Estetrol Inhibits Endometriosis Development in an In Vivo Murine Model.

Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus, and it is associated with alterations in the expression of hormone receptors and inflammation. Estetrol (E4) is a weak estrogen that recently has been approved for contraception. We evaluated the effect of E4 on the growth of endometriotic-like lesions and the expression of TNF-α, estrogen receptors (ERs), and progesterone receptors (PRs) in an in vivo murine model. Endometriosis was induced surgically in female C57BL/6 mice. E4 was delivered via Alzet pump (3 mg/kg/day) from the 15th postoperative day for 4 weeks. E4 significantly reduced the volume (p < 0.001) and weight (p < 0.05) of ectopic lesions. Histologically, E4 did not affect cell proliferation (PCNA immunohistochemistry) but it did increase cell apoptosis (TUNEL assay) (p < 0.05). Furthermore, it modulated oxidative stress (SOD, CAT, and GPX activity, p < 0.05) and increased lipid peroxidation (TBARS/MDA, p < 0.01). Molecular analysis showed mRNA (RT-qPCR) and protein (ELISA) expression of TNF-α decreased (p < 0.05) and mRNA expression of Esr2 reduced (p < 0.05), in contrast with the increased expression of Esr1 (p < 0.01) and Pgr (p < 0.05). The present study demonstrates for the first time that E4 limited the development and progression of endometriosis in vivo.

Heme metabolism and HO-1 in the pathogenesis and potential intervention of endometriosis.

Endometriosis (EM) is one of the diseases related to retrograded menstruation and hemoglobin. Heme, released from hemoglobin, is degraded by heme oxygenase-1 (HO-1). In EM lesions, heme metabolites regulate processes such as inflammation, redox balance, autophagy, dysmenorrhea, malignancy, and invasion, where macrophages (Mø) play a fundamental role in their interactions. Regulation occurs at molecular, cellular, and pathological levels. Numerous studies suggest that heme is an indispensable component in EM and may contribute to its pathogenesis. The regulatory role of heme in EM encompasses cytokines, signaling pathways, and kinases that mediate cellular responses to external stimuli. HO-1, a catalytic enzyme in the catabolic phase of heme, mitigates heme's cytotoxicity in EM due to its antioxidant, anti-inflammatory, and anti-proliferative properties. Certain compounds may intervene in EM by targeting heme metabolism, guiding the development of appropriate treatments for all stages of endometriosis.

Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial.

OBJECTIVES: To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain. DESIGN: The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial. SETTING: 34 UK hospitals. PARTICIPANTS: 405 women of reproductive age undergoing conservative surgery for endometriosis. INTERVENTIONS: Participants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill. MAIN OUTCOME MEASURES: The primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment). RESULTS: 405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference -0.8, 95% confidence interval -5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). CONCLUSIONS: Postoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some. TRIAL REGISTRATION: ISRCTN registry ISRCTN97865475.

The Role of Nanomedicine in Benign Gynecologic Disorders.

Nanomedicine has revolutionized drug delivery in the last two decades. Nanoparticles appear to be a promising drug delivery platform in the treatment of various gynecological disorders including uterine leiomyoma, endometriosis, polycystic ovarian syndrome (PCOS), and menopause. Nanoparticles are tiny (mean size < 1000 nm), biodegradable, biocompatible, non-toxic, safe, and relatively inexpensive materials commonly used in imaging and the drug delivery of various therapeutics, such as chemotherapeutics, small molecule inhibitors, immune mediators, protein peptides and non-coding RNA. We performed a literature review of published studies to examine the role of nanoparticles in treating uterine leiomyoma, endometriosis, PCOS, and menopause. In uterine leiomyoma, nanoparticles containing 2-methoxyestradiole and simvastatin, promising uterine fibroid treatments, have been effective in significantly inhibiting tumor growth compared to controls in in vivo mouse models with patient-derived leiomyoma xenografts. Nanoparticles have also shown efficacy in delivering magnetic hyperthermia to ablate endometriotic tissue. Moreover, nanoparticles can be used to deliver hormones and have shown efficacy as a mechanism for transdermal hormone replacement therapy in individuals with menopause. In this review, we aim to summarize research findings and report the efficacy of nanoparticles and nanotherapeutics in the treatment of various benign gynecologic conditions.

Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (Ki: 4.0 nM) and EPHA4 (Ki: 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC50: 461 nM) and EPHA4 (IC50: 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (Ki: 0.13 nM) and EPHA4 (Ki: 0.38 nM) with excellent cell-based potency EPHA2 (IC50: 8.0 nM) and EPHA4 (IC50: 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1ß-mediated expression of prostaglandin synthase 2 (PTGS2). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing's sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer.

Mindfulness in Facilitating Pelvic Floor Botulinum Toxin Injection in Women with Chronic Pelvic Pain.

Botulinum toxin (BoNT) injection can safely be done as an office-based procedure, but can be painful itself, especially when injecting pelvic floor muscles to treat chronic pelvic pain (CPP). Mindfulness interventions may reduce procedure-associated acute anxiety and pain. We applied mindfulness techniques to increase the tolerability of office-based pelvic floor BoNT injections in women with CPP. Women enrolled in a clinical trial of BoNT for endometriosis-associated CPP were offered a brief, guided mindfulness session before and/or after transvaginal injection. Anxiety, pain, and dysphoria were rated on a 0-10 numerical rating scale (NRS) before and after each mindfulness session. Eight women underwent mindfulness sessions. Five participants had a session before and two after the transvaginal injection. One participant had two sessions: one before and one after separate injections. All six women completing a session prior to injection had at least moderate anxiety, which lessened after the mindfulness session (median NRS change: -3.3/10). All three women reporting injection-associated pain experienced less intense pain following the post-injection session (median NRS change: -3/10). Three women experiencing dysphoria improved after the session (median NRS change: -3/10). A brief, guided mindfulness session may lessen acute pain, anxiety, and dysphoria associated with office-based transvaginal BoNT injection.

Long-term therapy with dienogest or other oral cyclic estrogen-progestogen can reduce the need for ovarian endometrioma surgery.

BACKGROUND: Almost 10% of women in reproductive age are diagnosed with ovarian endometriomas and can experience symptoms and infertility disorders. Ovarian endometriomas can be treated with medical or surgical therapy. OBJECTIVE: To assess whether long-term therapy with dienogest or oral cyclic estrogen-progestogens is effective in reducing the size of ovarian endometriomas, alleviating associated symptoms, and reducing the requirement for surgery. DESIGN: Prospective non-interventional cohort study. METHODS: We enrolled childbearing women diagnosed with ovarian endometriomas. We collected demographic, clinical, and surgical data, including the evaluation of ovarian endometrioma-associated symptoms and pain using the visual analog scale. We grouped the women according to treatment regimen into dienogest, estrogen-progestogens, and no-treatment. Patient's assessment was performed at baseline and after 12 months evaluating the largest ovarian endometrioma diameter (in millimeters) and the associated symptoms. Furthermore, we analyzed the impact of hormonal treatment in a sub-group of women fulfilling at baseline the criteria for a first-line surgical approach (ovarian endometrioma > 30 mm with visual analog scale > 8 or ovarian endometrioma > 40 mm before assisted reproductive treatments or any ovarian endometrioma(s) > 60 mm). RESULTS: We enrolled 142 patients: 62, 38, and 42 in dienogest, estrogen-progestogens, and no-treatment groups, respectively. No significant differences were found regarding baseline characteristics. After 12 months, the mean largest ovarian endometrioma diameter increased in the no-treatment group (31.1 versus 33.8; p < 0.01), while a significant reduction was registered in the dienogest (35.1 versus 25.8; p < 0.01) and estrogen-progestogens (28.4 versus 16.7; p < 0.01) groups; no significant difference in ovarian endometrioma diameter reduction between these two latter groups was noted (p = 0.18). Ovarian endometrioma-associated symptoms and pain improved in dienogest and estrogen-progestogens groups, with a significantly greater effect for dienogest than for estrogen-progestogens for dysmenorrhea (74% versus 59%; p < 0.01). In the sub-group of women eligible for first-line surgery at baseline, long-term treatment with dienogest and estrogen-progestogens reduced surgical eligibility by 30%. CONCLUSIONS: Decreased mean largest ovarian endometriomas'diameter after 12 months and reduction of the need for surgical treatment by 30% were observed in dienogest and estrogen-progestogens groups. Long-term treatment with dienogest had a greater effect in alleviating dysmenorrhea and pain.

Effects of herbal compounds on various aspects of endometriosis treatment: a systematic review.

