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OBJECTIVE: To evaluate gene expression associated with vaginal bleeding in the 52-mg hormonal intrauterine device (IUD) users. MATERIALS AND METHODS: We conducted a prospective study involving 100 women seeking to use the 52-mg hormonal IUD for contraception. We excluded women with a history or current condition of abnormal uterine bleeding and who were unable to attend a 1-year follow up. Women who expelled the device, removed it for reasons unrelated to vaginal bleeding, or were lost to follow up were discontinued. We collected endometrial biopsies immediately before IUD placement and assessed 20 selected genes using reverse transcription quantitative polymerase chain reaction. Users maintained a uterine bleeding diary for 12 months following IUD insertion. For statistical analysis, participants were categorized into groups with or without vaginal bleeding at 3 and 12 months. RESULTS: Women with elevated CXCL9 expression had an 8.15-fold higher likelihood of experiencing vaginal bleeding at 3 months (odds ratio [OR] 8.15, 95% confidence interval [CI] 2.24-29.61, P = 0.001). At 12 months of follow up, women with increased TIMP1 expression had a 2.74-fold higher chance of experiencing vaginal bleeding (OR 2.74, 95% CI 1.08-6.95, P = 0.033). CXCL9 ≥ 1.5 and IL17A ≥ 0.68 were associated with a higher probability of vaginal bleeding at 3 months, while TIMP1 levels ≥0.943 were linked to an increased risk of bleeding at 12 months. CONCLUSION: Users of the 52-mg hormonal IUD with elevated relative CXCL9 expression face an increased risk of vaginal bleeding at 3-month follow up, whereas those with heightened TIMP1 expression are more likely to experience vaginal bleeding at 12 months.

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BACKGROUND: The symptom of heavy menstrual bleeding has a substantial impact on professional, physical, and social functioning. In 2021, results from a randomized controlled trial comparing a 52-mg levonorgestrel-releasing intrauterine system and radiofrequency nonresectoscopic endometrial ablation as treatments for women with heavy menstrual bleeding were published. Both treatment strategies were equally effective in treating heavy menstrual bleeding during 2-year follow-up. However, long-term results are also relevant for both patients and healthcare providers. OBJECTIVE: This study aimed to assess long-term differences in reintervention risk and menstrual blood loss in women with the symptom of heavy menstrual bleeding treated according to a strategy starting with a 52-mg levonorgestrel-releasing intrauterine system or radiofrequency nonresectoscopic endometrial ablation. STUDY DESIGN: This study was a long-term follow-up study of a multicenter randomized controlled trial (MIRA trial), in which women were allocated to either a 52-mg levonorgestrel-releasing intrauterine device (n=132) or radiofrequency nonresectoscopic endometrial ablation (n=138). Women from the original trial were contacted to fill out 6 questionnaires. The primary outcome was the reintervention rate after allocated treatment. Secondary outcomes included surgical reintervention rate, menstrual bleeding measured by the Pictorial Blood Loss Assessment Chart, (disease-specific) quality of life, sexual function, and patient satisfaction. RESULTS: From the 270 women who were randomized in the original trial, 196 (52-mg levonorgestrel-releasing intrauterine system group: n=94; radiofrequency nonresectoscopic endometrial ablation group: n=102) participated in this long-term follow-up study. Mean follow-up duration was 7.4 years (range, 6-9 years). The cumulative reintervention rate (including both medical and surgical reinterventions) was 40.0% (34/85) in the 52-mg levonorgestrel-releasing intrauterine system group and 28.7% (27/94) in the radiofrequency nonresectoscopic endometrial ablation group (relative risk, 1.39; 95% confidence interval, 0.92-2.10). The cumulative rate of surgical reinterventions only was significantly higher among patients with a treatment strategy starting with a 52-mg levonorgestrel-releasing intrauterine system compared with radiofrequency nonresectoscopic endometrial ablation (35.3% [30/85] vs 19.1% [18/94]; relative risk, 1.84; 95% confidence interval, 1.11-3.10). However, the hysterectomy rate was similar (11.8% [10/94] in the 52-mg levonorgestrel-releasing intrauterine system group and 18.1% [17/102] in the radiofrequency nonresectoscopic endometrial ablation group; relative risk, 0.65; 95% confidence interval, 0.32-1.34). Most reinterventions occurred during the first 24 months of follow-up. A total of 171 Pictorial Blood Loss Assessment Chart scores showed a median bleeding score of 0.0. No clinically relevant differences were found regarding quality of life, sexual function, and patient satisfaction. CONCLUSION: The overall risk of reintervention after long-term follow-up was not different between women treated according to a treatment strategy starting with a 52-mg levonorgestrel-releasing intrauterine system and those treated using a strategy starting with radiofrequency nonresectoscopic endometrial ablation. However, women allocated to a treatment strategy starting with a 52-mg levonorgestrel-releasing intrauterine system had a higher risk of surgical reintervention, which was driven by an increase in subsequent endometrial ablation. Both treatment strategies were effective in lowering menstrual blood loss over the long term. The results of this long-term follow-up study can support physicians in optimizing the counseling of women with heavy menstrual bleeding, thus promoting informed decision-making regarding choice of treatment.

