Advanced Role of Hippo Signaling in Endometrial Fibrosis： Implications for Intrauterine Adhesion

Objective： Intrauterine adhesion （IUA） is a major health problem that causes infertility, menstrual irregularities, and recurrent pregnancy losses in women. Unfortunately, treatments for IUA are limited, and there are currently no effective strategies for preventing IUA recurrence. In this review, we introduced the role of Hippo signaling in the normal endometrium and IUA and described the mechanisms by which the Hippo pathway integrates with the Wnt and transforming growth factor-β （TGF-β） signaling pathways to form an intricate network governing the development of fibrosis. Data Sources： Original research articles in English that were published until July 2017 were collected from the PubMed database. Study Selection： Literature search was conducted using the search terms ＂endometrial fibrosis OR fibrosis AND or OR intrauterine adhesion OR Asherman syndrome OR IUA,＂ ＂Hippo AND or OR Hippo/TAZ,＂ ＂TGF-β,＂ and ＂Wnt.＂ Related original research articles were included in the comprehensive analysis. Results： Endometrial fibrosis is recognized as a key pathological event in the development of IUA, which is characterized by epithelial/fibroblast-myofibroblast transition. Myofibroblasts play crucial roles in the pathogenesis of fibrous scarring, and myofibroblast differentiation can be triggered by multiple signaling pathways. H ippo signaling is a critical regulator of the epithelial/fibroblast-myofibroblast transition and α-smooth muscle actin, which exhibits a specific spatiotemporal expression in the endometrium. Conclusions： Hippo signaling plays a critical role in fibrous diseases and participates in cross talks with Wnt and TGF-β signaling. Our findings not only contributed to knowledge on the pathogenesis of endometrial fibrosis, but can also serve as a useful resource for developing specific molecular inhibitors for IUA treatment and prevention.

Ovarian Fibrosis： A Phenomenon of Concern

Objective： Ovarian fibrosis is characterized by excessive proliferation of ovarian fibroblasts and deposition ofextracellular matrix （ECM） and it is one of the principal reasons for ovarian dysfunction. This review aimed to investigate the pathogenetic mechanism of ovarian fibrosis and to clarify the relationship between ovarian diseases and fibrosis. Data Sources： We searched PubMed for English language articles published up to November 2016. The search terms included ovarian fibrosis OR fibrosis, ovarian chocolate cyst OR ovarian endometrioma, polycystic ovarian syndrome （PCOS）, premature ovarian failure, ECM, matrix rnetalloproteinases （MMPs）, tissue inhibitors of matrix metalloproteinases （TIMPs）, transforming growth factor-beta 1 （TGF-[31）, connective tissue growth factor （CTGF）, peroxisome proliferator-activated receptor gamma （PPAR-T）, vascular endothelial growth factor （VEGF）, endothelin-1 （ET-1）, and combinations of these terms. Study Selection： Articles were obtained and reviewed to analyze the pathogenic mechanism of ovarian fibrosis and related ovarian diseases. Results： Many cytokines, such as MMPs, TIMPs, TGF-β1, CTGF, PPAR-γ, VEGK and ET- 1, are involved in ovarian fibrogenesis. Ovarian fibrogenesis is associated with various ovarian diseases, including ovarian chocolate cyst PCOS, and premature ovarian failure. One finding of particular interest is that fibrogenesis in peripheral tissues around an ovarian chocolate cyst commonly causes ovarian function diminution, and therefore, this medical problem should arouse widespread concern in clinicians worldwide. Conclusions： Patients with ovarian fibrosis are susceptible to infertility and tend to have decreased responses to assisted fertility treatment. Thus, protection of ovarian function should be a priority for women who wish to reproduce when making therapeutic decisions about ovarian fibrosis-related diseases.

NLRP3 inflammasome:a new therapeutic target for high-risk reproductive disorders?

The NOD-like receptor protein 3(NLRP3)inflammasome is a key regulator of the host’s immune response,and many immune and metabolic disorders are linked to its activation.This review aimed to investigate and clarify the relationship between this inflammasome and high-risk reproductive disorders.Papers cited here were retrieved from PubMed up to August 2020 using the keywords"NLRP3"or"NALP3","caspase-1","endometriosis","gestational diabetes","interleukin(IL)-18","IL-1β","pre-eclampsia(PE)","preterm birth","polycystic ovarian syndrome(PCOS)","recurrent spontaneous abortion(RSA)",and combinations of these terms.The results show that NLRP3 inflammasome is associated with various high-risk reproductive disorders and many inflammatory factors are secreted during its activation,such as IL-1βinduced during the development of endometriosis.PCOS is also associated with activation of the NLRP3 inflammasome,especially in overweight patients.It also participates in the pathogenesis of RSA and is activated in fetal membranes before preterm birth.The placentas of pregnant women with PE show higher expression of the NLRP3 inflammasome,and gestational diabetes mellitus occurs simultaneously with its activation.Current evidence suggest that the NLRP3 inflammasome plays an important role in female reproductive disorders.New treatment and management methods targeting it might help reduce the incidence of such disorders and improve neonatal outcomes.

Factors associated with the incidence of ectopic pregnancy in women undergoing assisted reproductive treatment

Background:Ectopic pregnancy(EP)is a common complication in women undergoing assisted reproductive treatment,but the underlying causes for this remain unclear.This study aimed to explore factors affecting the incidence of EP in in vitro fertilization(IVF)/intracytoplasmic sperm injection(ICSI).Methods:This was a retrospective study on the incidence of EP in IVF/ICSI cycles between January 1,2013 and December 31,2017.Patient age,infertility diagnosis(tubal factor or not),primary or secondary infertility,type of cycle(frozen-thawed or fresh),type of embryo(s)transferred(cleavage embryo or blastocyst),number of embryos transferred(one,two,or three),previous history of EP,and endometrial combined thickness were analyzed to explore their relationships with the incidence of EP.Based on clinical typing results,the patients were divided into an EP group or a non-EP group.Categorical variables were analyzed using Chi-squared test or Fisher exact test.Logistic regression analysis was performed to explore their associations with the incidence of EP.Results:The percentage of patients with primary infertility in EP group was significantly lower than that in non-EP group(31.3%vs.46.7%,χ^2=26.032,P<0.001).The percentage of patients with tubal infertility in EP group was also significantly higher than that in non-EP group(89.2%vs.63.6%,χ^2=77.410,P<0.001).The percentages of patients with transfer of cleavage-stage embryo or blastocyst(91.4%vs.84.4%,χ^2=10.132,P=0.001)and different endometrial combined thickness(ECT)(χ^2=18.373,P<0.001)differed significantly between EP and non-EP groups.For patients who had a previous history of one to four EPs,the percentage of patients undergoing transfer of a cleavage-stage embryo was significantly higher in EP group than that in non-EP group(92.2%vs.77.6%,χ^2=13.737,P<0.001).In multivariate logistic regression analysis,tubal infertility was strongly associated with EP(adjusted odds ratio:3.995,95%confidence interval:2.706-5.897,P<0.001).Conclusions:In IVF/ICSI cycles,transfer of a blastocyst-stage embryo,especially for patients with a previous history of EP,reduced the rate of EP.Tubal infertility was strongly associated with EP.

A Case of Thromboembolism After Injection of Gonadotropin-releasing Hormone Agonist

Gonadotropin-releasing hormone agonist （GnRH-a） was one of the most used therapies in the treatment of endometriosis. But unfortunately, no literatures realized GnRH-a may be related to thrombosis until now. The case below was exactly about thromboembolism taking place after using GnRH-a because ofestradiol （E2） peak short-time after injection.