Investigation of pharmacological regimens combined with focused ultrasound ablation surgery for alleviating dysmenorrhea in extrinsic adenomyosis

Objective: To compare the efficacy of dienogest (DNG) and levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of intrinsic and extrinsic subtypes of adenomyosis. Methods: Totally 232 patients were enrolled in the study who were diagnosed as adenomyosis by ultrasound or pelvic magnetic resonance imaging (MRI), and were classified into intrinsic and extrinsic subtypes according to different locations of lesions in MRI, treated with DNG (DNG group) or LNG-IUS (LNG-IUS group) in Peking University Third Hospital from July 2019 to December 2023. Clinical data of patients were retrospectively collected to analyze the clinical and imaging characteristics of different MRI subtypes of adenomyosis and whether there were differences in the therapeutic effects of DNG and LNG-IUS. Results: (1) Among the 232 patients enrolled, 129 were intrinsic subtype and 103 were extrinsic subtype. Among the 129 patients treated with DNG, the numbers of intrinsic and extrinsic subtype were 69 and 60, respectively. And among the 103 patients treated with LNG-IUS, the numbers of intrinsic and extrinsic subtype were 60 and 43, respectively. The mean age in DNG group [(37.5±5.6) years] was lower than that in LNG-IUS group [(40.3±4.3) years, P<0.001]. There were no significant differences in other clinical features (all P>0.05). (2) The visual analog scale (VAS) scores of dysmenorrhea and cancer antigen 125 (CA125) levels in DNG group and LNG-IUS group were significantly decreased after treatment (all P<0.001), and hemoglobin levels were increased (both P<0.01). Compared between the two groups, the VAS score after treatment was lower in DNG group (P<0.001), and the hemoglobin level was increased more significantly in DNG group (P=0.016). The complete remission rates of dysmenorrhea in DNG group and LNG-IUS group were 73.0% (89/122) and 29.5% (28/95), respectively (P=0.039). The incidence of irregular bleeding in DNG group was higher than LNG-IUS group, but there was no statistical significance [62.8% (81/129) vs 52.4% (54/103), P=0.112]. (3) Among patients with intrinsic adenomyosis, the incidence of menorrhagia was significantly higher than in those with extrinsic adenomyosis (P<0.001), while the incidence and severity of dysmenorrhea were lower compared to extrinsic adenomyosis (P=0.004, P=0.007, respectively). After treatment with DNG and LNG-IUS, there were no statistically significant differences in VAS scores between patients with intrinsic and extrinsic adenomyosis (all P>0.05). The incidence of irregular bleeding after DNG treatment was 78.3% (54/69) in intrinsic adenomyosis, which was higher than the 45.0% (27/60) observed in extrinsic adenomyosis (P<0.01). Similarly, the incidence of irregular bleeding after LNG-IUS treatment was 63.3% (38/60) in intrinsic adenomyosis, higher than the 37.2% (16/43) in extrinsic adenomyosis (P=0.009). (4) DNG treatment (OR=19.163, 95%CI: 7.564-48.544; P<0.01) and duration of treatment (OR=1.043, 95%CI: 1.012-1.075; P=0.007) were independent positive factors for complete remission of dysmenorrhea, while VAS score before treatment (OR=0.654, 95%CI: 0.454-0.942; P=0.023) was negative factor. Intrinsic subtype was an independent risk factor for irregular bleeding (OR=0.436, 95%CI: 0.235-0.811; P=0.009). Conclusions: DNG demonstrates greater advantages over LNG-IUS in terms of complete relief of dysmenorrhea and the degree of symptom alleviation. The incidence of irregular vaginal bleeding in patients with intrinsic adenomyosis is higher than in those with extrinsic adenomyosis. For patients with extrinsic adenomyosis, particularly those with prominent dysmenorrhea symptoms, DNG treatment offers greater benefits. However, for patients with intrinsic adenomyosis and those with significant menstrual disorders, a more cautious approach is required when selecting progestin therapy, along with enhanced monitoring and management.

