The role of different LNG-IUS therapies in the management of adenomyosis: a systematic review and meta-analysis

In the comparative study of LNG-IUS and etonogestrel, LNG-IUS showed a better effect than etonogestrel in reducing the volume of the uterus, but there was no difference in relieving dysmenorrhea measuring by visual analogue scale (VAS) and reducing the thickness of the endometrium at follow-up points of 6 and 12 months (Figs.  2 , 3 and 4 ). In terms of adverse effects, the incidence of weight gain in LNG-IUS was less, but there was no significant difference in acne or breast tenderness between LNG-IUS and etonogestrel at 12-month follow-up (Fig.  5 ) [ 13 – 16 ]. Fig. 2 Forest plot of the pain score after LNG-IUS insertion or etonogestrel subcutaneous implantation Forest plot of the pain score after LNG-IUS insertion or etonogestrel subcutaneous implantation Fig. 3 Forest plot of the uterus volume after LNG-IUS insertion or etonogestrel subcutaneous implantation Forest plot of the uterus volume after LNG-IUS insertion or etonogestrel subcutaneous implantation Fig. 4 Forest plot of the endometrial thickness after LNG-IUS insertion or etonogestrel subcutaneous implantation Forest plot of the endometrial thickness after LNG-IUS insertion or etonogestrel subcutaneous implantation Fig. 5 Forest plot of the adverse effects after LNG-IUS insertion or etonogestrel subcutaneous implantation Forest plot of the adverse effects after LNG-IUS insertion or etonogestrel subcutaneous implantation Between LNG-IUS and mifepristone, two studies [ 17 , 18 ] with a total of 248 patients were analyzed. Five aspects of quality of life were included in the two studies, which were thoughts/desires, arousal, pleasure/orgasm, receptivity/initiation, and abnormal sexual behavior. The forest plots exhibited that no difference in the quality of life was observed between groups at 6-month and 12-month follow-up (Figs.  6 and 7 ). Fig. 6 Forest plot of the quality of life after LNG-IUS insertion or mifepristone treatment at 6-month follow-up Forest plot of the quality of life after LNG-IUS insertion or mifepristone treatment at 6-month follow-up Fig. 7 Forest plot of the quality of life after LNG-IUS insertion or mifepristone treatment at 12-month follow-up Forest plot of the quality of life after LNG-IUS insertion or mifepristone treatment at 12-month follow-up For patients with AM, compared with LNG-IUS alone, GnRH-a + LNG-IUS had beneficial effects in reducing the intensity of dysmenorrhea within six-month period (Fig.  8 ) [ 19 – 24 ]. Regarding menstrual blood loss measuring by pictorial blood loss assessment chart (PBAC), six studies [ 20 – 25 ] with three cycles of GnRH-a (Fig.  9 ) reported a beneficial effect in the GnRH-a + LNG-IUS group at 6-month follow-up. Similar significant benefits were found in terms of reducing uterine volume, endometrial thickness, and adverse effects of expulsion, irregular bleeding and abdominal pain, except breast pain (Figs.  10 , 11 and 12 ) [ 19 – 27 ]. Fig. 8 Forest plot of the pain score after GnRH-a + LNG-IUS or LNG-IUS only Forest plot of the pain score after GnRH-a + LNG-IUS or LNG-IUS only Fig. 9 Forest plot of the PBAC after GnRH-a + LNG-IUS or LNG-IUS only Forest plot of the PBAC after GnRH-a + LNG-IUS or LNG-IUS only Fig. 10 Forest plot of the uterine volume after GnRH-a + LNG-IUS or LNG-IUS only Forest plot of the uterine volume after GnRH-a + LNG-IUS or LNG-IUS only Fig. 11 Forest plot of the endometrial thickness after GnRH-a + LNG-IUS or LNG-IUS only Forest plot of the endometrial thickness after GnRH-a + LNG-IUS or LNG-IUS only Fig. 12 Forest plot of the adverse effects after GnRH-a + LNG-IUS or LNG-IUS only Forest plot of the adverse effects after GnRH-a + LNG-IUS or LNG-IUS only Regarding the intensity of dysmenorrhea and menstrual blood loss, inconsistent results were observed. Compared with the expected, a beneficial effect was observed in the surgical excision + LNG-IUS at 12-month