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Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial.

ABSTRACT: The purpose of this study was to investigate if the levonorgestrel-impregnated intrauterine device (LNG-IUS, Mirena(®) ) is safe and effective as therapy for low-risk and medium-risk endometrial hyperplasia compared with oral medroxyprogesterone (MPA).A multicentre randomised trial.Norway.In all, 170 women aged 30-70 years with low- or medium-risk endometrial hyperplasia who met inclusion criteria.Patients were randomly assigned to one of three treatment arms: LNG-IUS; oral MPA 10 mg administered for 10 days per cycle, or continuous oral MPA 10 mg daily, for 6 months.The primary outcome measure was normalisation or persisting hyperplasia.After 6 months all three treatment regimens showed significant effect when the outcome was evaluated as therapy response or not (P < 0.001). Responses were obtained for all the women in the LNG-IUS group (53/53, 95% CI 0.93-1.0) and for 96% of the women in the continuous oral group (46/48, 95% CI 0.86-0.99). Only 69% of the women in the cyclic oral group were responders (36/52, 95% CI 0.55-0.81). Adverse effects were relatively common with minimal differences between therapy groups.In the first trial of its kind, women treated with the LNG-IUS showed histologically normal endometrium after 6 months of therapy for endometrial hyperplasia. Cyclical progestogens are found to be less effective compared with continuous oral therapy and LNG-IUS and should not be used for this purpose.

SUBMITTER: Orbo A

PROVIDER: S-EPMC4155866 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial.

Orbo A A Vereide Ab A Arnes M M Pettersen I I Straume B B

BJOG : an international journal of obstetrics and gynaecology 20131128 4

<h4>Objective</h4>The purpose of this study was to investigate if the levonorgestrel-impregnated intrauterine device (LNG-IUS, Mirena(®) ) is safe and effective as therapy for low-risk and medium-risk endometrial hyperplasia compared with oral medroxyprogesterone (MPA).<h4>Design</h4>A multicentre randomised trial.<h4>Setting</h4>Norway.<h4>Population</h4>In all, 170 women aged 30-70 years with low- or medium-risk endometrial hyperplasia who met inclusion criteria.<h4>Methods</h4>Patients were r ...[more]

PMID: 24286192

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Project description:BackgroundThe incidence of complex atypical hyperplasia and early-stage endometrioid endometrial cancer is increasing, in part owing to the epidemic of obesity, which is a risk factor tightly linked to the development of endometrial hyperplasia and cancer. The standard upfront treatment for complex atypical hyperplasia and early-stage endometrial cancer is hysterectomy. However, nonsurgical treatment of early-stage endometrial neoplasia may be necessary owing to medical comorbidities precluding surgery or desired future fertility.ObjectiveThis study aimed to evaluate the efficacy of the levonorgestrel intrauterine device to treat complex atypical hyperplasia and grade 1 endometrioid endometrial carcinoma.Study designA single-institution, single-arm, phase II study of the levonorgestrel intrauterine device (52 mg levonorgestrel, Mirena) was conducted in patients with complex atypical hyperplasia or grade 1 endometrioid endometrial cancer. The primary endpoint was pathologic response rate at 12 months, including complete or partial response. Quality of life and toxicity were assessed. Molecular analyses for proliferation markers, hormone-regulated genes, and wingless-related integration site pathway activation were performed at baseline and 3 months.ResultsA total of 57 patients were treated (21 endometrial cancer, 36 complex atypical hyperplasia). The median age was 48.0 years, and the median body mass index was 45.5 kg/m2. Of the 47 evaluable patients, 12-month response rate was 83% (90% credible interval, 72.7-90.3)-37 were complete responders (8 endometrial cancer; 29 complex atypical hyperplasia), 2 were partial responders (2 endometrial cancer), 3 had stable disease (2 endometrial cancer; 1 complex atypical hyperplasia), and 5 had progressive disease (3 endometrial cancer; 2 complex atypical hyperplasia). After stratification for histology, the response rate was 90.6% for complex atypical hyperplasia and 66.7% for grade 1 endometrioid endometrial cancer. Notably, 4 patients (9.5%) experienced relapse after the initial response. Adverse events were mild, primarily irregular bleeding and cramping. Quality of life was not negatively affected. At 3 months, exogenous progesterone effect was present in 96.9% of responders (31 of 32) vs 25% of nonresponders (2 of 8) (P=.001). Nonresponders had higher baseline proliferation (Ki67) and lower dickkopf homolog 3 gene expression than responders (P=.023 and P=.030). Nonresponders had significantly different changes in secreted frizzled-related protein 1, frizzled class receptor 8, and retinaldehyde dehydrogenase 2 compared with responders.ConclusionThe levonorgestrel intrauterine device has a substantial activity in complex atypical hyperplasia and grade 1 endometrioid endometrial cancer, with a modest proportion demonstrating upfront progesterone resistance. Potential biomarkers were identified that may correlate with resistance to therapy; further exploration is warranted.