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OBJECTIVE: Use of 52-mg levonorgestrel intrauterine system (LNG-IUS) in adolescents for heavy menstrual bleeding (HMB), dysmenorrhea, and contraception has increased, yet little is known about the factors predicting removal and dissatisfaction in adolescents. The aim of this study was to identify factors predicting LNG-IUS removal in adolescents. METHODS: This was a retrospective cohort study including all adolescents (9-19 years) who underwent LNG-IUS insertion between 2012 and 2021 (n = 536). A medical record review was conducted and data were collated on medical and gynecological history, age, indications for insertion, complications, expulsions, and removals. The data were analyzed using χ2 tests. RESULTS: Indications for LNG-IUS insertions (n = 536) among 517 individual patients (n = 517) included menstrual management (n = 142), HMB alone (n = 118), HMB and pelvic pain/dysmenorrhea (n = 105), dysmenorrhea/pelvic pain alone (n = 47), and contraception (n = 16). Associated diagnoses included intellectual disability (44.29%, 229/517), chronic pain conditions (12.77%, 66/517), and additional mental health concerns (24.37%, 126/517). Patient dissatisfaction with LNG-IUS led to removal in 61 (11.38%), mostly for pain or persistent bleeding. Higher removal rates occurred in those with associated chronic pain conditions (46.97%, χ2 = 55.9, P < .05), mental health concerns (16.67%, χ2 = 5.06, P < .05), and bleeding disorders (26.32%, χ2 = 5.09, P < .05). Among the cohort with an intellectual disability, lower rates of removal occurred (5.7%, χ2 = 11.2, P < .05). Whereas the LNG-IUS removal rate among gender-diverse youth was 23.07%, this was not statistically significant. Younger age was also not associated with a statistically significant increase in removals (13.72%, χ2 = 0.73, P > .05). DISCUSSION: Adolescents have a low dissatisfaction and removal rate (11.38%) of LNG-IUS. Chronic pain, bleeding tendency, and mental health concerns are associated with higher removal rates and intellectual disability with lower rates. These findings are useful in counselling patients and families about LNG-IUS.

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OBJECTIVE: To conduct a systematic review and meta-analysis of studies evaluating the oncological and fertility outcomes of early-stage endometrial cancer (EC) treated with the levonorgestrel-releasing intrauterine system (LIUS)-based regimens. METHODS: The Meta-analyses Of Observational Studies in Epidemiology statement for meta-analyses was followed. Searches were conducted on MEDLINE, Embase, PubMed, Preprints, and the Cochrane Central Register of Controlled Trials from January 1990 to August 4, 2022. The Joanna Briggs Institute Critical Appraisal Checklist was used for quality assessment. The primary endpoint was the complete response (CR) rate and the secondary endpoints were relapse, pregnancy, and live birth rate. RESULTS: A total of 25 studies (821 women) were included. The CR rate of LIUS-based regimens was 63.4% (95% confidence interval [CI]=52.3%-73.2%), with 29.6% (95% CI=23.3%-36.8%) of cases experiencing recurrence during follow-up. In sensitivity analyses, patients younger than 45 years of age with a body mass index <30 kg/m² who were treated with LIUS-based regimens achieved a high CR rate of 84.6% (95% CI=80.3%-88.1%) over a median follow-up of more than 24 months. Overall pregnancy and live birth rates were 37.9% (95% CI=24.1%-53.9%) and 39.3% (95% CI=24.0%-57.0%), respectively. No statistical differences were apparent in CR or relapse rates among the LIUS+GnRH agonist, LIUS+oral progesterone, or hysteroscopic resection followed by LIUS subgroups. CONCLUSION: LIUS-based therapies are viable for the conservative management of early-stage endometrioid EC on CR and fertility outcome. TRIAL REGISTRATION: PROSPERO Identifier: CRD42022352890.

