Hyperinsulinemia impairs decidualization via AKT-NR4A1 signaling: new insight into polycystic ovary syndrome (PCOS)-related infertility.

BACKGROUND: Investigating the underlying molecular mechanisms responsible for endometrial dysfunction in women with PCOS is essential, particularly focusing on the role of hyperinsulinemia. METHODS: We explored the role of insulin in the decidualization process using a synthetic decidualization assay. To dissect the effects of PI3K/AKT-NR4A signaling, we employed small interfering RNAs (siRNAs) targeting the NR4A genes and inhibitors of the PI3K/AKT pathway. We also investigated the disruption of AKT-NR4A1 signaling in the endometrium of PCOS female rats induced with dehydroepiandrosterone (DHEA). Quantitative real-time PCR (qRT-PCR) and Western blot (WB) analyses were utilized to evaluate gene expression regulation. RESULTS: Insulin was found to suppress the expression of decidualization markers in human endometrial stromal cells (hESC) in a dose-dependent manner, concurrently triggering an inappropriate activation of the PI3K/AKT pathway. Members of the NR4A family, as downstream effectors in the PI3K/AKT pathway, were implicated in the insulin-induced disruptions during the decidualization process. Moreover, the endometrium of PCOS models showed significantly elevated levels of phosphorylated (Ser473) AKT, with a corresponding reduction in Nr4a1 protein. CONCLUSIONS: Our research demonstrates that insulin negatively regulates decidualization in hESC via the PI3K/AKT-NR4A pathway. In vivo analysis revealed a significant dysregulation of the AKT-NR4A1 pathway in the endometrium of PCOS rats. These findings offer novel insights into the pathogenesis of infertility and endometrial disorders associated with hyperinsulinemia in PCOS.

The alterations of cytokeratin and vimentin protein expressions in primary esophageal spindle cell carcinoma.

BACKGROUND: The accumulated evidence has indicated the diagnostic role of cytokeratin (CK) and vimentin protein immunoassay in primary esophageal spindle cell carcinoma (PESC), which is a rare malignant tumor with epithelial and spindle components. However, it is largely unknown for the expression of CK and vimentin in pathological changes and prognosis of PESC. METHODS: Eighty-two PESC patients were identified from the esophageal and gastric cardia cancer database established by Henan Key Laboratory for Esophageal Cancer Research of Zhengzhou University. We retrospectively evaluated CK and vimentin protein expressions in PESC. Clinicopathological features were examined by means of univariate and multivariate survival analyses. Furthermore, the co-expression value of cytokeratin and vimentin was analyzed by receiver operating characteristic (ROC) curve. RESULTS: The positive pan-cytokeratins AE1/AE3 (AE1/AE3 for short) staining was chiefly observed in cytoplasm of epithelial component tumor cells, with a positive detection rate of 85.4% (70/82). Interestingly, 19 cases showed AE1/AE3 positive staining both in epithelial and spindle components (23.2%). However, AE1/AE3 expression was not observed with any significant association with age, gender, tumor location, gross appearance, lymph node metastasis and TNM stage. Furthermore, AE1/AE3 protein expression does not show any effect on survival. Similar results were observed for vimentin immunoassay. However, in comparison with a single protein, the predictive power of AE1/AE3 and vimentin proteins signature was increased apparently than with single signature [0.75 (95% CI = 0.68-0.82) with single protein v.s. 0.89 (95% CI = 0.85-0.94) with AE1/AE3 and vimentin proteins]. The 1-, 3-, 5- and 7-year survival rates for PESC patients in this study were 79.3%, 46.3%, 28.0% and 15.9%, respectively. Multivariate analysis demonstrated age and TNM stage were independent prognostic factors for overall survival (P = 0.036 and 0.003, respectively). It is noteworthy that only 17.1% patients had a PESC accurate diagnosis by biopsy pathology before surgery (14/82). 72.4% PESC patients with biopsy pathology before surgery had been diagnosed as squamous cell carcinoma. CONCLUSION: The present study demonstrates that cytokeratin and vimentin protein immunoassay is a useful biomarker for PESC accurate diagnosis, but not prognosis. The co-expression of cytokeratin and vimentin in both epithelial and spindle components suggest the possibility of single clone origination for PESC.

Leptin Levels in Women With Polycystic Ovary Syndrome: A Systematic Review and a Meta-Analysis.

