Ultra-low-dose estradiol and dydrogesterone for treatment of vasomotor symptoms in Europe and China.

OBJECTIVE: Among postmenopausal women, oral, ultra-low-dose continuous combined estradiol (E0.5 mg) plus dydrogesterone (D2.5 mg) reduces vasomotor symptoms (VMS). METHODS: This study was a post hoc analysis of data from two phase 3, double-blind studies. Postmenopausal women were randomized 2:1:2 to receive E0.5 mg/D2.5 mg, E1 mg/D5 mg (not included in this analysis) or placebo for 13 weeks (European study), or randomized 1:1 to receive E0.5 mg/D2.5 mg or placebo for 12 weeks (Chinese study). Endpoints assessed in ethnicity subgroups (European and Chinese) included changes from baseline in number of hot flushes, number of moderate-to-severe hot flushes and Menopause Rating Scale (MRS) score. RESULTS: Overall, 579 women were included in the analysis (E0.5 mg/D2.5 mg, n = 288; placebo, n = 291). European and Chinese women receiving E0.5 mg/D2.5 mg experienced greater reductions from baseline in mean daily number of hot flushes and mean daily number of moderate-to-severe hot flushes at week 4, week 8 and end of treatment versus those receiving placebo. Significant improvements in the 'hot flushes, sweating' MRS item score were reported in both European and Chinese women. CONCLUSION: Oral, ultra-low-dose continuous combined 0.5 mg 17ß-estradiol and 2.5 mg dydrogesterone improved VMS compared with placebo in European and Chinese postmenopausal women, with a positive impact on health-related quality of life.

Ultra-low-dose continuous combined estradiol and dydrogesterone in postmenopausal women: A pooled safety and tolerability analysis.

Objective: To assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone (E0.5 mg/D2.5 mg) among postmenopausal women. Methods: This pooled analysis of data from three clinical studies assessed the effects of continuous combined ultra-low-dose estradiol and dydrogesterone among postmenopausal women. Participants received E0.5 mg/D2.5 mg or placebo for 13 weeks (double-blind, randomized, European study), E0.5 mg/D2.5 mg or placebo for 12 weeks (double-blind, randomized, Chinese study), or E0.5 mg/D2.5 mg for 52 weeks (open-label, European study). Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), treatment discontinuation due to a TEAE, and adverse events of special interest (AESIs). Results: Overall, 1027 women were included in the pooled analysis (E0.5 mg/D2.5 mg, n = 736; placebo, n = 291). Mean treatment exposure was 288.9 days in the E0.5 mg/D2.5 mg group and 86.6 days in the placebo group. The proportion of women experiencing ≥1 TEAE was similar in the E0.5 mg/D2.5 mg and placebo groups (50.1% vs 49.5%, respectively). TESAEs occurred in 12 (1.6%) women receiving E0.5 mg/D2.5 mg and 9 (3.1%) women receiving placebo. Discontinuation of study treatment was infrequent in both groups (E0.5 mg/D2.5 mg: 1.5%; placebo: 2.4%). The occurrence of breast pain was more common in the E0.5 mg/D2.5 mg group than in the placebo group (2.0% vs 0.3%) as was uterine hemorrhage (6.5% vs 2.4%). The incidence of acne, hypertrichoses and weight increased was similar between groups. Conclusions: Across three studies, ultra-low-dose estradiol plus dydrogesterone was well tolerated among postmenopausal women, with no increase in TEAEs or TESAEs compared with placebo.

Long-term outcomes of vulvar or vaginal cancer patients undergoing laparoendoscopic single-site inguinal lymphadenectomy.

INTRODUCTION: Laparoendoscopic single-site inguinal lymphadenectomy (LESS-IL), a minimally invasive technique, has been reported in patients with vulvar or vaginal cancer regarding its safety and feasibility. However, the long-term outcomes, especially oncologic outcomes, are still lacking. We aimed to evaluate the long-term outcomes of LESS-IL to confirm its safety further. PATIENTS AND METHODS: Data were prospectively collected from patients with vulvar or vaginal cancer who underwent LESS-IL at our institution between July 2018 and June 2021. The patients were followed up for at least 12 months. All procedures were performed according to treatment standards. Short- and long-term complications and oncologic outcomes were analysed. RESULTS: A total of 16 patients undergoing 28 LESS-IL procedures were identified, amongst whom 4 underwent unilateral LESS-IL. The median numbers of excised groin lymph nodes were 9.0 (6.5-11.8) and 10.5 (8.3-12.0) in each left and right groin, respectively. Short-term complications occurred in 4 (25%) patients, including 18.7% lymphocele and 6.3% wound infection. Long-term complications regarding lower-limb lymphoedema appeared in 6 (37.5%) patients. Most short- and long-term complications were Clavien-Dindo 1 or 2, accounting for 90% of all post-operative issues. After a median follow-up of 27 (21.3-35.8) months, only 1 (6.3%) patient had isolated inguinal recurrence at 13 months postoperatively. No local or distant recurrence occurred. CONCLUSION: Our results suggest that LESS-IL is associated with little incidence of complications and promising oncologic outcomes, further demonstrating the safety and feasibility of the LESS-IL technique in patients requiring IL.

