Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia

  • Review
  • Intervention

Authors


Abstract

Background

Endometrial carcinoma is the most common gynaecologic malignancy in the world and develops through preliminary stages of endometrial hyperplasia. Typical endometrial hyperplasia suggests a significant pre-malignant state with frank progression to endometrial carcinoma. Because atypical endometrial hyperplasia tends to occur at a young age, it has become increasingly important and necessary to find a safe and effective fertility-sparing treatment with better tolerability and fewer side effects than the options for treatment that are currently available. The levonorgestrel-releasing intrauterine system has already been used to provide endometrial protection in women with breast cancer who are on adjuvant tamoxifen. The antiproliferative function of levonorgestrel is thought to reduce the risk of endometrial hyperplasia.

Objectives

To determine the efficacy and safety of the levonorgestrel-releasing intrauterine system in reversing atypical endometrial hyperplasia.

Search methods

In November 2012 we searched the Cochrane Menstrual Disorders and Subfertility Review Group Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library; MEDLINE; EMBASE; and the China National Knowledge Infrastructure for relevant trials. Attempts were made to identify trials from references in published studies. We also searched for ongoing trials in five major clinical trials registries.

Selection criteria

Randomised controlled trials (RCTs) of the levonorgestrel-releasing intrauterine system (LNG-IUS) versus progestin therapy in women with a confirmed histological diagnosis of simple or complex endometrial hyperplasia with atypia.

Data collection and analysis

No eligible study was found.

Main results

We did not identify any studies which met our full inclusion criteria.

Authors' conclusions

There is no evidence available from randomised controlled trials regarding the efficacy and safety of the levonorgestrel-releasing intrauterine system (LNG-IUS) for atypical endometrial hyperplasia. RCTS are required to determine whether the LNG-IUS is safe and effective for treating atypical endometrial hyperplasia.

Résumé scientifique

Dispositif intra-utérin libérant du lévonorgestrel dans l'hyperplasie endométriale atypique

Contexte

Le carcinome endométrial est la malignité gynécologique la plus répandue à l'échelle mondiale et se développe suite à différentes phases préliminaires d'une hyperplasie endométriale. L'hyperplasie endométriale typique suggère un stade précancéreux significatif avec une nette évolution en carcinome endométrial. Étant donné que l'hyperplasie endométriale atypique a tendance à se manifester à un jeune âge, il est devenu de plus en plus indispensable et nécessaire de trouver un traitement sûr et efficace de préservation de la fertilité présentant une meilleure tolérabilité et moins d'effets secondaires que les options de traitement actuellement disponibles. Un dispositif intra-utérin libérant du lévonorgestrel a déjà été utilisé pour assurer une protection endométriale chez les femmes atteintes d'un cancer du sein prenant du tamoxifène adjuvant. La fonction antiproliférative du lévonorgestrel permettrait de réduire les risques d'hyperplasie endométriale.

Objectifs

Déterminer l'efficacité et la tolérance d'un dispositif intra-utérin libérant du lévonorgestrel afin de retarder une hyperplasie endométriale atypique.

Stratégie de recherche documentaire

En novembre 2012, nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur les troubles menstruels et de la fertilité ; le registre Cochrane des essais contrôlés (CENTRAL) dans The Cochrane Library ; MEDLINE ; EMBASE et le China National Knowledge Infrastructure, afin d’identifier des essais pertinents. Nous avons essayé d'identifier des essais dans les références bibliographiques des études publiées. Nous avons également recherché des essais en cours dans les cinq principaux registres d'essais cliniques.

Critères de sélection

Des essais contrôlés randomisés (ECR) comparant un dispositif intra-utérin libérant du lévonorgestrel (DIU LNG) à un traitement à base de progestatifs chez des femmes présentant un diagnostic histologique confirmé d'une hyperplasie endométriale simple ou complexe accompagnée d'une atypie.

Recueil et analyse des données

Aucune étude éligible n'a été trouvée.

Résultats principaux

Nous n'avons identifié aucune étude répondant à l’ensemble de nos critères d'inclusion.

