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Obstet Gynecol Sci > Volume 56(2); 2013 > Article
Kim and Seong: Clinical applications of levonorgestrel-releasing intrauterine system to gynecologic diseases

Abstract

The levonorgestrel-releasing intrauterine system (LNG-IUS), originally designed for contraception, has since been applied to various gynecologic diseases. This article summarizes the current status of clinical applications of LNG-IUS to the treatment of gynecologic diseases such as heavy menstrual bleeding, endometriosis, leiomyoma, adenomyosis, endometrial hyperplasia, and early-stage endometrial cancer.

Introduction

The levonorgestrel-releasing intrauterine system (LNG-IUS), designed initially in the mid-1970s, provides highly effective, safe, and long-term reversible contraception. More than 120 countries, including Korea, have approved it for use [1]. The approved Korean applications include contraception, treatment of heavy menstrual bleeding, treatment of dysmenorrhea, and endometrial protection during estrogen replacement therapy in postmenopausal women. LNG-IUS is a T-shaped device that releases 20 µg/day of LNG into the uterine cavity over a 5-year period [2]. LNG-IUS provides, by contrast with the relatively low serum levels, locally high concentrations of LNG in the endometrium and adjacent tissues. This leads to decidualization of the stroma, mucosal thinning, and eventually, by suppression of endometrial growth, an inactive endometrium [3]. It has been demonstrated that LNG-IUS, additionally to its high contraceptive efficacy, benefits women also in the treatment of gynecologic diseases related to heavy menstrual bleeding and dysmenorrheal, which include endometriosis, leiomyoma, adenomyosis, endometrial hyperplasia, and early-stage endometrial cancer [4,5]. In this article, we summarize the current clinical applications status of LNG-IUS as relates to gynecologic diseases.

Heavy Menstrual Bleeding

Heavy menstrual bleeding (HMB), clinically defined as greater than 80 mL of blood loss per menstrual cycle, is a common health problem in women. Hysterectomy is an often-employed treatment option, though various alternative approaches, such as tranexamic acid, nonsteroidal anti-inflammatory drugs, danazol, combined oral pills, progestins, and LNG-IUS, also can be successful.
Hurskainen et al. [6] conducted a 5-year randomized comparison of clinical outcomes and costs associated with the use of LNG-IUS and hysterectomy for treatment of HMB. In the results, patient' satisfaction and quality of life were similar, but costs were 40% lower in the LNG-IUS group. Lethaby et al. [7] published a review of ten randomized controlled trials with reproductive-aged women treated with LNG-IUS versus medical (cyclic progestins) or surgical therapy (hysteroscopic endometrial resection, thermal ablation, or hysterectomy). LNG-IUS was more effective than cyclic progestins; and whereas side effects were more common, the LNG-IUS patients were more satisfied with their results. Endometrial ablation was more effective than LNG-IUS for reduction of menstrual blood loss, and yet there was no difference in patient' satisfaction between the groups. Once again, women treated with LNG-IUS experienced more drug-induced side effects, but there was no significant difference in their perceived quality of life. Comparing LNG-IUS with hysterectomy, the former was more cost effective, and there were no significant differences in the quality of life measures [7]. Gupta et al. [8] conducted a multicenter, randomized controlled trial involving 571 women with HMB who were treated with LNG-IUS or the usual medical therapy (tranexamic acid, mefenamic acid, combined estrogen-progestogen, or progestogen alone). In both groups, the patient-reported scores on the menorrhagia multi-attributes scale (MMAS) improved from the baseline to six months, though the LNG-IUS group showed significantly better improvement sustainment over a 2-year period (P<0.001). Moreover, all of the MMAS domains showed significantly superior improvements for the LNG-IUS group. Also, at 2 years, the LNG-IUS group had a higher continuation rate than the usual-medical-treatment group (64% vs. 38%, P<0.001), with no significant differences in the rates of hysterectomy, endometrial ablation or sexual activity scores [8]. The LNG-IUS is a good alternative to surgical management such as hysterectomy and endometrial ablation in heavy menstrual bleeding. In ESHRE Capri Workshop Group [9], they recommended that the LNG-IUS or other medical treatments firstly adopted in treatment of HMB. Overall, LNG-IUS was proved to be highly effective in reducing menstrual blood loss, was well tolerated, boasted a high user-satisfaction rate, and was cost effective [9]. Currently, LNG-IUS is considered to be the first-line treatment for HMB [10].

