Therapy For Endometriosis Research Articles

Melatonin: The First Noninvasive Causal Therapy for Both Endometriosis and Adenomyosis?

Melatonin: The First Noninvasive Causal Therapy for Both Endometriosis and Adenomyosis?

Anti-angiogenic treatment of endometriosis via anti-VEGFA siRNA delivery by means of peptide-based carrier in a rat subcutaneous model.

Development of gene therapy for endometriosis requires inhibition of vascularization in endometrial lesions. We have previously developed CXCR4 receptor-targeted siRNA carrier L1 and observed efficient RNAi-mediated down-regulation of VEGFA gene expression in endothelial cells followed by decrease in VEGFA protein production and inhibition of cell migration. In this study we evaluated L1 carrier as non-viral vector for anti-VEGFA siRNA delivery into endometrial implants in rat subcutaneous endometriosis model created by subcutaneous auto-transplantation of uterus horn's fragments. Therapeutic anti-angiogenic efficiency of anti-VEGFA siRNA/L1 polyplexes was evaluated by lesion size measurement, histopathologic examination, immunohistochemical staining and real-time reverse transcriptase-PCR analysis. After in vivo administration of anti-VEGFA siRNA we observed a 55-60% inhibition of endometriotic lesions growth and approximately two-fold decrease in VEGFA gene expression in comparison with untreated implants. Results of immunohistochemical examination of endometriotic lesions confirmed anti-angiogenic effects of anti-VEGFA siRNA/L1 polyplexes. Ultimately, our results demonstrate the efficiency of anti-angiogenic treatment of EM by means of anti-VEGFA siRNA delivery with L1 peptide-based carrier.

Endometriosis-associated recto-sigmoid cancer: a case report

BackgroundEndometriosis is a relatively common condition in women of reproductive age. Malignant transformation of intestinal endometriosis is a very rare event. We report a case in which a patient with a history of endometriosis underwent surgery for malignant intestinal endometriosis.Case presentationA 55-year-old woman complained of rectorrhagia and intermittent abdominal pain. A neoplasm was revealed by colonoscopy, CT scan and F18-FDG PET/CT of the recto-sigmoidal colon. The patient underwent a rectal anterior resection, hysterectomy and bilateral salpingo-oophorectomy for treatment. According to the histological and immunohistochemical presentation, the diagnosis of endometriosis-associated recto-sigmoid cancer was confirmed. The patient was treated with adjuvant chemotherapy for 6 months. During the follow-up appointment 22 months later, there was clinical and radiographic evidence of recurrence in the rectum. The patient received chemotherapy again and will receive another surgery after two more cycles of chemotherapy.ConclusionWe report a case of malignant intestinal endometriosis. Although there is no standard therapy for malignant intestinal endometriosis due to the rarity of this disease, surgery and adjuvant chemotherapy seemed to be rational. This case indicates that local recurrence may be a common situation after standard therapy.

ILK enhances migration and invasion abilities of human endometrial stromal cells by facilitating the epithelial–mesenchymal transition

Epithelial–mesenchymal transition (EMT) plays a significant part in the pathogenesis of endometriosis by facilitating the migration and invasion abilities of cells. Integrin-linked kinase (ILK) increases the cell migration and invasion abilities by inducing the EMT. Eutopic and control endometrial stromal cells (EuSCs and CSCs) were isolated and cultured. Cell migration and invasion abilities were detected by transwell assays. Levels of proteins were detected by Western blot. EuSCs showed higher levels of ILK, N-cadherin, vimentin and stronger migration and invasion abilities. After transfection of siRNA-ILK, E-cadherin and keratin levels were increased while N-cadherin and vimentin levels were decreased in EuSCs. Besides that, the migration and invasion abilities of EuSCs were significantly decreased after transfection of siRNA-ILK. On the contrary, levels of ILK, N-cadherin and vimentin were increased while levels of E-cadherin and keratin were decreased simultaneously after transfecting CSCs with pEGFP-C1-ILK. Simultaneously, the migration and invasion abilities of CSCs were increased after transfection of pEGFP-C1-ILK. Our study verified that high expression of ILK enhanced the migration and invasion abilities of ESCs by facilitating the EMT. Given that ILK played crucial roles in the pathogenesis of endometriosis, it may be considered as a promising targeted therapy for endometriosis.

