Estradiol valerate 2mg / Dienogest 3mg tablets

Background: Endometriosis, PCOS, adenomyosis, and dysmenorrhea are major illnesses. Hormonal as well as non-hormonal treatments were evaluated for COCs, progestins, GnRH analogues, LNG-IUS, relugolix, and adjunctive therapies. These treatments resulted in the categorization of the benefits in varying degrees. Methods: 149 clinical trials have been included. Evaluating the methodological quality was done through the Jadad scale, while the GRADE criteria were used to assess the reliability of the evidence. When these data were available, effect sizes, standardized mean differences (SMD), 95% confidence intervals (CI), and p-values were extracted. Results: It was observed that COCs and progestins considerably lowered pelvic pain and menstrual irregularities (SMD -0.35 to -0.58, 95% CI -0.90 to -0.08, p<0.05), and among various trials, dienogest was reported to be the most effective in alleviating dysmenorrhea (SMD -0.58, 95% CI -0.90 to -0.26, p<0.001). The use of relugolix in combination resulted in considerable pain reduction related to endometriosis (SMD -0.72, 95% CI -0.94 to -0.50, p<0.001), and the study was rated as excellent quality with GRADE and Jadad scores of 5. GnRH analogs led to pain reduction all the time (SMD -0.65, 95% CI -0.88 to -0.42, p<0.001), while the application of LNG-IUS was linked to less menorrhagia and lower recurrence after surgery (RR 0.51, 95% CI 0.33-0.79, p=0.002). Besides the main treatments, usage of the like of antioxidants, NAC, melatonin, and digital therapeutics, too, gave extra pain relief and quality-of-life benefits (SMD -0.40 to -0.62, p<0.05). the studies frequently proved to have a very rigorous quality of methodology (Jadad 3-5) and moderate-to-high grade certainty of evidence (GRADE). Conclusions: Endometriosis disorder have been treated well with hormonal therapies. Different endocrine therapies based on the patient's specific characteristics and the degree of tolerability should be used to achieve the maximum effect of clinical outcomes.

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Research Topic seeks to bring renewed clarity to how different estrogen-progestin combinations influence venous thromboembolism (VTE) risk. Beyond simply comparing formulations, it invites a broader reflection on the pharmacokinetic and pharmacodynamic properties of these hormones and how they shape the coagulation response. Ultimately, it raises an important question for the future of women's health: could dedicated screening tools or biomarkers help identify women at higher thrombotic risk before initiating COCs, and thereby guide safer contraceptive choices? Historically, COC formulations relied almost exclusively on synthetic estrogens-most commonly ethinyl estradiol (EE)-combined with various progestins. In recent years, however, the introduction of body identical estrogens, such as estradiol (E2) (and its valerate form) and estetrol (E4), have reshaped the landscape of COC development and reopened the discussion on estrogen choice. Comparative evaluations of estrogenic components used in hormonal contraception indicate that natural estrogens, particularly E4, offer notable advantages in terms of metabolic safety and tolerability, while exerting a reduced hepatic impact and a lower associated risk of VTE (2). Within this Research Topic, the review and meta-analysis by Douxfils The ESCONEC aims to articulate a clear rationale for shifting toward natural estrogens in COCs.By more closely reflecting the physiology of natural estrogens, E2(V) and E4 reduce hepatic burden and support a more favorable balance across coagulation, lipid, and bone health markers. Yet current contraceptive guidelines have not fully integrated the increasing body of evidence supporting their use. The project seeks to bridge this gap and stimulate a renewed, evidence-based dialogue on estrogen choice in women's health (6).The choice of progestin also plays a pivotal role. As highlighted by Gaspard et al. (7), progestins differ markedly in their pharmacokinetics, metabolic pathways, and receptor-binding profiles, confirming the absence of a class effect. In the context of EE-containing COCs, EE/levonorgestrel has consistently been associated with the lowest VTE risk. This apparent advantage, however, is largely driven by the androgenic properties of levonorgestrel, which partially counteract EEinduced increases in SHBG and hepatic protein synthesis. By contrast, combinations such as EE/desogestrel or EE/drospirenone-which involve less androgenic or even anti-androgenic progestins-allow the full hepatic impact of EE to be expressed, resulting in a higher thrombotic risk. Importantly, this does not reflect a genuinely favorable hemostatic profile for levonorgestrel itself, but rather a relative mitigation within an intrinsically high-risk EE environment.A different picture emerges when EE is replaced by natural estrogens such as E2(V) or E4. In this context, the properties of the progestin become essential in maintaining the inherently lower hepatic impact of these hormones. Non-androgenic or anti-androgenic progestins such as nomegestrol acetate, dienogest and drospirenone are particularly well suited to body identical estrogens. These progestins exhibit no affinity for SHBG and exert minimal hepatic stimulation, thereby avoiding the amplification of coagulation factors typically driven by EE. Their neutral-or even favorable-hemostatic profiles allow the intrinsic advantages of body identical estrogens to be fully expressed, including reduced SHBG induction, lower activated protein C(APC) resistance, and attenuated thrombin generation (8). As a result, combinations such as E2/nomegestrol acetate, E2V/dienogest, or E4/drospirenone create a more physiological endocrine environment and consistently demonstrate lower thrombotic signals across clinical studies, real-world pharmacovigilance, and mechanistic hemostasis data.Finally, the cost-effectiveness analysis conducted by Douxfils (9) adds an important societal dimension. His findings show that implementing a screening strategy prior to COC initiation could not only prevent thrombotic events but also yield substantial economic benefits for healthcare systems. It is estimated that replacing EE with E2 or E4 in COCs could prevent between 7,000 and 10,000 VTE cases annually in the European Union, potentially saving 400 to 600 lives per year. This evidence underscores the broader public health value of moving toward more individualized, and ultimately safer, contraceptive prescribing.Together, the evidence presented in this Research Topic converges toward a simple yet compelling message: estrogen choice matters. Body identical estrogens, when associated with non-androgenic or anti-androgenic progestins, offer a more physiological and ultimately safer alternative to conventional EE-based COCs, with reduced hepatic stimulation. They show that elevated thrombotic risk should no longer be viewed as an unavoidable consequence of COC use.As clinical, mechanistic, real-world, and economic data now align in favor of these newer combinations, the challenge ahead lies not in generating further evidence, but in translating it into practice. Updating contraceptive guidelines, developing individualized screening strategies, and ensuring equitable access to safer formulations will be essential steps in this evolution. The shift toward body identical estrogen-based COCs is no longer a theoretical proposition -it is an evidence-driven opportunity to improve women's health on a global scale.

