Predictive performance of Shock Index for postpartum hemorrhage during cesarean delivery.

BACKGROUND: The Shock Index (SI), defined as heart rate divided by systolic blood pressure, is reportedly an early surrogate indicator for postpartum hemorrhage (PPH). However, most previous studies have used clinical data of women who delivered vaginally. Therefore, we aimed to evaluate the SI pattern during cesarean delivery and determine its usefulness in detecting PPH. METHODS: This was a single-center retrospective study using the clinical data of women (n = 331) who underwent cesarean delivery under spinal anesthesia at term between 2018 and 2021. We assessed the SI pattern stratified by total blood loss and evaluated the predictive performance of each vital sign in detecting PPH (total blood loss ≥1000 mL) based on the area under the receiver operating characteristic curve (AUROC). RESULTS: At 10-15 min after delivery, the mean SI peaked between 0.84 and 0.90 and then decreased to a level between 0.72 and 0.77, which was similar to that upon entering the operating room. Among 331 women, 91 (27.5%) were diagnosed with PPH. There was no correlation between SI and total blood loss (rs = 0.02). The SI had low ability to detect PPH (AUROC 0.54, 95% confidence interval 0.47 to 0.61), which was similar to other vital signs (AUROCs 0.53-0.56). CONCLUSION: We determined the pattern of SI during cesarean delivery. We found no correlation between SI and total blood loss. Unlike in vaginal delivery, the prognostic accuracy of SI for PPH detection in cesarean delivery was low.

The correlation of urinary podocytes and podocalyxin with histological features of lupus nephritis.

Objectives The objective of this study was to test the correlation of urinary podocyte number (U-Pod) and urinary podocalyxin levels (U-PCX) with histology of lupus nephritis. Methods This was an observational, cross-sectional study. Sixty-four patients were enrolled: 40 with lupus nephritis and 24 without lupus nephritis (12 lupus nephritis patients in complete remission and 12 systemic lupus erythematosus patients without lupus nephritis). Urine samples were collected before initiating treatment. U-Pod was determined by counting podocalyxin-positive cells, and U-PCX was measured by sandwich ELISA, normalized to urinary creatinine levels (U-Pod/Cr, U-PCX/Cr). Results Lupus nephritis patients showed significantly higher U-Pod/Cr and U-PCX/Cr compared with patients without lupus nephritis. U-Pod/Cr was high in proliferative lupus nephritis (class III±V/IV±V), especially in pure class IV (4.57 (2.02-16.75)), but low in pure class V (0.30 (0.00-0.71)). U-Pod/Cr showed a positive correlation with activity index ( r=0.50, P=0.0012) and was independently associated with cellular crescent formation. In contrast, U-PCX/Cr was high in both proliferative and membranous lupus nephritis. Receiver operating characteristic analysis revealed significant correlation of U-Pod/Cr with pure class IV, class IV±V and cellular crescent formation, and the combined values of U-Pod/Cr and U-PCX/Cr were shown to be associated with pure class V. Conclusions U-Pod/Cr and U-PCX/Cr correlate with histological features of lupus nephritis.

Prognostic value of histological type in stage IV ovarian carcinoma: a retrospective analysis of 223 patients.

BACKGROUND: Patients with FIGO stage IV epithelial ovarian carcinoma have a poor but non-uniform prognosis. This study aimed to compare the survival of patients with serous or endometrioid tumours (S/E) and clear cell or mucinous tumours (non-S/E). METHODS: Data for 223 patients who underwent surgery between 1987 and 2010 and were diagnosed by centralized pathology review and were retrospectively analysed. The patients included 169 with S/E tumours and 54 with non-S/E tumours. RESULTS: The median overall survivals (OSs) of the S/E and non-S/E groups were 3.1 and 0.9 years, respectively (P<0.001). Six patients (2.7%), all with non-S/E tumours, died within 6 weeks after the initial surgery. Multivariate OS analysis revealed that performance status, residual tumor, metastatic sites, no debulking surgery, and non-S/E tumours were independent poor prognostic factors. For patients with non-S/E tumours, prognosis was more favourable for single-organ metastasis, except for liver or distant lymph nodes, no residual tumor, and resection of metastasis (median OS: 4.1, 4.6, and 2.6 years, respectively). CONCLUSIONS: In stage IV ovarian carcinoma, non-S/E tumours are associated with a significantly poorer prognosis and higher rates of early mortality compared to S/E tumours. Therefore, careful management and development of new strategies are required.