Methylation Profile of HOXA 11 Gene in Eutopic Endometrium on Endometriosis Patient with Infertility

Objective: To investigate the HOXA11 gene profile on endometriosispatients with infertility in Indonesia.Methods: This cross sectional study was conducted in Dr. CiptoMangunkusumo Hospital from July 2015- June 2016. The subjectswere endometriosis patients with infertility who have beenconfirmed histopathological. The control group was taken fromnon-endometriosis and fertile patients. Eutopic endometriumsamples were taken and examined for the methylation of HOXA 11gene.Results: Both groups consist of six patients. The difference ofmethylation of HOXA 11 gene between those two groups isstatistically significant (p=0.03). There was hyper methylation inendometriosis group.Conclusion: There is a hyper methylation of HOXA 11 gene ineutopic endometrium of endometriosis patients with infertility.Thus, possibly can explain the poor endometrial receptivityin endometriosis patient and give a broad research area inepigenetic therapy of endometriosis.[Indones J Obstet Gynecol 2018; 6-2: 110-113]Keywords: endometriosis, epigenetic, HOXA 11, infertility,methylation

Identification of LINC01279 as a cell cycle‑associated long non‑coding RNA in endometriosis with GBA analysis.

Endometriosis affects 6–10% of women of reproductive age. Though a significant amount of research has explored the pathogenesis of endometriosis, little is clear. Elucidating the mechanisms is urgently required for improving the therapeutic efficiency of endometriosis treatment. Long non-coding RNAs (lncRNAs) have recently acquired extensive attention as regulatory components in a variety of biological processes and diseases. However, the functions of many lncRNAs in endometriosis are poorly understood. Therefore, the exploration of the dysregulated genes in endometriosis, particularly lncRNAs, is of importance. In the present study, datasets for endometriosis, including GSE7305, GSE7846, GSE29981 and E-MTAB-694, were downloaded from Gene Expression Omnibus and ArrayExpress. Then, the limma and Affy packages were used to analyze the CEL file. The RankProd method was used to conduct meta-analysis. Long intergenic non-protein coding RNA 1279 (LINC01279) was significantly upregulated in the three datasets, and was the most upregulated lncRNA as determined by the RankProd method. Gene set enrichment and Gene Ontology analyses were conducted, which revealed that LINC01279 is likely to function as a cell cycle mediator in endometriosis. Finally, it was identified that LINC01279 is strongly associated with certain previously identified key factors in the development of endometriosis, including cyclin-dependent kinase 14 and C-X-C motif chemokine ligand 12. Thus, it was demonstrated that LINC01279 may be associated with the pathogenesis of endometriosis. This may potentially represent a target in the therapy of endometriosis.

MicroRNA Let-7b: A Novel treatment for endometriosis.

Endometriosis is an oestrogen‐dependent, chronic inflammatory disease that affects 10% of reproductive‐aged women. Current treatment options depend on female sex steroid hormone modulation; however, all have side effects and are not useful in women who want to conceive. microRNAs treatments have provided promising results for some chronic diseases and cancers. We have previously shown the microRNA Let‐7b is repressed in endometriosis and that loss of Let‐7 contributes to the pathophysiology of the disease. Here, we propose using microRNA Let‐7b for the treatment of endometriosis in a murine model. Endometriosis was treated using microRNA Let‐7b or a scrambled control microRNA. Let‐7b treatment resulted in reduced endometriosis lesion size. Decreased gene expression was noted in several genes known to promote endometriosis growth including ER‐α, ER‐ß, Cyp19a, KRAS 4A, KRAS 4B and IL‐6. These results indicate that microRNA Let‐7b has a pleiotropic role in endometriosis pathophysiology affecting oestrogen signalling, inflammation and growth factor receptors. Local treatment of endometriosis with Let‐7b is a promising therapy for endometriosis that simultaneously affects multiple pathways driving endometriosis without systemic hormonal side effects.

Aromatase as a target for treating endometriosis.

