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Objective To evaluate the value of using both HMG and recombinant FSH (r-FSH) in the GnRH antagonist protocol for women with high AMH. Materials and methods This retrospective, single-center cohort study was conducted from January 2013 to December 2018. Of 277 GnRH antagonist IVF/ICSI cycles in women with anti-Mullerian hormone (AMH) ≥5 μg/L, 170 cycles receiving the combination of r-FSH and HMG (77 with HMG added at the beginning of the GnRH antagonist cycle and 93 with HMG added after GnRH antagonist administration) and 107 cycles receiving r-FSH alone were analyzed. The dynamic hormone profiles and embryonic and clinical outcomes of the patients were evaluated. Results We observed significantly lower serum LH levels in the r-FSH + HMG groups during ovarian stimulation. The serum estradiol and progesterone levels were lower in the r-FSH + HMG groups on the trigger day. Nevertheless, there were no significant differences with respect to the number of oocytes retrieved, maturation, fertilization, blastocyst formation rate or ovarian hyperstimulation syndrome (OHSS). The implantation and live birth rates were increased in the r-FSH + HMG groups compared with the r-FSH alone group, with no statistical significance. Conclusions HMG for LH supplementation in the GnRH antagonist protocol for patients with high AMH is not significantly superior to r-FSH alone in terms of ovarian response and pregnancy outcome. Nevertheless, HMG supplementation might be appropriate for women with an initially inadequate response to r-FSH or intracycle LH deficiency.

Objective: Despite the great advance of assisted reproductive technology (ART) in recent decades, many IVF patients failed to achieve a pregnancy even after multiple IVF-ET attempts. These patients are considered to have repeated implantation failure (RIF). While exhausting efforts have been devoted to the improvement of pregnancy rate in RIF patients, it is not clear whether RIF patients have aberrant obstetric or perinatal outcomes after they eventually achieved a pregnancy. Materials and methods: Taking advantage of a relatively large database of IVF-ET cycles at the Chang Gung Memorial Hospital, we compared obstetric and perinatal outcomes of RIF patients who have a successful pregnancy after IVF-ET treatment(s) to those of control IVF-ET patients. Results: Because multiple pregnancies are associated with a high risk of obstetric complications, we restricted the analysis to patients who had singleton pregnancies. Analysis of a total of 596 control and 46 RIF cases showed the rates of almost all obstetric and perinatal outcomes investigated are not different between the two groups. However, the rate of placental abruption in the RIF group (4.35%) appeared to be significantly higher than that of controls (0.50%; OR = 8.99). This difference is still statistically significant after adjustment with the age (adjusted OR = 8.2). Conclusion: While the rates of a spectrum of obstetric and perinatal outcomes are normal in RIF patients, these patients could have an enhanced risk of placental abruption. However, investigations with a large sample size are needed to substantiate this inference. Keywords: RIF, Repeated implantation failure, Placental abruption, IVF, Embryo transfer

Objective: The current study tested the hypothesis that vascular endothelial function, as reflected by the reactive hyperemia index (RHI), and biochemical factors, including VEGF, TNFα, CRP, inhibin A, and inhibin B, were involved in the pathogenesis of ovarian hyperstimulation syndrome (OHSS). Materials and methods: This study was conducted between June 2010 and June 2012, enrolling 15 patients with OHSS and 6 healthy control subjects

Objective: We have recently reported that stress-induced phosphoprotein 1 (STIP1) is over-expressed in endometriosis/adenomyosis tissues. STIP1 may also be involved in immune regulation, thus we attempted to study the association between STIP1 single nucleotide polymorphisms (SNPs) and endometriosis/adenomyosis. Materials and methods: Five STIP1 SNPs (rs7941773, rs2845597, rs4980524, rs2282490, and rs2236647) were selected for genotyping with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) in 286 patients with endometriosis/adenomyosis and 288 healthy postmenopausal controls. In vitro studies included luciferase promoter reporter assays and western blot analysis for STIP1 and MMP9 proteins. Results: The frequency of the G allele at rs4980524 was significantly higher in patients with endometriosis/adenomyosis than in control women. The promoter reporter with rs4980524 GG genotype significantly increased luciferase activity than that with TT genotype in endometrial cancer RL95-2 cells, and the primary endometrial stromal cells carrying rs4980524 GG genotype expressed higher protein levels of STIP1 and MMP9 than those carrying the TT one. Conclusion: The G/G allele of STIP1 SNP rs4980524 is associated with the increased expression of STIP1 and MMP9 in endometriosis. Further validation in independent cohorts of endometriosis patients may prove its usefulness as a genetic risk maker for endometriosis/adenomyosis. Keywords: Endometriosis, SNP, STIP1

Objective Although major advances have greatly improved the outcomes of assisted reproductive technology in the last two cascades, there remains significant difficulty in achieving pregnancy for many patients even after repeated attempts of IVF. Interestingly, recent studies have shown that transcutaneous electrical acupoint stimulation (TEAS) can improve the reproductive outcomes of select IVF patients. To determine the utility of TEAS in improving IVF outcomes in patients with a history of implantation failure, we conducted a retrospective study of clinical outcomes of women, who had a prior history of unsuccessful pregnancy outcome after IVF-embryo transfer (IVF-ET), following TEAS treatment. Materials and methods A total of 25 patients, who had failed to conceive after multiple IVF cycles in which good embryos were transferred, received noninvasive low frequency TEAS treatment prior to and during an IVF-ET cycle. The clinical outcomes, including biochemical pregnancy rate, clinical pregnancy rate and implantation rate, were compared to those of prior cycles which received only standard IVF treatment. Results Analysis of reproductive outcomes showed that implantation rate and clinical pregnancy rate increased significantly in IVF cycles that included the TEAS treatment when compared to prior cycles that received only the standard IVF treatment in this cohort of patients. Conclusions This surprising finding indicated that TEAS treatment is a promising technique to improve reproductive outcomes in difficult cases of IVF-ET. Because TEAS treatment is noninvasive and has high reproducibility, and can be applied with limited training, further refinement of this procedure would not only substantiate the beneficial effects of TEAS, but also allow the technique to be more effective and reproducible.