Endometriosis is a common chronic disease in women of reproductive age, and long-term postoperative medical management is a key strategy for preventing recurrence. Currently used clinical medications include dienogest (DNG), GnRH agonists (GnRH-a), combined oral contraceptives (COC), and the levonorgestrel-releasing intrauterine system (LNG-IUS). However, comparative effectiveness of different hormonal therapies for preventing recurrence in real-world clinical practice and the basis for individualised patient selection remain insufficient. To systematically evaluate the efficacy and safety of DNG, GnRH-a, COC, and LNG-IUS in preventing postoperative recurrence of ovarian endometriomas; to analyse independent risk factors for postoperative recurrence, providing evidence-based support for individualised clinical treatment decisions. A retrospective cohort study design was adopted. A total of 167 patients who underwent laparoscopic cystectomy at our hospital between January 2020 and January 2022, had a postoperative pathological diagnosis, and received sequential GnRH-a maintenance therapy were enrolled. According to the sequential maintenance regimen, patients were divided into three groups: GnRH-a + DNG group (n = 61), GnRH-a + COC group (n = 64), and GnRH-a + LNG-IUS group (n = 42). The primary outcome was the recurrence rate within 3 years after surgery. Secondary outcomes included menstrual bleeding profiles, recurrent cyst diameter, and adverse drug reactions. Cumulative recurrence rates were calculated using the Kaplan‑Meier method, and intergroup comparisons were performed using the log‑rank test. Multivariate logistic regression analysis was used to identify independent risk factors for postoperative recurrence. There were no statistically significant differences in baseline data among the three groups (P > 0.05), indicating comparability. The 3‑year cumulative recurrence rate in the GnRH-a + DNG group was 19.67% (12/61), significantly lower than that in the GnRH-a + LNG-IUS group (45.24%, 19/42; P = 0.003). The recurrence rate in the GnRH-a + DNG group was also lower than that in the GnRH-a + COC group (34.38%, 22/64), although this difference did not reach statistical significance (P = 0.053). No significant differences were observed among the three groups in mean daily menstrual blood loss, incidence of dysmenorrhoea, or menstrual cycle length (P > 0.05). However, the incidence of spotting in the LNG-IUS group (52.38%) was significantly higher than that in the DNG group (24.59%) and the COC group (12.50%, P < 0.001). There were no statistically significant differences in the total incidence of adverse drug reactions (13.11%, 14.06%, 11.90%) or recurrent cyst diameter among the groups (P > 0.05). Multivariate logistic regression analysis suggested that higher dysmenorrhea VAS score (OR = 1.376), history of pelvic procedures (OR = 1.483), and r-AFS stage IV (OR = 2.676) were independent risk factors for postoperative recurrence (all P < 0.05), while older age at surgery was a protective factor (OR = 0.891) (P < 0.05). Among sequential GnRH-a maintenance regimens, DNG was associated with a lower recurrence rate than LNG-IUS in preventing 3‑year recurrence after laparoscopic cystectomy in this cohort. Although the recurrence rate in the DNG group was lower than that in the COC group, the difference did not reach statistical significance, indicating only a trend toward superiority. All three regimens have a favourable overall safety profile, but the LNG-IUS group has a higher incidence of spotting. Severe dysmenorrhoea, previous pelvic operation history, and r-AFS stage IV are independent risk factors for postoperative recurrence, whereas older age at surgery has a protective effect.