High expression of N-acetylglucosaminyltransferase IVa promotes invasion of choriocarcinoma.

BACKGROUND: Gestational trophoblastic diseases (GTDs) are related to trophoblasts, and human chorionic gonadotropin (hCG) is secreted by GTDs as well as normal placentas. However, the asparagine-linked sugar chains on hCG contain abnormal biantennary structures in invasive mole and choriocarcinoma, but not normal pregnancy or hydatidiform mole. N-acetylglucosaminyltransferase-IV (GnT-IV) catalyses ß1,4-N-acetylglucosamine branching on asparagine-linked oligosaccharides, which are consistent with the abnormal sugar chain structures on hCG. METHODS: We investigated GnT-IVa expression in GTDs and placentas by immunohistochemistry, western blot, and RT-PCR. We assessed the effects of GnT-IVa knockdown in choriocarcinoma cells in vitro and in vivo. RESULTS: The GnT-IVa was highly expressed in trophoblasts of invasive mole and choriocarcinoma, and moderately in extravillous trophoblasts during the first trimester, but not in hydatidiform mole or other normal trophoblasts. The GnT-IVa knockdown in choriocarcinoma cells significantly reduced migration and invasive capacities, and suppressed cellular adhesion to extracellular matrix proteins. The extent of ß1,4-N-acetylglucosamine branching on ß1 integrin was greatly reduced by GnT-IVa knockdown, although the expression of ß1 integrin was not changed. In vivo studies further demonstrated that GnT-IVa knockdown suppressed tumour engraftment and growth. CONCLUSION: These findings suggest that GnT-IVa is involved in regulating invasion of choriocarcinoma through modifications of the oligosaccharide chains of ß1 integrin.

Long-term survival of young women receiving fertility-sparing surgery for ovarian cancer in comparison with those undergoing radical surgery.

OBJECTIVES: To compare the clinical outcome of patients with stage I epithelial ovarian cancer (EOC) who received with fertility-sparing surgery (FSS) with those who underwent radical surgery (RS). METHODS: After a central pathological review and search of the medical records from multiple institutions, a total of 572 patients were retrospectively evaluated. All patients were divided into three groups: group A {FSS (n=74); age, ≤ 40}; groups B and C [RS; age, 40 ≥{(B), n=52}; 40<{(C), n=446}]. RESULTS: Five-year overall survival (OS) and disease-free survival (DFS) rates of patients in the groups were as follows: group A, 90.8% (OS)/87.9% (DFS); group B, 88.3% (OS)/84.4% (DFS); group C, 90.6% (OS)/85.3% (DFS), respectively (OS, P=0.802; DFS, P=0.765). Additionally, there was no significant difference in OS and DFS among the three groups stratified to stage IA or IC (OS (IA), P=0.387; DFS (IA), P=0.314; OS (IC), P=0.993; DFS (IC), P=0.990, respectively). Furthermore, patients with a grade 1-2 or 3 tumours in the FSS group did not have a poorer prognosis than those in the RS group. CONCLUSIONS: Stage I EOC patients treated with FSS showed an acceptable prognosis compared with those who underwent RS.

Association between dietary calcium and vitamin D intake and cervical carcinogenesis among Japanese women.

