Hepcidin as a key regulator of iron homeostasis triggers inflammatory features in the normal endometrium.

Menstrual blood, containing high iron levels, can undergo retrograde transport into the abdominal cavity. Excess iron causes oxidative stress and inflammation. Iron metabolism is regulated by hepcidin, and serum hepcidin levels are increased in patients with endometriosis; however, the functions of hepcidin in normal endometrium remain unclear. We therefore aimed to examine hepcidin concentrations in patients with endometriosis and to determine if iron accumulation and hepcidin increased the production of reactive oxygen species (ROS) and inflammation in normal endometrial cells. We determined hepcidin levels in peritoneal fluid and menstrual blood from patients with and without endometriosis (25/16 and 15/15 patients, respectively). We also examined the effects of hepcidin on ferroportin expression, iron accumulation, and ROS generation in normal endometrial stromal cells (NESCs) from 20 women who underwent surgery for uterine leiomyoma, using immunohistochemistry and immunofluorescence analyses and analyzed its effect on the expression of inflammatory cytokines by real-time polymerase chain reaction. There was no significant difference in iron concentrations in menstrual blood or peritoneal fluid between women with and without endometriosis; however, women with endometriosis had significantly higher hepcidin levels in menstrual blood. Hepcidin reduced the expression of ferroportin in NESCs and promoted the accumulation of ferrous iron. Hepcidin plus ferrous iron increased the production of ROS and inflammatory cytokines compared with ferrous iron alone. These results indicate that women with endometriosis have high hepcidin levels in menstrual blood, leading to increased iron production, oxidative stress, and inflammation, which may, in turn, promote the development of endometriosis.

Postoperative Pregnancy Outcomes Following Laparoscopic Surgical Management in Women with Stage III/IV Endometriosis: A Single-Center Follow-Up Study.

Objectives: The effects of laparoscopic surgical management in women with stage III/IV endometriosis remain controversial. The standard extent of resection for stage III/IV endometriosis with deep endometriosis to treat endometriosis-associated infertility is debatable. This study aimed to assess the postoperative pregnancy outcomes following a routine surgical intervention for stage III/IV endometriosis patients. Materials and Methods: Patients with stage III/IV endometriosis who underwent conservative laparoscopic surgery at our hospital between January 2010 and December 2018 were retrospectively analyzed. Statistical analyses were performed to determine the correlations between endometriosis features and postoperative pregnancy outcomes. Results: Of 256 patients enrolled, 94 wished to conceive. Exclusion criteria: ≥40 years, adenomyosis, partners with infertility issues. Finally, 71 women were included. The overall postoperative pregnancy rate was 76.1% (n = 54): 49 and five from non-assisted reproductive technology (ART) and ART, respectively. The postoperative pregnancy rate in patients diagnosed with infertility presurgery (40/71) was 70.0% (n = 28): 24 (non-ART) and four (ART). The endometriosis fertility index (EFI) score was higher in the pregnant than in the nonpregnant group (P = 0.03). The EFI score and surgical score of EFI were higher in the non-ART than in the ART group (P = 0.04; P = 0.02); in the infertile group, they were higher in the pregnant than in the nonpregnant group (P = 0.018; P = 0.027). Conclusion: Our postoperative pregnancy rate after conservative laparoscopic surgery for patients with stage III/IV endometriosis compared favorably with previous reports. EFI was a significant predictor of postoperative pregnancy. Our surgical approach to maintain a high surgical score of EFI might help treat endometriosis-associated infertility.

Low-Nutrient Environment-Induced Changes in Inflammation, Cell Proliferation, and PGC-1α Expression in Stromal Cells with Ovarian Endometriosis.

