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Ovarian endometrioma (OE) is a common gynecological disease that is often treated with surgery and hormonal treatment. However, ovarian cystectomy can impair the ovarian reserve (OR). Previously, we showed that perioperative administration of dienogest (DNG) is an effective option for OR preservation. However, there were differences in the extent of OR preservation among patients following perioperative DNG treatment. In the current study, we performed a global examination of serum microRNAs (miRNAs) to identify accurate biomarkers that predict post-operative restoration of OR following perioperative DNG treatment. We also sought to identify specific miRNAs related to the anti-Müllerian hormone (AMH). miRNA sequencing was performed on serum samples obtained from twenty-seven patients who received perioperative DNG treatment. Candidate miRNAs were selected by comparing patients whose ORs were restored postoperatively (responder group, n = 7) with those whose ORs were not (non-responder group, n = 7). miR-370-3p and miR-1307-3p were significantly upregulated in the responder group, whereas miR-27b-3p was upregulated in the non-responder group. The pretreatment value of each miRNA could predict DNG responsiveness for OR following ovarian cystectomy (area under the curve [AUC] > 0.8). The quantitative polymerase chain reaction (qPCR) revealed only miR-1307-3p was found to be significantly upregulated in the responder group (P < 0.05). In addition, we identified miR-139-3p, miR-140-3p, and miR-629-5p as AMH-associated miRNAs. The transition of AMH showed a correlation with miR-139-3p (P < 0.05, r = -0.76). The miRNAs identified herein represent potential serum biomarkers of clinical value in predicting OR prior to DNG treatment., Competing Interests: Declaration of Competing Interest The authors have declared that no conflicts of interest exist., (Copyright © 2023. Published by Elsevier B.V.)

The mainstay of treatment for endometriosis is hormonal therapy, which suppresses ovulation; therefore, patients cannot conceive during treatment. There is a dilemma with ovarian-sparing surgery, known as laparoscopic cystectomy, as it can potentially damage the ovaries. Therefore, there is a need for non-hormonal drug therapies. We addressed these challenges in endometriosis treatment, aiming to maintain ovarian function while achieving effective treatment through basic research. Herein, we present two studies using different mouse models of endometriosis. The first study investigates the effects of a nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3 inhibitor in a mouse model of ovarian endometriotic cysts. We confirmed the increased expression of NLRP in ovarian endometriotic cysts compared with that in the uterine endometrium in both patient-derived samples and mouse model lesions. Administering an NLRP3 inhibitor to model mice resulted in lesion reduction. The second study used a peritoneal lesion mouse model to examine bacterial infection in the endometrium and its association with endometriosis development. Using existing databases and patient-derived samples, we identified that Fusobacterium was involved in the development of endometriosis and lesion enlargement when infecting the endometrium in the model. Furthermore, antibiotic treatment led to a reduction in the lesions. These studies highlight the potential of repositioning existing drugs with NLRP3 inhibitory effects or antibiotics as new non-hormonal treatments for endometriosis.

Retrograde menstruation is a widely accepted cause of endometriosis. However, not all women who experience retrograde menstruation develop endometriosis, and the mechanisms underlying these observations are not yet understood. Here, we demonstrated a pathogenic role of Fusobacterium in the formation of ovarian endometriosis. In a cohort of women, 64% of patients with endometriosis but <10% of controls were found to have Fusobacterium infiltration in the endometrium. Immunohistochemical and biochemical analyses revealed that activated transforming growth factor-β (TGF-β) signaling resulting from Fusobacterium infection of endometrial cells led to the transition from quiescent fibroblasts to transgelin (TAGLN)-positive myofibroblasts, which gained the ability to proliferate, adhere, and migrate in vitro. Fusobacterium inoculation in a syngeneic mouse model of endometriosis resulted in a marked increase in TAGLN-positive myofibroblasts and increased number and weight of endometriotic lesions. Furthermore, antibiotic treatment largely prevented establishment of endometriosis and reduced the number and weight of established endometriotic lesions in the mouse model. Our data support a mechanism for the pathogenesis of endometriosis via Fusobacterium infection and suggest that eradication of this bacterium could be an approach to treat endometriosis.