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Resumen OBJETIVO: Determinar el costo del retiro anticipado de los métodos de planificación familiar. MATERIALES Y MÉTODOS: Estudio de costo efectuado con base en los expedientes de usuarias de métodos de planificación familiar en una institución de salud del estado de Querétaro, México (2018 a 2021). La unidad de observación fue el expediente de mujeres que se retiraron anticipadamente los métodos: dispositivo intaruterino T de cobre (DiuTcu), Diu Mirena (DiuM) e implante subdérmico (IMSD). Se definió como retiro anticipado al sucedido antes del tiempo estimado de uso. Se analizaron todos los expedientes en donde estaba registrado el retiro anticipado. Se incluyó a toda la población, de ahí que no fue necesario establecer el tamaño de muestra. El costo del retiro anticipado se identificó a partir del costo unitario del método, tiempo esperado de uso y tiempo de no uso. El análisis estadístico incluyó: promedios, porcentajes, intervalos de confianza y proyecciones, para esto se utilizaron supuestos. RESULTADOS: Se estudiaron 1361 expedientes. El costo unitario del retiro anticipado del DiuTcu fue de 5.59 pesos (IC95%: 5.04 a 6.14), del DiuM de 1210.73 pesos (IC95%: 1029.58 a 1391.87) y del IMSD de 658.41 pesos (IC95%: 557.37 a 759.44). La proyección a la población mexicana del costo del retiro anticipado de los métodos de planificación familiar es 219,272,470 de pesos. CONCLUSIÓN: El costo del retiro anticipado de los métodos de planificación familiar es alto.

Abstract OBJECTIVE: To determine the cost of early removal of family planning methods. MATERIALS AND METHODS: Cost study realized in records of women users of family planning method in a health institution in Querétaro, Mexico from 2018 to 2021. The unit of observation was considered to be the records of women who had early removal of the copper IUD, Mirena IUD and subdermal implant methods. Early removal was defined as the retirement of the method before the estimated time of use. Work was done with the total number of records (1361), with early removal in 148 (83 copper IUDs, 28 Mirena IUDs, 37 subdermal implants). The entire population was included, so no sampling technique was used. The cost of early removal was identified from the unit cost of the method, expected time of use, time of non-use. The statistical analysis plan included averages, percentages, confidence intervals and projections for which assumptions were used. RESULTS: The unit cost of early removal of copper IUD was $5.59 (95% CI; 5.04-6.14), Mirena IUD $1210.73 (95% CI; 1029.58 - 1391.87) Subdermal implant $658.41 (95% CI; 557.37- 759.44). The projection to the Mexican population of the cost of early removal of family planning methods is $359, 384,161. CONCLUSION: The cost of early removal of family planning methods is high.

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Abnormal uterine bleeding is the most frequently encountered complaint of the reproductive-age women. Heavy menstrual blood loss is responsible for interfering with women's physical, emotional, social, and quality of life. Levonorgestrel-releasing intrauterine device (LNG-IUS) is a highly effective reversible form of contraception. Besides this, its role in the treatment of heavy menstrual bleeding (HMB), endometrial hyperplasia, early-stage endometrial cancers, and endometrial protection as a part of hormone replacement therapy (HRT) is very well studied. This review will revisit the role of LNG-IUS as a nonsurgical option in the management of HMB.

