (range, 6 to 35 months) \nand 21 (10.3%) patients stopped at 2.4±1.0 months (range, \n1 to 4 months). Clinical characteristics of patients were then \ncompared between continued group and discontinued group \n(Table 1) and the following was noted.\nTable 1. Clinical characteristics of patients according to continuation of dienogest\nCharacteristics Continuous use (n=182) Discontinuation (n=21) P-value\nAge (yr) 33.8±7.1 36.9±8.1 0.100\nBMI (kg/m\n2\n) 20.7±2.9 21.4±4.0 0.406\nPre-operative blood test\nCA 125 (U/mL) 120.1±451.3 52.8±37.3 0.075\nCA 19-9 (U/mL) 46.4±122.7 23.9±12.2 0.035\nAMH (ng/mL) 4.5±3.4 3.6±3.2 0.484\nDiameter of endometrioma (cm) 5.6±3.0 5.6±2.8 0.953\nType of endometrioma 0.769\nUnilocular 127 (62.6) 14 (6.9)\nMultilocular 55 (27.1) 7 (3.4)\nLaterality of endometrioma 0.029\nUnilateral 93 (45.8) 16 (7.9)\nBilateral 89 (43.8) 5 (2.5)\nPresence of DIE 0.450\nAbsent 58 (28.6) 5 (2.4)\nPresent 124 (61.1) 16 (7.9)\nPost-operative GnRH agonist (mon) 3.7±2.5 2.8±2.7 0.170\nValues are presented as mean±standard deviation or number (%).\nBMI, body mass index; CA, cancer antigen; AMH, anti-Müllerian hormone; DIE, deep infiltrating endometriosis; GnRH, gonadotropin releasing \nhormone.\n\nwww.ogscience.org114\nVol. 61, No. 1, 2018\nTable 3. Three cases diagnosed as recurrence of endometrioma\nCases 1 2 3\nSonographic findings of recurrent endometrioma (side/mean diameter, cm) Right/2.1 Left/2.0 Left/3.4\nAge (yr) 34 33 30\nMethod of surgery LOC LOC LOC\nDuration of dienogest (mon) 18 6 9\nPeriod between recurrence and last dienogest treatment (mon) 6 6 0\nSide effects of dienogest Depression Weight gain None\nPost-operative GnRH agonist (mon) 3 6 6\nPre-operative blood test\nCA 125 (U/mL) 5,489  29.6 43.7\nCA 19-9 (U/mL) 945.3 17.7 41\nAMH (ng/mL) 3.88 7.48 5.7\nDiameter of the previous endometrioma (cm) 14.0 7.5 9.1\nType of endometriomas Multilocular Multilocular Multilocular\nLaterality of endometrioma Bilateral Bilateral Bilateral\nPresence of DIE Present Present Present\nStage of rASRM classification IV IV IV\nLOC, laparoscopic ovarian cystectomy; GnRH, gonadotropin releasing hormone; CA, cancer antigen; AMH, anti-Müllerian hormone; DIE, deep \ninfiltrating endometriosis; rASRM, revised American Society for Reproduction Medicine.\nIn continued dienogest group, the serum CA 19-9 level \nwas significantly higher and the discontinuation rate was \nsignificantly lower in patients operated for bilateral endome-\ntriomas. The most common side effect, following discontinu-\nation, was abnormal uterine bleeding. The occurrence rate \nof vaginal bleeding was 15.8%, which did not differ signifi -\ncantly in patients with/without post-operative GnRH agonist \nadministration. One hundred forty-seven patients (72.4%) \nwere injected GnRH agonists for 3.6±2.5 months before di -\nenogest medication.\nThe other reported side effects included gastrointestinal \ntrouble, constipation, depression, weight gain, edema, hot \nflashes, headache, and acne (Table 2). However, no serious \nside effects were documented.\nThe follow-up periods between recurrence and last dieno -\ngest treatment were 5.7±7.4 months. Three patients (1.5%) \nwere diagnosed with recurrence of endometrioma. These pa-\ntients had previously undergone surgeries which included lap-\naroscopic ovarian cystectomies for bilateral and multilocular \nendometriomas with DIE relevant to stage IV by rASRM clas-\nsification (Table 3). For all these patients, repeated surgery has \nnot been performed. A couple of recurrent endometriomas \ndecreased after dienogest re-administration for 6 months. The \nthird patient has been treated for infertility to get pregnant \ninstead of re-operation or medication of dienogest.\nDiscussion\nDue to increased post-operative recurrence rate of endome -\ntrioma and its related complications, a plan for prophylaxis \nwhich is to say, secondary prevention, is necessary to improve \nquality of life and enhance fertility of those suffering from \nchronic endometriosis. Usually, surgical re-intervention for \nTable 2. Side effects of dienogest treatment\nSide effects Occurrence rate\nUterine bleeding 32 (15.8)\nGI trouble/constipation 6 (3.0)\nDepression 6 (3.0)\nWeight gain/edema 5 (2.5)\nHot flashes 5 (2.5)\nHeadache 4 (2.0)\nAcne 1 (0.5)\nValues are presented as number (%).\nGI, gastrointestinal.\n\nwww.ogscience.org 115\nAnjali Chandra, et al. Long-term use of dienogest after surgery\nrecurrent endometrioma serves to produce greater loss of \novarian tissue and markedly decreased ovarian reserve [12]. \nTherefore, the risk of infertility increases and long-term medi-\ncal therapy is the best option for prevention of recurrence.\nAlthough several hormonal therapies are available, no con-\nsensus has been established as to which medication is the \nbest option for long-term prevention of recurrence. Though \noral contraceptive pills (OCPs) widely used is associated with \nseveral side effects, resistance to long-term therapy and has \nhigh rate of recurrence (55%) after discontinuation [16]. Da-\nnazol is not preferred as it causes masculinizing side effects \nincluding weight gain, edema, acne, vaginal dryness, hot \nflashes, hirsutism, liver toxicity, and breast atrophy. GnRH ago-\nnists are frequently used by many clinicians but are associated \nwith accelerated loss of bone mineral density (BMD) causing \nosteoporosis. In absence of add back therapy their use is thus \nlimited up to 6 months [17]. It also causes hot flashes and \nvaginal dryness, and these adverse symptoms are sometimes \nfelt to be intolerable by those so afflicted. A number of pro -\ngestins offer long-term efficacy but cause weight gain and \nandrogenic effect at high doses [18].