BACKGROUND/OBJECTIVES: To examine the association between dietary calcium and vitamin D intake and cervical neoplasia risk, we conducted a case-control study. SUBJECTS/METHODS: We selected 405 incident cervical neoplasias (333 invasive carcinomas and 72 cervical intraepithelial neoplasias grade III (CIN3)) and 2025 age-matched non-cancer controls. Dietary information was collected using a semiquantitative food-frequency questionnaire (FFQ). The effect on cervical neoplasia risk was evaluated using conditional logistic regression models. RESULTS: The inverse association between invasive carcinoma and milk, yogurt and fish was observed. On the other hand, the marginally significant inverse association between CIN3 and tofu and green leafy vegetables was observed. Compared with the lowest quartile (Q1) of calcium intake, adjusted odds ratios (ORs) for each of the three upper quartiles (Q2, Q3 and Q4) on invasive carcinoma risk were 0.86 (95% confidence interval (CI) 0.63-1.17), 0.50 (95% CI 0.34-0.73) and 0.68 (95% CI 0.48-0.97), respectively (P for trend=0.004). However, no association between calcium and cancer risk was evident among CIN3 cases (P for trend=0.528). Vitamin D intake showed a similar inverse association (Q2: OR 1.03, 95% CI 0.74-1.44; Q3: OR 0.80, 95% CI 0.56-1.15; and Q4: OR 0.64, 95% CI 0.43-0.94; P for trend=0.013). Similar to calcium, no association between vitamin D intake among CIN3 was evident (P for trend=0.109). An inverse association with calcium was evident in women whose vitamin D intake was low. However, this combined effect was not significant (invasive carcinoma: interaction P=0.819; and CIN3: interaction P=0.101). CONCLUSION: We found an inverse association between dietary calcium and vitamin D intake and cervical neoplasia risk among a group of Japanese women.

Fertility-sparing surgery in young women with invasive epithelial ovarian cancer.

OBJECTIVES: The purpose of this study was to clarify the clinical outcome of patients with stage IA or more advanced epithelial ovarian cancer (EOC) treated with fertility-sparing surgery (FSS). METHODS: After a central pathological review and search of the medical records from multiple institutions, a total of 60 stage I EOC patients treated with FSS were retrospectively evaluated in the current study. RESULTS: The median age was 30 years (range: 12-40 years). The median follow-up time was 54.7 months (range: 4.8-243.8 months). The stage was IA in 30, IB in one, and IC in 29 patients. Fifty-two patients were alive without relapse and 8 patient experienced recurrences {IA, 2; IB, 1; IC(surface involvement), 1; and IC(positive cytology), 4}. However, all patients with stage IC(capsule rupture) (n=17) were alive without recurrence. Collectively, there was no significant difference in the overall survival between the stage IA and IC groups (P=0.256). Moreover, there was no significant difference in DFS and OS between patients with stage IC(capsule rupture) and those with stage IA. In contrast, DFS and OS of the patients with stage IC(surface involvement/positive cytology) were poorer than those of patients with stage IA {OS; P=0.030, and DFS; P=0.005, respectively}. Thirteen pregnancies were observed in 9 patients. CONCLUSIONS: FSS may be considered a treatment option in women with stage I EOC, even in those with stage IC(capsule rupture) or more wishing to bear children.

Effectiveness of preoperative concurrent chemoradiation therapy (CCRT) for locally advanced adenocarcinoma of cervix.

AIM: To determine the efficacy of preoperative concurrent chemoradiation therapy (CCRT) to improve the prognosis of locally advanced adenocarcinoma of the uterine cervix. METHODS: Twenty-five patients with clinical stage IB2-IVB adenocarcinoma of the cervix were received preoperative CCRT. The CCRT protocol included: external radiotherapy to the pelvis: 39.6 Gy; intra-arterial or intravenous infusion of 70 mg/m2 cisplatin, days 1 and 22; 24-h continuous intravenous infusion of 700 mg/m2 5-FU, days 1-4 and 22-25. Two weeks after the end of CCRT, patients underwent restaging followed by appropriate surgery with pelvic lymphadenectomy. RESULTS: The overall clinical response rate was 96% (24/25), with a complete response (CR) in 12/25 patients and partial response (PR) in 12/25. On pathological examination, 5 of 19 patients (26%) undergoing surgery showed a pathological CR, 13 patients showed a PR, and 1 patient no change (NC) in their disease. Grade 3 or 4 hematological toxicity was observed in 15 patients. Grade 3 gastrointestinal toxicity was observed in 8 patients. The median follow-up period was 34 months (range, 6-69). The 5-year overall survival (OS) rate was 84%, and the progression-free survival (PFS) rate was 76%. CONCLUSIONS: Preoperative CCRT improves the survival of patients with locally advanced adenocarcinoma of the cervix, with manageable toxicities.

Is there any association between retroperitoneal lymphadenectomy and survival benefit in ovarian clear cell carcinoma patients?

