- Email: [email protected]
The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence
IJG-08718; No of Pages 4 International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence Mi-La Kim a,1, Yeon Jean Cho b,1, Mi Kyoung Kim a, Yong Wook Jung a, Bo Seong Yun a, Seok Ju Seong a,⁎ a b
Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, South Korea Department of Obstetrics and Gynecology, Dong-A University Medical Center, College of Medicine, Dong-A University, Busan, South Korea
a r t i c l e
i n f o
Article history: Received 19 November 2015 Received in revised form 2 March 2016 Accepted 23 May 2016 Keywords: Conservative surgery Endometriosis Levonorgestrel-releasing intrauterine system Ovarian endometrioma Recurrence rate
a b s t r a c t Objective: To evaluate the cumulative recurrence rates of ovarian endometrioma among patients using a levonorgestrel-releasing intrauterine system (LNG-IUS) after conservative laparoscopic surgery. Methods: A retrospective review was conducted of premenopausal women who underwent conservative laparoscopic surgery for ovarian endometrioma and subsequent treatment with LNG-IUS at two gynecologic surgery centers in South Korea between January 1, 2007, and September 30, 2014. Eligible patients had no residual ovarian lesions before LNG-IUS insertion, underwent insertion within 12 months of primary surgery, and were followed up for at least 6 months afterwards. Recurrence was defined as a cystic mass (≥ 2 cm in diameter) detected by transvaginal ultrasonography. Results: Overall, 61 patients were included. The mean duration of follow-up was 42.9 ± 22.0 months (range 8–98). Recurrence of ovarian endometrioma was detected among 7 (11%) of the patients. On Kaplan–Meier analysis, the cumulative recurrence rates were 4.0%, 6.3%, and 25.5% at 24, 36, and 60 months after surgery, respectively. In multivariate analysis, nulliparity at surgery was the only risk factor for recurrence (hazard ratio 5.892, 95% confidence interval 1.139–30.484; P=0.034). Conclusion: Long-term maintenance therapy with LNG-IUS after conservative surgery might be a treatment option to consider to prevent ovarian endometrioma recurrence among premenopausal women. © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Endometriosis is a chronic and recurrent condition characterized by the development and expansion of extrauterine endometrial stroma and/or glands. This condition affects 10%–20% of women of reproductive age worldwide [1], and negatively influences the physical, mental, and social well-being of affected individuals. Despite its invasive nature, surgery is considered the treatment of choice for endometriosis; however, treatment-related morbidity and complications can occur [2]. The recurrence rate following surgical intervention remains high, even among patients who receive postoperative medical therapy. A pooled analysis of 23 studies [3] estimated recurrence rates of 21.5% at 2 years and 40.0%–50.0% at 5 years after the primary surgery. A study by Weir et al. [4] found that 27% of patients were readmitted for additional surgical treatment of endometriosis within 4 years of the initial surgery. Furthermore, Cheong et al. [5]
⁎ *Corresponding author at: Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, 566, Nonhyeon-ro, Gangnam-gu, Seoul 135-081, South Korea. Tel.: +82 2 3468 3673; fax: +82 2 558 1112. E-mail address: [email protected] (S.J. Seong). 1 These authors contributed equally.
reported that greater than half of all patients with endometriosis underwent reoperation, with approximately 27% requiring three or more surgeries. In a Korean study [6], the cumulative recurrence rates of ovarian endometrioma after second-line treatment with conservative laparoscopic cyst enucleation were 13.7%, 21.3%, and 37.5% at 24, 36, and 60 months, respectively. Given that a curative treatment for endometriosis has not yet been established, the main goals of intervention are to reduce pain, increase fertility among women who plan to conceive, and delay the onset of recurrence [7]. In 2014, the European Society of Human Reproduction and Embryology published revised guidelines for the management of endometriosis, which addressed the issue of secondary prevention [8]. This document outlined various interventions to prevent recurrence of pain symptoms or disease during the postoperative period (N6 months after surgery). The choice of intervention should be made on the basis of patient preference, cost, availability, and adverse effects. Combined oral contraceptives can be used for secondary prevention of recurrent ovarian endometrioma if the patient does not wish to conceive straight after surgery. A levonorgestrel-releasing intrauterine system (LNG-IUS) or combined oral contraceptives can be used for the secondary prevention of endometriosis-associated dysmenorrhea, but not for nonmenstrual pelvic pain or dyspareunia, for at least 18–24 months after
http://dx.doi.org/10.1016/j.ijgo.2016.03.017 0020-7292/© 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Kim M-L, et al, The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.03.017
2
M.-L. Kim et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
surgery [8]. The non-contraceptive benefits of LNG-IUS, including effects on dysmenorrhea and heavy menstrual bleeding, make it an effective option for the treatment of endometriosis [9]. Although the LNG-IUS effectively reduces pain associated with endometriosis [10,11], its efficacy in preventing recurrence of ovarian endometrioma is not proven. The aim of the present study was to evaluate the efficacy of LNG-IUS as long-term maintenance therapy to prevent recurrence of ovarian endometrioma after conservative laparoscopic surgery. 