Long-term efficacy and safety of levonorgestrel releasing intrauterine system in the treatment of adenomyosis: evidence mapping.

PURPOSE: To summarize evidence on levonorgestrel releasing intrauterine system (LNG-IUS) in the treatment of adenomyosis (AM) and to identify potential research gaps. METHODS: Search was conducted in MEDLINE, The Cochrane Library, EMBASE, CBM, CNKI, and Wanfang. We included studies investigating patients with AM treated with LNG-IUS combined with conservative therapy. RESULTS: Thirty-nine studies compared LNG-IUS with other conservative therapeutic drugs. The most common comparison was GnRH-a + LNG-IUS vs. LNG-IUS alone, followed by LNG-IUS vs. mifepristone, expected treatment, and GnRH-a. GnRH-a + LNG-IUS was more beneficial in reducing the intensity of dysmenorrhea than LNG-IUS alone at the 6-month follow-up in patients with an enlarged uterus and moderate to severe dysmenorrhea. Large and well-designed studies are needed to confirm the efficacy of LNG-IUS and GnRH-a on reducing uterine volume at 6-month follow-up. Thirty-two studies investigated LNG-IUS as the postoperative management. The most common comparison was surgical excision + LNG-IUS vs. surgical excision. Results showed VAS scores were lower in the surgical excision + LNG-IUS group than in the surgical excision group at the 1-year follow-up. Evidence on endometrial thickness, quality of life, adverse events and beneficial effect at 3 and 5 years are needed. CONCLUSIONS: Combined GnRH-a and LNG-IUS treatment was more efficacious than LNG-IUS alone for patients with an enlarged uterus and moderate to severe dysmenorrhea. Moreover, LNG-IUS seemed to show potential long-term benefits in postoperative therapy, warranting further meta-analysis for confirmation.

The efficacy of medical treatment for adenomyosis after adenomyomectomy.

AIMS: To compare the efficacy of gonadotropin-releasing hormone agonist (GnRH-a) and GnRH-a + levonorgestrel-releasing intrauterine system (LNG-IUS) after adenomyomectomy for improved adenomyosis-associated symptoms. METHODS: Overall, 193 patients with adenomyosis included in this study were categorized into three groups: adenomyomectomy (n = 57, group 1), adenomyomectomy + GnRH-a (n = 83, group 2) and adenomyomectomy + GnRH-a + LNG-IUS (n = 53, group 3). Visual Analog Scale (VAS) scores and uterine volumes were determined to evaluate the severity of adenomyosis. Dysmenorrhea improvement and uterine volume were the main outcomes. RESULTS: The VAS scores of all patients reduced from 7.3 (6.0, 8.5) to 0 (0, 0.6) at the 6 months after surgery, which were significantly higher in group 1 compared to other groups (P < 0.05). In groups 1, 2 and 3, there were 14, 7 and 4 patients, respectively, who suffered dysmenorrhea recurrence. The mean recurrent-free-survival (RFS) was 51.6 ± 2.4, 58.0 ± 1.2 and 58.3 ± 1.0 months, respectively, which was significantly shorter in group 1 (P < 0.05). The dysmenorrhea recurrences were 26.3%, 6.1%, 5.9% in groups 1, 2 and 3, respectively, at the 36 months, which was significantly higher in group 1 (P < 0.01). Significantly decreased uterine volumes were observed in all patients from 222.2 (147.6, 350.4) to 77.0 (65.9, 94.1) mL (P < 0.05) at the 6 month after surgery. CONCLUSION: Treatment GnRH-a and LNG-IUS after surgery could significantly reduce the recurrence and prolong the RFS. It seemed that the use of LNG-IUS was beneficial for a lower recurrence in long-term follow-up.

[Value of using gonadotropin-releasing hormone agonist pretreatment in adenomyosis patients before adenomyomectomy].

Objective: To investigate the value of using gonadotropin-releasing hormone agonist (GnRH-a) pretreatment in adenomyosis patients before adenomyomectomy. Methods: From May 2012 to September 2015, 87 patients with adenomyosis who were non-effective to conservative therapy in Renmin Hospital of Wuhan University were enrolled in this study. According to the principle of randomized control, 41 patients were in the treatment group who were treated with GnRH-a 2-3 cycles before adenomyomectomy, while 46 patients in the control group. The control group paients were operated without any pretreatments. The blood loss, the number of penetrating into uterine cavity, duration of operation, duation of peritoneal drainage and the amount of drainage fluid, the difference of hemoglobin value before and after operation, total white blood cell count, duration of hospitalization, the maximum diameter of uterus and other indicators between the two groups were compared. Results: In the treatment group, before and after treatment with GnRH-a, the uterus size, blood hemoglobinand CA125 value were statistically different (all P<0.05); between the treatment group of GnRH-a treated for 2 cycles and for 3 cycles, there were statistical differences of blood hemoglobin value [(108 ± 20) versus (118 ± 24) g/L], CA125 value [(26 ± 11) versus(19 ± 4) kU/L; all P< 0.05]. There were statistical differences of blood loss in operation [(113 ± 32) versus (194 ± 42) ml], ratio of penetrating into uterine cavity [12% (5/41) versus 12% (8/46)], duration of operation[(79±23) versus (91±25) minutes], duration of peritoneal drainage after operation [(2.1±0.9) versus (3.0±1.2) days] and the amount of drainage fluid [(152±43) versus (232±32) ml], the difference of hemoglobin value before and after surgery [(-15.6±2.9) versus (-23.7±3.5) g/L], white blood cell count after 2-3 days of operation [(11.4±4.2)×109/L versus (13.5 ± 3.2) × 109/L], ratio of peri-operative blood transfusion [5% (2/41) versus 20% (9/46)] and duration of hospitalization [(11.2±1.9) versus (13.6±3.1) days] between the treatment group and the control group (all P<0.05). Conclusion: The pretreatment of using GnRH-a before adenomyomectomy in adenomyosis patients has benefits for implementation of surgery and reducing peri-operative and postoperative complications.

