Low-dose LNG-IUS as Therapy for Endometrial Hyperplasia. A Prospective Cohort Pilot Study

Abstract

Abstract. Background/Aim: Progestin therapy has been accepted as therapy for low-and medium-risk endometrial hyperplasia. The aim of this study was to investigate the efficacy of the low-dose levonorgestrel-impregnated intrauterine system (LNG-IUS) 13.5 mg (JaydessEndometrial carcinoma (EC) is presently the most frequent genital malignancy in women, showing a constant rise all over the Western world (1, 2). Endometrial hyperplasia, the preliminary stage of EC, undergoes malignant transformation in up to 29% of cases if left untreated (3). Women with atypical endometrial hyperplasia (AH), have been proven to have the highest risk of co-existent or future EC, have routinely been treated by hysterectomy (3-6). In contrast, conservative management with progestin therapy has been used in clinical practice for women with non-atypical endometrial hyperplasia (low-and medium risk), although consensus regarding optimal progestin agent, dose and therapy duration has never been established.During the recent decades the levonorgestrel-impregnated intrauterine system (LNG-IUS) has been introduced as an alternative to oral therapy for endometrial hyperplasia and cohort studies as well as case reports have shown promising results (7-12). The endometrial mucosal progestin concentration observed in LNG-IUS 63 mg users has been measured hundred-fold higher than in oral progestin users (13). A recent randomized national multicentre study comparing the high-dose LNG-IUS 52 mg (Mirena ® , Bayer Pharmaceuticals, Berlin, Germany) with oral progestin as therapy for low-and medium risk endometrial hyperplasia, reported 100% therapy response for LNG-IUS Mirena after 6 months therapy duration (14). Lower response rates were found for cyclic (67%) and continuous (96%) oral progestin (14).In selected cases progestin therapy has also been recommended for women with AH (high-risk). It has also been considered as an option for women desiring fertility preservation and for non-ideal surgical candidates. Recent results have demonstrated resolution of high-risk endometrial hyperplasia in 66%-85.6% after use of progestin therapy, intrauterine therapy being superior to oral administration (15)(16)(17). However, the ideal mucosal concentration of progestin for reversal of low-and medium versus high-risk endometrial hyperplasia is still unknown.

Intrauterine Progestin Therapy as a New Approach to Premalignant Endometrial Polyps: A Prospective Observational Study

“…However, ethical considerations prevented conservative management for these women as low-dose LNG-IUS had never before been explored as therapy for EHP. In the present study we hypothesized that hyperplastic foci within EP had the same risk of malignant progression as EH and that these hyperplastic foci would respond to progestin therapy in a similar manner as observed for nonpolypoid EH (10,17,26). Risk-stratification of EH by D-score analysis have been successfully used for years in our clinic and in a recent retrospective study with long-term follow-up, these methods were reported to be applicable as predictors of malignant transformation in EHP as well (15).…”

“…In a recent study, low-dose LNG-IUS (Jaydess ® , Bayer Pharmaceuticals, Berlin, Germany), with a total content of 13.5 mg levonorgestrel, was successfully given as therapy for six months in women with low-and medium-risk EH (17). Compared to the high-dose LNG-IUS, the thinner insertion tube and smaller T-frame might prove beneficial for young nulliparous women and for elderly women with stenotic cervical channel simultaneously reducing systemic side-effects to a minimum.…”

Data on RT-qPCR assay of nuclear progesterone receptors (nPR), membrane progesterone receptors (mPR) and progesterone receptor membrane components (PGRMC) from human uterine endometrial tissue and cancer cells of the Uterine Cervix

“…All endometrial tissue specimens (baseline and post therapy biopsies) were conserved in RNAlater stabilization solution (Ambion RNAlater™, ThermoFisher Scientific, Whatham, MA, USA, code AM7021) and immediately frozen and kept at-18 °C until further analysis. Details of the clinical investigations are reported earlier [ 3 , 4 ] .…”

“…The current data were a second gain of two clinical investigations [ 3 , 4 ] . The investigations were approved by the Regional Committees for Medical and Health Research Ethics (2015/381) and by the Norwegian Medicines Agency (EUDRACT nr 2015–000612- 17).…”

“…We conducted new investigations of endometrial hyperplasia, now with 6 months low dose levonorgestrel IUS treatment. Again, the growth disturbances were reversed with normalization of the endometrium [ 3 , 4 ]. In the context of these studies, RT-qPCR analyses of the endometrium were performed before and after treatment, to determine expression of nuclear progesterone receptors (nPRA+ B and nPRB), membrane progesterone receptors (mPR, α-, β- and γ-subtypes) and progesterone receptor membrane components (PGRMC1and PGRMC2).…”