Search Results (28)

Endometriosis is a chronic inflammatory condition affecting approximately 10% of women of reproductive age, characterized by pelvic pain, dysmenorrhea, and infertility. Emerging evidence suggests a potential link between gut microbiota dysbiosis and endometriosis pathogenesis, mediated through hormonal regulation, immune modulation, and systemic inflammation. Dienogest (DNG) is widely used for endometriosis management, but its effects on gut microbiota remain underexplored. This study investigates the impact of DNG on gut microbial composition in endometriosis patients, aiming to elucidate its therapeutic mechanisms beyond hormonal modulation. DNG therapy led to a significant reduction in the Bacillota/Bacteroidota ratio (p = 0.0421), driven by decreased Staphylococcus spp. (p = 0.0244) and increased commensal bacteria such as Lactobacillus spp. and Collinsella aerofaciens (p = 0.049). Species richness and alpha diversity indices showed a non-significant upward trend. Notably, C. aerofaciens, a butyrate producer linked to gut barrier integrity, was detected twice as frequently during therapy. The study also observed reductions in facultative anaerobes like Enterococcus spp. and a trend toward higher titers of beneficial Bacteroidota. This study provides the first evidence that DNG therapy modulates gut microbiota in endometriosis patients, favoring a composition associated with anti-inflammatory and barrier-protective effects. The observed shifts—reduced opportunistic pathogens and increased symbionts—suggest a novel mechanism for DNG’s efficacy, potentially involving the microbial regulation of estrogen metabolism and immune responses. Full article

Objective: To assess the long-term effects of Dienogest on clinical complaints and nodule sizes in women affected by recto-sigmoid deep endometriosis (DE). Methods: This was a single-center longitudinal prospective observational study comprising a consecutive series of women affected by recto-sigmoid DE, who underwent medical treatment with Dienogest (2 mg daily continuous). All women underwent clinical visits and transvaginal sonography (TVS) with bowel preparation prior to starting therapy and at 3–6-month intervals for at least 12 months. Clinical complaints such as dysmenorrhea, dyspareunia and dyschezia were assessed using a visual analog scale (VAS). The DE recto-sigmoid lesion was measured in the three orthogonal planes. The lesion’s volume was estimated using the prolate ellipsoid formula. The maximum diameter and lesion volume were used for analysis. Patients’ complaints and lesion sizes before starting the treatment and at final follow-up were compared. Results: From January 2017 to July 2020, 125 patients were consecutively recruited (mean age: 37 years, ranging from 20 to 50 years). The median follow-up period was 47.8 months (range: 12–74 months). We did not observe a significant correlation between the severity of the symptoms and the lesion size prior to starting therapy. Clinical complaints improved significantly during treatment (88% of women were symptomatic at initial visit, versus 53% at final follow-up, p < 0.001). The median lesion volume significantly decreased (median initial volume vs. final volume: 1.1 mL vs. 0.9 mL, p = 0.017). However, the median maximum lesion diameter did not change significantly (26.0 mm vs. 25.0 mm, p = 0.779). Conclusions: Long-term Dienogest therapy significantly relieves clinical symptoms related to recto-sigmoid DE. This is accompanied by a significant reduction in the lesion volume but not the maximum lesion diameter. Full article

Background: Endometriosis is one of the most common gynecological diseases, affecting up to 10–15% of women of reproductive age. It is a chronic, estrogen-dependent condition that often presents with heterogeneous symptoms, complicating diagnosis and delaying treatment. Methods: This is a narrative review based on a comprehensive analysis of recent literature regarding hormonal treatment options for endometriosis, including primary and adjuvant therapies. Results: Combined oral contraceptives (COCs) are effective in reducing dysmenorrhea, but show limited benefit for other symptoms and may not prevent disease progression. Progestins, particularly dienogest, demonstrate superior long-term efficacy with favorable side-effect profiles. GnRH agonists and antagonists are reserved for second-line treatment due to side effects and hypoestrogenism, but can significantly reduce endometriotic lesions. The levonorgestrel intrauterine system (LNG-IUS) is especially effective in patients with adenomyosis. Conclusions: Hormonal therapies are central to the management of endometriosis. Progestins are considered the most suitable long-term option. Despite promising results, evidence quality varies, and further studies are needed to establish long-term efficacy, patient-specific outcomes, and direct comparisons between agents. Full article

