YAP1 inhibits ovarian endometriosis stromal cell invasion through ESR2.

Endometriosis is an estrogen-dependent disease, and estrogen receptor 2 (ESR2) plays a critical role in the pathogenesis of ovarian endometriosis by promoting cell invasion. Yes-associated protein 1 (YAP1) plays suppressive roles in several types of tumors. However, the relationship between YAP1 and ESR2 is not fully understood. The aim of this study was to investigate the regulatory mechanism of YAP1 in terms of ESR2 and YAP1 regulation of endometriotic stromal cell (ECSC) invasion in ovarian endometriosis. Our results demonstrated that YAP1 mRNA and protein levels in eutopic endometrium (EU) tissues were higher than those in paired ectopic endometrium (EC) tissues. ECSCs transfected with siYAP1 exhibited a significant increase in both ESR2 mRNA levels and protein expression. Simultaneously, YAP1 overexpression in ECSCs yielded the opposite results. Co-IP assays demonstrated YAP1-NuRD complex formation by YAP1, CHD4 and MTA1 in ECSCs. YAP1 bound to two sites, (-539, -533) and (-158, -152), upstream of the ESR2 transcription initiation site. YAP1 binding to the two sites of the ESR2 promoter in ECSCs was significantly lower than that in eutopic endometrial stromal cells (EUSCs) from EU tissues. ECSCs transfected with siYAP1 exhibited increased invasion activity, while ECSCs transfected with siESR2 showed inhibition of invasion. However, transfection with siYAP1 and siESR2 together decreased the number of invading cells compared with transfection with siYAP1 alone. Therefore, we conclude that decreased levels of YAP1 in ovarian endometriomas enhance ESR2 expression via formation of a YAP1-NuRD complex, which further binds to the ESR2 promoters. Furthermore, YAP1 inhibits ECSCs invasion.

Reproductive performance after surgery for endometriosis: predictive value of the revised American Fertility Society classification and the endometriosis fertility index.

BACKGROUND/AIMS: To determine whether the revised American Fertility Society (rAFS) classification and endometriosis fertility index (EFI) predict pregnancy rates (PRs) in patients with surgically confirmed endometriosis attempting natural conception. METHODS: We retrospectively assessed 194 women with endometriosis who underwent laparoscopic surgery; 161 women completed the follow-up. Pregnancy outcomes, rAFS stages and EFI scores were documented. Cumulative PRs were compared using Kaplan-Meier survival analysis. RESULTS: The cumulative PR 36 months after surgery was 46.6% (stage I, 53.6%; stage II, 36.0%; stage III, 51.7%, and stage IV, 41.7%; log-rank test, χ(2) = 4.143, p = 0.246). In the 1st year, PRs significantly differed between patients with rAFS stage IV and those with stages I-III (Pearson's χ(2) test, χ(2) = 6.024, p = 0.014). Significant differences in cumulative PRs were observed among EFI scores (group 1, EFI score 0-3, 8.3%; group 2, EFI score 4-7 41.2%, and group 3, EFI score 8-10 60.9%; log-rank test, χ(2) = 16.254, p < 0.001). CONCLUSIONS: EFI scores, but not rAFS stage, predict PRs in patients with endometriosis-associated infertility. EFI scores may be used to guide postoperative treatment.

[Analysis of obstetric outcomes for different types of placenta previa].

OBJECTIVE: To explore the maternal and perinatal outcomes for different types of placenta previa (PP). METHODS: A total of 343 pregnancies with PP from January 2003 to December 2012 at our hospital were retrospectively reviewed. The general profiles, maternal and perinatal outcomes of different types of 325 singleton PP were evaluated. RESULTS: Among them, 221 pregnancies were of complete PP. There were partial (n = 22) and marginal (n = 82) PP. Proportions of previous vaginal and cesarean deliveries in women with complete and partial PP were higher than those with marginal PP (P < 0.05). Compared with marginal PP group, ratio of placenta in the uterus posterior wall prepartum hemorrhage and probability of blood transfusion and neonatal asphyxia were much higher in complete and partial PP. The gestational age at delivery and neonatal body weight with complete PP and partial PP marginal PP were higher than those of the other two groups (P < 0.05). As for the placenta adhesion, placenta accrete or postpartum hemorrhage, no difference existed among three groups placenta location. CONCLUSION: The gestational age at delivery, prepartum hemorrhage, probability of blood transfusion and perinatal outcome in women with PP are related with the type of PP. Both complete and partial PP have relatively worse outcomes. The type of PP has no effect on placenta adhesion, placenta accrete or postpartum hemorrhage.

