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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.

The delivery of active proteins into cells (protein transfection) for biological purposes offers considerable potential for clinical applications. Herein we demonstrate that, with a readily available, inexpensive organic agent, the 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) method can be used for simple and efficient protein transfection. By mixing proteins with a pure HEPES solution before they are applied to live cells, proteins with various molecular weights (including antibodies, recombinant proteins, and peptides) were successfully delivered into the cytoplasm of different cell types. The protein transfection efficiency of the HEPES method was not inferior to that of commercially available systems that are both more expensive and time consuming. Studies using endocytotic inhibitors and endosomal markers have revealed that cells internalize HEPES-protein mixtures through endocytosis. Results that HEPES-protein mixtures exhibited a low diffusion coefficient suggest that HEPES might neutralize the charges of proteins and, thus, facilitate their cellular internalization. Upon internalization, the cytosolic antibodies caused the degradation of targeted proteins in TRIM21-expressing cells. In summary, the HEPES method is efficient for protein transfection and has potential for myriad clinical applications. Keywords: HEPES, protein transfection, intracellularly targeting

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.

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.

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-Müllerian 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.

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

Stress-induced phosphoprotein 1 (STIP1), a cochaperone that organizes other chaperones, heat shock proteins (HSPs), was recently shown to be secreted by human ovarian cancer cells. In neuronal tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular-regulated MAP kinase) signaling pathways. However, we report that STIP1 binding to a bone morphogenetic protein (BMP) receptor, ALK2 (activin A receptor, type II-like kinase 2), was necessary and sufficient to stimulate proliferation of ovarian cancer cells. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3), promoting cell proliferation. In conclusion, ovarian-cancer-tissue-secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Although animal studies are needed to confirm these mechanisms in vivo, our results may pave the way for developing novel therapeutic strategies for ovarian cancer.

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

Genome-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.

Summary: Objective: Whole genome amplification (WGA) is a crucial procedure for genomic DNA analysis from limited sources, such as in forensic analysis, embryo biopsy for preimplantation genetic diagnosis, or needle aspiration biopsies. Several strategies for WGA have been developed for either genotyping or microarray-based comparative genome hybridization (array-CGH) during the past decade. Nevertheless, there were few studies in which various WGA methods had been performed side-by-side and results evaluated with multiple methods. Materials and Methods: Ease of performance, qualitative accuracy, and quantitative fidelity of different WGA methods, such as degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR), ligation-mediated PCR (LM-PCR) and strand displacement amplification (SDA), were compared in amplifyinggenomic DNA derived from karyotype-confirmed amniocytes and the cancer cell line SAOS2. Results: Using analysis with microsatellite markers, single nucleotide polymorphism markers, and array-CGH, our results suggested that: (1) genomic DNA amplified from DOP-PCR resulted in false positive and negative results by analysis with array-CGH; (2) SDA is the easiest performance method among the three WGA methods; and (3) amplified DNA products generated by LM-PCR best reflect the original genomic DNA. Conclusion: The amplified DNA products generated by LM-PCR best reflect the original genomic DNA. Key Words: array-CGH, DOP-PCR, LM-PCR, SDA, whole genome amplification

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