Although nutrient status plays an important role in cell metabolism, its significance in endometriosis is obscure. Herein, we investigated the effects of a low-nutrient microenvironment on endometriosis. Stromal cells (SCs) from ovarian endometrioma (OESCs) or normal endometrium without endometriosis (NESCs) were isolated and cultured. A low-nutrient microenvironment was replicated by replacing the culture medium with Hank's balanced salt solution. OESC and NESC proliferation under the low-nutrient condition was measured. The expression of exacerbating factors in endometriosis under the low-nutrient condition was examined at the mRNA and protein levels. OESCs showed higher proliferation than NESCs under the low-nutrient condition. In OESCs, the low-nutrient condition upregulated the mRNA expression of vascular endothelial growth factor (VEGF), interleukin-6 and -8, aromatase, Bcl-2, and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and downregulated that of BAX and induced transcription of PI.3, PII, and exon II. Western blotting revealed elevated VEGF and PGC-1α expression under the low-nutrient condition in OESCs. These changes coincided with the elevated expression of PGC-1α, which was reduced at the mRNA level upon nutrient status rescue. Endometriosis is exacerbated by altered angiogenesis, inflammation, anti-apoptosis, and local estrogen production while trying to survive under a low-nutrient microenvironment; it may be attributed to PGC-1α-mediated metabolic mechanisms.

Progesterone Receptor Status of Epithelial Cells as a Predictive Marker for Postoperative Recurrence of Endometriosis.

CONTEXT: Progesterone resistance including progesterone receptor (PR) deficiency contributes to the pathophysiology of endometriosis; however, whether the PR expression levels in ovarian endometrioma (OE) correlate with the postoperative recurrence of endometriosis remains unclear. OBJECTIVE: This study aimed to investigate the association between PR expression levels in OE and the recurrence of endometriosis. METHODS: OE specimens were obtained from 132 patients who underwent conservative surgery for endometriosis. The PR expression levels were evaluated using the H score after immunohistochemical staining. RESULTS: Of the 132 patients, 36 (27.3%) experienced recurrence and 96 (72.7%) did not. No differences were observed in the patient characteristics between the recurrence and nonrecurrence groups except for follow-up period. PR immunoreactivity in the epithelial cells (ECs) was statistically significantly lower in the recurrent group than in the nonrecurrent group (P < .01); however, this change was not observed in the stromal cells. Moreover, multivariable logistic regression analysis revealed that the H score of PR in ECs was an independent factor and was statistically significantly associated with the recurrence of endometriosis (P = .01). Furthermore, we divided the patients into PR-negative or PR-positive groups. The cumulative recurrence rate in the negative PR group was statistically significantly higher than that in the positive PR group (P = .046). CONCLUSION: Low PR expression levels in OE-ECs may predict the recurrence of endometriosis. The PR status in OE-ECs is associated with the pathophysiology of the recurrence of endometriosis, and optimized postoperative management for endometriosis may be provided by referring to the PR status.

Reduced innate lymphoid cells in the endometrium of women with endometriosis.

PROBLEM: Innate lymphoid cells (ILCs), a recently discovered family of innate immune cells, are responsible for the early immune response, and control both innate and adapted immune system via cytokine secretion. The role of ILCs in endometriosis has not been investigated; therefore, here, we aimed to investigate how the proportion of ILCs changes in endometriosis. METHOD OF STUDY: The percentage of each ILC group in CD45+ cells was examined in the peripheral blood, peritoneal fluid, endometrium, and ovarian endometrioma obtained from women with and without endometriosis (ERB-C-1216) using flow cytometry. RESULTS: Specimens were obtained from 19 women with endometriosis and 15 without endometriosis. In the endometrium, patients with endometriosis had lower proportion of ILC2 and 3 compared to control specimens (ILC2: .02±.01% vs .07±.03%; P < .05, ILC3: .31±.14% vs 1.10±.93%; P < .05). There was no significant change in the peripheral blood or the peritoneal fluid between the two groups. Additionally, ovarian endometrioma increased the proportion of ILCs (ILC1: .92±1.12%, ILC2: .08±.08%, ILC3: .70±.39%) compared to the endometrium samples of patients with endometriosis each with P < .05. Immunohistochemistry of IL-1ß and IL-23, which are ILC3-inducing factors, showed no significant change in the H-score of the epithelium of the two groups, but a significant increase was found in ovarian endometrioma. CONCLUSION: The proportion of ILC2 and 3 was reduced in the endometrium of patients with endometriosis, and ILCs were increased in ovarian endometrioma. Our findings may indicate a new immunological approach to understand the pathophysiology of endometriosis.

Primary Ovarian Leiomyoma Associated with Multiple Uterine Leiomyomas.