[Clinical effect on women with different types of endometriosis related infertility treated by conservative surgery].

OBJECTIVE: To study pregnancy outcome and recurrence in patients with different type of endometriosis related infertility treated by conservative surgery. METHODS: From January 2005 to December 2010, 79 patients with endometriosis related infertility underwent conservative laparoscopic surgery in Peking University First Hospital, including 16 cases with deep infiltrating endometriosis, 39 cases with ovarian endometriosis and 24 cases with peritoneal endometriosis. At 1 to 5 years follow-up after surgery, natural pregnancy outcome and recurrence were studied. RESULTS: (1) The accumulated pregnancy rate were 6/16 in deep infiltrating endometriosis group, 36% (14/39) in ovarian endometriosis group, and 46% (11/24) in peritoneal endometriosis group, which did not reached statistical difference (P > 0.05). (2) The median interval between pregnancy and surgery were 38.5 months in deep infiltrating endometriosis group, 9.5 in ovarian endometriosis group and 6.0 months in peritoneal endometriosis group. The median interval in deep infiltrating endometriosis was significantly longer than that in peritoneal endometriosis group and ovarian endometriosis group (P < 0.01). Total of 11 patients in peritoneal endometriosis group and 11 patients in ovarian endometriosis group acquired pregnancy at 18 months after surgery. (3) The recurrent rate were 5/16 in deep infiltrating endometriosis group, 13% (5/39) in ovarian endometriosis group and 4% (1/24) peritoneal endometriosis group, respectively (P > 0.05). CONCLUSIONS: There was no difference among these three groups in accumulated pregnancy rate. However, the interval between pregnancy and surgery was significantly longer in patients with deep infiltrating endometriosis when compared with those in the other groups.

Rapidly growing extensive polypoid endometriosis after gonadotropin-releasing hormone agonist discontinuation: A case report.

BACKGROUND: Polypoid endometriosis (PEM) is a rare and unique type of endometriosis. To date, no article has provided a systematic report of this disease. The current article provides a complete report on rare PEM based on ultrasound, magnetic resonance imaging, intraoperative findings and postoperative pathology data. CASE SUMMARY: A 38-year-old female patient was admitted to our hospital after complaining of "vague pain in the right lower quadrant with an aggravated menstrual period for 8 mo". The patient underwent laparoscopic exploratory surgery on January 7, 2022. The postoperative pathology revealed extensive PEM. CONCLUSION: PEM is a type of endometriosis that is a benign disease but has biological properties similar to malignant tumours.

Molecular Characterization and Phylogenetic Analysis of Spirometra Tapeworms from Snakes in Hunan Province.

Sparganosis is a neglected zoonotic parasitic disease that poses huge threats to humans worldwide. Snakes play an important role in sparganosis transmission because they are the most common second intermediate hosts for Spirometra parasites. However, the population genetics of Spirometra isolates from snakes is currently not well studied in China. The present study was performed to explore the molecular characteristics and phylogenetic analysis of Spirometra tapeworms from different species of snakes in Hunan Province. This study obtained 49 Spirometra isolates from 15 geographical areas in Hunan Province, Central China. Subsequently, the 18S and 28S ribosomal DNA (rDNA) fragments were amplified from the isolated parasites, and their sequences were analyzed to assess their genetic diversity. Phylogenetic analyses were performed using the maximum likelihood algorithm. The results showed that sequence variations among these isolates were 0-2.3% and 0-0.1% for 18S and 28S rDNA, respectively. The phylogenetic analysis showed that all Spirometra isolates from Hunan Province were clustered into the same branch with Spirometra erinaceieuropaei isolated from other areas (China, Vietnam, Australia). Moreover, the phylogenetic trees revealed that Spirometra is closely related to Adenocephalus, Pyramicocephalus, Ligula, Dibothriocephalus, Schistocephalus, and Diphyllobothrium. The Spirometra isolates of different hosts/regions in Hunan Province are not host segregated or geographically isolated, and support for the taxonomic status of Spirometra tapeworms in China has been added. These results provide reference values for future accurate identification and taxonomic status of Spirometra tapeworms in China.