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BACKGROUND: The 52-mg levonorgestrel-releasing intrauterine system is an established, long-acting contraceptive option with approved use for up to 7 years. OBJECTIVE: The Mirena Extension Trial evaluated the efficacy and safety of the 52-mg levonorgestrel-releasing intrauterine system during extended use beyond 5 and up to 8 years. STUDY DESIGN: This was a multicenter, single-arm study in the United States, enrolling existing users of the 52-mg levonorgestrel-releasing intrauterine system, aged 18 to 35 years, who have had the system for 4.5 to 5 years. We assessed the contraceptive efficacy (Pearl Index) and cumulative failure rate (using the Kaplan-Meier method) of the 52-mg levonorgestrel-releasing intrauterine system during extended use. We also evaluated bleeding outcomes and adverse events. RESULTS: Of the 362 participants starting year 6, 243 entered and 223 completed 8 years of 52-mg levonorgestrel-releasing intrauterine system use. Just more than half the participants were parous. The mean (standard deviation) age was 29.2 (±2.9) years, and all participants were aged ≤36 years at the end of year 8. Two pregnancies occurred, both with the device in situ. The year 6 pregnancy was of undetermined location and resolved spontaneously. The pregnancy in year 7 was ectopic and resolved with methotrexate treatment. In both cases, the 52-mg levonorgestrel-releasing intrauterine system was removed and the participants left the trial. For years 6 to 8, the 3-year Pearl Index (95% confidence interval) was 0.28 (0.03-1.00) with a 3-year cumulative failure rate of 0.68% (0.17-2.71). Pearl Indexes for years 6, 7, and 8 were 0.34 (0.01-1.88), 0.40 (0.01-2.25), and 0.00 (0.00-1.90), respectively. The 3-year (years 6-8) ectopic pregnancy Pearl Index was 0.14 (0.00-0.77). We found treatment-emergent adverse events in 249 of 362 participants (68.8%), with 65 (18.0%) events considered to be related to the 52-mg levonorgestrel-releasing intrauterine system. The discontinuation rate was 38.4% (139/362), most commonly because of desire for pregnancy (12.2%, 44/362). During extended use beyond 5 years and up to 8 years, participants reported a decrease in the mean number of bleeding or spotting days with approximately half of the women experiencing amenorrhea or infrequent bleeding. We did not enroll a sufficient number of women using the 52-mg levonorgestrel-releasing intrauterine system for contraception and heavy menstrual bleeding to assess extended use for that indication. At the end of year 8, most (98.7%, 220/223) of the participants who completed the study remained satisfied with the continued use of the 52-mg levonorgestrel-releasing intrauterine system. Of the 31 women who discontinued early because of desire for pregnancy with evaluable data for return-to-fertility analysis, 24 reported a posttreatment pregnancy within 1 year, giving a 12-month return-to-fertility rate of 77.4%. CONCLUSION: The 52-mg levonorgestrel-releasing intrauterine system, initially approved for 5 years, maintains high contraceptive efficacy, user satisfaction, and a favorable safety profile through 8 years of use. Participants reported 26 posttreatment pregnancies in total, of which 24 occurred in women who had discontinued the 52-mg levonorgestrel-releasing intrauterine system because of a desire for pregnancy. Of note, among women who elected to continue use through 8 years, bleeding patterns remained highly favorable. These findings support continued 52-mg levonorgestrel-releasing intrauterine system use for up to 8 years in women who wish to continue treatment.

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INTRODUCTION: Endometrial hyperplasia is associated with varying risk of endometrial cancer. The aim of this review is to assess effectiveness of levonorgestrel-releasing intrauterine system (LNG-IUS), compared to systemic progestins, in management of endometrial hyperplasia MATERIALS AND METHODS: A search on studies comparing LNG-IUS to systemic progestins was conducted on Scopus, Web of science, Cochrane, PubMed and Embase databases, from the date of inception to September 20th, 2020. Studies were excluded if they were non-comparative, animal studies, review articles, case reports, case series, and conference papers. Primary outcomes include resolution/regression rate, failure rate, and hysterectomy rate. Analysis was pooled using random effect model and was expressed as pooled odds ratios (OR) and 95% confidence interval (CI). Quality assessment was performed using Cochrane Risk of Bias Tool and the Newcastle-Ottawa Scale (NOS) assessment tool. MOGGE Meta-analysis Matrix was used to illustrate multiple subgroup analyses. RESULTS: Out of 341 studies retrieved from literature search, 12 were eligible. LNG-IUS yielded significantly higher resolution/regression rate (91.3% vs 68.6%, OR 3.42, 95% CI 1.86-6.30). Failure and hysterectomy rates were significantly lower in LNG-IUS group compared to systemic progestins' group (19.2% vs. 32.3%, OR 0.34, 95% CI 0.20-0.57 and 9.3% vs. 24.1%, OR 0.41, 95% CI 0.29-0.57, respectively). Subgroup analysis of studies including complex hyperplasia only did not show significant difference in resolution/regression rate was not statistically significant. CONCLUSION: LNG-IUS is associated with high success rate in management of women with endometrial hyperplasia. However, specific effectiveness of LNG-IUS on more advanced histologic subtypes is less studied.

