LIF-STAT signaling in decidual cells: a possible role in embryo implantation and early pregnancy.

In this study, we investigate the effects of miRNA-138-5p and probable G-protein coupled receptor 124 (GPR124)-regulated inflammasome and downstream leukemia inhibitory factor (LIF)-STAT and adhesion molecule signaling in human decidual stromal cells. After informed consent was obtained from women aged 25-38 years undergoing surgical termination of the normal pregnancy and spontaneous miscarriage after 6-9 weeks of gestation, human decidual stromal cells were extracted from the decidual tissue. Extracellular vesicles (EVs) with microRNA (miRNA) between cells have been regarded as critical factors for embryo-maternal interactions on embryo implantation and programming of human pregnancy. MicroRNA-138-5p acts as the transcriptional regulator of GPR124 and the mediator of downstream inflammasome. LIF-regulated STAT activation and expression of integrins might influence embryo implantation. Hence, a better understanding of LIF-STAT and adhesion molecule signaling would elucidate the mechanism of microRNA-138-5p- and GPR124-regulated inflammasome activation on embryo implantation and pregnancy. Our results show that microRNA-138-5p, purified from the EVs of decidual stromal cells, inhibits the expression of GPR124 and the inflammasome, and activates the expression of LIF-STAT and adhesion molecules in human decidual stromal cells. Additionally, the knockdown of GPR124 and NLRP3 through siRNA increases the expression of LIF-STAT and adhesion molecules. The findings of this study help us gain a better understanding the role of EVs, microRNA-138-5p, GPR124, inflammasomes, LIF-STAT, and adhesion molecules in embryo implantation and programming of human pregnancy.

Kisspeptin Regulates Cell Invasion and Migration in Endometrial Cancer.

Kisspeptin (a product of the KISS1 gene and its receptor) plays an important role in obstetrics, gynecology, and cancer cell metastasis and behavior. In hypothalamic-pituitary-gonadal axis and placentation, Kisspeptin/Kisspeptin receptor affects hormone release and represses trophoblast invasion into maternal deciduae. Endometrial cancer is one of the common gynecological cancers and is usually accompanied by metastasis, the risk factor that causes death. Recently, research has demonstrated that Kisspeptin/Kisspeptin receptor expression in aggressive-stage endometrial cancer tissues. However, the detailed mechanism of Kisspeptin/Kisspeptin receptor in regulating the motility of endometrial cancers is not well understood. In this study, we use endometrial cancer cell lines RL95-2, Ishikawa, HEC-1-A, and HEC-1-B as models to explore the molecular mechanism of Kisspeptin on cell motility. First, we discovered that Kisspeptin/Kisspeptin receptor was expressed in endometrial cancer cells, and Kisspeptin significantly regulated the migration and invasion of endometrial cancer cells. Furthermore, we explored the epithelial-mesenchymal transition marker expression and the underlying signals were regulated on Kisspeptin treatment. In conclusion, we suggest that Kisspeptin regulates endometrial cancer cell motility via FAK and Src expression and the ERK1/2, N-Cadherin, E-Cadherin, beta-Catenin, Twist, and matrix metalloproteinase signaling pathways. We expect these molecules could be candidates for the development of new approaches and therapeutic targets.

Priming of macrophage by glycosphingolipids from extracellular vesicles facilitates immune tolerance for embryo-maternal crosstalk.

Glycosphingolipids (GSLs) display diverse functions during embryonic development. Here, we examined the GSL profiles of extracellular vesicles (EVs) secreted from human embryonic stem cells (hESCs) and investigated their functions in priming macrophages to enhance immune tolerance of embryo implantation. When peripheral blood mononuclear cells were incubated with ESC-secreted EVs, globo-series GSLs (GHCer, SSEA3Cer, and SSEA4Cer) were transferred via EVs into monocytes/macrophages. Incubation of monocytes during their differentiation into macrophages with either EVs or synthetic globo-series GSLs induced macrophages to exhibit phenotypic features that imitate immune receptivity, i.e., macrophage polarization, augmented phagocytic activity, suppression of T cell proliferation, and the increased trophoblast invasion. It was also demonstrated that decidual macrophages in first-trimester tissues expressed globo-series GSLs. These findings highlight the role of globo-series GSLs via transfer from EVs in priming macrophages to display decidual macrophage phenotypes, which may facilitate healthy pregnancy.