Ovarian leiomyomas are very rare. We report the case of a primary ovarian leiomyoma accompanied by multiple uterine leiomyomas. A 50-year-old woman was referred to our department for heavy menstruation, and a hot spot in the uterine lumen was observed on positron emission tomography-computed tomography (PET-CT). Cervical and endometrial cytology and tumor marker tests were negative. Pelvic magnetic resonance imaging revealed an endometrial polyp and submucosal leiomyoma in the uterine lumen and a 5-cm right ovarian tumor. Laparoscopic total hysterectomy, right salpingo-oophorectomy, and left salpingectomy were performed for radical treatment. Histopathology showed that ovarian tumors contained interlacing bundles of fusiform cells encircled by normal ovarian tissue. Immunohistochemical staining showed strong and diffuse positive staining for α-smooth muscle actin. We diagnosed the tumor as a primary ovarian leiomyoma because the leiomyoma was localized in the ovary and was larger than the size of uterine leiomyomas. No metastatic lesion was found on PET-CT. There was no tumor recurrence at the 6-month follow-up.

Successful detection of rectal injury during laparoscopic surgery using a rectal probe in a patient with deep endometriosis.

Laparoscopic surgery has become the gold standard treatment for endometriosis. Surgical treatment of deep endometriosis with colorectal involvement is challenging. It requires complete surgical excision of lesions despite a high risk of complications that include rectal injury, rectovaginal fistula and pelvic abscess. An intraoperative air leak test allows detection of rectal injury and reduces postoperative complications. We report a case of successful management of rectal injury during laparoscopic surgery using a rectal probe even though air leak tests were negative. A 45-year-old woman with severe endometriosis and rectal involvement underwent total laparoscopic hysterectomy combined with rectal shaving. A pinhole injury that reached the rectal muscularis layer without breaching the mucosal layer was identified using a rectal probe after negative air leak tests. The injury was repaired uneventfully. Our experience suggests that using a rectal probe could be helpful for early detection and safe repair of rectal injury during surgery.

Interleukin-9 produced by helper T cells stimulates interleukin-8 expression in endometriosis.

PROBLEM: Inflammation and immune responses play crucial roles in the development of endometriosis. Although interleukin-9 (IL-9) has a pro-inflammatory function in chronic inflammatory diseases, its function in endometriosis remains unknown. Here, we aimed to investigate the significance of IL-9 and IL-9-producing lymphocytes in endometriosis. METHOD OF STUDY: Specimens were obtained from patients with and without endometriosis. Peritoneal fluid (PF), peripheral blood (PB), and ovarian endometrioma (OE) tissues were analyzed for the proportion of CD4+ IL-9+ lymphocytes and IL-9 concentration using flow cytometry and enzyme-linked immunosorbent assay. OE, endometrium with endometriosis (EE), and normal endometrium (NE) were analyzed for IL-9 receptor (IL-9R) expression using immunohistochemical staining. IL-9-dependent changes in Interleukin-8 (IL-8) expression in endometrial stromal cells from OE (OESCs) were evaluated using real-time PCR. RESULTS: The proportion of CD4+ IL-9+ lymphocytes was higher in the PF, but not the PB, of patients with endometriosis than individuals without endometriosis (p < .05). However, IL-9 levels in the PF did not differ between those with and without endometriosis. We detected CD4+ IL-9+ lymphocytes in OE tissues and IL-9R in OE tissues and OESCs. In OESC culture, IL-9 significantly elevated IL-8 expression in a dose-dependent manner (p < .05), which was nullified by the addition of the anti-IL-9 receptor antibody. Furthermore, IL-9 additively stimulated IL-8 expression in the presence of TNF-α (p < .05). CONCLUSION: Our findings show that IL-9 produced by helper T cells induces IL-8 expression, suggesting that IL-9 plays an important role in the development of endometriosis by stimulating IL-8 expression.

Atherosclerosis-related biomarkers in women with endometriosis: The effects of dienogest and oral contraceptive therapy.

