{"paper_id":"861efed5-91ca-48f3-9e4a-2c5546d004a6","body_text":"Citation: Kim HG, Song YJ and Na YJ. Is Long-Term Dienogest Treatment Tolerable in Korea?. Austin J Obstet \nGynecol. 2019; 6(1): 1131.\nAustin J Obstet Gynecol - Volume 6 Issue 1 - 2019\nSubmit your Manuscript | www.austinpublishinggroup.com \nNam et al. © All rights are reserved\nAustin Journal of Obstetrics and Gynecology\nOpen Access\nAbstract\nAim: To evaluate the adverse events and tolerability of dienogest \nadministration over an 18-month period for a prevention of recurrent symptoms \nand lesions after surgery for endometriosis.\nMethods: Dienogest was administered to 150 patients with endometriosis \nfor over an 18-month period after surgery. The adverse event profile and patient \nsatisfaction regarding dienogest was determined through a questionnaire. We \nevaluated the adverse events of dienogest, including through laboratory tests, \nbody weight, and bleeding patterns. Post-operation measurements of pain were \napplied before surgery, postoperatively, before treatment with dienogest, and \nafter dienogest treatment. The body weight was measured during the first visit, \nand measurements were repeated every six months.\nResults: The median duration of treatment was 24 months, with the longest \nfollow-up duration being 60 months. Adverse events include headaches, breast \ndiscomfort, acne, constipation, hot flushes, weight gain, and mild depression. \nMore than 70% of the patients experienced amenorrhea. However, this was \nnot a reason for discontinuation. The vaginal bleeding pattern associated with \ndienogest was shown to be tolerable, and only three patients stopped taking it \nbecause of heavy menstrual bleeding resulting in anemia. Rather, the major \ncause of discontinuation was unwanted weight gain. \nConclusions: The data indicate that dienogest is well tolerated and has \na favorable safety profile for long-term use as a prophylaxis in an effort to \npost-operatively obviate the recurrence of ovarian endometrioma. Our results \nsuggest that not only atypical vaginal bleeding but also unwanted weight gain \nshould be regarded as significant reactions, however.\nKeywords: Dienogest; Endometriosis; Adverse Events; Vaginal Bleeding; \nWeight Gain\nResearch Article\nIs Long-Term Dienogest Treatment Tolerable in Korea?\nKim HG1,2, Song YJ1,2 and Na YJ1,2*\n1Department of Obstetrics and Gynecology, Pusan \nNational University Yangsan Hospital, Yangsan, South \nKorea\n2Research Institute for Convergence of Biomedical \nScience and Technology, Pusan National University, \nYangsan Hospital, South Korea\n*Corresponding author:  Yong Jin Na, Department of \nObstetrics and Gynecology, Pusan National University, \nYangsan Hospital, Yangsan, South Korea\nReceived: November 30, 2018; Accepted: January 10, \n2019; Published: January 17, 2019\nIntroduction \nEndometriosis is defined as the presence of endometrial glands \nand stroma outside the uterine cavity. The prevalence rate of \nendometriosis is approximately 5-10% of all women of reproductive \nage, it reduces the patient’s quality of life through the occurrence of \npain, including dysmenorrhea, dyspareunia, and lower back pain [1-\n3]. \nIt is known that the primary treatment of endometriosis is surgery. \nThe European Society of Human Reproduction and Embryology \n(ESHRE) guidelines state that surgical treatment is warranted for an \novarian endometrioma of larger than 3 cm, and that laparoscopic \nstripping of the cyst wall is considered the gold standard for treatment \n[4]. Because the surgical excision of lesions has shown to improve the \nlevel of pain and enhance fertility, ovarian cystectomy is preferable to \noophorectomy, and most women who undergo endometriosis are of \nchildbearing age. However, a pooled analysis of 23 studies estimated \nthe recurrence rates as 40% to 50% 5 years after the primary surgery \n[5]. \nMedical treatment for the relief of symptoms and the prevention \nof recurrence after surgery include Gonadotropin-Releasing \nHormone (GnRH) analogs, progestin, danazol, and estrogen/\nprogestin combinations. However, these treatments have adverse \neffects including impaired hepatic function associated with danazol, \nas well as a decrease in bone mineral density, which may be caused by \nGnRH analogs. Thus, their long-term use is limited [6,7]. \nDienogest (Visanne, Bayer HealthCare, Berlin, Germany) is a \nselective progestin that has been approved for treating endometriosis \nat a low