// Angel Chao 1, 2, * , Chiao-Yun Lin 1, 2, * , An-Ning Chao 3, * , Chia-Lung Tsai 4 , Ming-Yu Chen 1 , Li-Yu Lee 5 , Ting-Chang Chang 1, 2 , Tzu-Hao Wang 1, 2 , Chyong-Huey Lai 1, 2 and Hsin-Shih Wang 1 1 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 2 Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Kaohsiung, Taiwan 3 Department of Ophthalmology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 4 Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan 5 Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Tzu-Hao Wang, email: knoxtn@cgmh.org.tw Chyong-Huey Lai, email: sh46erry@ms6.hinet.net Keywords: gynecologic malignancies, LSD1, autophagy, p62 Received: October 25, 2016 Accepted: June 19, 2017 Published: August 10, 2017 ABSTRACT Lysine-specific demethylase 1 (LSD1) – also known as KDM1A – is the first identified histone demethylase. LSD1 is highly expressed in numerous human malignancies and has recently emerged as a target for anticancer drugs. Owing to the presence of several functional domains, we speculated that LSD1 could have additional functions other than histone demethylation. P62 – also termed sequestasome 1 (SQSTM1) – plays a key role in malignant transformation, apoptosis, and autophagy. Here, we show that a high LSD1 expression promotes tumorigenesis in gynecologic malignancies. Notably, LSD1 inhibition with either siRNA or pharmacological agents activates autophagy. Mechanistically, LSD1 decreases p62 protein stability in a demethylation-independent manner. Inhibition of LSD1 reduces both tumor growth and p62 protein degradation in vivo . The combination of LSD1 inhibition and p62 knockdown exerts additive anticancer effects. We conclude that LSD1 destabilizes p62 and inhibits autophagy in gynecologic cancers. LSD1 inhibition reduces malignant cell growth and activates autophagy. The combinations of LSD1 inhibition and autophagy blockade display additive inhibitory effect on cancer cell viability. A better understanding of the role played by p62 will shed more light on the anticancer effects of LSD1 inhibitors.

Pazopanib-a multitargeted tyrosine kinase inhibitor with prominent antiangiogenic effects-has shown promise in the treatment of soft-tissue sarcomas. Hyperthermia has been also applied as an adjunctive treatment to chemotherapy for these malignancies. Here, we show that pazopanib and hyperthermia act synergistically in inhibiting uterine leiomyosarcoma (LMS) cell growth. Compared with either treatment alone, the combination of pazopanib and hyperthermia exerted the highest antitumor activity in a xenograft model. Mechanistically, we found that combined treatment with pazopanib and hyperthermia inhibited histone acetyltransferase 1 (HAT1) expression in LMS cells. The Clock element on the HAT1 promoter was critical for pazopanib- and hyperthermia-induced HAT1 downregulation. Inhibition of HAT1-either by pazopanib and hyperthermia or through HAT1 silencing-was mediated by suppression of Clock. Accordingly, Clock protein reconstitution rescued both HAT1 levels and HAT1-mediated histone acetylation. Immunohistochemistry revealed a higher expression of HAT1 in uterine LMS than in leiomyomas (p = 0.007), with high HAT1 expression levels being associated with poor clinical outcomes (p = 0.007). We conclude that pazopanib and hyperthermia exert synergistic effects against LMS growth by inhibiting HAT1. Further preclinical studies on HAT1 as a potential drug target in uterine LMS are warranted, especially in combination with hyperthermia. KEY MESSAGES: Pazopanib and hyperthermia inhibit the growth of leiomyosarcoma. Their combined use inhibits HAT1 expression in leiomyosarcoma cells. The promoter Clock element is required for HAT1 downregulation. HAT1 expression is higher in leiomyosarcoma than in leiomyomas. An increased HAT1 expression is associated with poor clinical outcomes.

Endometrial cancers expressing estrogen and progesterone receptors respond to hormonal therapy. The disappearance of steroid hormone receptor expression is common in patients with recurrent disease, ultimately hampering the clinical utility of hormonal therapy. Here, we demonstrate for the first time that nucleophosmin (NPM1/B23) suppression can restore the expression of estrogen receptor α (ESR1/ERα) in endometrial cancer cells. Mechanistically, B23 and activator protein-2γ (TFAP2C/AP2γ) form a complex that acts as a transcriptional repressor of ERα. Our results indicate that B23 or AP2γ knockdown can restore ERα levels and activate ERα-regulated genes (e.g., cathepsin D, EBAG9, and TFF1/pS2). Moreover, AP2γ knockdown in a xenograft model sensitizes endometrial cancer cells to megesterol acetate through the upregulation of ERα expression. An increased immunohistochemical expression of AP2γ is an adverse prognostic factor in endometrial cancer. In summary, B23 and AP2γ may act in combination to suppress ERα expression in endometrial cancer cells. The inhibition of B23 or AP2γ can restore ERα expression and can serve as a potential strategy for sensitizing hormone-refractory endometrial cancers to endocrine therapy.