[Expression of steroidogenic factor 1 in ovarian endometriosis and adenomyosis].

OBJECTIVE: To investigate the expression of steroidogenic factor 1 (SF-1) in eutopic endometrium, ovarian endometriosis (EM) and adenomyosis. METHODS: From Jan. 2008 to Dec. 2010, 30 patients with both ovarian endometriotic cysts and adenomyosis underwent hysterectomy, cystectomy or adenxectomy in Peking University First Hospital. The combination of ovarian EM and denomyosis were confirmed in 17 cases. In the mean time, endometria form 10 patients with cervical intraepithelial neoplasm (CIN) III underwent hysterectomy were selected as controls. The expression of SF-1 in eutopic endometrium, ovarian EM and adenomyosis was detected by immunohistochemistry staining. RESULTS: No immunoreactivity of SF-1 was observed glandular cell and stromal cell in eutopic endometrium of both groups. 14/17 of positive rate of SF-1 were observed in lesions of ovarian endometriosis. SF-1 protein was not expressed in the endometrial glandular cells of ovarian EM and in adenomyosis foci. CONCLUSION: The differences of SF-1 expression in ovarian endometrioma and adenomyosis foci might mediate the development of the disease.

[Influence of various hemostatic methods on ovarian reserve function in women with ovarian endometriotic cyst treated by laparoscopic cystectomy].

OBJECTIVE: To investigate the influence on ovarian reserve function in treatment of ovarian endometriotic cyst by laparoscopic cystectomy with various hemostasis management. METHODS: From September 2007 to August 2008, 61 patients with bilateral ovarian endometriotic cyst in Peking University First Hospital and Anzhen Hospital Affiliated to Capital University of Medicine were treated by laparoscopic cystectomy. Those patients were divided into two groups randomly, which were 28 patients in suture group and 33 patients in electro coagulation during the operation. Blood samples were obtained from the patients before the operation, on the day 2 or 3 of the second menstrual cycle after operation and the first menstrual cycle after 6 months operation. The serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E(2)) were tested. At the same time, total antral follicles (F(0)) and mean ovarian stromal peak systolic blood flow velocity (PSV) were detected by transvaginal ultrasonography to evaluate ovarian reserve function. RESULTS: There was no significant difference in patients' clinical characteristics and ovarian reserve function between two groups (P > 0.05). In the suture group, the serum level of FSH were (10.2 +/- 2.0) U/L before operation, (11.0 +/- 2.2) U/L on day 2 or 3 of the second menstrual cycle and (11.5 +/- 2.5) U/L on day 2 or 3 of the first menstrual cycle after 6 months'operation respectively. In comparison of data before operation, it exhibited significant difference (P < 0.05); F(0) were 8.9 +/- 2.6 before operation, 7.8 +/- 2.1 on day 2 or 3 of the second menstrual cycle and 7.6 +/- 2.4 on day 2 or 3 of the first menstrual cycle after 6 months' operation. When compared with data before operation, it showed significant difference (P < 0.05); PSV were (0.104 +/- 0.017) m/s before operation, (0.084 +/- 0.016) m/s on day 2 or 3 of the second menstrual cycle, (0.086 +/- 0.022) m/s on day 2 or 3 of the first menstrual cycle after 6 months' operation, it also showed significant difference between preoperation and postoperation (P < 0.01). In the electro coagulation group, the serum level of E(2) were (166 +/- 19), (196 +/- 57), (205 +/- 65) pmol/L, serum level of FSH were (10.0 +/- 1.5), (12.2 +/- 2.6), (13.4 +/- 4.5) U/L, F(0) were 8.9 +/- 2.0, 6.5 +/- 2.0, 6.2 +/- 2.5 (P < 0.01); PSV were (0.101 +/- 0.016), (0.072 +/- 0.021), (0.067 +/- 0.024) m/s before operation and on day 2 or 3 of the second menstrual cycle after operation and the first menstrual cycle after 6 months operation. They all showed significant difference between preoperation and postoperation. In the second menstrual cycle post operation (on day 2 or 3), the data of F(0) and PSV were statistically different between the two groups (P < 0.05); in the first menstrual cycle 6 months after the operation (on day 2 or 3), The serum level of E(2), F(0) and PSV were statistically different between the two groups (P < 0.05). CONCLUSION: It suggested that ovarian reserve function would be decreased in treatment of bilateral ovarian endometriotic cyst by laparoscopic cystectomy, it was more serious when electro coagulation hemostasis were given.

