Reversing endometrial hyperplasia with levonorgestrel-intrauterine system: a Cochrane review

December 8, 2020
Sandra Fyfe

Sandra Fyfe is a freelance writer for Contemporary OB/GYN.

In the largest meta-analysis study to date, researchers find that a levonorgestrel-intrauterine system (LNG-IUS) used for 3 to 6 months is likely more effective than non‐intrauterine progestogens for reversing endometrial hyperplasia (EH).

EH can progress to endometrial cancer, especially in cases with the presence of histologic nuclear atypia, so effective treatment is essential, according to researchers in New Zealand.1

Michelle Wise, MD, MSc, who is a fellow at the Royal Australian and New Zealand College of Obstetrics and Gynaecology and an assistant professor in the Department of Obstetrics and Gynaecology at the University of Auckland, and collaborating authors evaluated the efficacy and safety of levonorgestrel-intrauterine system (LNG-IUS) versus non‐intrauterine progestogens for women with EH with or without atypia. This is the largest meta-analysis study to date. Theirfindings are published online in the Cochrane Database of Systematic Reviews.

The authors searched the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and PsycINFO databases, as well as 10 relevant organizations’ conference proceedings. In addition, authors hand-searched relevant published studies, ongoing trials in the World Health Organization International Clinical Trials Registry,, and other trial registries.

They reviewed results of 13 randomized controlled trials of women aged 22 to 75 years that had a histologic diagnosis of EH comparing LNG-IUS treatment (1,657 women) with non‐intrauterine progestogens (1,327 women) and with no treatment (190 women). The authors reported 2 studies that did not have enough data to analyze, and that the results are current as of May 2020. All included trials had a treatment duration of 6 months or fewer. Main study limitations included bias risk, imprecision, and inconsistency.

Participants in the examined trials were randomized to a treatment of 3 or 6 months with either Mirena® IUS or non-intrauterine progestogen. A repeat biopsy was performed at 6 or 12 months of follow up, to assess the regression of EH to normal.

The authors reported that LNG-IUS is more effective than non-intrauterine progestogens in both the short and long term. They also reported that LNG-IUS use was associated with fewer hysterectomies, fewer withdrawals from treatment due to adverse hormone side effects, and better patient satisfaction when compared to non-intrauterine progestogens. LNG-IUS also was associated with more bleeding or spotting and less nausea than non-intrauterine progestogens.

“Data from single trials for mood swings and fatigue had a similar direction of effect as for bleeding/spotting, nausea and weight gain,” the authors wrote.1 They said that there is low-quality evidence that LNG‐IUS may be more effective in reversing EH from 12 months to up to 2 years in long-term follow-up. The authors noted that adverse device-related and hormone-related effects were incompletely and poorly reported across the examined studies.

In an interview with Contemporary OB/GYN, co-author Michelle R. Wise, MD, said that 3 ongoing trials will provide more information on treating EH. “The optimal duration of treatment, or the optimal timing of follow-up is not yet known,” she noted. She added that side effects and patient satisfaction also still need to be evaluated, as does cost-benefit analysis of the LNG-IUS compared to other treatments.

Wise highlighted that more women are being diagnosed with atypical EH and early endometrial cancer at a younger age, which she said was probably connected to the obesity epidemic. “It will be important to evaluate treatment with Mirena® IUS as a fertility-sparing alternative to hysterectomy in young women, and as an alternative to surgery in high-risk women,” Wise said. “If found to be effective in reversing this pre-cancerous condition, Mirena® IUS will enable many women to preserve their fertility or avoid major surgery. Ob/gyns in practice can be confident in recommending a short course of Mirena® IUS to patients with a new diagnosis of EH, or at least offering this as an alternative to oral or intramuscular routes, following an informed discussion with the patient,” she said.



  1. Mittermeier T, Farrant C, Wise MR. Levonorgestrel‐releasing intrauterine system for endometrial hyperplasia. Cochrane Database of Systematic Reviews 2020, Issue 9. Art. No.: CD012658. DOI: 10.1002/14651858.CD012658.pub2. Accessed 25 November 2020.

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