Background: Endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects 10% of women of reproductive age. Ovarian endometriosis (OE) is the most common lesion in endometriosis and may cause infertility, in addition to dysmenorrhea. Hormonal treatments, which are the conventional treatment methods for endometriosis, suppress ovulation and hence are not compatible with fertility. The inflammasome is a complex that includes Nod-like receptor (NLR) family proteins, which sense pathogen-associated molecular patterns and homeostasis-altering molecular processes. It has been reported that the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3 inflammasome, which contributes to the activation of interleukin-1 beta (IL-1β), might be related to the progression of endometriosis. Therefore, the aim of the present study was to evaluate non-hormonal therapies for OE, such as inhibitors of the NLRP3 inflammasome., Methods: The expression of NLRP3 was measured in the eutopic endometrium (EM) of patients with and without endometriosis and OE samples, as well as stromal cells derived from the endometrium of patients with and without endometriosis and OE samples (endometrial stromal cells with endometriosis [ESCs] and cyst-derived stromal cells [CSCs]). The effects of an NLRP3 inhibitor (MCC950) on ESCs and CSCs survival and IL-1β production were evaluated. We then administered MCC950 to a murine model of OE to evaluate its effects on OE lesions and ovarian function., Results: NLRP3 gene and protein expression levels were higher in OE and CSCs than in EM and ESCs, respectively. MCC950 treatment significantly reduced the survival of CSCs, but not that of ESCs. Moreover, MCC950 treatment reduced the co-localization of NLRP3 and IL-1β in CSCs, as well as IL-1β concentrations in CSCs supernatants. In the murine model, MCC950 treatment reduced OE lesion size compared to phosphate-buffered saline treatment (89 ± 15 vs. 49 ± 9.3 mm 3 per ovary; P < 0.05). In the MCC950-treated group, IL-1β and Ki67 levels in the OE-associated epithelia were reduced along with the oxidative stress markers of granulosa cells., Conclusions: These results indicated that NLRP3/IL-1β is involved in the pathogenesis of endometriosis and that NLRP3 inhibitors may be useful for suppressing OE and improving the function of ovaries with endometriosis., (© 2022. The Author(s).)

Background: Ovarian endometrioma is a common gynecological disease that is often treated with surgery or hormonal treatment. Ovarian cystectomy, a surgical procedure for ovarian endometrioma, can result in impaired ovarian reserve., Methods: We conducted a randomized controlled trial to evaluate the efficacy of hormonal treatment [gonadotropin-releasing hormone agonist (GnRHa) or dienogest (DNG)] for preserving ovarian reserve after cystectomy for ovarian endometrioma. The primary endpoint was the level of serum Anti-Müllerian hormone (AMH) as a marker of ovarian reserve., Results: Before and after laparoscopic surgery, 22 patients in the GnRHa group and 27 patients in the DNG group were administered hormonal treatment for a total of 4 months. After 1-year follow-up, >60% of the patients in the DNG group retained over 70% of their pretreatment AMH levels, whereas no patient in the GnRHa group retained their AMH levels after cystectomy (P < 0.01). Interleukin-6 (IL-6) is a key cytokine involved in inflammation. Compared with the GnRHa group, patients in the DNG group had lower IL-6 levels at the end of treatment., Conclusions: Our data revealed that DNG is more effective than GnRHa in preserving ovarian reserve after cystectomy of ovarian endometrioma. This is achieved through the reduction of the inflammatory response during the perioperative period and other endometriosis-related inflammatory reactions., Trial Registration: The registration number of this trial is UMIN-CTR, UMIN000018569, registered 6 August 2015, https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000021492 , and Japan Registry of Clinical Trials, jRCTs041180140, registered 29 March 2019, https://jrct.niph.go.jp/en-latest-detail/jRCTs041180140 . This randomized controlled trial was conducted in accordance with the CONSORT guidelines., (© 2021. The Author(s).)

Endometriosis has several distinguishing features in the ectopic endometrium, including chronic inflammation and fibrosis. According to the retrograde menstruation theory, endometriotic cells are derived from eutopic endometrial cells, and adhesion of endometrial cells to the extracellular matrix can be the initial step in the development of endometriosis. Therefore, we hypothesized that cell adhesion, which mediates a sequence of events in the development of endometriosis triggering inflammatory responses and tissue fibrosis could be a possible therapeutic target for endometriosis. We found co-upregulation of focal adhesion kinase (FAK) and monocyte chemoattractant protein-1 (MCP-1) in the endometriotic tissues compared with that in the normal endometrium. MCP-1 secretion was significantly higher in the endometriotic stromal cells than in the eutopic endometrial stromal cells. Furthermore, co-culture of U937 cells and endometriotic stromal cells upregulated secretion of transforming growth factor-β1 (TGF-β1). A FAK inhibitor significantly inhibited the secretion of MCP-1 in the endometriotic stromal cells and TGF-β1 in the co-culture with macrophages. FAK inhibitor treatment in the murine endometriosis model demonstrated a decrease in the formation of endometriotic lesions as well as the expression of MCP-1 and TGF-β1. Our results suggest that the FAK-mediated sequential development of endometriosis, including inflammatory response and tissue fibrosis, can be a new therapeutic target in endometriosis.