OBJECTIVE: Conflicting results regarding leptin levels in women with polycystic ovary syndrome (PCOS) have been reported. We summarize all available evidence from human participant studies to evaluate leptin levels in PCOS. DATA SOURCES: PubMed, ClinicalTrials.gov , and Web of Science databases were searched with English-language restriction for only human beings from the inception to December 31, 2015. Search terms included PCOS (polycystic ovary syndrome or PCOS) and leptin. METHODS OF STUDY SELECTION: A total of 238 studies were reviewed, and a total of 19 studies, involving 991 women with PCOS and 898 controls, were eligible for our meta-analysis. Studies were eligible if provided leptin means and standard deviation in women with PCOS and healthy women controls. RESULTS: Parameters, such as body mass index, insulin resistance (IR), and total testosterone, which may influence leptin levels were extracted. Data were collected and analyzed by RevMan 5.3 and Stata/SE14.0. The pooling analysis of all relevant studies revealed that leptin levels were significantly higher in patients with PCOS than in controls, with standardized mean difference of 1.62 (95% confidence interval: 1.01-2.23). However, the heterogeneity across studies was considerable and not eliminated in subgroup analyses. Meta-regression analysis further suggested that the heterogeneity might be relevant to variability in IR and study location. CONCLUSION: Elevated leptin levels are detected in women with PCOS compared with non-PCOS controls. Higher leptin levels may be correlated with IR, metabolic disorder, infertility, and even cardiovascular disease risk in PCOS, which may contribute to the etiology and development of PCOS.

The clinical experience of robot-assisted surgery in gynecologic cancer.

The comparison of robotic and conventional laparoscopic hysterectomy and pelvic lymphadenectomy in gynecologic cancer still needs to be studied. In all, 98 consecutive cases of patients with gynecologic cancer undergoing robot-assisted hysterectomy and pelvic lymphadenectomy, and another 98 consecutive cases of conventional laparoscopic hysterectomy and pelvic lymphadenectomy during the same period in the Obstetrics and Gynecology Hospital of Fudan University were included. The duration of the operation, blood loss, drainage during the first 24 h after the operation, total hospital stay, hospital stay after the operation, lymph nodes collected, perioperative complications, and the cost of each operation for both procedures were recorded. The duration of the operation was longer, and the cost of each operation was almost seven times higher in the robot group than that in the conventional laparoscopy group. But the differences with regard to blood loss, drainage during the first 24 h after the operation, total hospital stay, hospital stay after operation, the lymph nodes collected, and the rate of perioperative complications were not statistically significant. Robot-assisted surgery (RAS) in gynecologic cancer is as feasible as conventional laparoscopic surgery. We recommend further studies about the cost and effect of RAS in gynecologic cancer.

The learning curves of robotic and three-dimensional laparoscopic surgery in cervical cancer.

BACKGROUND: The 3D laparoscopy systems and robotic systems have been introduced into clinical practice for a few years. But the comparison of robotic and 3D laparoscopic gynecologic surgery is still needed. OBJECTIVE: To retrospectively compare the learning curves of robotic and 3D laparoscopic hysterectomy and pelvic lymphadenectomy in cervical cancer. STUDY DESIGN: The operational duration, blood loss, peritoneal drainage of first 24 hours after operation, total hospitalization days, hospitalization days after operation, lymph nodes collected, learning curves and cost of robotic and 3D laparoscopic hysterectomy and pelvic lymphadenectomy in cervical cancer performed by one experienced surgeon were studied. RESULTS: There was one surgeon who performed 37 cases of robotic and 24 cases of 3D laparoscopic hysterectomy and pelvic lymphadenectomy, and the turning point of learning curves was case 13th and case 10th. The differences of duration of operation, blood loss, peritoneal drainage of first 24 hours after operation, total hospitalization days, hospitalization days after operation, lymph nodes collected and perioperative complications were not statistically significant. But the cost of each robotic operation was higher than 3D operation. CONCLUSIONS: The turning point of the learning curve of 3D laparoscopic hysterectomy and pelvic lymphadenectomy is earlier than that of robotic sugery in patients with cervical cancer, and there is no obvious benefit from robotic surgery than 3D surgery in the terms of short-term medical index and hospitalization cost.

Expression of anti-Müllerian hormone in two rat models of polycystic ovary syndrome.

AIM: Anti-Müllerian hormone (AMH) levels are two to three times higher in patients with polycystic ovary syndrome (PCOS), but the mechanism of increased AMH levels in PCOS remains unclear. The purpose of our experiment was to investigate a change in AMH levels in two kinds of commonly used rat models and to determine an ideal model for future research of AMH in the pathogenesis of PCOS. METHODS: Thirty female Sprague Dawley rats were treated using two modeling methods: implantation of a levonorgestrel silastic implant or injection with sodium prasterone sulfate plus human chorionic gonadotropin (hCG). Rats in the control group were implanted with a blank silastic stick. Serum steroid concentrations, ovarian morphology and ovarian expression of AMH and AMH-receptor II (RII) proteins were determined and their correlations were studied. RESULTS: The results from the levonorgestrel and hCG group were closer to those displayed by human PCOS patients than the sodium prasterone sulfate and hCG group. Ovarian local expression of AMH and AMH-RII was increased in these both models compared with the control group; however, an elevation of serum AMH concentration was not observed (12.53 ± 0.99 ng/ml and 13.22 ± 1.09 ng/ml vs 16.30 ± 0.98 ng/ml). CONCLUSION: The levonorgestrel and hCG model is more suitable for the study of PCOS in puberty.