follow-up, but not at 6-month follow-up. (Figs  13 and 14 ) [ 28 – 31 ]. As for uterine volume, four studies [ 28 – 30 , 32 ] showed a statistically significant reduction in uterine volume in the surgical excision + LNG-IUS treatment group compared with the surgical excision only group at the 6-month, 12-month and 24-month follow-up (Fig.  15 ). Fig. 13 Forest plot of the pain score points after surgical excision + LNG-IUS insertion or surgical excision only Forest plot of the pain score points after surgical excision + LNG-IUS insertion or surgical excision only Fig. 14 Forest plot of the PBAC after surgical excision + LNG-IUS or surgical excision only Forest plot of the PBAC after surgical excision + LNG-IUS or surgical excision only Fig. 15 Forest plot of the uterine volume after surgical excision + LNG-IUS or surgical excision only Forest plot of the uterine volume after surgical excision + LNG-IUS or surgical excision only In terms of the intensity of dysmenorrhea, a significant benefit for FUA + LNG-IUS group at 6-month and 12-month follow-up (Fig.  16 ) [ 33 – 38 ]. Another two studies [ 39 , 40 ] showed better efficacy in reducing pain in the FUA + LNG-IUS than in the FUA group at 12-month follow-up (Fig.  17 ). Regarding menstrual blood loss, a statistically significant benefit was observed in the FUA + LNG-IUS group at 6 months in two studies [ 33 , 38 ]. But at 12-month follow-up, the other meta-analysis of two studies reported no statistically significant difference in menstrual blood loss reduction between FUA + LNG-IUS and FUA alone groups (Fig.  18 ). Fig. 16 Forest plot of the change in the pain score after FUA + LNG-IUS or FUA only Forest plot of the change in the pain score after FUA + LNG-IUS or FUA only Fig. 17 Forest plot of the effect of dysmenorrhea after FUA + LNG-IUS or FUA only Forest plot of the effect of dysmenorrhea after FUA + LNG-IUS or FUA only Fig. 18 Forest plot of the change in the PBAC after FUA + LNG-IUS or FUA only Forest plot of the change in the PBAC after FUA + LNG-IUS or FUA only The summary of the risk of bias assessment can be found in Additional file 3. Furthermore, the quality of judgement is summarized in Additional file 4.

After removing duplicates, we obtained 2367 unique references. By reading the title and abstract of the literature, we included 91 articles into the full text index, of which 3 articles could not be found. Finally, 28 comparative studies published in English journals or journals listed in China Technology from 2010 to 2024 were included in the present meta-analysis. Figure  1 shows the PRISMA chart. A total of 28 comparative studies involving 2530 patients, including 9 randomized controlled trials and 19 non-randomized controlled trials, were selected to compare LNG-IUS with alternative treatments in both conservative and postoperative therapeutic protocols (see Additional file 2). Fig. 1 PRISMA 2020 flowchart representing the study selection process PRISMA 2020 flowchart representing the study selection process

This study adhered to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews [ 10 ]. And the study was retrospectively registered in PROSPERO (CRD42024578824). A comprehensive systematic search was conducted across several databases, including Medical Literature Analysis and Retrieval System On-Line: Medline, The Cochrane Library, Embase, SinoMed, China National Knowledge Infrastructure, and Wanfang with a time-limit ranging from their inception until August 12, 2024 (see Additional file 1). The inclusion criteria targeted studies involving patients aged 18 and older who were diagnosed with AM, regardless of complications, severity, and diagnostic method, including clinical symptoms, imaging, or pathological diagnosis of a total hysterectomy. The primary focus was on the application of LNG-IUS as a part of conservative therapeutic strategies. The primary outcome was the efficacy of the treatment, which was evaluated based on factors such