Stress-induced phosphoprotein-1 (STIP1), an adaptor protein that coordinates the functions of HSP70 and HSP90 in protein folding, has been implicated in the development of human gynecologic malignancies. This case-control study investigates STIP1 serum levels and tissue expression in relation to endometriosis/adenomyosis in Taiwanese population. Female patients with surgically confirmed endometriosis/adenomyosis were compared with women free of endometriosis/adenomyosis. Serum STIP1 levels were measured using an enzyme-linked immunosorbent assay and surgical tissues were analyzed by immunohistochemistry. Both epithelial and stromal cells in surgical tissues of endometriosis and adenomyosis expressed STIP1 and MMP-9. Notably, MMP-9 expression was significantly decreased when STIP1 expression was knocked-down. In vitro experiments revealed that STIP1 was capable of binding to the MMP-9 promoter and enhanced its transcriptional expression. The preoperative serum STIP1 levels of patients with endometriosis/adenomyosis were significantly higher than those of the controls. In brief, our data suggest an association between STIP1 levels and endometriosis/adenomyosis.

Objective Benign mature teratoma during pregnancy is common, mostly discovered incidentally by antenatal sonography. However, repeated pregnancy coincident with ovarian mature teratoma is rarely reported. The cases of teratoma with rapid growing characteristics are even more unique. Case report A 17-year-old woman was pregnant at 6 weeks of gestation with a left ovarian teratoma. She underwent artificial abortion followed by surgical removal of the teratoma. However, eleven years after the surgery, a right ovarian teratoma was found incidentally by antepartum sonography at 21 weeks of gestation. The right ovarian teratoma developed uneventfully, with rapid growth during pregnancy. Abdominal delivery at term was accomplished without any complication. Conclusion Younger patients and patients with bilateral or large size dermoid cysts should be followed up closely. Further studies are needed for better understanding of its natural clinical course and the mechanism of progression. The treatment options should be made individually, weighing the risks of torsion, rupture, or obstruction of labor versus the potential for unnecessary surgical risk to mother and fetus.

Objectives: To analyze the relationship between in vitro fertilization (IVF) pregnancy rate and basal serum hormone levels before patients begin an IVF course. Materials and methods: In this retrospective study, we analyzed patients with anti-Müllerian hormone (AMH) data and IVF data from January 2009 to October 2012. Pregnancy rates were calculated by AMH and follicle stimulating hormone quartiles and analyzed using the independent samples t test. Furthermore, patients were divided into three groups by age. The Chi-square test was used to assess the association between the parameters and IVF pregnancy rates. Results: From the 910 IVF treatment courses, 377 (41.4%) clinical pregnancies resulted. The pregnant and nonpregnant groups differed significantly in age and FSH and AMH levels. The pregnancy rate was 53.3% for patients aged 38 years. The pregnancy rate was 53.4% for patients with FSH levels 8.9 mIU/mL. The pregnancy rate was 56.8% for patients with AMH levels >4.0 ng/mL and 20.0% for patients with AMH levels

Introduction The impact of maternal age on euploidy rate and the outcome of PGT-Aisdemonstrated by many studies. But less understanding of the probability of finding at least one euploidy embryoaccordingto maternal age. In this study, weassess patients of different maternal age group in PGT-A cyclesusing aCGH and NGS: 1. Number of biopsy blastocyst per cycle; 2. Numbers of 2PN needed for aeuploidy embryo; 3. Euploidy rate; 4. The proportion of cycles having at least aeuploidy embryo; 5. Livebirth rate through frozen embryo transfer (FET). Materialand Methods We retrospectively analyzed the PGT-A cycles enrolled from 2012 to 2016. To compare the clinical outcomes, the included data were separated into groups based on maternal age at IVF stimulation start. TE biopsy was performed on Day5 to 7 post-retrieval. All biopsied blastocysts were subjected to vitrification immediately. Biopsied TE cells were analyzed using array-CGH and NGS for all 23 chromosomes. Patients transferred euploidy embryo on progesterone Day6 in FET cycles. Results The age groups for analysis were: 42. The cycles having biopsy were88.0%(22/25), 100%(18/18), 88.5%(23/26), 60%(9/15) and 82.3%(14/17). The number of biopsy blastocyst per cycle were 4.9(108/22), 5.8(105/18), 3.9(90/23), 3.2(29/9) and 1.6(23/14) and the number of 2PN needed for aeuploidy embryo were 6.8(218/32), 4.1(158/39), 7(189/27), 7.8(8/62) and 7.1(50/7). Euploidy rates were 29.6% (32/108), 37.1% (39/105), 30.0% (27/90), 27.6% (8/29), and 30.4% (7/23). The proportion of cycles having at least a euploidy embryo were 68.2%(15/22), 83.3%(15/18), 65.2%(15/23), 66.7%(6/9) and 35.7%(5/14). Pregnancy rate per FET were63.6%(7/11), 77.8%(7/9), 53.3%(8/15), 100%(1/1) and 50%(2/4). Live birth rates per FET were 63.6% (7/11), 77.8% (7/9), 46.7% (7/15), 100%(1/1) and 25% (1/4). Conclusions In the course of PGT-A, the clinical outcomes and live birth rate can be predicted according to maternal age. Maternal age increase does not affect the number of 2PN needed for aeuploidy embryo, but it seems that women aged between 35 and 37are more likelyto benefit from PGT- A (the highestopportunity of having at least a euploidy embryo). The results of this research can assist doctors in patient consultations and help patients set realistic expectations.

To assess the role of diagnostic hysteroscopy in pregnancy outcome in patients starting the first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI).A total of 567 infertile women who underwent first IVF treatment were reviewed retrospectively. Two hundred and fifteen (37.9 %) women underwent diagnostic hysteroscopy before the scheduled controlled ovarian hyperstimulation (COH). Two hundred and eighty-four (50.1 %) women only accepted transvaginal ultrasonography (TVU), and 68 (12.0 %) woman did not receive hysteroscopy and TVU before COH. Primary outcome measure was the live birth rate. Secondary outcome measures were the implantation rate, clinical pregnancy rate, and miscarriage rate.There was no difference among three groups with regard to number of oocytes retrieved, fertilization rate, implantation rate, clinical pregnancy rate, miscarriage rate, and live birth rate per cycle. The implantation rate and clinical pregnancy rate were significantly lower in the cycles with endometrial thickness8 mm on human chorionic gonadotropin day (P = 0.001 and 0.018, respectively). Women with greater body mass index (22) were associated with higher incidence of intrauterine lesions (22 of 36, 61.1 %).Diagnostic hysteroscopy prior to COH may not increase the implantation rate and live birth rate for the first IVF/ICSI programs. The efficacy of routinely performing diagnostic hysteroscopy before the first IVF program is needed to re-evaluate.