OBJECTIVE: Chronic inflammation in endometriosis is associated with increased risk of future cardiovascular disease; however, no studies have investigated the cardiovascular risk of women who have undergone hormonal therapy for endometriosis. We investigated atherosclerosis-related biomarkers in women with and without endometriosis and the effects of dienogest (DNG) and oral contraceptive (OC) therapies. STUDY DESIGN: In this cross-sectional study, 109 women with endometriosis and 42 control women without endometriosis were enrolled. The endometriosis group was divided into the untreated (n = 34), DNG therapy (n = 33), and OC therapy (n = 42) groups. Lipid profile serum levels, inflammatory marker such as high-sensitivity C-reactive protein, oxidative stress markers such as oxidized low-density lipoprotein and diacron-reactive oxygen metabolites, and atherosclerosis indicators (cardio-ankle vascular index [CAVI] and ankle-brachial pressure index [ABI]) were measured. RESULTS: The median treatment duration was 28 months in the DNG group and 32.5 months in the OC group. Triglyceride levels were higher in the OC group than in the other three groups (P < 0.05). Regarding markers of inflammation and oxidative stress, log high-sensitivity C-reactive protein and diacron-reactive oxygen metabolites levels were higher in the untreated group than in the control group (P < 0.05), and these markers were further increased in the OC group (log high-sensitivity C-reactive protein: P < 0.05; diacron-reactive oxygen metabolites: P < 0.01), but not in the DNG group. There was no difference in the CAVI and ABI among all groups. Spearman correlation revealed a positive correlation between duration of OC therapy and CAVI (ρ = +0.49; P = 0.002), but no correlation between the duration of DNG therapy and CAVI (ρ = -0.04; P = 0.81). CONCLUSIONS: Inflammation and oxidative stress markers are increased in women with untreated endometriosis. Treatment with OC, but not with DNG, further increases these levels. There was a positive association between the duration of OC administration and atherosclerosis risk for women with endometriosis. Our results suggest that DNG could be administered to endometriosis without the increased atherosclerosis risk and short-term OC administration for endometriosis is not harmful, however, atherosclerosis risk should be strictly observed.

Unexpected tumor-to-tumor metastasis of synovial sarcoma within leiomyoma: A case report and literature review.

A tumor metastasis within another tumor is known as tumor-to-tumor metastasis (TTM). We report a 43-year-old woman who presented with hypermenorrhea and an abdominal mass. She had history of a soft tissue tumor on her left ankle at 38 years of age. Laboratory data showed slight elevation of CA125 and no other abnormal findings and magnetic resonance imaging revealed a circumscribed margin mass in the uterine fundus. We diagnosed the mass as benign leiomyoma and performed total laparoscopic hysterectomy. Postoperative pathological examination revealed TTM of synovial sarcoma within the uterine leiomyoma. A database search identified 29 cases of TTM within uterine leiomyoma. The donor tumor was mostly breast cancer (in 23 cases). To the best of our knowledge, this is the first report of a sarcoma TTM to a uterine leiomyoma. Despite the difficulty of preoperative diagnosis, TTM should be considered during the treatment approach for a patient with leiomyoma and a history of malignant tumors.

Protocol for a modified vaginal pipe for total laparoscopic hysterectomies: Experimental research.

BACKGROUND: The Vagi-Pipe® is a useful device for performing a total laparoscopic hysterectomy. The conventional model of the Vagi-Pipe® is unable to grasp the uterus during colpotomy for recovery of the resected uterus. However, the modified C-Type Vagi-Pipe® model has a shape that allows insertion into the vagina without removing the uterus manipulator. In this study, we will prospectively investigate the safety and efficacy of the C-Type Vagi-Pipe® in total laparoscopic hysterectomies. MATERIALS AND METHODS: In total, 25 female subjects aged between 20 and 60 years with uterine fibroids or adenomyosis will be included. Patients with complications regarded as unsuitable for this study by the investigators will be excluded. The C-Type Vagi-Pipe® will be used rather than the conventional Vagi-Pipe® when performing a total laparoscopic hysterectomy. The primary endpoint will be safety and the secondary endpoints will be operation time, bleeding volume, and presence of complications. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review boards. Written informed consent will be obtained from all patients before registration in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals.

Peroxisome proliferator-activated receptor-γ coactivator 1α-mediated pathway as a possible therapeutic target in endometriosis.