Endometriosis is a common gynecological disease that causes various clinical symptoms, such as chronic pelvic pain, dysmenorrhea and infertility, seriously affecting women's health and their quality of life. The symptoms and endometriotic lesions are relieved, in many cases, after menopause, when estrogen levels are lowered. Therefore, endometriosis is considered to be estrogen-dependent. Aromatase, the enzyme responsible for the last step of estrogen biosynthesis converting testosterone and androgen to estrogen, was previously reported to be more abundant in endometriotic tissues than in the normal endometrium, leading to an increased local estrogen concentration. Therefore, aromatase is considered a key therapeutic target for regulating local estrogen biosynthesis in endometriosis. A more complete understanding of the mechanisms that modulate aromatase and its activity is required to develop novel estrogen-targeted therapies for endometriosis. In this review article, we outline the current understanding of the pathological processes involved in estrogen production in endometriosis and propose novel strategies to treat this disorder.

The efficacy of selective cyclooxygenase 2 inhibitors in the treatment of genital endometriosis

External genital endometriosis is characterized by the processes of angiogenesis, neurogenesis, impaired apoptosis, local inflammation of the tissues, secretion of estradiol, and cell proliferation. In a similar manner, prostaglandin E2 affects tissues. The safest drugs that overwhelm COX-2 activity and inhibit the expression of prostaglandin E2 are selective COX-2 inhibitors. As a mediator of inflammation, prostaglandin E2 is involved in all inflammatory processes. It induces the expression of local P450 aromatase and the anti-apoptotic gene Bcl-2. E2 also possesses immunosuppressive-mediated activity and inhibits the synthesis of cytokines IFNγ, TNFα, and IL-12, IL-1β-mediated expression of chemokines, the proliferation of T- and B-cells and reduces the cytotoxic activity of NK cells, creating a background of the immunosuppressive characteristic of endometriosis [1–3].
 This study included 100 patients of reproductive age (aged 22-35 years) with a confirmed diagnosis of external genital endometriosis of degree II–IV. Fifty patients received 100 mg of celecoxib in monotherapy and in combination with 2 mg of dienoguest. The control group included 50 people receiving monotherapy with 2 mg of dienogest. The effectiveness of therapy was assessed using the visual analog scale (VAS) and on the basis of the dynamics of algodismenorrhea, pain during coitus, clinical examination, and the patient’s subjective assessment of the degree of irritability and severity of depressive syndrome. The effectiveness of the treatment was evaluated according to MRI and ultrasound of the pelvic organs throughout the study. To control for possible complications of the therapy, the patients performed a comprehensive dynamic survey assessing the indicators of general blood analysis and the blood coagulation system. In the group with the combined application of celecoxib and dienoguest, a clinically significant reduction in pain syndrome and a decrease in the degree of irritability and depressive syndrome were noted relative to the control group. No side effects of celecoxib on the body systems were identified throughout the study. Thus, celecoxib can be recommended as a safe and effective combination therapy for endometriosis.

EFFECTIVENESS OF THE COMPLEX TREATMENT OF ENDOMETRIOSIS OF WOMEN’S SITUATIVE BODIES

The purpose of the study is to study the effectiveness of complex treatment of external genital endometriosis and reduce the frequency of its relapse based on the improvement and implementation of algorithm for diagnostic, therapeutic and prophylactic and rehabilitation measures using modern endoscopic technologies and drug correction. Materials and methods. In the course of our study, all patients were divided into three clinical groups: 1 group consisted of 57 patients who in the postoperative period prescribed monotherapy dyenogest, 2 groups -60 patients, which in the postoperative period was complex therapy, in 3 groups included 53 patients, who refused for various reasons from conducting in the postoperative period of hormone therapy.Results of the research and their discussion. We analyzed the results of a comprehensive treatment of 170 patients with external genital endometriosis. The proposed therapy allowed to reduce the symptoms of endometriosis and restore the reproductive function of the woman. In the course of the study, it has been updated, as much exposure as the endometriosis affects the lives of women.Conclusions. Thus, the complex therapy of external endometriosis, which consists of laparoscopy in combination with hormone therapy in the postoperative period, leads to a decrease in pelvic pain, a decrease in the size and number of foci of the endometriosis, the restoration of fertility, and also prevents the occurrence of relapses, which in turn increases the quality life.

Current and Emerging Therapeutics for the Management of Endometriosis.