OBJECTIVE: Endometriosis means the presence of tissue similar to normal endometrium outside the uterus. Although surgical, hormonal, and analgesic treatment relieves symptoms and improves fertility, it is associated with side effects and a high recurrence rate. Alternative medicines like medicinal plants have been used for the treatment of chronic diseases. Given the global importance of endometriosis as a chronic disease affecting over 15% of all women in their fertile period, this systematic review aimed to give a comprehensive view of research on medicinal plants. MATERIALS AND METHODS: Comprehensive searches were performed on three databases, including PubMed/MEDLINE, Web of Science Core Collection (Indexes = SCI-EXPANDED, SSCI, A, and HCI Timespan), and Scopus, to identify papers published until June 2023. Keywords, such as "Endometriosis" and "Herbal Medicine", were used to search. A manual search of valid journals followed by a manual search of the references of the retrieved full-text articles was performed. All retrieved articles were imported into a database into Endnote X9. Articles that did not meet the inclusion criteria were excluded from the study, and the full texts of all the articles that met the inclusion criteria were assessed. Studies that evaluated the effects of herbal compounds on various aspects of endometriosis treatment were included in the review. RESULTS: In total, 11 studies were included in the present study. The evidence showed that in addition to safety, drugs available alongside treatments could play an effective role in improving the symptoms associated with endometriosis. In this study, the positive results of using Chinese treatments were reported in aspects such as fertility rate, pain, endometriosis recurrence rate, quality of life, sexual function, CA-125 level, and menopause symptoms. CONCLUSIONS: A wide range of preclinical and clinical studies evaluated the effectiveness and safety of medicinal plants in the treatment of endometriosis symptoms. Thus, alternative treatments for endometriosis with no or low side effects should be included in the holistic treatment of endometriosis upfront. However, there is still a need for well-designed trials to investigate standard interventions and specific and safe doses of herbal medicines.

Potential Mechanisms of Guizhi Fuling Wan in Treating Endometriosis: An Analysis Based on TCMSP and DisGeNET Databases.

ETHNOPHARMACOLOGICAL RELEVANCE: Guizhi Fuling Wan (GFW), is a traditional Chinese herbal formula that consists of Cinnamomi Ramulus (Guizhi), Poria Cocos(Schw.) Wolf. (Fuling), Persicae Semen (Taoren), Radix Paeoniae Rubra (Chishao), and Cortex Moutan (Mudanpi). This formula has been used in traditional Chinese medicine for more than 1800 years to treat disorders caused by stagnation of circulation and qi (air). AIM OF THE STUDY: Based on pre-clinical and clinical studies, this review aimed to reveal the potential mechanisms of GFW in inhibiting endometriosis. The enhancement of therapeutic effects of western medications on endometriosis by GFW was also shown. MATERIALS AND METHODS: A bibliographic assessment of publications on "Guizhi Fuling Wan" and "endometriosis" indexed in PubMed, Science Direct, and China National Knowledge Infrastructure (CNKI) was conducted. Five pre-clinical studies and 13 clinical studies were selected for this review. Moreover, the targeted molecules of each herb were first extracted from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform followed by obtaining the endometriosis-related genes from DisGeNET. Subsequently, pathway and gene ontology analyses using David Bioinformatics Resources explored the potential mechanisms of therapeutic effects of GFW in treating endometriosis. RESULTS: Pre-clinical and clinical studies showed that GFW might inhibit the growth of endometriotic lesion through the modulation of immunity, apoptosis-regulating molecules, and angiogenesis-associated factors, while enhancing the therapeutic effects of western medications in treating endometriosis. Furthermore, pathway and gene ontology analyses demonstrated that GFW might attenuate the disease primarily by affecting AGE-RAGE signaling pathway in diabetic complications (hsa04933) as well as pathways involved in Kaposi sarcoma-associated herpesvirus infection (hsa05167), human cytomegalovirus infection (has05163), and fluid shear stress and atherosclerosis (hsa05418). These pathways were all involved in the regulation of inflammation, angiogenesis, and apoptosis and commonly affected by all herbs. CONCLUSIONS: The current review revealed that endometriosis is highly associated with aberrant inflammatory, angiogenic, and apoptotic activities. The therapeutic effects of GFW on endometriosis are likely to act through regulating these activities.

Relugolix/Estradiol/Norethisterone Acetate: A Review in Endometriosis-Associated Pain.