STUDY QUESTION: Is a peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)-mediated pathway involved in the development of endometriosis? SUMMARY ANSWER: PGC-1α plays critical roles in inflammation and cell proliferation of endometriotic tissues and may be involved in the development of endometriosis. WHAT IS KNOWN ALREADY: Expression levels of PGC-1α are higher in ovarian endometrioma (OE) than normal endometrium (NE). PGC-1α also stimulates aromatase activity and promotes local estrogen biosynthesis in OE. STUDY DESIGN, SIZE, DURATION: This is a case-controlled biological study using endometrial cells and tissues derived from 23 women with, and 10 women without, OE. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ectopic endometriotic and eutopic endometrial stromal cells (SCs) were isolated and maintained in culture. PGC-1α was either overexpressed in the cells or knocked down using siRNA. The expression of PGC-1α and other factors during endometriosis was examined using real-time PCR and western blotting, cell proliferation was measured using Cell Counting Kit-8 (WST-8) assays and transcriptional activity was assessed using luciferase reporter assays. MAIN RESULTS AND THE ROLE OF CHANCE: PGC-1α overexpression promoted the proliferation of OESCs in a time-dependent manner (P < 0.01 versus control) but not NESCs. PGC-1α stimulated aromatase (P < 0.01 versus control) and interleukin (IL)-6/IL-8 mRNA expression levels (P < 0.05 versus control for each) and led to inhibitor kappa B phosphorylation protein expression and upregulation of the apoptosis inhibitors X-linked inhibitor of apoptosis protein and survivin at mRNA level (P < 0.05 versus control for each). HX531, a selective retinoid-X receptor-α (RXRα) antagonist, suppressed the PGC-1α-induced cell proliferation (P < 0.05 versus control), aromatase/IL-6/IL-8/survivin mRNA expression (P < 0.05 versus control for each) and transcription reporter activity of PGC-1α in a dose-dependent manner (P < 0.01 versus control). Moreover, HX531 downregulated PGC-1α-induced aromatase-promoter PI.3-II transcripts in OESCs, and PGC-1α knockdown reduced aromatase, IL-6/IL-8 and antiapoptotic factors mRNA expression (P < 0.05 versus control for each). Notably, the Histogram score, which was used for quantifying RXRα status, was markedly higher in OE than in NE tissue (P < 0.01). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Only OE tissues were included in this study, while peritoneal and deep infiltrating endometriotic tissues were not. Therefore, these findings might not be generalized to other types of endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: In OESC, PGC-1α stimulated cell proliferation and was involved in local estrogen biosynthesis, inflammation and apoptosis, and these effects of PGC-1α were inhibited by HX531. The suppression of PGC-1α-induced proliferation by HX531 in OESCs but not NESCs suggests that the PGC-1α-RXRα axis could play critical roles in promoting endometriosis. This is the first report of a relationship between PGC-1α and inhibitor of apoptosis proteins in endometriosis. Based on these findings, the PGC-1α-mediated pathway could represent a potential target in molecular therapy of endometriosis. STUDY FUNDING/COMPETING INTEREST(S): The study is supported in part by Grants-in-Aid for Scientific Research (15 K10681 and 15 K10726) from the Ministry of Education, Culture, Sports, Science, and Technology (Japan). The authors have no conflicts of interest to disclose.

Massive prolapsed submucous fibroid treated with laparoscopic surgery: A case report.

Prolapsed uterine fibroids are pedunculated submucous fibroids that prolapse through the cervical canal. Herein, we describe the laparoscopic treatment of massive prolapsed submucous fibroids. A 47-year-old woman had experienced frequent urination and abnormal vaginal bleeding for 7 years. She presented with persistent lower abdominal pain. The uterine fundus was palpable at 3 cm above the umbilicus. Vaginal examination revealed a dark purple and easily bleeding mass in her vagina. Pelvic magnetic resonance imaging revealed a large mass prolapsing from the uterine endometrium, which occupied the cervical canal and vagina, without evidence of malignancy. Under a preoperative diagnosis of uterine fibroids with edematous degeneration, we performed laparoscopic uterine artery cutting, transvaginal removal of the fibroid by twisting, and total laparoscopic hysterectomy. Histopathological examination revealed leiomyoma with partial ischemia. Six days postoperatively, the patient was discharged without complications. This approach may be appropriate for the treatment of massive prolapsed submucous fibroids.

Successful Laparoscopic Surgery without Neuromuscular Blockade in a Patient with Malignant Hyperthermia Susceptibility.