This feasibility study explores the potential of salivary microRNAs (miRNAs) as non-invasive biomarkers for diagnosing endometriosis and assessing treatment response. Almost one-third of patients with endometriosis do not respond to the standard progestin treatment due to various mechanisms of progesterone resistance. MiRNAs, recognized for their stability in body fluids and role in gene regulation, may offer new diagnostic and prognostic opportunities as they are involved in the pathogenic pathways of endometriosis and progesterone resistance. We sequenced salivary miRNAs in three cohorts of patients: control women without endometriosis and patients with endometriosis who responded and did not respond to standard progestin treatment. This aims to identify the differential miRNA expression profiles associated with therapeutic response to dienogest. The preliminary results demonstrate the feasibility of miRNA sequencing from saliva and reveal distinct miRNA profiles between responders, non-responders, and controls. Key miRNAs, including mir-3168, the mir-200a family, and mir-93-5p, emerged as potential biomarkers, showing significant differential expression linked to both endometriosis presence and treatment response. Further validation of these findings in larger cohorts could pave the way for miRNA-based diagnostic and prognostic tools, potentially reducing diagnostic delays and personalizing treatment approaches for endometriosis patients, also with new target therapies. Full article

Background/Objectives: Dienogest 0.5 mg tablets (DNG0.5) taken twice daily (1 mg/day) are more effective than cyclic low-dose estrogen/progestin/combined oral contraceptive (LEP/COC) in ameliorating dysmenorrhea pain and are recommended for dysmenorrhea treatment in Japan. However, their efficacy has not been directly compared with continuous LEP/COC regimens. Here, we evaluated the effectiveness of DNG0.5 compared to Yazflex^® (YZF), a continuous LEP, in treating dysmenorrhea. Methods: The efficacy of DNG0.5 in treating dysmenorrhea was compared retrospectively with that of Yazflex, the longest continuously administered LEP/COC available in Japan. Results: The improvement rates of dysmenorrhea scores at 3 and 6 months post-treatment were 59.1% and 66.4% in the LEP group (n = 113) and 88.1% and 96.4% in the DNG0.5 group (n = 125), respectively. The complete resolution rate of dysmenorrhea at 6 months was 88.0% in the DNG0.5 group and 23.9% in the LEP group. These findings indicate that DNG0.5 was significantly more effective than LEP (p < 0.01). DNG0.5 exerted an early pain-suppressing effect, which continued to increase thereafter. Furthermore, the presence of endometrial polyps, uterine fibroids, or adenomyosis, which are risk factors for irregular genital bleeding, was examined. Among these, endometrial polyps were particularly more likely to cause bleeding and potentially reduce the effect of DNG0.5; however, even with these three risk factors, DNG0.5 was more effective than LEP in reducing pain. Conclusions: Dienogest was more effective than LEP in managing dysmenorrhea, even at a dosage of 0.5 mg twice daily. However, factors affecting irregular vaginal bleeding should be considered when prescribing DNG0.5. Full article

Background/Objectives: Endometriosis affects up to 10% of women of reproductive age and about 47% of adolescents with pelvic pain. Symptoms include dysmenorrhea, dyspareunia, and chronic pelvic pain (CPP). Adolescents often present atypical symptoms that can make endometriosis more difficult to diagnose. This study aimed to compare characteristics of pain, atypical symptoms, and the effects of hormonal treatments between adolescents and adults with endometriosis. Methods: A total of 238 women with endometriosis were included: 92 aged 12–18 (group A) and 146 over 18 (group B). Data on menarches, cycle length, comorbidities, dysmenorrhea, dyspareunia, CPP, analgesic use, pain characteristics, atypical symptoms, and endometrioma size were recorded. The efficacy, compliance, and side effects of hormonal treatments were also assessed. Quality of life (QoL) was measured using the SF-12 questionnaire at baseline and after six months of therapy. Results: Adolescents had earlier menarche (p < 0.001), longer menstrual periods (p < 0.001), and higher analgesic use (p = 0.001) compared to adults. Dysmenorrhea was more frequent (p = 0.01), lasted longer (p < 0.001), and was associated with higher pain scores (p < 0.001) in adolescents. CPP was more common in adolescents (p < 0.001), often described as “confined” (p = 0.04) and “oppressive” (p = 0.038), while adults reported it as “widespread” (p = 0.007). Headaches (p < 0.001) and nausea (p = 0.001) were also more frequent in adolescents. Both groups showed significant improvement in QoL with hormonal treatment (p < 0.001) and reported minimal side effects. Conclusions: Adolescents with endometriosis often present with earlier menarche, longer menstrual periods, more severe dysmenorrhea, and atypical symptoms. Hormonal contraceptives and dienogest are effective and safe treatments that improve pain and QoL. Full article