Conclusions des auteurs

Il n'existe aucune preuve dans les essais contrôlés randomisés concernant l'efficacité et la tolérance d'un dispositif intra-utérin libérant du lévonorgestrel (DIU LNG) dans l'hyperplasie endométriale atypique. D'autres ECR seront nécessaires pour déterminer si un DIU LNG est sûr et efficace pour le traitement d'une hyperplasie endométriale atypique.

Plain language summary

The levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia

Atypical endometrial hyperplasia commonly develops into endometrial carcinoma, which is the most common gynaecologic cancer in the world. The levonorgestrel-releasing intrauterine system (LNG-IUS) is thought to reduce the risk of endometrial hyperplasia. However, this review of the evidence found no randomised controlled studies (RCTs) of the efficacy and safety of the LNG-IUS for treating women with a diagnosis of atypical endometrial hyperplasia. RCTS are required in this area.

Résumé simplifié

Dispositif intra-utérin libérant du lévonorgestrel dans l'hyperplasie endométriale atypique

L'hyperplasie endométriale atypique se développe généralement en carcinome endométrial qui est le cancer gynécologique le plus répandu à l'échelle mondiale. Un dispositif intra-utérin libérant du lévonorgestrel (DIU LNG) permettrait de réduire les risques d'hyperplasie endométriale. Toutefois, la présente revue de preuves n'a trouvé aucune étude contrôlée randomisée (ECR) concernant l'efficacité et la tolérance d'un DIU LNG dans le traitement de femmes chez lesquelles une hyperplasie endométriale atypique a été diagnostiquée. D'autres ECR sont nécessaires dans ce domaine.

Notes de traduction

Traduit par: French Cochrane Centre 16th July, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Background

 

Description of the condition

Endometrial carcinoma is the most common gynecologic malignancy in the western world and develops through preliminary stages of endometrial hyperplasia. Histologically, endometrial hyperplasia can be divided into three main categories of simple, complex and atypical hyperplasia. The classification is based on the degree of architectural and cytological abnormality. Cytological atypia is the most important prognostic factor for progression to carcinoma. Some 8% to 30% of atypical hyperplasias progress to carcinoma over a mean duration of four years, while only about 1% to 3% of non-atypical hyperplasias progress to endometrial carcinoma over a mean duration of 10 years (Kurman 1985). This means that the presence of atypical endometrial hyperplasia suggests a significant pre-malignant state with frank progression to endometrial adenocarcinoma. The optimal treatment of atypical endometrial hyperplastic lesions is essential to prevent the development of endometrial cancer. The standard treatment is hysterectomy. However, hysterectomy is not considered the optimal treatment for all women. For women who want to preserve fertility, who refuse an operation or have medical contraindications to surgery, conservative therapy is needed. Because atypical endometrial hyperplasia tends to occur at a young age (Guo 1993), it has become increasingly important and necessary to find a safe and effective fertility-sparing treatment with better tolerability and fewer side effects than the options for treatment that are currently available.

Description of the intervention

Since the 1960s, oral progestins have been used as conservative treatment in young women with atypical endometrial hyperplasia. However, oral progestins are associated with poor tolerability and numerous systemic side effects (for example headache, nausea) that may limit their overall efficacy. Furthermore, the long-term use of oral progestins often results in metabolic changes and exposes the woman to a higher risk of thromboembolic events (Randall 1997). Gonadotropin-releasing hormone (GnRH) analogues have also been proposed but hormonal side effects preclude their long-term use (Kullander 1992).

The levonorgestrel-releasing intrauterine system (LNG-IUS) was developed in the early 1970s. The Mirena is a T-shaped device composed of a cylinder containing 52 mg of levonorgestrel covered by a rate-controlling membrane which serves to regulate the rate of hormonal release; 20 μg of levonorgestrel is released every 24 hours from this polymer cylinder. The effect of levonorgestrel is to thin the endometrial lining of the uterus to make it less suitable for implantation and to change the cervical mucus and utero-tubal fluid in a way that inhibits the passage of sperm. It provides contraceptive protection for up to five or seven years (Luukkainen 1991). Although the LNG-IUS was developed for use as a contraceptive device, it is now commonly used for treating menorrhagia and for providing endometrial protection in women taking hormone therapy (HT) (Chi 1994; Sturridge 1996).