2. Materials and methods A retrospective review was conducted of patients who underwent conservative laparoscopic enucleation of ovarian endometrioma and subsequent treatment with LNG-IUS at two gynecologic surgery centers in South Korea between January 1, 2007, and September 30, 2014. The inclusion criteria were premenopausal status, pathologically proven ovarian endometrioma, treatment by conservative laparoscopic surgery, no residual ovarian lesions detected by transvaginal ultrasonography before LNG-IUS insertion, less than 12 months elapsed between primary surgery and LNG-IUS insertion, and at least 6 months of follow-up after LNG-IUS insertion. Among patients who received a gonadotropin-releasing hormone (GnRH) agonist after surgery, those who received 3.75 mg leuprorelin every 28 days after surgery for a period of 3–6 months before the LNG-IUS was inserted were included. Exclusion criteria were laparotomy or laparoscopic hysterectomy (with or without oophorectomy) and the use of postoperative treatments other than a GnRH agonist before LNG-IUS insertion (e.g. a progestin or combined oral contraceptive). The protocol was approved by the institutional review boards of the two study centers (CHA Gangnam Medical Center, Seoul, and Dong-A University Medical Center, Busan). Patient records and data were anonymized and de-identified before analysis, so informed consent was not required. Medical charts were reviewed to collect data on age at surgery, body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters), surgical history, symptoms of dysmenorrhea, parity, size of the ovarian endometrioma, location of the ovarian cysts; revised American Society for Reproductive Medicine stage [12], postoperative medications, and time to recurrence. The size of the ovarian endometrioma was defined as the diameter of the largest cyst in centimeters. The sum of the diameters of the largest cysts was recorded if the ovarian cysts were bilateral. Recurrence was recorded when transvaginal ultrasonography revealed a round cystic mass (diameter ≥2 cm), thick walls, irregular margins, homogenous low echogenic fluid content, and scattered internal echoes, without papillary proliferation, as previously described [13]. The use of LNG-IUS does not fully inhibit ovulation [14]; therefore, all newly developed hypoechoic masses with features characteristic of functional cysts were re-evaluated by transvaginal ultrasonography after 2–3 months. If a patient had two ovarian endometriomas (each b2 cm in diameter), recurrence was recorded when the sum of the diameters was at least 2 cm, as previously reported [15–17]. The time to recurrence was defined as the time in months from surgery to detection of a newly developed ovarian endometrioma greater than 2 cm in diameter. All patients underwent postoperative insertion of the LNG-IUS either for contraception or to control dysmenorrhea and/or heavy menstrual bleeding. The patients were fully informed of the advantages, disadvantages, and complications of LNG-IUS. If patients opted to use LNG-IUS immediately after surgery without GnRH agonist use because of the associated hypoestrogenic symptoms, insertion was performed either on the day of operation or at an outpatient clinic on days 5–7 of the next menstrual cycle. Clinical postoperative follow-up was conducted at regular intervals (every 3–6 months initially, then every 6–12 months) or whenever medical evaluation was required. Transvaginal ultrasonography was
performed at every follow-up visit; symptoms, medical treatment, and clinical data were also recorded. The data were analyzed using SPSS version 22 (IBM, Armonk, NY, USA). Descriptive data were compared using the Mann–Whitney U test. Categorical data were analyzed using the χ2 and Fisher exact tests, as appropriate. Univariate analysis and multivariate Cox proportional hazards models were fitted for recurrence-free experience, and adjusted for the effects of clinical characteristics among patients with or without recurrent disease. The Kaplan–Meier method was used to calculate the cumulative probability of recurrence. Pb 0.05 was considered statistically significant. 3. Results A total of 61 patients were included in the present study. The mean age was 36.2 ± 5.9 years (range 23–48). The mean duration of LNG-IUS use was 34.6 ± 20.2 months (range 4–77), with a mean duration of follow-up of 42.9 ± 22.0 months (range 8–98). Overall, 41 (67%) patients received postoperative treatment with a GnRH agonist before LNG-IUS placement; the remaining 20 (33%) patients opted for LNG-IUS insertion without GnRH agonist use. The baseline clinical and surgical characteristics by use of a GnRH agonist are shown in Table 1. No statistically significant differences were observed between patients who did and did not receive a GnRH agonist. Recurrence of ovarian endometrioma was detected among 7 (11%) patients on follow-up transvaginal ultrasonography. The cumulative recurrence rates at 24, 36, and 60 months after surgery were 4.0%, 6.3%, and 25.5%, respectively (Fig. 1). Univariate analysis suggested that younger age and nulliparity were possible risk factors for recurrence of ovarian endometrioma (Pb0.001 and P=0.004, respectively) (Table 2). Multivariate analysis identified nulliparity as the only statistically significant risk factor for recurrence of ovarian endometrioma during long-term postoperative maintenance therapy with LNG-IUS (Table 2). The hazard ratio was 5.892 (95% confidence interval 1.139–30.484; P=0.034). At the last follow-up during the study period, 44 (72%) patients were still using LNG-IUS; use of the LNG-IUS was discontinued by 17 (28%) patients. Six (10%) patients had the LNG-IUS removed to aid conception (1 conceived naturally 10 months after removal), 2 (3%) had the LNG-IUS removed after menopause, and 1 (2%) had the LNG-IUS removed after a diagnosis of progesterone-receptor-positive breast cancer. Three (5%) patients experienced dislocation or expulsion of Table 1 Baseline clinical and surgical characteristics (n=61).a Characteristic
GnRH agonist and LNG-IUS (n=41)
LNG-IUS only (n=20)
P value
Age at surgery, y Age at LNG-IUS insertion, y Parity 0 ≥1 Body mass index b Size of ovarian cyst, cm Revised American Society for Reproductive Medicine stage III IV Laterality Unilateral Bilateral Duration of LNG-IUS use, mo Duration of follow-up, mo
35.7 ± 6.3 36.2 ± 6.2
37.4 ± 5.0 37.7 ± 5.0
0.423 0.543 0.544
12 (29) 29 (71) 20.8 ± 1.9 7.2 ± 3.3
4 (20) 16 (80) 20.4 ± 2.5 6.4 ± 2.4
24 (59) 17 (41)
8 (40) 12 (60)
26 (63) 15 (37) 34.1 ± 18.5 43.3 ± 21.2
16 (80) 4 (20) 35.6 ± 23.9 42.2 ± 24.2
0.544 0.489 0.166
0.246
0.969 0.836
Abbreviations: GnRH, gonadotropin-releasing hormone; LNG-IUS, levonorgestrel-releasing intrauterine system. a Values given as mean ± standard deviation or number (percentage), unless indicated otherwise. b Calculated as weight in kilograms divided by the square of height in meters.