Malignant hyperthermia (MH) is a life-threatening clinical syndrome of hypermetabolism involving skeletal muscle. Susceptibility to MH is inherited in an autosomal dominant manner. Its common trigger is exposure to volatile anesthetic agents or depolarizing muscle relaxants. Deep neuromuscular blockade using muscle relaxants can improve the quality of surgical conditions and prevent cardiorespiratory adverse events during laparoscopic surgery. Here we report a case of successful laparoscopic surgery under anesthetic management without neuromuscular blockade in an MH-susceptible patient. A 22-year-old woman with a family history of MH underwent laparoscopic excision of ovarian endometrioma under total intravenous anesthesia and a posterior transversus abdominis plane block. The surgery was completed uneventfully. Our experience suggests that this type of anesthetic management is useful when performing laparoscopic surgery in MH-susceptible patients.

Dienogest therapy during the early stages of recurrence of endometrioma might be an alternative therapeutic option to avoid repeat surgeries.

AIM: We aimed to evaluate whether hormonal therapy immediately after postsurgical recurrence of ovarian endometrioma controls disease progression and can be an alternative therapeutic option to avoid multiple repeat surgeries. METHODS: We enrolled 146 patients treated for endometrioma at the University Hospital of Kyoto Prefectural University of Medicine between 2009 and 2015. After laparoscopic cystectomy using the stripping technique, opening of cul-de-sac obliterations and complete resection of the deep infiltrating endometriosis lesions, the patients either received no treatment (n = 83), oral contraceptives (OC; n = 32) or dienogest (DNG; n = 27), depending on their medical history. Four patients were excluded because they changed their regimens during the follow-up period. All patients were followed up every 3 months. Patients who developed recurrence of endometrioma immediately received DNG, OC or gonadotropin-releasing hormone agonist. RESULTS: Overall, 16 patients developed a recurrence of the endometrioma (12 in the nontreatment group, three in the OC group and one in the DNG group). The 11 patients with recurrence were treated with DNG immediately after the diagnosis of recurrent endometrioma. Among them, seven patients continued treatment with DNG (2 mg) for 24 months. After 24 months of treatment with DNG, complete resolution of recurrent endometrioma was achieved in four (57.1%) of seven patients. There was no improvement in the three patients who received OC and one patient who underwent secondary surgery. CONCLUSION: DNG therapy early after recurrence of postsurgical endometrioma appears to be viable for reducing the risk of repeated surgery.

Isolated fallopian tube torsion diagnosed and treated with laparoscopic surgery: A case report.

Among diseases causing acute lower abdominal pain in women, isolated fallopian tube torsion is very rare, with an annual prevalence of 1 in 1.5 million. Because it has fewer findings on imaging compared to adnexal torsion, the correct diagnosis can rarely be made before an operation. We present a case of isolated fallopian tube torsion that was suspected preoperatively by its clinical course and findings on computed tomography. A 24-year-old woman repeatedly experienced acute colicky pain in the right lower back. Transvaginal ultrasonography and magnetic resonance imaging showed a right pelvic cystic lesion with intact ovaries; these findings led us to schedule a laparoscopic examination. However, the patient presented to the emergency room with acute severe right back pain. The preoperative diagnosis considering the computed tomography findings and clinical course was consistent with fallopian tube torsion. An earlier diagnosis may have helped to preserve the fallopian tube and future fertility.

Effects of low-dose combined drospirenone-ethinylestradiol on perimenstrual symptoms experienced by women with endometriosis.

OBJECTIVE: To determine the effectiveness of a 24/4-day regimen of a low-dose combination drospirenone-ethinylestradiol oral contraceptive in alleviating perimenstrual symptoms among Japanese women with endometriosis. METHODS: The present prospective, non-randomized study enrolled women diagnosed with endometriosis radiographically or surgically at the Kyoto Prefectural University of Medicine hospital, Japan, between December 1, 2010 and August 31, 2013. Patients received treatment with oral drospirenone-ethinylestradiol for six treatment cycles. Dysmenorrhea, chronic pelvic pain, and dyspareunia severity were assessed using visual analog scale scores after three and six treatment cycles, and changes in perimenstrual symptoms were assessed using the menstrual distress questionnaire (MDQ) scores. RESULTS: In total, 46 patients were recruited for the study. Dysmenorrhea, chronic pelvic pain, and dyspareunia were all significantly reduced after both three and six treatment cycles in comparison with baseline (P<0.001 for all comparisons). After six treatment cycles, significant reductions were observed for all menstrual MDQ measures and for the premenstrual water retention and negative-effect MDQ measures (all P<0.05). CONCLUSIONS: Combination drospirenone-ethinylestradiol was effective in the treatment of dysmenorrhea, chronic pelvic pain, dyspareunia, and somatic/psychological symptoms in Japanese women with endometriosis.