Objective: To investigate the efficacy and safety of dienogest (DNG) alone and gonadotropin-releasing hormone agonist (GnRH-a) combined with DNG sequential treatment to adenomyosis. Methods: The clinical data of 110 patients with adenomyosis attending the First Affiliated Hospital of Nanjing Medical University from December 2019 to March 2022 were retrospectively analyzed, including 40 patients treated with DNG (2 mg/day) alone (DNG group) and 70 patients treated with sequential DNG (2 mg/day) after 3-6 injections of GnRH-a (GnRH-a+DNG group). The clinical data before and after treatment were compared between the two groups. Results: (1) The dysmenorrhea visual analogue scale (VAS) scores, cancer antigen 125 (CA125) and cancer antigen 19-9 (CA19-9) levels at different time periods after treatment were significantly lower than before treatment in both groups (median before treatment: DNG group 70.0 mm, 68.55 kU/L, 22.45 kU/L respectively, GnRH-a+DNG group 80.0 mm, 151.50 kU/L, 20.44 kU/L respectively; all P<0.001). (2) The hemoglobin (Hb) levels of patients in both groups at different time periods after treatment were significantly higher than those before treatment (median: DNG group 102.00 g/L, GnRH-a+DNG group 94.00 g/L; all P<0.001). (3) Treatment with DNG alone did not have a significant effect on uterine volume in patients of DNG group (P>0.05), and uterine volume decreased significantly in the 15th-24th months of GnRH-a+DNG group compared with that before treatment (median: 167.76 vs 227.77 cm3; P<0.05). (4) There were no significant differences in hepatic and renal function and coagulation indexes between the two groups before and after treatment (all P>0.05), and no significant abnormal lesions were observed in breast tissue during the follow-up period. (5) The incidence of amenorrhea of GnRH-a+DNG group was higher than that of DNG group, and the incidences of irregular spotting bleeding and breakthrough hemorrhage were lower than those in DNG group. Conclusions: Whether DNG is used alone or in combination with GnRH-a in sequence, it could significantly relieve dysmenorrhea symptoms, improve the level of Hb, reduce the levels of CA125 and CA19-9 in patients with adenomyosis, with no adverse effects on coagulation and hepatic or renal function. GnRH-a sequential DNG therapy is superior to DNG alone in improving uterine bleeding patterns and controlling the growth of uterine volume in patients with adenomyosis.

Deep infiltrating endometriosis (DIE) is commonly associated with severe pain. The pain can be managed successfully with GnRH agonists or continuous progestins. The precise molecular mechanism by which DIE causes pain or why hormonal treatment is effective, however, remains unclear. We recently identified three potential candidate genes that might be involved in DIE pain pathways: tyrosine kinase receptor B (TrKB), mu-opioid receptor (MOR) and serotonin transporter (5HTT). We hypothesized that if these three genes were involved in DIE-associated pain, their expression levels would probably be modulated by GnRH agonist or progestin. In this study, we compared mRNA expression levels of TrKB, MOR and 5HTT in DIE among patients pre-operatively treated with GnRH agonist, progestin or without pre-operative medical treatments. The expression levels of TrKB, MOR and 5HTT mRNA in DIE were determined using laser capture microdissection and real-time RT-PCR techniques. The expression levels of TrKB in epithelial cells and MOR in stromal cells from DIE were significantly decreased in patients with pre-operative GnRH agonist or progestin. There was no significant difference in 5HTT expression levels among untreated, GnRH agonist- and progestin-treated patients. The expression levels of TrKB and MOR genes in DIE appeared to be modulated by GnRH agonist or progestin. However, the functional roles of TrKB and MOR in DIE remain to be clarified.

ObjectiveTo summarize evidence on the efficacy and safety of the levonorgestrel-releasing intrauterine system (LNG-IUS) in managing adenomyosis (AM), both as a monotherapy and in combination with other therapies.MethodsWe searched Medical Literature Analysis and Retrieval System On-Line: Medline, The Cochrane Library, Embase, SinoMed, China National Knowledge Infrastructure, and Wanfang from the inception to Aug 12, 2024 for articles using the LNG-IUS both alone and combined with other therapies in patients with AM. The primary outcome included dysmenorrhea, menstrual bleeding, uterine volume, endometrial thickness and quality of life. The secondary outcome was the assessment of adverse events. Data synthesis was conducted using random-effects model with significant heterogeneity (I2 > 50%), otherwise using fixed-effects model.ResultsThe final analysis included 28 studies. Compared with etonogestrel, LNG-IUS was more effective in reducing uterine volume and associated with a lower risk of weight gain, but showed no significant difference in reducing dysmenorrhea and endometrial thickness. Comparing LNG-IUS with mifepristone, there was no significant difference in terms of quality of life. The combination of LNG-IUS with Gonadotropin-releasing hormone agonists (GnRH-a) was more effective than LNG-IUS alone, providing benefits in reducing dysmenorrhea (mean deviation, MD: -1.14), menstrual bleeding (MD: -11.94), uterine volume (MD: -30.39), endometrial thickness (MD: -0.89), and adverse events. The combination of LNG-IUS with surgical excision was more effective than surgical excision alone, providing benefits in reducing dysmenorrhea (MD: -1.49), menstrual bleeding (MD: -5.13) at 12 months, reducing uterine volume at 6 (MD: -9.23), 12 (MD: -16.53) and 24 (MD: -27.17) months. The combination of LNG-IUS with focused ultrasound ablation (FUA) was more effective than FUA alone, providing benefits in reducing dysmenorrhea (MD: -0.62), menstrual bleeding (MD: 0.17).ConclusionsThis study found no clear evidence to recommend single-drug therapy for improving pain and quality of life in AM management within 12 months. Combining LNG-IUS with GnRH-a is effective in alleviating pain, controlling heavy bleeding, reducing lesion volume, reducing the probability of expulsion and irregular bleeding. Postoperative LNG-IUS helps reduce long-term pain and bleeding. In combined FUA, LNG-IUS is effective for managing short-term pain and bleeding.Trial registrationPROSPERO registration number: CRD42024578824.