Please cite this article as: Kim M-L, et al, The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.03.017
M.-L. Kim et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
Fig. 1. The cumulative probability of recurrent ovarian endometrioma with postoperative use of a levonorgestrel-releasing intrauterine system. Vertical lines indicate censoring.
the device, despite relief of dysmenorrhea following insertion. Five (8%) patients had the LNG-IUS removed as a result of complications (depressive mood changes in 1 [2%] patient, hair loss in 1 [2%], vaginal discharge in 1 [2%], and recurrent dysmenorrhea and subsequent detection of recurrent ovarian endometrioma in 2 [3%]). Only 1 (2%) patient underwent repeat laparoscopic surgery after a diagnosis of recurrent ovarian endometrioma. 4. Discussion The present study found that long-term postoperative maintenance therapy with LNG-IUS was a valid approach to prevent recurrence of
3
ovarian endometrioma among premenopausal women. Univariate analysis indicated that younger age at surgery and nulliparity were possible risk factors for endometrioma recurrence. However, only nulliparity exhibited a statistically significant risk for recurrence on multivariate analysis. Combined oral contraceptives are the most widely used agents for long-term medical treatment after surgical intervention for ovarian endometrioma [17–19]. Theoretically, the use of combined oral contraceptives can effectively prevent recurrence, with the benefits of long-term safety and contraceptive effects. Continuous or cyclical administration of combined oral contraceptives has proven effective for the prevention of recurrent ovarian endometrioma and reduction of endometriosis-associated pain [17–19]. Nevertheless, regular and prolonged administration of this medication—as well as treatment compliance—is required to prevent recurrence. Additionally, the risk of venous thromboembolism increases with age among women receiving combined oral contraceptives [20]. The use of LNG-IUS is predominantly reserved for contraception; however, additional benefits have been investigated for the control of dysmenorrhea and gynecologic conditions related to heavy menstrual bleeding [11]. Several hypotheses potentially explain the mechanism of action of LNG-IUS for treatment of endometriosis-related pain and reduction of menstrual blood loss. First, a local effect on the ectopic endometrium might arise following inhibition of the expression of the receptors for estrogen and progestin [21,22]. Second, increased expression of Fas might cause an anti-proliferative effect through expression of estrogen receptor-α and progesterone receptor-α in both the eutopic and ectopic endometrium, leading to stromal pseudodecidualization and epithelial glandular atrophy [23]. Finally, increased apoptosis might occur owing to modifications in the production of cytokines responsible for the maintenance of the endometriotic lesions, pain, and reduction of local vascular angiogenesis, pelvic-vessel congestion, and the activity of peritoneal fluid macrophages [24–26]. Two studies have retrospectively compared rates of postoperative recurrence of ovarian endometrioma after use of combined oral contraceptives and LNG-IUS [14,27]. Cho et al. [14] evaluated 57 patients treated with combined oral contraceptives and 42 patients treated with LNG-IUS following three cycles of GnRH agonist therapy. Recurrence
Table 2 Possible risk factors for recurrence of ovarian endometrioma during long-term treatment with a levonorgestrel-releasing intrauterine system.a Variable Age, y ≤30 31–40 N40 Body mass index c Parity 0 ≥1 Tumor size, cm Preoperative CA125 level, U/mL d Revised American Society for Reproductive Medicine stage III IV Laterality Unilateral Bilateral Previous surgery for ovarian endometrioma Yes No Postoperative medication GnRH agonist and LNG-IUS LNG-IUS only
Non-recurrent disease (n=54)
Recurrent disease (n=7)
7 (13) 29 (54) 18 (33) 20.8 ± 2.2
4 (57) 3 (43) 0 20.2 ± 1.6
10 (19) 44 (81) 6.7 ± 3.0 156.5 ± 715.2
5 (71) 2 (29) 8.0 ± 3.6 52.3 ± 40.8
26 (48) 28 (52)
6 (86) 1 (14)
37 (69) 17 (31)
5 (71) 2 (29)
10 (19) 44 (81)
1 (14) 6 (86)
34 (63) 20 (37)
6 (86) 1 (14)
P value (univariate analysis)
P value (multivariate analysis) b
b0.001
0.340
0.490 0.004
NA 0.034
0.298 0.866 0.061
NA NA
0.876
NA
0.784
NA
0.268
NA
Abbreviations: NA, not applicable; CA125, cancer antigen 125; GnRH, gonadotropin-releasing hormone; LNG-IUS, levonorgestrel-releasing intrauterine system. a Values given as mean ± standard deviation or number (percentage), unless otherwise stated. b The multivariate analysis was applied only for variables with a P value b0.05 in the univariate analysis. c Calculated as weight in kilograms divided by the square of height in meters. d Non-recurrent disease (n=52); recurrent disease (n=5).
Please cite this article as: Kim M-L, et al, The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.03.017
4
M.-L. Kim et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
rates during a median follow-up of 17 months were 10.5% for the combined oral contraceptives group and 4.8% for the LNG-IUS group (P = 0.461). However, the cumulative recurrence-free survival rate indicated that the mean disease-free survival time was longer in the LNG-IUS group (34.4 ± 1.0 months) than in the combined oral contraceptive group (33.4 ± 1.3 months; P = 0.045). Morelli et al. [27] assessed 48 patients treated with estradiol valerate plus dienogest and 44 patients treated with LNG-IUS for a period of 24 months after conservative surgery. The levels of cancer antigen 125 and the pain scores were reduced among patients treated with the combined oral contraceptive. However, rates of disease recurrence did not differ between the two groups. The recurrence rate at 12 months was 8.3% in the combined oral contraceptives group versus 12.5% in the LNG-IUS group (P = 0.41). Likewise, the recurrence rate at 24 months was 13.6% in the combined oral contraceptive group versus 20.5% in the LNG-IUS group (P = 0.30). Interestingly, treatment satisfaction at 24 months was markedly higher in the LNG-IUS group than in the combined oral contraceptives group. These results suggest that provision of postoperative LNG-IUS for long-term prevention of recurrence could be comparable to the use of combined oral contraceptives. The present study did not compare the postoperative recurrence rate achieved by LNG-IUS with that of combined oral contraceptives. Nonetheless, the cumulative recurrence rates for LNG-IUS use at 24 months (4.0%) and 36 months (6.3%) were similar to those previously reported [14,27]. The advantages of LNG-IUS over combined oral contraceptives include fewer systemic hormonal effects, freedom from daily medication, efficacy lasting at least 5 years, and proven effects for reduction of endometriosis-related pain. Consequently, LNG-IUS might be used as an alternative to combined oral contraceptives for the longterm postoperative prevention of recurrent ovarian endometrioma, either alone or in combination with a GnRH agonist. Considering the lower risk of recurrence among parous women than among nulliparous individuals, LNG-IUS could be considered a suitable option for patients who are not planning to conceive and who wish for long-term prevention of recurrent disease. A major strength of the present study was the long duration of follow-up, with 35 of the 61 patients followed up for longer than 3 years. Additionally, the cumulative probability of recurrent ovarian endometrioma at 5 years after LNG-IUS placement could be calculated in the present study. Nevertheless, some limitations must be addressed. First, the present study was based on retrospective data obtained from a small sample by medical record review. Thus, the follow-up period was not uniform and the exact timing of recurrence was unclear. Second, recurrence of pain was not considered as an outcome measure. This aspect is one of the most challenging to manage during the surgical treatment of endometriosis; however, an evaluation of pain recurrence in the present study would have required exclusion of other gynecologic conditions associated with pelvic pain or dysmenorrhea, such as leiomyoma or adenomyosis. Finally, diagnosis of recurrent ovarian endometrioma was primarily based on previously defined transvaginal ultrasonographic findings in the absence of pathologic confirmation [13]. In conclusion, the findings of the present study suggested that longterm maintenance therapy with LNG-IUS might be a viable treatment option for the prevention of recurrent ovarian endometrioma after surgery among premenopausal women, especially for those not planning any further pregnancies and requiring long-term prevention of recurrent disease. Large-scale prospective multicenter studies are now required to confirm these findings. Conflict of interest The authors have no conflicts of interest.
