Review question
Researchers in Cochrane reviewed the evidence about the effectiveness and safety of the levonorgestrel-intrauterine system (LNG-IUS) compared with other forms of treatment in women with endometrial hyperplasia.
Background
Endometrial hyperplasia (EH) is a thickening (or overgrowth) of the endometrium (inner lining) of the uterus (womb) resulting from an excess of the hormone oestrogen, which is not balanced by the hormone progesterone. Women with EH commonly present to their doctor with abnormal vaginal bleeding. EH increases the risk of developing endometrial cancer, and can be described as without atypia (associated with a low risk of progression to atypia and cancer) or with atypia (where the cells are structurally abnormal, and have a higher risk of developing cancer). Endometrial cancer is the sixth most common cancer in women worldwide and is most commonly diagnosed in women after the menopause, particularly around the sixth and seventh decades of life. The goal of treatment of EH is to prevent endometrial cancer from developing, and depends on the degree of atypia, menopausal status, and fertility preferences. Treatment can be medical (hormonal) or surgical (hysterectomy).
Progestogen tablets taken daily is the usual treatment for EH without atypia and in some cases of EH with atypia in women wishing to preserve fertility or unable to tolerate surgery. Progestogen is not always successful at reversing EH and has side effects. The LNG-IUS is a T-shaped device placed into the uterus which slowly releases progestogen with a direct effect on the endometrium. It can be inserted in clinic and remain in place for up to five years. LNG-IUS is an alternative approach to treat EH which may be more effective, have fewer side effects and be preferred by women.
Study characteristics
We included 13 randomised controlled trials (RCTs) comparing the LNG-IUS in 1657 women with EH to non-intrauterine progestogens (1327 women) or no treatment (190 women). We found no trials comparing the LNG-IUS with surgery or placebo. The women were aged between 22 and 70 years. All studies evaluated women with EH without atypia, and one of the studies also included women with EH with atypia. Two studies did not have enough data to analyse. The evidence is current to May 2020.
Key results
There is moderate-quality evidence that three to six months of treatment with the LNG-IUS is probably more effective than non-intrauterine progestogens in reversing EH at short-term follow-up (up to six months). This suggests that if regression of EH following treatment with a non-intrauterine progestogen is assumed to be 72%, regression of EH following treatment with LNG-IUS would be between 85% and 92%. There is low-quality evidence that LNG-IUS may be more effective in reversing EH at long-term follow-up (12 months up to two years). We found no studies that looked at longer-term duration of treatment or follow-up.
There was insufficient evidence to determine adverse effects associated with the LNG-IUS device; only one study reported on expulsion (when the device falls out of the womb).
Very low quality to low-quality evidence suggests the LNG-IUS may be more acceptable to women, with fewer hysterectomies, fewer women experiencing nausea, fewer withdrawals from treatment secondary to side effects, and higher patient satisfaction with treatment scores. Very low quality evidence suggests the LNG-IUS may be associated with more bleeding/spotting, and we are uncertain regarding effects on other hormone-related side effects such as weight gain or mood changes. There was insufficient evidence to reach a conclusion regarding safety or cost or resource use, as no studies reported data suitable for analysis.
One study demonstrated that compared with no treatment, the LNG-IUS reversed EH without atypia, suggesting that if regression of EH with no treatment is assumed to be 27%, regression of EH following treatment with LNG-IUS would be between 89% and 99%.
Quality of the evidence
The evidence was of low or moderate quality for the primary outcome of 'Regression of EH' in both review comparisons. The evidence was of low and very-low quality for the other outcomes. The main limitations were risk of bias (associated with lack of blinding and poor reporting of study methods), variation in results, small study numbers and low numbers of events reported.
There is moderate-quality evidence that treatment with LNG-IUS used for three to six months is probably more effective than non-intrauterine progestogens at reversing EH in the short term (up to six months) and long term (up to two years). Adverse effects (device-related and hormone-related) were poorly and incompletely reported across studies. Very low quality to low-quality evidence suggests the LNG-IUS may reduce the risk of hysterectomy, and may be associated with more bleeding/spotting, less nausea, less withdrawal from treatment due to adverse effects, and increased satisfaction with treatment, compared to non-intrauterine progestogens. There was insufficient evidence to reach conclusions regarding device-related adverse effects, or cost or resource use.
