Hsien-Ming Wu

Cadmium level in seminal plasma may affect the pregnancy rate for patients undergoing infertility evaluation and treatment

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<0.0001) after adjusting for related variables. Each tenfold increase in semen cadmium concentration was associated with a 4.17-fold increase in infertility ratio in nonsmoking patients. In smokers, Cox multi-variable fertility ratio analysis demonstrated that sperm count and semen cadmium concentration are associated with fertility (fertility ratio of log semen cadmium=0.17; 95% CI=0.04-0.63, P=0.0085) after adjusting for related variables. In smokers, each tenfold increase in semen cadmium concentration was associated with a 5.88-fold increase in infertility ratio. In conclusion, low levels of cadmium accumulation in semen may contribute to male infertility by reducing sperm quality.

Estradiol and Tamoxifen Induce Cell Migration through GPR30 and Activation of Focal Adhesion Kinase (FAK) in Endometrial Cancers with Low or without Nuclear Estrogen Receptor α (ERα)

Estrogens and tamoxifen (an antiestrogen) exert their actions by activation of estrogen receptor (ER) through genomic and non-genomic mechanisms and are implicated in the development of endometrial cancer. Previous reports have demonstrated that estradiol and tamoxifen induce proliferation of human endometrial cancer cells through GPR30 (non-genomic ER) signaling pathway. Herein, we demonstrate that phosphorylation of focal adhesion kinase (FAK) is involved in cell migration induced by estradiol, tamoxifen and G1 (a GPR30 agonist) through the transmembrane ER (GPR30) in endometrial cancer cell lines with or without ERα (Ishikawa and RL95-2). Additionally, the GPR30-mediated cell migration was further abolished by administration of either specific RNA interference targeting GPR30 or an FAK inhibitor. Moreover, we have validated that the signaling between GPR30 and phosphorylated FAK is indeed mediated by the EGFR/PI3K/ERK pathway. Clinically, a significant correlation between levels of GPR30 and phophorylated FAK (pFAK) observed in human endometrial cancer tissues with low or without ERα further suggested that estrogen-induced phosphorylation of FAK and cell migration were most likely triggered by GPR30 activation. These results provided new insights for understanding the pathophysiological functions of GPR30 in human endometrial cancers.

Lead level in seminal plasma may affect semen quality for men without occupational exposure to lead

BackgroundInfertility 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.MethodsThis 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.ResultsAll 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.ConclusionsWe 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.

Gonadotropin-Releasing Hormone Type II Induces Apoptosis of Human Endometrial Cancer Cells by Activating GADD45α

Gonadotropin-releasing hormone type II (GnRH-II) has an antiproliferative effect on human endometrial cancer cells. Apoptosis in cancer cells may play a critical role in regulating cell proliferation. However, more studies are necessary to elucidate the underlying molecular mechanisms and develop potential applications of GnRH-II. Therefore, we explored the mechanisms of GnRH-II-induced apoptosis and the effects of GnRH-II on GADD45alpha activation in human endometrial cancer cell lines. GnRH-II decreased cell viability in a dose- and time-dependent manner. Apoptosis was induced with increased terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling apoptotic cells after GnRH-II treatment. Knockdown of the endogenous GnRH-I receptor with small interfering RNA (siRNA) rescued the cells from GnRH-II-mediated cell growth inhibition and abolished the induction of apoptosis. GnRH-II activated extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein kinase (MAPK) in a time-dependent manner, and the activation was abolished by GnRH-I receptor siRNA and MAPK inhibitors. Cells pretreated with MAPK inhibitors were rescued from GnRH-II-mediated cell growth inhibition. Moreover, both inhibitors abolished GnRH-II-induced apoptosis. GnRH-II induced GADD45alpha expression, which was abolished by knockdown of endogenous GnRH-I receptors and MAPK inhibitors. GnRH-II-stimulated cell growth inhibition was rescued by knockdown of endogenous GADD45alpha with siRNA. Cells treated with GADD45alpha siRNA were refractory to GnRH-II-induced apoptosis. Thus, GnRH-II inhibits cell growth by inducing apoptosis through binding of the GnRH-I receptor, activation of the ERK1/2 and p38 MAPK pathways, and induction of GADD45alpha signaling. This finding may provide a new concept relating to the mechanism of GnRH-II-induced antiproliferation and apoptosis in endometrial cancer cells, indicating the possibility of GnRH-II as a promising therapeutic intervention for human endometrial cancer.

A mutant single nucleotide polymorphism of follicle-stimulating hormone receptor is associated with a lower risk of endometriosis

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.

Functional Analyses of Endometriosis-Related Polymorphisms in the Estrogen Synthesis and Metabolism-Related Genes

Endometriosis is determined by genetic factors, and the prevalence of genetic polymorphisms varies greatly depending on the ethnic group studied. The objective of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of 9 genes involved in estrogen biosynthesis and metabolism and the risks of endometriosis. Three hundred patients with endometriosis and 337 non-endometriotic controls were recruited. Thirty four non-synonymous SNPs, which change amino acid residues, were analyzed using matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS). The functions of SNP-resulted amino acid changes were analyzed using multiple web-accessible databases and phosphorylation predicting algorithms. Among the 34 NCBI-listed SNPs, 22 did not exhibit polymorphism in this study of more than 600 Taiwanese Chinese women. However, homozygous and heterozygous mutants of 4 SNPs - rs6165 (genotype GG+GA, 307Ala/Ala+307Ala/Thr) of FSHR, rs 6166 (genotype GG+GA, 680Ser/Asn+680Ser/Ser) of FSHR, rs2066479 (genotype AA+AG, 289Ser/Ser+289Ser/Gly) of HSD17B3 and rs700519 (genotype TT+TC, 264Cys/Cys+264Cys/Arg) of CYP19, alone or in combination, were significantly associated with decreased risks of endometriosis. Bioinformatics results identified 307Thr of FSHR to be a site for O-linked glycosylation, 680Ser of FSHR a phosphorylated site by protein kinase B, and 289Ser of HSD17B3 a phosphorylated site by protein kinase B or ribosomal protein S6 kinase 1. Results of this study suggest that non-synonymous polymorphisms of FSHR, HSD17B3 and CYP19 genes may modulate the risk of endometriosis in Taiwanese Chinese women. Identification of the endometrosis-preferential non-synonymous SNPs and the conformational changes in those proteins may pave the way for the development of more disease-specific drugs.

Gonadotropin-Releasing Hormone Type II (GnRH-II) Agonist Regulates the Motility of Human Decidual Endometrial Stromal Cells: Possible Effect on Embryo Implantation and Pregnancy

ABSTRACT 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.

Effects of anti-Müllerian hormone and follicle stimulating hormone levels on in vitro fertilization pregnancy rate.

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 <32 years and 22.1% for patients aged >38 years. The pregnancy rate was 53.4% for patients with FSH levels <5.6 mIU/mL and 25.8% 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 <1.1 ng/mL. Furthermore, among patients aged <40 years, AMH and FSH were significantly associated with pregnancy rate. Higher pregnancy rates were found among the groups with higher AMH levels than in groups with lower AMH levels. CONCLUSION For patients aged <40 years, basal serum AMH level and FSH level affected the IVF pregnancy rate, and patients with higher AMH levels had better pregnancy rates.

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.