An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate [Myfembree® (USA); Ryeqo® (EU)] (hereafter referred to as relugolix combination therapy) has been approved in the USA for the management of moderate to severe pain associated with endometriosis in premenopausal women and in the EU for the symptomatic treatment of endometriosis in adult women of reproductive age with a history of previous medical or surgical treatment for their endometriosis. The gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix decreases estradiol and progesterone levels, while the addition of estradiol/norethisterone acetate mitigates hypoestrogenic effects including bone mineral density (BMD) loss and vasomotor symptoms. In two pivotal phase III trials, relugolix combination therapy significantly improved dysmenorrhoea and non-menstrual pelvic pain in premenopausal women with moderate to severe endometriosis. The combination also reduced overall pelvic pain and dyspareunia, reduced analgesic and opioid use, and improved health-related quality of life. The efficacy of relugolix combination therapy was sustained over the longer term (up to 2 years). Relugolix combination therapy was generally well tolerated and BMD loss over time was minimal. With the convenience of a once daily oral dosing regimen, relugolix combination therapy is a valuable addition to the options currently available for the management of endometriosis-associated pain.

Endometriosis is a disease where tissue similar to the lining of the uterus grows outside the uterus and may reach other organs. This causes chronic pain as a result of increased inflammation and scar tissue. Women with endometriosis may experience painful menstrual periods, pelvic pain between periods, pain during sex, painful bowel movements and painful urination. Recently, a fixed-dose tablet comprising relugolix, estradiol and norethisterone (also known as norethindrone) acetate [Myfembree^® (USA); Ryeqo^® (EU)] (hereafter referred to as relugolix combination therapy) has been approved to treat endometriosis-associated pain. The treatment works by decreasing levels of ovarian hormones (estrogen and progesterone). In clinical trials, relugolix combination therapy improved period pain and pain between periods in women with moderate to severe pain associated with endometriosis. The treatment also improved other symptoms (overall pelvic pain and pain during sex), reduced the need for pain medications and improved health-related quality of life. Relugolix combination therapy was generally well tolerated and caused minimal bone loss, which is known to occur with some hormone therapies. With the convenience of a once daily oral pill, relugolix combination therapy is a valuable addition to the options currently available for women with endometriosis-associated pain.

Methyl 3,4-dihydroxybenzoate alleviates oxidative damage in granulosa cells by activating Nrf2 antioxidant pathway.

Oxidative damage induced granulosa cells (GCs) apoptosis was considered as a significant cause of compromised follicle quality, antioxidants therapy has emerged as a potential method for improving endometriosis pregnancy outcomes. Here, we found that GCs from endometriosis patients show increased oxidative stress level. Methyl 3,4-dihydroxybenzoate (MDHB), a small molecule compound that is extracted from natural plants, reversed tert-butyl hydroperoxide (TBHP) induced GCs oxidative damage. Therefore, the aim of this study was to assess the protective effect of MDHB for GCs and its potential mechanisms. TUNEL staining and immunoblotting of cleaved caspase-3/7/9 showed MDHB attenuated TBHP induced GCs apoptosis. Mechanistically, MDHB treatment decreased cellular and mitochondria ROS production, improved the mitochondrial function by rescuing the mitochondrial membrane potential (MMP) and ATP production. Meanwhile, MDHB protein upregulated the expression of vital antioxidant transcriptional factor Nrf2 and antioxidant enzymes SOD1, NQO1 and GCLC to inhibited oxidative stress state, further beneficial to oocytes and embryos quality. Therefore, MDHB may represent a potential drug candidate in protecting granulosa cells in endometriosis, which can improve pregnancy outcomes for endometriosis-associated infertility.

Efficacy and safety of dienogest in the treatment of deep infiltrating endometriosis: A meta-analysis.

OBJECTIVE: To systematically review and conduct a meta-analysis to assess the effectiveness of dienogest (DNG) in the prolonged conservative drug management of deep infiltrating endometriosis (DIE). The findings from this study are intended to serve as a valuable reference for clinical decision-making regarding medication in the context of DIE. METHODS: Following the PRISMA Statement, we searched EMBASE, PubMed, The Cochrane Library, Web of Science, and Medline databases for relevant literature published in the public domain from the date of establishment of the database until October 2023. Subsequently, all English publications on clinical studies using DNG for the treatment of DIE were included. Studies involving surgical intervention or drug therapy for postoperative recurrence were excluded. All literature included in the review underwent risk assessment of bias. Two evaluators independently screened the publications, conducted a quality assessment of each article and extracted data. We used Revman 5.4 for the meta-analysis of the included literature. RESULTS: Our final analysis consisted of five clinical studies, involving a total of 256 patients. We found that there were significant improvements in the following indicators post-medication as compared to levels before taking the medication: dysmenorrhea (MD = 4.24, 95 % CI: 2.92-5.56, P < 0.00001), non-menstrual pelvic pain (MD = 3.11, 95 % CI: 2.34-3.88, P < 0.00001), dyspareunia (MD = 1.93, 95 % CI: 1.50-2.37, P < 0.00001), dyschezia (MD = 2.48, 95 % CI: 1.83-3.12, P < 0.00001), and rectosigmoid nodule size (MD = 0.32, 95 % CI: 0.18-0.46, P < 0.00001). Compared with pre-medication levels, the following indicators were significantly worse: headache (RR = 0.03, 95 % CI: 0.00-0.23, P = 0.0006), decreased libido (RR = 0.08, 95 % CI: 0.01-0.62, P = 0.02); and there was no significant improvement in dysuria (P > 0.05). CONCLUSION: DNG showed efficacy in relieving pain-related symptoms and significantly reducing the size of the lesions when used in the drug conservative treatment of DIE.