2604 A Comparison of Efficacy Between Postoperative Medical Treatment and Expectant Treatment in Relieving Dysmenorrhea After Conservative Laparoscopic Surgery for Deep-Infiltrating Endometriosis Accompanied by Dysmenorrhea

Comparison of the treatment efficacies of HIFU, HIFU combined with GnRH-a, and HIFU combined with GnRH-a and LNG-IUS for adenomyosis: A systematic review and meta-analysis.

Endometriosis remains a cause of significant morbidity in&#13;\nreproductive-aged women resulting in pelvic pain, pelvic&#13;\nmasses, and infertility. Endometriosis is defined as the presence&#13;\nof endometrial glands and stroma outside of their normal&#13;\nintrauterine location, most commonly in the dependent&#13;\nportions of the pelvis. Endometriosis is treated with medical&#13;\ntherapies, surgery or both.Themedical therapies include oral&#13;\ncontraceptive pills, progestins, gonadotropin releasing hormone&#13;\nanalogues, and danazol. All of these medical therapies&#13;\ninduce a hormonal steady state that results in an environment&#13;\nnot conducive to the growth of endometriosis. Surgical therapies&#13;\nfor endometriosis-associated pain include the removal&#13;\nof endometriotic implants and adhesions with restoration&#13;\nof normal anatomy. Laparoscopy is an effective surgical&#13;\napproach with the goal of excising visible endometriosis.&#13;\nSince endometriosis is a chronic condition, it is not uncommon&#13;\nfor recurrences to occur. While endometriosis remains&#13;\nan enigmatic disease, the introduction of new pharmacologic&#13;\nagents and newer endoscopic methods of surgical treatment&#13;\nhas facilitated and improved the overall management of this&#13;\ndisease.&#13;\nThis special issue contains some papers that refer to&#13;\nmolecular and cellular mechanisms of endometriosis physiopathology&#13;\nand some papers that refer to biomarker development&#13;\nfor improved early diagnosis and risk of disease,&#13;\nwhile the other papers refer minimally to invasive treatment&#13;\nfor endometriosis and new medical therapies. Finally, there&#13;\nare somemanuscripts about prevention of endometriosis and&#13;\nnovel models in endometriosis research.

Levonorgestrel-releasing intrauterine system (LNG-IUS) as an effective treatment option for endometrial hyperplasia: a 15-year follow-up study

The LNG-IUS may improve HMB and quality of life compared to other medical therapy; the LNG-IUS is probably similar for HMB compared to endometrial destruction techniques; and we are uncertain if it is better or worse than hysterectomy. The LNG-IUS probably has similar serious adverse events to other medical therapy and it is more likely to have any adverse events than EA.