References [1] Winkel CA. Evaluation and management of women with endometriosis. Obstet Gynecol 2003;102(2):397–408. [2] Garry R. The effectiveness of laparoscopic excision of endometriosis. Curr Opin Obstet Gynecol 2004;16(4):299–303. [3] Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update 2009; 15(4):441–61. [4] Weir E, Mustard C, Cohen M, Kung R. Endometriosis: what is the risk of hospital admission, readmission, and major surgical intervention? J Minim Invasive Gynecol 2005;12(6):486–93. [5] Cheong Y, Tay P, Luk F, Gan HC, Li TC, Cooke I. Laparoscopic surgery for endometriosis: How often do we need to re-operate? J Obstet Gynaecol 2008;28(1):82–5. [6] Kim ML, Kim JM, Seong SJ, Lee SY, Han M, Cho YJ. Recurrence of ovarian endometrioma after second-line, conservative, laparoscopic cyst enucleation. Am J Obstet Gynecol 2014;210(3):216.e1–6. [7] Donnez J, Pirard C, Smets M, Jadoul P, Squifflet J. Surgical management of endometriosis. Best Pract Res Clin Obstet Gynaecol 2004;18(2):329–48. [8] Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014; 29(3):400–12. [9] Kim ML, Seong SJ. Clinical applications of levonorgestrel-releasing intrauterine system to gynecologic diseases. Obstet Gynecol Sci 2013;56(2):67–75. [10] Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Crosignani PG. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril 2003;80(2):305–9. [11] Tanmahasamut P, Rattanachaiyanont M, Angsuwathana S, Techatraisak K, Indhavivadhana S, Leerasiri P. Postoperative levonorgestrel-releasing intrauterine system for pelvic endometriosis-related pain: a randomized controlled trial. Obstet Gynecol 2012;119(3):519–26. [12] American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997;67(5): 817–21. [13] Exacoustos C, Zupi E, Carusotti C, Rinaldo D, Marconi D, Lanzi G, et al. Staging of pelvic endometriosis: role of sonographic appearance in determining extension of disease and modulating surgical approach. J Am Assoc Gynecol Laparosc 2003; 10(3):378–82. [14] Cho S, Jung JA, Lee Y, Kim HY, Seo SK, Choi YS, et al. Postoperative levonorgestrelreleasing intrauterine system versus oral contraceptives after gonadotropinreleasing hormone agonist treatment for preventing endometrioma recurrence. Acta Obstet Gynecol Scand 2014;93(1):38–44. [15] Kikuchi I, Takeuchi H, Kitade M, Shimanuki H, Kumakiri J, Kinoshita K. Recurrence rate of endometriomas following a laparoscopic cystectomy. Acta Obstet Gynecol Scand 2006;85(9):1120–4. [16] Koga K, Takemura Y, Osuga Y, Yoshino O, Hirota Y, Hirata T, et al. Recurrence of ovarian endometrioma after laparoscopic excision. Hum Reprod 2006;21(8):2171–4. [17] Vercellini P, Somigliana E, Daguati R, Vigano P, Meroni F, Crosignani PG. Postoperative oral contraceptive exposure and risk of endometrioma recurrence. Am J Obstet Gynecol 2008;198(5):504.e1–5. [18] Vercellini P, Somigliana E, Viganò P, De Matteis S, Barbara G, Fedele L. Post-operative endometriosis recurrence: a plea for prevention based on pathogenetic, epidemiological and clinical evidence. Reprod Biomed Online 2010;21(2):259–65. [19] Lee DY, Bae DS, Yoon BK, Choi D. Post-operative cyclic oral contraceptive use after gonadotrophin-releasing hormone agonist treatment effectively prevents endometrioma recurrence. Hum Reprod 2010;25(12):3050–4. [20] Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Populationbased study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997;349(9045):83–8. [21] Nilsson CG, Luukkainen T, Arko H. Endometrial morphology of women using a d-norgestrel-releasing intrauterine device. Fertil Steril 1978;29(4):397–401. [22] Hurskainen R, Salmi A, Paavonen J, Teperi J, Rutanen E. Expression of sex steroid receptors and Ki-67 in the endometria of menorrhagic women: effects of intrauterine levonorgestrel. Mol Hum Reprod 2000;6(11):1013–8. [23] Engemise SL, Willets JM, Taylor AH, Emembolu JO, Konje JC. Changes in glandular and stromal estrogen and progesterone receptor isoform expression in eutopic and ectopic endometrium following treatment with the levonorgestrel-releasing intrauterine system. Eur J Obstet Gynecol Reprod Biol 2011;157(1):101–6. [24] Maruo T, Laoag-Fernandez JB, Pakarinen P, Murakoshi H, Spitz IM, Johansson E. Effects of the levonorgestrel-releasing intrauterine system on proliferation and apoptosis in the endometrium. Hum Reprod 2001;16(10):2103–8. [25] Küpker W, Schultze-Mosgau A, Diedrich K. Paracrine changes in the peritoneal environment of women with endometriosis. Hum Reprod Update 1998;4(5):719–23. [26] McLaren J, Prentice A, Charnock-Jones DS, Millican SA, Müller KH, Sharkey AM, et al. Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest 1996;98(2): 482–9. [27] Morelli M, Sacchinelli A, Venturella R, Mocciaro R, Zullo F. Postoperative administration of dienogest plus estradiol valerate versus levonorgestrel-releasing intrauterine device for prevention of pain relapse and disease recurrence in endometriosis patients. J Obstet Gynaecol Res 2013;39(5):985–90.