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An intrauterine system (IUS) can be implanted in the uterus and deliver drug directly at the site of pharmacological action. Mirena was the first FDA-approved levonorgestrel (LNG) releasing IUS without an approved generic form. Its 5-year application duration presents challenges for bioequivalence (BE) assessment using the conventional in vivo studies with pharmacokinetic and/or comparative clinical endpoints. Conventionally, along with other conditions, BE could be established if the 90% confidence interval (CI) of the ratio of geometric means of residual LNG at the end of 5 years is within the BE limits of 80.00% and 125.00%. Modeling and simulation were conducted to identify a shortened BE study duration and its corresponding BE acceptance limit that can be used as a surrogate for the conventional limit for a 5-year study. Simulation results suggest that having the 90% CI of the residual LNG 12 months post insertion within 95.00-105.26% would ensure that residual LNG amount at 5 years to be within 80.00-125.00%. This modeling and simulation practice leads to the current BE recommendation: if a test IUS is made of the same material in the same concentration and has the same physical dimensions as the Mirena, its BE could be established by showing (1) comparative physicochemical and mechanical properties; (2) comparative in vitro drug release behavior for 5 years; and (3) performance in a comparative short-term in vivo study and BE based on 90% confidence interval of test and reference ratio of residual LNG to be within 95.00-105.26% at month 12.

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OBJECTIVE: To compare efficacy of lidocaine-prilocaine (LP) cream versus misoprostol versus placebo before levonorgestrel-releasing intrauterine device (LNG-IUD) insertion. METHODS: This randomized controlled trial (RCT) was conducted in a tertiary referral hospital from April 30, 2020 to March 1, 2021 on 210 parous women willing to receive LNG-IUD and delivered only by elective cesarean delivery (CD). Participants received 200 µg vaginal misoprostol or 5 ml of LP cream 5% or placebo 3 h before LNG-IUS insertion. Primary outcome was pain during LNG-IUD insertion, while secondary outcomes were pain 10 min post-procedure, ease of insertion, patient satisfaction, insertion time, and drug side effects. RESULTS: Pain during LNG-IUS insertion was reduced in LP group and misoprostol group compared to placebo group (2.1 ± 1.0 vs 3.7 ± 1.6; p <0.001) and (2.3 ± 1.3 vs 3.7 ± 1.6; p <0.001), respectively. Ease of procedure and patient satisfaction were significantly higher in LP and misoprostol groups than placebo (P <0.001). Need for additional analgesia was significantly higher in placebo group than in the other two groups (P = 0.009). Adverse events were not significantly different between the three groups except vomiting and abdominal cramps, which were higher with misoprostol. CONCLUSION: LP cream and 200 µg of vaginal misoprostol administration before LNG-IUD insertion in women delivered only by elective CD effectively reduced pain during insertion and 10 min post-procedure with easier insertions, high patient satisfaction, and tolerable side effects. Pain reduction with LP cream was clinically significant.