Molecular Mechanism of Resveratrol and Its Therapeutic Potential on Female Infertility.

Resveratrol is a polyphenol present in various plant sources. Studies have reported numerous potential health benefits of resveratrol, exhibiting anti-aging, anti-inflammatory, anti-microbial, and anti-carcinogenic activity. Due to the reported effects, resveratrol is also being tested in reproductive disorders, including female infertility. Numerous cellular, animal, and even human studies were performed with a focus on the effect of resveratrol on female infertility. In this review, we reviewed some of its molecular mechanisms of action and summarized animal and human studies regarding resveratrol and female infertility, with a focus on age-related infertility, polycystic ovary syndrome, and endometriosis.

CGRP neuropeptide levels in patients with endometriosis-related pain treated with dienogest: a comparative study.

BACKGROUND AND OBJECTIVE: Endometriosis (EM) involves the peripheral nervous system and causes chronic pain. Sensory nerves innervating endometriotic lesions contribute to chronic pain and influence the growth phenotype by releasing neurotrophic factors and interacting with nearby immune cells. Calcitonin gene-related peptide (CGRP), a pain-signaling neurotransmitter, has a significant role. This study examines the effect of Dienogest (DNG), a hormone therapy used for managing EM -related pain, on serum CGRP levels in EM patients. MATERIALS AND METHODS: The Visual Analog Scale (VAS) assessed pain in diagnosed EM. INDIVIDUALS: Serum samples were obtained to measure CGRP concentration. Participants received a 2 mg/day oral dose of DNG for six months as prescribed treatment. Additional serum samples were collected after this period to measure CGRP levels. RESULTS: In the EM group, 6.7%, 33.3%, and 20% had ovarian EM, ovarian plus uterosacral, and ovarian plus bladder, respectively. The EM group showed higher CGRP serum levels than the control group (80.53 ± 16.13 vs. 58.55 ± 6.93, P < 0.0001). Still, after drug administration, CGRP serum levels significantly decreased compared to pre-treatment levels (69.66 ± 11.53 vs. 80.53 ± 16.13, P < 0.05). The EM group showed higher pain compared to the control group (7.93 ± 1.58 vs. 0.13 ± 0.35, P < 0.0001), but after drug administration, pain significantly decreased compared to pre-treatment levels (1.00 ± 2.00 vs. 7.93 ± 1.58, P < 0.05). CONCLUSION: DNG administration reduces pain and serum CGRP levels in EM patients, offering the potential for innovative treatments and tailored options. Understanding neurotransmitter roles and drug effects can aid in discovering more effective modulators for these pathways.

Long-term treatment for endometriosis with dienogest: efficacy, side effects and tolerability.

BACKGROUND: Dienogest (DNG) improves endometriosis-associated pain (EAP) and patients' quality of life; however, the modern cornerstone of the management of endometriosis is the long-term adherence of the patient to medical treatment. OBJECTIVE: To evaluate DNG as a long-term treatment of endometriosis, focusing on patients' compliance and side effects, also correlating with different phenotypes of endometriosis. METHODS: This was a cohort study on a group of patients with endometriosis (n = 114) undergoing long-term treatment with DNG. During the follow up visits (12, 24, and 36 months) patients were interviewed: an assessment of EAP was performed by using a visual analogue scale (VAS) and side effects were evaluated by using a specific questionnaire of 15 items. RESULTS: At 12 months, 81% were continuing the DNG treatment, with a significant reduction of dysmenorrhea, dyspareunia, dyschezia, dysuria and chronic pelvic pain. Of the 19% that discontinued the treatment: 62% was due to spotting, reduced sexual drive, vaginal dryness, and mood disorders. The improvement of EAP was significant for all endometriosis phenotypes, especially in patients with the deep infiltrating type. At 36 months, 73% of patients were continuing the treatment, showing a significant reduction of EAP through the follow up, along with an increase of amenorrhea (from 77% at 12 months to 93% at 36 months). In a subgroup of 18 patients with gastrointestinal disorders, DNG was administered vaginally at the same dosage, showing similar results in terms of efficacy and tolerability. CONCLUSIONS: DNG was an effective long-term treatment for all endometriosis phenotypes, with few side effects that caused the discontinuation of the treatment mainly during the first year. Thus, the course of 1-year treatment is a predictive indicator for long-term treatment adherence.