Please cite this article as: Kim M-L, et al, The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.03.017
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence Mi-La Kim a,1, Yeon Jean Cho b,1, Mi Kyoung Kim a, Yong Wook Jung a, Bo Seong Yun a, Seok Ju Seong a,⁎ a b
Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, South Korea Department of Obstetrics and Gynecology, Dong-A University Medical Center, College of Medicine, Dong-A University, Busan, South Korea
a r t i c l e
i n f o
Article history: Received 19 November 2015 Received in revised form 2 March 2016 Accepted 23 May 2016 Keywords: Conservative surgery Endometriosis Levonorgestrel-releasing intrauterine system Ovarian endometrioma Recurrence rate
a b s t r a c t Objective: To evaluate the cumulative recurrence rates of ovarian endometrioma among patients using a levonorgestrel-releasing intrauterine system (LNG-IUS) after conservative laparoscopic surgery. Methods: A retrospective review was conducted of premenopausal women who underwent conservative laparoscopic surgery for ovarian endometrioma and subsequent treatment with LNG-IUS at two gynecologic surgery centers in South Korea between January 1, 2007, and September 30, 2014. Eligible patients had no residual ovarian lesions before LNG-IUS insertion, underwent insertion within 12 months of primary surgery, and were followed up for at least 6 months afterwards. Recurrence was defined as a cystic mass (≥ 2 cm in diameter) detected by transvaginal ultrasonography. Results: Overall, 61 patients were included. The mean duration of follow-up was 42.9 ± 22.0 months (range 8–98). Recurrence of ovarian endometrioma was detected among 7 (11%) of the patients. On Kaplan–Meier analysis, the cumulative recurrence rates were 4.0%, 6.3%, and 25.5% at 24, 36, and 60 months after surgery, respectively. In multivariate analysis, nulliparity at surgery was the only risk factor for recurrence (hazard ratio 5.892, 95% confidence interval 1.139–30.484; P=0.034). Conclusion: Long-term maintenance therapy with LNG-IUS after conservative surgery might be a treatment option to consider to prevent ovarian endometrioma recurrence among premenopausal women. © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Endometriosis is a chronic and recurrent condition characterized by the development and expansion of extrauterine endometrial stroma and/or glands. This condition affects 10%–20% of women of reproductive age worldwide [1], and negatively influences the physical, mental, and social well-being of affected individuals. Despite its invasive nature, surgery is considered the treatment of choice for endometriosis; however, treatment-related morbidity and complications can occur [2]. The recurrence rate following surgical intervention remains high, even among patients who receive postoperative medical therapy. A pooled analysis of 23 studies [3] estimated recurrence rates of 21.5% at 2 years and 40.0%–50.0% at 5 years after the primary surgery. A study by Weir et al. [4] found that 27% of patients were readmitted for additional surgical treatment of endometriosis within 4 years of the initial surgery. Furthermore, Cheong et al. [5]
⁎ *Corresponding author at: Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, 566, Nonhyeon-ro, Gangnam-gu, Seoul 135-081, South Korea. Tel.: +82 2 3468 3673; fax: +82 2 558 1112. E-mail address: [email protected] (S.J. Seong). 1 These authors contributed equally.
reported that greater than half of all patients with endometriosis underwent reoperation, with approximately 27% requiring three or more surgeries. In a Korean study [6], the cumulative recurrence rates of ovarian endometrioma after second-line treatment with conservative laparoscopic cyst enucleation were 13.7%, 21.3%, and 37.5% at 24, 36, and 60 months, respectively. Given that a curative treatment for endometriosis has not yet been established, the main goals of intervention are to reduce pain, increase fertility among women who plan to conceive, and delay the onset of recurrence [7]. In 2014, the European Society of Human Reproduction and Embryology published revised guidelines for the management of endometriosis, which addressed the issue of secondary prevention [8]. This document outlined various interventions to prevent recurrence of pain symptoms or disease during the postoperative period (N6 months after surgery). The choice of intervention should be made on the basis of patient preference, cost, availability, and adverse effects. Combined oral contraceptives can be used for secondary prevention of recurrent ovarian endometrioma if the patient does not wish to conceive straight after surgery. A levonorgestrel-releasing intrauterine system (LNG-IUS) or combined oral contraceptives can be used for the secondary prevention of endometriosis-associated dysmenorrhea, but not for nonmenstrual pelvic pain or dyspareunia, for at least 18–24 months after
http://dx.doi.org/10.1016/j.ijgo.2016.03.017 0020-7292/© 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Kim M-L, et al, The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.03.017
2
M.-L. Kim et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
surgery [8]. The non-contraceptive benefits of LNG-IUS, including effects on dysmenorrhea and heavy menstrual bleeding, make it an effective option for the treatment of endometriosis [9]. Although the LNG-IUS effectively reduces pain associated with endometriosis [10,11], its efficacy in preventing recurrence of ovarian endometrioma is not proven. The aim of the present study was to evaluate the efficacy of LNG-IUS as long-term maintenance therapy to prevent recurrence of ovarian endometrioma after conservative laparoscopic surgery. 