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BACKGROUND: The treatment of endometriosis includes analgesics, hormone therapy, and surgery. Even after surgical removal of endometriotic lesions, the risk of recurrence remains high once the normal menstrual cycle resumes. Therefore, long-term hormone therapy is essential to prevent recurrence. Among hormonal treatments, low-dose estrogen progestin preparations are not recommended for patients older than 40 years due to the increased risk of thrombotic side effects. In contrast, dienogest does not carry a thrombotic risk, making it a suitable option for older patients. Although dienogest requires long-term administration until menopause in patients with endometriosis, data on its long-term efficacy and potential adverse effects remain limited. In particular, comparative studies assessing the safety and effectiveness of long-term use of dienogest at different doses (1 mg/day vs 2 mg/day) have not been conducted, highlighting the need for further investigation. OBJECTIVE: The purpose of this study is to investigate the efficacy and the incidence of adverse events of dienogest 1 mg/day after 48 weeks in patients with dysmenorrhea due to endometriosis, compared with dienogest 2 mg/day. METHODS: This randomized, open-label, parallel-group, dose-comparison, multicenter trial follows the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 guidelines and is conducted at 6 centers in Japan. Participants are randomly assigned in a 1:1 ratio to receive either dienogest 1 mg/day or 2 mg/day. The drug is administered for 48 weeks, and its therapeutic effects and side effects are evaluated. Hospital visits include the use of questionnaires, vital sign measurements, imaging studies (magnetic resonance imaging and ultrasound), blood tests, and bone density assessments. The primary endpoint is the change in the pain visual analog scale (VAS) score from baseline to 48 weeks. The VAS is a 10 cm horizontal scale where 0 cm represents no pain and 10 cm represents the maximum imaginable pain; participants indicate their pain level on the scale, and the change is analyzed over time. The target sample size is 88, determined with a noninferiority margin based on existing literature. The protocol was approved by the Nagoya City University Hospital Clinical Research Review Board. Findings will be presented at academic conferences and published in peer-reviewed journals. RESULTS: Currently, data collection is ongoing. The first participant was enrolled in August 2021. As of March 22, 2025, a total of 88 participants had been enrolled in this clinical trial. CONCLUSIONS: This is the first trial to compare efficacy and safety between 1 mg/day and 2 mg/day of long-term dienogest use in patients with dysmenorrhea caused by endometriosis. Combining diagnostic imaging with patient questionnaires and blood tests allows the determination of efficacy against endometriosis itself. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs041210016; https://jrct.mhlw.go.jp/en-latest-detail/jRCTs041210016. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/66246.