In the absence of treatment, endometrial hyperplasia (EH) can progress to endometrial cancer, particularly in the presence of histologic nuclear atypia. The development of EH results from exposure of the endometrium to oestrogen unopposed by progesterone. Oral progestogens have been used as treatment for EH without atypia, and in some cases of EH with atypia in women who wish to preserve fertility or who cannot tolerate surgery. EH without atypia is associated with a low risk of progression to atypia and cancer; EH with atypia is where the cells are structurally abnormal, and has a higher risk of developing cancer. Oral progestogen is not always effective at reversing the hyperplasia, can be associated with side effects, and depends on patient adherence. The levonorgestrel-intrauterine system (LNG-IUS) is an alternative method of administration of progestogen and may have some advantages over non-intrauterine progestogens.
To evaluate the effectiveness and safety of the levonorgestrel intrauterine system (LNG-IUS) in women with endometrial hyperplasia (EH) with or without atypia compared to medical treatment with non-intrauterine progestogens, placebo, surgery or no treatment.
We searched the following databases: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and PsycINFO, and conference proceedings of 10 relevant organisations. We handsearched references in relevant published studies. We also searched ongoing trials in ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry, and other trial registries. We performed the final search in May 2020.
Randomised controlled trials (RCTs) and cross-over trials of women with a histological diagnosis of endometrial hyperplasia with or without atypia comparing LNG-IUS with non-intrauterine progestogens, placebo, surgery or no treatment.
Two review authors independently performed study selection, risk of bias assessment and data extraction. Our primary outcome measures were regression of EH and adverse effects associated with the LNG-IUS device (such as pelvic inflammatory disease, device expulsion, uterine perforation) when compared to treatment with non-intrauterine progestogens, placebo, surgery or no treatment. Secondary outcomes included hysterectomy, hormone-related adverse effects (such as bleeding/spotting, pelvic pain, breast tenderness, ovarian cysts, weight gain, acne), withdrawal from treatment due to adverse effects, satisfaction with treatment, and cost or resource use. We rated the overall quality of evidence using GRADE methods.
Thirteen RCTs (1657 women aged 22 to 75 years) met the inclusion criteria. Two studies had insufficient data for meta-analysis, thus the quantitative analysis included 11 RCTs. All trials evaluated treatment duration of six months or less. The evidence ranged from very low to moderate quality: the main limitations were risk of bias (associated with lack of blinding and poor reporting of study methods), inconsistency and imprecision.
LNG-IUS versus non-intrauterine progestogens
Primary outcomes
Regression of endometrial hyperplasia
The LNG-IUS probably improves regression of EH compared with non-intrauterine progestogens at short-term follow-up (up to six months) (OR 2.94, 95% CI 2.10 to 4.13; I² = 0%; 10 RCTs, 1108 participants; moderate-quality evidence). This suggests that if regression of EH following treatment with a non-intrauterine progestogen is assumed to be 72%, regression of EH following treatment with LNG-IUS would be between 85% and 92%. Regression of EH may be improved by LNG-IUS compared with non-intrauterine progestogens at long-term follow-up (12 months) (OR 3.80, 95% CI 1.75 to 8.23; 1 RCT, 138 participants; low-quality evidence),
Adverse effects associated with LNG-IUS
There was insufficient evidence to determine device-related adverse effects; only one study reported on expulsion with insufficient data for analysis.
Secondary outcomes
The LNG-IUS may be associated with fewer hysterectomies (OR 0.26, 95% CI 0.15 to 0.46; I² = 19%; 4 RCTs, 452 participants; low-quality evidence), fewer withdrawals from treatment due to hormone-related adverse effects (OR 0.41, 95% CI 0.12 to 1.35; I² = 0%; 4 RCTs, 360 participants; low-quality evidence) and improved patient satisfaction with treatment (OR 5.28, 95% CI 2.51 to 11.10; I² = 0%; 2 RCTs, 202 participants; very low-quality evidence) compared to non-intrauterine progestogens. The LNG-IUS may be associated with more bleeding/spotting (OR 2.13, 95% CI 1.33 to 3.43; I² = 78%; 3 RCTs, 428 participants) and less nausea (OR 0.52, 95% CI 0.28 to 0.95; I² = 0%; 3 RCTs, 428 participants) compared to 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. There was insufficient evidence to determine cost or resource use.
LNG-IUS versus no treatment
Regression of endometrial hyperplasia
One study demonstrated that the LNG-IUS is associated with regression of EH without atypia (OR 78.41, 95% CI 22.86 to 268.97; I² = 0%; 1 RCT, 190 participants; moderate-quality evidence) compared with no treatment. This study did not report on any other review outcome.