[Expression of integrin beta3 and osteopontin in endometrium of patients with adenomyosis].

OBJECTIVE: To investigate the expression of integrin beta3 and osteopontin (OPN) in eutopic and ectopic endometrium of adenomyosis. METHODS: From January 2007 to July 2008, the endometrium specimens were collected from 43 patients with adenomyosis undergoing hysterectomy in Peking University First Hospital. Eutopic endometrium were 11 in proliferative phase and 32 in secretory phase (18 cases in mid-secretory phase) were collected. Ectopic endometriums were also collected. In the mean time, it was chosen 41 cases with pure subserous uterine myoma or cervical intraepithelial neoplasia (CIN) II-III treated by hysterectomy as controls including 12 endometrium in proliferative phase and 29 endometrium in secretory phase (19 cases in mid-secretory phase). The expression of Integrin beta3 subunit and OPN in the endometrium were assessed by immunohistochemical staining and quantitative real-time polymerase chain reaction. RESULTS: (1) Immunohistochemical staining showed that positive staining of integrin beta3 and OPN were present predominantly in eutopic and ectopic endometrial glandular epithelium. There was significant different protein expression of integrin beta3 and OPN, which were 1.6 +/- 0.8 and 1.7 +/- 0.7 in eutopic endometrium, 1.7 +/- 0.7 and 1.8 +/- 0.9 in ectopic endometrium, 2.1 +/- 0.9 and 2.0 +/- 0.9 in control endometrium (P < 0.05). The protein expression of integrin beta3 and OPN in eutopic endometrium of adenomyosis in the proliferative phase (0.8 +/- 0.4 and 0.7 +/- 0.3) were remarkably lower than those of the secretory phase (1.8 +/- 0.8 and 1.9 +/- 0.8, P < 0.01). The protein expression of integrin beta3 and OPN in the endometrium of controls in the proliferative phase (1.0 +/- 0.4 and 1.0 +/- 0.4) were significantly lower than those of the secretory phase (2.5 +/- 0.7 and 2.5 +/- 0.7) (P = 0.000). In the mid-secretory phase, the protein expression of integrin beta3 (2.0 +/- 0.9) and OPN (2.1 +/- 0.8) in eutopic endometrium of adenomyosis were significantly lower than that of control endometrium (2.7 +/- 0.5 and 2.7 +/- 0.7) (P < 0.01). (2) The mRNA expression level of integrin beta and OPN in eutopic and ectopic endometrium were assessed by quantitative real-time PCR (result was shown by median index). It was observed that integrin beta3 mRNA and OPN mRNA were significantly lower in the eutopic endometrium of adenomyosis (4.69 and 4.23), when compared with ectopic endometrium (7.96 and 14.84) and controls (13.47 and 17.40) (P < 0.05). Eutopic endometrium had higher mRNA expression of integrin beta and OPN mRNA in the secretory phase (5.54 and 11.40) than that in the proliferative phase (2.69 and 3.30) (P < 0.01). The mRNA expression level of integrin beta and OPN of control endometrium in the proliferative phase (3.12 and 4.75) were significantly lower than that in the secretory phase (19.94 and 21.00, P = 0.000). The mRNA expression of integrin beta and OPN were 10.10 and 14.34 in the mid-secretory phase, which were significantly lower than 21.50 and 24.18 in control endometrium (P < 0.05). CONCLUSIONS: High expression of integrin beta3 and OPN in ectopic endometrium of adenomyosis may cause endometriotic lesions; abnormal expression of integrin beta3 and OPN in the endometrium of adenomyosis during the implantation window may contribute to infertility in some patients.

Farnesoid X Receptor Agonist GW4064 Inhibits Aromatase and ERß Expression in Human Endometriotic Stromal Cells.