\nTherefore, we need a medication that has minimal side \neffects, higher compliance and can be used as long-term \ntherapy. One might consider dienogest with its tolerable pro-\nfile, higher rate of patient compliance, low problematic with-\ndrawal rate and safe for long-term use, it was chosen for the \npresent study [17]. Strowitzki et al. [19] showed the results \nthat dienogest can be safely used over a period extending up \nto 65 weeks.\nIn the present study, we found that rate of recurrence with \ndienogest therapy was only 1.5%. Our findings are compa -\nrable to the study of Ouchi et al. [13] who reported that no \nrecurrence was seen in continual dienogest group whereas \n25% recurrence was noted in GnRH group and 55.5% after \ndiscontinuation of OCP .\nOur 3 patients with recurrence were in young age less than \n35 years. Ouchi et al. [13] reported similar results, suggesting \nthat the disease is more aggressive in young patients and with \na higher rate of recurrence [20]. This perhaps explains why \nyouth is considered an actual a risk factor, and greater effort \nshould be made to obviate recurrence of the pathology in \nyouthful patients after surgery.\nOf the group studied, 89.7% of the women received dieno-\ngest continuously for 12.0±7.1 months without complaint of \nany intolerable symptoms, while 10.3% patients stopped at \n2.4±1.0 months. Hence patient’s acceptance for dienogest \ntherapy was fairly good. The medical indication for discon -\ntinuation can be explained by irregular bleeding (15.8%) and \nchange of planning for conception. Unexpected irregular \nbleeding was common and troublesome side effect. Consti -\npation (3.0%), depression (3.0%), weight gain (2.5%), hot \nflashes (2.5%), headache (2.0%), and acne (0.5%) were also \nnoted but were minimal and did not adversely affect the qual-\nity of life. Takaesu et al. [17] reported that side effects were \nnotably seen in GnRH agonist group as compared to dieno -\ngest group. In the dienogest group 100% of the patients had \nirregular bleeding but all were mild (i.e., spotting), and none \ndeveloped anemia. Marked side-effects were observed in the \ngoserelin group, when comparted to the dienogest group [19].\nWe observed that in continued dienogest group, serum \nCA 19-9 level was significantly higher and discontinuation \nrate was significantly lower in patients operated for bilateral \nendometriomas. Endometriosis is significantly associated with \nelevated serum CA 125 and CA 19-9 concentrations, and CA \n19-9 is increased further in the more advanced stages of dis-\nease. Serum CA 125 and CA 19-9 may represent useful bio-\nmarkers for the noninvasive diagnosis of endometriosis [21-\n23]. This relation could be explained that the patients with \nincreased risk of recurrence might accept uncritically the post-\noperative medical treatment for prevention [24,25].\nIt was also noted that all recurrent endometriomas were \nbilateral, multilocular, associated with DIE and stage IV by \nrASRM classification.\nThe major strength of this study is that follow-up observa -\ntion period extended over 30.2±20.9 months from surgery till \nrecurrence of ovarian endometrioma. As other previous stud-\nies, our study has some limitations. This study was based on \nthe results of small numbers in a single-center. The data from \nretrospective chart review lacks description of some clinical \noutcomes and the nature and duration of reported side ef -\nfects might have been under-estimated. The change of endo-\nmetriosis-associated pain using a visual analog scale and BMD \ncould not be compared because the results were inadequate, \ndepending on clinicians although long-term treatment with \ndienogest which seems effective in reducing pain and possible \nbone loss [26].\nIn the present study, we did not divide laparoscopic or ro -\nbotic surgery. The meticulous surgical technique could provide \ncomplete destruction of endometriotic lesions to decrease the \nrecurrence rate as well as preserving the remained ovarian re-\n\nwww.ogscience.org116\nVol. 61, No. 1, 2018\nserve.\nWe suggest the clinical experience of post-operative long-\nterm use of dienogest, which was safe and tolerable preven-\ntion to avoid reoperation for recurrence of ovarian endome -\ntrioma. Therefore, therapeutic application of dienogest could \nbe extended for a longer time until the patient desires to \nbecome pregnant. Further studies are warranted to establish \nup to what age long-term dienogest therapy can be given in \npatients effectively.\nConflict of Interest\nNo potential conflict of interest relevant to this article was re-\nported.\nReferences\n  1.  Rogers PA, D'Hooghe TM, Fazleabas A, Gargett CE, Giu-\ndice LC, Montgomery GW, et al. Priorities for endome -\ntriosis research: recommendations from an international \nconsensus workshop. Reprod Sci 2009;16:335-46.\n  2.  Allen C, Hopewell S, Prentice A. Non-steroidal anti-\ninflammatory drugs for pain in women with endome -\ntriosis. Cochrane Database Syst Rev 2005:CD004753.\n  3.  D'Hooghe TM. Endometriosis. In: Berek JS, Novak E. \nBerek & Novak's gynaecology. 15th ed. Philadelphia (PA): \nLippincott Williams & Wilkins; 2012. p.505-56.\n  4.  Liu X, Yuan L, Shen F, Zhu Z, Jiang H, Guo SW. 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