How the intervention might work

Levonorgestrel released from the intrauterine system inhibits the endometrial synthesis of estrogen receptors and induces atrophy of the endometrial glands. During this process, the stroma undergoes a wide-spread decidual reaction and the mucosa and the epithelium become inactive (Sitruk-Ware 2004; Critchley 2007). The device also suppresses the spiral arterioles of the mucosa and thickens the arteriole wall and reduces capillary thrombosis. These changes result in markedly decreased menstrual blood loss or amenorrhoea and endometrial growth suppression, which is seen three months after insertion of the LNG-IUS. Moreover, the LNG-IUS provides very high local concentrations of progestins to the uterine mucosa and acts many times more strongly on the endometrium than when levonorgestrel is given systemically (Xiao 1990). The dosage can, therefore, be reduced significantly to minimize side effects associated with hormonal problems and to optimize tolerability by women. However, side effects related to the intrauterine device such as pelvic inflammatory disease, ectopic pregnancy, expulsion and perforation may occur.

Some analyses have shown an 89% regression rate for atypical hyperplasia. Other prospective cohort studies reported that the LNG-IUS was effective in the reversion of atypical endometrial hyperplasia (Wildemeersch 2003; Wildemeersch 2007; Qi 2008; Buttini 2009), suggesting that LNG-IUS may be an appropriate conservative treatment for atypical hyperplasia. Nevertheless this effect needs to be supported and confirmed by more evidence-based studies, especially randomised controlled trials.

Why it is important to do this review

The Cochrane review of LNG-IUS for endometrial protection in women with breast cancer who are on adjuvant tamoxifen has been published. The antiproliferative function of levonorgestrel is thought to reduce the risk of endometrial hyperplasia, although larger studies are needed to further assess the effects (Chin 2009). LNG-IUS appears to be a promising conservative treatment that is safe, convenient and reversible, thus it could provide a valuable alternative to hysterectomy and oral progestin, especially in younger women who still want to preserve fertility and in women who refuse an operation or are in poor health. Herein, we intend to determine the efficacy and safety of the LNG-IUS in treating atypical endometrial hyperplasia.

Objectives

To determine the efficacy and safety of the levonorgestrel-releasing intrauterine system (LNG-IUS) in treating atypical endometrial hyperplasia.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) that evaluated the effects of the LNG-IUS on the endometrium in women with atypical endometrial hyperplasia were included.

Types of participants

Inclusion:

  • women with a confirmed histological diagnosis of simple or complex endometrial hyperplasia with atypia by pipelle biopsy or by curettage.

Exclusion:

  • women with contraindications to the LNG-IUS (acute genital tract inflammatory disease, genital bleeding of unknown aetiology, pregnancy or suspicion of pregnancy, hypersensitivity to any component of this product, congenital or acquired uterine anomaly, known or suspected breast cancer, known or suspected uterine and cervical neoplasia or unresolved or abnormal Pap smear, acute liver disease or liver tumour, etc);

  • women with concurrent endometrial cancer;

  • women with a history of any other malignancy.

Types of interventions

Intervention:

  •  LNG-IUS insertion (Nova-T®, Levonova®/Mirena®, Femilis®, Fibroplant®, Mirena®).

Comparator:

  •  progestins (including medroxyprogesterone acetate; megestrol acetate; 17a-hydroxyprogesterone caproate; 6,17 adimethyl-6-dehydroprogesterone, 6-methyl-6-dehydroprogesterone acetate).

Types of outcome measures

Primary outcomes

1. Rate of regression (complete or partial): a 'complete regression' is defined as a return of the atypical endometrium to normal, often with associated secretory glandular changes and atrophy; a 'partial regression' is defined as a change from atypical to non-atypical hyperplasia. The regression rate includes the complete and partial regression rate.

2. Adverse effects associated with hormonal problems: weight gain, acne, nausea, headache, dizziness, vomiting, depression, breast tenderness.