Effects of bisphenol A on uterine leiomyoma: In vitro and in vivo evaluation with mechanistic insights related to XBP1.

The incidence rate of human uterine leiomyomas is over 70% in the women of childbearing age, which has caused serious health and financial burden. Our previous study confirmed that Bisphenol A (BPA)，representative environmental estrogen, promoted the proliferation of human uterine leiomyomas and up-regulated the expression of cell proliferation-related genes. In this study, by combining ChIP-seq and RNA-seq, it was shown that after BPA intervention, H3K27ac modification levels and gene expression levels were altered in uterine leiomyomas cells. Moreover experimental verification found that BPA can regulate ITGA2 through the transcription factor XBP1, activate the downstream PI3K/AKT signaling pathway, eventually promote the proliferation of uterine leiomyomas. The present study provides new insights into the pathogenesis associated with exposure to BPA and other endocrine disruptors with similar effects by defining XBP1 as an important regulator, and which may act as an intervention and treatment target for uterine leiomyomas.

The influence of phenolic environmental estrogen on the transcriptome of uterine leiomyoma cells: A whole transcriptome profiling-based analysis.

OBJECTIVE: The study aimed to recognize potential molecular targets and signal pathways whereby phenolic environmental estrogen promotes the proliferation of uterine leiomyoma cells. METHODS: Primary cultured cell lines of uterine leiomyoma were treated with 0.1% DMSO, 10.0µmol/L Bisphenol A (BPA), and 32.0µmol/L Nonylphenol (NP) for 48 h before RNA-seq was performed. Those genes affected by BPA and NP were identified. Then, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Protein-protein Interaction (PPI) analysis were performed. Quantitative real-time polymerase chain reaction (q-PCR) and western blot were used to verify the differentially expressed gene and protein. RESULTS: Compared to with the control group, 739 differentially expressed genes were identified in both the BPA group and the NP group. GO enrichment analysis showed that the most enriched GO terms were connective tissue development and G1/S transition of mitotic cell cycle, and extracellular matrix. The results of KEGG enrichment analysis showed that differentially expressed mRNA were enriched mainly in three primary pathways, including environmental information processing, human diseases, and cellular processes. The cell cycle, PI3K-Akt signaling pathway are significantly enriched. The q-PCR and western blot verified the cell cycle associated genes and proteins were upregulated in both BPA group and NP group. Both BPA and NP activated the PI3K-AKT signaling pathway. CONCLUSION: Phenolic environmental estrogens may promote the proliferation and cell cycle progression of uterine leiomyoma cells through rapid non-genomic ER signaling, which leads to disordered cell cycle regulation and accelerates the transition of the cell cycle from G0/G1 phase to S phase. In addition, as an external stimulant, phenolic estrogen promotes the upregulation of inflammatory factors in uterine leiomyomas.

Prognostic Significance of CA125 Dynamic Change for Progression Free Survival in Patients with Epithelial Ovarian Carcinoma.