Effect of Mifepristone vs Placebo for Treatment of Adenomyosis With Pain Symptoms: A Randomized Clinical Trial.

Importance: Adenomyosis is a common chronic gynecological disorder, and its treatment is an unmet need. New therapies need to be developed. Mifepristone is being tested for adenomyosis treatment. Objective: To determine whether mifepristone is effective and safe for adenomyosis treatment. Design, Setting, and Participants: This multicenter, placebo-controlled, double-blind randomized clinical trial was conducted in 10 hospitals in China. In total, 134 patients with adenomyosis pain symptoms were enrolled. Trial enrollment began in May 2018 and was completed in April 2019, and analyses were conducted from October 2019 to February 2020. Interventions: Participants were randomized 1:1 to receive mifepristone 10 mg or placebo orally once a day for 12 weeks. Main Outcomes and Measures: The primary end point was the change in adenomyosis-associated dysmenorrhea intensity, evaluated by the visual analog scale (VAS) after 12 weeks of treatment. Secondary end points included the change in menstrual blood loss, increased level of hemoglobin in patients with anemia, CA125 level, platelet count, and uterine volume after 12 weeks of treatment. Safety was assessed according to adverse events, vital signs, gynecological examinations, and laboratory evaluations. Results: In total, 134 patients with adenomyosis and dysmenorrhea were randomly assigned, and 126 patients were included in the efficacy analysis, including 61 patients (mean [SD] age, 40.2 [4.6] years) randomized to receive mifepristone and 65 patients (mean [SD] age, 41.7 [5.0] years) randomized to received the placebo. The characteristics of the included patients at baseline were similar between groups. The mean (SD) change in VAS score was -6.63 (1.92) in the mifepristone group and -0.95 (1.75) in the placebo group (P < .001). The total remission rates for dysmenorrhea in the mifepristone group were significantly better than those in the placebo group (effective remission: 56 patients [91.8%] vs 15 patients [23.1%]; complete remission: 54 patients [88.5%] vs 4 patients [6.2%]). All the secondary end points showed significant improvements after mifepristone treatment for menstrual blood loss, hemoglobin (mean [SD] change from baseline: 2.13 [1.38] g/dL vs 0.48 [0.97] g/dL; P < .001), CA125 (mean [SD] change from baseline: -62.23 [76.99] U/mL vs 26.89 [118.70] U/mL; P < .001), platelet count (mean [SD] change from baseline: -28.87 [54.30]×103/µL vs 2.06 [41.78]×103/µL; P < .001), and uterine volume (mean [SD] change from baseline: -29.32 [39.34] cm3 vs 18.39 [66.46] cm3; P < .001). Safety analysis revealed no significant difference between groups, and no serious adverse events were reported. Conclusions and Relevance: This randomized clinical trial showed that mifepristone could be a new option for treating patients with adenomyosis, based on its efficacy and acceptable tolerability. Trial Registration: ClinicalTrials.gov Identifier: NCT03520439.

Triptorelin for the treatment of adenomyosis: A multicenter observational study of 465 women in Russia.

OBJECTIVE: To evaluate the effectiveness of triptorelin for the treatment of adenomyosis, the benign invasion of endometrial tissue into the myometrium, as a fertility-preserving alternative to the gold standard hysterectomy. METHODS: In this multicenter, open-label, observational study in Russia, performed from November 3, 2011, to August 24, 2015, we assessed the efficacy and safety of triptorelin 3.75 mg administered intramuscularly every 28 days in Russian women who were gonadotropin-releasing hormone agonist treatment-naïve, aged 25-40 years, and had a diagnosis of endometriosis or adenomyosis with heavy menstrual bleeding. We performed a medical record review, interviews to assess symptom severity, and pelvic assessments including transvaginal ultrasound. Data were obtained at first injection of triptorelin (visit 1), on the day of last injection (visit 2), 6 months after last injection (visit 3), and 9 months after last injection (visit 4). Significance was assessed by Wilcoxon signed rank test. RESULTS: A total of 465 women were included. There was a significant improvement from baseline in severity of heavy menstrual bleeding in 390/463 (84.2%) of women 6 months after last injection (P<0.0001). Severity of dysmenorrhea, abnormal uterine bleeding, and pelvic pain was decreased at visit 3 compared with baseline (P<0.0001). Endometriosis symptoms stopped in 253/262 (96.6%) of women at visit 2 and in 243/263 (92.4%) of women at visit 3. Pregnancy was reported in 116/465 (24.9%) women within 9 months following the end of treatment. CONCLUSION: Triptorelin has a favorable safety profile, is highly efficacious in treating clinical symptoms of adenomyosis, and improves reproductive function. ClinicalTrials.gov registration number: A-38-52014-191, registered October 2011.