Secondary outcomes

3. Rate of recurrence

4. Proportion of women undergoing hysterectomy (histologically indicated or non-histologically indicated)

5. Other adverse effects: bleeding (spotting, amenorrhoea, prolonged or heavy bleeding), pelvic inflammatory disease (PID), ovarian cyst, uterine myoma, device-related problems (expulsion, perforation)

6. Withdrawal from treatment because of adverse events

7. Satisfaction with treatment

8. Quality of life (QoL), measured using a scale that has been validated through reporting of norms in a peer-reviewed publication

Search methods for identification of studies

Electronic searches

See: Cochrane Menstrual Disorders and Subfertility Group (MDSG) methods used in reviews. A comprehensive search strategy was formulated in order to identify all RCTs regardless of language. The following electronic databases were searched:

  • Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 8);

  • Menstrual Disorders and Subfertility Specialised Register;

  • MEDLINE (1948 to 2012 November);

  • EMBASE (1986 to 2012 November);

  • Chinese National Knowledge Infrastructure (CNKI) (1977 to 2012 November);

  • CBM (China Biomedicine Database) (1995 to 2012 November);

  • PsycINFO (1988 to 2012 November).

The search strategies, based on terms related to the review topic, are presented for each database in Appendices 1 to 7. The PubMed 'related articles' feature was used to check for articles related to eligible studies. The bibliographies of all relevant papers selected through this strategy were searched. Where possible, personal communications with corresponding authors and clinical experts were established to enquire about other published or unpublished relevant studies.

Searching other resources

  • Trials Registries

Five major clinical trials registries (listed below) were searched for ongoing and registered trials using the following words: levonorgestrel, intrauterine device, randomized, endometrial simple hyperplasia, endometrial complex hyperplasia, endometrial atypia. We searched:

1. National Research Register;

2. Meta-register of Controlled Trials;

3. Chinese Clinical Trial Registry;

4. World Health Organization (WHO) International Clinical Trials Registry Platform;

5. Clinical Trials gov.

  • Grey literature

Grey literature was searched on the European OpenSingle (http://opensigle.inist.fr/).

  • Conference abstracts

The abstracts of scientific meetings were also searched on the ISI Web of Knowledge (http://isiwebofknowledge.com/).

  • Contact with Schering, a company that produces progesterone and progestogen-releasing intrauterine devices

Data collection and analysis

Selection of studies

All titles and abstracts retrieved by electronic searching were downloaded to the reference management database (EndNote), duplicates removed and the remaining references independently examined by two review authors (LL, LB). Those studies which clearly did not meet the inclusion criteria were excluded and copies of the full texts of potentially relevant references were obtained. The eligibility of retrieved papers was assessed independently by two review authors (LL, LB). Disagreements were resolved by discussion. Reasons for exclusion were documented.

Data extraction and management

Data on the characteristics of participants and interventions, study quality and endpoints were independently extracted by LL and LB using a piloted data extraction form designed according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Differences between review authors were resolved by discussion or by appeal to a third review author (ZY or LJ).

Assessment of risk of bias in included studies

We planned to assess the methodological quality using the Cochrane Collaboration's tool and the criteria specified in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We planned to assess sequence generation; allocation concealment; blinding of outcome assessors; completeness of outcome data; selective outcome reporting; and other potential sources of bias. We planned that two authors would assess these domains, with any disagreements resolved by consensus or by discussion with a third author. All judgments would be fully described. The conclusions would be presented in the 'Risk of bias' table and incorporated into the interpretation of review findings by means of sensitivity analyses.

Measures of treatment effect

We planned to use the following measures for the effect of treatment.

  • For dichotomous data (e.g. regression rate), the numbers of events in the control and intervention groups of each study woul be used to calculate Peto odds ratios.    

  • For continuous outcomes (e.g. QoL scores), mean differences between treatment arms would be calculated if all studies reported exactly the same outcomes. If similar outcomes were reported on different scales (e.g. change in weight) the standardised mean differences would be calculated.

  • The 95% confidence intervals would be presented for all outcomes.

Unit of analysis issues

We anticipated that no unit of analysis issues would arise.

