Endometriosis is defined as the presence of endometrial-like glands and stroma outside of the uterus. There are three types of endometriotic lesions: superficial or peritoneal endometriosis, ovarian endometrioma, and deep infiltrating disease. Endometriosis not only occurs in the pelvis but also can be found in extrapelvic sites such as the gastrointestinal tract, upper abdominal viscera, genitourinary tract, abdominal wall, diaphragm, and thoracic cavity. After thorough history and physical examination is performed, imaging, such as ultrasound or magnetic resonance imaging (MRI), should be obtained if there is high suspicion for deep-infiltrating endometriosis to better assess visceral involvement. Endometriosis can be suspected based on symptoms, physical examination findings, and imaging. However, a definitive diagnosis requires histopathologic confirmation. Treatment options include expectant, medical, and surgical management. Endometriosis is largely a quality-of-life issue, and treatment should be tailored accordingly with empiric medical therapy frequently utilized. Medical management focuses on symptom improvement. Surgical management with excision of endometriosis is preferred over ablation or fulguration of endometriotic lesions. In the case of deep or extrapelvic endometriosis, treatment with a multidisciplinary team with experience in the treatment of advanced-stage endometriosis is essential to minimizing morbidity and increasing long-term success.

To evaluate the effectiveness of various medications for the treatment of endometriosis-related pain through a network meta-analysis.

A comprehensive search was conducted in PubMed, Embase, Web of Science, and the Cochrane Controlled Trials Register until July 22, 2024. We also searched ClinicalTrials.gov for additional data on recently completed trials or potentially eligible randomized controlled trials (RCTs) but found nothing.

The analysis included randomized RCTs that used pharmacologic interventions for managing endometriosis-related pain. The primary efficacy outcome was endometriosis-associated pelvic pain, which included dysmenorrhea, dyspareunia, and nonmenstrual pelvic pain. The analysis adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines.

A total of 31 RCTs involving 8,665 patients were included in the analysis. In terms of endometriosis-associated pelvic pain, four interventions demonstrated significantly greater efficacy compared with placebo: leuprolide combined with combined oral contraceptive pills (OCPs) (standardized mean difference [SMD] -1.40, 95% CI, -2.41 to -0.38), dienogest (SMD -1.20, 95% CI, -1.78 to -0.61), leuprolide alone (SMD -1.05, 95% CI, -1.64 to -0.45), and combined OCP (SMD -0.67, 95% CI, -1.25 to -0.09). Leuprolide combined with combined OCP emerged as the most effective treatment modality. In addition, elagolix and the combination of vitamin C and vitamin E were identified as the most effective interventions for dysmenorrhea and dyspareunia. For nonmenstrual pelvic pain, gestrinone demonstrated superior efficacy compared with placebo and all other interventions.

This network meta-analysis indicates that leuprolide in combination with combined OCP, elagolix, vitamins C and E, and gestrinone may represent the most effective therapeutic options for alleviating endometriosis-associated pelvic pain, dysmenorrhea, dyspareunia, and nonmenstrual pelvic pain. These findings enhance our understanding of the relative efficacy of treatment strategies for pain associated with endometriosis. Future research should focus on conducting larger-scale and rigorously designed clinical trials within the target patient populations to further validate these results.

Dienogest is a synthetic fourth-generation progestin that has been approved for the medical treatment of endometriosis, and its efficacy on pain symptoms and quality of life is well established even in the long term. Nowadays, only a few controlled trials evaluating the safety of dienogest compared with other hormonal therapies have been published. This systematic review and meta-analysis aims to compare efficacy and tolerability data between dienogest and combined oral contraceptives (COC) in patients taking hormonal therapy for endometriosis treatment in order to inform evidence-based guidelines.

PubMed (Medline), Web of Science, and Google Scholar were systematically searched from the inception of each database until October 2024. Selection criteria included any articles comparing efficacy outcomes and at least one tolerability data between dienogest and COC in patients diagnosed with endometriosis. Studies comparing COC containing Dienogest or another type of hormonal treatment were excluded. A random-effects meta-analysis was conducted if adequate data were available from at least three studies, reporting pooled mean differences and odds ratios between groups using Review Manager V.7.9.0. PROSPERO registration number: CRD42024598455.

A total of four randomized control trials and one observational study were included, showing moderate risk at bias assessment. Meta-analysis did not show any statistical difference in improving pelvic pain after treatment [CI 95% (-1.45-1.17); I2 = 86%; p = 0.84]. In contrast, dyspareunia after treatment was significantly lower in the COC group [CI 95% (0.64-1.33); I2 = 0%; p < 0.00001]. No statistical difference was found in terms of vaginal bleeding [OR = 0.88; CI 95% (0.39-1.96); I2 = 41%; p = 0.75], nausea and vomiting [OR = 0.51; CI 95% (0.16-1.63); I2 = 67%; p = 0.26], headache [OR = 0.91; CI 95% (0.38-2.21); I2 = 59%; p = 0.84], hot flushes [OR = 1.16; CI 95% (0.54-2.48); I2 = 0%; p = 0.71], and hair loss [OR = 1.69; CI 95% (0.52-5.53); I2 = 46%; p = 0.39]. Treatment discontinuation rate was similar between groups.

Dienogest is comparable to COC in terms of efficacy and tolerability. The therapeutic choice should be based on the patient's preference, clinical history, and experience.

Endometriosis is currently considered a systemic inflammatory disease and different non-invasive inflammatory markers, such as cell-free DNA (cfDNA), have recently been evaluated. Hormonal treatments are frequently prescribed as first-line treatments to improve symptoms, reduce lesions and improve the quality of life of patients with endometriosis. The most frequently used hormonal treatments are estroprogestins and progestins due to their effectiveness and well-tolerated clinical profile. However, the impact these hormonal treatments may have on these markers has yet to be determined. The aim of this study was to assess whether cfDNA levels are modified under the two main first-line hormonal treatments in patients with deep endometriosis (DE).

Ninety patients diagnosed with DE were analyzed in this prospective, observational study. Forty-five received daily oral treatment with dienogest 2 mg, and 45 with 2 mg dienogest/30 μg ethinylestradiol. Plasma cfDNA levels were evaluated by fluorescent assay prior to initiation of treatment and at 6 and 12 months of treatment.

An increase in cfDNA levels was observed during the follow-up at 6 and 12 months. However, these higher levels were only statistically significant at 12 months of treatment. The increase of cfDNA levels was similar with both treatments.

Higher cfDNA levels were observed in DE patients at 12 months of oral hormonal treatment showing similar results with dienogest or dienogest/ethinylestradiol. This increase could be explained by apoptosis of the endometriosis foci due to the treatment.

Endometriosis and pelvic inflammatory disease (PID) are gynecological conditions affecting women of reproductive age and causing pain symptoms. The symptoms caused by these conditions are similar; thus, the differential diagnosis may be challenging. The treatment of these conditions is very different because PID is treated with antibiotic therapy, while endometriosis is treated with hormonal therapies suppressing estrogen levels.

A narrative review was conducted through a comprehensive literature search on endometriosis and PID. The search strategy incorporated relevant keywords and MeSH terms related to these topics.

The antibiotics used to manage PID have high efficacy and safety profiles. Commonly prescribed regimens include a combination of ceftriaxone, doxycycline, and metronidazole. These antibiotics are generally well-tolerated, with most adverse effects being mild and manageable (gastrointestinal disturbances or hypersensitivity reactions). Hormonal therapies are a cornerstone in the management of endometriosis; they include combined oral contraceptives (COCs), progestins, gonadotropin-releasing hormone (GnRH) agonists, and antagonists. COCs and progestins are generally well-tolerated with a favorable safety profile, though they may cause side effects (breakthrough bleeding and mood changes). Oral GnRH antagonists have emerged as a noteworthy option, offering partial estrogen suppression and thereby overcoming the limitations associated with previously used GnRH agonists.