Endometriosis afflicts 10% of women in their reproductive years and nearly half of women with infertility, and its etiology is not yet clear. Pharmacological therapy is generally based on progestins like progestogen. This drug binds to progesterone receptors with many known side effects. Here, we describe the case of a 33-year-old woman surgically treated for endometriosis who continued with drug therapy based on estradiol valerate and dienogest. Approximately 21 months after treatment, she reported ocular symptoms with vision alteration, diplopia, and metamorphopsia related to central serous chorioretinopathy (CSC). After the discontinuation of combined progestin-based treatment, the CSC fully subsided. Semeiological, clinical, and laboratory approaches were adopted, and urinary steroids were measured. A slight increase in prolactinemia in the absence of macro-prolactinemia was reported. The steroidal profile appeared without abnormalities, although a slight alteration of estrogen balance was noted. Considering the pharmacodynamics of dienogest versus selective progesterone receptor modulators, it can be assumed that patients’ clinical events are related to specific site response to steroids that bind the progesterone receptor. Dienogest may have induced the CSC as a not yet characterized side effect of the drug. Undoubtedly, further specific studies are needed concerning the metabolic and pharmacodynamic aspects that cannot be exhaustively covered here. Full article

Background: This prospective study aims to identify the effect of the dienogest 2 mg/day and aspirin 150 mg/day combined treatment for two months before frozen ET on the assisted reproduction outcome in women with adenomyosis and recurrent implantation failure (RIF). Methods: Patients were selected based on specific criteria and divided into two groups (with and without treatment). Preimplantation biochemical parameters and ultrasonographic features (endometrial thickness, uterine peristalsis, and junctional zone thickness) were compared with pregnancy rate in a non-natural cycle frozen embryo transfer technique. A comparison between the two study groups indicated an increased successful implantation rate and clinical pregnancy rate (25% vs. 7.4%). Results: These results were attributed to the reduced uterine peristalsis and the reduction in thickness of the junctional zone following treatment. Available data were limited due to the nature of the study though maximal effort was exerted for the selected patients between groups to be as demographically similar and free from other potential pathology that may affect the results. Conclusions: In conclusion, it appears that the above stated treatment improves outcomes in women with adenomyosis and RIF; the parameters used may provide an insight as to the reasons why this occurs, though an explanation of the molecular mechanisms is still elusive. Full article

Objective: To provide a brief summary of the high incidence, symptomatology, different types, and diagnosis of adenomyosis and to explore various aspects of the disease, with the primary aim of raising awareness among gynecologists for appropriate and early detection. Background: Adenomyosis, a benign gynecological condition characterized by the infiltration of endometrial tissue into the myometrium, poses significant challenges to women’s reproductive health. Methods: A narrative review was conducted by searching PubMed, Scopus, and Cochrane databases and offering a non-systematic summary and critical analysis of current knowledge on the impact of adenomyosis on women’s health. Articles published in the English language up to May 2023, including original scientific papers, clinical trials, meta-analyses, and reviews focusing on various aspects of adenomyosis, were included in the synthesis of this review. Conclusions: Approximately 20% of women are affected by adenomyosis, which manifests with various subtypes, distinct epidemiological profiles, symptomatology, and treatment responses. Despite its clinical significance, adenomyosis remains understudied, resulting in a significant disparity in research and the literature compared to other gynecological conditions. The severity of adenomyosis is compounded when coexisting with endometriosis, particularly deep-infiltrating endometriosis (DIE), leading to exacerbated fertility issues and severe symptomatology. The wide range of symptoms, including adverse pregnancy outcomes such as pre-eclampsia, highlights its wider impact and emphasizes the need for increased awareness of the condition. Adenomyosis is frequently associated with treatment failure in endometriosis, contributing to dienogest resistance, elevated discontinuation rates, and persistent pain post-endometriosis surgery. Additionally, the lack of specific treatments tailored to adenomyosis poses a considerable challenge in clinical management. Full article