2. Materials and methods A retrospective review was conducted of patients who underwent conservative laparoscopic enucleation of ovarian endometrioma and subsequent treatment with LNG-IUS at two gynecologic surgery centers in South Korea between January 1, 2007, and September 30, 2014. The inclusion criteria were premenopausal status, pathologically proven ovarian endometrioma, treatment by conservative laparoscopic surgery, no residual ovarian lesions detected by transvaginal ultrasonography before LNG-IUS insertion, less than 12 months elapsed between primary surgery and LNG-IUS insertion, and at least 6 months of follow-up after LNG-IUS insertion. Among patients who received a gonadotropin-releasing hormone (GnRH) agonist after surgery, those who received 3.75 mg leuprorelin every 28 days after surgery for a period of 3–6 months before the LNG-IUS was inserted were included. Exclusion criteria were laparotomy or laparoscopic hysterectomy (with or without oophorectomy) and the use of postoperative treatments other than a GnRH agonist before LNG-IUS insertion (e.g. a progestin or combined oral contraceptive). The protocol was approved by the institutional review boards of the two study centers (CHA Gangnam Medical Center, Seoul, and Dong-A University Medical Center, Busan). Patient records and data were anonymized and de-identified before analysis, so informed consent was not required. Medical charts were reviewed to collect data on age at surgery, body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters), surgical history, symptoms of dysmenorrhea, parity, size of the ovarian endometrioma, location of the ovarian cysts; revised American Society for Reproductive Medicine stage [12], postoperative medications, and time to recurrence. The size of the ovarian endometrioma was defined as the diameter of the largest cyst in centimeters. The sum of the diameters of the largest cysts was recorded if the ovarian cysts were bilateral. Recurrence was recorded when transvaginal ultrasonography revealed a round cystic mass (diameter ≥2 cm), thick walls, irregular margins, homogenous low echogenic fluid content, and scattered internal echoes, without papillary proliferation, as previously described [13]. The use of LNG-IUS does not fully inhibit ovulation [14]; therefore, all newly developed hypoechoic masses with features characteristic of functional cysts were re-evaluated by transvaginal ultrasonography after 2–3 months. If a patient had two ovarian endometriomas (each b2 cm in diameter), recurrence was recorded when the sum of the diameters was at least 2 cm, as previously reported [15–17]. The time to recurrence was defined as the time in months from surgery to detection of a newly developed ovarian endometrioma greater than 2 cm in diameter. All patients underwent postoperative insertion of the LNG-IUS either for contraception or to control dysmenorrhea and/or heavy menstrual bleeding. The patients were fully informed of the advantages, disadvantages, and complications of LNG-IUS. If patients opted to use LNG-IUS immediately after surgery without GnRH agonist use because of the associated hypoestrogenic symptoms, insertion was performed either on the day of operation or at an outpatient clinic on days 5–7 of the next menstrual cycle. Clinical postoperative follow-up was conducted at regular intervals (every 3–6 months initially, then every 6–12 months) or whenever medical evaluation was required. Transvaginal ultrasonography was
performed at every follow-up visit; symptoms, medical treatment, and clinical data were also recorded. The data were analyzed using SPSS version 22 (IBM, Armonk, NY, USA). Descriptive data were compared using the Mann–Whitney U test. Categorical data were analyzed using the χ2 and Fisher exact tests, as appropriate. Univariate analysis and multivariate Cox proportional hazards models were fitted for recurrence-free experience, and adjusted for the effects of clinical characteristics among patients with or without recurrent disease. The Kaplan–Meier method was used to calculate the cumulative probability of recurrence. Pb 0.05 was considered statistically significant. 3. Results A total of 61 patients were included in the present study. The mean age was 36.2 ± 5.9 years (range 23–48). The mean duration of LNG-IUS use was 34.6 ± 20.2 months (range 4–77), with a mean duration of follow-up of 42.9 ± 22.0 months (range 8–98). Overall, 41 (67%) patients received postoperative treatment with a GnRH agonist before LNG-IUS placement; the remaining 20 (33%) patients opted for LNG-IUS insertion without GnRH agonist use. The baseline clinical and surgical characteristics by use of a GnRH agonist are shown in Table 1. No statistically significant differences were observed between patients who did and did not receive a GnRH agonist. Recurrence of ovarian endometrioma was detected among 7 (11%) patients on follow-up transvaginal ultrasonography. The cumulative recurrence rates at 24, 36, and 60 months after surgery were 4.0%, 6.3%, and 25.5%, respectively (Fig. 1). Univariate analysis suggested that younger age and nulliparity were possible risk factors for recurrence of ovarian endometrioma (Pb0.001 and P=0.004, respectively) (Table 2). Multivariate analysis identified nulliparity as the only statistically significant risk factor for recurrence of ovarian endometrioma during long-term postoperative maintenance therapy with LNG-IUS (Table 2). The hazard ratio was 5.892 (95% confidence interval 1.139–30.484; P=0.034). At the last follow-up during the study period, 44 (72%) patients were still using LNG-IUS; use of the LNG-IUS was discontinued by 17 (28%) patients. Six (10%) patients had the LNG-IUS removed to aid conception (1 conceived naturally 10 months after removal), 2 (3%) had the LNG-IUS removed after menopause, and 1 (2%) had the LNG-IUS removed after a diagnosis of progesterone-receptor-positive breast cancer. Three (5%) patients experienced dislocation or expulsion of Table 1 Baseline clinical and surgical characteristics (n=61).a Characteristic
GnRH agonist and LNG-IUS (n=41)
LNG-IUS only (n=20)
P value
Age at surgery, y Age at LNG-IUS insertion, y Parity 0 ≥1 Body mass index b Size of ovarian cyst, cm Revised American Society for Reproductive Medicine stage III IV Laterality Unilateral Bilateral Duration of LNG-IUS use, mo Duration of follow-up, mo
35.7 ± 6.3 36.2 ± 6.2
37.4 ± 5.0 37.7 ± 5.0
0.423 0.543 0.544
12 (29) 29 (71) 20.8 ± 1.9 7.2 ± 3.3
4 (20) 16 (80) 20.4 ± 2.5 6.4 ± 2.4
24 (59) 17 (41)
8 (40) 12 (60)
26 (63) 15 (37) 34.1 ± 18.5 43.3 ± 21.2
16 (80) 4 (20) 35.6 ± 23.9 42.2 ± 24.2
0.544 0.489 0.166
0.246
0.969 0.836
Abbreviations: GnRH, gonadotropin-releasing hormone; LNG-IUS, levonorgestrel-releasing intrauterine system. a Values given as mean ± standard deviation or number (percentage), unless indicated otherwise. b Calculated as weight in kilograms divided by the square of height in meters.
Please cite this article as: Kim M-L, et al, The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.03.017
M.-L. Kim et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
Fig. 1. The cumulative probability of recurrent ovarian endometrioma with postoperative use of a levonorgestrel-releasing intrauterine system. Vertical lines indicate censoring.