Endometriosis

Endometriosis is associated with dysmenorrhea, dyspareunia, non-cyclic pelvic pain, and subfertility. For women with dysmenorrhea, reported endometriosis incidences have been as high as 40% to 60% [11,12]. Endometriosis is a chronic disease that has a recurrence rate of approximately 10% to 15% one year after conservative surgical treatment alone, and fully 40% to 50% at 5 years' follow-up [13,14]. Cheong et al. [15], having conducted a retrospective study, reported re-operation rate as high as 51% for a 10-year period. Recurrence is a important issue indeed, as repeated surgery can significantly impact upon the patient's quality of life and endanger her future fertility [16]. In order to prolong symptom-free interval and prevent recurrence, postoperative adjunctive hormonal therapy usually is prescribed. Gonadotropin releasing hormone (GnRH) agonist, danazol, combined oral contraceptives, and progestins are the common hormonal methods employed for the management of endometriosis-related pain. GnRH agonist is the gold standard for adjunctive treatment of endometriosis [17]. Such treatment often needs to be continued many years or until pregnancy is desired. Although effective, the hypoestrogenism induced by the GnRH agonist is associated with systemic side effects, which can affect patient' compliance and preclude long-term use. Thus, new therapeutic options, including the continuous use of oral pills or LNG-IUS, are being explored [18-21].
Several hypotheses have been formulated to explain the mechanism of action of LNG-IUS in endometriosis-related pain. One is a local effect on the ectopic endometrium resulting from depletion of the estrogen and progesterone receptors though inhibition of synthesis and expression of estrogen and progestin receptors [22,23]. Other possibilities are a direct effect on the eutopic endometrium by inhibition of endometrial production of estrogen-induced growth factors or growth factor-binding protein, as resulting in an anti-proliferative effect, glandular atrophy and decidualization [24]. Or, the LNG-IUS effect might be a function of a reduction of local vascular angiogenesis, a reduction in pelvic-vessel congestion and an increase in apoptosis, a reduction in peritoneal fluid macrophage activity and a modification in the production of cytokines responsible for maintenance of lesions and pain [25-28].
LNG-IUS was first used for endometriosis-related dysmenorrhea by Vercellini et al. [29]. They reported that it greatly reduced menstrual pain and was highly rated in terms of patient satisfaction. As a follow-up to this pilot study, Vercellini et al. [30] thoroughly investigated the application of LNG-IUS to endometriosis in a randomized controlled trial, comparing it with expectant management after laparoscopic conservative surgery. According to a post-12-month evaluation, and an intention-to-treat analysis, postoperative recurrence of dysmenorrhea was significantly decreased in the LNG-IUS group (10% vs. 45%, P=0.03). Tanmahasamut et al. [31], similarly, conducted a double-blind randomized controlled trial with 55 post-conservative-surgery patients. At 12 months, the LNG-IUS group relative to an expectant group, showed a greater reduction in dysmenorrhea visual analogue scale (VAS) (-81 mm vs. -50 mm, P=0.06) and pelvic pain VAS (-48.5 mm vs. -22 mm, P=0.038). Recurrent dysmenorrhea within one year also was reduced in the LNG-IUS group (7.4% vs. 39.1%, P=0.014) [31]. Petta et al. [32] conducted a multicenter randomized controlled trial to compare LNG-IUS (n=39) with a GnRH agonist (n=43), finding no statistical differences in VAS pain score or quality-of-life improvement. However, Bayoglu et al. [33] reported different results for a 12-month prospective randomized study involving 40 severe endometriosis patients. They reported that the total endometriosis severity profile (TESP) score decreased in the LNG-IUS group over the initial 6 months, but that by 12 months of follow-up, the TESP scores had risen back to values similar to those at pretreatment. At the end of the study, the LNG-IUS group relative to the GnRH subjects showed a significant increase in VAS and TESP scores, and recorded lower levels of satisfaction [33]. Even so, given the additional advantages of LNG-IUS, namely the facts that it is not associated with hypoestrogenism and the possibility of long-term (5-year) use, it may yet be used for chronic pelvic pain-associated endometriosis in women who do not wish to conceive.

Leiomyoma

Leiomyoma is the most common benign gynecologic tumor in reproductive-aged women, producing symptoms including HMB, dysmenorrhea, pelvic pressure and pain, and reproductive dysfunction, though many patients remain asymptomatic [34,35].
In many studies, LNG-IUS use by leiomyoma patients ameliorated leiomyoma-related menorrhagia. This treatment modality is utilized primarily in cases of leiomyoma-related HMB, though treatment is not as effective as for idiopathtic HMB [36-41]. Sivin and Stern [42] reported a multicenter prospective 7-year randomized study, the chief finding of thich was that long-term use of LNG-IUS reduced the incidence of newly developed myoma and myoma-related surgery in comparison with copper T. However, there is no coherence to changes of uterine volume or leiomyoma volume in users of LNG-IUS [36,41,43].
There are some limitations on the suitability of LNG-IUS for women with leiomyoma, including leiomyomas causing distortion of the uterine cavity or cases of submucosal myoma [44]. The reported LNG-IUS expulsion rates among women with uterine leiomyomas range between 0% and 20%, and are higher than those without uterine leiomyoma (0% to 3%). Also, significantly higher rates of expulsion have been noted among women with greater uterine volumes (a possible proxy for fibroid size) than among those with smaller ones [36-39,45,46].