BACKGROUND This study aimed to investigate the value of CA125 dynamic change in PFS prediction for patients with epithelial ovarian carcinoma (EOC). MATERIAL AND METHODS Data analysis was performed using SPSS 24.0 statistical software with progression-free survival (PFS) as an outcome measure. Kaplan-Meier method was used to analyze the relationship between PFS and preoperative and postoperative NLR, PLR and CA125 levels, CA125 half-life, CA125-negative time, age, FIGO stage, histopathology, differentiation, vessel carcinoma embolus, and ascites. The survival curves were compared by the log-rank test. Based on the results of single-factor analysis, the Cox model was used for multifactor analysis to analyze independent risk factors affecting the PFS of epithelial ovarian carcinoma. RESULTS A total of 117 patients with EOC were selected from January 2012 to January 2019 to carry out a retrospective study. Univariate analyses showed that PFS of the patients with EOC was associated with differentiation, vessel carcinoma embolus, FIGO stage, CA125 half-life, CA12- negative time, and preoperative NLR (P<0.05). Multivariate analysis by the Cox model showed that vessel carcinoma embolus, CA125 half-life, differentiation, and preoperative NLR are the independent risk factors for PFS in patients with EOC. CONCLUSIONS The serum CA125 dynamic as reflected by CA125 half-life is the most important independent prognostic factor in patients with EOC. The simplicity of CA125 monitoring and its correlation with EOC patient survival can identify patients with poor prognosis through monitoring CA125 half-life, which can provide a reference value for use in clinical practice.

Laparoendoscopic single-site inguinal lymphadenectomy in gynecology: preliminary experience at a single institution.

PURPOSE: Laparoendoscopic single-site surgery (LESS), a promising innovation in minimally invasive surgery, has been used in treating gynecologic oncology diseases. There have been no reports in the literature regarding LESS for inguinal lymphadenectomy (LESS-IL) in gynecologic conditions. We aimed to evaluate the feasibility, safety, and outcomes of LESS-IL. METHODS: Six patients with vulvar or vaginal cancer underwent LESS-IL from July 2018 to March 2019. Data regarding the intraoperative and postoperative outcomes were analyzed. RESULTS: All patients successfully underwent a bilateral LESS-IL without conversion. LESS pelvic lymphadenectomy via an umbilical incision was also performed in a patient with vaginal cancer. The median operation time for the single-port laparoendoscopic inguinal lymphadenectomies was 105 min (range 70-134), with a median estimated blood loss of 108 ml (range 40-170). Median time of hospitalization was 7.5 days (range 5-10). A median of 11 (6-15) lymph nodes were dissected in a unilateral groin. The suction drains were removed after a median duration of 5 days (range 3-7). There were no skin-related or lymph-related postoperative complications. At a median follow-up period of 9 months, all the patients were alive and no recurrence was found. CONCLUSION: LESS-IL is a feasible and safe technique for the surgical management of gynecologic cancers.

Transforming growth factor-ß signaling pathway cross-talking with ERα signaling pathway on regulating the growth of uterine leiomyoma activated by phenolic environmental estrogens in vitro.

The aim of this paper is to study the participation of transforming growth factor-ß (TGF-ß) signaling pathway in mediating the growth of human uterine leiomyoma (UL) activated by phenolic environmental estrogens (EEs), via the interaction between TGF-ß and ER signaling pathways. The UL cells were prepared by primary culture and subculture methods. To validate the role of TGF-ß3 (5 ng/ml) for the viability of human uterine leiomyoma cells, CCK-8 assay was performed in each of five treatment groups including E2 group (E2 10(9) mol/l), BPA group (bisphenol A 10 µmol/l), NP group (nonylphenol 32 µmol/l), OP group (octylphenol 8 µmol/l), or control group (DMSO only). Subsequently, qRT-PCR was applied to detect mRNA expressions of ERα and c-fos, while western blot assay was used to test the expressions of p-Smad3, SnoN, and c-fos proteins in all settings mentioned above; the expressions were compared among different groups, and also in settings with and without synchronous treatment of ICI 182,780. Primarily cultured UL cells were successfully established. Compared with the control group, there were statistically significant increases in the proliferation rate of the UL cells in all EE groups or treated with TGF-ß3 only (p < 0.05). Nevertheless, a slight decrease in proliferation rate of UL was detected in coexistence with TGF-ß3 in all EE groups (p > 0.05). Interestingly, mRNA expressions of ERα and c-fos reduced in the setting of coexistence of TGF-ß3 and EEs compared to isolated EE treatment (p < 0.05). Compared with the control group, the expression of p-Smad3 and c-fos proteins significantly decreased (p < 0.05) in each of E2, BPA, NP, and OP group, and the expression of SnoN protein also significantly reduced only in BPA and NP groups (p < 0.05), followed by TGF-ß3 treatment. When adding ICI 182,780, the expression of p-Smad3 protein significantly increased in OP group (p < 0.05), but slightly increased in E2, BPA, NP, and OP groups (p > 0.05). However, compared with the control group, the expressions of SnoN and c-fos proteins significantly decreased (p < 0.05) after adding ICI182,780. Moreover, there was a significant statistical difference in the expression of p-Smad3, SnoN, and c-fos proteins between pre- and post-treatment of ICI 182,780 in all groups (p < 0.05). The ERα signaling pathway and TGF-ß signaling pathway have different roles in the control of UL cell proliferation. The phenolic EEs can be a promoter of UL cell proliferation, which is mediated by ERα signaling pathway and its cross-talking with TGF-ß signaling pathway. Both less exposure to EEs and blockade of TGF signaling pathway are necessary strategies to prevent UL.