as the intensity of dysmenorrhea, menstrual blood loss, uterine volume, endometrial thickness, and quality of life. The secondary outcome included the assessment of adverse events. The treatment effect was categorized into three timeframes: up to six months, six months to one year, and beyond one year. This review encompassed a wide range of study types, including randomized controlled trials (RCTs), non-randomized controlled trials (non-RCTs), and observational studies. However, letters, editorials, case reports, and case series were excluded. Two independent reviewers screened the search results by examining titles and abstracts. Full-text versions of potentially relevant studies were thoroughly reviewed. Any disagreements were resolved through discussion, with the involvement of a third-party researcher if needed. The entire study selection process was illustrated using a PRISMA flow diagram. Data extraction was performed independently by two reviewers using a standardized extraction form. Any differences in interpretation were discussed and resolved, again with the aid of a third-party researcher if necessary. Only studies published in English-language journals or Chinese technological publications were considered to assess the efficacy of LNG-IUS in managing AM. Extracted data included details such as study author, publication year, country, study period, evidence types, intervention categories, comparators, participants’ age. Treatment-related details included product name, LNG-IUS placement date, management specifics of the intervention, and treatment duration. Outcomes were pre-specified and included follow-up length and both dichotomous and continuous results. The treatment efficacy of interventions was synthesized from comparative studies. Meta-analyses were conducted using Review Manager (RevMan) 5.3 to calculate pooled treatment effects where data were available. Dichotomous outcomes were reported as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes were presented as mean deviations (MDs) with 95% CIs. A statistically significant difference was indicated when the 95% CI did not include 0 for MDs or 1 for RRs. Forest plots were visually inspected to identify potential statistical heterogeneity. An I 2 estimate greater ≥ 50% accompanied by a statistically significant Chi 2 statistic was interpreted as evidence of substantial levels of heterogeneity. A random-effects model was applied in cases of statistically significant heterogeneity; otherwise, a fixed-effects model was applied. For included RCTs, the risk of bias was assessed using the Cochrane risk-of-bias tool [ 11 ]. For non-RCTs, qualitative judgments were made in the areas of selection, comparability and exposure/outcome according to the Newcastle-Ottawa Scale (NOS) [ 12 ].

In conclusion, this study shows that for single-drug therapy aimed at improving pain and quality of life, current evidence does not support a definitive recommendation for a preferred treatment within 12 months. In the management of moderate to severe AM, LNG-IUS combined with GnRH-a is recommended, as this approach has demonstrated significant efficacy in reducing lesion volume, alleviating pain, controlling heavy menstrual bleeding, inducing endometrial atrophy, reducing the probability of expulsion, and mitigating irregular bleeding. Regarding surgical interventions, the addition of postoperative LNG-IUS offers benefits in reducing long-term pain and menstrual bleeding, so we speculated that younger patients or those experiencing significant pain and bleeding might benefit from this combined therapy with LNG-IUS. Additionally, in the context of combined FUA, LNG-IUS has shown advantages in managing short-term pain and menstrual bleeding. It is advised that patients presenting with severe symptoms receive LNG-IUS as soon as possible following the intervention. However, more research with high quality is needed to further evaluate the effect and safety in more than 12 months.