Endometrioid adenocarcinoma arising from deep infiltrating endometriosis involving the bladder: A case report and review of the literature.

•Malignant transformation of deep infiltrating endometriosis involving the bladder is quite rare.•We review eight relevant cases which have been reported.•This is the second case fulfilling Sampson and Scott criteria.

G protein-coupled estrogen receptor 1 agonist G-1 induces cell cycle arrest in the mitotic phase, leading to apoptosis in endometriosis.

OBJECTIVE: To demonstrate the effects of the selective G protein-coupled estrogen receptor 1 (GPER) agonist G-1 in human ovarian endometriotic stromal cells (ESCs). DESIGN: Experimental in vitro study. SETTING: University hospital. PATIENT(S): A total of 33 patients with ovarian endometrioma. INTERVENTION(S): Endometriotic stromal cells from ovarian chocolate cysts were treated with the GPER agonist G-1. MAIN OUTCOME MEASURE(S): The primary outcomes were cell proliferation, measured using the WST-8 assay; cell cycle, as analyzed using flow cytometry, fluorescent immunocytochemistry, and cytotoxicity; caspase activity, as measured by fluorescent and luminescent enzyme assays; and protein expression levels, as determined by Western blot analysis. RESULT(S): G-1 suppressed ESC proliferation in a concentration-dependent manner. The inhibitory effect was not blocked when GPER signaling pathways, including the GPER itself, were inhibited. G-1 induced cell cycle arrest and accumulation in the sub-G1 phase in ESCs. Immunofluorescence analysis demonstrated that G-1 interrupted microtubule assembly at the mitotic phase. G-1 also induced caspase-3-dependent apoptosis without significant cytotoxicity. CONCLUSION(S): G-1 suppressed proliferation and induced apoptosis in ESCs, suggesting the potential use of this compound as a therapeutic drug for the treatment of endometriosis.

Dienogest reduces HSD17ß1 expression and activity in endometriosis.

Endometriosis is an estrogen-dependent disease. Abnormally biosynthesized estrogens in endometriotic tissues induce the growth of the lesion and worsen endometriosis-associated pelvic pain. Dienogest (DNG), a selective progesterone receptor agonist, is widely used to treat endometriosis and efficiently relieves the symptoms. However, its pharmacological action remains unknown. In this study, we elucidated the effect of DNG on enzymes involved in local estrogen metabolism in endometriosis. Surgically obtained specimens of 23 ovarian endometriomas (OE) and their homologous endometrium (EE), ten OE treated with DNG (OE w/D), and 19 normal endometria without endometriosis (NE) were analyzed. Spheroid cultures of stromal cells (SCs) were treated with DNG and progesterone. The expression of aromatase, 17ß-hydroxysteroid dehydrogenase 1 (HSD17ß1), HSD17ß2, HSD17ß7, HSD17ß12, steroid sulfatase (STS), and estrogen sulfotransferase (EST) was evaluated by real-time quantitative PCR. The activity and protein level of HSD17ß1 were measured with an enzyme assay using radiolabeled estrogens and immunohistochemistry respectively. OESCs showed increased expression of aromatase, HSD17ß1, STS, and EST, along with decreased HSD17ß2 expression, when compared with stromal cells from normal endometria without endometriosis (NESCs) (P<0.01) or stromal cells from homologous endometrium (EESCs) (P<0.01). In OESCs, DNG inhibited HSD17ß1 expression and enzyme activity at 10(-7) M (P<0.01). Results of immunohistochemical analysis displayed reduced HSD17ß1 staining intensity in OE w/D (P<0.05). In conclusion, DNG exerts comprehensive inhibition of abnormal estrogen production through inhibition of aromatase and HSD17ß1, contributing to a therapeutic effect of DNG on endometriosis.