oral dose of 2 mg/day. Dienogest has many beneficial \npharmacological uses, such as a potential progestogenic effect, \nmoderate suppression of estrogen, and low concern for increased \nandrogen and corticoid levels. Progestogenic effects lead to an effective \nreduction in endometrial lesions, and no significant androgenic, \nmineralocorticoid, or glucocorticoid activity. Dienogest has been \ndeveloped to reduce side effects, such as a decreasing estradiol (E2) \nconcentration, along with an elongation of the tolerable dose period \n[8-10]. \nRecent studies have reported that repeated surgeries for recurrent \nendometriomas mark a decrease in ovarian reserve and the success \nrate of in vitro fertilization [11,12]. \nDienogest is able to prevent the recurrence of endometriosis after \nsurgery for more than 15 months. However, most of the clinical data \nreflect follow-up durations of up to 6 months, and few data have \nbeen published beyond 12 months. To determine the tolerability of \nlong-term treatment using dienogest, we evaluated patients who had \n\nAustin J Obstet Gynecol 6(1): id1131 (2019)  - Page - 02\nNa YJ Austin Publishing Group\nSubmit your Manuscript | www.austinpublishinggroup.com\nundergone ovarian cystectomy for endometriosis. \nMethods \nData were collected retrospectively from a chart review of 150 \npatients treated with 2 mg of dienogest over an 18-month period \nafter a conservative surgery at Yangsan Hospital of Pusan National \nUniversity. The subjects included 150 patients, 103 of whom had \nundergone laparoscopic unilateral cystectomy, 35 had undergone \na laparoscopic bilateral cystectomy, and 12 had undergone a \nlaparoscopic unilateral adnexectomy. Oral administration of dienogest \nwas initiated on day 3 of the first menstruation following surgery. The \nprimary modality of the diagnosis was through imaging (magnetic \nresonance or transvaginal ultrasonography). The Institutional Review \nBoard of Pusan National University’s Yangsan Hospital approved \nthis study, although written informed consent was not obtained \nbecause the present study was based only on a retrospective review of \nmedical records. Transvaginal ultrasonography was used to measure \nthe largest diameter of an endometriotic cyst. These measurements \nwere repeated every 6 months after surgery. The serum cancer antigen \n125 (CA125), cancer antigen 19-9 (CA19-9), and estradiol (E2) and \nAnti-Mullerian Hormone (AMH) concentrations were determined \nat baseline before treatment, and were repeatedly measured every 6 \nmonths to assist in assessing the clinical states of the patients. \nThe adverse event profile and patient satisfaction regarding \ndienogest treatment was determined through a questionnaire. \nMenstrual pain was determined before surgery, after surgery, before \ndienogest treatment, and after dienogest treatment. The severity of \npain was measured on a 10-point visual analog scale (VAS; 0 mm, \nabsence of pain; 100 mm, unbearable pain) during the outpatient \nvisits. \nTransvaginal ultrasonography was conducted on the patients \nevery 6 months to assess the presence of endometrioma. Recurrent \nendometriosis was diagnosed when a round mass was identified with \na thick wall, having a diameter of 2 cm or more, regular margins, and \na homogenous low echogenic fluid content with scattered internal \nechoes. The patients were also evaluated according to the r-ASRM \nstage classification.\nAdverse events were defined as any unfavorable or unintended \nsigns or symptoms occurring with the use of dienogest. Serious \nadverse events were defined and documented according to the \ninternational standards.\nBody weight was measured (at minimum) during the initial visit, \nand then repeatedly measured every 6 months. Weight gain was \ndefined as an increase of over 1 kg.\nThe patients were instructed to record bleeding events daily on \na diary card to provide information on the mean number of days, \nnumber of episodes, and duration of episodes of bleeding. Uterine \nbleeding was defined as bleeding for more than 10 days.\nContinuous variables were analyzed using a paired t-test or \nStudent’s t-test. A Wilcoxon signed rank test was used to compare \nthe continuous variables if the data were not normally distributed. \nCategorical variables were presented as percentages and compared \nFigure 1: Changes in visual analog scale (VAS) score following dienogest \ntreatment for 18 months.