Repeated tissue injury and repair and fibrosis play a pivotal role in endometriosis. Fibrotic tissue consists of extracellular matrix proteins, regulated by transcriptional factors promoting cell proliferation and survival. Periostin is one of the putative key extracellular matrix proteins. This study aimed to determine whether transcription factor 21 (TCF21) is involved in the development of endometriosis as an upstream regulatory gene of periostin. Formalin-fixed, paraffin-embedded tissue samples [normal endometrium of women without endometriosis; eutopic endometrium of women with endometriosis; ovarian endometriosis (OE); and deep infiltrating endometriosis (DIE)] and respective cells were analyzed. Basal, transiently stimulated, and knocked down periostin and TCF21 concentrations in stromal cells of women with or without endometriosis were examined. Periostin and TCF21 expressions were undetected in normal endometrium of women without endometriosis, weakly positive in eutopic endometrium of women with endometriosis, moderately positive in OE, and strongly positive in DIE. Type 2 helper T-cell cytokines (IL-4, IL-13, and transforming growth factor-β1) increased the mRNA expression of periostin and TCF21. These cytokines, periostin, and TCF21 colocalized in the stroma of OE and DIE. siRNA against human TCF21 gene suppressed periostin expression. Transfection of TCF21 plasmid vector into stromal cells of women without endometriosis, which originally expressed neither periostin nor TCF21, resulted in TCF21 and periostin expression. TCF21 and periostin are involved in the regulation of fibrosis in endometriosis. TCF21 may be a promising therapeutic target and biomarker in endometriosis., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Uterine adenomyosis is a benign disorder that often co-occurs with endometriosis and/or leiomyoma, and impairs quality of life. The genomic features of adenomyosis are unknown. Here we apply next-generation sequencing to adenomyosis (70 individuals and 192 multi-regional samples), as well as co-occurring leiomyoma and endometriosis, and find recurring KRAS mutations in 26/70 (37.1%) of adenomyosis cases. Multi-regional sequencing reveals oligoclonality in adenomyosis, with some mutations also detected in normal endometrium and/or co-occurring endometriosis. KRAS mutations are more frequent in cases of adenomyosis with co-occurring endometriosis, low progesterone receptor (PR) expression, or progestin (dienogest; DNG) pretreatment. DNG's anti-proliferative effect is diminished via epigenetic silencing of PR in immortalized cells with mutant KRAS. Our genomic analyses suggest that adenomyotic lesions frequently contain KRAS mutations that may reduce DNG efficacy, and that adenomyosis and endometriosis may share molecular etiology, explaining their co-occurrence. These findings could lead to genetically guided therapy and/or relapse risk assessment after uterine-sparing surgery.

Background: Endometriosis is a common disease occurring in 1-2% of all women of reproductive age. Although there is increasing evidence on the association between endometriosis and adverse perinatal outcomes, little is known about the effect of pre-pregnancy treatments for endometriosis on subsequent perinatal outcomes. Thus, this study aimed to evaluate maternal and neonatal outcomes in pregnant women with endometriosis and to investigate whether pre-pregnancy surgical treatment would affect these outcomes., Methods: This case-control study included 2769 patients who gave birth at Nagoya University Hospital located in Japan between 2010 and 2017. Maternal and neonatal outcomes were compared between the endometriosis group (n = 80) and the control group (n = 2689). The endometriosis group was further divided into two groups: patients with a history of surgical treatment such as cystectomy for ovarian endometriosis, ablation or excision of endometriotic implants, or adhesiolysis (surgical treatment group, n = 49) and those treated with only medications or without any treatment (non-surgical treatment group, n = 31)., Results: In the univariate analysis, placenta previa and postpartum hemorrhage were significantly increased in the endometriosis group compared to the control group (12.5% vs. 4.1%, p <  0.01 and 27.5% vs. 18.2%, p = 0.04, respectively). In the multivariate analysis, endometriosis significantly increased the odds ratio (OR) for placenta previa (adjusted OR, 3.19; 95% confidence interval [CI], 1.56-6.50, p <  0.01) but not for postpartum hemorrhage (adjusted OR, 1.14; 95% CI, 0.66-1.98, p = 0.64). Other maternal and neonatal outcomes were similar between the two groups. In patients with endometriosis, patients in the surgical treatment group were significantly associated with an increased risk of placenta previa (OR. 4.62; 95% CI, 2.11-10.10, p <  0.01); however, patients in the non-surgical treatment group were not associated with a high risk (OR, 1.63; 95% CI, 0.19-6.59, p = 0.36). Additionally, other maternal and neonatal outcomes were similar between the two groups., Conclusion: Women who have had surgical treatment for their endometriosis appear to have a higher risk for placenta previa. This may be due to the more severe stage of endometriosis often found in these patients. However, clinicians should be alert to this potential increased risk and manage these patients accordingly.