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BACKGROUND: Improper methods of contraception greatly increase the risk of abortion, cervical or endometrial lesions, and the number of recurrent artificial abortions. These complications result in the deterioration of a patient's outcome. Further, the proportion of artificial abortions is highest among unmarried females. Placement of an intrauterine device, such as the Mirena, after an artificial abortion may decrease the likelihood of an endometrial injury caused by recurrent abortions while significantly improving its contraceptive effects. AIM: To discuss the effect of Mirena placement on reproductive hormone levels at different time points after an artificial abortion. METHODS: Women (n = 119) undergoing an artificial abortion operation were divided into the study (n = 56) and control (n = 63) groups. In the study group, the Mirena was inserted immediately after the artificial abortion, whereas in the control group, it was inserted 4-7 d after the onset of the first menstrual cycle after abortion. All participants were followed-up for 6 mo to observe the continuation and expulsion rates and adverse reactions and to measure the levels of serum estradiol (E2), follicle stimulating hormone (FSH), and luteinizing hormone (LH). RESULTS: The continuation rates were 94.64% and 93.65% in the study group and the control group, respectively. The expulsion rates were 1.79% and 3.17% in the study group and the control group, respectively. There was no statistically significant difference between the two groups (P > 0.05). There were also no statistically significant differences in the proportion of patients with bacterial vaginitis, trichomonas vaginitis, or cervicitis between the groups (P > 0.05). Six months after Mirena placement, E2 Levels were 45.50 ± 7.13 pg/mL and 42.91 ± 8.10 pg/mL, FSH 13.60 ± 3.24 mIU/mL and 14.54 ± 3.11 mIU/mL, and LH 15.11 ± 2.08 mIU/mL and 14.60 ± 3.55 mIU/mL in the study and control groups, respectively. There were no significant differences in hormone levels between the two groups (P > 0.05). There were also no statistically significant differences in the proportions of abnormal menstruation, prolonged menstruation, or pain during intercourse between the study and control groups after Mirena placement (P > 0.05). There were no statistically significant differences in uterine volume, sexual desire, sexual activity, or the sexual satisfaction score between the study and control groups before and after Mirena placement (P > 0.05). CONCLUSION: Placement of a Mirena intrauterine device immediately after an artificial abortion does not increase the risk of adverse reactions and can help prevent endometrial injury caused by recurrent abortions.

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OBJECTIVE: To evaluate the costs and non-inferiority of a strategy starting with the levonorgestrel intrauterine system (LNG-IUS) compared with endometrial ablation (EA) in the treatment of heavy menstrual bleeding (HMB). DESIGN: Cost-effectiveness analysis from a societal perspective alongside a multicentre randomised non-inferiority trial. SETTING: General practices and gynaecology departments in the Netherlands. POPULATION: In all, 270 women with HMB, aged ≥34 years old, without intracavitary pathology or wish for a future child. METHODS: Randomisation to a strategy starting with the LNG-IUS (n = 132) or EA (n = 138). The incremental cost-effectiveness ratio was estimated. MAIN OUTCOME MEASURES: Direct medical costs and (in)direct non-medical costs were calculated. The primary outcome was menstrual blood loss after 24 months, measured with the mean Pictorial Blood Assessment Chart (PBAC)-score (non-inferiority margin 25 points). A secondary outcome was successful blood loss reduction (PBAC-score ≤75 points). RESULTS: Total costs per patient were €2,285 in the LNG-IUS strategy and €3,465 in the EA strategy (difference: €1,180). At 24 months, mean PBAC-scores were 64.8 in the LNG-IUS group (n = 115) and 14.2 in the EA group (n = 132); difference 50.5 points (95% CI 4.3-96.7). In the LNG-IUS group, 87% of women had a PBAC-score ≤75 points versus 94% in the EA group (relative risk [RR] 0.93, 95% CI 0.85-1.01). The ICER was €23 (95% CI €5-111) per PBAC-point. CONCLUSIONS: A strategy starting with the LNG-IUS was cheaper than starting with EA, but non-inferiority could not be demonstrated. The LNG-IUS is reversible and less invasive and can be a cost-effective treatment option, depending on the success rate women are willing to accept. TWEETABLE ABSTRACT: Treatment of heavy menstrual bleeding starting with LNG-IUS is cheaper but slightly less effective than endometrial ablation.