Objective: To evaluate the pregnancy courses and obstetric outcomes in patients conceived after conservative treatment of endometrial cancer. Materials and Methods: Case series and systemic review of pregnancy women after fertility-sparing treatment of endometrial cancer. Patients with early stage endometrial cancer were identified through Tumor Registry in Chang Gung Memorial Hospital between 1990 and 2005 and MEDLINE search. Diagnosed cases were managed by fertility-sparing therapies. Pregnancies followed by assisted reproductive technology and spontaneous or ovulation with intrauterine insemination were designated as Group 1 and Group 2, respectively. Results: Five livebirths in three patients with two sets of twin pregnancy were delivered. Adding 47 women in the MEDLINE search literature, there were 65 deliveries with 77 livebirths. Groups 1 and 2 had 15 and 50 deliveries, respectively. Group 1 had 23 livebirths including four sets of twins and two sets of triplets, whereas 54 livebirths consisted of two sets of twins and one set of triplets were noted in Group 2 (p = 0.003). Seven preterm deliveries were noted in Group 1 and three in Group 2 (p = 0.001). Cesarean rate was 93.3% versus 22.0% (p

Objective To investigate the eutopic endometrial interleukin-18 (IL-18) system including interleukin-18 (IL-18), IL-18 receptor (IL-18R), and IL-18 binding protein (IL-18BP), mRNA, and protein expression in patients with adenomyosis. Design A clinical and molecular study. Setting Clinical and academic research setting in a university medical center. Patient(s) Twenty-eight samples of human eutopic endometria were obtained from surgical specimens of normal cycling women undergoing hysterectomy for uterine adenomyosis (n = 19); the control group (n = 9) was women undergoing hysterectomy for benign reason including uterine fibroids. Intervention(s) Quantitative competitive polymerase chain reaction (QC PCR) and immunohistochemistry studies were performed. Main Outcome Measurement(s) The differences of the IL-18 system mRNA and the ratio of IL-18BP to IL-18 in the eutopic endometrium of uterine adenomyosis and control group were analyzed. Result(s) IL-18 system mRNA and protein expression was demonstrated in the eutopic endometrium of both adenomyosis and control women. Quantitative competitive PCR demonstrated that endometrial IL-18R mRNA and the ratio of IL-18BP to IL-18 were significantly increased in adenomyosis patients in comparison to the control group. Pearson's correlation showed a significant correlation between IL-18 and IL-18R in the eutopic endometrium of women with uterine adenomyosis, but not the control group. Conclusion(s) The expression of the eutopic endometrial IL-18 system and the ratio of antagonist to agonist at the level of the endometrial-myometrial interface (EMI) may possibly be responsible for the pathologic process of adenomyosis.

Objective to understand postpartum weight retention among women of different body sizes at pre-pregnancy, and to explore factors influencing this weight retention. Design a comparative, descriptive study. Pre-pregnancy body mass indices (BMIs) were determined from hospital records. Dependent variables were measured by self-report questionnaires. Setting a 3,900-bed medical centre in northern Taiwan that delivers approximately 4,000 children each year. Participants a systematic sample of 810 women who had delivered children at a medical centre. In total, 602 valid questionnaires were collected. Findings the average pre-pregnancy and six month postpartum BMIs were 21.5 [standard deviation (S.D.)=3.32] and 22.48 (S.D.=3.39), respectively. Overweight (OW) and obesity (OB) increased from 18.27% before pregnancy to 27.57% at six months postpartum. Gestational weight gain (GWG) was 14.36, 14.37, 13.07 and 11.15kg among women in the underweight (UW), normal weight (NW), OW and OB groups, respectively; and six month postpartum weight retention was 3.32, 2.57, 1.67 and −0.29kg. GWG was the most significant predictor of postpartum weight change across groups. Key conclusions women with different body sizes at pre-pregnancy have common and specific risks for postpartum weight retention. Implications for practice individualised interventions should be developed to manage postpartum weight for women of different body sizes. Interventions should establish criteria for GWG and provide strategies to improve body image and modify lifestyle. The overall goal should be to manage postpartum weight gain and to promote women's health.

This study evaluated the relationship between pregnancy rate and semen cadmium concentration. This prospective and nonrandomized clinical study analyzed 341 male partners of infertile couples undergoing infertility evaluation and management. Semen samples were collected to analyze semen quality and cadmium concentrations. The main outcome was pregnancy during 60-day infertility treatment. Simple linear regression analysis revealed an association between semen cadmium concentration NS sperm count (r = −0.150, P = 0.0416) in nonsmoking subjects (n = 184). In both smokers and nonsmokers, semen cadmium concentrations were significantly higher in non-pregnant patients than in pregnant patients. In nonsmokers, Cox multi-variable fertility ratio analysis demonstrated an association between semen cadmium concentration and fertility (fertility ratio of log semen cadmium = 0.24; 95% confidence intervals (CI) = 0.12–0.47, P

