Dataset Information

Relapse risk of endometrial hyperplasia after treatment with the levonorgestrel-impregnated intrauterine system or oral progestogens.

ABSTRACT:

Objective

To investigate relapse rates after the successful treatment of patients with non-atypical endometrial hyperplasia who were randomised to either a levonorgestrel-impregnated intrauterine system (LNG-IUS; Mirena(®) ) or two regimens of oral medroxyprogesterone acetate (MPA) after primary histological response.

Design

A multicentre randomised trial.

Setting

Ten different outpatient clinics localised in hospitals and seven gynaecological private practices in Norway.

Population

One hundred and fifty-three women aged 30-70 years with low- or medium-risk endometrial hyperplasia met the inclusion criteria, and 153 completed the therapy.

Methods

Patients were randomly assigned to one of the following three treatment arms: LNG-IUS; 10 mg of oral MPA administered for 10 days per cycle for 6 months; or 10 mg of oral MPA administered daily for 6 months. The women were followed for 24 months after ending therapy.

Main outcome measures

Histological relapse of endometrial hyperplasia.

Results

Histological relapse was observed in 55/135 (41%) women who had an initial complete treatment response. The relapse rates were similar in the three therapy groups (P = 0.66). In the multivariable analyses relapse was dependent on menopausal status (P = 0.0005) and estrogen level (P = 0.0007).

Conclusions

The risk of histological relapse of non-atypical endometrial hyperplasia is high within 24 months of ceasing therapy with either the LNG-IUS or oral MPA. Continued endometrial surveillance and prolonging progestogen therapy should be considered.

Tweetable abstract

Relapse of endometrial hyperplasia after successful treatment is independent of therapy regime.

SUBMITTER: Orbo A

PROVIDER: S-EPMC5215722 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Publications

Relapse risk of endometrial hyperplasia after treatment with the levonorgestrel-impregnated intrauterine system or oral progestogens.

Ørbo A A Arnes M M Vereide A B AB Straume B B

BJOG : an international journal of obstetrics and gynaecology 20151202 9

<h4>Objective</h4>To investigate relapse rates after the successful treatment of patients with non-atypical endometrial hyperplasia who were randomised to either a levonorgestrel-impregnated intrauterine system (LNG-IUS; Mirena(®) ) or two regimens of oral medroxyprogesterone acetate (MPA) after primary histological response.<h4>Design</h4>A multicentre randomised trial.<h4>Setting</h4>Ten different outpatient clinics localised in hospitals and seven gynaecological private practices in Norway.<h ...[more]

PMID: 26630538

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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.

Dataset Information

Relapse risk of endometrial hyperplasia after treatment with the levonorgestrel-impregnated intrauterine system or oral progestogens.

Objective

Design

Setting

Population

Methods

Main outcome measures

Results

Conclusions

Tweetable abstract

Publications

Relapse risk of endometrial hyperplasia after treatment with the levonorgestrel-impregnated intrauterine system or oral progestogens.

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