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PURPOSE: To evaluate the levonorgestrel-releasing intrauterine system Donasert® (also known as Levosert®) compared with the reference product Mirena® for the alleviation of heavy menstrual bleeding (HMB). MATERIALS AND METHODS: A phase 3 multicentre, non-inferiority, active-controlled study in non-menopausal women with HMB (menstrual blood loss [MBL] ≥ 80 mL) as the primary symptom randomised to either Donasert® or Mirena® and followed for 6 months. MBL was evaluated using a validated, modified version of the Wyatt pictogram. RESULTS: Overall, 312 were randomised (158 to Donasert® and 154 to Mirena®). The mean (standard deviation) absolute change in MBL from baseline to 6 months in the per-protocol population (N = 300) was -130 (71.8) mL and -127 (67.3) mL in the Donasert® and Mirena® groups, respectively; non-inferiority of Donasert® was confirmed (p-value <0.0001). Successful treatment of HMB (MBL <80 mL) and a decrease to ≤50% of baseline MBL was achieved in 139/154 (90.3%) and 126/146 (86.3%) participants in the Donasert® and Mirena® groups, respectively and the between-treatment difference was non-significant. Most adverse events were mild in severity. Only two device expulsions occurred in the study and there were no uterine perforations. CONCLUSIONS: Donasert® has equivalent efficacy and safety during the first 6 months foralleviation of HMB compared to the reference device, Mirena®. TRIAL REGISTRATION NUMBER: 348 (Clinical Trials Registry of the Ministry of Health of the Russian Federation, http://grls.rosminzdrav.ru/default.aspx).

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Women with atypical hyperplasia (AH) or well-differentiated early-stage endometrioid endometrial carcinoma (EEC) who wish to retain fertility and/or with comorbidities precluding surgery, are treated with progestin. Clinically approved predictive biomarkers for progestin therapy remain an unmet need. The objectives of this study were to document the overall response rate (ORR) of levonorgestrel intrauterine device (LNG-IUD) treatment, and determine the association of FGFR2b and FGFR2c expression with treatment outcome. BaseScope RNA ISH assay was utilized to detect expression of FGFR2b and FGFR2c mRNA in the diagnostic biopsies of 89 women (40 AH and 49 EEC) treated with LNG-IUD. Detailed clinical follow-up was available for 69 women which revealed an overall response rate (ORR) of 44% (30/69) with a higher ORR seen in AH (64%) compared to EEC (23%). The recurrence rate in women who initially responded to LNG-IUD was 10/30 (33.3%). RNA ISH was successful in 72 patients and showed FGFR2c expression in 12/72 (16.7%) samples. In the 59 women with detailed clinical follow-up and RNA-ISH data, women with tumours expressing FGFR2c were 5-times more likely to have treatment failure in both univariable (HR 5.08, p < 0.0001) and multivariable (HR 4.5, p < 0.002) Cox regression analyses. In conclusion, FGFR2c expression appears to be strongly associated with progestin treatment failure, albeit the ORR is lower in this cohort than previously reported. Future work to validate these findings in an independent multi-institutional cohort is needed.

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Endometrial Cancer (EC) is the most common gynaecologic malignancy in the developed world, and is increasing in premenopausal women. The surgical standard of care for early-stage EC is not possible in women with concurrent comorbidities or women who desire a fertility sparing approach. The Levonorgestrel Intrauterine System (LNG-IUS) is gaining traction as an alternative treatment for endometrial hyperplasia and early stage EC in inoperable women. Whilst early evidence appears promising, predictive biomarkers need to be established to determine non-responders, which make up one in three women. This timely review discusses the current literature around the identification of clinical, molecular and novel biomarkers that show potential to predict response to progesterone treatment, including the LNG-IUS.

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BACKGROUND: The presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature. CASE PRESENTATION: A 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later. CONCLUSION: Migration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.

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From 1995 to 2014, intrauterine devices (IUDs) rose from ranking 10th (out of 11) among contraceptive methods to being the fourth most popular, outnumbered only by the pill, sterilization, and condoms. In 1995, the IUD had been largely abandoned by American doctors; two decades later, major medical associations promoted it as a "first line" method for prospective users of all ages. This paper explains the rapid and dramatic increase in intrauterine contraception by exploring three influential factors from the 1970s-1980s - the Dalkon Shield disaster, the lack of innovation in contraceptive research and development, and the moral panic over teen pregnancy in America - that created circumstances by the early 2000s in which health care providers became more receptive to long-acting reversible contraception. Key thought leaders in obstetrics and gynecology took it upon themselves to rehabilitate the IUD in the court of medical opinion and succeeded in securing professional approval of the device as the initial step in its resurrection.

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