Dysmenorrhea treatment with 0.5 mg dienogest tablets twice daily (1 mg/day) has proven useful, but its effect on premenstrual disorders has not yet been evaluated. This study aimed to evaluate the efficacy of 0.5 mg dienogest tablets in relieving premenstrual syndrome (PMS)-like symptoms during the treatment of dysmenorrhea in comparison with that of continuous low-dose estrogen–progestin (LEP/COC) drospirenone/ethinylestradiol combination, which is considered effective in treating premenstrual dysphoric disorder. During the standard course of dysmenorrhea treatment with dienogest or LEP/COC, PMS-like symptoms were scored based on patients’ reports, and the treatment effects were compared. As a result, the dienogest group experienced a significant improvement in PMS-like symptoms compared with the LEP/COC group over the 6-month study period (p < 0.01). Furthermore, dienogest was more effective in providing relief from PMS-like symptoms, with 89.7% of patients reporting a complete resolution of PMS-like symptoms at 6 months, compared with 47.1% in the LEP/COC group (p < 0.01). These results indicate that dienogest is effective in relieving PMS-like symptoms, similar to LEP/COC. Further studies are needed to determine whether 0.5 mg dienogest tablets, which are only available in Japan, are effective in treating premenstrual disorders diagnosed via standard methods. Full article

Background/Objectives: Adenomyosis is a benign condition characterized by the presence of endometrial tissue within the myometrium. Despite surgery being a valuable approach, medical options are considered as the first-line approach and have been investigated in the treatment of adenomyosis, although strong evidence in favor of these is still lacking. This study aims to gather all available data and determine the effectiveness of the aforementioned medical options in patients with associated pain and not currently seeking pregnancy, both in comparison to placebo and to one another. Methods: For this study, PubMed and EMBASE were used as data sources, searched up to January 2024. A systematic review and meta-analysis were performed in accordance to guidelines from the Cochrane Collaboration. The primary outcomes investigated were changes in dysmenorrhea, quantified by means of VAS scores, HMB in terms of number of bleeding days, and changes in uterine volume determined at ultrasound. Twelve eligible studies were selected. Results: The results highlighted that dienogest yields a reduction in dysmenorrhea that is significantly superior to that of the rest of the medical treatments investigated (p-value of <0.0002). On the other hand, GnRH agonists seem to play a more prominent role in reducing uterine volume (p-value of 0.003). While it was not possible to determine which medical treatment better decreased the number of bleeding days, it was observed that COC performed significantly worse than the other treatments studied (p-value of 0.02). Conclusions: While this meta-analysis provides valuable insights in the comparative efficacy of different treatments, the paucity of relevant studies on the topic might impact the reliability of some of the conclusions drawn. Full article

There are fewer investigations conducted on human primary endometrial epithelial cells (HPEECs) compared to human primary endometrial stromal cells (HPESCs). One of the main reasons is the scarcity of protocols enabling prolonged epithelial cell culture. Even though it is possible to culture HPEECs in 3D over a longer period of time, it is technically demanding. In this study, we successfully established a highly pure, stable, and long-term viable human conditionally reprogrammed endometrial epithelial cell line, designated as eCRC560. These cells stained positive for epithelial markers, estrogen and progesterone receptors, and epithelial cell–cell contacts but negative for stromal and endothelial cell markers. Estradiol (ES) reduced the abundance of ZO-1 in a time- and dose-dependent manner, in contrast to the dose-dependent increase with the progestin dienogest (DNG) when co-cultured with HPESCs. Moreover, ES significantly increased cell viability, cell migration, and invasion of the eCRC560 cells; all these effects were inhibited by pretreatment with DNG. DNG withdrawal led to a significantly disrupted monolayer of eCRC560 cells in co-culture with HPESCs, yet it markedly increased the adhesion of eCRC560 to the human mesothelial MeT-5A cells. The long-term viable eCRC560 cells are suitable for in vitro analysis of HPEECs to study the epithelial compartment of the human endometrium and endometrial pathologies. Full article