the device, despite relief of dysmenorrhea following insertion. Five (8%) patients had the LNG-IUS removed as a result of complications (depressive mood changes in 1 [2%] patient, hair loss in 1 [2%], vaginal discharge in 1 [2%], and recurrent dysmenorrhea and subsequent detection of recurrent ovarian endometrioma in 2 [3%]). Only 1 (2%) patient underwent repeat laparoscopic surgery after a diagnosis of recurrent ovarian endometrioma. 4. Discussion The present study found that long-term postoperative maintenance therapy with LNG-IUS was a valid approach to prevent recurrence of
3
ovarian endometrioma among premenopausal women. Univariate analysis indicated that younger age at surgery and nulliparity were possible risk factors for endometrioma recurrence. However, only nulliparity exhibited a statistically significant risk for recurrence on multivariate analysis. Combined oral contraceptives are the most widely used agents for long-term medical treatment after surgical intervention for ovarian endometrioma [17–19]. Theoretically, the use of combined oral contraceptives can effectively prevent recurrence, with the benefits of long-term safety and contraceptive effects. Continuous or cyclical administration of combined oral contraceptives has proven effective for the prevention of recurrent ovarian endometrioma and reduction of endometriosis-associated pain [17–19]. Nevertheless, regular and prolonged administration of this medication—as well as treatment compliance—is required to prevent recurrence. Additionally, the risk of venous thromboembolism increases with age among women receiving combined oral contraceptives [20]. The use of LNG-IUS is predominantly reserved for contraception; however, additional benefits have been investigated for the control of dysmenorrhea and gynecologic conditions related to heavy menstrual bleeding [11]. Several hypotheses potentially explain the mechanism of action of LNG-IUS for treatment of endometriosis-related pain and reduction of menstrual blood loss. First, a local effect on the ectopic endometrium might arise following inhibition of the expression of the receptors for estrogen and progestin [21,22]. Second, increased expression of Fas might cause an anti-proliferative effect through expression of estrogen receptor-α and progesterone receptor-α in both the eutopic and ectopic endometrium, leading to stromal pseudodecidualization and epithelial glandular atrophy [23]. Finally, increased apoptosis might occur owing to modifications in the production of cytokines responsible for the maintenance of the endometriotic lesions, pain, and reduction of local vascular angiogenesis, pelvic-vessel congestion, and the activity of peritoneal fluid macrophages [24–26]. Two studies have retrospectively compared rates of postoperative recurrence of ovarian endometrioma after use of combined oral contraceptives and LNG-IUS [14,27]. Cho et al. [14] evaluated 57 patients treated with combined oral contraceptives and 42 patients treated with LNG-IUS following three cycles of GnRH agonist therapy. Recurrence
Table 2 Possible risk factors for recurrence of ovarian endometrioma during long-term treatment with a levonorgestrel-releasing intrauterine system.a Variable Age, y ≤30 31–40 N40 Body mass index c Parity 0 ≥1 Tumor size, cm Preoperative CA125 level, U/mL d Revised American Society for Reproductive Medicine stage III IV Laterality Unilateral Bilateral Previous surgery for ovarian endometrioma Yes No Postoperative medication GnRH agonist and LNG-IUS LNG-IUS only
Non-recurrent disease (n=54)
Recurrent disease (n=7)
7 (13) 29 (54) 18 (33) 20.8 ± 2.2
4 (57) 3 (43) 0 20.2 ± 1.6
10 (19) 44 (81) 6.7 ± 3.0 156.5 ± 715.2
5 (71) 2 (29) 8.0 ± 3.6 52.3 ± 40.8
26 (48) 28 (52)
6 (86) 1 (14)
37 (69) 17 (31)
5 (71) 2 (29)
10 (19) 44 (81)
1 (14) 6 (86)
34 (63) 20 (37)
6 (86) 1 (14)
P value (univariate analysis)
P value (multivariate analysis) b
b0.001
0.340
0.490 0.004
NA 0.034
0.298 0.866 0.061
NA NA
0.876
NA
0.784
NA
0.268
NA
Abbreviations: NA, not applicable; CA125, cancer antigen 125; GnRH, gonadotropin-releasing hormone; LNG-IUS, levonorgestrel-releasing intrauterine system. a Values given as mean ± standard deviation or number (percentage), unless otherwise stated. b The multivariate analysis was applied only for variables with a P value b0.05 in the univariate analysis. c Calculated as weight in kilograms divided by the square of height in meters. d Non-recurrent disease (n=52); recurrent disease (n=5).
Please cite this article as: Kim M-L, et al, The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.03.017
4
M.-L. Kim et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx
rates during a median follow-up of 17 months were 10.5% for the combined oral contraceptives group and 4.8% for the LNG-IUS group (P = 0.461). However, the cumulative recurrence-free survival rate indicated that the mean disease-free survival time was longer in the LNG-IUS group (34.4 ± 1.0 months) than in the combined oral contraceptive group (33.4 ± 1.3 months; P = 0.045). Morelli et al. [27] assessed 48 patients treated with estradiol valerate plus dienogest and 44 patients treated with LNG-IUS for a period of 24 months after conservative surgery. The levels of cancer antigen 125 and the pain scores were reduced among patients treated with the combined oral contraceptive. However, rates of disease recurrence did not differ between the two groups. The recurrence rate at 12 months was 8.3% in the combined oral contraceptives group versus 12.5% in the LNG-IUS group (P = 0.41). Likewise, the recurrence rate at 24 months was 13.6% in the combined oral contraceptive group versus 20.5% in the LNG-IUS group (P = 0.30). Interestingly, treatment satisfaction at 24 months was markedly higher in the LNG-IUS group than in the combined oral contraceptives group. These results suggest that provision of postoperative LNG-IUS for long-term prevention of recurrence could be comparable to the use of combined oral contraceptives. The present study did not compare the postoperative recurrence rate achieved by LNG-IUS with that of combined oral contraceptives. Nonetheless, the cumulative recurrence rates for LNG-IUS use at 24 months (4.0%) and 36 months (6.3%) were similar to those previously reported [14,27]. The advantages of LNG-IUS over combined oral contraceptives include fewer systemic hormonal effects, freedom from daily medication, efficacy lasting at least 5 years, and proven effects for reduction of endometriosis-related pain. Consequently, LNG-IUS might be used as an alternative to combined oral contraceptives for the longterm postoperative prevention of recurrent ovarian endometrioma, either alone or in combination with a GnRH agonist. Considering the lower risk of recurrence among parous women than among nulliparous individuals, LNG-IUS could be considered a suitable option for patients who are not planning to conceive and who wish for long-term prevention of recurrent disease. A major strength of the present study was the long duration of follow-up, with 35 of the 61 patients followed up for longer than 3 years. Additionally, the cumulative probability of recurrent ovarian endometrioma at 5 years after LNG-IUS placement could be calculated in the present study. Nevertheless, some limitations must be addressed. First, the present study was based on retrospective data obtained from a small sample by medical record review. Thus, the follow-up period was not uniform and the exact timing of recurrence was unclear. Second, recurrence of pain was not considered as an outcome measure. This aspect is one of the most challenging to manage during the surgical treatment of endometriosis; however, an evaluation of pain recurrence in the present study would have required exclusion of other gynecologic conditions associated with pelvic pain or dysmenorrhea, such as leiomyoma or adenomyosis. Finally, diagnosis of recurrent ovarian endometrioma was primarily based on previously defined transvaginal ultrasonographic findings in the absence of pathologic confirmation [13]. In conclusion, the findings of the present study suggested that longterm maintenance therapy with LNG-IUS might be a viable treatment option for the prevention of recurrent ovarian endometrioma after surgery among premenopausal women, especially for those not planning any further pregnancies and requiring long-term prevention of recurrent disease. Large-scale prospective multicenter studies are now required to confirm these findings. Conflict of interest The authors have no conflicts of interest.