Endometriosis is an estrogen-dependent disease. Farnesoid X receptor (FXR) activation has been shown to inhibit estrogen signaling in breast cancer and testicular tumors. However, the role of FXR in endometriosis is still poorly understood. Here, we aimed to investigate whether FXR activation by its synthetic agonist GW4064 has a therapeutic effect on endometriosis and the underlying molecular mechanisms. We found that the expression of FXR (encoded by the NR1H4 gene) in endometriotic tissues and stromal cells (ESCs) was higher than that in eutopic endometrial tissues and stromal cells. The GW4064 treatment led to a dose-dependent decrease in aromatase and estrogen receptor ß (ERß) expression and induced ERK1/2, p38, AMPK, and Stat3 activation in ESCs. In contrast, ERK1/2 inhibitor reversed the GW4064-induced reduction in aromatase expression. In addition, treatment with p38, AMPK, and Stat3 inhibitors or small interfering RNAs could also reverse the GW4064-induced reduction of ERß expression in ESCs. The GW4064 treatment markedly increased Stat3 phosphorylation, enhancing the binding of Stat3 to the ESR2 promoter, which resulted in the downregulation of ERß. Coimmunoprecipitation assay and chromatin immunoprecipitation analysis revealed that FXR was able to compete with cyclic AMP response element-binding (CREB) protein for binding to a common sequence on the aromatase promoter region after GW4064 treatment in ESCs. Moreover, treatment of endometriosis xenografts with GW4064 suppressed aromatase and ERß expression in nude mice. Our results suggest that FXR may represent a potential therapeutic target for future therapy.

Transcription factor 21 regulates expression of ERß and SF-1 via upstream stimulatory factor-2 in endometriotic tissues.

Steroidogenic factor-1 (SF-1, encoded by NR5A1) and estrogen receptor beta (ERß, encoded by ESR2), which are highly expressed in endometriotic stromal cells (ESCs), contribute to the pathogenesis of endometriosis, but the regulation mechanism remains largely unknown. Transcription factor 21 (TCF21) belongs to the helix-loop-helix (bHLH) family characterized by regulating gene expression via binding to E-box element. Here, we attempted to determine the molecular mechanism of TCF21 on SF-1 and ERß expression in endometriosis. We found that TCF21 expression in ESCs was higher than that in endometrial stromal cells (EMs), and positively correlated with SF-1 and ERß expression in ESCs. Since the importance of E-box element for NR5A1 promoter activity has been previously reported, we performed site-mutation and luciferase assay, revealing that the E-box sequence in the ESR2 promoter is also a critical element modulating ERß expression. Upstream stimulatory factor 2 (USF2) is another bHLH factor implicated in transcriptional regulation. Further analyses elucidated that it is not TCF21, but USF2 exhibited higher binding affinities in ESCs to NR5A1 and ESR2 promoters than in EMs. Additionally, TCF21 knockdown significantly decreased the binding activities of USF2 to NR5A1 and ESR2 promoters via disruption of the TCF21-USF2 complex. Meanwhile, manipulating TCF21 expression significantly affected MMP9 and cyclinD1 expression, as wells as proliferation and invasion of ESCs. Moreover, TCF21 depletion in endometriotic xenografts reduced SF-1 and ERß expression, abrogating ectopic lesion growth in mice. Cumulatively, a critical role of TCF21 in the pathogenesis of endometriosis is demonstrated, suggesting a potential druggable target for future therapy.

Endometriosis Fertility Index for Predicting Pregnancy after Endometriosis Surgery.

BACKGROUND: The endometriosis fertility index (EFI) has a predictive value for pregnancy after surgery. In vitro fertilization and embryo transfer (IVF-ET) is a good treatment to infertility. This study aimed to provide external validation of EFI, assess the factors affecting the ability of EFI to predict cumulative spontaneous pregnancy rates (PRs), and propose reasonable advice for treatment by evaluating the effect of infertility management combining surgery and IVF-ET. METHODS: This retrospective study enrolled 345 endometriosis-related infertile women after laparoscopic surgery from January 2012 to January 2016. Among them, 234 patients tried to conceive naturally and were divided into six groups according to their different EFI scores. Of the 345 patients, 307 with an EFI score ≥5 were divided into non-IVF-ET group (n = 209) and IVE-ET group (n = 98) to compare the cumulative PRs. Cumulative PRs' curves were calculated using the Kaplan-Meier product limit estimate and the differences were evaluated by log-rank test. Independent predictive factors for pregnancy were assessed using the Cox regression model. RESULTS: Significant differences in spontaneous PRs among different EFI scores were identified (χ2=29.945, P< 0.05). The least function score was proved to be the most important factor for EFI (χ2 = 6.931, P< 0.05) staging system. In patients with an EFI score ≥5 after 12 months from surgery, the cumulative PRs of those who received both surgery and IVF-ET were much higher than the spontaneous PRs of those who received surgery alone (χ2=4.160, P= 0.041). CONCLUSIONS: The EFI is a reliable staging system to predict the spontaneous PR of patients. The least function score was the most influential factor to predict the spontaneous PR. Patients with an EFI score ≥5 after 12 months from surgery are recommended to receive IVF-ET to achieve a higher PR.

