{"paper_id":"5fd786d7-d0dc-4626-adc7-02f0101446f8","body_text":"Original Article\nJ Gynecol Oncol Vol. 21, No. 2:102-105, June 2010  DOI:10.3802/jgo.2010.21.2.102\n102\nThe effectiveness of levonorgestrel releasing \nintrauterine system in the treatment of endometrial \nhyperplasia in Korean women\nSeo Yeong Lee, Mi Kyoung Kim, Hyun Park, Bo Sung Yoon, \nSeok Ju Seong, Jin Hee Kang, Hye Sun Jun, Chong T aik Park\nDepartment of Obstetrics and Gynecology, CHA University School of Medicine, Seoul, Korea\nObjective: Levonorgestrel releasing intrauterine system (LNG-IUS) has been shown to treat patients with non-atypical \n& atypical endometrial hyperplasia (EH) successfully in many western studies. Our purpose was to examine the \neffectiveness of LNG-IUS in the treatment of Korean women with EH.\nMethods: We conducted a prospective observational study of 12 women diagnosed with EH and treated with \nLNG-IUS insertion between February 2007 and August 2009 at the Department of Gynecology of Gangnam CHA \nHospital, CHA University School of Medicine. Baseline endometrial biopsies were done before insertion of LNG-IUS, \nand outpatient follow-up endometrial biopsies were undertaken at 3-month intervals after insertion of LNG-IUS. We \ninvestigated the regression rate and the time to regression. \nResults: Four patients had simple hyperplasia without atypia, 7 patients complex hyperplasia without atypia, and just \n1 patient complex atypical hyperplasia. Complete regression of EH was achieved in all cases (100%, 12/12), with the \nsignificant proportion (66%, 8/12) achieving it within 3 months. The mean duration to regression was 4.5 months. \nAll cases had regression within 9 months. In the case of complex atypical hyperplasia, the regression was attained at \nthe 9th month after insertion of LNG-IUS. The mean follow-up duration was 12 months (range, 3 to 27 months). As \nlong as LNG-IUS was maintained, the EH did not recur. \nConclusion: LNG-IUS appears to be as highly effective in treating Korean women with EH.\nKey Words: Endometrial hyperplasia, LNG-IUS, Korean women, Progestin, Mirena\nReceived January 10, 2010, Revised March 4, 2010,\nAccepted March 11, 2010\nCorrespondence to Seok Ju Seong\nDepartment of Obstetrics and Gynecology, CHA Gangnam Medical \nCenter, CHA University, 650-9 Yoksam-dong, Gangnam-gu, Seoul \n135-913, Korea\nTel: 82-2-3468-3672, Fax: 82-2-558-1112\nE-mail: sjseongcheil@yahoo.co.kr\nINTRODUCTION\nEndometrial hyperplasia (EH) is defined as a morphologic \nand biologic alteration of endometrium as a result of pro-\ntracted estrogen stimulation in the absence of progestin \ninfluence. EH has been regarded as a premalignant lesion. \nCytologic atypia is the most important factor for progression \nto carcinoma.\n1-3 About 1-3% of hyperplasia without atypia \nwere observed to progress to carcinoma over 10 years' fol-\nlow-up. On the contrary, 8-29% of atypical hyperplasia prog-\nress to carcinoma over 4 years' follow up.\n1 \nThe goals of treating women with EH include not only reliev-\ning the symptoms of abnormal uterine bleeding but also pre-\nventing progression to carcinoma.4,5 From the viewpoint of \noncogenic potential of EH, hysterectomy has been generally \nrecommended for the treatment of atypical EH except when \nthe women have strong desire for fertility or have serious sur-\ngical risk factors.\n4,6,7 Oral progesterone has been used to treat \nwomen with EH who want to the conserve uterus. But some \nsystemic side effects and poor compliance have been reported \nto be associated with oral progesterone. Compared with oral \nprogesterone, LNG-IUS has been reported to have less sys-\ntemic side effects and higher efficacy for the treatment of EH \nin many studies targeting the women of western countries.