Paris polyphylla ethanol extract and polyphyllin I ameliorate adenomyosis by inhibiting epithelial-mesenchymal transition.

BACKGROUND: The active ingredients of the Chinese medical herb Paris polyphylla, P. polyphylla ethanol extract (PPE) and polyphyllin I (PPI), potentially inhibit epithelial-mesenchymal transition (EMT) in tumors. However, the roles of these ingredients in inhibiting EMT in adenomyosis (AM) remain to be explored. PURPOSE: The primary goal of the study was to uncover the underlying molecular processes through which PPE and PPI suppress EMT in AM, alongside assessing the safety profiles of these substances. METHODS: To assess the suppressive impact of PPE on adenomyosis-derived cells (AMDCs), we employed Transwell and wound healing assays. The polyphyllins (PPI, PPII, PPVII) contained in PPE were characterized using high-performance liquid chromatography (HPLC). Then, bioinformatics techniques were performed to pinpoint potential PPI targets that could be effective in treating AM. Immunoblotting was used to verify the key proteins and pathways identified via bioinformatics. Furthermore, we examined the efficacy of PPE and PPI in treating Institute of Cancer Research (ICR) mice with AM by observing the morphological and pathological features of the uterus and performing immunohistochemistry. In addition, we assessed safety by evaluating liver, kidney and spleen pathologic features and serum test results. RESULTS: Three major polyphyllins of PPE were revealed by HPLC, and PPI had the highest concentration. In vitro experiments indicated that PPE and PPI effectively prevent AMDCs invasion and migration. Bioinformatics revealed that the primary targets E-cadherin, N-cadherin and TGFß1, as well as the EMT biological process, were enriched in PPI-treated AM. Immunoblotting assays corroborated the hypothesis that PPE and PPI suppress the TGFß1/Smad2/3 pathway in AMDCs to prevent EMT from progressing. Additionally, in vivo studies showed that PPE (3 mg/kg and 6 mg/kg) and PPI (3 mg/kg and 6 mg/kg), successfully suppressed the EMT process through targeting the TGFß1/Smad2/3 signaling pathway. Besides, it was observed that lower doses of PPE (3 mg/kg) and PPI (3 mg/kg) exerted minimal effects on the liver, kidneys, and spleen. CONCLUSIONS: PPE and PPI efficiently impede the development of EMT by inhibiting the TGFß1/Smad2/3 pathway, revealing an alternative pathway for the pharmacological treatment of AM.

The adenomyosis/endometriosis IVF patient - call for clinical focus.

Endometriosis and adenomyosis are distinct clinical conditions that carry the same pathophysiological features. In recent years the clinical focus on assisted reproductive technology patients with either condition (E/A) has increased, in the recognition that this subgroup of patients might need special attention to obtain reproductive success. Endometriosis and adenomyosis are characterized by a disruption of progesterone and oestrogen signalling pathways, resulting in local oestrogen dominance and progesterone resistance at the receptor level. Recent scientific evidence suggests that the endometrial progesterone receptor resistance encountered in E/A patients can be overcome by a freeze-all policy, followed by down-regulating circulating oestradiol concentrations prior to frozen embryo transfer (FET), in combination with an increase in exogenous luteal phase progesterone supplementation in hormonal replacement therapy (HRT) FET cycles. Specifically, for adenomyosis patients who do not respond to gonadotrophin-releasing hormone agonist down-regulation in terms of a decrease in circulating oestradiol concentrations, a small case series has suggested that the addition of an aromatase inhibitor for 21 days prior to HRT-FET is a valid option. Endometriosis and adenomyosis are hormonally active diseases, which need to be treated by controlling local hyperoestrogenism and progesterone resistance. Based on physiology and recent preliminary clinical data, the authors of this opinion paper wish to stimulate discussion and spark interest in research in E/A patients.

Effects of different treatment methods on clinical efficacy and fertility outcomes of patients with adenomyosis.