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INTRODUCTION: Dienogest (DNG) is widely used to manage endometriosis-associated pain; however, long-term data comparing low and standard doses are limited. Therefore, this study aimed to evaluate the efficacy and safety of 48-week DNG treatment (1 mg/day vs. 2 mg/day) in patients with endometriosis-related dysmenorrhea (composite score). METHODS: In this randomized, open-label, parallel-group, trial, 88 patients with endometriosis were enrolled, all of whom had at least one ovarian endometriotic cyst confirmed by imaging. Other phenotypes of endometriosis, such as deep infiltrating or peritoneal lesions, were not systematically assessed and may have been present. Patients were randomized to receive either 1-mg/day or 2-mg/day DNG. The primary endpoint was the change in menstrual pain measured using a visual analog scale (VAS). Secondary endpoints included changes in the dysmenorrhea score, ovarian endometrioma volume, serum estradiol levels, bone mineral density (BMD), and menopausal symptoms. RESULTS: Both groups demonstrated a significant reduction in menstrual pain (VAS). The mean VAS scores decreased by 44.63 and 54.19 mm in the 1-mg and 2-mg groups, respectively. However, the between-group difference (- 9.57 mm; 95% confidence interval: - 22.7 to 3.56) was not above the predefined non-inferiority margin of - 15 mm; thus, non-inferiority of the 1-mg dose could not be confirmed. Improvements in dysmenorrhea scores and endometrioma volume were also observed in both groups, although greater effects were noted in the 2-mg group than in the 1-mg group. Serum estradiol suppression was comparable between the groups, whereas BMD loss was less pronounced in the 1-mg group than in the 2-mg group. CONCLUSIONS: This study did not demonstrate statistical non-inferiority of 1-mg/day DNG treatment over 2-mg/day DNG treatment for pain relief. These results suggest that the 2-mg/day dose may offer more robust analgesic effects, particularly during the early treatment phase. However, 1-mg/day DNG still showed meaningful symptom improvement with fewer adverse events than 2-mg/day DNG, supporting its potential use in selected patients requiring long-term therapy. Trial Registration Japan Registry of Clinical Trials, trial registration number: jRCTs041210016.

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Adenomyosis, an estrogen-dependent disorder, requires long-term therapy as current treatments (GnRH agonists, danazol, etc.) show symptom recurrence post-discontinuation. Dienogest (DNG), a selective progesterone receptor agonist, effectively reduces adenomyosis-related pain but causes abnormal uterine bleeding (AUB) in some patients, likely due to pseudodecidual breakthrough bleeding, significantly impacting treatment compliance. This review examines risk factors for DNG-associated AUB and advances in management strategies to improve patient adherence during prolonged therapy.

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Objective: To review the real benefits of using combined oral contraceptives (COCs) containing natural hormones, also known as estradiol-containing COC (estradiol and estradiol valerate) in controlling abnormal uterine bleeding (AUB) compared to the already established data on treatment with combined pills containing ethinylestradiol (EE). Methods: Narrative review with analysis of studies published between 2010 and 2023, comparing the effects of EE and natural estrogen in the treatment of AUB, indexed in the PUBMED, WebOfScience, and Scielo databases. Results: A total of 342 articles were found in the selected databases. Of these, 235 articles were excluded because they were published before 2010 or lacked an explicit relationship with the topic; 107 articles were selected for title and abstract screening, of which 27 were fully read by the researchers, and 6 were included in the study. It was observed that the use of natural estrogens is effective in controlling abnormal uterine bleeding, often with fewer side effects and less cardiovascular and prothrombotic impact compared to ethinylestradiol (EE). However, some non-contraceptive benefits of EE, such as less water retention, improved skin oiliness, and acne, were not consistently observed with the use of natural estrogens. Conclusion: Estradiol-containing COC have proven to be effective in controlling AUB, in addition to reducing spotting and intermenstrual bleeding, with fewer undesirable side effects when compared to COCs with EE. On the other hand, COCs with estradiol and estradiol valerate less frequently present other non-contraceptive benefits.

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