Although endometriosis is a benign disease, it is associated with cancer-related gene mutations, such as KRAS or PIK3CA. Endometriosis is associated with elevated levels of inflammatory factors that cause severe pain. In a previous study, we demonstrated that KRAS or PIK3CA mutations are associated with the activation of cell proliferation, migration, and invasion in a patient-derived immortalized endometriotic cell line, HMOsisEC10. In this study, we investigated the effects of these mutations on progesterone resistance. Since the HMOsisEC10 had suppressed progesterone receptor (PR) expression, we transduced PR-B to HMOsisEc10 cell lines including KRAS mutant and PIK3CA mutant cell lines. We conducted a migration assay, invasion assay, and MTT assay using dienogest and medroxyprogestrone acetate. All cell lines showed progesterone sensitivity with or without mutations. Regarding inflammatory factors, real-time quantitative RT-PCR revealed that the KRAS mutation cell line exhibited no suppression of Cox-2 and mPGES-1 on progesterone treatment, whereas IL-6, MCP-1, VEGF, and CYP19A1 were significantly suppressed by progesterone in both mutated cell lines. Our results suggest that KRAS mutation and PIK3CA mutation in endometriotic cells may not be associated with progesterone resistance in terms of aggressiveness. However, KRAS mutations may be associated with progesterone resistance in the context of pain. Full article

Endometriosis is a common gynecological condition with a complex physio-pathological background. This study aimed to assess the role of Rubus idaeus leaf extract (RiDE) as a potential therapeutic agent in reducing the size of the endometriotic lesions and modulate the plasma expression of MMP-2, MMP-9, and TGF-β1. The endometriotic lesions were induced in a rat model by the autologous transplant of endometrium. Thirty-six female rats, Wistar breed, with induced endometriosis, were divided into four groups and underwent treatment for 28 days. The CTRL group received 0.5 mL/day of the vehicle; the DG group received 1 mg/kg b.w./day dienogest; the RiDG group received 0.25 mL/kg b.w./day RiDE and the D+RiDG group received 1 mg/kg b.w./day dienogest and 0.25 mL/kg b.w./day RiDE, respectively. Rats’ weight, endometriotic lesion diameter and grade, and plasma levels of MMP-2, MMP-9, and TGF-β1 were assessed before and after treatment. The administration of RiDE in association with dienogest vs. dienogest determined a lower weight gain and a reduction in diameter of the endometriotic lesions. RiDE administration restored MMP2 and MMP9 plasma levels to initial conditions. Rubus idaeus extract may help in reducing dienogest-associated weight gain, lower the size of endometriotic lesions, and have anti-inflammatory effects through MMP2 and MMP9 reduction. Full article

A comparative analysis of the cytostatic effects of progestins (gestobutanoyl, megestrol acetate, amol, dienogest, and medroxyprogesterone acetate), glucocorticoids (hydrocortisone, dexamethasone), and diclofenac on tumor cells was carried out in order to confirm their in silico predicted probabilities experimentally. The results showed the different sensitivity of HeLa, MCF-7, Hep-2, K-562, and Wi-38 cell lines to progestins, glucocorticoids, and diclofenac. The minimum IC₅₀ was found for progestin gestobutanoyl (GB) as 18 µM for HeLa cells, and varied from 31 to 38 µM for MCF-7, Hep-2, and K-562. Glucocorticoids and diclofenac were much less cytotoxic in the HeLa, MCF-7, and Hep-2 cell lines than progestins, with IC₅₀ values in the range of 150–3000 μM. Myelogenous leukemia K-562 cells were the least sensitive to the action of progestins and glucocorticoids but the most sensitive to diclofenac, which showed a pronounced cytotoxic effect with an IC₅₀ of 31 μM. As we have shown earlier, progestins can uniquely modulate MPTP opening via the binding of adenine nucleotide translocase. On this basis, we evaluated the expression of adenylate nucleotide translocase ANT1 (SLC25 A4) as a possible participant in cytotoxic action in these cell lines after 48 h incubation with drugs. The results showed that progestins differently regulated ANT1 expression in different cell lines. Gestobutanoyl had the opposite effect on ANT1 expression in the HeLa, K562, and Wi-38 cells compared with the other progestins. It increased the ANT1 expression more than twofold in the HeLa and K562 cells but had no influence on the Wi-38 cells. Glucocorticoids and diclofenac increased ANT1 expression in the Wi-38 cells and decreased it in the K562, MCF-7, and Hep-2 cells. The modulation of ANT1 expression discovered in our study can be a new explanation of the cytotoxic and cytoprotective effects of hormones, which can vary depending on the cell type. ANT isoforms in normal and cancerous cells could be a new target for steroid hormone and anti-inflammatory drug action. Full article