BACKGROUND: To estimate the survival impact of systemic retroperitoneal lymphadenectomy in patients diagnosed with International Federation of Gynecology and Obstetrics pTI-IIb clear cell carcinoma of the ovary (CCC). PATIENTS AND METHODS: Demographic and clinicopathologic data were obtained from the Tokai Ovarian Tumor Study Group between 1986 and 2006. Survival curves were calculated using the Kaplan-Meier method. Differences in survival rates were analyzed using the log-rank test. RESULTS: A total of 205 patients had clinical pTI-IIb CCC (median age: 52 years, range: 30-75). One hundred and four (50.7%) patients underwent systemic retroperitoneal lymphadenectomy. Lymphadenectomy was not associated with improved disease-free and overall survival in all patients (P = 0.353 and P = 0.645, respectively). Moreover, lymphadenectomy did not improve the overall survival in those with pTIc CCC (P = 0.433). Similarly, on univariate analysis, age, volume of ascites, preoperative CA 125 values, and regimen of chemotherapy were not significant factors. In addition, there was no significant difference in the ratio of positive lymph node metastases regardless of the completion of lymphadenectomy (P = 0.955). CONCLUSION: Our data suggest that patients with pTI-IIb CCC who underwent lymphadenectomy did not show a significant improvement in survival. There was no significant difference in the overall and disease-free survival rates in pTI-IIb CCC patients regardless of the completion of surgical staging lymphadenectomy.

Twist expression in patients with cervical cancer is associated with poor disease outcome.

BACKGROUND: Twist, a basic helix--loop-helix transcription factor, has been reported to be associated with the development and progression of human cancer. We examined the distribution and expression of Twist in cervical cancer to examine its clinical significance. PATIENTS AND METHODS: We examined the distribution and expression of Twist in 101 cervical cancer specimens and determined the association between their expression and the clinico-pathological features observed, including patient outcome. RESULTS: Of the 101 specimens, 55 cases were negative for Twist immuno-expression, whereas 46 were positive. When categorized into negative versus positive expression, Twist was not associated with any of the clinico-pathological parameters examined. Positive Twist expression significantly predicted poorer overall survival (OS) and progression-free survival (PFS) when compared with negative expression (P < 0.01). In the multivariate analyses, positive Twist expression was an independent prognostic factor for OS (P < 0.05). CONCLUSIONS: Our data imply that positive Twist expression seems to be a useful marker in patients with cervical cancer likely to have an unfavorable clinical outcome.

Expression of N-acetylglucosaminyltransferase V in endometrial cancer correlates with poor prognosis.

N-acetylglucosaminyltransferase V (GnT-V) is an enzyme that catalyses beta1-6 branching of N-acetylglucosamine on asparagine-linked oligosaccharides of cell proteins. The present study aimed to investigate GnT-V expression and its prognostic significance in endometrial cancer. N-acetylglucosaminyltransferase V expression was studied by immunohistochemistry in 74 surgically resected endometrial cancers, and the staining intensity was evaluated. High GnT-V expression in tumour cells was found in 43 (58.1%) of the 74 cases, and was positively correlated with advanced patient age, histological grade, and lymph vascular space involvement. Patients with high GnT-V expression had significantly impaired overall survival and progression-free survival (PFS) (P=0.0041 and P=0.0023, respectively) compared to patients with low expression of GnT-V. On multivariate analysis, GnT-V expression was an independent prognostic factor for PFS (P=0.0364). beta1-6 branching of asparagine-linked oligosaccharides was also detected in GnT-V-positive endometrial cancer cells by leukoagglutinating phytohaemagglutinin (L(4)-PHA) staining, and the molecular size of the major glycoproteins recognised by L(4)-PHA was approximately 60-200 kDa by lectin blot analysis. These results suggested that high GnT-V expression was correlated with an unfavourable clinical outcome, and that GnT-V is involved in the malignant potential of endometrial cancer by increasing the synthesis of beta1-6 branching of asparagine-linked oligosaccharides.

Expression of Twist increases the risk for recurrence and for poor survival in epithelial ovarian carcinoma patients.