Gut Microbiome-Estrobolome Profile in Reproductive-Age Women with Endometriosis.

Microbiota is associated with our bodily functions and microenvironment. A healthy, balanced gut microbiome not only helps maintain mucosal integrity, prevents translocation of bacterial content, and contributes to immune status, but also associates with estrogen metabolism. Gut dysbiosis and estrobolome dysfunction have hence been linked to certain estrogen-dependent diseases, including endometriosis. While prior studies on microbiomes and endometriosis have shown conflicting results, most of the observed microbial differences are seen in the genital tract. This case-control study of reproductive-age women utilizes their fecal and urine samples for enzymatic, microbial, and metabolic studies to explore if patients with endometriosis have distinguishable gut microbiota or altered estrogen metabolism. While gut ß-glucuronidase activities, microbial diversity, and abundance did not vary significantly between patients with or without endometriosis, fecal samples of patients with endometriosis were more enriched by the Erysipelotrichia class and had higher folds of four estrogen/estrogen metabolites. Further studies are needed to elucidate what these results imply and whether there indeed is an association or causation between gut microbiota and endometriosis.

EGF-Enhanced GnRH-II Regulation in Decidual Stromal Cell Motility through Twist and N-Cadherin Signaling.

Crucial roles in embryo implantation and placentation in humans include the invasion of the maternal decidua by extravillous trophoblasts and the motile behavior of decidual endometrial stromal cells. The effects of the epidermal growth factor (EGF) and GnRH-II in the endometrium take part in early pregnancy. In the present study, we demonstrated the coaction of EGF- and GnRH-II-promoted motility of human decidual endometrial stromal cells, indicating the possible roles of EGF and GnRH-II in embryo implantation and early pregnancy. After obtaining informed consent, we obtained human decidual endometrial stromal cells from decidual tissues from normal pregnancies at 6 to 12 weeks of gestation in healthy women undergoing suction dilation and curettage. Cell motility was evaluated with invasion and migration assays. The mechanisms of EGF and GnRH-II were performed using real-time PCR and immunoblot analysis. The results showed that human decidual tissue and stromal cells expressed the EGF and GnRH-I receptors. GnRH-II-mediated cell motility was enhanced by EGF and was suppressed by the knockdown of the endogenous GnRH-I receptor and EGF receptor with siRNA, revealing that GnRH-II promoted the cell motility of human decidual endometrial stromal cells through the GnRH-I receptor and the activation of Twist and N-cadherin signaling. This new concept regarding the coaction of EGF- and GnRH-promoted cell motility suggests that EGF and GnRH-II potentially affect embryo implantation and the decidual programming of human pregnancy.

A Lifelong Impact on Endometriosis: Pathophysiology and Pharmacological Treatment.

Endometriosis is a chronic inflammatory disease associated with bothersome symptoms in premenopausal women and is complicated with long-term systemic impacts in the post-menopausal stage. It is generally defined by the presence of endometrial-like tissue outside the uterine cavity, which causes menstrual disorders, chronic pelvic pain, and infertility. Endometriotic lesions can also spread and grow in extra-pelvic sites; the chronic inflammatory status can cause systemic effects, including metabolic disorder, immune dysregulation, and cardiovascular diseases. The uncertain etiologies of endometriosis and their diverse presentations limit the treatment efficacy. High recurrence risk and intolerable side effects result in poor compliance. Current studies for endometriosis have paid attention to the advances in hormonal, neurological, and immunological approaches to the pathophysiology and their potential pharmacological intervention. Here we provide an overview of the lifelong impacts of endometriosis and summarize the updated consensus on therapeutic strategies.

Endothelial dysfunction in subfertile women with polycystic ovary syndrome.