Treatment of pain associated with deep endometriosis: alternatives and evidence

Objectives: To examine the effects of Levonorgestrel-releasing Intrauterine System (LNG-IUS) and Gonadotropin-releasing Hormone agonist (GnRHa) therapy on adenomyosis symptoms and the outcomes of frozen blastocyst transfer (FBT).Patients & Methods: In this study, 184 women with adenomyosis who underwent ICSI and achieved good quality FB were randomly divided into two groups (n= 92). They received either LNG-IUS or GnRHa (3.75mg monthly for three months) before FBT. Patients were monitored for changes in menstrual patterns, PEG scale (pain intensity, enjoyment of life, general activity), and FBT outcomes.Results: At 3-m after treatment 62 women of LNG-IUS group and 10 of GnRHa group resumed normal menstrual pattern (P<0.001) and 30 women of LNG-IUS group and 25 of GnRHa group had oligomenorrhea (P= 0.421), while 57 women of GnRHa group developed amenorrhea. Pain frequency and severity significantly decreased in both groups at the end of treatment. Positive chemical pregnancy rate was 67.4%, while clinical pregnancy rate was 54.3% with insignificantly higher chemical, but significantly (P= 0.038) higher clinical pregnancy rates among women of GnRH group. The ectopic pregnancy rates were 4.7% and 1.8% and the early pregnancy loss rates were 23.3% and 31.6% among women of LNG-IUS and GnRHa groups, respectively with insignificant differences between both therapies.Conclusion: Medical management using LNG-IUS or GnRHa significantly controlled adenomyosis manifestation in terms of pain; bleeding and menstrual pattern in infertile adenomyosis women planned to have FBT, but LNG-IUS provided superior outcomes. Also, LNG-IUS preparation optimized outcomes of FBT with results comparable to the GnRHa treatment.

The aim of this study was to evaluate the effectiveness of postoperative levonorgestrel-releasing intrauterine system (LNG-IUS) insertion after gonadotropin-releasing hormone agonist (GnRH-a) treatment for preventing endometriotic cyst recurrence. The LNG-IUS was applied to 28 women who had undergone surgery for endometriosis followed by 6 cycles of GnRH-a treatment. Clinical characteristics, endometriosis recurrence, and adverse effects were analyzed. Student t test was performed for analysis. Before surgery, 20 (71.4%) patients had dysmenorrhea, and the mean pain score (visual analog scale [VAS]) was 4.26. The numbers of women diagnosed with stage III endometriosis and stage IV endometriosis were 15 (53.6%) and 13 (46.4%), respectively, according to the revised American Fertility Society scoring system. The mean cancer antigen 125 levels and VAS scores were significantly lower after treatment than before treatment (11.61 vs 75.66 U/mL, P < .0001 and 0.50 vs 4.26 U/mL, P < .0001, respectively). Of the 28 patients, 13 (46.4%) simultaneously had adenomyosis, and 2 (7.1%) underwent LNG-IUS removal because of unresolved vaginal bleeding and dysmenorrhea. Recurrence was noted in 2 (7.1%) women. Postoperative LNG-IUS insertion after GnRH-a treatment is an effective approach for preventing endometriotic cyst recurrence, especially in women who do not desire to conceive.

Effects of hormonal treatment on the expression of collagen type I, matrix metalloproteinase-1, and tissue inhibitor of metalloproteinases-1 in endometriosis.

For women with pain and endometriosis, suppression of menstrual cycles with gonadotrophin-releasing hormone (GnRH) analogues, the levonorgestrel-releasing intrauterine system (LNG-IUD) and danazol were beneficial interventions. Laparoscopic treatment of endometriosis and excision of endometriomata were also associated with improvements in pain. The evidence on NSAIDs was inconclusive. There was no evidence of benefit with post-surgical medical treatment.In women with endometriosis undergoing assisted reproduction, three months of treatment with GnRH agonist improved pregnancy rates. Excisional surgery improved spontaneous pregnancy rates in the nine to 12 months after surgery compared to ablative surgery. Laparoscopic surgery improved live birth and pregnancy rates compared to diagnostic laparoscopy alone. There was no evidence that medical treatment improved clinical pregnancy rates.Evidence on harms was scanty, but GnRH analogues, danazol and depot progestagens were associated with higher rates than other interventions.