// Chia-Lung Tsai 1, * , Angel Chao 1, 2, * , Shih-Ming Jung 3 , Chi-Neu Tsai 4 , Chiao-Yun Lin 2 , Shun-Hua Chen 2, 5 , Shih-Che Sue 6 , Tzu-Hao Wang 1, 2, 7 , Hsin-Shih Wang 2 , Chyong-Huey Lai 2 1 Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan 2 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 3 Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 4 Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan 5 Graduate Institute of Biomedical Science, School of Medicine, Chang Gung University, Taoyuan, Taiwan 6 Department of Life Sciences, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Taiwan 7 School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Tzu-Hao Wang, email: knoxtn@cgmh.org.tw Keywords: JAK2, STIP1, cancer Received: March 08, 2016 Accepted: June 17, 2016 Published: July 8, 2016 ABSTRACT Overexpression of stress-induced phosphoprotein 1 (STIP1) − a co-chaperone of heat shock protein (HSP) 70/HSP90 – and activation of the JAK2-STAT3 pathway occur in several tumors. Combined treatment with a HSP90 inhibitor and a JAK2 inhibitor exert synergistic anti-cancer effects. Here, we show that STIP1 stabilizes JAK2 protein in ovarian and endometrial cancer cells. Knock-down of endogenous STIP1 decreased JAK2 and phospho-STAT3 protein levels. The N-terminal fragment of STIP1 interacts with the N-terminus of JAK2, whereas the C-terminal DP2 domain of STIP1 mediates the interaction with HSP90 and STAT3. A peptide fragment in the DP2 domain of STIP1 (peptide 520) disrupted the interaction between STIP1 and HSP90 and induced cell death through JAK2 suppression. In an animal model, treatment with peptide 520 inhibited tumor growth. In summary, STIP1 modulates the function of the HSP90-JAK2-STAT3 complex. Peptide 520 may have therapeutic potential in the treatment of JAK2-overexpressing tumors.

Six hundred thirty-seven Taiwanese Chinese women including 300 patients with endometriosis and 337 controls without endometriosis were enrolled to investigate the association between nonsynonymous single nucleotide polymorphism of the FSH receptor gene and the risk of endometriosis. For the A/G polymorphism of FSH receptor gene (Asn680Ser), a univariate analysis for women with endometriosis demonstrated that both the GG genotype (680Ser/Ser) and GA genotype (680Ser/Asn) were associated with a significantly lower risk of endometriosis.

Purpose We studied the relationship between high myopia and the MMP3 and TIMP1 genes. Design Case-control study. Methods We enrolled 150 high myopic individuals (≤ −6 diopters) and 262 controls (≥ −1.5 diopters) initially, and another 216 cases and 474 controls were enrolled for genotyping promising polymorphisms for replication. Thirteen polymorphisms were genotyped in the initial data. Logistic regression was used to test for genetic effects. Subset analyses were performed according to the education level and family history. Results There was no significant association between any polymorphism and high myopia in the initial data. Among the highly educated subjects, the 5A/6A polymorphism at the MMP3 gene suggested a potential relationship with high myopia, and it was genotyped in the follow-up samples. However, this polymorphism failed to show any significant results in the overall subjects. Conclusions The two genes may not play a crucial role for high myopia in young Taiwanese men.

Objective To investigate circulating levels of insulin-like growth factor-binding protein 1 (IGFBP-1) and IGFBP-3 in the mother and the fetus in pregnancies complicated by pre-eclampsia, and the relationship between serum levels of IGFBPs and fetal birthweight. Design A prospective study over an 18 month period. Setting A tertiary care academic medical centre. Participants Sixty-six pregnant women with pre-eclampsia (35 cases of mild/moderate pre-eclampsia and 31 cases of severe pre-eclampsia) and 78 nonpra-eclamptic pregnant women of matched gestational weeks and maternal ages. Main outcome measures Serum concentrations of IGFBP-1 and IGFBP-3 at the time of delivery. Results In pre-eclampsia associated with intrauterine growth retardation (IUGR), maternal and cord serum IGFBP-1 levels at the time of delivery were elevated. By contrast, circulating IGFBP-3 levels in both the mother and the fetus were lower in pre-eclampsia with IUGR than in nonpre-eclamptic pregnancy. However, there was no difference in serum IGFBP-1 and IGFBP-3 levels between pre-eclampsia without IUGR and nonpre-eclamptic pregnancy in both the mother and the fetus. Conclusions In pre-eclampsia, elevated concentrations of circulating IGFBP-1 and decreased serum IGFBP-3 levels were observed in both the mother and the fetus. However, these changes may simply reflect low birthweight in pre-eclampsia.

The aim of this study was to investigate circulating levels of insulin-like growth factor-binding protein-3 (IGFBP-3) in women with normal pregnancy. A total of 468 pregnant women at various gestational ages and 30 non-pregnant females were recruited in this study. Serum concentration of IGFBP-3 was determined by radioimmunoassay. Maternal serum levels of IGFBP-3 increased as pregnancy progressed. The concentration of IGFBP-3 in pregnancy serum was positively associated with the gestational age. The mean values of circulating IGFBP-3 in the second and third trimesters of pregnancy were higher than those in the first trimester of pregnancy and in non-pregnant females. In addition, there was a highly significant correlation between IGFBP-3 and IGF-I in pregnancy serum. We conclude that, during pregnancy, IGFBP-3 appears to be the principal binding protein for circulating IGF-I and may be involved in the regulation of fetal growth.

Background Infertility affects approximately 10–15% of reproductive-age couples. Poor semen quality contributes to about 25% of infertile cases. Resulting from the direct effect on testicular function or hormonal alterations, heavy metals exposure has been related to impaired semen quality. The objective of this study was to assess the level of lead in the seminal plasma in men without occupational exposure to lead, and to determine the relationship between semen quality and lead concentration in the semen. Methods This is a prospective and nonrandomized clinical study conducted in University infertility clinic and academic research laboratory. Three hundred and forty-one male partners of infertile couples undergoing infertility evaluation and management were recruited to the study. Semen samples collected for the analyses of semen quality were also used for the measurement of lead concentrations. Semen samples were evaluated according to the WHO standards. Results All subjects were married and from infertile couples without occupational exposure to lead. There is a significant inverse correlation between the lead concentration in seminal plasma and sperm count. A higher semen lead concentration was correlated with lower sperm count, but not with semen volume, sperm motility or sperm morphology as assessed by simple linear regression. Conclusions We found that semen lead concentration was significantly higher among the patients with lower sperm count. To our knowledge, this is the first study to demonstrate that a high level of lead accumulation in semen may reduce the sperm count contributing to infertility of men without occupational exposure to lead.