Endometriosis is a chronic benign disease that affects women of reproductive age. Medical therapy is often the first line of management for women with endometriosis in order to ameliorate symptoms or to prevent post-surgical disease recurrence. Currently, there are several medical options for the management of patients with endometriosis. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of chronic inflammatory conditions, being efficacious in relieving primary dysmenorrhea. Combined oral contraceptives (COCs) and progestins, available for multiple routes of administration, are effective first-line hormonal options. In fact, several randomized controlled trials (RCTs) demonstrated that they succeed in improving pain symptoms in the majority of patients, are well tolerated and not expensive. Second-line therapy is represented by gonadotropin-releasing hormone (GnRH) agonists. Even if these drugs are efficacious in treating women not responding to COCs or progestins, they are not orally available and have a less favorable tolerability profile (needing an appropriate add-back therapy). The use of danazol is limited by the large availability of other better-tolerated hormonal drugs. Because few data are available on long-term efficacy and safety of aromatase inhibitors they should be administered only in women with symptoms refractory to other conventional therapies in a clinical research setting. Promising preliminary data have emerged from multicenter Phase III trials on elagolix, a new oral GnRH antagonist but non-inferiority RCT data are required to compare elagolix with first-line therapies for endometriosis.

Therapeutic strategies involving uterine stem cells in reproductive medicine.

The current review provides an update on recent advances in stem cell biology relevant to female reproduction. Stem cells are undifferentiated cells that often serve as a reservoir of cells to regenerate tissue in settings or injury or cell loss. The endometrium has progenitor stem cells that can replace all of the endometrium during each menstrual cycle. In addition, multipotent endometrial cells replace these progenitor cells when depleted. Recruitment of stem cells from outside of the uterus occurs in setting of increased demand such as ischemia or injury. Bone marrow-derived multipotent stem cells are recruited to the uterus by estrogen or injury-induced expression of the chemokine CXCL12. In the setting of overwhelming injury, especially in the setting of low estrogen levels, there may be insufficient stem cell recruitment to adequately repair the uterus resulting in conditions such as Asherman syndrome or other endometrial defects. In contrast, excessive recruitment of stem cells underlies endometriosis. Enhanced understanding of stem-cell mobilization, recruitment, and engraftment has created the possibility of improved therapy for endometrial defects and endometriosis through enhanced manipulation of stem-cell trafficking. Further, the normal endometrium is a rich source of multipotent stem cells that can be used for numerous applications in regenerative medicine beyond reproduction. A better understanding of reproductive stem-cell biology may allow improved treatment of endometrial disease such as Asherman syndrome and other endometrial receptivity defects. Inhibiting stem-cell mobilization may also be helpful in endometriosis therapy. Finally, endometrial derived multipotent stem cells may play a crucial role in cell therapy for regenerative medicine.

Гестагены в терапии эндометриоза

Гестагены в терапии эндометриоза

Альтернатива гормональным и нестероидным противовоспалительным средствам в лечении вторичной дисменореи, обусловленной аденомиозом

Secondary dysmenorrhea or painful menstruation are observed in almost half of young women and significantly affect the quality of life, primarily in the emotional, psychic and communication spheres, and also often cause the loss of temporary work capacity. Secondary (organic) dysmenorrhea is caused by various pathological diseases in the pelvic organs (uterine leiomyoma, ovarian tumors, pelvic inflammatory processes, malformation of the genital organs, adhesive process in the small pelvis, etc.) and in particular adenomyosis (internal endometriosis). This disease, leads to disruption of reproductive function and disability, causes feelings of inferiority, causing physical and moral harm to women aged 20–40 years. According to different data, the incidence of endometriosis in populations varies from 7 to 65%. In a significant number of cases, conservative (hormonal) therapy of endometriosis does not reach its goal and has many negative effects on the woman’s body. In this regard, the search for safer and more effective treatment is an extremely urgent task. The use of drugs of natural origin regulating the blood supply, tropism, metabolism and functional state of the reproductive endocrine system in the treatment of secondary dysmenorrhea finds a more favorable ground for compliance and is increasingly prevalent. The advantage of such drugs is low toxicity and the possibility of prolonged use without the risk of serious adverse reactions. Positive changes in the hormonal status and a good clinical effect with the use of drugs of natural origin in patients with secondary dysmenorrhea associated with adenomyosis, confirm the advisability of its use in the pathogenetic treatment of this pathology. Key words: secondary dysmenorrhea, endometriosis, adenomyosis, nonsteroidal anti-inflammatory drugs, adverse reactions, combined oral contraceptives, multi-component non-hormonal drug.