IGF-I stimulates ERß and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation in endometriosis.

UNLABELLED: Estrogen receptor beta (ERß, encoded by ESR2 gene) and cytochrome P450 aromatase (encoded by CYP19A1 gene) play critical roles in endometriosis, and the levels of insulin-like growth factor-I (IGF-I) in the peritoneal fluid are significantly higher in patients with endometriosis compared with those in normal women. However, the effects and mechanisms of IGF-I on ERß and aromatase expression remain to be fully elucidated. In this study, human endometriotic stromal cells (ESCs) and endometrial cells (EMs) derived from ovarian endometriomas and eutopic endometrial tissues. ESCs were cultured with IGF-I, signal pathway inhibitors, and siRNAs. ERß and aromatase expression were measured by real-time PCR and Western, respectively. The binding of c-Jun and CREB to the ESR2 and CYP19A1 promoters was assessed by chromatin immunoprecipitation assay. Animal experiments were performed in a xenograft mouse model. Levels of IGF-I mRNA in ESCs were markedly higher than those in EMs. IGF-I upregulated ERß and aromatase expression in ESCs after stimulation of the IGF1R/PI3K/AKT pathway. Following IGF-I treatment, a marked increase in c-Jun and CREB phosphorylation occurred, enhancing binding to the ESR2 and CYP19A1 promoters. An IGF1R inhibitor in vivo reduced IGF-I-induced endometriosis graft growth and ERß and aromatase expression. In conclusion, this is the first report to describe a mechanistic analysis of ERß and aromatase expression regulated by IGF-I in ESCs. Moreover, an IGF1R inhibitor impeded ectopic lesion growth in nude mice. These findings suggest that an inhibitor of IGF1R might have therapeutic potential as an antiendometriotic drug. KEY MESSAGES: Level of IGF-I mRNA in ESCs is markedly higher than that in EMs. IGF-I up-regulates ERß and aromatase expression via IGF1R/PI3K/AKT pathway. C-Jun and CREB are recruited to ESR2 or CYP19A1 promoter by IGF-I stimulation. IGF-1R inhibitors in vivo impede the growth of ectopic lesions in nude mice.

[Clinical trial on the effectiveness and safety of triptorelin in treatment of uterine leiomyoma].

OBJECTIVE: To evaluate the effectiveness and safety of triptorelin in the treatment of uterine leiomyoma. METHODS: A multi-center, prospective, randomly controlled clinical trial was carried out from Dec. 2002 to Mar. 2004 in three university hospitals. A total of 125 qualified patients with uterine leiomyoma were randomly divided into either triptorelin group (63 cases) treated with 3.75 mg triptorelin injected intramuscularly or leuprorelin group (62 cases) treated with 3.75 mg leuprorelin injected subcutaneously. Both drugs were injected every 28 days for a total of 3 months. RESULTS: All 125 patients finished the trial. The uterine volumes were similar before treatment between the triptorelin group and the leuprorelin group and were decreased significantly after drug therapy (P < 0.01) in both groups, with a median decrease rate of 51% and 49%, respectively, without significant difference between two groups (P > 0.05). The volumes of the largest leiomyoma decreased significantly after drug therapy (P < 0.01) in both groups, with a median decrease rate of 50% and 48% in the triptorelin and leuprorelin groups, respectively, without significant difference between them (P > 0.05). Patients with serum level of 17beta-estradiol < 183 pmol/L accounted for 94% in both groups. The hemoglobin and serum ferrum levels were both significantly increased in the two groups after treatment (P < 0.05). The amenorrhea rates after 3 months of treatment were 97% in the triptorelin group and 95% in the leuprorelin group (P > 0.05). Dysmenorrhea, noncyclic pelvic pain and pressure-like symptoms were relieved quickly and remarkably in both groups after treatment. The rates of adverse event occurred in 71% of patients in both groups. The main side effects included flare-up effects and hypoestrogenic symptoms. Nine patients in the triptorelin group and 6 in the leuprorelin group received add-back therapy with tibolone 1.25-2.50 mg/d because of remarkable climacteric-like symptoms. CONCLUSION: Treatment of uterine leiomyoma with triptorelin for 3 months is both effective and safe in Chinese women.