Project description:The contraceptive effectiveness of intrauterine devices has been attributed in part to effects of a foreign body reaction on the endometrium. We performed this study to identify compare the effects on the endometrial transcriptome of intrauterine devices and combined oral contraceptives, to better understand their mechanisms of action. We collected endometrial and cervical biopsies from women using the levonorgestrel-intrauterine device, copper intrauterine device or levonorgestrel-containing combined oral contraceptives, and from women not using contraceptives (control group). Transcriptional profiling was performed with Affymetrix arrays, Principal Component Analysis and the bioconductor package limma. Pathway analysis was performed using EnrichR and Reactome 2016. In endometrial samples from copper intrauterine device users (n=13), there were no genes with statistically significant differential expression compared to controls (n=11), whereas in levonorgestrel-intrauterine device users (n=11), 2509 genes were significantly dysregulated and mapped onto several immune and inflammatory pathways. In combined oral contraceptive users (n=12), 133 genes were significantly dysregulated and mapped predominantly onto pathways involving regulation of metal ions. Both levonorgestrel-intrauterine device and combined oral contraceptive use were associated with significant downregulation of members of the metallothionein gene family. In cervical samples, none of the groups showed statistically significant differential gene expression compared to controls. In conclusion, hormonal and copper intrauterine devices differ significantly in their effects on the endometrial transcriptome, with endometrium from copper intrauterine device users being indistinguishable from luteal phase endometrium. These results suggest that the contraceptive mechanisms of intrauterine devices are unlikely to rely on a common pathway involving a foreign body reaction in the endometrium.

Project description:Background It is estimated that between 12 to 25% of women who undergo an endometrial ablation for heavy menstrual bleeding (HMB) are dissatisfied after two years because of recurrent menstrual bleeding and/or cyclical pelvic pain, with around 15% of these women ultimately having a hysterectomy. The insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) immediately after endometrial ablation may inactivate residual untreated endometrium and/or inhibit the regeneration of endometrial tissue. Furthermore, the LNG-IUS may prevent agglutination of the uterine walls preventing intrauterine adhesion formation associated with endometrial ablation. In these ways, insertion of an LNG-IUS immediately after endometrial ablation might prevent subsequent hysterectomies because of persisting uterine bleeding and cyclical pelvic pain or pain that arises de novo. Hence, we evaluate if the combination of endometrial ablation and an LNG-IUS is superior to endometrial ablation alone in terms of reducing subsequent rates of hysterectomy at two years following the initial ablative procedure. Methods/design We perform a multicentre randomised controlled trial in 35 hospitals in the Netherlands. Women with heavy menstrual bleeding, who opt for treatment with endometrial ablation and without contraindication for an LNG-IUS are eligible. After informed consent, participants are randomly allocated to either endometrial ablation plus LNG-IUS or endometrial ablation alone. The primary outcome is the hysterectomy rate at 24 months following endometrial ablation. Secondary outcomes include women’s satisfaction, reinterventions, complications, side effects, menstrual bleeding patterns, quality of life, societal costs. Discussion The results of this study will help clinicians inform women with HMB who opt for treatment with endometrial ablation about whether concomitant use of the LNG-IUS is beneficial for reducing the need for hysterectomy due to ongoing bleeding and/or pain symptoms. Trial registration Dutch Trial registration: NL7817. Registered 20 June 2019, https://www.trialregister.nl/trial/7817. Supplementary Information The online version contains supplementary material available at 10.1186/s12905-022-01843-6.

Project description:BackgroundThough hysterectomy remains the standard treatment for complex atypical hyperplasia, patients who desire fertility or who are poor surgical candidates may opt for progestin therapy. However, the effectiveness of the levonorgestrel-releasing intrauterine device compared to systemic therapy in the treatment of complex atypical hyperplasia has not been well studied.ObjectiveWe sought to examine differences in treatment response between local progestin therapy with the levonorgestrel-releasing intrauterine device and systemic progestin therapy in women with complex atypical hyperplasia.MethodsThis single-institution retrospective study examined women with complex atypical hyperplasia who received progestin therapy between 2003 and 2018. Treatment response was assessed by histopathology on subsequent biopsies. Time-dependent analyses of complete response and progression to cancer were performed comparing the levonorgestrel-releasing intrauterine device and systemic therapy. A propensity score inverse probability of treatment weighting model was used to create a weighted cohort that differed based on treatment type but was similar with respect to other characteristics. An interaction-term analysis was performed to examine the impact of body habitus on treatment response, and an interrupted time-series analysis was employed to assess if changes in treatment patterns correlated with outcomes over time.ResultsA total of 245 women with complex atypical hyperplasia received progestin therapy (levonorgestrel-releasing intrauterine device n = 69 and systemic therapy n = 176). The mean age and body mass index were 36.9 years and 40.0 kg/m2, respectively. In the patient-level analysis, women who received the levonorgestrel-releasing intrauterine device had higher rates of complete response (78.7% vs 46.7%; adjusted hazard ratio, 3.32; 95% confidence interval, 2.39-4.62) and a lower likelihood of progression to cancer (4.5% vs 15.7%; adjusted hazard ratio, 0.28; 95% confidence interval, 0.11-0.73) compared to those who received systemic therapy. In particular, women with class III obesity derived a higher relative benefit from levonorgestrel-releasing intrauterine device therapy in achieving complete response compared to systemic therapy: class III obesity, adjusted hazard ratio 4.72, 95% confidence interval 2.83-7.89; class I-II obesity, adjusted hazard ratio 1.83, 95% confidence interval 1.09-3.09; and nonobese, adjusted hazard ratio 1.26, 95% confidence interval 0.40-3.95. In the cohort-level analysis, the obesity rate increased during the study period (77.8% to 88.2%, 13.4% relative increase, P = .033) and levonorgestrel-releasing intrauterine device use significantly increased after 2007 (6.3% to 82.7%, 13.2-fold increase, P < .001), both concomitant with a higher proportion of women achieving complete response (32.9% to 81.4%, 2.5-fold increase, P = .005).ConclusionOur study suggests that local therapy with the levonorgestrel-releasing intrauterine device may be more effective than systemic therapy for women with complex atypical hyperplasia who opt for nonsurgical treatment, particularly in morbidly obese women. Shifts in treatment paradigm during the study period toward increased levonorgestrel-releasing intrauterine device use also led to improved complete response rates despite increasing rates of obesity.

Dataset Information

Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial.

Publications

Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial.

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