Predictors of IVF/ICSI success following treatment of endometriosis as the cause of primary infertility.

Treatment of endometriosis prior to IVF/ICSI could be followed by the significant reduction of ovarian reserve. The aim is to identify potential markers of the IVF/ICSI outcome in patients with endometriosis associated infertility and to evaluate their clinical significance. The prospective cohort study included 73 patients with primary infertility caused by endometriosis that were subjected to 77 IVF/ICSI cycles. Patients were classified into two groups. In the first group some type of treatment had previously been applied, and in the second group patients were immediately subjected to the IVF/ICSI procedures. When pregnancy was achieved, there were significantly more patients under 35 years of age, more patients with primary infertility duration up to 3 years, and more patients with endometriosis that was previously treated (77.4%) (p < 0.039). In the cases of the successful outcome Endometriosis Fertility Index > 7, lower basal FSH and FSH/LH ratio were found, as well as significantly higher basal E2, basal P4 and AMH. Significantly lower doses of gonadotropins were needed in cases of the successful outcome, and long protocol with agonists was more frequently used. Multivariate logistic regres-sion analysis showed that previous therapy of endometriosis, P4 ≥ 0.7 ng/mL, AMH ≥ 0.9 ng/mL, A class of embryos, and the use of long protocol with agonists were predictors of the successful IVF/ICSI outcome. Therapy for endometriosis, AMH and P4 levels appeared to be predictors for the successful IVF/ICSI outcome and the use of long protocol with agonists could be advised in these cycles.

Shifting from Oral Contraceptives to Norethisterone Acetate, or Vice Versa, because of Drug Intolerance: Does the Change Benefit Women with Endometriosis?

Background/Aims: Oral contraceptives (OC) and norethisterone acetate (NETA) are among first-line medical therapies for symptomatic endometriosis, but their use is sometimes associated with intolerable side effects. We investigated whether shifting from low-dose OC to NETA (2.5 mg/day), or vice versa, improved tolerability. Methods: Sixty-seven women willing to discontinue their treatment because of intolerable side effects despite good pain relief, were enrolled in a self-controlled study, and shifted from OC to NETA (n = 35) or from NETA to OC (n = 32). The main study outcome was satisfaction with treatment 12 months after the change. Tolerability, pain symptoms, health-related quality of life, psychological status, and sexual functioning were also evaluated. Results: After treatment change, good tolerability was reported by 37% of participants who shifted to NETA, and by 52% of those who shifted to OC. At 12-month assessment, 51% of women intolerant to OC were satisfied with NETA, and 65% of those intolerant to NETA were satisfied with OC (intention-to-treat analysis). Other study variables did not vary substantially. Conclusions: In selected endometriosis patients, shifting from OC to NETA, or vice versa, because of side effects, improved tolerability. Better results were observed when substituting NETA with OC rather than the other way round.

Endometriosis: necessary and sequential therapeutic procedures and guidelines

To define the actual guidelines about the therapy of endometriosis. A brief review of the literature for the correct diagnosis of endometriosis and the medical and surgical approach. It is well accepted that the gold standard of endometriosis diagnosis is the direct vision of the disease with laparoscopy or the presence of endometriosis implants in vagina or cervix. Staging must be performed along with the distribution, and depth and bowel involvement must be noted. Symptoms intensity is not related to the degree of endometriosis. Therapy, medical or surgical, should be chosen in relation to symptoms and the disease degree, keeping in mind that surgery is the approach that may offer better results. The direct vision of the disease is the only method to obtain the correct diagnosis and an accurate staging. However, ultrasound can be helpful in cases of pelvic localization and in the follow-up of the disease. Moreover, MRI can be employed, especially in cases with particular endometriosis implant, e.g. gluteus muscle. Surgery offers the best results but some medical therapy, especially hormonal therapy, is often employed for the relief of pains.