The effect of antiangiogenic agent aflibercept on surgically induced endometriosis in a rat model.

OBJECTIVE: The aim of the study is to show for the first time how aflibercept affects endometriosis lesions. MATERIAL AND METHODS: Surgically induced endometriosis in Wistar albino female rats. Rats with endometriosis were randomly divided into three groups: control (Co), aflibercept (Af), and leuprolide acetate (Le). Then, Af, aflibercept, and Le received leuprolide acetate. The control group was not treated. The weights and changes in intra-abdominal adhesions of the rats before and after treatment were recorded according to the Blauer adhesion score. Blood extracted for sacrifice was analyzed. Endometriotic lesions were evaluated for size, volume, histology, and immunohistochemistry (vascular endothelial growth factor [VEGF] and CD31). Significance level was accepted as p < 0.05. RESULTS: Aflibercept significantly reduced endometrial implant volume (p = 0.002). The explant epithelial histological score showed a significant difference between aflibercept and leuprolide acetate (p = 0.006) and between aflibercept and control groups (p = 0.002). Aflibercept decreased VEGF-H and CD31 expression (p = 0.001) more than leuprolide acetate. Aflibercept improved adhesions (p = 0.006). CONCLUSION: Aflibercept is more successful than leuprolide acetate in the treatment of endometriosis.

OBJETIVO: Mostrar por primera vez cómo afecta aflibercept a las lesiones de endometriosis. MATERIAL Y MÉTODOS: Endometriosis inducida quirúrgicamente en ratas hembras albinas Wistar. Las ratas con endometriosis se dividieron aleatoriamente en tres grupos: control (Co), aflibercept (Af) y acetato de leuprolida (Le). Luego, Af, aflibercept y Le recibieron acetato de leuprolida. El grupo de control no fue tratado. Los pesos y cambios en las adherencias intraabdominales de las ratas antes y después del tratamiento se registraron de acuerdo con la puntuación de adherencia de Blauer. La sangre extraída para el sacrificio fue analizada. Las lesiones endometriósicas se evaluaron en tamaño, volumen, histología e inmunohistoquímica (factor de crecimiento endotelial vascular [VEGF] y CD31). El nivel de significación se aceptó como p < 0.05. RESULTADOS: Aflibercept redujo significativamente el volumen del implante endometrial (p = 0.002). La puntuación histológica epitelial (EHS) del explante mostró una diferencia significativa entre aflibercept y acetato de leuprolida (p = 0.006) y entre los grupos de aflibercept y control (p = 0.002). Aflibercept disminuyó la expresión de VEGF-H y CD31 (p = 0.001) más que el acetato de leuprolida. Aflibercept mejoró las adherencias (p = 0.006). CONCLUSIÓN: Aflibercept tiene más éxito que el acetato de leuprolide en el tratamiento de la endometriosis.

Research progress of dydrogesterone in the treatment of endometriosis.

Endometriosis is a common gynecological disease among women of reproductive age. It is a chronic estrogen and progestin related inflammatory disease. At present, the main treatments for endometriosis are drug therapy and surgery. In drug therapy, progesterone is listed as the first-line recommendation in multinational guidelines. Dydrogesterone, as an oral reversal progesterone, can slow down the metabolism of progesterone, inhibit angiogenesis and extracellular matrix degradation to inhibit the proliferation of the ectopic endometrium, induce the atrophy of the ectopic endometrium through the pro-apoptotic pathway, and treat endometriosis through multiple mechanisms of regulating inflammatory factors to reduce inflammation. Clinically, dydrogesterone treatment of endometriosis can relieve patients' symptoms, promote fertility, be used in combination, and is safe. This article will review the mechanism and clinical application of dydrogesterone in the treatment of endometriosis.