To investigate the impact of preoperative hormonal medication, including combined oral contraceptives or dienogest, on operative findings in ovarian endometrioma surgery.

A single-center, retrospective study.

Department of Gynecology, Samsung Medical Center, Republic of Korea.

Among patients who underwent ovarian endometrioma surgery for the first time at Samsung Medical Center between January 2020 and July 2023, those who started hormonal medication at another institution before their initial visit to our center, those with a waiting period of less than 3 months until the surgery date, and those with an endometrioma size of less than 4 cm at the initial visit were excluded. A total 140 remaining patients were included in the study. The patients were divided into two groups: the group that received preoperative hormonal medication (combined oral contraceptives or dienogest) and the group that did not receive medication.

To evaluate the impacts of preoperative hormonal medication on ovarian endometrioma patients, the operative findings were compared between the groups.

Of the 140 patients, 65 were in the no-medication group and 75 were in the medication group. Except for the median duration of follow-up and age, there were no differences in the baseline characteristics between the two groups. Operative findings were quantified using the revised American Society for Reproductive Medicine score. Although medication significantly reduced the size of the ovarian endometrioma, there were no significant differences in revised American Society for Reproductive Medicine score between the two groups. However, the medication group experienced significant preoperative pain relief.

Preoperative hormonal medication can reduce the size of ovarian endometriomas but does not significantly affect the overall operative findings. Nevertheless, preoperative medication is helpful in reducing pain in patients before surgery.

Background/Objectives: Endometriosis is a chronic condition that affects 6-10% of women of reproductive age, with pain and infertility being its primary symptoms. The most common aspects of pain are overall pelvic pain, dysmenorrhea, and dyspareunia. Our aim was to compare the available medical treatments for endometriosis-related pain. Methods: A systematic search was conducted in three medical databases to assess available drug options for pain management. Randomized controlled trials (RCTs) investigating various medical treatments for endometriosis-related pain on different pain scales were included. Results were presented as p-scores and, in cases of placebo controls, as mean differences (MD) with 95% confidence intervals (CI). From the available data, a network meta-analysis was carried out. Results: The search yielded 1314 records, of which 45 were eligible for data extraction. Eight networks were created, and a total of 16 treatments were analyzed. The highest p-score, meaning greatest pain relief (p-score: 0.618), for the treatment of dysmenorrhea was achieved using gonadotropin-releasing hormone (GnRH) agonists for 3 months on a scale of 0-100. Additionally, a p-score of 0.649 was attained following a 6-month treatment with GnRH agonists combined with hormonal contraceptives (CHCs). In the case of dyspareunia on a scale of 0-100 following 3 months of treatment, CHCs (p-score: 0.805) were the most effective, and CHCs combined with aromatase inhibitors (p-score: 0.677) were the best treatment option following 6 months of treatment. In the case of overall pelvic pain, CHCs (p-score: 0.751) yielded the highest p-score on a scale of 0-100 following 3 months of treatment, and progestins combined with aromatase inhibitors (p-score: 0.873) following 6 months of treatment. Progestins (p-score: 0.901) were most effective in cases of overall pelvic pain on a scale of 0-3 following 3 months of treatment. Conclusions: Our network meta-analysis showed that in cases of dysmenorrhea, GnRH agonists supplemented with CHCs reduced pain the most following 3 months of treatment. Regarding dyspareunia CHCs were most effective, and in the case of overall pelvic pain, CHCs or progestins combined with aromatase inhibitors yielded the most desirable results.

To evaluate the efficacy and safety of 24-week cyclic administration of estetrol (E4) (15 mg)/drospirenone (DRSP) (3 mg) in Japanese patients with endometriosis.

A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

Twenty-five study centers in Japan.

A total of 162 Japanese women diagnosed with endometriosis.

Participants were randomly allocated to the E4/DRSP group or the placebo group. In the E4/DRSP group, participants were orally administered one tablet containing E4 (15 mg) and DRSP (3 mg) daily for 24 days, followed by one placebo tablet for 4 days for a hormone-free interval, constituting a 1-cycle regimen. One placebo tablet was administered once daily for 28 days to participants in the placebo group. The treatments were continued for six cycles (24 weeks) throughout the confirmatory period.

Changes in visual analogue scale (VAS) scores for the most severe pelvic pain (lower abdominal and back pain) from baseline to six treatment cycles at the end of the confirmatory study period.

Estetrol/drospirenone showed changes in the mean VAS scores for the most severe pelvic pain (-33.2 mm) from baseline to the end of the 6-cycle treatment. The between-group difference was significant (-8.5 mm; 2-sided 95% confidence interval, -16.1 to -0.9 mm), showing superiority to placebo. The responder rates, ≥30% and ≥50% reductions in the VAS scores from baseline, were higher in the E4/DRSP group than in the placebo group: 53.2% vs. 29.6% and 36.4% vs. 12.3%. Objective gynecological findings (induration of the cul-de-sac, pelvic tenderness, and limited uterine mobility) were significantly improved by E4/DRSP treatment, and the proportions of stable and worsened participants were significantly lower than in the placebo group. Estetrol/drospirenone decreased the size of endometriomas and improved quality of life, on the basis of quality of life-related questionnaires and global impression scores. No safety concerns were observed with E4/DRSP treatment. Few differences were observed in the proportion of participants with hemostasis parameters outside the reference range between the E4/DRSP and placebo groups.

Estetrol/drospirenone effectively treats endometriosis-associated pain and improves gynecological findings. Estetrol/drospirenone may be a safe, new option for endometriosis treatment with a potentially decreased risk of thromboembolic events.

jRCT2011210027.

Endometriosis, a common cause for chronic pelvic pain, significantly affects quality of life, fertility, and overall productivity of those affected. Therapeutic options remain limited, and collating evidence on treatment efficacy is complicated. One reason could be the heterogeneity of assessed outcomes in nonsurgical clinical trials, impeding meaningful result comparisons. This systematic literature review examines outcome domains and patient-reported outcome measures (PROMs) used in clinical trials. Through comprehensive search of Embase, MEDLINE, and CENTRAL up until July 2022, we screened 1286 records, of which 191 were included in our analyses. Methodological quality (GRADE criteria), information about publication, patient population, and intervention were assessed, and domains as well as PROMs were extracted and analyzed. In accordance with IMMPACT domain framework, the domain pain was assessed in almost all studies (98.4%), followed by adverse events (73.8%). By contrast, assessment of physical functioning (29.8%), improvement and satisfaction (14.1%), and emotional functioning (6.8%) occurred less frequently. Studies of a better methodological quality tended to use more different domains. Nevertheless, combinations of more than 2 domains were rare, failing to comprehensively capture the bio-psycho-social aspects of endometriosis-associated pain. The PROMs used showed an even broader heterogeneity across all studies. Our findings underscore the large heterogeneity of assessed domains and PROMs in clinical pain-related endometriosis trials. This highlights the urgent need for a standardized approach to both, assessed domains and high-quality PROMs ideally realized through development and implementation of a core outcome set, encompassing the most pivotal domains and PROMs for both, stakeholders and patients.