Adenomyosis

Adenomyosis characterized by the presence of heterotopic endometrial glands and stroma in the myometrium, is a common cause of menorrhagia and dysmenorrhea. The definitive treatment is hysterectomy, at least traditionally. However, alternative management, including oral pills, danazol, GnRH agonist, LNG-IUS, endometrial ablation/resection, uterine artery embolization, and magnetic resonance guided focused ultrasound also can be considered [47-55].
The use of LNG-IUS for adenomyosis was first reported by Fedele et al. [50], in 1997. They evaluated the efficacy of LNG-IUS in 25 patients suffering from adenomyosis-associated menorrhagia, and found that 92% of them showed decreases on the pictorial blood loss assessment chart (PBAC) and diminished dysmenorrheal symptoms, along with significant increases in hemoglobin, hematocrit, and serum ferritin levels [50]. Bragheto et al. [56] reported on the employment of LNG-IUS in the treatment of 29 adenomyosis patients diagnosed and monitored by magnetic resonance imaging. After 6 months, significant reductions of junctional zone thickness and VAS pain scores were observed, though there was no significant change in uterine volume. Cho et al. [57] and Sheng et al. [58] reported 3-year follow-up data on the application of LNG-IUS for the treatment of adenomyosis, in which indicated significantly decreased menorrhagia and VAS pain scores and high patient' satisfaction. Additionally to these observational study, Ozdegirmenci et al. [59] compared LNG-IUS with hysterectomy in a prospective randomized trial, the results of which showed that the LNG-IUS group enjoyed significant and comparable improvements in hemoglobin levels and along with superior health-related quality of life improvements during the first year. Conclusively, LNG-IUS is an effective treatment option for management of dysmenorrhea and menorrhagia in patients with clinically diagnosed adenomyosis. As such, it offers patients a practical alternative to hysterectomy.

Endometrial Hyperplasia

Endometrial hyperplasia is defined as a morphologic and biologic alteration of the endometrium as a result of continuous estrogenic stimulation unopposed by adequate levels of progesterone. Among reproductive-aged women, chronic anovulation, commonly seen in those diagnosed with polycystic ovarian syndrome, is the most common cause of endogenous unopposed estrogen [60].
Hormonal therapy is regarded as the standard management plan for endometrial hyperplasia without atypia or benign endometrial hyperplasia, owing to the facts that the malignany potential is low, the spontaneous resolution rate is high, and the response to hormonal therapy, moreover, also is high [61,62]. In the case of atypical endometrial hyperplasia, total hysterectomy with or without bilateral salpingooophorectomy is the current standard treatment option [63]. However, hormonal therapy can be selected in atypical endometrial hyperplasia patients who desire to preserve their fertility or in patients who are poor surgical candidates due to severe medical comorbidities. The hormonal classes with potential therapeutic options include progestins, selective estrogen receptor modulators, aromatase inhibitors, and gonadotropin-releasing hormone agonists. Among these, progestin is most commonly used as the safe, uterus-preserving alternative to hysterectomy. Nonetheless, systemic side effects and poor compliance reportedly are associated with oral progesterone; clinical trials of progestin therapies for atypical endometrial hyperplasia, furthermore, have not yet established a standard regimen [64-66].
Compared with oral progestin, LNG-IUS in many studies has been found to have less severe systemic side effects and higher efficacy as a treatment for endometrial hyperplasia [66-71]. Gallos et al. [72] recently published a systematic review and meta-analysis of 24 studies that had compared endometrial hyperplasia regression rates between oral progestin and LNG-IUS for a total of 1,001 patients. In cases of simple hyperplasia, 213 women (9 studies) treated with oral progestin showed a pooled regression rate of 89%, versus the 96% rate for 72 LNG-IUS patients (6 studies). Meta-regression confirmed that these rates were not statistically significant (P=0.41). In cases of complex hyperplasia, 389 patients (9 studies) administered oral progestin showed a pooled regression rate of 66%, versus the 92% rate for 102 LNG-IUS patients (4 studies). Overall, the treatment outcomes for LNG-IUS were statistically more significant than those for oral progestin (P<0.01). In atypical hyperplasia, 189 women (14 studies) treated with oral progestin showed a pooled regression rate of 69%, versus the 90% rate for 36 LNG-IUS patients (7 studies) (P=0.03) [72].
Lee et al. [73] reported on the effectiveness of LNG-IUS in 12 patients (4 simple, 7 complex, 1 atypical complex hyperplasia) evaluated at our institution in Korea. In all of the cases, complete regression of endometrial hyperplasia was achieved. The mean duration to regression was 4.5 months (66% achieved compete regression within 3 months), and all of the patients had achieved regression within 9 months. Additionally, a prospective multicenter trial on Korean women (planned number of patients: 80), this one by the Korean Gynecologic Oncology Group (KGOG2006), has been ongoing since 2006 [74].