OBJECTIVE: This trial was to investigate the effect of different treatment methods on the clinical efficacy and fertility outcome of patients with adenomyosis. METHODS: In total, 140 patients with adenomyosis were evenly and randomly allocated into group A (laparoscopic surgery), group B (laparoscopic surgery combined with gonadotropin-releasing hormone analogs [GnRH-a]), group C (ultrasound-guided percutaneous radiofrequency ablation), and group D (ultrasound-guided percutaneous radiofrequency ablation combined with GnRH-a). On the 3rd day after surgery, patients in group B and group D were subcutaneously injected with GnRH-a (Leuprorelin Acetate SR for Injection) at 3.75 mg/time, once every 4 weeks, for a total of 3 months. The therapeutic effects of the 4 groups were compared, including menstrual volume, dysmenorrhea score, uterine volume, clinical efficacy, luteinizing hormone (LH), estradiol (E2), and follicle-stimulating hormone (FSH) levels, CA125 levels, recurrence, pregnancy status, and pregnancy outcomes. RESULTS: After treatment, the menstrual volume of 4 groups was lowered, dysmenorrhea, Visual Analog Scale (VAS) score, LH, FSH, E2, and CA125 levels were reduced, and uterine volume was decreased. The menstrual volume, VAS score, levels of LH, FSH, E2, and CA125, and uterine volume were reduced in groups B, C, and D compared with group A, and the decrease was more significant in group D. The total effective rate of group D was 100.00%, which was higher than that of group A (71.43%), group B (80.00%), and group C (82.86%). After one year of drug withdrawal, the recurrence of hypermenorrhea, dysmenorrhea, uterine enlargement, and excessive CA125 in group D was significantly lower than that in groups A, B and C, and the recurrence in groups B and C was significantly lower than that in group A (P < 0.05). Compared with groups A, B, and C, group D had a higher pregnancy rate, natural pregnancy rate, and lower in vitro fertilization-embryo transfer rate (P < 0.05), but showed no significant difference in pregnancy outcomes. CONCLUSION: Ultrasound-guided percutaneous radiofrequency ablation combined with Leuprorelin Acetate is effective in the treatment of adenomyosis, which can effectively relieve clinical symptoms, protect postoperative ovarian function, reduce recurrence rate, alleviate pain, and improve quality of life.

Feasibility and Effectiveness of Hysteroscopic Suture Fixation of the Levonorgestrel-Releasing Intrauterine System in the Treatment of Adenomyosis.

STUDY OBJECTIVE: To evaluate the feasibility and effectiveness of hysteroscopic suture fixation of the levonorgestrel-releasing intrauterine system (LNG-IUS) for the treatment of adenomyosis. DESIGN: A retrospective case series. SETTING: Two teaching hospitals with the technology of hysteroscopic suture fixation of the LNG-IUS. PATIENTS: The study reviewed 79 adenomyosis patients who received the hysteroscopic suture fixation of the LNG-IUS from January 2021 to May 2022. INTERVENTION: Hysteroscopic suture fixation of the LNG-IUS to the posterior uterine wall with nondissolvable suture. MEASUREMENTS AND MAIN RESULTS: All patients underwent one-year postoperative follow-up to evaluate the LNG-IUS expulsion rate, postoperative efficacy, and side effects. Two patients (2.6%) experienced expulsion of the LNG-IUS at 8 months and 12 months postoperatively, respectively. The visual analog pain scale, pictorial blood loss assessment chart score and carbohydrate antigen 125 markedly decreased after the suture fixation of the LNG-IUS compared with baseline in all patients (p <.001). Hemoglobin increased significantly (p <.001). The most common side effect was irregular bleeding, which accounted for 44.3%. The second common side effect was weight gain, which accounted for 29.2%. The composite effectiveness based on pain and bleeding showed that the effective treatment rates at 1, 3, 6, and 12 months after surgery were 92.4%, 97.4%, 96.2%, and 97.4% respectively. CONCLUSIONS: Hysteroscopic suture fixation of the LNG-IUS to the uterine fundus was associated with low expulsion rates and significantly improved dysmenorrhea and bleeding.

Risk factors of heavy uterine bleeding in patients with endometriosis and adenomyosis treated with dienogest.