Twist is a transcription factor that regulates the expression of tumour suppressors such as E-cadherin. We examined the distribution and expression of Twist in human epithelial ovarian carcinoma (EOC) to examine its clinical significance. Paraffin sections from EOC tissues (n=82) were immunostained with Twist antibody, and the staining intensity was evaluated. The clinicopathological factors examined were age, International Federation of Gynecology and Obstetrics staging, histological type, tumour grade, preoperative value of CA125, peritoneal cytology, volume of ascites and residual tumour after cytoreductive surgery. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. Of the 82 carcinomas, 49 (59.8%) cases were negative for Twist immunoexpression, and 33 (40.2%) were positive immunoexpression. When categorized into negative vs positive expression, Twist was not associated with any of the clinicopathological parameters examined. However, positive Twist expression significantly predicted poorer OS and PFS when compared with negative expression (P<0.0001). In the multivariate analyses, positive Twist expression was the only independent prognostic factor for survival in this study (P<0.0001). Positive Twist expression seems to be a useful marker in patients with EOC likely to have an unfavourable clinical outcome.

Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer.

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolising enzyme inducing immune tolerance. The present study aimed to investigate IDO expression and its prognostic significance in endometrial cancer. Indoleamine 2,3-dioxygenase expression in endometrial cancer tissues (n = 80) was immunohistochemically scored as four groups (IDO-, 1+, 2+, and 3+). The high IDO expression (IDO2+ or 3+) in tumour cells was found in 37 (46.3%) of the 80 cases, and was positively correlated with surgical stage, myometrial invasion, lymph-vascular space involvement, and lymph node metastasis, but not with the histological grade. Patients with high IDO expression had significantly impaired overall survival and progression-free survival (PFS) (P = 0.002 and P = 0.001, respectively) compared to patients with no or weak expression of IDO (IDO- or 1+). The 5-year PFS for IDO-/1+, 2+, and 3+ were 97.7, 72.9, and 36.4%, respectively. Even in patients with early-stage disease (International Federation of Gynecology and Obstetrics I/II, n = 64), the PFS for IDO2+/3+ was significantly poor (P = 0.001) compared to that for IDO-/1+. On multivariate analysis, IDO expression was an independent prognostic factor for PFS (P = 0.020). These results indicated that the high IDO expression was involved in the progression of endometrial cancer and correlated with the impaired clinical outcome, suggesting that IDO is a novel and reliable prognostic indicator for endometrial cancer.

Angiotensin II type 1 receptor expression in ovarian cancer and its correlation with tumour angiogenesis and patient survival.

Angiotensin II, a main effector peptide in the renin-angiotensin system, acts as a growth-promoting and angiogenic factor via type 1 angiotensin II receptors (AT(1)R). We have recently demonstrated that angiotensin II enhanced tumour cell invasion and vascular endothelial growth factor (VEGF) secretion via AT1R in ovarian cancer cell lines in vitro. The aim of the present study was to determine whether AT1R expression in ovarian cancer is correlated with clinicopathological parameters, angiogenic factors and patient survival. Immunohistochemical staining for AT1R, VEGF, CD34 and proliferating cell nuclear antigen (PCNA) were analysed in ovarian cancer tissues (n = 67). Intratumour microvessel density (MVD) was analysed by counting the CD34-positive endothelial cells. Type 1 angiotensin II receptors were expressed in 85% of the cases examined, of which 55% were strongly positive. Type 1 angiotensin II receptors expression was positively correlated with VEGF expression intensity and MVD, but not with histological subtype, grade, FIGO stage or PCNA labelling index. In patients who had positive staining for AT1R, the overall survival and progression-free survival were significantly poor (P = 0.041 and 0.017, respectively) as compared to those in patients who had negative staining for AT1R, although VEGF, but not AT1R, was an independent prognostic factor on multivariate analysis. These results demonstrated that AT1R correlated with tumour angiogenesis and poor patient outcome in ovarian cancer, suggesting its clinical potential for a novel molecular target in strategies for ovarian cancer treatment.

Angiotensin II augmented migration and invasion of choriocarcinoma cells involves PI3K activation through the AT1 receptor.