Vegetarian diet and reduced uterine fibroids risk: A case-control study in Nanjing, China.

AIM: The aim of this study was to investigate whether a vegetarian diet correlates with a potential reduced risk of uterine fibroids. MATERIAL AND METHODS: We used data from a case-control study conducted in Southeast University Zhongda Hospital between February 2010 and December 2014. Cases included 600 Chinese Han women with uterine fibroids (case group) whose clinical diagnosis dated back no more than 1 year. Controls were 600 patients without uterine fibroids as well as healthy volunteers (control group). All of the information gathered through the questionnaire survey was analyzed for the risk factors of the uterine fibroids pathogenesis. RESULTS: The multifactor analysis showed that women with uterine fibroids reported a less frequent consumption of broccoli (odds ratio [OR]: 0.552; 95% confidence interval [CI]: 0.316-0.964), cabbage (OR: 0.446; 95%CI: 0.211-0.943), Chinese cabbage (OR: 0.311; 95%CI: 0.102-0.946), tomato (OR: 0.453; 95%CI: 0.241-0.853), and apple (OR: 0.416; 95%CI: 0.213-0.814) (P < 0.05). CONCLUSION: The original evidence from this epidemiological investigation shows that a high consumption of broccoli, cabbage, Chinese cabbage, tomato and apple seems to be a protective factor for uterine fibroids. We suggest that greater intake of fresh fruits and cruciferous vegetables may be able to reduce the incidence of uterine fibroids.

Phenolic environmental estrogens in urine and blood plasma from women with uterine leiomyoma: Epidemiological survey.

AIM: To explore the effect of phenolic environmental estrogens (EE) on women with uterine leiomyoma (UL). METHODS: Urine and blood plasma samples were collected from 300 patients diagnosed with UL at the Affiliated Zhongda Hospital of Southeast University between December 2013 and December 2014. Control urine and blood plasma samples were collected from 300 women who are either patients without UL or healthy volunteers presenting to the same hospital for physical examination during the same period. Bisphenol A (BPA), nonylphenol (NP) and octylphenol (OP) concentration in these samples was measured using solid phase extraction (SPE) coupled with liquid chromatography-tandem mass spectrometry. RESULTS: The OP concentration in urine and blood plasma was significantly higher in the UL group compared with the control group (r = 0.224, P = 0.001). Urine BPA concentration was not significantly different between the UL group and the control group (r = 0.009, P = 0.896). There was also no statistically significant difference in urine NP concentration between the two groups (r = 0.057, P = 0.419). On logistic regression, exposure concentration of urine BPA (OR, 1.129; 95%CI: 1.081-1.179) and NP (OR, 1.165; 95%CI: 1.025-1.324) was associated with UL genesis (P < 0.05). Nevertheless, there was no significant difference in blood plasma concentration of BPA, OP and NP between the two groups (P > 0.05). CONCLUSION: Urine and blood plasma EE exposure levels in women, especially the urine level, was related to the incidence of UL.

Efficacy and safety of the contraceptive vaginal ring (NuvaRing) compared with a combined oral contraceptive in Chinese women: a 1-year randomised trial.