Integration analysis of microRNA and mRNA paired expression profiling identifies deregulated microRNA-transcription factor-gene regulatory networks in ovarian endometriosis

BackgroundThe etiology and pathophysiology of endometriosis remain unclear. Accumulating evidence suggests that aberrant microRNA (miRNA) and transcription factor (TF) expression may be involved in the pathogenesis and development of endometriosis. This study therefore aims to survey the key miRNAs, TFs and genes and further understand the mechanism of endometriosis.MethodsPaired expression profiling of miRNA and mRNA in ectopic endometria compared with eutopic endometria were determined by high-throughput sequencing techniques in eight patients with ovarian endometriosis. Binary interactions and circuits among the miRNAs, TFs, and corresponding genes were identified by the Pearson correlation coefficients. miRNA-TF-gene regulatory networks were constructed using bioinformatic methods. Eleven selected miRNAs and TFs were validated by quantitative reverse transcription-polymerase chain reaction in 22 patients.ResultsOverall, 107 differentially expressed miRNAs and 6112 differentially expressed mRNAs were identified by comparing the sequencing of the ectopic endometrium group and the eutopic endometrium group. The miRNA-TF-gene regulatory network consists of 22 miRNAs, 12 TFs and 430 corresponding genes. Specifically, some key regulators from the miR-449 and miR-34b/c cluster, miR-200 family, miR-106a-363 cluster, miR-182/183, FOX family, GATA family, and E2F family as well as CEBPA, SOX9 and HNF4A were suggested to play vital regulatory roles in the pathogenesis of endometriosis.ConclusionIntegration analysis of the miRNA and mRNA expression profiles presents a unique insight into the regulatory network of this enigmatic disorder and possibly provides clues regarding replacement therapy for endometriosis.

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

Background/Aims: Mitochondrial homeostasis is implicated in the development and progression of endometriosis through poorly defined mechanisms. Mst1 is the major growth suppressor related to cancer migration, apoptosis and proliferation. However, whether Mst1 is involved in endometriosis apoptosis and migration via regulating the mitochondrial function remains to be elucidated. Methods: Expression of Mst1 in endometriosis was examined via western blots. Cellular apoptosis was detected via MTT and TUNEL assay. Gain of function assay about Mst1 was conducted via adenovirus over-expression. Mitochondrial functions were evaluated via mitochondrial membrane potential JC-1 staining, ROS flow cytometry analysis, mPTP opening assessment and immunofluorescence of HtrA2/Omi. The mitophagy activity were examined via western blots and immunofluorescence. Results: First, we found that Mst1 was significantly downregulated in the ectopic endometrium of endometriosis compared to the normal endometrium. However, the recovery of Mst1 function was closely associated with the inability of endometrial stromal cells (ESCs) to migrate and survive. A functional study indicated that regaining Mst1 enhanced Drp1 post-transcriptional phosphorylation at Ser616 and repressed Parkin transcription activity via p53, leading to mitochondrial fission activation and mitophagy inhibition. Excessive Drp1-related fission forced the mitochondria to liberate HtrA2/Omi into the cytoplasm. Moreover, Mst1-induced defective mitophagy evoked cellular oxidative stress, energy metabolism and calcium overload. Through excessive mitochondrial fission and aberrant mitophagy, Mst1 launched caspase 9-related mitochondrial apoptosis and abrogated F-actin/lamellipodium-dependent cellular migration. Notably, we also defined NR4A/miR181c as the upstream signal for Mst1 dysfunction in endometriosis. Conclusion: Collectively, our results comprehensively described the important role of the NR4A-miR181c-Mst1 pathway in endometriosis, which handled mitochondrial apoptosis and F-actin/ lamellipodium-based migration via the regulation of Drp1-related mitochondrial fission and Parkin-required mitophagy, with a potential application in endometriosis therapy by limiting ESCs migration and promoting apoptosis.

Advisory Board Resolution on the subject: 'Possibilities of personalized hormone-based therapies for endometriosis using dydrogesterone / Approval of the protocol of an Observational Open-Label Multicenter Study of Real Clinical Practice to Evaluate the Effects of Hormonal therapy with Oral Dydrogesterone for Treatment of Confirmed Endometriosis (the ORCHIDEA study)'

Advisory Board Resolution on the subject: 'Possibilities of personalized hormone-based therapies for endometriosis using dydrogesterone / Approval of the protocol of an Observational Open-Label Multicenter Study of Real Clinical Practice to Evaluate the Effects of Hormonal therapy with Oral Dydrogesterone for Treatment of Confirmed Endometriosis (the ORCHIDEA study)'