Contraceptive methods are well-established in their ability to prevent pregnancy and increase individual agency in childbearing. Evidence suggests that contraceptives can also be used to treat adverse conditions associated with menstruation, including abnormal and prolonged uterine bleeding, heavy menstrual bleeding, painful menstruation, endometriosis, uterine fibroids, and premenstrual dysphoric disorders.This review investigates the effects of contraceptive techniques such as contraceptive pills, and long-acting reversible contraceptives (e.g. intrauterine devices, implants) on menstrual morbidity.

Over ten databases with no geographical boundaries were searched from inception until October 2023. Study designs were one of the following types to be included: parallel or cluster randomised controlled trials, controlled clinical trials, controlled before and after studies, interrupted time series studies, cohort or longitudinal analyses, regression discontinuity designs, and case-control studies. Ten team members screened the papers in pairs with a Kappa score of more than 7, and Covidence was used. Conflicts were resolved by discussion, and the full papers were divided among the reviewers to extract the data from eligible studies.

Hormonal contraceptives are considered a well-tolerated, non-invasive, and clinically effective treatment for abnormal and prolonged uterine bleeding, heavy menstrual bleeding, painful menstruation, endometriosis, uterine fibroids, and premenstrual dysphoric disorders. Our studies investigating quality of life or well-being in women with heavy menstrual bleeding, endometriosis, or uterine fibroids have found improvements in all dimensions assessed.

Hormonal contraceptives significantly reduce pain, symptom severity, and abnormal bleeding patterns associated with women who suffer from heavy menstrual bleeding, endometriosis, and uterine fibroids.

Endometriosis is one of the most frequent gynecologic disorders. The pathognomonic symptom of endometriosis is pelvic pain. The recommended pain medications are oral hormonal contraceptives, progestin therapy, danazol, gonadotropin-releasing hormone analogs, nonsteroidal anti-inflammatory drugs, and aromatase inhibitors. In this study, we aimed to compare the efficiency of costing dienogest (DNG) and low-cost oral contraceptives regarding visual analog scores (VAS) score of pelvic pain and also cancer antigen-125 (CA-125), anti-Mullerian hormone (AMH) levels, and size of endometrioma in the patients with endometriosis which is a chronic disease that requires a lifelong management plan. In our study, 18 to 45-year-old patients presented to our institution's gynecology and obstetrician department for various complaints over 2 years, and endometriosis diagnoses were included. Patients were divided into 3 groups (20 patients in each medication group) according to the given medication: cyclic DNG (Visanne) or 0.03 mg ethinylestradiol combined with 2 mg DNG (Dienille) or estradiol valerate combined with 2 mg DNG (Qlarista). We recorded all patients' CA-125/AMH values and VAS scores of pelvic pain. All patients gave informed consent. There was no statistically significant difference between pre-medication and post-medication levels of CA-125, AMH, VAS score, and cyst size in all groups. However, statistically, significant decreases were seen in the cyst size and VAS score, indicating response to therapy in all groups. In conclusion, we think it is more reasonable to use cost-effective oral contraceptive medications, which also cause common side effects, instead of costing DNG since all drugs have the same efficiency and success.

To assess the reporting quality of published RCT abstracts regarding patients with endometriosis pelvic pain and investigate the prevalence and characteristics of spin in these abstracts.

PubMed and Scopus were searched for RCT abstracts addressing endometriosis pelvic pain published from January 1st, 2010 to December 1st, 2023.The reporting quality of RCT abstracts was assessed using the CONSORT statement for abstracts. Additionally, spin was evaluated in the results and conclusions section of the abstracts, defined as the misleading reporting of study findings to emphasize the perceived benefits of an intervention or to confound readers from statistically non-significant results. Assessing factors affecting the reporting quality and spin existence, linear and logistic regression was used, respectively.

A total of 47 RCT abstracts were included. Out of 16 checklist items, only three items including objective, intervention and conclusions were sufficiently reported in the most abstracts (more than 95%), and none of the abstracts presented precise data as required by the CONSORT-A guidelines. In the reporting quality of material and method section, trial design, type of randomization, the generation of random allocation sequences, the allocation concealment and blinding were most items identified that were suboptimal. The total score for the quality varied between 5 and 15 (mean: 9.59, SD: 3.03, median: 9, IQR: 5). Word count (beta = 0.015, p-value = 0.005) and publishing in open-accessed journals (beta = 2.023, p-value = 0.023) were the significant factors that affecting the reporting quality. Evaluating spin within each included paper, we found that 18 (51.43%) papers had statistically non-significant results. From these studies, 12 (66.66%) had spin in both results and conclusion sections. Furthermore, the spin intensity increased during 2010-2023 and 38.29% of abstracts had spin in both results and conclusion sections.

Overall poor adherence to CONSORT-A was observed, with spin detected in several RCTs featuring non-significant primary endpoints in obstetrics and gynecology literature.

Endometriosis is a complex and chronic gynaecological disorder that affects millions of women worldwide, leading to significant morbidity and impacting reproductive health. This condition affects up to 10% of women of reproductive age and is characterised by the presence of endometrial-like tissue outside the uterus, potentially leading to symptoms such as chronic pelvic pain, dysmenorrhoea, dyspareunia, and infertility. The Montreux summit brought a number of experts in this field together to provide a platform for discussion and exchange of ideas. These proceedings summarise the six main topics that were discussed at this summit to shed light on future directions of endometriosis classification, diagnosis, and therapeutical management. The first question addressed the possibility of preventing endometriosis in the future by identifying risk factors, genetic predispositions, and further understanding of the pathophysiology of the condition to develop targeted interventions. The clinical presentation of endometriosis is varied, and the correlation between symptoms severity and disease extent is unclear. While there is currently no universally accepted optimal classification system for endometriosis, several attempts striving towards its optimisation - each with its own advantages and limitations - were discussed. The ideal classification should be able to reconcile disease status based on the various diagnostic tools, and prognosis to guide proper patient tailored management. Regarding diagnosis, we focused on future tools and critically discussed emerging approaches aimed at reducing diagnostic delay. Preserving fertility in endometriosis patients was another debatable aspect of management that was reviewed. Moreover, besides current treatment modalities, potential novel medical therapies that can target underlying mechanisms, provide effective symptom relief, and minimise side effects in endometriotic patients were considered, including hormonal therapies, immunomodulation, and regenerative medicine. Finally, the question of hormonal substitution therapy after radical treatment for endometriosis was debated, weighing the benefits of hormone replacement.

To estimate the effect of medical management on the size of ovarian endometriomas.

Online databases were searched from inception to October 2022, including Ovid MEDLINE, Ovid EMBASE, PubMed, EBM Reviews-Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov , and Web of Science.

Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we included all English-language, full-text articles that reported on change in endometrioma size (either diameter or volume) after medical interventions. Studies evaluating surgical interventions or postoperative recurrence were excluded. All screening and data extraction were performed independently by two authors. Risk of bias assessment was performed with either the Cochrane Risk of Bias Tool for randomized controlled trials or a modified Newcastle-Ottawa Scale for observational studies.

After removal of duplicates, 9,332 studies were screened, with 33 full-text articles deemed eligible for inclusion. In the meta-analysis, dienogest showed significant reduction in cyst diameter (reduction 1.32 cm, 95% CI, 0.91-1.73, eight studies, n=418 cysts) and volume (mean difference of log-transformed volume 1.35, 95% CI, 0.87-1.83, seven studies, n=282 cysts). Similarly, significant reductions were seen with the oral contraceptive pill (OCP) (1.06 cm, 95% CI, 0.59-1.53, nine studies, n=455), gonadotropin-releasing hormone (GnRH) agonists (1.17 cm, 95% CI, 0.42-1.92, four studies, n=128 cysts), norethindrone acetate (0.6 cm, 95% CI, 0.27-0.94, two studies, n=88 cysts), and danazol (1.95 cm, 95% CI, 1.18-2.73, two studies, n=34 cysts). Norethindrone acetate with aromatase inhibitor was also effective in reducing endometrioma volume (mean difference of log-transformed volume 1.47, 95% CI, 0.16-2.78, two studies, n=34 cysts).