OBJECTIVES: The aim of the study was to assess the efficacy and tolerability of the monthly vaginal ring (NuvaRing; 15 µg ethinylestradiol [EE] and 120 µg etonogestrel per day) compared with a monophasic (21/7) combined oral contraceptive (COC) containing 30 µg EE and 3 mg drospirenone in healthy Chinese women aged 18-40 years. METHODS: This was a phase III, open-label, randomised multicentre trial conducted in China. Participants received NuvaRing or COC for 13 cycles (3 weeks of ring/pill treatment followed by a 1-week ring-free/pill-free period). Contraceptive efficacy was assessed by in-treatment pregnancies and expressed by the Pearl Index (PI; number of pregnancies/100 woman-years of use). Cycle control was assessed by unscheduled (breakthrough) and absence of scheduled (withdrawal) bleeding events. Safety and tolerability were assessed throughout the study. RESULTS: Participants were randomised either to the NuvaRing (n = 732) or to the COC (n = 214); 588 (82.4%) and 182 (78.4%) participants, respectively, completed the study. There were 10 in-treatment pregnancies in the NuvaRing group (PI 1.92; 95% confidence interval [CI] 0.92, 3.53) and five in the COC group (PI 3.12; 95% CI 1.01, 7.29). Breakthrough bleeding/spotting ranged from 18.6% (Cycle 1) to 4.2% (Cycle 11) for NuvaRing and from 21.6% (Cycle 1) to 7.9% (Cycle 11) for COC. Absence of withdrawal bleeding ranged from 8.6% (Cycle 1) to 3.0% (Cycle 11) for NuvaRing and from 14.6% (Cycle 1) to 6.4% (Cycle 5) for COC. For NuvaRing and COC, respectively, 26.6% and 25.0% of participants had treatment-related adverse events, and 7.0% and 9.1% discontinued the study as a result. CONCLUSIONS: Once-monthly NuvaRing is efficacious and safe for use in Chinese women.

[Efficacy and safety of mifepristone combined with misoprostol for termination of pregnancy between 8 and 16 weeks of gestation].

OBJECTIVE: To assess the efficacy and safety of mifepristone combined with oral or vaginal misoprostol for termination of pregnancy between 8 and 16 weeks of gestation. METHODS: This was a randomized, multi-center, open clinical trial. A total of 625 women at 8-16 weeks of gestation were randomized to receive 200 mg oral mifepristone followed by either oral misoprostol 400 µg every 3 hours or vaginal misoprostol 400 µg every 6 hours for a maximum of 4 doses 36-48 hours later. There were 417 women in oral group with 198 at 8-9 weeks and 219 at 10-16 weeks, while 208 women in vaginal group with 99 at 8-9 weeks and 109 at 10-16 weeks. The outcome measures were the success abortion rate, induction to abortion interval, the amount of bleeding, reoccurrence of menstruation and adverse events. RESULTS: Abortion rate was significantly higher in vaginal group [98.1% (202/206)] than that in oral group [94.0% (390/415), P = 0.023]; concerning termination of pregnancy at 8-9 weeks and 10-16 weeks respectively, there were no significant differences between oral and vaginal groups (P = 0.156, P = 0.073). The induction to abortion interval was no significant difference in oral and vaginal group in different gestational weeks (P = 0.238, P = 0.273). The average induction to abortion interval was (4.1 ± 6.6) hours and (6.0 ± 4.5) hours respectively in terminating 8-9 weeks and 10-16 weeks of gestation. Concerning the amount of bleeding within 2 hours of placenta expulsion, there was significant difference between oral group [(63 ± 46) ml] and vaginal group [(55 ± 45) ml] in terminating 8-9 weeks of gestation (P = 0.047), while there was no significant difference between groups in terminating 10-16 weeks of gestation [oral group (76 ± 52) ml versus vaginal group (76 ± 61) ml, P = 0.507]. The reoccurrence of menstruation was about 37 days in both oral and vaginal groups. Two cases of incomplete abortion were serious adverse events (SAE) relating to treatment. The common adverse events (AE) of nausea and vomiting were significantly higher in oral group [57.2% (239/417), 36.3% (151/417)] than those in vaginal group [45.4% (94/208), 26.1% (54/208); P = 0.005, 0.011]. CONCLUSION: Oral or vaginal misoprostol combined with mifepristone, is effective and safe for termination of pregnancy between 8 and 16 weeks of gestation.

Prognostic value of HER-2/neu expression in epithelial ovarian cancer: a meta-analysis.

Various studies examined the relationship between human epidermal growth factor receptor 2 (HER-2/neu) overexpression and the clinical outcome in patients with ovarian cancer, but yielded conflicting results. Electronic databases updated in May 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between HER-2/neu overexpression and survival of patients with ovarian cancer. Survival data were aggregated and quantitatively analyzed. We conducted a final analysis of 3,055 patients from 20 eligible studies and evaluated the correlation between HER-2/neu overexpression and survival in patients with ovarian cancer. Combined hazard ratios suggested that HER-2/neu overexpression was not associated with a significant impact on survival, with the hazard ratio (HR) and 95% confidence interval (CI) being 1.05 and 0.92-1.19, respectively, overall. When grouped according to the study design type, a statistically significant combined HR was found in retrospective studies (HR = 1.44, 95% CI 1.14-1.75) and no statistically significant combined HR was found (HR = 0.96, 95% CI 0.81-1.11) for prospective studies. HER-2/neu overexpression seems to have no significant impact on survival of ovarian cancer patients. However, a statistically significant combined HR was found in retrospective studies, but not in prospective studies.