Early-stage Endometrial Cancer

Endometrial carcinoma is the most common gynecologic malignancy in developed countries [75,76]. The majority of cases are diagnosed in postmenopausal women, and up to 14% of patients are premenopausal, among whom 3% to 5% are aged under 40 years, 70% of those 3% to 5% being nulliparous at the time of diagnosis [77,78]. On histologic examination, 84% of all endometrial cancers are endometroid adenocarcinomas, which typically have a good prognosis [79]. Endometrial cancer in younger women usually is most commonly of the early clinical stage, well-differentiated and endometrioid type, which also carries a good prognosis [80]. The current standard treatment is total hysterectomy and bilateral salpingo-oophorectomy with or without surgical staging [81-83]. However, the data from multiple studies suggest that for select patients with early clinical stage carcinoma and a strong desire to maintain fertility, hormonal therapy is an attractive and effective alternative [84-88].
Progestins are the first medical treatment option for endometrial cancer. Progestins effect secretory differentiation of endometrial glands, inhibit estrogen receptor function and endometrial cell mitosis, and promote apoptosis; additionally, some progestins have an anti-angiogenic effect [89]. According to a meta-analysis by Gallos et al. [90], a total 408 women (32 studies) who underwent fertility-sparing treatment by various methods, including progestin, LNG-IUS, GnRH agonist, aromatase inhibitor, and hysteroscopic resection, showed a pooled regression rate of 76.2%, a relapse rate of 40.6%, and a live birth rate of 28%.
Montz et al. [91] reported the results of LNG-IUS-based treatment of the International Federation of Gynecology and Obstetrics (FIGO) stage IA, grade 1 endometrioid cancer patients at high risk for perioperative complications. Among 12 patients, the biopsy results were negative for 64% at 6 months and 75% at 12 months. Cade et al. [92] reported on 16 patients who had been treated with MPA (4 patients), LNG-IUS (3 patients), or both (9 patients). Ten of the patients responded to treatment (MPA only, 2; LNG-IUS only, 1; both, 7), and the mean time to response was 5.5 months. The results of 5 young patients who had been treated, at our institution, with a daily 500 mg dose of MPA plus LNG-IUS insertion were published in 2010. Complete remission was achieved for 4 patients, and another one showed partial remission. During the mean 10.2 months follow-up period, there was no recurrence of disease [93]. Also in Korea, a prospective multicenter study (KGOG2009), initiated in 2009, has been treating patients with 500 mg of MPA plus LNG-IUS for early-stage endometrial cancer in young women [94].
Hormonal management with LNG-IUS and supplemental oral progestin appears to be a safe and moderately effective option for early-stage endometrial cancer patients who want to retain their reproductive potential. However, given that the relapse rate is higher than 40% [90], post-childbirth women should consider hysterectomy, which remains the standard of care.

Conclusion

The non-contraceptive benefits of LNG-IUS, particularly the effects on heavy menstrual bleeding and dysmenorrhea, as well as the option for 5-year use, add to its utility and efficacy as an alternative to long-term contraception. LNG-IUS in fact has proved to be an effective treatment modality for a great variety of gynecologic conditions: idiopathic, myoma- or adenomyosis-related HMB, endometriosis- or adenomyosis-related pelvic pain, as well as endometrial hyperplasia and early-stage endometrial cancer. However, further large-scale randomized study and comparion with conventional treatment methods, along with long-term follow-up data, are needed.

References

1. Salem RM. New attention to the IUD: expanding women's contraceptive options to meet their needs. Popul Rep B 2006;1-26. PMID: 16671535.
pmid
2. Mirena [Internet]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; c2013. cited 2013 Feb 15. Available from: http://berlex.bayerhealthcare.com/html/products/pi/Mirena_PI.pdf.