When comparing LNG-IUS to mifepristone, there was no significant difference observed in terms of quality of life. Compared with etonogestrel, LNG-IUS had a better effect on reducing the size of the uterus and less incidence of weight gain, but there was no difference in reducing pain and reducing the thickness of the endometrium. In terms of follow-up time, the comparative study of monotherapy was mostly 6–12 months. Data over a longer period of time is lacking to determine whether LNG-IUS differs from other monotherapy treatments. The most frequently compared treatments were the combination of GnRH-a with LNG-IUS versus LNG-IUS alone. The meta-analysis indicated that the combination of LNG-IUS with GnRH-a was more effective, providing statistically significant benefits in reducing dysmenorrhea, menstrual volume, uterine volume, and endometrial thickness. Additionally, preconditioning with GnRH-a prior to the insertion of LNG-IUS was associated with a reduced likelihood of device expulsion, irregular vaginal bleeding and abdominal pain. This outcome may be attributed to the reduction in uterine volume achieved by GnRH-a, which mitigates the risk of LNG-IUS expulsion, particularly in patients with uterine enlargement due to AM [ 41 ]. LNG-IUS releases progesterone into the uterine cavity, resulting in a high local concentration of levonorgestrel. This downregulates the expression of estrogen and progesterone receptors, rendering the endometrium less responsive to circulating estradiol, thereby inhibiting endometrial hyperplasia and reducing menstrual bleeding [ 42 ]. While GnRH-a suppresses the secretion of LH and FSH from the pituitary gland, leading to decreased production of estrogen and progesterone [ 43 ]. Therefore, GnRH-a preconditioning is recommended for patients with an enlarged uterus or a history of LNG-IUS expulsion. All studies included in this review involved the administration of GnRH-a were three cycles. One study [ 44 ] utilized a sustained release of GnRH-a before LNG-IUS insertion, demonstrating similar results in alleviating dysmenorrhea, reducing menstrual volume, and improving hemoglobin and CA125 levels without increasing adverse reactions. However, the number of GnRH-a cycles may influence the outcomes. GnRH-a exerts a moderate inhibitory effect on the pituitary-ovarian axis, reducing estrogen release. Long-term use can decrease the sensitivity of the hypothalamic-pituitary pathway, leading to reduced secretion of pituitary gonadotropins [ 45 ]. One study [ 46 ] reported that after six cycles of GnRH-a, 54 patients developed symptoms such as hot flashes and restlessness, which resolved spontaneously two weeks post-treatment cessation. Therefore, further comparative studies are necessary to determine the optimal dosage, formulation, and treatment duration for GnRH-a to balance symptom management and side effect reduction. In the context of post-surgical excision therapy, the combination of surgical excision with LNG-IUS has demonstrated superior efficacy in preventing recurrence compared to surgical excision alone. This is particularly evident in the long-term reduction of uterine size. Over extended follow-up periods, such as three years, the combination therapy has shown increasing success in controlling symptoms and reducing the recurrence of AM [ 47 ]. This may be related to the lesion cannot be fully identified or completely excised during surgery. Without additional intervention post-surgery, long-term estrogen stimulation and repeated endometrial shedding may lead to recurrence or progression of the condition [ 48 ]. Therefore, the post-operative application of LNG-IUS is advised to achieve more favorable outcomes. With advancements in image-guided technology, FUA has emerged as a novel surgical approach for the treatment of AM in recent years [ 49 ]. Utilizing real-time ultrasound or MRI monitoring, FUA precisely determines the size of the lesion and surrounding tissue, enabling the application of high-intensity ultrasound energy to ablate the targeted tissue [ 50 ]. This meta-analysis incorporated seven studies to evaluate the outcomes associated with the use of LNG-IUS following FUA treatment. The findings indicate that the application of LNG-IUS after FUA significantly control over patients’ pain. However, at the 12-month follow-up point, combination therapy did not show a significant advantage in reducing menstrual blood loss. Regarding the use of additional medications post-FUA, Fang et al. [ 9 ] found that GnRH-a combined with FUA was significantly more effective in alleviating dysmenorrhea, reducing uterine volume, and decreasing blood loss after 12 months. Conversely, Zhu et al. [ 38 ] compared the effects of mifepristone following FUA and observed differences in the rate of uterine volume reduction and dysmenorrhea scores within 12 