Dealing with missing data

We planned to contact trial authors to ask for any missing data. If suitable data were available, intention-to-treat analysis would be conducted. Where these were unobtainable, we planned that imputation of individual values would be undertaken for the primary outcomes only. Endometrial regression would be assumed not to have occurred in participants with an unreported outcome.

If studies reported sufficient detail to calculate mean differences but gave no information on the associated standard deviation (SD), we planned to assume the outcome had an SD equal to the highest SD from other studies within the same analysis.

For other outcomes, we planned that only the available data would be analysed. Any imputation that was undertaken would be subjected to sensitivity analysis.

Assessment of heterogeneity

The authors planned to consider whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta-analysis to provide a meaningful summary. Statistical heterogeneity would be assessed by a measure of the I2 statistic. An I2 statistic greater than 50% would be taken to indicate substantial (high level) heterogeneity; 25% to 50% as moderate level; less than 25% as low level (Higgins 2002; Higgins 2003). If substantial heterogeneity was detected, possible explanations would have been explored in sensitivity analyses.

Assessment of reporting biases

In view of the difficulty in detecting and correcting for publication bias and other reporting biases, we aimed to minimize their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there were 10 or more studies in an analysis, we planned to use a funnel plot to explore the possibility of small study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies).

Data synthesis

If the RCTs were considered not appropriate for pooled analysis, only a descriptive analysis would have been conducted. Otherwise, we planned that the data from primary studies would be combined using fixed-effect models in the following comparisons.

1. LNG-IUS versus oral progestin, stratified by duration and dose:

(i) low dose and short duration;

(ii) high dose and short duration;

(iii) low dose and long duration;

(iv) high dose and long duration.

2. LNG-IUS (low dose) versus LNG-IUS (high dose), stratified by duration:

(i) short duration;

(ii) long duration.

3. LNG-IUS (short duration) versus LNG-IUS (long duration), stratified by dose:

(i) low dose;

(ii) high dose.

An increase in the odds of a particular outcome, which may be beneficial (for example endometrial regression) or detrimental (for example adverse effects), would be displayed graphically in the meta-analyses to the right of the centre-line and a decrease in the odds of an outcome to the left of the centre-line.

Subgroup analysis and investigation of heterogeneity

We planned to conduct subgroup analyses grouping the trials by the following variables.

1. Type of LNG-IUS used:

  •   frameless LNG-IUS, releasing 14 μg LNG/day;

  •   framed LNG–IUS, releasing 20 μg LNG/day.

 2.Type of atypical endometrial hyperplasia:

  •  simple hyperplasia with atypia;

  •  complex hyperplasia with atypia.

Factors such as age, the duration of LNG-IUS intervention, length of follow-up, different diagnostic criteria of atypical endometrial hyperplasia, and adjusted or unadjusted analysis were to be considered in interpretation of any heterogeneity.

Sensitivity analysis

We planned to use sensitivity analysis to explore the influence of the following factors on effect size:

1. if eligibility was restricted to studies without high risk of bias;

2. if alternative imputation strategies were adopted;

3. if a random-effects model was adopted.

Results

Description of studies

We found no studies meeting all the inclusion criteria.

Results of the search

The search retrieved 127 articles. Three studies were potentially eligible and were retrieved in full text. Three trials (Buttini 2009; Lee 2010; George A 2011) which initially seemed to conform to our inclusion criteria were excluded after assessing the full articles.

Included studies

No studies were included.

Excluded studies

Three studies were excluded (Buttini 2009; Lee 2010; George A 2011).

Please refer to the Characteristics of excluded studies table for details of these studies.

Risk of bias in included studies

No studies were included.

Effects of interventions

Since no studies were included, we could not evaluate the effects of the intervention.

Discussion

Summary of main results

No studies were included.

Agreements and disagreements with other studies or reviews

No RCTs were found testing the effects and safety of the LNG-IUS in treating atypical endometrial hyperplasia. Among the excluded studies, all of which were observational studies, two reported that the regression of complex atypical hyperplasia was attained at the 37th week and ninth month after LNG-IUS insertion, respectively (Buttini 2009; Lee 2010). The third excluded study (George A 2011) reported that two women required hysterectomy for endometrioid carcinoma, evident on endometrial biopsy at six months and 24 months respectively. These studies reported that LNG-IUS was a safe and effective method for treating non-atypical endometrial hyperplasia, and that whether LNG-IUS could provide a safe and cost-effective alternative to hysterectomy for atypical endometrial hyperplasia warranted further investigation.