3. Perino A, Quartararo P, Catinella E, Genova G, Cittadini E. Treatment of endometrial hyperplasia with levonorgestrel releasing intrauterine devices. Acta Eur Fertil 1987;18:137-140. PMID: 3115027.
pmid
4. Inki P. Long-term use of the levonorgestrel-releasing intrauterine system. Contraception 2007;75:S161-S166. PMID: 17531611.
crossref pmid
5. Heikinheimo O, Gemzell-Danielsson K. Emerging indications for the levonorgestrel-releasing intrauterine system (LNG-IUS). Acta Obstet Gynecol Scand 2012;91:3-9. PMID: 22007693.
crossref pmid
6. Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivela A, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. JAMA 2004;291:1456-1463. PMID: 15039412.
crossref pmid
7. Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev 2005;(4):CD002126PMID: 16235297.
pmid
8. Gupta J, Kai J, Middleton L, Pattison H, Gray R, Daniels J, et al. Levonorgestrel intrauterine system versus medical therapy for menorrhagia. N Engl J Med 2013;368:128-137. PMID: 23301731.
crossref pmid
9. ESHRE Capri Workshop Group. Intrauterine devices and intrauterine systems. Hum Reprod Update 2008;14:197-208. PMID: 18400840.
crossref pmid
10. Espey E. Levonorgestrel intrauterine system: first-line therapy for heavy menstrual bleeding. N Engl J Med 2013;368:184-185. PMID: 23301736.
crossref pmid
11. Gruppoitaliano per lo studio dell'endometriosi. Prevalence and anatomical distribution of endometriosis in women with selected gynaecological conditions: results from a multicentric Italian study. Hum Reprod 1994;9:1158-1162. PMID: 7962393.
crossref pmid
12. Ajossa S, Mais V, Guerriero S, Paoletti AM, Caffiero A, Murgia C, et al. The prevalence of endometriosis in premenopausal women undergoing gynecological surgery. Clin Exp Obstet Gynecol 1994;21:195-197. PMID: 7923803.
pmid
13. Evers JL, Dunselman GA, Land JA, Bouckaert PX. Is there a solution for recurrent endometriosis? Br J Clin Pract Suppl 1991;72:45-50. PMID: 1807361.
pmid
14. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update 2009;15:441-461. PMID: 19279046.
crossref pmid
15. 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;28:82-85. PMID: 18259906.
crossref pmid
16. Park HJ, Koo YA, Yoon BK, Choi D. Postoperative long-term maintenance therapy with oral contraceptives after gonadotropin-releasing hormone analog treatment in women with ovarian endometrioma. J Minim Invasive Gynecol 2009;16:34-39. PMID: 18976968.
crossref pmid
17. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev 2000;(2):CD000346PMID: 10796530.
crossref pmid
18. Yap C, Furness S, Farquhar C. Pre and post operative medical therapy for endometriosis surgery. Cochrane Database Syst Rev 2004;(3):CD003678PMID: 15266496.
crossref pmid pmc
19. Abou-Setta AM, Al-Inany HG, Farquhar CM. Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database Syst Rev 2006;(4):CD005072PMID: 17054236.
pmid
20. Parazzini F, Fedele L, Busacca M, Falsetti L, Pellegrini S, Venturini PL, et al. Postsurgical medical treatment of advanced endometriosis: results of a randomized clinical trial. Am J Obstet Gynecol 1994;171:1205-1207. PMID: 7977520.
crossref pmid
21. Busacca M, Somigliana E, Bianchi S, De Marinis S, Calia C, Candiani M, et al. Post-operative GnRH analogue treatment after conservative surgery for symptomatic endometriosis stage III-IV: a randomized controlled trial. Hum Reprod 2001;16:2399-2402. PMID: 11679528.
crossref pmid
22. Nilsson CG, Luukkainen T, Arko H. Endometrial morphology of women using a d-norgestrel-releasing intrauterine device. Fertil Steril 1978;29:397-401. PMID: 648644.
crossref pmid
23. 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;6:1013-1018. PMID: 11044464.
crossref pmid
24. Luukkainen T. The levonorgestrel intrauterine system: therapeutic aspects. Steroids 2000;65:699-702. PMID: 11108879.
crossref pmid
25. 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;16:2103-2108. PMID: 11574499.
crossref pmid
26. Ramey JW, Archer DF. Peritoneal fluid: its relevance to the development of endometriosis. Fertil Steril 1993;60:1-14. PMID: 8513924.
crossref pmid
27. Kupker W, Schultze-Mosgau A, Diedrich K. Paracrine changes in the peritoneal environment of women with endometriosis. Hum Reprod Update 1998;4:719-723. PMID: 10027625.
crossref pmid
28. McLaren J, Prentice A, Charnock-Jones DS, Millican SA, Muller 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;98:482-489. PMID: 8755660.
crossref pmid pmc
29. Vercellini P, Aimi G, Panazza S, De Giorgi O, Pesole A, Crosignani PG. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril 1999;72:505-508. PMID: 10519624.
crossref pmid
30. 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;80:305-309. PMID: 12909492.
pmid
31. 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;119:519-526. PMID: 22314873.
crossref pmid
32. Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa ESJC, Podgaec S, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod 2005;20:1993-1998. PMID: 15790607.
crossref pmid
33. Bayoglu Tekin Y, Dilbaz B, Altinbas SK, Dilbaz S. Postoperative medical treatment of chronic pelvic pain related to severe endometriosis: levonorgestrel-releasing intrauterine system versus gonadotropin-releasing hormone analogue. Fertil Steril 2011;95:492-496. PMID: 20883991.
crossref pmid
34. Kjerulff KH, Langenberg P, Seidman JD, Stolley PD, Guzinski GM. Uterine leiomyomas. Racial differences in severity, symptoms and age at diagnosis. J Reprod Med 1996;41:483-490. PMID: 8829060.
pmid
35. Stewart EA. Uterine fibroids. Lancet 2001;357:293-298. PMID: 11214143.
crossref pmid
36. Magalhaes J, Aldrighi JM, de Lima GR. Uterine volume and menstrual patterns in users of the levonorgestrel-releasing intrauterine system with idiopathic menorrhagia or menorrhagia due to leiomyomas. Contraception 2007;75:193-198. PMID: 17303488.
crossref pmid
37. Soysal S, Soysal ME. The efficacy of levonorgestrel-releasing intrauterine device in selected cases of myoma-related menorrhagia: a prospective controlled trial. Gynecol Obstet Invest 2005;59:29-35. PMID: 15377823.
crossref pmid
38. Grigorieva V, Chen-Mok M, Tarasova M, Mikhailov A. Use of a levonorgestrel-releasing intrauterine system to treat bleeding related to uterine leiomyomas. Fertil Steril 2003;79:1194-1198. PMID: 12738516.
crossref pmid
39. Mercorio F, De Simone R, Di Spiezio Sardo A, Cerrota G, Bifulco G, Vanacore F, et al. The effect of a levonorgestrel-releasing intrauterine device in the treatment of myoma-related menorrhagia. Contraception 2003;67:277-280. PMID: 12684148.
crossref pmid
40. Gunes M, Ozdegirmenci O, Kayikcioglu F, Haberal A, Kaplan M. The effect of levonorgestrel intrauterine system on uterine myomas: a 1-year follow-up study. J Minim Invasive Gynecol 2008;15:735-738. PMID: 18971138.
crossref pmid
41. Murat Naki M, Tekcan C, Ozcan N, Cebi M. Levonorgestrel-releasing intrauterine device insertion ameliorates leiomyoma-dependent menorrhagia among women of reproductive age without a significant regression in the uterine and leiomyoma volumes. Fertil Steril 2010;94:371-374. PMID: 19896649.
crossref pmid
42. Sivin I, Stern J. International Committee for Contraception Research (ICCR). Health during prolonged use of levonorgestrel 20 micrograms/d and the copper TCu 380Ag intrauterine contraceptive devices: a multicenter study. Fertil Steril 1994;61:70-77. PMID: 8293847.
crossref pmid
43. Kriplani A, Awasthi D, Kulshrestha V, Agarwal N. Efficacy of the levonorgestrel-releasing intrauterine system in uterine leiomyoma. Int J Gynaecol Obstet 2012;116:35-38. PMID: 21959070.
crossref pmid
44. Backman T, Huhtala S, Luoto R, Tuominen J, Rauramo I, Koskenvuo M. Advance information improves user satisfaction with the levonorgestrel intrauterine system. Obstet Gynecol 2002;99:608-613. PMID: 12039121.
pmid
45. Ikomi A, Mansell E, Spence-Jones C, Singer A. Treatment of menorrhagia with the levonorgestrel intrauterine system: can we learn from our failures? J Obstet Gynaecol 2000;20:630-631. PMID: 15512683.
crossref pmid
46. Rosa e Silva JC, de Sa Rosa e Silva AC, Candido dos Reis FJ, Manetta LA, Ferriani RA, Nogueira AA. Use of a levonorgestrel-releasing intrauterine device for the symptomatic treatment of uterine myomas. J Reprod Med 2005;50:613-617. PMID: 16220768.
crossref pmid
47. Rabinovici J, Stewart EA. New interventional techniques for adenomyosis. Best Pract Res Clin Obstet Gynaecol 2006;20:617-636. PMID: 16934530.
crossref
48. Takebayashi T, Fujino Y, Umesaki N, Ogita S. Danazol suspension injected into the uterine cervix of patients with adenomyosis and myoma: preliminary study. Gynecol Obstet Invest 1995;39:207-211. PMID: 7789919.
crossref pmid
49. Nelson JR, Corson SL. Long-term management of adenomyosis with a gonadotropin-releasing hormone agonist: a case report. Fertil Steril 1993;59:441-443. PMID: 8425643.
crossref pmid
50. Fedele L, Bianchi S, Raffaelli R, Portuese A, Dorta M. Treatment of adenomyosis-associated menorrhagia with a levonorgestrel-releasing intrauterine device. Fertil Steril 1997;68:426-429. PMID: 9314908.
crossref pmid
51. Wood C. Surgical and medical treatment of adenomyosis. Hum Reprod Update 1998;4:323-336. PMID: 9825848.
crossref pmid
52. Benagiano G, Brosens I, Carrara S. Adenomyosis: new knowledge is generating new treatment strategies. Womens Health (Lond Engl) 2009;5:297-311. PMID: 19392615.
crossref
53. Phillips DR. Endometrial ablation for postmenopausal uterine bleeding induced by hormone replacement therapy. J Am Assoc Gynecol Laparosc 1995;2:389-393. PMID: 9050590.
crossref pmid
54. Englander MJ. Uterine artery embolization for the treatment of adenomyosis. Semin Intervent Radiol 2008;25:387-393. PMID: 21326580.
crossref pmid pmc