\n8-12 \nTo our knowledge, there has been no study reporting the effec-\ntiveness of LNG-IUS in treating Korean women with EH. Con-\nsidering the variation of treatment responses among the varia-\nble ethnicity, we investigated the effectiveness of LNG-IUS in \ntreating non-atypical and atypical EH in Korean women. \nMATERIALS AND METHODS\nTwelve patients participating in this study had presented \n\nThe effectiveness of levonorgestrel releasing intrauterine system in the treatment of endometrial hyperplasia in Korean women\n103\nTable 1. Baseline characteristics\nCharacteristics Mean values\nAge (yr)\nBody weight (kg)\nBody mass index (kg/m2)\nParity \n　0\n　1\n　2\nMenopause premenopausal\nDiabetes mellitus \nHypertension\n39.1 (25-46)\n53.5 (46-62)\n21.40 (17.47-25.51)\n6 (50)\n   2 (16.7)\n   4 (33.3)\n12 (100)\n1 (10)\n1 (10)\nValues are presented as mean (range) or number (%).\nTa b l e  2 . Levonorgestrel releasing intrauterine system (LNG-IUS) insertion and follow-up of regression of endometrial hyperplasia\nCase no. Age Parity T ype Time to regression (mo)* Biopsy result Follow-up (mo)\n    1†\n  2\n  3\n  4\n  5\n  6\n  7\n  8\n  9\n10\n11\n12\n44\n25\n29\n40\n46\n41\n37\n32\n43\n34\n45\n44\n2\n0\n0\n2\n2\n1\n0\n0\n0\n0\n2\n1\nSH\nCHA\nSH\nSH\nCH\nCH\nCH\nCH\nCH\nCH\nSH\nCH\n6\n9\n6\n9\n3\n3\n3\n3\n3\n3\n3\n3\nSD, AG, PE\nSD, AG, PE\nSD, AG, PE\nSD, PE\nSD, IG, PE\nSD, AG\nSD, IG, PE\nSD, IG, PE\nSD, IG, PE\nSD, IG, PE \nSD, IG, PE\nSD, IG, PE\n30\n27\n24\n  9\n12\n11\n  6\n  6\n  6\n  3\n  3\n  3\nSH: simple hyperplasia without atypia, CHA: atypical complex hyperplasia, CH: complex hyperplasia without atypia, SD: stromal pseudodeci-\ndualization, AG: atrophic glands, IG: inactive glands, PE: consistent with Progeterone effect. \n*Complete regression was defined as endometrial atrophy, pseudodecidualization of stroma without evidence of hyperplasia. It could be ac-\ncompanied by secretory change of glandular tissue or metaplasia.\n4,14 †This patient got the regression after LNG-IUS insertion, but she wanted \nto remove her LNG-IUS because of breast pain. It was removed at 24th month later.\nwith abnormal uterine bleeding to the Gynecologic Depart-\nment, Gangnam CHA Hospital. All women were diagnosed \nwith EH and treated with LNG-IUS (Mirena\n®) from February \n2007 to August 2009. \nFor diagnosis and assessment of treatment responses, we \nperformed transvaginal sonography (TVS) and outpatient en-\ndometrial biopsy. The methods of endometrial biopsy were \nendometrial sampling with a catheter (8 women, 66.6%), \nD&C (3 women, 25%), and hysterscopic biopsy (1 woman, \n8.3%). One patient who had been suspected of an endometrial \npolyp on TVS was eventually diagnosed with EH after hystero-\nscopic polypectomy, and she entered the study. \nEH was divided into 4 categories by the Kurman criteria: \nsimple hyperplasia without atypia, complex hyperplasia with-\nout atypia, simple hyperplasia with atypia, and complex hy-\nperplasia with atypia.\n13 In assessing the histological treatment \nresponse, complete regression was defined as endometrial \natrophy, pseudodecidualization of stroma without evidence \nof hyperplasia. Complete regression could be accompanied by \nsecretory change of glandular tissue or metaplasia.\n4,14\nWe collected the demographic data including age and risk \nfactors for EH, such as parity, weight, height, diabetes, and \nhypertension. The method of initial diagnosis and the type of \nEH were recorded. During follow-up at scheduled intervals, \nwe conducted TVS and endometrial biopsy using a Walleth \ncatheter with IUD in situ. The first two follow-ups were \nscheduled at the 3rd month and 6th month after insertion. If \ncomplete regression was achieved within 6 months, the fol-\nlow-up interval was extended to 6 months thereafter.   