Medical management with dienogest, OCPs, GnRH agonists, norethindrone acetate, norethindrone acetate with aromatase inhibitor, or danazol can reduce the size of ovarian endometriomas.

PROSPERO, CRD 42022363319.

Endometriosis is a common gynecological disease affecting women of reproductive age. Patients with endometriosis frequently experience severe chronic pain and have higher chances to experience infertility. Progesterone resistance is a major problem that develops during the medical treatment of endometriosis, which often leads to treatment failure of hormonal therapies. Previous studies indicated that the dysregulation of progesterone receptors (PR) is the primary factor leading to progesterone resistance in endometriosis.

This review article systematically reviewed and summarized findings extracted from previously published papers available on PubMed, encompassing both experimental studies and clinical trials.

Various determinants influencing PR expression in endometriosis have been identified, including the environmental toxins, microRNAs, cell signaling pathways, genetic mutations, and the pro-inflammatory cytokines. The selective estrogen/progesterone receptor modulators have emerged as novel therapeutic approaches for treating endometriosis, offering potential improvements in overcoming progesterone resistance.

Concerns and limitations persist despite the newly developed drugs. Therefore, studies on unraveling new therapeutic targets based on the molecular mechanisms of progesterone resistance is warranted for the development potential alternatives to overcome hormonal treatment failure in endometriosis.

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.

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.

Prospective non-interventional cohort study.

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).

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%.

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.

Venous thromboembolism is a serious safety concern in women using combined oral contraceptives; ethinyl estradiol (EE) is widely used as an estrogen. Estetrol (E4) is a native estrogen with selective tissue activity and exclusively produced by the fetal liver. This study used a multicenter, randomized, open-label, active-controlled, parallel-group design to evaluate the effects of E4 combined with drospirenone (DRSP) on coagulation and fibrinolysis in Japanese patients with endometriosis. Participants were randomized to receive either E4 15 mg/DRSP 3 mg or EE 20 µg/DRSP 3 mg for 12 weeks. E4/DRSP and EE/DRSP were administered orally once a day in a cyclic regimen, ie, 24-day active use followed by a 4-day hormone-free period, and a flexible extended regimen, respectively, and blood coagulation and fibrinolysis markers were measured. The effect on coagulation and fibrinolysis was considerably less in the E4/DRSP group than in the EE/DRSP group. Major anticoagulant proteins, protein S (free, total) and tissue factor pathway inhibitor (free), were reduced following EE/DRSP treatment. Consequently, thrombin generation determined by the activated protein C sensitivity ratio was increased by approximately 4-fold in the EE/DRSP group than in the E4/DRSP group. Eventually, the fibrinolysis cascade was triggered to compensate for disturbed coagulation, and D-dimer levels were 4.7-fold higher in the EE/DRSP group than in the E4/DRSP group. This study demonstrated that the effect of E4/DRSP on the blood coagulation and fibrinolysis cascades was significantly less than that of EE/DRSP in participants with endometriosis, a disease of women of advanced and reproductive age (jRCT2080225090, https://jrct.niph.go.jp/en-latest-detail/jRCT2080225090).

To evaluate a saliva diagnostic test (Endotest®) for endometriosis compared with the conventional algorithm.

A cost-effectiveness analysis with a decision-tree model based on literature data.

France.

Women with chronic pelvic pain.

Strategy I is the French algorithm, representing the comparator. For strategy II, all patients have an Endotest®. For strategy III, patients undergo ultrasonography to detect endometrioma and patients with no endometrioma detected have an Endotest®. For strategy IV, patients with no endometrioma detected on ultrasonography undergo pelvic magnetic resonance imaging (MRI) to detect endometrioma and/or deep endometriosis. An Endotest® is then performed for patients with a negative result on MRI.

Costs and accuracy rates and incremental cost-effectiveness ratios (ICERs). Three analyses were performed with an Endotest® priced at €500, €750, and €1000. Probabilistic sensitivity analysis was conducted with Monte Carlo simulations.

With an Endotest® priced at €750, the cost per correctly diagnosed case was €1542, €990, €919 and €1000, respectively, for strategies I, II, III and IV. Strategy I was dominated by all other strategies. Strategies IV, III and II were, respectively, preferred for a willingness-to-pay threshold below €473, between €473 and €4670, and beyond €4670 per correctly diagnosed case. At a price of €500 per Endotest®, strategy I was dominated by all other strategies. At €1000, the ICERs of strategies II and III were €724 and €387 per correctly diagnosed case, respectively, compared with strategy I.

The present study demonstrates the value of the Endotest® from an economic perspective.

Nowadays, combined oral contraceptives (COCs) are successfully employed for the treatment of endometriosis (END) and adenomyosis (AD) in a large proportion of patients. However, literature focusing on the clinical and sonographic response to treatment in the long-term follow-up of patients with deep endometriosis (DE) and AD is scarce. The aim of this study was to evaluate the changes in the symptoms and the sonographic exams at 12 and 24 months of follow-up in patients who had received a flexible extended COC regimen containing 2 mg of dienogest/30 μg ethinyl estradiol. This prospective, longitudinal, observational study included women diagnosed with DE and AD presenting no surgical indication and were candidates to treatment with COCs. The presence and severity of dysmenorrhea, non-menstrual pelvic pain, deep dyspareunia, dyschezia and dysuria were evaluated using the Numerical Rating Scale (NRS) at baseline, and at 12 and 24 months of treatment. Transvaginal ultrasound was also performed at these check points searching for criteria of AD and reporting the size of the DE nodules and ovarian endometriomas (OE). Sixty-four patients were included. A significant decrease in the number of patients with severe dysmenorrhea and non-menstrual pelvic pain was reported during follow-up. The mean NRS score for dysmenorrhea, non-menstrual pelvic pain, deep dyspareunia, dyschezia and dysuria was also significantly lower at follow-up. There was a significant reduction in the sonographic number and type of AD criteria during follow-up after treatment. Similarly, a significant decrease in the size of OE and uterosacral ligament involvement in DE was observed at the 12-month follow-up, with a further, albeit not statistically significant, decrease in the 12- to 24-month follow-up. Additionally, torus and rectosigmoid DE decreased in size, although the reduction was not statistically significant at any study point. This prospective study suggests a clinical and sonographic improvement after a flexible extended COC regimen in DE and AD patients, which was significant at 12 months of follow-up. The improvement was more evident in AD and OEs compared with DE. Further research with a longer follow-up, larger sample size and comparison with other treatments is needed.

This systematic review aimed to assess the efficacy and safety of Drospirenone and Ethinylestradiol Tablets (II) in the treatment of dysmenorrhea.

Electronic databases, namely PubMed, Embase, Cochrane Controlled Register of Trials (CENTRAL), Scopus, Science, CBM, CNKI, Wanfang, and VIP, were searched before September 2022. Randomized controlled trials (RCTs), non-randomized controlled trials, cohort studies, case-control studies, and single-arm studies were included. Furthermore, the Cochrane Risk of Bias Tool for Systematic Reviews version 1 was used for the risk of bias assessment on RCTs. The Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool was used for risk of bias assessment on non-randomized studies. The risk ratio (RR) was calculated for dichotomous data. Mean difference (MD) or standardized MD (SMD) were used as the effect size for continuous data.