The Effect of Salpingectomy on Ovarian Reserve and Ovarian Function.

BACKGROUND: The effect of salpingectomy on ovarian reserve and ovarian function is still a controversial issue, and more investigations are needed. OBJECTIVE: The aim of this study was to determine the effect of salpingectomy on ovarian reserve and ovarian function. STUDY STRATEGY: PubMed, Embase, Medline, Web of Knowledge, and the Cochrane trial register were searched. SELECTION CRITERIA: Studies must have similar study method and be published in English; clear data can be extracted from full test. DATA COLLECTION AND ANALYSIS: Data were collected and analyzed by Review Manager 5.3. MAIN RESULTS: A total of 13 studies were eligible. The level of anti-müllerian hormone is lower, and early follicular phase follicle-stimulating hormone is higher in salpingectomy groups. The level of early follicular phase estradiol and the ovarian volume of salpingectomy groups are the same as control. The total dose of follicle-stimulating hormone needed during in vitro fertilization and embryo transfer (IVF-ET) treatment cycles, the number of collected oocytes, and the clinical pregnancy rate are similar in salpingectomy and control groups. CONCLUSIONS: Salpingectomy does not appear to affect ovarian function, ovarian response to gonadotropin stimulation, or outcome of IVF-ET in the short run. It may, however, impair ovarian reserve in the long run.

Trends in ectopic pregnancy, hydatidiform mole and miscarriage in the largest obstetrics and gynaecology hospital in China from 2003 to 2013.

BACKGROUND: Ectopic pregnancies, miscarriages and hydatidiform moles are the major types of pathological pregnancies in the early gestations of pregnancy and constitute an important public health problem. The trends and incidences of these pathological pregnancies may vary by ethnicity and geographical regions. This has not been fully investigated in the Chinese population. In this study we retrospectively report the trends of pathological pregnancies in Chinese population. METHODS: Data on 22,511 women with ectopic pregnancy, hydatidiform mole and miscarriage were collected from the largest obstetrics and gynaecology hospital in China from 2003 to 2013. Data included age at diagnosis and the annual number of women with diagnosed ectopic pregnancy, hydatidiform mole and miscarriage. RESULTS: The total number of ectopic pregnancy, hydatidiform mole and miscarriage was increased 3.5folds in 2013 compared to 2003. Ectopic pregnancy is the leading pathological pregnancy and miscarriage is increasing at a greater rate among the pathological pregnancies. The median age of women with hydatidiform mole at diagnosis significantly increased from 25.5 years to 29 years (p = 0.002), however the median age for other pathological pregnancies was not different between 2003 and 2013. The number of women with hydatidiform mole at diagnosis who were over 40 years old has increased. The mean maternal age is increased from 28.1 years old in 2003 to 29.4 years old in 2013 in this hospital. CONCLUSION: We speculate that the increased maternal age may contribute to the increase in these pathological pregnancies between 2003 and 2013 in China.

Expression of anti-Müllerian hormone in letrozole rat model of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age with anti-müllerian hormone (AMH) two to three times higher, but the mechanism of increased AMH, excessive follicles and follicle stagnation in PCOS still needs further research. METHODS: Female Sprague-Dawley rats were treated with a gavage of 1.0 mg/kg of letrozole carboxymethylcellulose solution once daily for 21 consecutive days. Serum steroid concentrations, ovarian morphology, ovarian expression of AMH and AMH-RII protein were determined and their relationships were studied. RESULTS: According to the morphology and endocrinology, the letrozole model group was a successful PCOS model. Serum AMH and ovarian local expression of AMH and AMH-RII were both increased in letrozole model group. The elevated AMH had a positive correlation with T, growing follicle count and a negative correlation with body weight. CONCLUSIONS: The letrozole model group is a good animal model for the study of AMH in PCOS patients with obesity or insulin resistance. The increased serum AMH level in PCOS is the consequence of the androgen-induced excess of small antral follicles. These results lead to the hypothesis that reducing AMH may become a therapeutic target of PCOS, which is worth further research.