55. Yoon SW, Kim KA, Cha SH, Kim YM, Lee C, Na YJ, et al. Successful use of magnetic resonance-guided focused ultrasound surgery to relieve symptoms in a patient with symptomatic focal adenomyosis. Fertil Steril 2008;90:2018.e13-2018.e15. PMID: 18692791.
crossref
56. Bragheto AM, Caserta N, Bahamondes L, Petta CA. Effectiveness of the levonorgestrel-releasing intrauterine system in the treatment of adenomyosis diagnosed and monitored by magnetic resonance imaging. Contraception 2007;76:195-199. PMID: 17707716.
crossref pmid
57. Cho S, Nam A, Kim H, Chay D, Park K, Cho DJ, et al. Clinical effects of the levonorgestrel-releasing intrauterine device in patients with adenomyosis. Am J Obstet Gynecol 2008;198:373.e1-373.e7. PMID: 18177833.
crossref
58. Sheng J, Zhang WY, Zhang JP, Lu D. The LNG-IUS study on adenomyosis: a 3-year follow-up study on the efficacy and side effects of the use of levonorgestrel intrauterine system for the treatment of dysmenorrhea associated with adenomyosis. Contraception 2009;79:189-193. PMID: 19185671.
crossref pmid
59. Ozdegirmenci O, Kayikcioglu F, Akgul MA, Kaplan M, Karcaaltincaba M, Haberal A, et al. Comparison of levonorgestrel intrauterine system versus hysterectomy on efficacy and quality of life in patients with adenomyosis. Fertil Steril 2011;95:497-502. PMID: 21074150.
crossref pmid
60. Whiteman MK, Zapata LB, Tepper NK, Marchbanks PA, Curtis KM. Use of contraceptive methods among women with endometrial hyperplasia: a systematic review. Contraception 2010;82:56-63. PMID: 20682143.
crossref pmid
61. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer 1985;56:403-412. PMID: 4005805.
crossref pmid
62. Tabata T, Yamawaki T, Yabana T, Ida M, Nishimura K, Nose Y. Natural history of endometrial hyperplasia. Study of 77 patients. Arch Gynecol Obstet 2001;265:85-88. PMID: 11409481.
crossref pmid
63. Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke JJ 2nd, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;106:812-819. PMID: 16400639.
crossref pmid
64. Clark TJ, Neelakantan D, Gupta JK. The management of endometrial hyperplasia: an evaluation of current practice. Eur J Obstet Gynecol Reprod Biol 2006;125:259-264. PMID: 16246481.
crossref
65. Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, et al. Management of endometrial precancers. Obstet Gynecol 2012;120:1160-1175. PMID: 23090535.
crossref pmid pmc
66. Marsden DE, Hacker NF. Optimal management of endometrial hyperplasia. Best Pract Res Clin Obstet Gynaecol 2001;15:393-405. PMID: 11476561.
crossref pmid
67. Wildemeersch D, Janssens D, Pylyser K, De Wever N, Verbeeck G, Dhont M, et al. Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: long-term follow-up. Maturitas 2007;57:210-213. PMID: 17270370.
crossref pmid
68. Orbo A, Arnes M, Hancke C, Vereide AB, Pettersen I, Larsen K. Treatment results of endometrial hyperplasia after prospective D-score classification: a follow-up study comparing effect of LNG-IUD and oral progestins versus observation only. Gynecol Oncol 2008;111:68-73. PMID: 18684496.
crossref pmid
69. Varma R, Soneja H, Bhatia K, Ganesan R, Rollason T, Clark TJ, et al. The effectiveness of a levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of endometrial hyperplasia--a long-term follow-up study. Eur J Obstet Gynecol Reprod Biol 2008;139:169-175. PMID: 18440693.
crossref pmid
70. Vereide AB, Kaino T, Sager G, Arnes M, Orbo A. Effect of levonorgestrel IUD and oral medroxyprogesterone acetate on glandular and stromal progesterone receptors (PRA and PRB), and estrogen receptors (ER-alpha and ER-beta) in human endometrial hyperplasia. Gynecol Oncol 2006;101:214-223. PMID: 16325240.
crossref pmid
71. Vereide AB, Arnes M, Straume B, Maltau JM, Orbo A. Nuclear morphometric changes and therapy monitoring in patients with endometrial hyperplasia: a study comparing effects of intrauterine levonorgestrel and systemic medroxyprogesterone. Gynecol Oncol 2003;91:526-533. PMID: 14675671.
crossref pmid
72. Gallos ID, Shehmar M, Thangaratinam S, Papapostolou TK, Coomarasamy A, Gupta JK. Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2010;203:547.e1-547.e10. PMID: 20934679.
crossref
73. Lee SY, Kim MK, Park H, Yoon BS, Seong SJ, Kang JH, et al. The effectiveness of levonorgestrel releasing intrauterine system in the treatment of endometrial hyperplasia in Korean women. J Gynecol Oncol 2010;21:102-105. PMID: 20613900.
crossref pmid pmc
74. Lee TS, Seong SJ, Kim JW, Ryu HS, Song ES, Nam BH. Management of endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: single arm, prospective multicenter study: Korean gynecologic oncology group study (KGOG2006). Jpn J Clin Oncol 2011;41:817-819. PMID: 21478178.
crossref
75. Surveillance epidemiology and end results. SEER Stat fact sheets: corpus and uterus, NOS [Internet][. Bethesda, MD: US National Cancer Institute; cited 2013 Feb 15. Available from: http://seer.cancer.gov/statfacts/html/corp.html.