A total of 11 studies involving 2,251 participants with dysmenorrhea were included. When Drospirenone and Ethinylestradiol Tablets (II) conventional 24/4-day regimen was compared with placebo, the total efficiency rate (defined as pain symptom disappearing or being relieved) in Drospirenone and Ethinylestradiol Tablets (II) 24/4-day regimen group was higher than in placebo group (RR = 5.55, 95%CI: 2.48-12.39, P < 0.0001). No clear differences were found on risk of overall adverse events or specific adverse events. When Drospirenone and Ethinylestradiol Tablets (II) was compared with active control drugs, no clear differences were found on the total efficiency rate or visual analog scale (VAS) scores for dysmenorrhea and other related pain. The risk of overall adverse events decreased in Drospirenone and Ethinylestradiol Tablets (II) conventional 24/4-day regimen (13/53 vs. 66/148, RR = 0.55, 95%CI: 0.33-0.91) when compared with active control drugs group. When Drospirenone and Ethinylestradiol Tablets (II) flexible extended regimen was compared with conventional 24/4-day regimen, the number of days of dysmenorrhea (MD=-3.98, 95%CI: -5.69 to -2.27), and dysmenorrhea associated with unscheduled bleedings (MD = -1.6, 95%CI: -2.8 to -0.5), were fewer in flexible extended regimen. In addition, there were no differences found on risk of adverse events (including mood changes, spotting, headache, breast pain, nausea, and vomiting) between compared groups (P > 0.05).

Drospirenone and Ethinylestradiol Tablets (II) could improve symptoms of dysmenorrhea and decrease other related pain symptoms. More high-quality evidence is needed to confirm the advantages.

[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021271605], identifier [CRD42021271605].

Iatrogeny due to drug-drug interactions is insufficiently documented, due to the high number of possible combinations.

This study aimed to design a simple but general method to predict the variation of adverse events (AE) frequency due to a pharmacokinetic or pharmacodynamic interaction.

Three prediction models were designed using a logistic probability density function. Each prediction model was based on three components: the AE odds ratio of each drug in the combination, and the area under the curve ratio (Rauc) of the pharmacokinetic interaction, if any. Pharmacodynamic interaction was assumed to be additive on logit scale. Rauc was predicted using a well-validated mechanistic static model, freely available online. No combination study is required. The method was evaluated against a wide range of AEs (28 High Level Terms) and 211 drug combinations (involving 43 victim drugs and 55 perpetrators), by comparing the observed and predicted frequencies. The observed odds ratios were estimated with a disproportionality analysis from the FDA Adverse Event Reporting System, using an approach that minimizes biases.

With the best model, the rate of prediction considered as correct (within 50-200% of the observed value) was 72%, and the bias was negligible (-5%). The AE odds ratio due to pharmacokinetic and pharmacodynamic interactions was equally well predicted.

A simple workflow to implement the method in practice is proposed. This method may help to foresee and to anticipate the harmful consequences associated with drug-drug interactions, at virtually no experimental cost, when the odds ratio of an AE is known for each drug alone and the AUC ratio is known or predicted by a suitable model.

Endometriosis is a benign uterine disorder characterized by menstrual pain and infertility, deeply affecting women's health. It is a chronic disease and requires a long term management. Hormonal drugs are currently the most used for the medical treatment and are based on the endocrine pathogenetic aspects. Estrogen-dependency and progesterone-resistance are the key events which cause the ectopic implantation of endometrial cells, decreasing apoptosis and increasing oxidative stress, inflammation and neuroangiogenesis. Endometriotic cells express AMH, TGF-related growth factors (inhibin, activin, follistatin) CRH and stress related peptides. Endocrine and inflammatory changes explain pain and infertility, and the systemic comorbidities described in these patients, such as autoimmune (thyroiditis, arthritis, allergies), inflammatory (gastrointestinal/urinary diseases) and mental health disorders.The hormonal treatment of endometriosis aims to block of menstruation through an inhibition of hypothalamus-pituitary-ovary axis or by causing a pseudodecidualization with consequent amenorrhea, impairing the progression of endometriotic implants. GnRH agonists and antagonists are effective on endometriosis by acting on pituitary-ovarian function. Progestins are mostly used for long term treatments (dienogest, NETA, MPA) and act on multiple sites of action. Combined oral contraceptives are also used for reducing endometriosis symptoms by inhibiting ovarian function. Clinical trials are currently going on selective progesterone receptor modulators, selective estrogen receptor modulators and aromatase inhibitors. Nowadays, all these hormonal drugs are considered the first-line treatment for women with endometriosis to improve their symptoms, to postpone surgery or to prevent post-surgical disease recurrence. This review aims to provide a comprehensive state-of-the-art on the current and future hormonal treatments for endometriosis, exploring the endocrine background of the disease.

Endometriosis, classically viewed as a localized disease, is increasingly recognized as a systemic disease with multi-organ effects. This disease is highlighted by systemic inflammation in affected organs and by high comorbidity with immune-mediated diseases.

We provide genomic evidence to support the recognition of endometriosis as an inflammatory systemic disease. This was achieved through our genomics-led target prioritization, called 'END', that leverages the value of multi-layered genomic datasets (including genome-wide associations in disease, regulatory genomics, and protein interactome). Our prioritization recovered existing proof-of-concept therapeutic targeting in endometriosis and outperformed competing prioritization approaches (Open Targets and Naïve prioritization). Target genes at the leading prioritization revealed molecular hallmarks (and possibly the cellular basis as well) that are consistent with systemic disease manifestations. Pathway crosstalk-based attack analysis identified the critical gene AKT1. In the context of this gene, we further identified genes that are already targeted by licensed medications in other diseases, such as ESR1. Such analysis was supported by current interests targeting the PI3K/AKT/mTOR pathway in endometriosis and by the fact that therapeutic agents targeting ESR1 are now under active clinical trials in disease. The construction of cross-disease prioritization map enabled the identification of shared and distinct targets between endometriosis and immune-mediated diseases. Shared target genes identified opportunities for repurposing existing immunomodulators, particularly disease-modifying anti-rheumatic drugs (such as TNF, IL6 and IL6R blockades, and JAK inhibitors). Genes highly prioritized only in endometriosis revealed disease-specific therapeutic potentials of targeting neutrophil degranulation - the exocytosis that can facilitate metastasis-like spread to distant organs causing inflammatory-like microenvironments.

Improved target prioritization, along with an atlas of in silico predicted targets and repurposed drugs (available at https://23verse.github.io/end), provides genomic insights into endometriosis, reveals disease-specific therapeutic potentials, and expands the existing theories on the origin of disease.

The quality of life of women with deep infiltrating endometriosis (DIE) is impaired and may improve with combined oral contraceptives (COCs).

To compare the overall and sexual quality of life of patients diagnosed with DIE with or without associated adenomyosis (AD) with that of healthy controls and determine the influence of a COC containing 2 mg dienogest/30 μg ethinyl estradiol on these aspects.

We enrolled 42 women diagnosed with DIE; 31 diagnosed with DIE + AD by transvaginal ultrasound, and 39 non-AD/DIE controls. All patients were interviewed regarding pain symptoms (dysmenorrhea, dyspareunia, dyschezia, and dysuria), heavy menstrual bleeding using the Pictorial Blood Loss Assessment Chart, quality of life using the Short Form-36 questionnaire (SF-36), and sexual quality of life using the Sexual Quality of Life-Female questionnaire (SQOL-F) and the Brief Profile of Female Sexual Function (B-PFSF) before starting COCs and after 12 months of treatment.

There was significant improvement in overall and sexual quality of life after treatment in DIE and DIE + AD patients.