[Clinical comparison of transvaginal hysterectomy and laparoscopic hysterectomy].

OBJECTIVE: To compare the clinical characteristics of transvaginal hysterectomy (TVH) and total laparoscopic hysterectomy (TLH). METHOD: Clinical data about 301 cases who received TVH and TLH were collected and the hospital stay days, medical expenses, diagnoses, operation and recovery status were compared between TVH and TLH groups. RESULTS: The ratio of cervical atypical hyperplasia (9.64%), multipara (96.45%) in TVH was higher than that in TLH (2.88%, 89.42%). The ratio of adenoma (29.44%), adnexal disease (4.55%), pelvic endometriosis (4.06%), history of cesarean section (7.11%) in TVH were lower than that in TLH (43.27%, 31.73%, 12.50%, 24.04%). The operation time (76 +/- 28) minutes, bleeding during operation (170 +/- 125) ml, additional operations (5.08%), pelvic adhesion (4.57%), loosening of pelvic adhesion (0.51%), the diameter of the largest myoma or adenoma (49 +/- 17) mm, expenses for operation and hospitalization (1073 +/- 203) yuan in TVH were lower than those in TLH, which were (139 +/- 52) minutes, (206 +/- 153) ml, 36.54%, 41.35%, 17.31%, (57 +/- 22) mm, (1526 +/- 676) yuan respectively. The differences were significant (all P < 0.05). There was no difference of the uterine weight, complication and length of hospitalization duration between the two kinds of operation. CONCLUSIONS: TVH is recommended in cases of few pelvic adhesion, or adnexal disease, cervical disease and of multipara. The uterine weight is not a decisive factor.

C-Jun NH2-Terminal Kinase and p38 Inhibition Suppresses Prostaglandin E2-Stimulated Aromatase and Estrogen Receptor Levels in Human Endometriosis.

CONTEXT: Endometriosis is an estrogen-dependent disease. P38 and C-jun NH2-terminal kinase (JNK) inhibitors may have a therapeutic effect on endometriosis through regulation of prostaglandin E2 (PGE2)-induced estrogen metabolism. OBJECTIVE: The objective of this study was to determine whether the activated MAPKs signaling pathway observed in human ectopic endometrial stromal cells (ESCs) from ovarian endometriomas influences levels of aromatase and estrogen receptor ß (ERß) protein regulated by PGE2. In turn, the effects of inhibiting MAPKs in the presence of PGE2 on estrogen production were investigated in vitro and in vivo. RESULTS: Expression of aromatase and ERß regulated by PGE2 were much higher in ESCs than eutopic ESCs from the same person. Activation of p38, JNK, ERK 1/2 and ERK 5 MAPKs by PGE2 were observed in ESCs, where PGE2-stimulated aromatase and ERß expression mainly through p38 and JNK pathway. P38 and JNK inhibition or small interfering RNA knockdown blocked PGE2-induced aromatase and ERß expression. PGE2 enhanced binding of downstream p38 and JNK transcription factors activating transcription factor-2 and c-Jun to aromatase and ERB promoter regions in ESCs. Moreover, treatment of endometriosis xenografts with inhibitors of p38 and JNK abrogated PGE2-amplified estradiol synthesis and xenograft growth. CONCLUSIONS: PGE2 activates p38 and JNK signaling pathways, further stimulating c-Jun and activating transcription factor-2 binding to aromatase and ERB promoter regions with elevated estradiol production. Inhibition of JNK and P38 may be a potential method of treating human endometriosis.

Metformin Suppresses Prostaglandin E2-Induced Cytochrome P450 Aromatase Gene Expression and Activity via Stimulation of AMP-Activated Protein Kinase in Human Endometriotic Stromal Cells.