months, though no significant differences were noted after 24 months of follow-up. FUA induces coagulative necrosis in the treated area, blocks blood supply to the lesion, and inhibits its progression. Over time, the necrotic fibroid tissue is typically absorbed by the body’s metabolic processes [ 51 ]. Therefore, as these necrotic areas are resorbed, the long-term effectiveness of FUA combined with LNG-IUS therapy may not surpass that of monotherapy. Moreover, the ongoing debate regarding the long-term efficacy of combination therapy could be influenced by the specific effects of FUA. FUA presents certain limitations. Specifically, there may be regions that cannot be effectively ablated during the procedure. In cases where the AM lesion is located deep within the posterior wall of the uterus, the ultrasound may lack sufficient penetration depth to completely ablate the lesion. This limitation is notable given that the posterior uterine wall is often the most severely affected area in patients with AM. One study [ 52 ] reported a markedly higher efficacy of FUA in patients with AM located in the anterior uterine wall compared to those with lesions in the posterior wall. Consequently, the use of LNG-IUS following FUA is recommended to mitigate the risk of AM recurrence. It is important to note that most follow-up periods in this systematic review and meta-analysis were limited to 6 and 12 months. Currently, a cohort study with a 5-year follow-up of patients with adenomyosis who received LNG-IUS treatment has demonstrated that LNG-IUS significantly reduces uterine volume and improves menstrual patterns in patients [ 53 ]. Further research with longer follow-up durations is warranted to more comprehensively assess the long-term efficacy and safety of LNG-IUS therapy relative to other treatments. Additionally, emerging evidence suggests that LNG-IUS may improve sustained pregnancy rates, clinical pregnancy outcomes, and implantation rates in patients with AM [ 54 ]. Therefore, it may be necessary to pay attention to the fertility of patients. More research is needed to further evaluate not only the relief of symptoms, but also the fertility of patients.

Adenomyosis (AM) is a condition characterized by the infiltration of endometrial glands and stroma into the myometrium. The primary clinical manifestations include menorrhagia, dysmenorrhea, and infertility, which can severely impact patients’ physical and mental health as well as their overall quality of life [ 1 ]. Surgical excision is a common clinical approach for treating this disease. However, it often results in varying degrees of tissue damage and a prolonged recovery period [ 2 ]. Consequently, current clinical guidelines recommend the use of non-steroidal anti-inflammatory drugs, oral contraceptives, progesterone, and gonadotropin-releasing hormone agonists (GnRH-a) as standard options for the long-term management of AM. These pharmacological treatments are particularly important for patients desiring to preserve fertility, allowing symptom control without resorting to surgical intervention [ 3 ]. The levonorgestrel-releasing intrauterine system (LNG-IUS), has been utilized in clinical settings to manage AM. When placed in the uterine cavity, this system provides a sustained release of progesterone, thereby inhibiting endometrial growth and alleviating symptoms of AM [ 4 ]. In recent years, LNG-IUS has gained recognition as an effective treatment for AM, with multiple studies indicating its efficacy in reducing menstrual bleeding, pelvic pain, and other associated symptoms [ 5 – 7 ]. An increasing number of studies have reported the clinical efficacy of the LNG-IUS in the management of AM. LNG-IUS is employed not only as a monotherapy but also in combination with other pharmacological agents to more effectively alleviate patient symptoms. LNG-IUS also follows surgical or interventional procedures to reduce the recurrence rate of AM [ 8 , 9 ]. However, there is currently no comprehensive research summarizing the optimal treatment strategies for AM patients. To address this gap, we conducted a systematic review and meta-analysis of the available literature to assess the efficacy and safety of LNG-IUS, both as a monotherapy and in combination with other therapies. The goal is to provide robust, evidence-based data to inform clinical decision-making.

Below is the link to the electronic supplementary material. Supplementary Material 1: Search strategy Supplementary Material 1: Search strategy Supplementary Material 2: Characteristics of studies Supplementary Material 2: Characteristics of studies Supplementary Material 3: Risk of bias assessment of RCTs Supplementary Material 3: Risk of bias assessment of RCTs Supplementary Material 4: Quality judgement of non-RCTs Supplementary Material 4: Quality judgement of non-RCTs