OBJECTIVE: Dienogest (DNG), a fourth-generation progestin, reduces pain associated with endometriosis and uterine adenomyosis; however, it is associated with irregular uterine bleeding that can cause anemia and poor quality of life. We investigated risk factors for heavy bleeding following DNG administration. MATERIALS AND METHODS: We retrospectively investigated patients who received DNG for risk factors of heavy uterine bleeding, including clinical diagnosis, use of pretreatment gonadotropin-releasing hormone agonist, smoking, cancer antigen 125, and blood hormone levels. We additionally assessed the uterine area in patients with uterine adenomyosis, the major axis of the uterine body, the major axis of myometrial thickness, the site of tumor development, and the site of myoma development in patients with uterine fibroids. RESULTS: Eighty Japanese patients were administered DNG. The median age was 41 (range: 24-51) years. The odds ratio (OR) for moderate-to-severe bleeding according to clinical diagnosis were 0.33 (P = 0.011) for endometrioma and 9.00 (P = 0.049) for uterine adenomyosis. Receiver operating characteristic curve analysis of the uterine area associated with uterine adenomyosis showed an area under the curve (AUC) of 0.909 between those with major and minor bleeding, with an optimal cut-off value of 7388.2 mm2. The uterine body major axis had an AUC of 0.946, with an optimal cut-off value of 78.3 mm. The major axis of myometrial thickness had an AUC of 0.855, with an optimal cut-off value of 46.8 mm. CONCLUSION: Patients with endometrioma treated with DNG were less likely to experience heavy uterine bleeding. Uterine bleeding in patients with uterine adenomyosis and adenomyosis associated with uterine fibroids should be closely monitored while administering DNG.

Current Medical Therapy for Adenomyosis: From Bench to Bedside.

Adenomyosis, characterized by the growth of endometrial tissue within the uterine wall, poses significant challenges in treatment. The literature primarily focuses on managing abnormal uterine bleeding (AUB) and dysmenorrhea, the main symptoms of adenomyosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) and tranexamic acid provide limited support for mild symptoms or symptom re-exacerbation during hormone therapy. The levonorgestrel-releasing intrauterine system (LNG-IUS) is commonly employed in adenomyosis management, showing promise in symptom improvement and reducing uterine size, despite the lack of standardized guidelines. Dienogest (DNG) also exhibits potential benefits, but limited evidence hinders treatment recommendations. Danazol, while effective, is limited by androgenic side effects. Combined oral contraceptives (COCs) may be less effective than progestins but can be considered for contraception in young patients. Gonadotropin-releasing hormone (GnRH) agonists effectively manage symptoms but induce menopausal symptoms with prolonged use. GnRH antagonists are a recent option requiring further investigation. Aromatase inhibitors (AIs) show promise in alleviating AUB and pelvic pain, but their safety necessitates exploration and limited use within trials for refractory patients. This review highlights the complexity of diagnosing adenomyosis, its coexistence with endometriosis and uterine leiomyomas, and its impact on fertility and quality of life, complicating treatment decisions. It emphasizes the need for research on guidelines for medical management, fertility outcomes, long-term effects of therapies, and exploration of new investigational targets. Future research should optimize therapeutic strategies, expand our understanding of adenomyosis and its management, and establish evidence-based guidelines to improve patient outcomes and quality of life.

Compare the Efficacy of Dienogest and the Levonorgestrel Intrauterine System in Women with Adenomyosis.

PURPOSE: The goal of this study was to examine the efficacy and safety of the levonorgestrel intrauterine system (LNG-IUS) versus dienogest (DNG) in female subjects with symptomatic uterine adenomyosis. METHODS: This study enrolled 117 women with symptomatic adenomyosis who visited our hospital from May 1, 2019, to June 30, 2022. Participants were randomized to either the LNG-IUS group (n = 48) or the DNG group (n = 79) in an as-controlled clinical trial for 36 months. Visual analog scale (VAS) scores, uterine volume, endometrial thickness, serum carcinoma antigen 125 level, estradiol, follicle-stimulating hormone, luteinizing hormone, and side effects were assessed to compare the efficacy of LNG-IUS and DNG. FINDINGS: The VAS pain score was significantly decreased in both groups after 3 months of treatment. Three months later, patients receiving DNG reported significantly lower VAS scores compared with those treated with LNG- IUS (P < 0.05). Compared with LNG-IUS, DNG effectively controlled uterine volume growth after 12 months of treatment but neither significantly reduced uterine volume. During the treatment period, endometrial thickness in both groups was maintained at 0.4 to 0.7 cm. IMPLICATIONS: Both DNG and LNG-IUS significantly improved adenomyosis-associated pain after 3 months of treatment. Compared with LNG-IUS, DNG was shown to continuously relieve the symptoms of pain and effectively control the growth of uterine volume.