Non-AD/DIE controls showed significantly higher scores in the B-PFSF, the SQOL-F and the SF-36 questionnaires (P < .05) at baseline versus the other groups. DIE + AD patients showed poorer quality of sexual life and greater intensity in pain symptoms compared with DIE patients. After 12 months of treatment, there was a significant improvement in overall and sexual quality of life in the DIE and DIE + AD groups, with improvement in sexual quality of life being slightly greater in DIE + AD patients compared with DIE patients. Pain symptoms also decreased in both groups.

Patients with DIE + AD showed greater impairment in overall and sexual quality of life compared with patients with isolated DIE which seems to improve with a COC containing 2 mg dienogest/30 μg ethinyl estradiol.

Strengths include the long-term follow up, assessment of the impact of two associated conditions, and administration of the same COC in all patients. Limitations include the relatively small sample size, and the fact that we did not assess the effectiveness of a flexible extended COC regimen containing 2 mg dienogest/30 μg ethinyl estradiol since the groups were different at baseline.

Patients diagnosed with DIE with or without AD have a decreased quality of life which may improve with a COC containing 2 mg dienogest/30 μg ethinyl estradiol. Further research is needed to confirm our results. Alcalde AM, Martínez-Zamora MÁ, Gracia M, et al. Assessment of Quality of Life, Sexual Quality of Life, and Pain Symptoms in Deep Infiltrating Endometriosis Patients With or Without Associated Adenomyosis and the Influence of a Flexible Extended Combined Oral Contraceptive Regimen: Results of a Prospective, Observational Study. J Sex Med 2022;19:311-318.

Dysmenorrhea and endometriosis are common gynecologic disorders among women of reproductive age that significantly impact health-related quality of life (HRQL) as well as productivity. Although there are treatment options listed in Japanese guidelines, a gap remains in unmet medical needs for maximizing treatment outcome. The extended regimen of ethinylestradiol and drospirenone (EE/DRSP) (taken daily for up to 120 consecutive days) has been available in Japan for treating dysmenorrhea and/or endometriosis-associated pain since 2016. Yet, the effectiveness of its usage on HRQL has not been investigated elsewhere to date. Therefore, in this study, we aim to observe changes in HRQL of Japanese women treated with an extended regimen of EE/DRSP for dysmenorrhea and/or endometriosis-associated pain.

As part of a 2-year post-marketing surveillance study, women with dysmenorrhea or endometriosis-associated pelvic pain were prescribed extended EE/DRSP during routine clinical practice. Data were collected 1 month before and 3 and 6 months after initiating treatment. Primary outcomes were the Menstrual Distress Questionnaire (MDQ) (before, during, and after menstruation) in patients with dysmenorrhea, and the Endometriosis Impact Scale (EIS) and European Quality of Life 5-dimensions 5-level instrument (EQ-5D-5L) in patients with endometriosis.

The study cohort included 315 patients (mean age 28.9 years) with dysmenorrhea and 262 patients (mean age 31.3 years) with endometriosis. Mean MDQ total scores before and during menstruation decreased significantly after 6 months with extended EE/DRSP; there was no improvement in after-menstruation MDQ score. Mean EIS domain scores improved significantly by 6 months, with improvement in most EIS individual item scores. Mean EQ-5D-5L scores increased slightly during 6 months of treatment.

Extended EE/DRSP treatment improved HRQL outcomes in Japanese women with dysmenorrhea or endometriosis-associated pelvic pain.

Registered at ClinicalTrials.gov (NCT03126747) on June 2017.

To evaluate the efficacy and safety of 40-mg relugolix (REL) compared with those of leuprorelin (LEU) in women with endometriosis-associated pain.

Phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study in Japanese patients.

Hospitals and clinics.

Women aged ≥20 years with regular menstrual cycles (25-38 days) experiencing endometriosis or ovarian endometrioma and reporting pelvic pain.

In the REL group, 40 mg of REL was orally administered once a day for 24 weeks. In the LEU group, 3.75 or 1.88 mg of LEU was subcutaneously injected every 4 weeks for 24 weeks.

The primary endpoint was the change in the maximum visual analog scale score for pelvic pain from baseline until 28 days before the end of treatment.

Changes in the maximum visual analog scale score were -52.6 ± 1.3 for REL and -57.5 ± 1.4 for LEU. Ovarian endometrioma decreased by 12.26 ± 17.52 cm³ for REL and 14.10 ± 18.81 cm³ for LEU. Drug-related treatment emergent adverse events with an incidence of >10% for both groups were hot flush, metrorrhagia, headache, and genital hemorrhage. Discontinuations from treatment emergent adverse events were 2.9% for REL and 4.3% for LEU.

Relugolix was noninferior to LEU for treating endometriosis-associated pelvic pain. Safety profiles of both medications were comparable, although menses returned earlier in patients taking REL, a huge benefit for women who plan to conceive after treatment.

ClinicalTrials.gov: NCT03931915.

Endometriosis is an oestrogen-dependent disorder where endometrial tissue forms lesions outside the uterus, causing chronic inflammation and scarring. Women who have endometriosis may experience a highly variable range of non-specific signs and symptoms, including pelvic pain. Endometriosis is often misdiagnosed, partly because its signs and symptoms can easily be attributed to more common conditions that cause pelvic pain in women, resulting in delayed diagnosis and treatment. This article describes the pathophysiology, aetiology, risk factors for, and signs and symptoms of endometriosis. It also outlines how endometriosis should be investigated and treated in the emergency department (ED). Its aim is to support nurses to deliver effective care to women of reproductive age presenting to the ED with severe pelvic pain.

To study the measurement properties, the responsiveness and the minimal clinically important difference of the ENDOPAIN-4D: a new questionnaire for assessing pain in endometriosis.

A prospective, observational, multicentre study was conducted including all women ≥18 years consulting for symptomatic proven endometriosis between 1 January 2017 and 30 June 2018 and volunteering to participate. Each patient had to answer a new self-administered patient-reported outcome (PRO) questionnaires (the ENDOPAIN-4D) at inclusion (T0) and 12 months after medical or surgical treatment (T1). Criteria defined by COSMIN were used to validate the questionnaire's measurement properties. The minimal clinically important difference was estimated by the anchor-based method.

The study included 199 women. The ENDOPAIN-4D score had a four dimensional structure with good internal consistency (measured by Cronbach α): (I) pain-related disability (α = 0.79), (II) painful bowel symptoms (α = 0.80), (III) dyspareunia (α = 0.83), and (IV) painful urinary tract symptoms (α = 0.77). They produced four subscores that can be summed to obtain a single score (α = 0.61). The ENDOPAIN-4D total score ranged from 0 to 94.00 (mean ± SD: 46.7 ± 22). The total score was significantly correlated with the PROs used in endometriosis. Sensitivity to change was good with large effect sizes (ES) (mean of the differences: 36.3 p = 1.8 10-7, ES 0.76). The minimal clinically important difference of the global score was determined to be 10.9.

The ENDOPAIN-4D questionnaire is easy to use, valid, and effective in assessing patient reported pain symptoms in women treated for endometriosis. This new instrument can be used as the primary outcome for future clinical trials and as a tool for routine patient follow-up.