\nFigure 2: Change in body weight for patients who received 2 mg of dienogest \nfor more than an 18-month period. \nCharacteristics Patients (n = 150)\nAge (yr) 39.4 ± 8.1\nBody mass index (kg/m2) 19.8 ± 2.5\nPrevious pregnancy 68 (45)\nPrevious surgery for endometriosis 12 (8)\nr-ASRM stage of endometriosis   \nStage I-II 39 (26)\nStage III-IV 111 (74)\nType of endometriosis\n Deep infiltrating 11 (7.3)\n Unilateral 115 (76.7)\n Bilateral 35 (23.3)\nPresence of Other diseases\n Leiomyoma 56 (37.3)\n Adenomyosis 28 (18.7)\n Ovarian cyst 19 (12.7)\n Paratubal cyst 11 (7.3)\nTable 1: Clinical characteristics.\nValues are presented as mean ± standard deviation or number (%).\n\nAustin J Obstet Gynecol 6(1): id1131 (2019)  - Page - 03\nNa YJ Austin Publishing Group\nSubmit your Manuscript | www.austinpublishinggroup.com\nusing a chi-square test. All statistical analyses were conducted using \nSPSS ver. 21.0 (IBM Co., Armonk, NY, USA), and p-values <0.05 \nwere considered to indicate a statistical significance.\nResults\nDemographic characteristics of the participants who received \n2 mg of dienogest are shown in Table 1. The average age of the \npatients was 39.4±8.1 years (range of 18-47 years in age), and the \nmedian duration of dienogest administration was 24 months (range \nof 18–60 months). All patients were diagnosed with endometriosis \nthrough a laparoscopy. A total of 111 patients (74%) were classified \nwith stage III (moderate) or higher endometriosis, and 39 (26%) with \nstage I-II. However, the pain and staging were not correlated. The \nmost common type of endometriosis was unilateral endometrioma \n(76.7%), followed by bilateral endometrioma (23.3%).\nSerum cancer antigen 125 (CA 125), cancer antigen 19-9 (CA 19-\n9), and estradiol (E2) were determined at baseline prior to treatment, \nand were repeatedly measured every 6 months to assist in assessing \nthe clinical state (Table 2). The mean serum cancer antigen CA 125, \nCA 19-9, and E2 levels before surgery were measured as 90.65±18.99 \nU/mL, 63.20±16.64 U/mL, and 231.82±98.13 pmol/L, respectively. \nDuring treatment of dienogest, the CA 125, CA 19-9, and E2 levels \ngradually decreased to 18.7±13.52 U/mL, 18.6±11.29 U/mL, and \n27.56±53.29 pmol/L after 18 months.\nThe effects of dienogest on endometriosis-associated pain were \ndetermined by measuring pain-using VAS before surgery, after \nsurgery, and after the dienogest treatment. The pain was significantly \nreduced after 18 months of medication as compared to pre-treatment \n(40.8±28.6 mm versus 7.3±14.6 mm, p<0.01) (Figure 1). Eleven \npatients showed no changes in their VAS scores after dienogest \ntreatment during the 18-month period, whereas 139 patients showed \ndecreased VAS scores. We observed that 92.7% of the patients \ndemonstrated an improvement in terms of pain after surgery and \nlong-term dienogest administration.\nBecause the goal of the study was to determine the effects of \ndienogest treatment for an 18-month period or longer, we analyzed \nthe adverse events 18 months after dienogest administration. The most \ncommon adverse drug reaction was weight gain (24.0%), followed \nby headaches (6.0%), breast discomfort (5.3%), depression (2.0%), \nacne (1.3%), nausea (5.3%), and abdominal pain (3.3%) (Table 3). All \nadverse events except weight gain were generally mild to moderate, \nand only two women (1.3%) reported bleeding events as the primary \nreason for their discontinuation. However, the rate of discontinuation \nof treatment from weight gain was very high. The mean value of \nweight change during dienogest treatment was 2.8 kg, but 36 patients \nshowed weight gain of over 4 kg during the 18-month period. Among \nthe 36 patients, 12 women (8%) discontinued dienogest treatment \non their own despite its effectiveness and an adequate explanation. \nA body weight analysis includes patients who provided both the \nbaseline and highest end of the treatment data (Figure 2). \nDiscussion\nBecause of an increased post-operative recurrence rate of \nendometrium and its related complications, secondary prevention is \nnecessary to enhance the quality of life and fertility of those suffering \nfrom chronic endometriosis [13-16]. In the current retrospective \nanalysis, we analyzed the efficacy and safety of long-term oral \ndienogest therapy for 150 patients under treatment in a single \ninstitution. In addition, we found the following effects of dienogest \nafter 18 months or more of use. \nOur study showed that, in patients who had taken dienogest \ntreatment for