Hsin-Shih Wang

Detection of the subendometrial vascularization flow index by three-dimensional ultrasound may be useful for predicting the pregnancy rate for patients undergoing in vitro fertilization–embryo transfer

OBJECTIVE To obtain quantitative data on endometrial volume and subendometrial blood flow by three-dimensional ultrasound clue to endometrial receptivity. DESIGN A prospective, nonrandomized clinical study. SETTING One tertiary center for assisted reproduction. PATIENT(S) Fifty-four patients aged <38 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. INTERVENTION(S) Ultrasound evaluation was performed for all patients with 3-D facility by a single operator on the day of hCG administration. MAIN OUTCOME MEASURE(S) Ultrasonographic parameters and conception rates. RESULT(S) 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 of >0.24. CONCLUSION(S) 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.

Serum levels of insulin-like growth factor I and insulin-like growth factor-binding protein-1 and -3 in women with regular menstrual cycles

OBJECTIVE To investigate the cyclic changes of serum insulin-like growth factor (IGF-I), IGF-binding protein-1 (IGFBP-1) and IGFBP-3 levels during ovulatory menstrual cycle. DESIGN A prospective study following a preset protocol. SETTING A tertiary-care academic medical center. PARTICIPANTS Thirty young female adults with regular menstrual cycles were recruited (18 with normal luteal phase and 12 with inadequate luteal function confirmed by serum P levels). MAIN OUTCOME MEASURES Serum concentrations of IGF-I, IGFBP-1, and IGFBP-3 from women with regular menstrual cycles were assayed. Circulating E2 and P levels also were determined to certify the ovulatory cycles. RESULTS In women with normal luteal function, there was a peak of serum IGFBP-1 levels before ovulation concomitant with the preovulatory E2 peak. The nadir of serum IGFBP-1 levels was in the midluteal phase. Circulating IGFBP-1 elevated rapidly during late luteal phase and reached a peak on the 1st day of menstruation then declined slightly until a preovulatory IGFBP-1 peak occurred. In women with inadequate luteal function (midluteal serum levels of P < 10 ng/mL [conversion factor to SI unit, 3.180]), the preovulatory increase in serum IGFBP-1 was not significant and the circulating IGFBP-1 levels fluctuated throughout the menstrual cycle except for a unique peak of serum IGFBP-1 on the 1st day of menstruation. By contrast, there were no cyclic changes of serum IGF-I and IGFBP-3 levels in women with regular menstrual cycles, including both normal nad inadequate luteal functions. CONCLUSIONS The preovulatory increase in serum IGFBP-1 levels may be of follicular origin and associated with the subsequent luteal function in females with ovulatory cycles. However, the involvement of IGFBP-1 in the process of follicular maturation and luteogenesis, as well as the regulation of luteal function, needs to be explored further.

GnRH signaling in intrauterine tissues

Type I GnRH (GnRH-I, GNRH1) and type II GnRH (GnRH-II, GNRH2), each encoded by separate genes, have been identified in humans. The tissue distribution and functional regulation of GnRH-I and GnRH-II clearly differ despite their comparable cDNA and genomic structures. These hormones exert their effects by binding to cell surface transmembrane G protein coupled receptors and stimulating the Gq/11 subfamily of G proteins. The hypothalamus and pituitary are the main origin and target sites of GnRH, but numerous studies have demonstrated that extra-hypothalamic GnRH and extra-pituitary GnRH receptors exist in different reproductive tissues such as the ovary, endometrium, placenta, and endometrial cancer cells. In addition to endocrine regulation, GnRH is also known to act in an autocrine and paracrine manner to suppress cell proliferation and activate apoptosis in the endometrium and endometrial cancer cells through several mechanisms. Both GnRH-I and GnRH-II exhibit regulatory roles in tissue remodelling during embryo implantation and placentation, which suggests that these hormones may have important roles in embryo implantation and early pregnancy. The presence of varied GnRH and GnRH receptor systems demonstrate their different roles in distinct tissues using dissimilar mechanisms. These may result in the generation of new GnRH analogues used for several hormone-related diseases.