A multicenter case-control study on screening of single nucleotide polymorphisms in estrogen-metabolizing enzymes and susceptibility to uterine leiomyoma in han chinese.

Uterine leiomyoma (UL) is an estrogen-responsive benign tumor in the female reproductive system and the main risk of hysterectomy for women. However, gene polymorphism of estrogen-metabolizing enzymes may lead to the different susceptibility to UL. We detected 10 single mucleotide polymorphisms in three key estrogen metabolite enzymes (COMT, CYP1A1, CYP1B1) in a Chinese Han population consisting of 800 patients and 800 healthy women from five different medical centers. The genetic polymorphism of rs3087869 (IVS1+2329C>T) (OR 3.200, 95% CI 1.614-6.345) and rs4680 (Val158Met) (OR 5.675, 95% CI 2.696-11.942) loci on COMT, rs1048943 (Ile462Val) (OR 4.629, 95% CI 2.216-9.672) and rs4646422 (Gly45Asp) (OR 3.240, 95% CI 1.624-6.461) loci on CYP1A1 and rs1065827 (Ala119Ser) (OR 5.635, 95% CI 2.990-10.619) locus on CYP1B1 were the risk factors to UL development and rs1056836 (Leu432Val) (OR 0.188, 95% CI 0.061-0.575) locus on CYB1B1 may be the protective factor to UL. The results provide a theoretical basis for genetic screening and early intervention to UL-susceptible populations.

Role of single nucleotide polymorphisms in estrogen-metabolizing enzymes and susceptibility to uterine leiomyoma in Han Chinese: a case-control study.

AIM: To explore the relationship between estrogen metabolism enzyme gene polymorphism and susceptibility to uterine fibroids, and to seek the screening molecular markers for genetic traits in uterine fibroid populations. METHODS: A total of 300 female Han Chinese patients and 300 healthy female Han Chinese volunteers in Nanjing (age range, 30-50 years) were recruited from Zhongda Hospital, Southeast University from February 2011 to March 2012. The single nucleotide polymorphisms (SNP) of estrogen-metabolizing enzyme genes from the two groups of women were examined by polymerase chain reaction denaturing high-performance liquid chromatography, which were four COMT gene loci including rs3087869, rs165774, rs165599 and rs4680, three CYP1A1 gene loci including rs1048943, rs4646421 and rs4646422, and three CYP1B1 gene loci including rs1056827, rs1056836 and rs1056837. Genotype frequencies among cases and controls were calculated and analyzed by binary logistic regression. RESULTS: Regression analysis of SNP showed that COMT IVS1+2329C>T (odds ratio [OR], 2.872; 95% CI, 1.690-4.882) and Val158Met (OR, 2.593; 95% CI, 1.546-4.350), CYP1A1 Ile462Val (OR, 2.383; 95% CI, 1.418-4.005) and Gly45Asp (OR, 2.489; 95% CI, 1.49-4.159), and CYP1B1 Ala119Ser (OR, 3.361; 95% CI, 2.035-5.552) and Leu432Val (OR, 0.164; 95% CI, 0.061-0.441) influenced uterine fibroids significantly (P < 0.05). Allele and genotype frequencies among cases and control were calculated and examined to match the Hardy-Weinberg equilibrium with the χ²-test. CONCLUSION: The genetic polymorphisms of IVS1+2329C>T and Val158Met loci in COMT, Ile462Val and Gly45Asp loci in CYP1A1 and Ala119Ser loci in CYP1B1 were risk factors for uterine leiomyoma development, and Leu432Val locus in CYB1B1 may be a protective factor. The results provide a theoretical basis for genetic screening and early intervention for uterine leiomyoma-susceptible populations.

The relationship between maternal serum prenatal screening combined with epidemiological study and early onset preeclampsia.