Rapid reduction of adenomyosis coexisting with leiomyoma volume during treatment with Relugolix.

OBJECTIVE: This study elucidated the efficacy of Relugolix (REL) on the reduction of uterine volume and clinical symptoms for the treatment of adenomyosis. METHODS: We conducted a retrospective cohort study of patients who received REL (40 mg for about 20 weeks) and who underwent a hysterectomy for adenomyosis or fibroids. We divided patients into two groups: adenomyosis coexisting with fibroids (Group A) and fibroids only (Group B); the groups were determined by a postoperative pathological examination. The primary end points were the percent reduction in uterine volume, adenomyotic lesion, and the largest fibroid volume at week 16. The secondary end points were the rate of amenorrhea, pelvic pain, and anemia at week 12. RESULTS: A total of 56 patients participated in the current study: 20 in Group A and 36 in Group B. Regarding the largest fibroid volume, there was no significant difference between the two groups. Uterine volume after REL treatment was significantly decreased in Group A (43%), as compared to Group B (27%) (p = .00972), In Group A, adenomyotic lesion was decreased by 61%. Irrespective of the group, adenomyosis showed a significant reduction compared to uterine fibroids (p < .001). There was no statistically significant difference in the mitigation of symptoms (amenorrhea, pelvic pain, and anemia) between the two groups. CONCLUSIONS: REL is more effective in reducing adenomyotic lesion than uterine fibroids and in relieving symptoms (amenorrhea, pelvic pain, and anemia). It can be expected that REL will also be used as a preoperative treatment for adenomyosis.

Malformação arteriovenosa uterina: um relato de caso / Uterine arteriovenous malformation: a case report

O presente estudo tem como objetivo relatar o caso de uma paciente com malformação arteriovenosa uterina, efetivamente tratada com embolização seletiva e com fertilidade preservada. A malformação arteriovenosa uterina é uma alteração vascular rara até então pouco descrita na literatura. A paciente do sexo feminino apresentou quadro de sangramento uterino anormal, com início 30 dias após um abortamento, sem realização de curetagem, de uma gestação resultante de fertilização in vitro. Foram, então, realizados exames de imagem, que levaram ao diagnóstico de malformação arteriovenosa uterina. O tratamento de escolha foi a embolização arterial seletiva, com resolução do caso. Após sete meses, nova fertilização in vitro foi realizada, encontrando-se na 36a semana de gestação. São necessários mais estudos sobre essa malformação a fim de que sejam estabelecidos os métodos mais eficazes para o manejo de casos futuros, especialmente quando há desejo de gestar.

The present study aims to report the case of a patient with uterine arteriovenous malformation, effectively treated with selective embolization and with preserved fertility. Uterine arteriovenous malformation is a rare vascular disorder that has so far been rarely described in the literature. Female patient presented with abnormal uterine bleeding, starting 30 days after an abortion without subsequent curettage, of a pregnancy resulting from in vitro fertilization. Imaging tests were then performed that led to the diagnosis of uterine arteriovenous malformation. The treatment of choice was selective arterial embolization, with successful results. After seven months, a new in vitro fertilization was performed, being in the 36th week of pregnancy. Further studies on this pathology are needed in order to establish the most effective methods for the management of future cases, especially when there is a desire to become pregnant.

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.

A Case of Adenomyosis Showing Size Reduction in a Follicular Lymphoma Patient Receiving Chemotherapy With R-Bendamustine.

ABSTRACT: We describe a case of adenomyosis that reduced in size in a patient with lymphoma on receiving chemotherapy. A 48-year-old woman with worsening left flank pain was diagnosed with follicular lymphoma. [ 18 F]FDG PET/CT revealed multiple hypermetabolic lymph nodes in the bilateral cervical, axillary, mediastinal, mesenteric, retroperitoneal, iliac, and inguinal regions. In addition, adenomyosis with mild hypermetabolism was demonstrated on [ 18 F]FDG PET/CT. The size and metabolism of adenomyosis decreased after chemotherapy with R-bendamustine; in addition, along with decrease in estradiol levels, the patient experienced amenorrhea and hot flushes. The patient was diagnosed with chemotherapy-induced early menopause.