at least 18 months after laparoscopic endometriosis \nsurgery, the pain was decreased compared to the preoperative status, \nand the pain was relieved gradually with the use of dienogest. Our \ndata indicate that dienogest was helpful in relieving endometriosis-\nassociated pain based on a VAS. Laboratory findings also suggested \nnoticeable therapeutic effects. CA125 and CA19-9 were slightly \ndecreased after surgery, and gradually decreased with dienogest \ntreatment during 6 months of interval follow-ups. Elevated serum CA \n125 and CA 19-9 concentrations were significantly associated with \nendometriosis, and CA 19-9 is increased further in the more advanced \nstages of disease. The decrease in CA125 and CA19-9 suggest that \ndienogest treatment is effective in preventing the recurrence of \nendometriosis. Though the mechanism is not evident, dienogest \ntreatment is suggested to inhibit extracellular signal-regulated kinase \npathways, suppress the mammalian target of rapamycin, induce \nautophagy, and accelerate the apoptosis of endometriotic cells [17]. \nIt is also possible that dienogest creates a high progesterone receptor \nratio, and therefore enhances the responsiveness to progestin \nBlood test Pre-treatment Post-treatment Post-treatment Post-treatment P-value\n6 months 12 months 18 months\nCA125 (U/mL) 90.65±18.99 32.7±12.42 27.3±15.42 18.7±13.52 0.042\nCA19-9 (U/mL) 63.20±16.64 28.7±17.32 21.3±9.26 18.6±11.29 0.025\nE2 (pmol/L) 231.82±98.13 89.83±28.17 56.82±30.81 27.56±53.29 0.019\nTable 2: Laboratory parameters in 2 mg dienogest administered group: categorized based on treatment period.\nValue are presented as mean ± SE.\nCA125, cancer antigen 125; CA19-9, cancer antigen 19-9; E2, estradiol.\nAdverse drug reactions No (%) patients (n = 150)\nHeadache 9 (6.0%)\nBreast discomfort 8 (5.3%)\nDepressed mood 3 (2.0%)\nAcne 2 (1.3%)\nNausea 8 (5.3%)\nWeight gain 36 (24.0%)\nAbdominal pain 5 (3.3%)\nTable 3: Adverse drug reactions for patients who received 2 mg of dienogest for \nmore than an 18-month period.\nNote: Mean treatment duration: 21 months. Values are presented as number \n(%) of patients.\n\nAustin J Obstet Gynecol 6(1): id1131 (2019)  - Page - 04\nNa YJ Austin Publishing Group\nSubmit your Manuscript | www.austinpublishinggroup.com\ntreatment in endometriotic tissue [18].\nThe adverse effects were mild to moderate in intensity, and were \nassociated with low discontinuation rates. The most common adverse \neffects were atypical genital bleeding. It is known that the cause of \natypical genital bleeding was a breakthrough of pseudodecidualized \nendometrium [19]. The initial increase in bleeding with dienogest \ntreatment was followed by a progressive reduction during the \ncontinued treatment, accompanied by an increase in the amenorrhea \nrate. These observations suggest that the amount of atypical genital \nbleeding may depend on the space of the endometrium or the \nvolume of the pseudodecidua. Thus, we can conclude that the \npatients in the dienogest treatment group showed irregular bleeding, \nbut they all experienced only mild symptoms and none developed \nanemia. Furthermore, atypical genital bleeding rarely resulted in a \ndiscontinuation of treatment. In our cases, only two patients stopped \ntreatment. In addition, headaches (6.0%), breast discomfort (8.7%), \ndepression (2.0%), acne (4.7%), nausea (5.3%), weight gain (12.0%), \nand abdominal pain (3.3%) were also noted, but the symptoms were \nnegligible. Weight gain turned out to be a common adverse effect \nof progestins [20-23]. The mean value of the weight change during \ndienogest treatment was 2.8 kg, but 36 of the patients showed a weight \ngain of over 4 kg during the 18-month period. Among the 36 patients, \n12 women discontinued Progestin treatment despite the advantages \nof the treatment being mentioned again. Concern regarding weight \ngain in Korean women seems particularly high.\nIn other studies, the recurrence rate of ovarian endometriotic \ncysts was reported to be 25% for patients who underwent an \noperation within a 24-month period. The rate increases to 40–50% \nafter 36 months post-operation [24]. Patients who received GnRHa \nas a post-operative treatment showed a 5.3% recurrence within 24 \nmonths [25]. In contrast, others have reported that GnRHa has no \neffect on the recurrence rate [26,27]. In contrast, a previous study \nwith a smaller pool reported the effectiveness of administering 2 mg \nof dienogest for a 13-month period after an operation, suggesting \nits potential effectiveness as a treatment for endometriosis [28,29]. \nIn our study, the recurrence rate after dienogest therapy was merely \n4.5%. Among the group studied, 89.7% of the patients who were given \ndienogest continuously for 18.0±7.1 months described no complaints \nof any intolerable side effects, whereas 10.3% patients stopped at \n2.4±1.0 months. The cause of discontinuation was weight gain for all \ncases, and other adverse effects were moderate.