Endometriosis is a benign gynecologic disorder that is defined as functional endometrial tissue outside of the uterine cavity. It is an estrogen-dependent, inflammatory disease that leads to symptoms of pelvic pain, dysmenorrhea, dyspareunia, and infertility, occurring in 6-10% of reproductive aged women. The severity of the disease ranges from asymptomatic to debilitating symptoms that have a major impact on women's lives. It is a chronic, recurrent disease, frequently requiring long term management until menopause and beyond. It is considered a chronic disorder that is managed with surgery, medical treatment, and oftentimes, both. Current medical therapy for endometriosis is considered suppressive of the disease, rather than curative. Fortunately, many patients do experience improvement and control of their symptoms with medical therapy. However, long-term efficacy of the medical treatments is often limited by side effects and the cost of therapy, and symptoms do tend to recur after discontinuation of these medications.

This review summarizes our understanding of the pathogenesis of endometriosis and provides more in-depth discussion of specific medical management options used to treat endometriosis, including mechanism of action and side effects. It also provides recommendations on strategy with a forward look to novel endometriosis treatments in the future.

The authors emphasize that endometriosis is a chronic disorder requiring long term medical therapy. Early diagnosis of endometriosis is key in preventing severe, debilitating symptoms and progression of disease. By utilizing our current knowledge of the pathophysiology of endometriosis and by correctly implementing currently available medical and surgical therapies we can significantly reduce the physical, psychosocial and financial burden of this chronic, recurrent and indolent disease. Current available medications are suppressive therapies, but the authors are looking forward to future therapies that can effectively cure or at least control endometriosis with minimal side effects. Future research should continue to look for the genetic trigger for endometriosis which can lead us to its underlying pathogenesis and eventually a cure or prevention.

To assess the efficacy and safety of dydrogesterone in Japanese women with ovarian endometrioma in a real-world setting.

The post-marketing study involved 15 sites in Japan. Dydrogesterone 10 mg twice daily orally was administered for 21 days (day 5-25 of each menstrual cycle) for 4 cycles. The primary outcome measure was the change in ovarian endometrioma volume from baseline. Secondary outcome measures included total dysmenorrhea score (0 = absent to 3 = severe), severity of dysmenorrhea pain [0-10cm visual analog scale (VAS)], serum carbohydrate antigen 125 (CA-125) levels, and safety.

The study group comprised women with an endometrioma aged 20 to 49 (47.4% cases aged ≥40 years). Endometrioma volume was reduced in 50% (26/52), unchanged in 25% (13/52), and increased in 25% (13/52) of women from baseline to the end of cycle 5; three-quarters of patients thus had either reduced or unchanged ovarian endometrioma volume. Dydrogesterone significantly reduced total dysmenorrhea scores and severity of dysmenorrhea pain VAS during treatment compared with baseline. CA-125 levels were not significantly changed during the study. The incidence of adverse events and adverse drug reactions in 59 subjects was 13.6% and 11.9%.

Dydrogesterone prevented an increase in endometrioma size in many women, and it also significantly improved total dysmenorrhea scores and severity of dysmenorrhea pain, and was well tolerated. The ClinicalTrials.gov identifier of the study was NCT02921763.

Endometriosis is a major health concern in the adolescent population and significantly impacts daily physical and psychosocial functioning. Endometriosis can have differing presentations in this population, and the diagnosis often involves long delays and multiple visits to specialists.

The aim of this review is to discuss adolescent endometriosis, factors specific to this population, accurate diagnosis, and evidence-based surgical and medical management.

Computerized searches on the topic of endometriosis and adolescent endometriosis were completed. References from identified sources were then searched manually to allow for a thorough review. Data from relevant sources were synthesized to create the review.

The literature supports endometriosis as a frequent cause of secondary dysmenorrhea. The characteristics of adolescents with endometriosis are shown to differ from those of adults. Initial medical therapy includes nonsteroidal anti-inflammatory drugs and combined hormonal contraceptives, but laparoscopy does have a role in the adolescent population, particularly those who have inadequate response to these treatments. Adolescent endometriosis may have a different appearance and be of all stages. Medical therapies are similar to that of the adult population; however, the benefits of medical and surgical management must be tailored to the adolescent patient.

Adolescent endometriosis is likely a more prevalent cause of dysmenorrhea than currently appreciated. A high index of suspicion combined with recognition of risk factors and history-based markers of endometriosis may help identify adolescent endometriosis earlier and avoid delays in diagnosis. Expert opinion supports earlier laparoscopic evaluation in patients with symptoms unresponsive to oral medications, those who have failed initial medical therapy, or those who have evidence of deeply invasive disease, such as an endometrioma. Surgeons should be familiar with the unique appearance of lesions in the adolescent and understand the evidence as it relates to surgical therapy. Postoperative medical management is generally advocated by many, although the efficacy remains unclear at present.

We aimed to evaluate the efficacy and safety of 28-day Cyclic and 84-day Extended regimens of NPC-16 (ethinylestradiol 0.02 mg plus levonorgestrel 0.09 mg) in patients with dysmenorrhea.

This was a placebo-controlled, double-blind, randomized trial conducted in Japan. A total of 251 primary and secondary dysmenorrhea patients were randomly assigned to the NPC-16-Cyclic group, NPC-16-Extended group, or the Placebo group. The primary end point was a comparison of the efficacy and safety of the Cyclic and Extended NPC-16 regimen for the treatment of dysmenorrhea relative to the Placebo.

Significantly greater reductions in total dysmenorrhea score and visual analog scale score were observed in the Cyclic and Extended groups compared with the Placebo group. Compared with the Cyclic regimen as a secondary end point, the Extended regimen exhibited greater efficacy in the treatment of dysmenorrhea over the course of the study period, particularly in patients with severe dysmenorrhea. The incidence of adverse drug reactions (ADRs) was significantly higher in the Cyclic and Extended groups than in the Placebo group.

The Cyclic and Extended regimens of NPC-16 significantly reduced dysmenorrhea severity compared to placebo. The Extended regimen was superior to cyclic regimen in reducing the dysmenorrhea.

Studies have been published on the efficacy of Dienogest in the management of pain symptoms in endometriosis. Nonetheless, few data are available on the reducing effect on endometrioma's size. The aim of the study was to evaluate if Dienogest could determine significant changes in size, as well as in symptoms. In this prospective observational study, patients were enrolled with pain symptoms and at least one endometrioma diagnosed via TV-US. The volume of the endometrioma and pain symptoms was measured according to the LxDxWx0.5233 formula and VAS, respectively. Dienogest 2 mg was administered daily. Follow-up visits were scheduled after 6 and 12 months of treatment to assess changes in patients' symptoms and endometrioma's volume. Seventy patients were enrolled, 63 patients completed a 6-month treatment. The reduction of the mean volume after 6 months was 66.71%. Fifty-eight patients completed the 12 month-treatment. The reduction of the mean volume after 12 months was 76.19%. Dysmenorrhea showed a 74.05% reduction after 6 months and a 96.55% reduction after 12 months. Patients reported a reduction in dyspareunia and chronic pelvic pain of 42.71% and 48.91% after 6 months and 51.93% and 59.96% after 12 months, respectively. Dienogest leads to a statistically significant reduction of endometrioma's volume and pain symptoms.

Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis.

We review here the action mechanisms of progesterone receptor ligands in endometriosis, identify critical differences between the effects of progestins on normal endometrium and endometriosis and envisage pathways to escape drug resistance and improve the therapeutic response of endometriotic lesions to such treatments.

We performed a systematic Pubmed search covering articles published since 1958 about the use of progestins, estro-progestins and selective progesterone receptor modulators, to treat endometriosis and its related symptoms. Two reviewers screened the titles and abstracts to select articles for full-text assessment.