Low-dose letrozole - an effective option for women with symptomatic adenomyosis awaiting IVF: a pilot randomized controlled trial.

RESEARCH QUESTION: Can low-dose letrozole reduce dysmenorrhoea, menorrhagia and sonographic features in symptomatic women with adenomyosis awaiting IVF? DESIGN: This was a longitudinal randomized prospective pilot study to explore the effectiveness of low-dose letrozole and compare it with a gonadotropin releasing hormone (GnRH) agonist in reducing dysmenorrhoea, menorrhagia and sonographic features in symptomatic women with adenomyosis awaiting IVF. The women were treated for 3 months, either with the GnRH agonist goserelin 3.6 mg/month (n = 77) or the aromatase inhibitor letrozole 2.5 mg three times weekly (n = 79). Dysmenorrhoea and menorrhagia were evaluated at randomization and followed up monthly using a visual analogue score (VAS) and pictorial blood loss assessment chart (PBAC), respectively. A quantitative scoring method was used to assess the improvement of sonographic features after 3 months of treatment. RESULTS: Both groups reported a marked improvement in symptoms after 3 months of treatment. In both the letrozole and GnRH agonist groups, VAS and PBAC scores decreased significantly over the 3 months (letrozole: P = 0.0001 and P = 0.0001 for VAS and PBAC, respectively; GnRH agonist: P = 0.0001 and P = 0.0001 for VAS and PBAC, respectively). Participants on letrozole had regular menstruation cycles, while most of the women who received the GnRH agonist were amenorrhoeic, with only four women reporting mild bleeding. Haemoglobin concentrations also improved after both treatments (letrozole P = 0.0001, GnRH agonist P = 0.0001). A quantitative assessment of sonographic features showed significant improvements following both treatments (diffuse adenomyosis of the myometrium: letrozole P = 0.015, GnRH agonist P = 0.039; diffuse adenomyosis of the junctional zone: letrozole P = 0.025, GnRH agonist P = 0.001). Women with adenomyoma also responded well to both therapies (letrozole P = 0.049, GnRH agonist P = 0.024), whereas the letrozole group responded comparatively better in focal adenomyosis when the outer myometrium was involved (letrozole P < 0.001, GnRH agonist P = 0.26). No noticeable side effects were observed in women receiving letrozole therapy. Additionally, letrozole therapy was found to be more cost-effective than GnRH agonist treatment. CONCLUSIONS: Low-dose letrozole treatment is a low-cost alternative to a GnRH agonist, with comparable effects in improving the symptoms and sonographic features of adenomyosis in women awaiting IVF.

Impact of adenomyosis and endometriosis on IVF/ICSI pregnancy outcome in patients undergoing gonadotropin-releasing hormone agonist treatment and frozen embryo transfer.

Although numerous studies have attempted to establish the relationship between adenomyosis and infertility, no consensus has emerged. Our aim was to investigate whether adenomyosis and endometriosis affected IVF outcomes in our patients. This was a retrospective study of 1720 patients from January 2016 to December 2019. In total, 1389 cycles were included: 229 cycles in the endometriosis group (group E), 89 cycles in the adenomyosis group (group A), 69 cycles in the endometriosis and adenomyosis group (group EA), and 1002 cycles in the control group (group C). Most patients in groups A and EA received GnRH agonist treatment before FET. The 1st FET live birth rates (LBR) were 39.3%, 32.1%, 25% and 48.1% in groups E, A, EA, and C. The miscarriage rates were 19.9%, 34.7%, 39%, and 17.6%. The per retrieval cycle cumulative live birth rates (cLBRs) in patients < 38 y/o were 56.4%, 58.1%, 44.8%, and 63%. The per retrieval cycle cLBRs in patients ≥ 38 y/o were 25%, 9.8%, 17.2%, and 29.5%. Among groups A and EA, LBRs were 25.58% and 18.89% in patients with a ≥ sevenfold decrease and a < sevenfold decrease in CA-125 level, respectively, after GnRH agonist treatment. Endometriosis was not associated with a poorer pregnancy outcome. Patients with adenomyosis with/without endometriosis had higher miscarriage rates, lower LBRs, and lower cLBRs, especially in patients aged ≥ 38 years, even after GnRH agonist treatment before FET cycles. Patients who have a greater than sevenfold decrease in CA-125 level after GnRH agonist treatment might have better clinical pregnancy outcomes.

Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis.

Objective: Bromocriptine treatment has been shown to reduce menstrual bleeding and pain in women with adenomyosis in a pilot clinical trial. The underlying mechanism contributing to the treatment effect is however unknown. The purpose of this study was to explore the effect of bromocriptine on the proliferation and migration properties of the endometrium in women with adenomyosis, by assessing cellular and molecular changes after six months of vaginal bromocriptine treatment. Methods: Endometrial specimens were collected during the proliferative phase from women with adenomyosis (n=6) before (baseline) and after six months of treatment with vaginal bromocriptine. Immunohistochemistry was used to determine changes in the protein expression of Ki67 in the endometrium of women with adenomyosis. Primary endometrial stromal cells isolated at baseline were expanded in vitro and exposed to different doses of bromocriptine to determine the optimal half-maximum inhibitory concentration (IC50) using CellTiter-Blue® Cell Viability Assay. Cell proliferation was assessed by bromodeoxyuridine ELISA assay and Ki67 gene expression was checked by real-time PCR. The migratory ability of endometrial stromal cells was determined by wound healing and transwell migration assays. Small RNA sequencing was applied on tissues collected from women with adenomyosis before and after bromocriptine treatment to identify differentially expressed microRNAs (miRNAs) after bromocriptine treatment. Bioinformatic methods were used for target gene prediction and the identification of biological pathways by enrichment procedures. Results: Vaginal bromocriptine treatment reduced the Ki67 protein expression in the endometrium of women with adenomyosis and did not change the prolactin mRNA expression and protein concentration of prolactin in endometrial tissues. Bromocriptine significantly inhibited the proliferative and migrative abilities of endometrial stromal cells derived from women with adenomyosis in vitro. Moreover, small RNA sequencing revealed 27 differentially expressed miRNAs between the endometrium of women with adenomyosis before and after six months of vaginal bromocriptine treatment. KEGG pathway analysis on targeted genes of 27 miRNAs showed that several signaling pathways associated with cell proliferation and apoptosis were enriched after bromocriptine treatment. Conclusion: Bromocriptine treatment exhibits an anti-proliferative effect in the endometrium of women with adenomyosis in vivo and in vitro. Bromocriptine might inhibit the proliferation of endometrial tissue in adenomyosis in part through the regulation of dysregulated microRNAs and proliferation-associated signaling pathways.

Various types of adenomyosis and endometriosis: in search of optimal management.

Currently, hormonal drugs are the mainstay for treating endometriosis or adenomyosis. Aside from staying within the "therapeutic window" and cutting off the hormonal support to the ectopic endometrium, none of these treatments were developed with a previously identified target. The current lack of innovation is humbling, especially considering that among >34,000 PubMed-indexed publications on endometriosis or adenomyosis, approximately 65% of them were published in the last 2 decades, many of them presumably with all the benefits of omics and molecular biology. One major reason for so many doomed research and development (R&D) projects on nonhormonal drugs is the failure to understand the natural history of the ectopic endometrium. Other reasons include, but are not limited to, the number of side effects that these nonhormonal drug candidates presented, which the developers were either unaware of or simply had ignored when pursuing a too narrowly minded development-a common cognitive trap known as invisible gorillas. Unless we have a clear global picture with a good grasp of the natural history of ectopic endometrium, "potholes" and "blind alleys" in drug R&D are difficult to avoid. This review shall explore some new concepts in the progression of ectopic endometrium and explain how these new perspectives offer insights for devising better therapeutic options, explain why some drug R&D projects for endometriosis or adenomyosis have failed, provide a critical analysis of some issues encountered in everyday practice, expose knowledge gaps in need of further research, and, finally, offer possible ways to circumvent hurdles and potholes and avoid cul-de-sacs in nonhormonal drug R&D.