The \nprimary outcome was the proportion of women with complete \nregression of EH. The secondary outcome was the time to \ncomplete regression. \nRESULTS\n1. Baseline characteristics\nTwelve women with EH (simple hyperplasia without atypia \n4, complex hyperplasia without atypia 7, complex hyperplasia \nwith atypia 1) were included in this study. The summary of \nthe baseline characteristics are shown in Table 1. The mean \nage was 39.1 years (range, 25 to 46 years). All women included \nwere premenopausal. Six among the twelve women were \nnulliparous. \n2. Endometrial regression after LNG-IUS insertion\nThe outcomes of the study is summarized in Table 2. All \nwomen developed a thin endometrium (≤4 mm) on TVS \nexamination. All women achieved endometrial regression \nwithin 9 months after LNG-IUS insertion. In eight women out \nof twelve (66%), the regression was achieved at the 3rd \nmonth. The mean time to regression was 4.5 months. EH re-\ncurred in 1 patient whose LNG-IUS had been removed be-\ncause of breast pains associated with LNG-IUS. Except for \n\nJ Gynecol Oncol Vol. 21, No. 2:102-105, 2010 Seo Yeong Lee, et al.\n104\nthis case, there has been no other recurrence to date. \nIn the patient with CAH, complete regression was achieved \nat the 9th month, and has sustained until now for 21 months. \nDISCUSSION\nEH represents a spectrum from an exaggerated physiologic \nstate to carcinoma in situ, as a result of unopposed estrogen \nstimulation in the absence of progestin influence. EH are im-\nportant clinically because they may cause abnormal uterine \nbleeding, and precede or occur concurrently with endometrial \ncarcinoma. Cytologic atypia is the most important risk factor \nfor progression to carcinoma. \nWhen it comes to EH without atypia, the malignant potential \nis low, the rate of spontaneous resolution is high\n1-3 and the thera-\npeutic response to oral progesterone is also high. Therefore, \nhysterectomy for EH without atypia may be regarded as an \nover-treatment.\n4-8 According to three observational studies, \nthe rate of spontaneous resolution for EH without atypia was \n72% which was higher than 54% of atypical hyperplasias.\n2-4 \nRecently, conservative treatment has been considered to be ac-\nceptable when the strict follow-up is possible to detect cases \nof persistence, recurrence, and progress to carcinoma.\n15\nOral progesterone has been used to treat women with EH \nwho wish to conserve the uterus. But some systemic side ef-\nfects and poor compliance have been reported to be associated \nwith oral progesterone. Compared with oral progesterone, \nLNG-IUS has been reported to have less systemic side effects \nand higher efficacy for the treatment of EH in many studies \ntargeting the women of western countries.\n6-12 LNG-IUS has \nbeen regarded as a beneficial conservative treatment modality \nfor non-atypical and atypical EH.\n8-12 But none of these studies \nhave targeted Korean women. Thus, we do not have any reli-\nable data for Korean women with EH. Besides, we had to con-\nsider the variation of treatment responses and the side effects \nof LNG-IUS according to Korean ethnicity. The results of this \nstudy support that LNG-IUS may also be a highly effective \nmethod for suppressing non-atypical and atypical EH in \nKorean women. The regression rate was 100%. The advanta-\ngeous effects were observed within 9 months in all cases. \nA significant proportion of the patients with non-atypical hy-\nperplasia achieved regression at the 3rd month after LNG-IUS \ninsertion. This success can be compared with the results of a \nrecent long-term follow-up large observational European study, \nin which the regression rates of non-atypical hyperplasia and \natypical hyperplasia were 90% and 54%, respectively.\n10 In this \nstudy, one patient with atypical hyperplasia achieved com-\nplete regression with LNG-IUS insertion at the 9th month. \nThe results of our study targeting Korean women were in \nagreement with the beneficial effects of LNG-IUS on non- \natypical and atypical EH observed in many other studies tar-\ngeting western women.