RESEARCH QUESTION: Is there an association between post-occlusive reactive hyperaemia (PORH) and ovarian stimulation in women with normoandrogenaemic polycystic ovary syndrome (PCOS)? DESIGN: Women eligible for IVF at an academic fertility centre were invited to join this prospective study. Microvascular endothelial function was measured as PORH by laser Doppler flowmetry (LDF) before and after ovarian stimulation. Metabolic characteristics, hormone profiles and biochemical markers were analysed. RESULTS: Thirty-four normoandrogenaemic women with PCOS and 36 normoandrogenaemic women without PCOS were included. The PCOS group displayed higher C-reactive protein levels and insulin resistance (P = 0.048 and P = 0.025, respectively). No significant difference was found in microcirculatory function between the groups at baseline. After ovarian stimulation, PORH was enhanced in the control group (slope 7.1 ± 3.3 versus 9.7 ± 4.5; P = 0.007; peak flow 30.7 ± 16.3 versus 43.5 ± 17.3, P = 0.008; however, the PCOS group experienced a blunting response to supraphysiological hormone status (slope 8.2 ± 5.1 versus 7.2 ± 4.3, P = 0.212; peak flow, 38.8 ± 19.4 versus 37.0 ± 21.8, P = 0.895). CONCLUSIONS: Impaired microcirculatory function could be found using a non-invasive LDF technique in normoandrogenaemic women with PCOS undergoing IVF, indicating early changes in vascular endothelial dysfunction. Future observational studies should clarify whether PORH measurement might help predict IVF prognosis or obstetric complications.

Immune Tolerance of Embryo Implantation and Pregnancy: The Role of Human Decidual Stromal Cell- and Embryonic-Derived Extracellular Vesicles.

Embryo-endometrial communication plays a critical role in embryo implantation and the establishment of a successful pregnancy. Successful pregnancy outcomes involve maternal immune modulation during embryo implantation. The endometrium is usually primed and immunomodulated by steroid hormones and embryo signals for subsequent embryo implantation and the maintenance of pregnancy. The roles of extracellular vesicles (EVs) and microRNAs for the embryo-maternal interactions have been elucidated recently. New evidence shows that endometrial EVs and trophectoderm-originated EV cargo, including microRNAs, proteins, and lipids in the physiological microenvironment, regulate maternal immunomodulation for embryo implantation and subsequent pregnancy. On the other hand, trophoblast-derived EVs also control the cross-communication between the trophoblasts and immune cells. The exploration of EV functions and mechanisms in the processes of embryo implantation and pregnancy will shed light on a practical tool for the diagnostic or therapeutic approaches to reproductive medicine and infertility.

Altered Expression of Interleukin-18 System mRNA at the Level of Endometrial Myometrial Interface in Women with Adenomyosis.

Adenomyosis is a uterine pathology characterized by a deep invasion of endometrial glands and stroma, disrupting the endometrial−myometrial interface (EMI). Interleukin-18 (IL-18) system is a dominant cytokine involved in the menstrual cycle of human endometrium. IL-18 may play a defensive role against maternal immune response in the uterine cavity. The present study was designed to determine IL-18-mediated immune response at the level of EMI. We uncovered that mRNA of IL-18 system, including IL-18, IL-18 receptor (IL-18R), and its antagonist, IL-18 binding protein (IL-18BP), expressed in eutopic, ectopic endometrium, and corresponding myometrium in patients with adenomyosis. IL-18 system was demonstrated in paired tissue samples by immunochemistry and immunofluorescence study. According to RT-PCR with CT value quantification and 2−∆∆Ct method, a significant down-regulation of IL-18BP in corresponding myometrium in comparison to eutopic endometrium (p < 0.05) indicates that the IL-18 system acts as a local immune modulator at the level of EMI and regulating cytokine networks in the pathogenesis of adenomyosis. Furthermore, an increased IL-18 antagonist to agonist ratio was noted in ectopic endometrium compared with corresponding myometrium. We suggest that altered IL-18 system expression contributes to immunological dysfunction and junctional zone disturbance in women with adenomyosis.

Segmented in vitro fertilization and frozen embryo transfer in dienogest-treated patient with adenomyosis: A case report and lierature review.