OBJECTIVE: To explore the major risk factors and early prediction methods in the pathogenesis of early onset preeclampsia through combining prenatal screening markers and epidemiological characteristics. METHODS: Prenatal screening was performed in second trimester using enzyme-linked immunosorbent assay in 1,011 gravidas and epidemiological correlation factors were got by telephone with prospective cohort study. Predictive model of early onset preeclampsia was established and evaluated by single and multiple factor logistic analysis in 30 cases of preeclampsia and 867 cases of normal gravidas. RESULTS: As compared with the control group, the maternal serum level of human chorionic gonadotropin (hCG) in second trimester of patients with early onset preeclampsia elevated significantly (P < 0.001). Pregestational BMI ≥ 24 kg/m(2) (OR = 3.649, 95 % CI 1.600-8.321, P = 0.002), history of hypertension, diabetes and nephritis (OR = 55.724, 95 % CI 8.223-377.614, P < 0.001), family history of hypertension (OR = 6.777, 95 % CI 2.917-15.742, P < 0.001), and risk coefficient for trisomy 21 (OR = 3.688, 95 % CI 1.013-13.429, P = 0.048) were major risk factors of early onset preeclampsia. The sensitivity and specificity of predictive model were 70.0 and 75.1 %, when cutoff point was 0.249. The diagnostic accuracy of the logistic model was better than hCG. CONCLUSIONS: In order to early prevent the onset and development of EOPE, it is necessary to strengthen pregestational and prenatal care for women in these aspects including pregestational BMI ≥ 24 kg/m(2), history of hypertension, diabetes, nephritis, family history of hypertension, and high risk for trisomy 21 syndrom.

[Effects of estrogen replacement therapy on cognitive function of ovariectomized rats].

OBJECTIVE: To investigate the effect of estrogen replacement therapy applied in different periods to ovariectomized rats and to evaluate the cognitive function of the rats. METHODS: Totally 40 rats were ovariectomized to be postmenopausal models. They were divided into early hormone replacement therapy group (n = 10, managed by estradiol valerate at day 3 after surgery), early control group (n = 10, managed by saline at day 3 after surgery), late hormone replacement therapy (n = 10, managed by estradiol valerate at day 90 after surgery for 30 days) and late control group (n = 10, managed by saline at day 90 after surgery for 30 days). The behavior indicators of the rats were evaluated by Morris watermaze and hippocampal metabolite was detected by proton magnetic resonance spectroscopy, including N-acetylaspartate (NAA), choline containing compounds (Cho), creatine (Cr), myoinositol (mI), NAA/Cr, Cho/Cr and mI/Cr. RESULTS: (1)Navigation test: escape latency were (43 ± 13) s at the early control group, (28 ± 9) s at the early HRT group, (82 ± 26) s at the late control group and (48 ± 18) s at late HRT group. Swimming distance were (1 404 ± 238) cm at the early control group, (878 ± 354) cm at the early HRT group, (2 411 ± 818) cm at the late control group and (1 310 ± 434) cm at the late HRT group. The escape latency and swimming distance of the early and late HRT groups were significantly shorter than those at the control groups (P < 0.05). (2) Spatial probe test: the swimming time in the target quadrant of rats in the early HRT group (34.0 ± 3.0) s were longer than those in other groups (P < 0.05). (3) Proton magnetic resonance spectroscopy: NAA/Cr were 1.12 ± 0.17 at the early control group, 1.26 ± 0.12 at the early HRT group, 1.57 ± 0.21 at the late control group and 1.38 ± 0.28 at the late HRT group. The late HRT group and the late control group were higher than their early groups (F = 6.05, P = 0.040). There was no significant difference between the HRT groups and the control groups (F = 0.04, P = 0.860). mI/Cr were 0.69 ± 0.04 at the early control group, 0.46 ± 0.12 at the early HRT group, 0.70 ± 0.03 at the late control group and 0.75 ± 0.08 at the late HRT group. There were statistically significant differences of the experimental time between the early and late groups(F = 16.45, P = 0.004). The differences between the early HRT group and the early control group, and the late HRT group and the late control group were significant (F = 6.01, P = 0.040). And there was an interaction with the experimental time and HRT measures (F = 13.79, P = 0.006); early HRT can reduce the average level of mI/Cr. Cho/Cr were 0.95 ± 0.09 at the early control group, 0.80 ± 0.12 at the early HRT group, 0.87 ± 0.09 at the late control group and 0.85 ± 0.12 at the late HRT group. There was no significant difference among those groups (P > 0.05). NAA/mI: there was an interaction with the experimental time and HRT measures (F = 12.95, P = 0.007). Early HRT can elevated levels of NAA/mI, while the late results were reversed. CONCLUSION: Earlier estrogen replacement therapy may play a positive role in improving cognitive function of the ovariectomized rats.