Progesterone receptor signalling leads to down-regulation of estrogen receptors and restrains local estradiol production through interference with aromatase and 17 beta-hydroxysteroid dehydrogenase type 1. Progestins inhibit cell proliferation, inflammation, neovascularisation and neurogenesis in endometriosis. However, progesterone receptor expression is reduced and disrupted in endometriotic lesions, with predominance of the less active isoform (PRA) over the full-length, active isoform (PRB), due to epigenetic abnormalities affecting the PGR gene transcription. Oxidative stress is another mechanism involved in progesterone resistance in endometriosis. Among the molecular targets of progesterone in the normal endometrium that resist progestin action in endometriotic cells are the nuclear transcription factor FOXO1, matrix metalloproteinases, the transmembrane gap junction protein connexin 43 and paracrine regulators of estradiol metabolism. Compared to other phenotypes, deep endometriosis appears to be more resistant to size regression upon medical treatments. Individual genetic characteristics can affect the bioavailability and pharmacodynamics of hormonal drugs used to treat endometriosis and, hence, explain part of the variability in the therapeutic response.

Medical treatment of endometriosis needs urgent innovation, which should start by deeper understanding of the disease core features and diverse phenotypes and idiosyncrasies, while moving from pure hormonal treatments to drug combinations or novel molecules capable of restoring the various homeostatic mechanisms disrupted by endometriotic lesions.

The role of the radiologist in the diagnosis and management of patients with endometriosis is increasing. Improvement in MRI imaging techniques has improved detection rate of subtle manifestations of endometriosis by radiologists. Therefore, the role of imaging in the diagnosis and follow-up after treatment is also likely to increase. Knowledge of new medical management pathways used in treating patients with endometriosis-related pain is important. The knowledge of various medication regimens will allow radiologists to continue to evaluate baseline disease, and to potentially assess for imaging response/stability to these medications. This article will review the current medical therapies in use in the management of endometriosis-related pain and describe potential imaging-related findings expected with these therapies.

Endometriosis is a disease of reproductive age women that is commonly characterized by symptoms that often negatively impact quality of life. The clinical management of endometriosis remains highly variable and mostly influenced by geographic location, practice patterns, and breadth of clinician experience. This variability in treatment has inspired a trend towards multidisciplinary and specialized care of patients suffering from this disease. Surgical sampling, followed by histologic confirmation of endometrial-like tissue, remains the standard for the definitive diagnosis of endometriosis. However, the high sensitivity and specificity of MRI and ultrasound has shed light on the path towards non-surgical diagnosis of deep infiltrating endometriosis. Molecular variability and intricacy of this disease has limited the development of biologic markers to target for non-invasive diagnosis and pharmacologic therapies. Surgical management of advanced-stage endometriosis can be difficult, mostly secondary to the invasive nature of the disease, and anatomical distortion requiring advanced surgical skills to manage. The high prevalence of chronic pelvic pain and other complex pain syndromes in patients with endometriosis also requires knowledge in the management of these types of issues in order to provide comprehensive care. Menopausal endometriosis, extrapelvic presentation, and potential malignant transformation of lesions are infrequent, requiring a high index of suspicion for timely diagnosis and treatment.

To evaluate the efficacy and safety of dienogest (DNG), a progestational 19-norsteroid, in patients with primary and secondary dysmenorrhea.

Phase III, randomized, double-blind, multicenter, placebo-controlled study.

Clinical study sites in Japan.

Ninety-four women with dysmenorrhea.

Random assignment to receive DNG (1 mg/day, orally) or placebo for 12 weeks; patients treated for anemia before randomization in cases of complicated anemia.

Change in the dysmenorrhea score from baseline to week 12 of treatment with visual analog scale used for pain assessment.

The DNG group was superior to the placebo group in terms of the change from baseline in the dysmenorrhea score at week 12 of treatment in patients with dysmenorrhea. In both primary and secondary dysmenorrhea, the DNG group was superior to the placebo group for each diagnostic category. The mean serum estradiol concentrations were similar between the DNG and the placebo groups. Although the incidence of irregular uterine bleeding was higher in the DNG group, there were no severe or serious events. Most events of genital bleeding were spotting or breakthrough bleeding, suggesting DNG was well tolerated.

In both primary and secondary dysmenorrhea, DNG at 1 mg/day relieved pain and was well tolerated.

JapicCTI-173547(en).

Endometriosis is estimated to affect 10% of reproductive-aged women. The gold standard for treatment is surgery; however, surgery carries a significant morbidity and cost burden. There is an ongoing need for safe, effective medical therapies for endometriosis patients, both in conjunction with and independent of surgical interventions. Most conventional therapies for endometriosis work by a similar mechanism, and efficacy is variable. In recent years, there has been increased interest in the development and testing of novel pharmacotherapies for endometriosis.

This review discusses both conventional and emerging treatments for endometriosis. The authors present the application of these drugs in different presentations of endometriosis across the lifespan and discuss how emerging therapies might fit into future medical management of endometriosis. Conventional therapies include nonsteroidal anti-inflammatory drugs, combined oral contraceptives, progestins, GnRH agonists/antagonists, and aromatase inhibitors. Emerging therapies are focused on disease-specific targets such as endothelial growth factor receptors.

The field of endometriosis therapy is moving toward modifying the immune and inflammatory milieu surrounding endometrial implants. If these drugs show efficacy in clinical trials, combining them with current medical treatment is expected to result in a profound impact on symptom and disease burden for patients who suffer from endometriosis worldwide.

To evaluate the efficacy, safety, and clinically recommended dose of dienogest (DNG; 0.5 mg/d, 1 mg/d, and 2 mg/d) in the treatment of primary dysmenorrhea.

A phase II, randomized, double-blind, multicenter, placebo-controlled study.

Twenty study sites.

A total of 235 patients with primary dysmenorrhea.

Patients were randomized to receive orally a placebo, DNG (0.5 mg/d, 1 mg/d, or 2 mg/d) or ethinylestradiol 0.02 mg/drospirenone 3 mg (an open-label reference drug) for 12 weeks.

The primary endpoint was the change from baseline in the dysmenorrhea score at week 12 of treatment. The secondary endpoint was the change from baseline in the visual analogue scale at week 12 of treatment. Subjects were assessed for lower abdominal pain and/or low back pain.

All DNG arms were superior to the placebo arm in terms of the change from baseline in the dysmenorrhea score. The results suggest an equal or greater effect of DNG 1 and 2 mg/d in relieving pain, when compared to the reference drug. In the safety profile of DNG, including irregular uterine bleeding, there was no obvious difference among the doses of DNG. A significant decrease in the serum estradiol concentration compared to that in the placebo arm was not observed in the DNG 1 mg/d arm but was observed in the DNG 2 mg/d arm.

The results suggest that DNG at a dose of 1 mg/d is an effective and well-tolerated treatment for primary dysmenorrhea.

JapicCTI-152977 (en).

In the healthy endometrium, progesterone and estrogen signaling coordinate in a tightly regulated, dynamic interplay to drive a normal menstrual cycle and promote an embryo-receptive state to allow implantation during the window of receptivity. It is well-established that progesterone and estrogen act primarily through their cognate receptors to set off cascades of signaling pathways and enact large-scale gene expression programs. In endometriosis, when endometrial tissue grows outside the uterine cavity, progesterone and estrogen signaling are disrupted, commonly resulting in progesterone resistance and estrogen dominance. This hormone imbalance leads to heightened inflammation and may also increase the pelvic pain of the disease and decrease endometrial receptivity to embryo implantation. This review focuses on the molecular mechanisms governing progesterone and estrogen signaling supporting endometrial function and how they become dysregulated in endometriosis. Understanding how these mechanisms contribute to the pelvic pain and infertility associated with endometriosis will open new avenues of targeted medical therapies to give relief to the millions of women suffering its effects.