Insulin‐like growth factor‐binding protein 1 and insulin‐like growth factor‐binding protein 3 in pre‐eclampsia

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.

Effects of labor on serum levels of insulin and insulin‐like growth factor‐binding proteins at the time of delivery

Background. 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.

Eutopic endometrial interleukin-18 system mRNA and protein expression at the level of endometrial-myometrial interface in adenomyosis patients

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. Pearsons 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.

Granulosa-lutein cell growth differentiation factor-9 (GDF-9) messenger RNA and protein expression in in vitro fertilization (IVF) cycles : relation to characteristics of ovulation induction and IVF

Granulosa-lutein cell growth differentiation factor-9 (GDF-9), a member of the transforming growth factor beta (TGF-beta) superfamily, is an oocyte-derived factor expressed throughout the development of the maturing follicle and is essential in early follicular development and fertility. Both GDF-9 messenger RNA and protein are detected in granulosa-lutein cells. A statistically significant correlation between GDF-9 expression and the number of dominant follicles on the day human chorionic gonadotropin is administered also is demonstrated. Human granulosa-lutein cell GDF-9 expression may play a role in folliculogenesis dependent on follicle-stimulating hormone in the in vitro fertilization cycle.

Gonadotrophin-releasing hormone antagonist induces apoptosis in human decidual stromal cells: effect on GADD45α and MAPK signaling

BACKGROUND The impact of gonadotrophin-releasing hormone (GnRH) antagonists used in IVF protocols on endometrial tissue remodeling, embryo implantation and the programming of early pregnancy is still unclear. Pregnancy and infant outcomes after treatment with GnRH antagonist for IVF are particular causes of concern. The purpose of this study was to investigate the mechanisms of GnRH antagonist-induced apoptosis of human decidual stromal cells and the effects of GnRH antagonist on the activation of ERK1/2, JNK and GADD45α signaling. METHODS Human decidual stromal cells were isolated from decidual tissue. The expression of GnRH-I receptor (GnRH-IR) was examined by immunoblot analysis and immunohistochemistry. The cells were treated with the GnRH antagonist, Cetrorelix. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay was used to examine cell viability. Cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUDP nick-end labeling assay were used as indicators for cell apoptosis. Mitogen-activated protein kinase function was tested for the elucidation of intracellular signalings through the pre-treatment of stromal cells with ERK1/2 (U0126) and JNK (SP600125) inhibitors prior to the Cetrorelix treatment. To characterize the signaling pathway of GnRH antagonist, the endogenous GnRH-IR and GADD45α were knocked down by specific small-interfering RNA (siRNA). RESULTS The GnRH-IR is expressed in human decidual stromal cells. Treatment with GnRH antagonist decreased cell viability, induced apoptosis and increased the phosphorylation of ERK1/2 and JNK. Cells pre-treated with U0126 and SP600125 were rescued from the GnRH antagonist-mediated inhibition of cell growth and did not exhibit GnRH antagonist-induced apoptosis and downstream GADD45α signaling. GnRH antagonist-mediated cell growth inhibition and apoptosis were also abolished by the knockdown of the endogenous GnRH-IR or GADD45α with siRNAs. CONCLUSIONS The GnRH antagonist suppresses the growth of decidual stromal cells by inducing apoptosis through the GnRH-IR and through the ERK1/2 and JNK phosphorylation-dependent induction of GADD45α signaling. These results indicate that ERK1/2, JNK and GADD45α are coordinately regulated by the GnRH antagonist through the GnRH-IR to induce apoptosis in human decidual stromal cells, suggesting that the GnRH antagonist may play a role in decidual programming in human pregnancy.

Serum levels of insulin-like growth factor-binding protein-3 in normal pregnancy

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.