Several features exist that distinguish endometriotic cells from eutopic endometrial cells. Progesterone resistance is one of the main distinguishing features, although how progesterone resistance affects the phenotype of endometriotic cells is not fully elucidated. Heart and neural crest derivatives expressed 2 (HAND2) is a transcriptional factor that plays an important role in maintaining endometrial function in a progesterone-dependent manner. Therefore, we explored whether progesterone-dependent HAND2 is implicated in the progression of endometriosis. HAND2 was less expressed by endometriotic tissues compared to endometrial tissues. Suppression of HAND2 expression induced fibroblast growth factor 1 (FGF1), FGF2, and FGF9 in endometriotic stromal cells and consequently enhanced migration and invasion capacity. AZD4547, a FGF receptor inhibitor, diminished the migration and invasion of endometriotic cells in vitro. In the murine model of endometriosis, AZD4547 showed suppressive effects on the development of endometriotic lesions at a relatively low concentration. In conclusion, we demonstrated that FGF1, FGF2, and FGF9 are downstream effectors of HAND2 in endometriotic cells. Since HAND2-dependent FGFs play roles in enhancing invasive capacity of endometriotic cells, our results suggest that FGF receptor inhibitors, such as AZD4547, can be promising therapeutic targets for endometriosis.

Background: Serum anti-Müllerian hormone (AMH) concentration has been used to assess ovarian reserve in patients with endometriosis, especially when endometrioma surgery is involved. Previously, we reported that decreased serum AMH levels after cystectomy for endometriomas can recover to preoperative levels in some cases. In this present study, we assessed the sequential changes in serum AMH levels before and after cystectomy in terms of the state of the mesosalpinx prior to surgery., Methods: The retrospective cohort study recruited 53 patients from a series of prospective studies conducted from 2009 to 2015. All patients underwent laparoscopic cystectomy for endometriomas. If either mesosalpinx was involved in the endometrioma or adnexal adhesion before cystectomy, the case was defined as 'involved mesosalpinx' (n = 14). If both mesosalpinx remained anatomically correct, the case was classified as 'intact mesosalpinx' (n = 39). Blood samples were obtained from the patients 2 weeks before surgery, and at 1 month and 1 year after surgery to assess serum AMH levels., Results: The serum AMH levels (the involved group vs. the intact group) were 1.92 vs. 0.98 (P = 0.552) preoperatively, 0.59 vs. 1.99 (P = 0.049) at 1 month postoperatively, and 0.48 vs. 2.37 ng/mL (P = 0.007) at 1 year postoperatively. The involved mesosalpinx group showed a further decrease in serum AMH levels at 1 year postoperatively, while serum AMH levels in the intact mesosalpinx group tended to recover., Conclusion: These results suggest that pre-existing mesosalpinx disturbance, in combination with adhesiolysis, may be involved in the medium- and long-term decrease in ovarian reserve after endometrioma surgery. A disturbance in ovarian blood supply via the mesosalpinx may underlie this., Trial Registration: UMIN-CTR UMIN000019369 . Retrospectively registered October 15, 2015.