OBJECTIVE: To assess the effects of dienogest on segmented in vitro fertilization (IVF) and frozen-thawed embryo transfer (FET) for a patient with adenomyosis. CASE REPORT: A 33-year-old female with primary infertility for 3 years had dysmenorrhea and hypermenorrhea. Diagnosis of adenomyosis was made with a sonographic exam and an elevated cancer antigen 125 (CA-125, 310 U/mL). Her early follicular hormone profile (anti-müllerian hormone, AMH, 8 ng/mL) was normal. After repeated controlled ovarian stimulation (COS) and failed intrauterine insemination (IUI), she underwent IVF. Controlled ovarian stimulation using gonadotropin-releasing hormone (GnRH) antagonist protocol was performed with the blastocyst freeze-all IVF cycle. Pretreatment with two months of GnRH agonist (GnRHa) and frozen-thawed embryo transfer did not result in pregnancy. Subsequently, three months of long-term pretreatment with dienogest was given, and the CA-125 level was markedly reduced. Frozen-thawed blastocyst stage embryo transfer was provided, and a singleton pregnancy was achieved. CONCLUSION: Dienogest, a novel progestin highly selective for progesterone receptors, may benefit the pregnancy outcomes of infertile patients with adenomyosis adopting segmented IVF with FET.

Impact of growth hormone-releasing hormone antagonist on decidual stromal cell growth and apoptosis in vitro†.

Endometrial stromal cells remodeling is critical during human pregnancy. Growth hormone-releasing hormone and its functional receptor have been shown to be expressed in gynecological cancer cells and eutopic endometrial stromal cells. Recent studies have demonstrated the potential clinical uses of antagonists of growth hormone-releasing hormone as effective antitumor agents because of its directly antagonistic effect on the locally produced growth hormone-releasing hormone in gynecological tumors. However, the impact of growth hormone-releasing hormone antagonists on normal endometrial stromal cell growth remained to be elucidated. The aim of this study was to investigate the effect of a growth hormone-releasing hormone antagonist (JMR-132) on cell proliferation and apoptosis of human decidual stromal cells and the underlying molecular mechanisms. Our results showed that growth hormone-releasing hormone and the splice variant 1 of growth hormone-releasing hormone receptor are expressed in human decidual stromal cells isolated from the decidual tissues of early pregnant women receiving surgical abortion. In addition, treatment of stroma cells with JMR-132 induced cell apoptosis with increasing cleaved caspase-3 and caspase-9 activities and decrease cell viability in a time- and dose-dependent manner. Using a dual inhibition approach (pharmacological inhibitors and siRNA-mediated knockdown), we showed that JMR-132-induced activation of apoptotic signals are mediated by the activation of ERK1/2 and JNK signaling pathways and the subsequent upregulation of GADD45alpha. Taken together, JMR-132 suppresses cell survival of decidual stromal cells by inducing apoptosis through the activation of ERK1/2- and JNK-mediated upregulation of GADD45alpha in human endometrial stromal cells. Our findings provide new insights into the potential impact of growth hormone-releasing hormone antagonist on the decidual programming in humans.

Supplementation with human menopausal gonadotropin in the gonadotropin-releasing hormone antagonist cycles of women with high AMH: Pregnancy outcomes and serial hormone levels.

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.

Gonadotropin-releasing hormone analogs: Mechanisms of action and clinical applications in female reproduction.

Extra-hypothalamic GnRH and extra-pituitary GnRH receptors exist in multiple human reproductive tissues, including the ovary, endometrium and myometrium. Recently, new analogs (agonists and antagonists) and modes of GnRH have been developed for clinical application during controlled ovarian hyperstimulation for assisted reproductive technology (ART). Additionally, the analogs and upstream regulators of GnRH suppress gonadotropin secretion and regulate the functions of the reproductive axis. GnRH signaling is primarily involved in the direct control of female reproduction. The cellular mechanisms and action of the GnRH/GnRH receptor system have been clinically applied for the treatment of reproductive disorders and have widely been introduced in ART. New GnRH analogs, such as long-acting GnRH analogs and oral nonpeptide GnRH antagonists, are being continuously developed for clinical application. The identification of the upstream regulators of GnRH, such as kisspeptin and neurokinin B, provides promising potential to develop these upstream regulator-related analogs to control the hypothalamus-pituitary-ovarian axis.

Application of non-invasive detection of peripheral vascular dysfunction in ovarian hyperstimulation syndrome (OHSS): A pilot study of clinical relevance.