\nThere are weaknesses in this study. The first one is the small \nsample size of this study. Especially, there was only one case \nof atypical hyperplasia included in this study. The second one \nis that we conducted follow-up endometrial biopsies with the \nLNG-IUS in situ. The presence of the LNG-IUS in the uterine \ncavity may affect the accuracy of the endometrial biopsy. A \nlarge, long-term follow-up study may overcome these weak-\nnesses. Nevertheless, this is the first study to evaluate the ef-\nfectiveness of LNG-IUS for treatment of EH in Korean wom-\nen, and the result was successful.\nCONFLICT OF INTEREST\nNo potential conflict of interest relevant to this article was \nreported.\nREFERENCES\n1. Kurman RJ, Kaminski PF , Norris HJ. The behavior of endo-\nmetrial hyperplasia: a long-term study of \"untreated\" hyper-\nplasia in 170 patients. Cancer 1985; 56: 403-12.\n2. T abata T , Y amawaki T , Y abana T , Ida M, Nishimura K, Nose Y . \nNatural history of endometrial hyperplasia: study of 77 \npatients. Arch Gynecol Obstet 2001; 265: 85-8.\n3 . T e r a k a w a  N ,  K i g a w a  J ,  T a k e t a n i  Y ,  Y o s h i k a w a  H ,  Y a j i m a  A ,  \nNoda K, et al. The behavior of endometrial hyperplasia: a pro-\nspective study. Endometrial Hyperplasia Study Group. J Obstet \nGynaecol Res 1997; 23: 223-30.\n4. Clark TJ, Neelakantan D, Gupta JK. The management of endo-\nmetrial hyperplasia: an evaluation of current practice. Eur J \nObstet Gynecol Reprod Biol 2006; 125: 259-64.\n5. Montgomery BE, Daum GS, Dunton CJ. Endometrial hyper-\nplasia: a review. Obstet Gynecol Surv 2004; 59: 368-78.\n6. Marsden DE, Hacker NF . Optimal management of endometrial \nhyperplasia. Best Pract Res Clin Obstet Gynaecol 2001; 15: \n393-405.\n7 . F e r e n c z y  A ,  G e l f a n d  M .  T h e  b i o l o g i c  s i g n i f i c a n c e  o f  c y t o l o g i c \natypia in progestogen-treated endometrial hyperplasia. Am J \nObstet Gynecol 1989; 160: 126-31.\n8. Wildemeersch D, Janssens D, Pylyser K, De Wever N, Verbeeck G, \nDhont M, et al. Management of patients with non-atypical and \natypical endometrial hyperplasia with a levonorgestrel-releasing \nintrauterine system: long-term follow-up. Maturitas 2007; 57: \n210-3.\n9. Orbo A, Arnes M, Hancke C, Vereide AB, Pettersen I, Larsen K. \nTreatment results of endometrial hyperplasia after prospective \nD-score classification: a follow-up study comparing effect of \nLNG-IUD and oral progestins versus observation only. Gynecol \nOncol 2008; 111: 68-73.\n10. Varma R, Soneja H, Bhatia K, Ganesan R, Rollason T , Clark TJ, \net al. The effectiveness of a levonorgestrel-releasing intra-\nuterine system (LNG-IUS) in the treatment of endometrial hy-\nperplasia: a long-term follow-up study. Eur J Obstet Gynecol \nReprod Biol 2008; 139: 169-75.\n11. Vereide AB, Kaino T , Sager G, Arnes M, Orbo A. Effect of levo-\nnorgestrel IUD and oral medroxyprogesterone acetate on glan-\ndular and stromal progesterone receptors (PRA and PRB), and \nestrogen receptors (ER-alpha and ER-beta) in human endo-\nmetrial hyperplasia. Gynecol Oncol 2006; 101: 214-23.\n12. Vereide AB, Arnes M, Straume B, Maltau JM, Orbo A. Nuclear \nmorphometric changes and therapy monitoring in patients \nwith endometrial hyperplasia: a study comparing effects of in-\ntrauterine levonorgestrel and systemic medroxyprogesterone. \nGynecol Oncol 2003; 91: 526-33.\n\nThe effectiveness of levonorgestrel releasing intrauterine system in the treatment of endometrial hyperplasia in Korean women\n105\n13. Lurain JR. Uterine cancer. In: Berek JS, editor. Berek & Novak's \ngynecology. 14th ed. Philadelphia: Lippincott Williams & Wilkins; \n2007. p.1343-402.\n14. Phillips V , Graham CT , Manek S, McCluggage WG. The effects \nof the levonorgestrel intrauterine system (Mirena coil) on en-\ndometrial morphology. J Clin Pathol 2003; 56: 305-7.\n15. Jadoul P , Donnez J. Conservative treatment may be beneficial \nfor young women with atypical endometrial hyperplasia or en-\ndometrial adenocarcinoma. Fertil Steril 2003; 80: 1315-24.","source_license":"CC0","license_restricted":false}