76. Elit L, Hirte H. Current status and future innovations of hormonal agents, chemotherapy and investigational agents in endometrial cancer. Curr Opin Obstet Gynecol 2002;14:67-73. PMID: 11801879.
crossref pmid
77. Gallup DG, Stock RJ. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 1984;64:417-420. PMID: 6462572.
pmid
78. Soliman PT, Oh JC, Schmeler KM, Sun CC, Slomovitz BM, Gershenson DM, et al. Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol 2005;105:575-580. PMID: 15738027.
crossref pmid
79. Creasman WT, Odicino F, Maisonneuve P, Quinn MA, Beller U, Benedet JL, et al. Carcinoma of the corpus uteri. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 2006;95(Suppl 1):S105-S143. PMID: 17161155.
crossref
80. Benshushan A. Endometrial adenocarcinoma in young patients: evaluation and fertility-preserving treatment. Eur J Obstet Gynecol Reprod Biol 2004;117:132-137. PMID: 15541846.
crossref pmid
81. Rose PG. Endometrial carcinoma. N Engl J Med 1996;335:640-649. PMID: 8692240.
crossref pmid
82. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987;60:2035-2041. PMID: 3652025.
crossref pmid
83. Leitao MM, Barakat RR. Advances in the management of endometrial carcinoma. Gynecol Oncol 2011;120:489-492. PMID: 21215997.
crossref pmid
84. Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997;90:434-440. PMID: 9277658.
crossref pmid
85. Ramirez PT, Frumovitz M, Bodurka DC, Sun CC, Levenback C. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol 2004;95:133-138. PMID: 15385122.
crossref pmid
86. Kim YB, Holschneider CH, Ghosh K, Nieberg RK, Montz FJ. Progestin alone as primary treatment of endometrial carcinoma in premenopausal women. Report of seven cases and review of the literature. Cancer 1997;79:320-327. PMID: 9010105.
crossref pmid
87. Kaku T, Yoshikawa H, Tsuda H, Sakamoto A, Fukunaga M, Kuwabara Y, et al. Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome. Cancer Lett 2001;167:39-48. PMID: 11323097.
crossref pmid
88. Gotlieb WH, Beiner ME, Shalmon B, Korach Y, Segal Y, Zmira N, et al. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol 2003;102:718-725. PMID: 14551001.
pmid
89. Saegusa M, Okayasu I. Progesterone therapy for endometrial carcinoma reduces cell proliferation but does not alter apoptosis. Cancer 1998;83:111-121. PMID: 9655300.
crossref pmid
90. Gallos ID, Yap J, Rajkhowa M, Luesley DM, Coomarasamy A, Gupta JK. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2012;207:266.e1-266.e12. PMID: 23021687.
crossref
91. Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002;186:651-657. PMID: 11967486.
crossref pmid
92. Cade TJ, Quinn MA, Rome RM, Neesham D. Progestogen treatment options for early endometrial cancer. BJOG 2010;117:879-884. PMID: 20394609.
crossref pmid
93. Kim MK, Yoon BS, Park H, Seong SJ, Chung HH, Kim JW, et al. Conservative treatment with medroxyprogesterone acetate plus levonorgestrel intrauterine system for early-stage endometrial cancer in young women: pilot study. Int J Gynecol Cancer 2011;21:673-677. PMID: 21546871.
pmid
94. Kim MK, Seong SJ, Lee TS, Kim JW, Nam BH, Hong SR, et al. Treatment with medroxyprogesterone acetate plus levonorgestrel-releasing intrauterine system for early-stage endometrial cancer in young women: single-arm, prospective multicenter study: Korean gynecologic oncology group study (KGOG2009). Jpn J Clin Oncol 2012;42:1215-1218. PMID: 23071290.
crossref pmid


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