Background To test whether a site-specific hysteroscopic biopsy-induced injury in the endometrium during the controlled ovarian hyperstimulation cycle improves subsequent embryo implantation in patients with repeated implantation failure, a total of 30 patients who have had good responses to controlled ovulation stimulation but have failed to achieve pregnancy after two or more transfers of good-quality embryos were recruited in this prospective study. Methods A single, site-specific hysteroscopic biopsy-induced injury was generated on the posterior endometrium at midline 10-15 mm from the fundus during the D4-D7 period of the ongoing controlled ovarian hyperstimulation cycle in six patients. Results Patients received endometrial biopsy protocol achieved a pregnancy rate of 100%. By contrast, only 46% of patients with similar clinical characteristics (N = 24) achieved pregnancy without the hysteroscopic biopsy-induced endometrium injury (p < 0.05). Conclusions Our proof-of-concept study demonstrates that a site-specific hysteroscopic endometrium injury performed during the ongoing in vitro fertilization (IVF) cycle, instead of injuries received during prior cycles, significantly improves clinical outcomes in patients with repeated implantation failure.

Context: The cause of preeclampsia remains unknown. Excessive antiangiogenic proteins have been proposed to play a pathogenic role in preeclampsia.Objective: Our objective was to determine the differences in soluble endoglin (sEndoglin), soluble fms-like tyrosine kinase receptor-1 (sFLT1), leptin, adiponectin, and endothelin 1 concentrations between normal and preeclampsia amniotic fluid (AF). Such results may help us understand the pathophysiology of preeclampsia.Methods: We performed a nested case-control study. Seventy-one women with preeclampsia were matched to 71 normotensive controls. The preeclamptic women were broken into two subgroups according to the association with fetal intrauterine growth restriction (IUGR). AF concentrations of sEndoglin, sFLT1, leptin, adiponectin, and endothelin 1 were measured by ELISA. Receiver-operating characteristics curve analysis was used to compare the discriminative values of these potential biomarkers. Functional network analysis was performed using MetaCore to reveal the common functions of the interacting proteins.Results: Increased AF concentrations of sFLT1, sEndoglin, endothelin 1, and leptin were found in women who later developed preeclampsia. sFLT1, sEndoglin, leptin, and adiponectin were significantly higher in the preeclampsia with IUGR than those without IUGR. Leptin has the largest area under the curve (0.753). Network analysis revealed that elevated amniotic proteins are involved in the inflammatory process of the human placenta.Conclusions: Significant elevation of leptin can be detected in AF 2 months earlier than the appearance of symptoms; thus, it may be used as a predictive marker for preeclampsia. The increase of these antiangiogenic proteins supports the roles of inflammation and oxidative stress in pathogenesis of preeclampsia.

SummaryGenome-wide association studies (GWAS) use high-throughput genotyping technology to relate hundreds of thousands of genetic markers (genotypes) to clinical conditions and measurable traits (phenotypes). This review is intended to serve as an introduction to GWAS for clinicians, to allow them to better appreciate the value and limitations of GWAS for genotype-disease association studies. The input of clinicians is vital for GWAS, since disease heterogeneity is frequently a confounding factor that can only really be solved by clinicians. For diseases that are difficult to diagnose, clinicians should ensure that the cases do indeed have the disease; for common diseases, clinicians should ensure that the controls are truly disease-free.

Tamoxifen has been reported to be oestrogenic on the lower genital tract. To evaluate its potential positive effect on the endometrium, and consequently early miscarriage and ongoing pregnancy rate, a prospective study was employed in patients for intrauterine insemination who failed to develop an adequate endometrial thickness in a previous ovulatory cycle. Ovarian stimulation was initiated with tamoxifen 40 mg/day from day 3 of the menstrual cycle for 7 days or clomiphene 100 mg/day for 5 days, in combination with 150 IU of human menopausal gonadotrophin on alternate days starting on day 4. Human chorionic gonadotrophin (HCG) was administered when at least one leading follicle was larger than 20 mm. Intrauterine insemination was accomplished 24-36 h after HCG injection and luteal phase supplement was achieved with micronized progesterone 200 mg transvaginally per day. It was found that tamoxifen-treated patients required more stimulation days and used more gonadotrophin, but recruited less follicles larger than 14 mm than clomiphene-treated patients. However, a significantly increased endometrial thickness (P < 0.001) and pregnancy rate (P = 0.015), decreased early miscarriage rate (P = 0.001) and thus improved ongoing pregnancy (P < 0.001) rate were noted in tamoxifen-treated patients. These results suggest that although tamoxifen may not be a first-line treatment in patients with adequate endometrium, it may be a promising alternative for patients with thin endometrium.

Traditional approaches of auto-gain control (AGC) need to collect long period of data and estimate the average power. It results in the large hardware complexity. Moreover, the accuracy of traditional approaches will be seriously degraded by noise and inter-symbol interference (ISI). In this paper, we propose an equalizer-based auto-gain control (EQ-AGC), which employs very small hardware and does not use extra memory devices. Furthermore, the AGC can find out the accuracy gain under large ISI environment. Our EQ-AGC is already silicon-proven for the application of fast Ethernet transceiver using Faraday/UMC 0.18/spl mu/m cell libraries.