References [1] Winkel CA. Evaluation and management of women with endometriosis. Obstet Gynecol 2003;102(2):397–408. [2] Garry R. The effectiveness of laparoscopic excision of endometriosis. Curr Opin Obstet Gynecol 2004;16(4):299–303. [3] Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update 2009; 15(4):441–61. [4] Weir E, Mustard C, Cohen M, Kung R. Endometriosis: what is the risk of hospital admission, readmission, and major surgical intervention? J Minim Invasive Gynecol 2005;12(6):486–93. [5] Cheong Y, Tay P, Luk F, Gan HC, Li TC, Cooke I. Laparoscopic surgery for endometriosis: How often do we need to re-operate? J Obstet Gynaecol 2008;28(1):82–5. [6] Kim ML, Kim JM, Seong SJ, Lee SY, Han M, Cho YJ. Recurrence of ovarian endometrioma after second-line, conservative, laparoscopic cyst enucleation. Am J Obstet Gynecol 2014;210(3):216.e1–6. [7] Donnez J, Pirard C, Smets M, Jadoul P, Squifflet J. Surgical management of endometriosis. Best Pract Res Clin Obstet Gynaecol 2004;18(2):329–48. [8] Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014; 29(3):400–12. [9] Kim ML, Seong SJ. Clinical applications of levonorgestrel-releasing intrauterine system to gynecologic diseases. Obstet Gynecol Sci 2013;56(2):67–75. [10] Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Crosignani PG. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril 2003;80(2):305–9. [11] Tanmahasamut P, Rattanachaiyanont M, Angsuwathana S, Techatraisak K, Indhavivadhana S, Leerasiri P. Postoperative levonorgestrel-releasing intrauterine system for pelvic endometriosis-related pain: a randomized controlled trial. Obstet Gynecol 2012;119(3):519–26. [12] American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997;67(5): 817–21. [13] Exacoustos C, Zupi E, Carusotti C, Rinaldo D, Marconi D, Lanzi G, et al. Staging of pelvic endometriosis: role of sonographic appearance in determining extension of disease and modulating surgical approach. J Am Assoc Gynecol Laparosc 2003; 10(3):378–82. [14] Cho S, Jung JA, Lee Y, Kim HY, Seo SK, Choi YS, et al. Postoperative levonorgestrelreleasing intrauterine system versus oral contraceptives after gonadotropinreleasing hormone agonist treatment for preventing endometrioma recurrence. Acta Obstet Gynecol Scand 2014;93(1):38–44. [15] Kikuchi I, Takeuchi H, Kitade M, Shimanuki H, Kumakiri J, Kinoshita K. Recurrence rate of endometriomas following a laparoscopic cystectomy. Acta Obstet Gynecol Scand 2006;85(9):1120–4. [16] Koga K, Takemura Y, Osuga Y, Yoshino O, Hirota Y, Hirata T, et al. Recurrence of ovarian endometrioma after laparoscopic excision. Hum Reprod 2006;21(8):2171–4. [17] Vercellini P, Somigliana E, Daguati R, Vigano P, Meroni F, Crosignani PG. Postoperative oral contraceptive exposure and risk of endometrioma recurrence. Am J Obstet Gynecol 2008;198(5):504.e1–5. [18] Vercellini P, Somigliana E, Viganò P, De Matteis S, Barbara G, Fedele L. Post-operative endometriosis recurrence: a plea for prevention based on pathogenetic, epidemiological and clinical evidence. Reprod Biomed Online 2010;21(2):259–65. [19] Lee DY, Bae DS, Yoon BK, Choi D. Post-operative cyclic oral contraceptive use after gonadotrophin-releasing hormone agonist treatment effectively prevents endometrioma recurrence. Hum Reprod 2010;25(12):3050–4. [20] Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Populationbased study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997;349(9045):83–8. [21] Nilsson CG, Luukkainen T, Arko H. Endometrial morphology of women using a d-norgestrel-releasing intrauterine device. Fertil Steril 1978;29(4):397–401. [22] Hurskainen R, Salmi A, Paavonen J, Teperi J, Rutanen E. Expression of sex steroid receptors and Ki-67 in the endometria of menorrhagic women: effects of intrauterine levonorgestrel. Mol Hum Reprod 2000;6(11):1013–8. [23] Engemise SL, Willets JM, Taylor AH, Emembolu JO, Konje JC. Changes in glandular and stromal estrogen and progesterone receptor isoform expression in eutopic and ectopic endometrium following treatment with the levonorgestrel-releasing intrauterine system. Eur J Obstet Gynecol Reprod Biol 2011;157(1):101–6. [24] Maruo T, Laoag-Fernandez JB, Pakarinen P, Murakoshi H, Spitz IM, Johansson E. Effects of the levonorgestrel-releasing intrauterine system on proliferation and apoptosis in the endometrium. Hum Reprod 2001;16(10):2103–8. [25] Küpker W, Schultze-Mosgau A, Diedrich K. Paracrine changes in the peritoneal environment of women with endometriosis. Hum Reprod Update 1998;4(5):719–23. [26] McLaren J, Prentice A, Charnock-Jones DS, Millican SA, Müller KH, Sharkey AM, et al. Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest 1996;98(2): 482–9. [27] Morelli M, Sacchinelli A, Venturella R, Mocciaro R, Zullo F. Postoperative administration of dienogest plus estradiol valerate versus levonorgestrel-releasing intrauterine device for prevention of pain relapse and disease recurrence in endometriosis patients. J Obstet Gynaecol Res 2013;39(5):985–90.
Please cite this article as: Kim M-L, et al, The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.03.017