Heng-Kien Au

Assessment of changes in utero‐ovarian arterial impedance during the peri‐implantation period by Doppler sonography in women undergoing assisted reproduction

To investigate changes in utero‐ovarian blood flow during the peri‐implantation period and their significance in successful embryo implantation.

Abnormal mitochondrial structure in human unfertilized oocytes and arrested embryos

Abstract: To clarify the relationship between mitochondria and embryo development, we collected human unfertilized oocytes, early embryos, and arrested embryos. Unfertilized oocytes and poor‐quality embryos were collected, and the ultrastructure of mitochondria was determined by transmission electron micrography. Four criteria for determining the mitochondrial state were mitochondrial morphology, cristae shape, location, and number of mitochondria. In mature oocytes, mitochondria were rounded with arched cristae and a dense matrix and were distributed evenly in the ooplasm. In pronuclear zygotes, the size and shape of mitochondria were similar to those in mature oocytes; however, mitochondria appeared to migrate and concentrate around pronuclei. In this study, 67% of examined unfertilized oocytes had fewer mitochondria in the cytoplasm. A decreased number of mitochondria located near the nucleus was also demonstrated in 60% of arrested embryos. Fewer differentiated cristae were determined in all three arrested blastocyst stages of embryos. The relative expressions of oxidative phosphorylation genes in oocytes and embryos were also determined. These data imply that inadequate redistribution of mitochondria, unsuccessful mitochondrial differentiation, or decreased mitochondrial transcription may result in poor oocyte fertilization and compromised embryo development.

Moderate to High Concentrations of High-Density Lipoprotein From Healthy Subjects Paradoxically Impair Human Endothelial Progenitor Cells and Related Angiogenesis by Activating Rho-Associated Kinase Pathways

Objective—Recent clinical evidence has failed to demonstrate the benefits of elevation of serum high-density lipoprotein (HDL), suggesting potential loss of protective effects of HDL at high concentrations. This study aimed to investigate the concentration-related effects of HDL on in vitro and in vivo functions of human endothelial progenitor cells (EPCs) and related angiogenesis. Methods and Results—Early and late outgrowth EPCs were generated from human circulating mononuclear cells. Oxidized low-density lipoprotein reduced viability of late outgrowth EPCs, which was reversed dose dependently by HDL. In the absence of oxidized low-density lipoprotein, HDL at low concentrations (5–50 &mgr;g/mL, equal to 0.5–5 mg/dL in human) enhanced EPC tube formation by activating phosphatidylinositol-3 kinase/Akt/endothelial NO synthase pathways. Moderate to high concentrations (400–800 &mgr;g/mL) of HDL paradoxically enhanced EPC senescence and impaired tube formation by activating Rho-associated kinase (ROCK) and inhibiting phosphatidylinositol-3 kinase/Akt and p38 mitogen-activated protein kinase pathways. Rho-associated kinase inhibitors, either Y27632 or statins, prevented high HDL–induced EPC senescence and improved in vitro tube formation, as well as in vivo capacity of angiogenesis of EPCs. Conclusion—While protecting EPCs from the injury of oxidized low-density lipoprotein, moderate to high concentrations of HDL paradoxically impaired EPCs and related angiogenesis in the absence of oxidized low-density lipoprotein by activating Rho-associated kinase pathways, providing mechanistic evidence of potential hazard effects of HDL.

Uterine preservation in a woman with spontaneous uterine rupture secondary to placenta percreta on the posterior wall: A case report

Several cases in which uteruses have been preserved in women with placenta percreta have been reported. We herein report a 38‐year‐old woman with a history of previous cesarean section who was admitted with lower abdominal pain and vaginal bleeding at 31 weeks of gestation. An urgent exploratory laparotomy revealed active bleeding from the uterine rupture on the posterior uterine wall. A female infant weighing 1560 g, with Apgar scores of 1, 1, and 3 at 1, 5, and 10 min, respectively, was delivered, and the placenta was removed. We performed bilateral uterine vessel occlusion, followed by wedge resection of the ruptured uterine wall with the aid of an intrauterine muscle injection of 20 IU oxytocin, a local injection of diluted vasopressin (1:60) into the myometrium around and into the rupture site, and an intramuscular injection of 0.2 mg methylergonovine, primary repair of the defect, and an additional 24‐h postoperative oxytocin infusion (30 IU in 5% dextrose 500 mL) to preserve the uterus successfully. Although the overall blood loss was 3700 mL, no disseminated intravascular coagulopathy occurred after the patient had received adequate blood transfusion. The postoperative pathological diagnosis was placenta percreta with uterine rupture. The patient and her baby were discharged uneventfully. In some cases of spontaneous uterine rupture secondary to placenta percreta, we can preserve the uterus by performing bilateral uterine vessel occlusion and wedge resection of the ruptured uterine wall.

Deleted mitochondrial DNA in human luteinized granulosa cells

Abstract: The rearrangement of mitochondrial DNA in luteinized granulosa cells was determined in order to evaluate the fertilization capacity of oocytes and the development of embryos. Multiple deletions of mtDNA were found in luteinized granulosa cells from in vitro fertilization (IVF) patients. The 4977‐base pair (bp) deletion was the most frequent deletion found in human granulosa cells. No significant difference was noted between mtDNA deletions of granulosa cells based on the fertilization capacity of oocytes and the development of embryos. To determine the relationship of proportions of mtDNA rearrangements with the aging process, granulosa cells were grouped into three different cohorts according to maternal age: younger than 32 years, between 32 and 37 years, and older than 37 years. No statistical correlation was noted between patient age and the frequency of occurrence of multiple mtDNA deletions. However, an increase in granulosa cell apoptosis was associated with an increase in mtDNA deletions. Accumulation of mtDNA deletions may contribute to mitochondrial dysfunction and impaired ATP production. We concluded that the accumulation of rearranged mtDNA in granulosa cells might not interfere with fertilization of human oocytes and further embryonic development; it was, however, associated with apoptosis processes.

Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies

Endometriosis is an estrogen-dependent inflammatory disease that affects up to 10% of women of reproductive age and accounts for up to 50% of female infertility cases. It has been highly associated with poorer outcomes of assisted reproductive technology (ART), including decreased oocyte retrieval, lower implantation, and pregnancy rates. A better understanding of the pathogenesis of endometriosis-associated infertility is crucial for improving infertility treatment outcomes. Current theories regarding how endometriosis reduces fertility include anatomical distortion, ovulatory dysfunction, and niche inflammation-associated peritoneal or implantation defects. This review will survey the latest evidence on the role of inflammatory niche in the peritoneal cavity, ovaries, and uterus of endometriosis patients. Nonhormone treatment strategies that target these inflammation processes are also included. Furthermore, mesenchymal stem cell-based therapies are highlighted for potential endometriosis treatment because of their immunomodulatory effects and tropism toward inflamed lesion foci. Potential applications of stem cell therapy in treatment of endometriosis-associated infertility in particular for safety and efficacy are discussed.

Association between ultrasonographic parameters of Cesarean scar defect and outcome of early termination of pregnancy

To determine whether Cesarean scar defect (CSD) parameters assessed by transvaginal sonography (TVS) might affect the outcome of early termination of pregnancy (TOP) with mifepristone–misoprostol.

Ultrasonographic parameters of cesarean scar defect in correlation with the outcome of early medical abortion

To determine whether Cesarean scar defect (CSD) parameters assessed by transvaginal sonography (TVS) might affect the outcome of early termination of pregnancy (TOP) with mifepristone–misoprostol.

Abstract 5580: TGF-β1 enhanced cell migration involving pluripotent transcription factor OCT4 in endometriosis

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Endometriosis is the eutopic and/or ectopic growth of endometrial tissues. High levels of TGF-β in peritoneal fluid and increased expression of OCT4 have been well documented in endometriosis. However, the molecular mechanism between TGF-β and OCT4 expression in endometriosis still remains largely unknown. In this study, we examined the roles of OCT4 in TGF-β-induced endometrial cell migration and the progression of human ectopic endometriosis. We analyzed the plasma levels of TGF-β (n = 80) and gene expression levels of TGF-βR1 in patient tissues (n = 60) by an ELISA assay and quantitative real-time RT-PCR. The serum TGF-β and tissue TGF-βR1 expressions were significantly increased in the ectopic endometriotic tissues (n = 54, 29 for adenomyosis tissues and 25 for chocolate cysts) comparing with the normal endometrium (n = 5). The TGFβR1 transcriptional level in endometriotic tissues was positively correlated with expressions of OCT4 and genes associated with cell migration, such as VIMENTIN, TWIST, SNAIL and SLUG. TGF-β dose-dependently increased the OCT4 expression both in gene and protein levels in human endometriotic stromal cells and, at a less intensity, in HEC1A endometrial carcinoma cell line. Additionally, TGF-βincreased the expression of migration-associated genes and proteins (SNAIL and N-CAD) dose-dependently both in gene and protein levels in human endometriotic stromal cells. Knockdown of OCT4 significantly suppressed the TGF-β-induced the expressions of migration-associated genes and proteins (N-CAD and SNAIL), and promoted the migration of endometrial cells as evidenced by wound-closure and transwell assays. Conclusions: TGF-β,TGF-βRI, and OCT4 are significantly upregulated in human ectopic endometriotic tissues. The significant OCT4 expression may be involved in the pathology of ectopic endometrial growth through TGF-β-induced migration of endometrial cells. Citation Format: Te-Sheng Chang, Heng-Kien Au, Thai-Yen Ling, Ching-Chi Chi, Chii-Ruey Tzeng, Jui-Hung Chang, Yen-Hua Huang. TGF-β1 enhanced cell migration involving pluripotent transcription factor OCT4 in endometriosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5580. doi:10.1158/1538-7445.AM2014-5580

Matrix remodeling and endometriosis

The physiological changes in endometriosis involving multiple steps of matrix remodeling include abnormal tissue growth, invasion, and adhesion formation. Endometriosis-associated abnormal matrix remodeling is affected by several molecular factors including proteolytic enzymes and their inhibitors, which mediate tissue turnover throughout the reproductive tract to maintain the integrity of the endometrium, and ovarian steroids, which normally regulate reconstruction and breakdown of endometrium in the menstrual cycle. In addition, various growth factors, such as platelet-derived growth factor, transform growth factor β, and epidermal growth factor, direct modulation of growth, activation, and chemotaxis which may facilitate endometrial cell adhesion onto the peritoneal mesothelium during the development of endometriosis. Furthermore, cell adhesion molecules are believed to be critically involved in most cellular-level processes including cellular differentiation, motility, and attachment with the extracellular matrix. The present review focuses on the abnormal matrix remodeling process and its possible regulatory mechanism in association with endometriosis development. As a greater understanding of the cause of endometriosis is achieved, better treatment of the disease and its prevention become possible.