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 <45 years of age. Detailed clinical parameters were reviewed, including serum VEGF, TNFα, CRP, inhibin A, inhibin B, and hematocrit. RHI assessed by novel automatic peripheral arterial tonography was used to evaluate the vascular endothelial function. RESULTS: Twenty-one subjects were evaluated. There was no significant difference between patients with OHSS and control subjects with respect to VEGF, TNFα, CRP, inhibin A and inhibin B. The RHI was not significantly different between patients with OHSS and control subjects (mean, 1.8 ± 0.4 vs. 1.7 ± 0.2). The hematocrit was significantly different between patients with OHSS and control subjects. CONCLUSIONS: Our preliminary data did not reveal direct evidence of vascular endothelial dysfunction in patients with OHSS. To identify whether RHI could reflect vascular endothelial dysfunction in patients with OHSS, more cases with different severities of OHSS should be recruited in the future study.

Effectiveness and appropriateness in the application of office hysteroscopy.

With the advances in miniature instruments, office hysteroscopy on conscious patients has been the standard to explore the intrauterine pathology, with the ability to perform some minor procedures concomitantly. Patients usually appreciate the efficient "see and treat" procedures with such minimal discomfort that exempt from the inconvenience of going into the operating room and the need for anesthesia. However, controversies exist in the appropriateness of its application in some clinical situations. Concerns include (1) the criteria for hysteroscopy applied in the vast number of patients suffering from abnormal uterine bleeding or subfertility, and (2) the frequency for repeated hysteroscopy on some kinds of patients, such as those of endometrial cancer with fertility-sparing treatment for monitoring the disease, or those of severe intrauterine adhesion who need adhesiolysis for subsequent conception, in whom the appropriate protocol of repeatedly applying hysteroscopy lacks consensus. This article reviews the literature to find the best available evidence on the effectiveness of office hysteroscopy in comparison with other clinical diagnostic tools, as well as the current opinions on such controversies in its application.

Population-based trends and risk factors of early- and late-onset preeclampsia in Taiwan 2001-2014.

BACKGROUND: Preeclampsia, a multisystem disorder in pregnancies complicates with maternal and fetal morbidity. Early- and late-onset preeclampsia, defined as preeclampsia developed before and after 34 weeks of gestation, respectively. The early-onset disease was less prevalent but associated with poorer outcomes. Moreover, the risk factors between early -and late- onset preeclampsia could be differed owing to the varied pathophysiology. In the study, we evaluated the incidences, trends, and risk factors of early- and late- onset preeclampsia in Taiwan. METHODS: This retrospective population-based cohort study included all ≧20 weeks singleton pregnancies resulting in live-born babies or stillbirths in Taiwan between January 1, 2001 and December 31, 2014 (n = 2,884,347). The data was collected electronically in Taiwanese Birth Register and National Health Insurance Research Database. The incidences and trends of early- and late-onset preeclampsia were assessed through Joinpoint analysis. Multivariate logistic regression was used to analyze the risk factors of both diseases. RESULTS: The age-adjusted overall preeclampsia rate was slightly increased from 1.1%(95%confidence interval [CI], 1.1-1.2) in 2001 to 1.3% (95%CI, 1.2-1.3) in 2012 with average annual percentage change (AAPC) 0.1%/year (95%CI, 0-0.2%). However, the incidence was remarkably increased from 1.3% (95%CI, 1.3-1.4) in 2012 to 1.7% (95%CI, 1.6-1.8) in 2014 with AAPC 1.3%/year (95%CI,0.3-2.5). Over the study period, the incidence trend in late-onset preeclampsia was steadily increasing from 0.7% (95%CI, 0.6-0.7) in 2001 to 0.9% (95%CI, 0.8-0.9) in 2014 with AAPC 0.2%/year (95%CI, 0.2-0.3) but in early-onset preeclampsia was predominantly increase from 0.5% (95%CI, 0.4-0.5) in 2012 to 0.8% (95%CI, 0.8-0.9) in 2014 with AAPC 2.3%/year (95%CI, 0.8-4.0). Advanced maternal age, primiparity, stroke, diabetes mellitus, chronic hypertension, and hyperthyroidism were risk factors of preeclampsia. Comparing early- and late-onset diseases, chronic hypertension (ratio of relative risk [RRR], 1.71; 95%CI, 1.55-1.88) and older age (RRR, 1.41; 95%CI 1.29-1.54) were more strongly associated with early-onset disease, whereas primiparity (RRR 0.71, 95%CI, 0.68-0.75) had stronger association with late-onset preeclampsia. CONCLUSIONS: The incidences of overall, and early- and late-onset preeclampsia were increasing in Taiwan from 2001 to 2014, predominantly for early-onset disease. Pregnant women with older age and chronic hypertension had significantly higher risk of early-onset preeclampsia.