Authors' conclusions

Implications for practice

Since there is no evidence from randomised controlled trials (RCTs) on the efficacy and safety of the levonorgestrel-releasing intrauterine system (LNG-IUS) in treating atypical endometrial hyperplasia, we cannot comment about its use in clinical practice.

Implications for research

Well-designed RCTs with sufficient power are needed to test the efficacy and safety of the LNG-IUS in treating atypical endometrial hyperplasia.

Acknowledgements

We thank Lin Dongtao for her contribution to the English revision process. We also thank the Cochrane Menstrual Disorders and Subfertility Group for providing us with support and advice.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. MEDLINE search strategy

  1. exp Levonorgestrel/

  2. d-norgestrel.tw.

  3. exp Intrauterine Devices, Medicated/

  4. Levonorgestrel.tw.

  5. (LNG-IUS or LNG-IUD).tw.

  6. Levonova$.tw.

  7. Mirena$.tw.

  8. Femilis$.tw.

  9. Fibroplant$.tw.

  10. or/1-9

  11. exp Endometrial Hyperplasia/

  12. (endometri$ adj4 hyperplasia$).tw.

  13. (proliferat$ adj4 endometri$).tw.

  14. (endometri$ adj4 atypi$).tw.

  15. or/11-14

  16. 10 and 15

  17. randomized controlled trial.pt.

  18. controlled clinical trial.pt.

  19. randomized.ab.

  20. placebo.tw.

  21. clinical trials as topic.sh.

  22. randomly.ab.

  23. trial.ti.

  24. (crossover or cross-over or cross over).tw.

  25. or/17-24

  26. exp animals/ not humans.sh.

  27. 25 not 26

  28. 16 and 27

Appendix 2. EMBASE search strategy

  1. exp LEVONORGESTREL/

  2. d-norgestrel.tw.

  3. exp intrauterine contraceptive device/

  4. Levonorgestrel.tw.

  5. (LNG-IUS or LNG-IUD).tw.

  6. Levonova$.tw.

  7. Mirena$.tw.

  8. Femilis$.tw.

  9. Fibroplant$.tw.

  10. or/1-9

  11. exp endometrium hyperplasia/

  12. (endometri$ adj4 hyperplasia$).tw.

  13. (proliferat$ adj4 endometri$).tw.

  14. (endometri$ adj4 atypi$).tw.

  15. or/11-14

  16. 10 and 15

  17. Clinical Trial/

  18. Randomized Controlled Trial/

  19. exp randomization/

  20. Single Blind Procedure/

  21. Double Blind Procedure/

  22. Crossover Procedure/

  23. Placebo/

  24. Randomi?ed controlled trial$.tw.

  25. Rct.tw.

  26. random allocation.tw.

  27. randomly allocated.tw.

  28. allocated randomly.tw.

  29. (allocated adj2 random).tw.

  30. Single blind$.tw.

  31. Double blind$.tw.

  32. ((treble or triple) adj blind$).tw.

  33. placebo$.tw.

  34. prospective study/

  35. or/17-34

  36. case study/

  37. case report.tw.

  38. abstract report/ or letter/

  39. or/36-38

  40. 35 not 39

  41. 16 and 40

Appendix 3. CNKI search strategy

  1. Levonorgestrel

  2. Intrauterine Devices

  3. Mirena

  4. Or 1-3

  5. endometrial hyperplasis

  6. endometrial simple hyperplasia

  7. endometrial complex hyperplasia

  8. endometrial atypia

  9. or 5-8

  10. 4 and 9

  11. and randomised controlled trial

Appendix 4. CBM search strategy

  1. Levonorgestrel

  2. Intrauterine Devices

  3. Mirena

  4. or 1-3

  5. endometrium

  6. endometrial simple hyperplasia

  7. endometrial complex hyperplasia

  8. endometrial atypia

  9. or 5-8

  10. 4 and 9

  11. randomised controlled trial

  12. controlled clinical trial

  13. Randomized

  14. placebo

  15. clinical trials as topic

  16. randomly

  17. trial

  18. (crossover or cross-over or cross over)

  19. or/11-18

  20. exp animals/ not humans.sh.