While angiotensin II (Ang II) has been shown to inhibit migration of extravillous trophoblasts via plasminogen activator inhibitor-1 (PAI-1) activation, it has remained unclear whether it stimulates or inhibits malignant behavior of choriocarcinoma cells. Since we previously found an involvement of the renin-angiotensin system (RAS) in the proliferative potential in choriocarcinoma cells (BeWo), mediated via the Ang II type 1 receptor (AT1R), in the present study we investigated the effects of Ang II on choriocarcinoma cell migration/invasion in vitro using Transwell cell culture chambers. Ang II (10(-8)M) promoted migration and invasion by a choriocarcinoma cell line and augmented random cell mobility on checkerboard analysis. Immunoblotting showed Ang II to activate the phosphorylation of FAK and Akt in BeWo cells. Furthermore Ang II effects on cell migration were abolished by a selective AT1R antagonist and a phosphatidylinositol 3-kinase (PI3K) inhibitor. The present results suggest that Ang II-induced migration and invasion of choriocarcinoma cells probably involves PI3K following binding to the AT1R.

Changes in placental dipeptidyl peptidase IV in preeclampsia with intrauterine growth restriction.

The purpose of this study was to examine alterations in placental expression of dipeptidyl peptidase IV (DPPIV). The localization of DPPIV was compared in control and preeclamptic placentas. Enzyme activity, mRNA, and protein expression were also measured. In term placentas, DPPIV was expressed preferentially in the fetal vascular endothelial cells within stem villi and only weakly in the villous stromal cells. DPPIV activity in control placentas showed no remarkable changes throughout gestation. Levels of activity in samples from normotensive control cases and women having preeclampsia with or without intrauterine growth restriction were 11.8 +/- 2.1, 13.4 +/- 1.1, and 15.3 +/- 0.62 pmol pNA/min/mg protein, respectively. The preeclamptic placentas with intrauterine growth restriction thus showed significantly higher levels of activity than the controls (p < 0.05). We propose that placental DPPIV influences fetal metabolism via the degradation of fetoplacental circulating bioactive peptides, including incretins, resulting in the regulation of fetal growth.

Prognostic importance of vascular endothelial growth factor and its receptors in the uterine sarcoma.

Vascular endothelial growth factor (VEGF) and its receptors play an important role in tumor progression; however, there is no report regarding this factor in uterine sarcoma. Thirty-nine patients with uterine sarcoma, 14 carcinosarcomas, 4 endometrial stromal sarcomas, and 21 leiomyosarcomas, were studied. By immunohistochemical staining, VEGF was not detected in normal uterine smooth muscle, but VEGF receptor-1 (flt-1) and VEGF receptor-2 (flk-1) were observed in 14 and 4 of 14 normal smooth muscles, respectively. Of 39 sarcomas, 25 expressed VEGF, and 38 and 34 sarcomas expressed flt-1 and flk-1 at various intensities, respectively. The staining intensity of VEGF, flt-1, and flk-1 was significantly higher in sarcoma than in normal uterine smooth muscle, but that of phospho-flt-1 (p-flt-1) was significantly lower in sarcoma than in normal uterine smooth muscle. When sarcomas were divided into two groups according to staining intensity, a significant difference in survival curves was observed in only p-flt-1 of leiomyosarcoma (P= 0.008), and in all sarcomas, a lower survival curve was also observed in the high staining intensity group than in the low staining intensity group, although there was no significant difference (P= 0.102). In conclusion, VEGF and its receptors are suggested to be involved in progression of uterine sarcoma, but only the p-flt-1 level significantly affected the survival of leiomyosarcoma patients.

Signal pathway involved in increased expression of neutral endopeptidase 24.11 by gonadotropin releasing hormone in choriocarcinoma cells.

Neutral endopeptidase 24.11 (NEP) is known to regulate cellular functions by degrading several bioactive peptides, such as gonadotropin-releasing hormone (GnRH). The present study was performed to clarify the mechanisms of NEP expression by GnRH in human choriocarcinoma (BeWo) cells. GnRH increased NEP expression and enzyme activity in a dose- and time-dependent manner in BeWo cells. The phosphorylation levels of protein kinase C (PKC) delta, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK1 and 2) were enhanced after 10 min exposure of 10(-6)m GnRH. The effect of GnRH on both NEP expression and enzyme activity was completely inhibited by inhibitors of PKC, PKC delta, and p38MAPK. Cell number was reduced by 54.4 per cent of the control by culture with 10(-6)m GnRH for 24 h. However, phosphoramidon, a NEP specific inhibitor, inhibited antiproliferative effect of GnRH and reverted to the control level. In conclusion, GnRH induces NEP expression by PKC delta and p38MAPK, and increased NEP expression may be involved in antiproliferative effect in BeWo cells.