Levonorgestrel-Releasing Intrauterine System for Endometrial Hyperplasia

Endometrial hyperplasia (EH) is a histological diagnosis of excessive production of cells in the endometriumthat represents a precursor in the development of endometrial cancer (EC), the sixth most common cancer in women globally. Obesity is the leading risk factor for both EH and EC in premenopausal women with abnormal uterine bleeding (AUB). Atypical hyperplasia progresses to EC in >25% of women and is associated with concurrent EC in up to 50% of women. Progesterone is the traditional medical treatment for EH without atypia, and hysterectomy, the treatment for atypical EH; however, observational studies suggest the levonorgestrel intrauterine system (LNG-IUS) may be used as an alternative in both cases. This review aims to assess the efficacy and safety of the LNG-IUS system in women with EH with or without atypia compared with medical treatment with nonintrauterine progestogens, placebo, surgery, or no treatment. Published and unpublished randomized controlled trials assessing the use of LNG-IUS in the treatment of EH were eligible for inclusion in meta-analyses. Women with contraindications to LNG-IUS, concurrent EC, history of hormone-dependent malignancy, and women taking tamoxifen were excluded. The primary outcomes were defined as regression of EH on subsequent biopsy or final histology following LNG-IUS, as well as adverse effects associated with LNG-IUS use, compared with nonintrauterine progestogens. Odds ratios (ORs) were calculated for dichotomous data with 95% confidence intervals (CIs) for all outcomes. A sensitivity analysis was conducted to remove studies at high or unclear risk of bias with respect to sequence generation and allocation concealment. A total of 13 studies from 7 countries met the inclusion criteria for this analysis, totaling 1657 patients. Eight studies used the standard-dose LNG-IUS (20 mu g daily), 1 trial used a low dose (14 mu g daily), and 4 did not specify dose. The meta-analysis included 10 trials, all of which provided data on endometrial histology at time of treatment completion or within 6 months, with one trial reporting pathology results at 12 months' follow-up. The LNG-IUS improved regression of EH compared with nonintrauterine progestogens at time of completion of treatment (OR, 2.94; 95% CI, 2.10-4.13; I-2 = 0%; 10 studies, 1108 participants). At 12 months' follow-up, 1 study demonstrated improved regression (OR, 3.80; 95% CI, 1.75-8.23; 1 study, 138 participants). The sensitivity analysis did not appreciably change the effect size for short-term follow-up. Analysis revealed LNG-IUS may be associated with fewer hysterectomies (OR, 0.26; 95% CI, 0.15-0.46; I-2 = 19%; 4 studies, 452 participants), less nausea (OR, 0.52; 95% CI, 0.28-0.95; I-2 = 0%; 3 studies, 428 participants), and fewer women withdrawing from treatment because of adverse effects (OR, 0.41; 95% CI, 0.12-1.35; I-2 = 0%; 4 studies, 360 participants) compared with nonintrauterine progestogens. Compared with no treatment, LNG-IUS was effective in EH regression (OR, 78.41; 95% CI, 22.86-268.97; I-2 = 0%; 1 study, 190 participants). The results of this study demonstrate moderate-quality evidence that treatment for EH with or without atypia with LNGIUS at short-term follow-up is probably more effective than nonintrauterine progestogens or no treatment. Future studies are needed to evaluate adverse effect profiles as well as long-term follow-up.