Inhibition of PI3K/Akt/mTOR signaling pathway enhances the sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin in vitro.

The activation of the PI3K/AKT/mTOR pathway plays a key role in ovarian cancer tumorigenesis, progression and chemotherapy resistance. This study aimed to explore the possible mechanism that PI-103, a dual inhibitor of phosphatidylinositide 3-kinase and mTOR, enhances the sensitivity of SKOV3/DDP ovarian cancer cell line to cisplatin chemotherapy. The results showed that PI-103 could significantly increase the sensitivity of SKVO3/DDP cells to cisplatin through inhibiting the activation of PI3K/Akt/mTOR signaling pathway and inducing cell cycle arrest and apoptosis.

Long-term safety of fezolinetant in Chinese women with vasomotor symptoms associated with menopause: the phase 3 open-label MOONLIGHT 3 clinical trial.

OBJECTIVE: We aimed to assess long-term safety and tolerability of fezolinetant, a nonhormonal neurokinin 3 receptor antagonist, among Chinese women with vasomotor symptoms associated with menopause participating in the MOONLIGHT 3 trial. METHODS: In this phase 3 open-label study, women in menopause aged 40-65 years received fezolinetant 30 mg once daily for 52 weeks. The primary endpoint was frequency and severity of treatment-emergent adverse events (TEAEs), assessed at every visit through week 52 and one follow-up visit at week 55. RESULTS: Overall, 150 women were enrolled (mean age, 54 years) and 105 completed treatment. The frequency of TEAEs was 88.7%. Most TEAEs were mild (63.3%) or moderate (22.7%). The most common TEAE was upper respiratory tract infection (16.0%), followed by dizziness, headache, and protein urine present (10.7% each). There was no clinically relevant change (mean ± standard deviation) in endometrial thickness (baseline, 2.95 ± 1.11 mm; week 52, 2.94 ± 1.18 mm). Alanine aminotransferase and/or aspartate aminotransferase levels >3 times the upper limit of normal were reported in 1.4% of women; no Hy's Law cases occurred. CONCLUSIONS: Fezolinetant 30 mg once daily was generally safe and well tolerated over a 52-week period among women in China with vasomotor symptoms associated with menopause.ClinicalTrials.gov Identifier: NCT04451226.

Evaluating the cost utility of estradiol plus dydrogesterone for the treatment of menopausal women in China.

AIM: Evaluate the cost utility of menopausal hormone therapy for women in China. MATERIALS AND METHODS: A bespoke Markov cost utility model was developed to evaluate a cohort of symptomatic perimenopausal women (>45 years) with intact uterus in China in accordance with China's Pharmacoeconomic guideline. Short (5-year) and long (10-year) treatment durations were evaluated over a lifetime model time horizon with 12-month cycle duration. Societal and healthcare payer perspectives were evaluated in the context of a primary care provider/prescriber, outpatient setting with inpatient care for patients with chronic conditions. Disease risk and mortality parameters were derived from focused literature searches, and China Diagnosis-related Group cost data was included. Comprehensive scenario, univariate and probabilistic sensitivity analysis were undertaken along with independent validation. This is the first model to include MHT-related disease risks. RESULTS: According to base case results, the total cost for MHT was 22,516$ (150,106¥) and total quality adjusted life years 12.32 versus total cost of no MHT 30,824$ (205,495¥) and total quality adjusted life years 11.16 resulting in a dominant incremental cost effectiveness ratio of -7,184$ (-47,898¥) per QALY. Results hold true over a range of univariate deterministic sensitivity and scenario analyses. Probabilistic analysis showed a 91% probability of being cost effective at a willingness to pay threshold of three times Gross Domestic Product per capita in China. CONCLUSION: Contingent on the structure and assumptions of the model, combination of estradiol plus dydrogesterone MHT is potentially cost saving in symptomatic women over the age of 45 years in China.

Menopausal hormone therapy is publicly funded in many countries to alleviate symptoms of menopause; however, uptake has been comparatively slow in China. This has implications for the estimated 168 million menopausal-aged women. This analysis is the first to evaluate the cost effectiveness of menopausal hormone therapy in China using best practice principles and incorporating longer term disease risks. Menopausal hormone therapy is potentially cost saving in the context of China.