\nThe serum E2 levels decreased steadily until reaching lower than \n60 pg/ml at 18 months. However, the E2 range was relatively broad, \nand reached approximately 280 pg/ml in certain cases. These elevated \nE2 levels were regarded as a result of follicle growth without ovulation \nunder dienogest treatment. In this regard, dienogest appears to be a \ngood candidate for the long-term treatment of endometriosis because \nit does not reduce the serum estradiol to the postmenopausal level, as \ndoes GnRH agonist. Long-term use of dienogest could be beneficial \nfor patients who want to preserve their fertility. Dienogest prohibits \nan exacerbation of endometriosis, and may preserve the ovarian \nfunction. Therefore, dienogest can be considered effective for not only \nshort-term but also long-term treatment in patients suffering from \ninfertility. In accordance with our findings, the guidelines from the \nWorld Endometriosis Society recommends dienogest as an empirical \ntreatment option for patients without a laparoscopic diagnosis, and as \na suitable post-endometriosis surgery treatment [4].\nOwing to its retrospective nature, the present study has several \nlimitations. A large amount of data on certain important clinical \noutcomes in a few of the patients was missing. Because the data were \nsolely based on a review of medical records written by clinicians, it \nwas possible that the adverse events, such as uterine bleeding, could \nhave been underestimated. In spite of these limitations, the present \nstudy shows that dienogest administration over an 18-month period \nis highly effective in preventing the recurrence of endometriosis after \nsurgery, weakening endometriosis-associated pain, and reducing the \nsize of recurrent endometriomas. Further prospective studies will \nbe needed to evaluate the effects of long-term dienogest medication \non the bone quality, the future risk of osteoporosis, and the ultimate \nreproductive outcomes in women with endometriosis.\nAcknowledgements\nThis work was supported by a 2-year research grant from Pusan \nNational University.\nReferences\n1. D’Hooghe TM, Bambra CS, Raeymaekers BM, Koninckx PR. Increased \nprevalence and recurrence of retrograde menstruation in baboons with \nspontaneous endometriosis. Hum Reprod. 1996; 11: 2022-2025.\n2. Propst AM, Laufer MR. Endometriosis in adolescents. Incidence, diagnosis \nand treatment. J Reprod Med. 1999; 44: 751-758.\n3. 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Dimitrijevic D, Vasiljevic M, Anicic R, Brankovic S, Ristic A, Devic A, et al. \nRecurrence rate of ovarian endometriosis in patients treated with laparoscopic \nsurgery and postoperative suppressive therapy. Clin Exp Obstet Gynecol. \n2015; 42: 339-343.\n26. Fedele L, Bianchi S, Zanconato G, Tozzi L, Raffaelli R. Gonadotropin-\nreleasing hormone agonist treatment for endometriosis of the rectovaginal \nseptum. Am J Obstet Gynecol. 2000; 183: 1462-1467.\n27. Zhong YJ, Zhang W, Zhang WT, Cheng J, Lu QY, Zeng KK, et al. [Efficacy \nand safety of GnRH-a combine with laparoscope conservative surgery in the \ntreatment of the moderate or severe endometriosis]. Zhonghua Fu Chan Ke \nZa Zhi. 2013; 48: 180-182.\n28. Lee SR, Yi KW, Song JY, Seo SK, Lee DY, Cho S, et al. Efficacy and Safety \nof Long-Term Use of Dienogest in Women With Ovarian Endometrioma. \nReprod Sci. 2018; 25: 341-346.\n29. Yamanaka A, Hada T, Matsumoto T, Kanno K, Shirane A, Yanai S, et al. \nEffect of dienogest on pain and ovarian endometrioma occurrence after \nlaparoscopic resection of uterosacral ligaments with deep infiltrating \nendometriosis. Eur J Obstet Gynecol Reprod Biol. 2017; 216: 51-55.\nCitation: Kim HG, Song YJ and Na YJ. Is Long-Term Dienogest Treatment Tolerable in Korea?. Austin J Obstet \nGynecol. 2019; 6(1): 1131.\nAustin J Obstet Gynecol - Volume 6 Issue 1 - 2019\nSubmit your Manuscript | www.austinpublishinggroup.com \nNam et al. © All rights are reserved","source_license":"CC0","license_restricted":false}