To obtain quantitative data on endometrial volume and subendometrial blood flow by three-dimensional ultrasound clue to endometrial receptivity.A prospective, nonrandomized clinical study.One tertiary center for assisted reproduction.Fifty-four patients aged38 years with normal basal serum FSH level experiencing their first IVF cycle, whose uteri were morphologically normal as confirmed by 3-dimensional (3-D) ultrasound, were studied.Ultrasound evaluation was performed for all patients with 3-D facility by a single operator on the day of hCG administration.Ultrasonographic parameters and conception rates.Subendometrial vascularization flow index (VFI) in predicting the pregnancy rate of IVF was superior to that using vascularization index, flow index, or endometrial volume in the receiver operating characteristics curve analysis. The best prediction rate was achieved by a VFI cutoff value of0.24.The detection of subendometrial blood flow by 3-D power Doppler ultrasound may be a useful ultrasound parameter in the prediction of pregnancy rate of IVF, especially subendometrial VFI.

Adequate vascular development of the placental bed is essential for normal pregnancy. We assessed serum levels of placenta growth factor, an angiogenic factor, throughout normal pregnancy and determined its association with preeclampsia.Serum samples were collected from (1) 308 healthy pregnant women throughout normal gestation, (2) at delivery from 30 each gestational age-matched patients with normal pregnancy and preeclampsia, and (3) maternal and cord blood samples from normal deliveries with and without labor (n = 37 each). Placenta growth factor levels were determined with an antigen-capture enzyme-linked immunosorbent assay.Maternal placenta growth factor levels during normal pregnancy increased from the first trimester to the late second trimester; they subsequently declined from 30 weeks' gestation to delivery. Significantly less maternal placenta growth factor (P.0001) was found in pregnancies complicated by preeclampsia, and labor significantly lowered placenta growth factor levels in both maternal (P =.0189) and cord serum samples (P.0001).Decreased levels of placenta growth factor during preeclampsia could influence endothelial cell and trophoblast function, thereby contributing to the pathogenesis of the disease.

Despite the expanding role of laparoscopic surgery in many gynaecological fields, some discrepancies still exist regarding the efficacy of laparoscopic myomectomy in treating patients with large symptomatic leiomyoma. In this report, a better operative procedure and the results of treatment are evaluated. Patients (n = 14) presenting with infertility, menorrhagia, pressure symptoms or pelvic mass associated with a large leiomyoma were managed with laparoscopic myomectomy using airlift gasless laparoscopy. Uterine size ranged from 14 to 24 weeks gestational age and the weight of the myoma ranged from 246 to 669 g (mean 454); operative time ranged from 78 to 165 min (mean 104) and blood loss from 90 to 580 ml (mean 201). No major complication occurred during the operation or follow-up. All except one patient were discharged within 72 h of the operation and resumed normal activity within 1 week. When myomectomy is indicated, the airlift gasless laparoscopic approach appears to offer a better alternative to abdominal or pneumoperitoneum laparoscopic surgery in selected cases. Airlift gasless laparoscopy has several advantages: (i) small abdominal incisions and minimal endoscopic equipment are required; (ii) the excised leiomyomata mass can be easily cut into strips and removed through the small abdominal incision; (iii) the uterine defect can be more efficiently repaired using easily performed suture techniques; (iv) high-pressure irrigation and large-volume suction devices can be used without fear of decompressing the pneumoperitoneum; and (v) the potential risk of metabolic and haemodynamic derangements during pneumoperitoneum laparoscopy are obviated. Gasless laparoscopy also has some disadvantages. The exposure obtained with gasless laparoscopy is not as good, under some circumstances, as that achieved by pneumoperitoneum. For patients who are thin, and even those with moderate obesity, the exposure obtained with airlift mechanical suspension is adequate; however, morbidly obese patients with previous abdominal surgery with suspected pelvic adhesions can incur some problems during the operation because of a poor operative field.

The purposes of this study were to explore whether serum levels of insulin, insulin-like growth factor-I (IGF-I), insulin-like growth factor-binding protein-1 (IGFBP-1) and IGFBP-3 in both maternal and fetal compartments were affected by the stress of labor, and to investigate the relationship between the fetal birthweight and serum levels of insulin, IGF-I and IGFBPs.Blood samples were collected at the time of delivery from 147 parturients with vaginal delivery and 128 cases of Cesarean section (112 cases without labor and 16 cases with arrest of cervical dilatation during the active phase of labor). Serum concentrations of insulin, IGF-I, IGFBP-1 and IGFBP-3 were determined by radioimmunoassays (insulin, IGFBP-1 and IGFBP-3) and immunoradiometric assay (IGF-I).Maternal circulating IGFBP-1 levels in parturients with normal spontaneous delivery (NSD) and in subjects receiving Cesarean section (CS) due to arrest of cervical dilatation during active phase of labor were higher than those undergoing scheduled CS without labor. By contrast, insulin levels in both maternal and umbilical cord serum were higher in parturients with CS without labor than those with NSD. No difference in maternal serum IGFBP-3 levels was observed between NSD and CS at the time of delivery. As for all measurements (insulin, IGF-I, IGFBP-1 and IGFBP-3), serum levels in pregnant women (from both NSD and CS) were strikingly higher than those in the fetus. Serum levels of IGFBP-1 in umbilical cords from both groups of NSD (p0.02) and scheduled CS (p0.01) were inversely correlated with birthweight (BW). By contrast, serum concentration of insulin and IGF-I in umbilical cords from NSD (p0.005 and p0.01; respectively) and scheduled CS (p0.01 and p0.05; respectively) were positively related to BW.From the present results, we conclude that insulin appears to be a regulator for circulating IGFBP-1 during pregnancy. The fetal growth may not be well reflected by maternal serum IGFBP-1 levels, nor by IGFBP-3. By contrast, cord serum IGFBP-1 from CS group without labor may preeminently reflect fetal weight. In additional, serum concentration of insulin and IGF-I in umbilical cord may also be good indicators to reflect the result of neonatal birthweight.