Pentraxin 3 (PTX3) is an inflammatory mediator that is released by a wide range of tissues and cells. Elevated PTX3 levels may represent a useful diagnostic and/or prognostic marker for a number of diseases. The purpose of this study was to investigate serum PTX3 levels in benign gynecological conditions including mature cystic teratomas (MCTs), endometriomas, and uterine leiomyomas. Serum PTX3 levels of the MCT group were found to be significantly higher compared to those of the other groups, including healthy controls (p = 0.001), although carbohydrate antigen 19-9 (CA19-9) did not exhibit a significant difference. Serum PTX3 levels of the MCT, but not the endometrioma group, were also found to have significantly decreased post-operatively (mean ± standard deviation, 4.98 ± 2.10 to 3.61 ± 1.53 ng/mL). Immunohistochemical analyses demonstrated positive staining for PTX3 protein in the sebaceous glands, epidermal tissues, and hair roots of MCT specimens. PTX3 is expressed by MCTs and is associated with increased serum concentrations compared to healthy controls and patients with either endometriomas or uterine leiomyomas. We conclude that serum PTX3 levels could be used as a potential diagnostic marker for MCTs, especially helpful in differentiating them from endometriomas with elevated expression of CA19-9.

We assessed the associations between preoperative and postoperative serum anti-Müllerian hormone (AMH) levels and parameters of endometriosis and endometriomas surgery with the success of infertility treatments after cystectomy. Seventeen out of 54 patients got pregnant during the infertility treatments. In these patients, the median interval from surgery to conception was 16.3 months. The serum AMH levels 1-year postoperatively were significantly higher in the pregnant group compared to the non-pregnant group (3.44 ± 1.78 versus 2.17 ± 2.24 ng/ml, p = 0.049). The median interval from surgery to recurrence was 34.4 months, and no significant differences were found in the serum AMH levels at any time point between the recurrence and non-recurrence groups. Serum AMH levels 1 year after laparoscopic cystectomy for endometriomas may predict the success of postoperative infertility treatments, but not a recurrence of endometriomas.

Objective: To investigate whether the serum antimüllerian hormone (AMH) levels recover within 1 year after cystectomy for endometriomas, and to analyze the pattern of sequential changes in the serum AMH levels., Design: Prospective study., Setting: University hospital., Patient(s): Thirty-nine patients undergoing cystectomy for unilateral endometrioma (n = 22) and bilateral endometriomas (n = 17)., Intervention(s): Serum samples collected 2 weeks before, and 1 month and 1 year after surgery were assayed for AMH levels., Main Outcome Measure(s): Assessment of the ovarian reserve damage based on alterations in the serum AMH levels and the association with parameters of endometriosis and surgery for endometriomas., Result(s): The median AMH levels were 3.56, 1.90, and 2.10 ng/mL before, 1 month after, and 1 year after surgery, respectively. Twenty patients showed higher AMH levels 1 year after surgery than 1 month after surgery (increase group); 19 patients showed lower AMH levels (decrease group). We found a statistically significant difference in the number of follicles removed by surgery between the two groups., Conclusion(s): The decrease in the serum AMH levels caused by cystectomy can recover. Our results suggest that removal of ovarian cortex might be involved in the decrease of the ovarian reserve just after surgery, and that a continuous decrease of the ovarian reserve after cystectomy might be attributed to other mechanisms., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aimed to investigate whether serum leucine‐rich α2‐glycoprotein (LRG) is a useful diagnostic biomarker for endometriosis, including the evaluation of treatment efficacy and exploration of LRG production in endometriotic lesions. Methods: Forty‐three women with endometriomas were compared to 22 women with benign ovarian cysts and 30 women who underwent assisted reproduction as controls. Changes in serum LRG levels were assessed before and after surgery, and during dienogest treatment. LRG expression in endometriotic tissue samples was evaluated using immunoblotting. Results: Serum LRG levels in the endometrioma group (80.0 ± 36.3 μg/mL) were significantly higher than those in the benign ovarian cyst (65.1 ± 27.0 μg/mL, p = 0.0265) and control (57.8 ± 22.3 μg/mL, p = 0.0028) groups. Serum LRG levels after endometrioma surgery were significantly lower than preoperative levels (p = 0.0484). Serum LRG levels consistently decreased during dienogest treatment. LRG expression levels were significantly higher in endometriotic tissues than in the normal endometrium. Conclusion: Serum LRG, possibly derived from local and systemic origins, could be used as a potential biomarker for the diagnosis and treatment of endometriosis. Serum leucine‐rich a2‐glycoprotein (LRG) levels in the endometrioma group were significantly higher than those in the benign ovarian cyst and control groups. In addition, serum LRG levels decreased after the surgery and during the dienogest treatment. Therefore, serum LRG can be used as a potential biomarker for diagnosis and treatment response in endometriosis. [ABSTRACT FROM AUTHOR]