Repeated pregnancy with concomitant presence of ovarian teratoma: A case report and literature review.

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.

Growth hormone-releasing hormone antagonist inhibits the invasiveness of human endometrial cancer cells by down-regulating twist and N-cadherin expression.

More than 25% of patients diagnosed with endometrial carcinoma have invasive primary cancer accompanied by metastases. Growth hormone-releasing hormone (GHRH) plays an important role in reproduction. Here, we examined the effect of a GHRH antagonist on the motility of endometrial cancer cells and the mechanisms of action of the antagonist in endometrial cancer. Western blotting and immunohistochemistry (IHC) were used to determine the expression of the GHRH receptor protein. The activity of Twist and N-cadherin was determined by Western blotting. Cell motility was assessed by an invasion and migration assay. GHRH receptor siRNA was applied to knockdown the GHRH receptor in endometrial cancer cells. The GHRH antagonist inhibited cell motility in a dose-dependent manner. The GHRH antagonist inhibited cell motility and suppressed the expression of Twist and N-cadherin, and the suppression was abolished by GHRH receptor siRNA pretreatment. Moreover, the inhibition of Twist and N-cadherin with Twist siRNA and N-cadherin siRNA, respectively, suppressed cell motility. Our study indicates that the GHRH antagonist inhibited the cell motility of endometrial cancer cells through the GHRH receptor via the suppression of Twist and N-cadherin. Our findings represent a new concept in the mechanism of GHRH antagonist-suppressed cell motility in endometrial cancer cells and suggest the possibility of exploring GHRH antagonists as potential therapeutics for the treatment of human endometrial cancer.

A gonadotropin releasing hormone agonist trigger of ovulation with aggressive luteal phase support for patients at risk of ovarian hyperstimulation syndrome undergoing controlled ovarian hyperstimulation.

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.

Gonadotropin-releasing hormone type II (GnRH-II) agonist regulates the motility of human decidual endometrial stromal cells: possible effect on embryo implantation and pregnancy.

Invasion of the maternal decidua by extravillous trophoblast is an important process for embryo implantation and placentation in humans. Motile behavior of decidual endometrial stromal cells has been considered of critical importance for embryo implantation and programming of human pregnancy. The gonadotropin-releasing hormone (GnRH) effects in endometrium have raised concerns in reproduction. In the present study, we examined the action of GnRH-II agonist-promoted motility of human decidual endometrial stromal cells and the mechanisms of the action, indicating the role of GnRH-II agonist in embryo implantation and early pregnancy. Human decidual endometrial stromal cells were isolated from the decidual tissue from healthy women undergoing elective pregnancy termination of a normal pregnancy at 6- to 12-wk gestation, after informed consent. Cell motility was estimated by invasion and migration assay. Zymography and immunoblot analysis were performed to investigate the mechanisms of the GnRH-II action. The GnRH-I receptor (GnRH-IR) was expressed in human decidual tissue and endometrial stromal cells. The GnRH-II agonist promoted cell motility. Mitogen-activated protein kinase inhibitors abolished GnRH-II agonist-induced cell motility and activation of MMP-2 and MMP-9. GnRH-II agonist-mediated cell motility was suppressed by knockdown of endogenous GnRH-IR, MMP (matrix metalloproteinase)-2, and MMP-9 with small interfering RNA and MMP inhibitors. Our study demonstrates that the GnRH-II agonist promoted the cell motility of human decidual endometrial stromal cells through the GnRH-IR and the phosphorylation of extracellular signal-regulated protein kinase 1/2 and JNK-dependent activation of MMP-2 and MMP-9. Our findings represent a new concept regarding the mechanisms of GnRH-II-promoted cell motility, suggesting that GnRH-II agonist has strong effects on embryo implantation and decidual programming of human pregnancy.