BACKGROUND: Cytochrome P450 aromatase (encoded by the CYP19A1/aromatase gene) plays a critical physiologic role in endometriosis. Metformin is known to suppress prostaglandin E2 (PGE2)-induced CYP19A1 messenger RNA (mRNA) expression in human endometriotic stromal cells (ESCs). However, the possible mechanism behind this suppression remains to be determined. METHODS: In this study, ESCs were cultured with metformin, PGE2, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitors. Expression of CYP19A1 mRNA and aromatase activity were measured by quantitative polymerase chain reaction and aromatase activity assay, respectively. The binding of the cyclic AMP response element-binding (CREB) protein to CYP19A1 promoter II (PII) was assessed by chromatin immunoprecipitation assay. RESULTS: We demonstrated that metformin downregulated the expression of aromatase mRNA (32%) and activity (25%) stimulated by PGE2 (4.18-fold and 2.14-fold) in ESCs via stimulation of AMPK. Following PGE2 treatment, there was a marked increase in CREB binding to aromatase PII, while metformin attenuated the above-mentioned stimulation by 67%. CONCLUSION: Metformin could inhibit PGE2-induced CYP19A1 mRNA expression and aromatase activity via AMPK activation and inhibition of CREB to CYP19A1 PII in human ESCs. The results of the present study suggest that metformin may have unique therapeutic potential as an antiendometriotic drug in the future.

Effects of angiogenesis inhibitor TNP-470 on the development of uterine adenomyosis in mice.

OBJECTIVE: To investigate the effects of angiogenesis inhibitor TNP-470 on uterine microvessels in mice. Pituitary grafting frequently induced uterine adenomyosis. DESIGN: In vivo experimental study. SETTING: Department of Biological Sciences, University of Tokyo and Medical Research Institute, Tokyo Medical and Dental University. ANIMAL(S): SHN mice, which are known to develop uterine adenomyosis spontaneously, and also very soon after pituitary grafting. INTERVENTION(S): Immunohistochemical study on uterine blood vessels using an antibody to von Willebrand factor in pituitary gland-implanted mice with or without TNP-470. MAIN OUTCOME MEASURE(S): Reduced incidence of uterine adenomyosis. RESULT(S): Twelve of 15 mice developed uterine adenomyosis with dilated blood vessels, but none of the TNP-470-treated mice with shrunken microvessels. The number of bromodeoxyuridine immunoreactive cells and activities of thymidylate synthase and thymidine kinase in uterine tissues were markedly reduced in TNP-470-treated mice. CONCLUSION(S): TNP-470, a potent inhibitor of the development of vascular endothelium, reduced the development of endometrial blood vessels resulting in a lowered incidence of uterine adenomyosis induced by pituitary grafting in mice, and reduced the increase in S-phase cells and enzyme activity for pyrimidine nucleotide synthesis.

Priming effects of novel nonsteroidal progesterone receptor modulators CP8816 and CP8863 on the development of adenomyosis in the mouse uterus.

The possibility of therapeutic application of novel nonsteroidal progesterone receptor modulators CP8816 and CP8863 for preventing the development of uterine adenomyosis was investigated in mice. First priming effects of CP8816 on 17beta-estradiol (E2)-induced cell division in uterine tissues were examined. As a result, pretreatment with CP8816 or progesterone significantly suppressed the elevation of the mitotic activity in the luminal epithelial cells of mice treated with E2 later. Priming with CP8816 had little effect on the stromal cells, but progesterone priming caused an increase of stromal mitotic activity in mice treated with E2 later. To evaluate the inhibitory effect of these compounds on the development of adenomyosis induced experimentally by pituitary grafting, 7-week-old female mice were isografted with a single anterior pituitary in the uterus and divided into four groups. Two groups of mice were given daily subcutaneous injections of 1 mg of CP8816 or the vehicle alone for 6 weeks from the day after the grafting. Remaining two groups of mice were given oral administration of 1 mg of CP8863 or the vehicle only for 5 weeks starting one week after the grafting. The incidence of adenomyosis was significantly lower in the groups of mice treated with CP8816 and CP8863 than in the respective control groups. The mechanism by which CP compounds inhibited the development of adenomyosis might be related to their priming effects, i.e., their inhibitory effect on epithelial cell division and lack of effect on stromal cell division after subsequent exposure to E2.