Objective To present a case of cesarean scar pregnancy combined with intrauterine pregnancy after IVF–embryo transfer. Successful embryo reduction was performed and preserved the normal intrauterine gestation. Design Case report. Setting Tertiary referral case center. Patient(s) A woman with cesarean scar pregnancy combined with intrauterine pregnancy after IVF–embryo transfer. Intervention(s) Early diagnosis of heterotopic cesarean scar pregnancy and selective embryo reduction was performed by ultrasound-guided potassium chloride (KCl) directed injection. Main Outcome Measure(s) Successful pregnancy outcome. Result(s) A 38-year-old woman achieve pregnancy by IVF–embryo transfer. Heterotopic cesarean scar pregnancy was diagnosed at 7 weeks gestational age. A transvaginal ultrasound-guided KCl injection was given to terminate the cesarean scar embryo and a healthy infant was delivered 6 months later. Conclusion(s) Heterotopic cesarean scar pregnancy after IVF is extremely rare. Transvaginal intracardiac injection of KCl is a safe and reliable method to terminate the cesarean scar pregnancy. Satisfactory pregnancy outcome should be achieved.

Objective The aim of this study was to determine the efficacy and safety of luteal phase support using human chorionic gonadotropin (hCG) in cycles that are triggered with a gonadotropin-releasing hormone (GnRH) agonist in a moderate-to-high risk population undergoing a GnRH antagonist protocol. Materials and methods We retrospectively reviewed the charts of patients undergoing an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle with a GnRH antagonist protocol from September 2011 to August 2012. The patients were defined as at high risk for ovarian hyperstimulation syndrome (OHSS) in terms of anti-Mullerian hormone (AMH) and antral follicle counts (AFCs). The patients were divided into two groups depending on whether ovulation was triggered with hCG or a GnRH agonist. Modified luteal support was provided for the cycles triggered by the GnRH agonist via low dose hCG (1500∼5000 IU). For the cycles that were triggered by hCG, urinary hCG (5000 IU) following two doses of recombinant hCG (250 μg) were administered. The primary outcomes of this study were the clinical pregnancy rate and the OHSS rate of the two groups. The secondary outcomes were the number of oocytes retrieved and the number of good quality embryos obtained. Results The study group and the control group were similar in terms of the primary and secondary outcome measures. Conclusion Aggressive luteal support with low dose hCG following a GnRH agonist trigger can result in a comparable pregnancy rate to that with the use of a traditional hCG ovulation trigger. However, OHSS can still occur in patients with risk factors. Therefore, other OHSS prevention strategies should be considered.

Ethnopharmacological relevance Indigo naturalis has been used to treat inflammatory diseases and dermatosis, including psoriasis, since thousands of years in China. It has been proven effective in our previous clinical studies on treating psoriasis, but the active component and the mechanism of how indigo naturalis working still needs to be clarified. Since the dysregulated angiogenesis is known to play an important role in the pathogenesis of psoriasis, the anti-angiogenic effect of indigo naturalis and tryptanthrin, a pure component of indigo naturalis, was investigated. Materials and methods The in vivo angiogenesis was studied by chick chorioallantoic membrane assay. The in vitro studies were performed using human vascular endothelial cells. Cell viability was determined by MTT assay. Cell cycle distribution was revealed by flow cytometry. The cellular messenger (m)RNA or protein expression level was analyzed by real-time RT-PCR or Western blot, respectively. Transwell filter migration assay and matrix gel-induced tube formation method were applied to examine the angiogenic potential. Results Indigo naturalis significantly inhibited the in vivo vascular endothelial growth factor (VEGF)-induced angiogenesis, as well as tryptanthrin. In vitro studies confirmed that indigo naturalis and tryptanthrin reduced the number of viable vascular endothelial cells. Tryptanthrin resulted in a cell cycle arrest and dose-dependently decreased the expressions of cyclin A, cyclin B, cyclin dependent kinase(CDK) 1 and 2, but not cyclin D and cyclin E, at both the mRNA and protein levels. The migration and tube formation of vascular endothelial cells were significantly inhibited by tryptanthrin in a dose-dependent manner. Result also showed that tryptanthrin could reduce the phosphorylated levels of both protein kinase B (PKB or Akt) and focal adhesion kinase (FAK). Conclusions All together, these results demonstrated the anti-angiogenic effect of tryptanthrin, the acting component of indigo naturalis and revealed the underlying mechanism by inhibiting the cell cycle progression, cell migration and tube formation, likely mediated through blocking the Akt and FAK pathways.

Adenomyosis, which manifests with focally or diffusely scattered endometrial tissue within the uterine myometrium, is an endometriosis-like disease with controversial pathogenesis and compromised reproductive outcomes. This review, including the in vitro and in vivo studies performed on human or mouse models, is aimed to summarize the specific molecular characteristics of endometrium in the biochemical microenvironments of uterine adenomyosis. Many studies attributed the endometrium as the main cause of pathogenesis, with evidence of differential genetic expression and/or epigenetic modulation as well as estrogen-induced epithelial-mesenchymal transition. However, some studies indicated that the myometrium could play a role in the development of disease, based on findings of smooth muscle metaplasia and/or fibroblast-to-myofibroblast transdifferentiation by the influence of local biochemical factors. To date, it remains unclear whether adenomyosis is a genetically determined or a microenvironmentally induced disorder or whether the dysregulation of local factors may elicit the alteration of genetic expression in the endometrium. Similarly, it is uncertain whether the endometrial characteristics would remain consistent or could change along with a woman's reproductive life. Further longitudinal studies of the epigenetic controls or system biology are needed to elucidate the pathogenesis. Discovery of effective conservative treatments to improve the reproductive outcomes of patients with adenomyosis is still warranted.