  21. 19 not 20

  22. 10 and 21

Appendix 5. Cochrane Central Register of Controlled Trials search strategy

  1. exp Levonorgestrel/

  2. d-norgestrel.tw.

  3. exp Intrauterine Devices, Medicated/

  4. Levonorgestrel.tw.

  5. (LNG-IUS or LNG-IUD).tw.

  6. Levonova$.tw.

  7. Mirena$.tw.

  8. Femilis$.tw.

  9. Fibroplant$.tw.

  10. or/1-9

  11. exp Endometrial Hyperplasia/

  12. (endometri$ adj4 hyperplasia$).tw.

  13. (proliferat$ adj4 endometri$).tw.

  14. (endometri$ adj4 atypi$).tw.

  15. or/11-14

  16. 10 and 15

Appendix 6. PsycINFO search strategy

  1. exp Intrauterine Devices/

  2. d-norgestrel.tw.

  3. Levonorgestrel.tw.

  4. (LNG-IUS or LNG-IUD).tw.

  5. Levonova$.tw.

  6. Mirena$.tw.

  7. Femilis$.tw.

  8. Fibroplant$.tw.

  9. or/1-8 (88)

  10. (endometri$ adj4 hyperplasia$).tw.

  11. (proliferat$ adj4 endometri$).tw.

  12. (endometri$ adj4 atypi$).tw.

  13. or/10-12

  14. 9 and 13

Appendix 7. MDSG search strategy

Keywords CONTAINS "Levonorgestrel" or "Levonorgestrel-Therapeutic -Use" or "levonorgestrel-releasing intrauterine system" or "levonorgestrel-releasing intrauterine device" or "levonorgestrel intrauterine system" or "intrauterine contraceptive devices" or "intrauterine device" or "intrauterine devices" or "Intrauterine Devices, Medicated" or "Mirena" or "LNG-IUS" or "Nova T 380" or Title CONTAINS "Levonorgestrel" or " Levonorgestrel-Therapeutic-Use "or "levonorgestrel-releasing intrauterine system" or "levonorgestrel-releasing intrauterine device" or "levonorgestrel intrauterine system" or "intrauterine contraceptive devices" or "intrauterine device" or "intrauterine devices" or "Intrauterine Devices, Medicated" or "Mirena" or "LNG-IUS" or "Nova T 380"

AND

Keywords CONTAINS "endometrial abnormalities" or "endometrial hyperplasia" or "endometrial thickness" or "endometrial vascularity" or "hyperplasia" or "proliferation" or "endometrial proliferation" or "endometrial safety" or Title CONTAINS"endometrial abnormalities"or "endometrial hyperplasia" or "endometrial thickness" or "endometrial vascularity" or "hyperplasia" or "proliferation" or "endometrial proliferation" or "endometrial safety"

Contributions of authors

Zheng Ying and Li Jing provided clinical expertise and designed the protocol. Luo Li, Luo Bing and Zhang Heng assisted with writing the protocol and review. Neil Sidell was responsible for the English writing.

Declarations of interest

 None

Sources of support

Internal sources

  • Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, China.

    support of clinic advices and salary.

External sources

  • Menstrual Disorders and Subfertility Group, New Zealand.

    Support of search strategy, advice and statistical analysis

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Buttini 2009Non-randomised clinical trial. A retrospective study of 21 cases of endometrial hyperplasia without any randomisation, control or blinding.
George A 2011Non-randomised clinical trial. A retrospective study of 56 cases of endometrial hyperplasia without any randomisation, control or blinding.
Lee 2010Non-randomised clinical trial. An observational study to evaluate the effectiveness of the levonorgestrel-releasing intrauterine system for endometrial hyperplasia after three months of therapy.

Ancillary